1

Kent Holtorf MD Kathleen OrsquoNeil Smith MD

Introduction to Peptide Therapy

Lecture Goals

2

GoalsObjectives

To understand how immune dysfunction and inflammation contribute to age-related diseases and how peptide therapy can address many abnormalities underlying chronic illness and age-related illness

Be able to identify which patients and conditions would likely benefit from peptide therapy

To understand new treatment options for immune dysfunction chronic illness TBI ADHD autism and aging

Peptide Therapy

3

Short chain of amino acids

Generally lt 50-70 AA (gt 50-70 becomes a protein)

Natural bioidentical or altered (synthetic)

Seemingly simple peptides are found to regulate most every known process and system in the body in a tissue-specific manner

While hormone therapy and optimization has been a mainstay of antiaging medicine it is being understood that regulatory peptides are the master controls of many functions of the body including hormone production

Peptides

Peptides are naturally occurring bio-regulatory chemicals in the body that act as master controls of many functions including hormone production cell signaling and cell to cell communication

To date gt7000 naturally occurring peptides identified in our bodies

Peptide Therapy

5

Currently peptides are available that are shown to safely and effectively improve and modulate specific parts of hormone production immune function the sleep cycle the production of inflammatory mediators DNA replication cell division and renewal cancer cell destruction and apoptosis libido and sexual arousal tissue healing and specific biological functioning of the brain skin eyes and urinary and reproductive systems

Hormones work on nuclear receptors with resultant gene activation and protein synthesis

Peptides are non-genomic that act on membrane receptors to activate an intracellular signaling cascade

Peptide signaling molecules have more of a rapid response with less side-effects when compared to hormones

Peptides have more precise tissue-selective effects while hormones have less precise broader effects

6

Peptides vs Hormones

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Lecture Goals

2

GoalsObjectives

To understand how immune dysfunction and inflammation contribute to age-related diseases and how peptide therapy can address many abnormalities underlying chronic illness and age-related illness

Be able to identify which patients and conditions would likely benefit from peptide therapy

To understand new treatment options for immune dysfunction chronic illness TBI ADHD autism and aging

Peptide Therapy

3

Short chain of amino acids

Generally lt 50-70 AA (gt 50-70 becomes a protein)

Natural bioidentical or altered (synthetic)

Seemingly simple peptides are found to regulate most every known process and system in the body in a tissue-specific manner

While hormone therapy and optimization has been a mainstay of antiaging medicine it is being understood that regulatory peptides are the master controls of many functions of the body including hormone production

Peptides

Peptides are naturally occurring bio-regulatory chemicals in the body that act as master controls of many functions including hormone production cell signaling and cell to cell communication

To date gt7000 naturally occurring peptides identified in our bodies

Peptide Therapy

5

Currently peptides are available that are shown to safely and effectively improve and modulate specific parts of hormone production immune function the sleep cycle the production of inflammatory mediators DNA replication cell division and renewal cancer cell destruction and apoptosis libido and sexual arousal tissue healing and specific biological functioning of the brain skin eyes and urinary and reproductive systems

Hormones work on nuclear receptors with resultant gene activation and protein synthesis

Peptides are non-genomic that act on membrane receptors to activate an intracellular signaling cascade

Peptide signaling molecules have more of a rapid response with less side-effects when compared to hormones

Peptides have more precise tissue-selective effects while hormones have less precise broader effects

6

Peptides vs Hormones

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Peptide Therapy

3

Short chain of amino acids

Generally lt 50-70 AA (gt 50-70 becomes a protein)

Natural bioidentical or altered (synthetic)

Seemingly simple peptides are found to regulate most every known process and system in the body in a tissue-specific manner

While hormone therapy and optimization has been a mainstay of antiaging medicine it is being understood that regulatory peptides are the master controls of many functions of the body including hormone production

Peptides

Peptides are naturally occurring bio-regulatory chemicals in the body that act as master controls of many functions including hormone production cell signaling and cell to cell communication

To date gt7000 naturally occurring peptides identified in our bodies

Peptide Therapy

5

Currently peptides are available that are shown to safely and effectively improve and modulate specific parts of hormone production immune function the sleep cycle the production of inflammatory mediators DNA replication cell division and renewal cancer cell destruction and apoptosis libido and sexual arousal tissue healing and specific biological functioning of the brain skin eyes and urinary and reproductive systems

Hormones work on nuclear receptors with resultant gene activation and protein synthesis

Peptides are non-genomic that act on membrane receptors to activate an intracellular signaling cascade

Peptide signaling molecules have more of a rapid response with less side-effects when compared to hormones

Peptides have more precise tissue-selective effects while hormones have less precise broader effects

6

Peptides vs Hormones

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Peptides

Peptides are naturally occurring bio-regulatory chemicals in the body that act as master controls of many functions including hormone production cell signaling and cell to cell communication

To date gt7000 naturally occurring peptides identified in our bodies

Peptide Therapy

5

Currently peptides are available that are shown to safely and effectively improve and modulate specific parts of hormone production immune function the sleep cycle the production of inflammatory mediators DNA replication cell division and renewal cancer cell destruction and apoptosis libido and sexual arousal tissue healing and specific biological functioning of the brain skin eyes and urinary and reproductive systems

Hormones work on nuclear receptors with resultant gene activation and protein synthesis

Peptides are non-genomic that act on membrane receptors to activate an intracellular signaling cascade

Peptide signaling molecules have more of a rapid response with less side-effects when compared to hormones

Peptides have more precise tissue-selective effects while hormones have less precise broader effects

6

Peptides vs Hormones

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Peptide Therapy

5

Currently peptides are available that are shown to safely and effectively improve and modulate specific parts of hormone production immune function the sleep cycle the production of inflammatory mediators DNA replication cell division and renewal cancer cell destruction and apoptosis libido and sexual arousal tissue healing and specific biological functioning of the brain skin eyes and urinary and reproductive systems

Hormones work on nuclear receptors with resultant gene activation and protein synthesis

Peptides are non-genomic that act on membrane receptors to activate an intracellular signaling cascade

Peptide signaling molecules have more of a rapid response with less side-effects when compared to hormones

Peptides have more precise tissue-selective effects while hormones have less precise broader effects

6

Peptides vs Hormones

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Hormones work on nuclear receptors with resultant gene activation and protein synthesis

Peptides are non-genomic that act on membrane receptors to activate an intracellular signaling cascade

Peptide signaling molecules have more of a rapid response with less side-effects when compared to hormones

Peptides have more precise tissue-selective effects while hormones have less precise broader effects

6

Peptides vs Hormones

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Thymosins (immune modulators)

Pineal hormones

Nootropics

Growth Hormone Secretaogoues (GHSs)

Melanocyte Stimulating Hormone (MSH) analogues

Myostatin Inhibitors

Others

7

Peptide Classes

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Immune decline and dysfunction (immumosenescence)66

Increased inflammation and oxidative damage Multi-hormonal decline Reduced neurologic functioning and

connectivity Decreased energy production Decreased protein synthesis66

Decreased detoxification Tissue and organ atrophy66

8

Aspects of Aging

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Immunosenescence Multifactorial

9

Decreased telomere length in immune cells bull For T and B cells the ability to undergo extensive cell

division and clonal expansion is crucial for effective immune function

Thymic involution bull Results in TH1-TH2 shift

o increased risk of opportunistic and intracellular infections autoimmunity inflammation and risk of caner1

o Chronic illness becomes a vicious cycle of immune dysfunction

1 Lynch HE et al Thymic involution and immune reconstitution Trends in Immunology 2009 30(7) p 366-373

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Immune Dysfunction (TH1-TH2 Shift)

Studies show that immune dysfunction is associated with a wide-variety of common chronic illnesses including Emotional stress27276

Depression56

Dieting Insulin resistance obesity and diabetes

Aging1 Chronic fatigue syndromefibromyalgia3487879

Autoimmune disease80

Cancer Chronic pain amp pain meds

Heavy metals toxin and plastics73

Chronic infections including Lyme viruses candida and many parasites (infections make TH1 more susceptible to stress and glucocorticoid suppression)97075

Oxidative stress Glutathione depletion consistently results in TH1-TH2 shift GMOs Glucose tobacco alcohol Dysbiosis Food allergies or sensitivities74

Hormones (estrogens stimulate TH2 progesterone and testosterone TH1) Zinc and other mineral deficiencies77

10

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Cycle of Dysfunction with Chronic Illness

11 Holtorf K Cycle of Dysfunction of CFSFM 2003

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

12

Immune Dysregulation (TH1-TH2)

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

TH1-TH2 Shift in HIV Determines Progression of Illness

13 97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new

insights Immunology Today 199415(12)575-581

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

14

Thymic peptides Thymosin Alpha 1 (TA1) Thymosin Beta 4 (Tβ4) Thymulin Thymogen

Nootropics Semax Selank Cerebrolysin

Pineal proteins Epithalon

Antimicrobial peptides LL-37

Others Follistatin BPC-157

Peptides

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

TH1-TH2 Shift in CFS

15

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Immune modulation

Increase TH1 and decrease TH2 Boosting NK cell and lowering inflammatory cytokines

Peptides (Thymosin alpha-1BPC 157Epithalon) LDN IVIG (low dose or high dose-give 10-20 iu pitocin IV with each treatment if possible) Ozone (MAHDirectHigh-dose10-pass) UVBI LDALDI Allergy elimination (gluten) Antivirals (The deterioration in HIV is in direct correlation to the TH1TH2 balance) Antibiotics (do provoked WB ECP and other immune markers whenever possible) Transfer factors Mushroom extracts Isoprinosine High dose B12 GcMAFLeukineNeupogen Probiotics Silver Heparin AntioxidantsGlutathione (low glutathione decreases TH1 and increases TH2) Chelation (heavy metals stimulate TH2 and lower TH1) Bee venom Acupuncture

16

Immune Modulating Therapies

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

17 68 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

Thymic Proteins and Age

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

Thymus involution is influenced by age obesity caloric intake genetics inflammation stress pregnancy toxins hypothyroidism low growth hormone chronic infections and zinc deficiency

Progressive thymic dysfunction and immunosenescence naturally occur with aging and results in bull Increased susceptibility to infections bull Inadequate immune response to vaccinations bull Increased propensity for autoimmune diseases bull Increased cancer risk bull Increased CV disease

18

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

19

According to the US Center for Disease Control (CDC) approximately 80 of aged individuals are afflicted with at least one chronic disease as a result of a declination of thymic-related immune function73

Obesity and calorie intake are strongly associated with thymic involution

The majority of people have pineal gland calcification by age 30

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titres in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

ThymicPineal Peptides and Age

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

20

Improved tissue repair and healing35363741

Improved host defense to infection2627282930

Reverse immunosuppression of chronic infection (Lyme)2426272829333437

Increases antioxidant and glutathione production2627283128296366

Boost NK function2635

TH2-TH1 immune modulation (infections cancer herxheimer autoimmune)262728303133

Bind neuroendotoxins111

Cardiac regeneration and protection post-MI CHF etc39659899100 Neurologic regeneration and protection post-stroke TBI Lyme Alzheimerrsquos

neuropathy Parkinsonlsquos etc636742 Stimulate stem cell activity and proliferation32343638404142

Increases longevity899091 Almost non-existent side effects at 100-fold dose+ excess103104 Excellent safety profile with large therapeutic window (over 1000 fold)103104

Thymic Peptides ndash Clinical Effects (Thymosin alpha-1 thymosin beta-4 thymulin thymogen)

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

TA1 Applications

Approved in over 30 countries Cancer treatmentchemotherapy

adjunct29303133

Treatment of Hepatitis B and C2830 Treatment of AIDS28

Approved in USA as orphan drug Vaccine adjunct29

21

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

TA1

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

TA1 Effects

23

TA1 Dual Mode of Action

STEM

CELL

NK CELL

ZADAXIN Dual Mechanism of Action

VIRALLY INFECTED CELL

VIRALLY INFECTED CELL

Immunomodulatory

Antiviral

MHC I

Viral replication

T-cell apoptosis

CD4+ T-CELL

CD8+ T-CELL

T-cell production

IL-2 IFN-g

IL-4 IL-10

Dual mechanism of action

• Immunomodulatory
• Increases NK CD4 and CD8 by stimulating stem cell differentiation and by reducing T-cell apoptosis
• Shifts immune response towards Th1 by
• Increasing Th1 cytokines (IL-2 IFN)
• Decreasing Th2 cytokines (IL-4 IL-10)
• Direct antiviral
• Increases expression of MHC class 1 molecules on infected cells
• Directly inhibits viral replication (perhaps through effects on intracellular glutathione levels)
• Also directly inhibits cancer cell growth

• TA1 Effects

  bull T Helper Cells

  24

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  TA1 Effects

  bull T Helper Cells

  25

  0

  1000

  2000

  3000

  4000

  Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

  CD

  4+ (c

  ells

  mm

  3)

  Silecchia et al (1999) Cancer Immunotherapy 48 172-178

  p lt 0001 versus control p lt 0001 versus 5-FU

  Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

  with localized unresectable non-small cell lung cancer

  TA1treatment given for up to 1 year following radiation therapy

  Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

  26

  15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

  Antiaging properties of thymic protein

  Bioidentical thymic protein was injected into mice staring at the age of 35

  months prolonged mean life span by 28 decreased rate of cancer 28 fold

  27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

  TB4

  28

  ldquoThymosin b4 (Tb4) has recently been

  described as a powerful regenerative agent

  with angiogenic anti-inflammatory and cardioprotective

  effects on the heart and which specifically

  acts on its resident cardiac progenitor

  cellsrdquo

  TB4

  29

  ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

  TB4

  30

  ldquoThese data indicate that Tβ4 likely acts on

  endothelial cells and Schwann cells to preserve

  andor restore vascularfunction in the

  sciatic nerve which facilitates improvement

  of peripheral nerve function underdiabetic

  neuropathy Thus Tβ4 has potential for the

  treatment of diabetic peripheral neuropathyrdquo

  31

  Tβ4 and Neurologic Regeneration

  Peptide MSC Synergy

  32

  ldquoExtended-release Tβ4 administration

  improves the retention survival and regenerative

  potency of transplanted MSCs after myocardial

  injuryrdquo

  BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

  acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

  bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

  Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

  BPC 157 increases growth hormone receptors

  BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

  This peptide is also shown to decrease pain in damaged areas

  53

  BPC-157

  Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

  disease Protects liver from toxic insults (alcohol antibiotics etc) and

  promotes healing Traumatic brain injury27

  May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

  bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

  54

  16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

  17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

  18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

  BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

  anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

  stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

  reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

  propertiesrdquo17

  55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

  CPD 2011 17(16) p 1612-1632

  BPC-157 Potential target conditions

  Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

  56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

  Peptides 2010 160(1-3) p 26-32

  EpithalonEpithalamin

  A four AA peptide isolated from Pineal gland22

  bull Ala-Glu-Asp-Gly

  Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

  Increases mean and maximal life span in humans and animals5758

  Inhibits spontaneous and induced carcinogenesis242558

  57

  EpithalonEpithalamin

  Increases pineal synthesis of serotonin and melatonin

  Increases and restores telomere length2627 Slows down aging of the reproductive system

  and restores estrous and fertility in old female rats58

  Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

  insulin and triglyceride levels58

  Activate gene expression and protein synthesis in specific target tissues66 58

  Average Cellular Protein Synthesis Decreases with Age

  59 70 Arking B Biology of Aging Observations and Principles

  3rd Edition Oxford University Press 2006

  Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

  Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

  Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

  60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

  Telomerase

  It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

  Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

  While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

  Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

  61

  62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

  Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

  ThymosinsPineal peptides

  63

  66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

  71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

  Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

  Epitalon and Thymic Peptide and aging

  Effect of Peptide Bioregulators on the Lifespan of Mice

  64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

  Epithalon

  20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

  At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

  No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

  65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

  treatment Exp Pathol 197917539-545

  Epithalon

  Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

  The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

  Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

  66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

  spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

  Epithalon and Longevity

  Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

  All patients received standard basic therapy

  Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

  The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

  The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

  Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

  67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

  Epithalon

  ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

  prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

  pathological processes and to extend human life spansrdquo58

  68

  58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

  306

  Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

  investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

  RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

  ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

  A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

  69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

  Aug24(3-4)233-40

  Nootropics

  Semax Cerebrolysin Selank

  70

  Nootropics

  Neurotrophic action similar to that of nerve growth factors72-74

  Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

  bull TBI69

  bull Alzheimerrsquos1569-72

  bull Parkinsonsrsquo bull Stroke6973

  bull Toxin induced No significant side effects reported1569707273

  71

  Nootropics (Cerebrolysin)

  Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

  pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

  assessment scale) AD assessment score was significantly higher in the

  Cerebrolysin group (p=0007) Authors conclude

  bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

  72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

  disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

  Nootropics (Cerebrolysin)

  Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

  Authors conclude

  bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

  73

  71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

  Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

  Nootropics (SEMAX)

  74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

  of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

  The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

  In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

  Nootropics (SEMAX)

  75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

  for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

  Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

  Nootropics (SEMAX)

  76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

  experience in its design and study) ZVNDIP 199747(2)420-30

  ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

  ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

  In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

  Nootropics (Selank)

  77

  ldquoThe data obtained indicate that the individual

  administration of Selank was the most effective in

  reducing elevated levels of anxiety induced by the

  administration of a course of test substances whereas

  the combination of diazepam with Selank was

  the most effective in reducing anxiety in

  unpredictable chronic mild stress conditionsrdquo

  Nootropics (Selank)

  78

  ldquoIt was established that Selank can

  enhance memory storage processes

  Nootrope activity of the Selank is probably caused by its obvious effect on the level of

  serotonin and its metabolite in the

  brainrdquo

  79

  Markers of Immune Dysfunction (QuestAdvanced Labs)

  80

  Peptide Suggestions

  Lyme diseaseCFSMEFibromyalgia

  81

  Conclusions Summary

  Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

  Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

  Effective for prevention and treatment for a wide-range of chronic and acute illnesses

  Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

  -

  82

  Thank You

  Questions

  Kent Holtorf KholtHoltorfmedcom

  310-375-2705 Kathleen OrsquoNeil Smith

  mdkathyoneilsmithgmailcom 617-630-2882

TA1 Effects

bull T Helper Cells

24

0

1000

2000

3000

4000

Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

CD

4+ (c

ells

mm

3)

Silecchia et al (1999) Cancer Immunotherapy 48 172-178

p lt 0001 versus control p lt 0001 versus 5-FU

TA1 Effects

bull T Helper Cells

25

0

1000

2000

3000

4000

Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

CD

4+ (c

ells

mm

3)

Silecchia et al (1999) Cancer Immunotherapy 48 172-178

p lt 0001 versus control p lt 0001 versus 5-FU

Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

with localized unresectable non-small cell lung cancer

TA1treatment given for up to 1 year following radiation therapy

Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

26

15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

Antiaging properties of thymic protein

Bioidentical thymic protein was injected into mice staring at the age of 35

months prolonged mean life span by 28 decreased rate of cancer 28 fold

27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

TB4

28

ldquoThymosin b4 (Tb4) has recently been

described as a powerful regenerative agent

with angiogenic anti-inflammatory and cardioprotective

effects on the heart and which specifically

acts on its resident cardiac progenitor

cellsrdquo

TB4

29

ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

TA1 Effects

bull T Helper Cells

25

0

1000

2000

3000

4000

Control Tumor 5-FU 5-FU + IL2 5-FU + IL2 +ZDX

CD

4+ (c

ells

mm

3)

Silecchia et al (1999) Cancer Immunotherapy 48 172-178

p lt 0001 versus control p lt 0001 versus 5-FU

Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

with localized unresectable non-small cell lung cancer

TA1treatment given for up to 1 year following radiation therapy

Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

26

15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

Antiaging properties of thymic protein

Bioidentical thymic protein was injected into mice staring at the age of 35

months prolonged mean life span by 28 decreased rate of cancer 28 fold

27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

TB4

28

ldquoThymosin b4 (Tb4) has recently been

described as a powerful regenerative agent

with angiogenic anti-inflammatory and cardioprotective

effects on the heart and which specifically

acts on its resident cardiac progenitor

cellsrdquo

TB4

29

ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Immunorestorative Properties of TA1 in Lung Cancer Patients Double blind randomized trial with 42 pts

with localized unresectable non-small cell lung cancer

TA1treatment given for up to 1 year following radiation therapy

Statistically significant improvement in relapse-free survival (P=004) and overall survival (P=0009) which correlated to T cell levels previously depleted by radiation

26

15 Schulof RS A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 1985 4 p 12

Antiaging properties of thymic protein

Bioidentical thymic protein was injected into mice staring at the age of 35

months prolonged mean life span by 28 decreased rate of cancer 28 fold

27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

TB4

28

ldquoThymosin b4 (Tb4) has recently been

described as a powerful regenerative agent

with angiogenic anti-inflammatory and cardioprotective

effects on the heart and which specifically

acts on its resident cardiac progenitor

cellsrdquo

TB4

29

ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Antiaging properties of thymic protein

Bioidentical thymic protein was injected into mice staring at the age of 35

months prolonged mean life span by 28 decreased rate of cancer 28 fold

27 10 Morozov VG and VK Khavinson Natural and synthetic thymic peptides as therapeutics for immune dysfunction International Journal of Immunopharmacology 1997 19(9-10) p 501-505

TB4

28

ldquoThymosin b4 (Tb4) has recently been

described as a powerful regenerative agent

with angiogenic anti-inflammatory and cardioprotective

effects on the heart and which specifically

acts on its resident cardiac progenitor

cellsrdquo

TB4

29

ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

TB4

28

ldquoThymosin b4 (Tb4) has recently been

described as a powerful regenerative agent

with angiogenic anti-inflammatory and cardioprotective

effects on the heart and which specifically

acts on its resident cardiac progenitor

cellsrdquo

TB4

29

ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

TB4

29

ldquoThese data indicate that TBeta4 treatment improved functional recovery after encepalomyelitis possibly via reducing inflammatory infiltrates and stimulating oligodendrogenesisrdquo

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

TB4

30

ldquoThese data indicate that Tβ4 likely acts on

endothelial cells and Schwann cells to preserve

andor restore vascularfunction in the

sciatic nerve which facilitates improvement

of peripheral nerve function underdiabetic

neuropathy Thus Tβ4 has potential for the

treatment of diabetic peripheral neuropathyrdquo

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

31

Tβ4 and Neurologic Regeneration

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Peptide MSC Synergy

32

ldquoExtended-release Tβ4 administration

improves the retention survival and regenerative

potency of transplanted MSCs after myocardial

injuryrdquo

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

BPC-157 Pentadecapeptide BPC 157 composed of 15 amino

acids is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice

bull H-Gly-Glu-Pro-Pro-Pro-Gly-DL-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val-OH

Accelerates the healing of many different wounds including tendon gastrointestinal ligaments muscles nervous system and other organs

BPC 157 increases growth hormone receptors

BPC 157 also promotes the outgrowth of tendon fibroblasts cell survival under stress and the migration of tendon fibroblasts

This peptide is also shown to decrease pain in damaged areas

53

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

BPC-157

Protects and prevents gastric ulcers Improves digestive function Protects and heals inflamed intestinal epithelium (leaky gut) Eosinophilic esophagitis It has also been shown to help in Inflammatory bowel

disease Protects liver from toxic insults (alcohol antibiotics etc) and

promotes healing Traumatic brain injury27

May protect against acute and chronic toxic effects of alcohol symptoms of alcohol withdrawal

bull May antagonize 5HT2 receptor (high numbers of 5HT2 receptors found in depression and suicidal patients)

54

16 Blagaic AB et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice European Journal of Pharmacology 2004 499(3) p 285-290

17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract CPD 2011 17(16) 612-1632

18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Reg Peptides 2010 160(1-3) p26-32

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

BPC-157 ldquoStable gastric pentadecapeptide BPC 157 is an

anti-ulcer peptidergic agent safe in inflammatory bowel disease clinical trials and wound healing

stable in human gastric juice and has no reported toxicity Particularly it has a prominent effect on alcohol-lesions (ie acute chronic) and NSAIDs-lesions (interestingly BPC 157 both prevents and

reverses arthritis)hellip and acts as a free radical scavenger and exhibits neuroprotective

propertiesrdquo17

55 17 Sikiric P et al Stable Gastric Pentadecapeptide BPC 157 Novel Therapy in Gastrointestinal Tract

CPD 2011 17(16) p 1612-1632

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

BPC-157 Potential target conditions

Lyme diseaseHIV (especially in conjunction with TA1) Chronic viral or intracellular infections CFSFibromyalgia Autoimmune disease (asthma lupus etc) Inflammatory conditions (markers CRP C4a ESR HTGFB) CVD Post surgical Diabetes Aging Allergies Chemical sensitivity GI ulcersinflammation Inflammatory bowel disease Leaky gut H-pylori Preventtreat heart arrhythmias18

56 18 Tudor M et al Traumatic brain injury in mice and pentadecapeptide BPC 157 effect Regulatory

Peptides 2010 160(1-3) p 26-32

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

EpithalonEpithalamin

A four AA peptide isolated from Pineal gland22

bull Ala-Glu-Asp-Gly

Restores impaired aged and damaged neurologic immune and cardiovascular system improves neuroendocrine and immune regulation and prevents multiple age-related diseases such as HTN memory loss cancer osteoarthritis and overall mortality and morbidity in humans and animals23242555565758

Increases mean and maximal life span in humans and animals5758

Inhibits spontaneous and induced carcinogenesis242558

57

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

EpithalonEpithalamin

Increases pineal synthesis of serotonin and melatonin

Increases and restores telomere length2627 Slows down aging of the reproductive system

and restores estrous and fertility in old female rats58

Increases T4 to T3 conversion58 Improves glucose tolerance and decreases

insulin and triglyceride levels58

Activate gene expression and protein synthesis in specific target tissues66 58

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Average Cellular Protein Synthesis Decreases with Age

59 70 Arking B Biology of Aging Observations and Principles

3rd Edition Oxford University Press 2006

Aging is associated with decreasing cellular energy production (mitochondrial dysfunction) with resultant reduction in cellular metabolic activity

Subsequent reduction in protein synthesis age related tissue hypoplasia and atrophy of many tissues and organ systems including thymus pineal gland and reproductive organs

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Effect of the Pineal Gland Preparation on Melatonin Level in Elderly People

60 68 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Telomerase

It is now known that age-associated healing and rejuvenation is limited secondary to critical shortening of telomeres in the course of cell division26

Human somatic cells have very low levels of telomerase activity that is required to elongate telomeres26

While malignant sex early embryonic and some stem cells have relatively higher amounts of telomerase

Epithalon induces the expression of telomerase telomerase activity and elongation of in somatic telomeres2627

61

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

62 58 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

Overcoming of the Limit of Fibroblasts Division by Adding Epithalon

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

ThymosinsPineal peptides

63

66 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

71 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

Increase in mean and maximum lifespan in animals consistently seen with both thymic and pineal gland peptides with direct correlation to increased cellular immunity with the subsequent reliable reduction in cancer in both animals and humans

Epitalon and Thymic Peptide and aging

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Effect of Peptide Bioregulators on the Lifespan of Mice

64 69 Anisimov V et al Mechanisms of Ageing and Development 2001

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Epithalon

20 month long treatment of 05 mg per day epithalamin in female rats increased lifespan by 2557

At age 16-18 months 38 of control rates became menopausal or perimenopausal vs only 7 of treated rats

No 16-18 month control rats were able to get pregnant after repeated mating compared to 25 of treatment group with 5-9 healthy off-spring each

65 57 Dilman VM Anisimov VN Ostroumova MN et al Inrcrease in lifespan of rats following polypeptide pineal extract

treatment Exp Pathol 197917539-545

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Epithalon

Female mice carrying the breast cancer gene HER-2neu (genetically prone) received epithalon five times per week from 2nd month of life until death34

The percent of mice that developed breast cancer was 37 fold higher in control group (73 reduction in treatment group)

Epithalon also decelerated the rate of aging of the reproductive system with only 8 of aged mice having irregular menstrual cycles vs 52 of aged control mice

66 25 V N Anisimov V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of

spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Epithalon and Longevity

Randomized trial of 79 patients age 60-69 with severe CAD with half receiving 6 courses of Epithalon (6 courses over 3 years of 10 mg q 3 days for 15 days with 6 months between courses) The patients were then monitored for another 10 years with no further Epithalon treatments28

All patients received standard basic therapy

Over the subsequent 13 years the CVS functional age was 16 years older compared to 7 years for the Epithalon group

The CV morality of the treatment group was approximately half of control group 46 vs 833 respectively

The control group showed that there was a significant reduction in agendashassociated physical endurance by approximately 10 while the Epithalon group improved during the test period by almost 10

Also the Epithalon treated patients had a normalization of their circadian rhythm increased melatonin production and improved carbohydrate and lipid metabolism 28

67 28 O V Korkushko V Kh Khavinson V B Shatilo and I A Antonyk-Sheglova Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Epithalon

ldquoThe obtained results demonstrate a high efficiency of epithalon therapy for

prophylaxis of age-related pathology including cancer showing a new physiological way to slow down

pathological processes and to extend human life spansrdquo58

68

58 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-

306

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Peptide synergism The geroprotective effects of thymic and pineal (Epithalamin) peptides were

investigated over a 6-8 years period in 266 elderly patients after being treated for the first two to three years of the study

RESULTS ldquoThe obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism ie to improve the indices of cardiovascular endocrine immune and nervous systems homeostasis and metabolism Homeostasis restoration was accompanied by a 20-24-fold decrease in acute respiratory disease incidence reduced incidence of the clinical manifestations of ischemic heart disease hypertension disease deforming osteoarthrosis and osteoporosis as compared to the controlrdquo

ldquoSuch a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation 20-21-fold in the Thymalin-treated group 16-18-fold in the Epithalamin-treated group and a 25-fold in the patients treated with Thymalin plus Epithalamin as compared to the controlrdquo

A separate group of patients was treated with the peptides annually for 6 years and their mortality rate decreased 41 times as compared to the controls

69 10 Vkh Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-

Aug24(3-4)233-40

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics

Semax Cerebrolysin Selank

70

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics

Neurotrophic action similar to that of nerve growth factors72-74

Peripheral and central nervous system stimulation Neuroprotective effects Shields neurons from neurotoxins inflammation and injury Protects from stress and depression Improves memory (even in healthy adults) Neurological regeneration

bull TBI69

bull Alzheimerrsquos1569-72

bull Parkinsonsrsquo bull Stroke6973

bull Toxin induced No significant side effects reported1569707273

71

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (Cerebrolysin)

Double-blind placebo-controlled trial Patients injected intravenously with 30 mL Cerebrolysin (97

pts)or placebo (94 pts) 5 days a week for 4 weeks Evaluated effects on cognition and global function (via AD

assessment scale) AD assessment score was significantly higher in the

Cerebrolysin group (p=0007) Authors conclude

bull ldquoCere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatmentrdquo

72 15 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers

disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (Cerebrolysin)

Another double-blind placebo-controlled study looking at efficacy of Cerebrolysin for AD

Authors conclude

bull ldquoNotably improvements were largely maintained in the Cere group until week 28 3 months after the end of treatmenthellipCere treatment was well tolerated and led to significant improvement in cognition and global clinical impression A sustained benefit was still evident 3 months after drug withdrawalrdquo

73

71 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate

Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (SEMAX)

74 Yatsenko KA Glazova LS et al Heptapeptide Semax Attenuates the Effects

of Chronic Unpredictable Stress in Rats ISSN 00124966 Doklady Biological Sciences 2013453 353ndash7

The heptapeptide Semax is a clinically used nootropic and neuroprotective drug [6] It stimulates learning of animals [7] and increases the expression of BDNF and its high affinity trkB (tropromyosin kinase) receptors in the hippocampus [8]

In addition it has been shown that chronic Semax injection under conditions of stress load exerts anxiolytic and antidepressant effects [9]

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (SEMAX)

75 Tsai SJ Semax an analogue of adrenocorticotropin (4-10) is a potential agent

for the treatment of attention-deficit hyperactivity disorder and Rett syndrome Med Hypo 200768(5)1146-6

Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis In addition Semax could improve selective attention and modulate brain development and improve symptoms of ADHD

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (SEMAX)

76 Asmarin IP nezavibat VN Miasoedor NF et al A nootropic adrenocorticotropin analog 4-10-semax (l5 years

experience in its design and study) ZVNDIP 199747(2)420-30

ldquoSemax is one of the rare analogues of regulatory peptides which underwent all stages from fundamental investigations to practical usage It has been demonstrated that this peptide is capable to stimulate operative memory and attention to increase resistance to hypoxia and to improve brain circulation in experimental animals and human beings over prolonged period (20-24 h after intranasal administration in doses 0015-0050 mgkg)rdquo

ldquoSemax significantly improves memory and attention in healthy men under extreme conditions of activities Moreover at present semax is successfully used in treatment of patients with different diseases of CNS

In the majority of cases the peptide exhibited positive effects and in no case it produced negative side actions or complications connected with its administrationrdquo

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (Selank)

77

ldquoThe data obtained indicate that the individual

administration of Selank was the most effective in

reducing elevated levels of anxiety induced by the

administration of a course of test substances whereas

the combination of diazepam with Selank was

the most effective in reducing anxiety in

unpredictable chronic mild stress conditionsrdquo

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Nootropics (Selank)

78

ldquoIt was established that Selank can

enhance memory storage processes

Nootrope activity of the Selank is probably caused by its obvious effect on the level of

serotonin and its metabolite in the

brainrdquo

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

79

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Markers of Immune Dysfunction (QuestAdvanced Labs)

80

Peptide Suggestions

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

Lyme diseaseCFSMEFibromyalgia

81

Conclusions Summary

Peptides are demonstrating to be a highly effective therapy for a wide-range of diseases and aging with little risk of side-effects

Peptide therapy can address underlying dysfunction of he immune system and cellular dysfunction

Effective for prevention and treatment for a wide-range of chronic and acute illnesses

Synergistic effects of umbilical cord stem cells and peptides can be very effective and may be replacing standard medications and therapies for chronic illness

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

-

82

Thank You

Questions

Kent Holtorf KholtHoltorfmedcom

310-375-2705 Kathleen OrsquoNeil Smith

mdkathyoneilsmithgmailcom 617-630-2882

References

83

1 Holtorf K A Confounding Condition Treating chronic fatigue syndrome and fibromyalgia requires addressing the underlying problems Healthy Aging 2008Nov1-7

2 Holtorf K Cycle of Dysfunction of CFSFMLD 2004

3 McManus M Cincotta A Advances in Integrative Medicine Adv Integ Med 2015281-89

4 Ribeiro JM Weis JJ Telford 3rd SR Saliva of the tick Ixodes dammini inhibits neutrophil function Exp Parasitol 199070(May (4))382ndash8

5 Hovius JW van Dam AP Fikrig E Tickndashhostndashpathogen interactions in Lyme borreliosis Trends Parasitol 200723(September (9))434ndash8

6 Sapi E Bastian SL Mpoy CM Scott S Rattelle A Pabbati N et al Characterization of biofilm formation by Borrelia burgdorferi in vitro PLoS One 20127(10)e48277

7 Bunikis I Kutschan-Bunikis S Bonde M Bergstroumlm S Multiplex PCR as a tool for validating plasmid content of Borrelia burgdorferi J Microbiol Methods 201186(2)243ndash7

8 Rupprecht TA Koedel U Fingerle V Pfister HW The pathogenesis of Lyme neuroborreliosis from infection to inflammation Mol Med 200814(34)205ndash12

9 Jutras BL Chenail AM Stevenson B Changes in bacterial growth rate govern expression of the Borrelia burgdorferi OspC and Erp infection-associated surface proteins J Bacteriol 2013195(4)757ndash64

10 Scott S Rattelle A Pabbati N et al Characterization of biofilm formation by Borrelia burgdorferi in vitro PLoS One 20127(10)e48277

11 Stevenson B Babb K Lux-S mediated quorum sensing in Borrelia burgdorferi Lyme disease spirochete Infect Immun 2002704099ndash105

12 Beermann C Wunderli-Allenspach H et al Lipoproteins from Borrelia burgdorferi applied in liposomes and presented by dendritic cells induce CD8(+) T-lymphocytes in vitro Cell Immunol 2000201(2)124ndash31

13 Results of Palatin Technologiesrsquo PT-141 phase 2b study in men with erectile dysfunction May 10 2004 wwwpalatincom

14 Wessells H Gralnek D Dorr R Hruby VJ Hadley ME Levine N Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction Urology 2000 Oct 3156(4)641-6

15 Ionescu M Frohman LA Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295 a long-acting GH-releasing hormone analog The Journal of Clinical Endocrinology amp Metabolism 2006 Dec91(12)4792-7

16 Alba M Fintini D Sagazio A Lawrence B Castaigne JP Frohman LA Salvatori R Once-daily administration of CJC-1295 a long-acting growth hormone-releasing hormone (GHRH) analog normalizes growth in the GHRH knockout mouse American Journal of Physiology-Endocrinology and Metabolism 2006 Dec 1291(6)E1290-4

References

84

17 Jette L Le ger R Thibaudeau K Benquet C Robitaille M Pellerin I Paradis V van Wyk P Pham K and Bridon DP 2005 Human growth hormone-releasing factor (hGRF) 1ndash29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats Identification of CJC-1295 as a long-lasting GRF analogEndocrinology 146(7) pp3052-3058

18 Sackmann-Sala L Ding J Frohman LA Kopchick JJ Activation of the GHIGF-1 axis by CJC-1295 a long-acting GHRH analog results in serum protein profile changes in normal adult subjects Growth Hormone amp IGF Research 2009 Dec 3119(6)471-7

19 Dickinson GS Alugupalli KR Deciphering the role of Toll Like receptors to Borrelia Front Biosci 20124699ndash712

20 Kean IR Irvine KL Lyme disease aetiopathogenesis factors for disease development and control Inflammopharmacology 201321101ndash11

21 Holtorf K Unpublished data

22 Donahue RN McLaughlin PJ Zagon IS Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation mechanistic evidence from a tissue culture model Experil Biology Med 2011236(9)1036

23 Younger J Mackey S Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone A Pilot Study Pain Med 2009 10(4) 663ndash672

24 Younger J Noor N McCue R Mackey S Low-Dose Naltrexone for the Treatment of Fibromyalgia Arthritis amp Rheum 201365(2)529-538

25 Horowitz open labeled study HVHAC (2009-2016)

26 Morozov VG Khavinson KH Natural and synthetic peptides and immune dysfunction Int J Immunopharmac 199719(910)501-5

27 Tuthill C Rios I McBeath R Thymosin alpha 1 past clinical experience and future promise Annals of the New York Academy of Sciences 2010 May 11194(1)130-5

28 Li J Liu CH Wang FS Thymosin alpha 1 biological activities applications and genetic engineering production Peptides 2010 Nov 3031(11)2151-8

29 Ershler WB Gravenstein S Geloo ZS Thymosin alpha 1 as an adjunct to influenza vaccination in the elderly Annals of the New York Academy of Sciences 2007 Sep 11112(1)375-84

30 Garaci E Favalli C Pica Fet al Thymosin alpha 1 Annals of the New York Academy of Sciences 2007 Sep 11112(1)225-34

31 Qin Y Chen FD Zhou L Gong XG Han QF Proliferative and anti-proliferative effects of thymosin α1 on cells are associated with manipulation of cellular ROS levels Chemico-biological interactions 2009 Aug 14180(3)383-8

32 Matteucci C Minutolo A Sinibaldi‐Vallebona P et al Transcription profile of human lymphocytes following in vitro treatment with thymosin alpha‐1 Annals of the New York Academy of Sciences 2010 May 11194(1)6-19

References

85

33 Schulof RS et al 1985 A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 4 147ndash158

34 Freeman KW Bowman BR Zetter BR Regenerative protein thymosin β-4 is a novel regulator of purinergic signaling The FASEB Journal 2011 Mar 125(3)907-15

35 Lee HR Yoon SY Song SB et alchopp Interleukin-18-mediated interferon-gamma secretion is regulated by thymosin beta 4 in human NK cells Immunobiology 2011 Oct 31216(10)1155-62

36 Kim S Kwon J Effect of thymosin beta 4 in the presence of up-regulation of the insulin-like growth factor-1 signaling pathway on high-glucose-exposed vascular endothelial cells Molecular and cellular endocrinology 2015 Feb 5401238-47

37 Philp D Kleinman HK Animal studies with thymosin β4 a multifunctional tissue repair and regeneration peptide Annals of the New York Academy of Sciences 2010 May 11194(1)81-6

38 Jeon BJ Yang Y Shim SK Yang HM Cho D Bang SI Thymosin beta-4 promotes mesenchymal stem cell proliferation via an interleukin-8-dependent mechanism Experimental cell research 2013 Oct 15319(17)2526-34

39 Stark C Taimen P Tarkia M et alTherapeutic potential of thymosin β4 in myocardial infarct and heart failure Annals of the New York Academy of Sciences 2012 Oct 11269(1)117-24

40 Ershler N Smart CA Risebro AA Melville K Moses RJ Schwartz KR Chien PR Riley et al Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization Nature 445 (2007) 177ndash182

41 AL Goldstein E Hannappel HK Kleinman et al Thymosin beta4 actin-sequestering protein moonlights to repair injured tissues Trends Molecul Med 11 (2005) 421ndash429

42 Wang L Chopp M Szalad A et al Thymosin β4 Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice Neurobiol Dis 201248(3) 546ndash555

43 Sikiric P Seiwerth S Rucman R et al Stable gastric pentadecapeptide BPC 157 novel therapy in gastrointestinal tract Curr Pharm Des 201117(16)1612-32

44 Boban-Blagaic A Vladimir Blagaic et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice The effect of NG -nitro-L-arginine methyl ester and L-arginine Med Sci Monit 2006 12(1) BR36-45

45 Wong GK Zhu XL Poon WS Beneficial effect of cerebrolysin on moderate and severe head injury patients result of a cohort study InIntracranial Pressure and Brain Monitoring XII 2005 (pp 59-60) Springer Vienna

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86

46 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A 28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

47 Rockenstein E Torrance M Mante M Adame A Paulino A Rose JB Crews L Moessler H Masliah E Cerebrolysin decreases amyloid‐β production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimers disease Journal of neuroscience research 2006 May 1583(7)1252-61

48 Alvarez XA Cacabelos R Laredo M Couceiro V Sampedro C Varela M Corzo L Fernandez‐Novoa L Vargas M Aleixandre M Linares C A 24‐week double‐blind placebo‐controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimers disease European journal of neurology 2006 Jan 113(1)43-54

49 Ladurner G Kalvach P Moessler H Neuroprotective treatment with cerebrolysin in patients with acute stroke a randomised controlled trial Journal of neural transmission 2005 Mar 1112(3)415-28

50 Masliah E Armasolo F Veinbergs I Mallory M Samuel W Cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice Pharmacology Biochemistry and Behavior 1999 Feb 2862(2)239-45

51 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

52 Ojo-Amaize EA Conley EJ Peter JB Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome Clin Infect Dis 1994 Jan18 Suppl 1S157-9

53 Stricker RB Winger EE Decreased CD57 lymphocyte subset in patients with chronic Lyme disease Immunol Lett 2001 Feb 176(1)43-8

54 Lee SJ McPherron AC Regulation of myostatin activity and muscle growth Proc Nat Acad Sci 2001 98(16)9306-11

55 Kota J Handy CR Haidet AM et al Follistatin gene delivery enhances muscle growth and strength in nonhuman primates Sci Trans Med 2009 Nov 111(6)6ra15

56 Calvo RM Villuendas G Sancho J San Millaacuten JL Escobar-Morreale HF Role of the follistatin gene in women with polycystic ovary syndrome Fertility and sterility 2001 May 3175(5)1020-3

57 McPherron AC Lawler AM SJ L Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member Nature 199738783ndash90

58 Milan G Nora D Pagano C Changes in muscle myostatin expression in obese subjects after weight loss JCEM 2004 Jun89(6)2724-7

References

87

60 Berende A Oosting M Kullberg BJ et al Activation of innate host defense mechanisms by Borrelia Eur Cytokine Netw 201021(1)7ndash18

61 Cadavid D London˜o D Understanding tropismand immunopathological mechanisms of relapsing fever spirochaetes Clin Microbiol Infect 200915(May(5))415ndash21

62 Kraiczy P Hartman K Hellwage J Skerka C Kirschwink M Brade V et al Immunological characteristics of the complement regulation factor H binds CRASP and Erp proteins of Borrelia burgdorferi Int J Med Microbiol 2004293152ndash7

63 de Taeye SW Kreuk L van Dam AP Hovius JW Schuijt TJ Complement evasion by Borrelia burgdorferi it takes 3 to tango Trends Parasitol 20101171ndash10

64 Kennedy M Lenhart TR Akins DR The role of Borrelia burgdorferi outer surface proteins Immunol Med Microbiol 2012661ndash26

65 Rui L Yu N Hong Let al Extending the time window of mammalian heart regeneration by thymosin beta 4 Journal of cellular and molecular medicine 2014 Dec 118(12)2417-24

66 Wei C Kumar S Kim IK Gupta S Thymosin beta 4 protects cardiomyocytes from oxidative stress by targeting anti-oxidative enzymes and anti-apoptotic genes PloS one 2012 Aug 37(8)e42586

67 Xiong Y Zhang Y Mahmood A et al Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours post injury following traumatic brain injury in rats Journal of neurosurgery 2012 May116(5)1081

68 Matarese G Moschos S Mantzoros CS Leptin in Immunology J of Immunology 2005174(6)3137-3142

69 Grier TM The Complexities of Lyme Disease A microbiology tutorial Part 1 Lyme Disease Survival manual LymeNet Europe

70 McDonald AB Borrelia Burdoferi group spirochetes detected in blood and cerebrospinal fluid in seronegative patients Current Research Discoveries May 2016 London England

71 Christ Berg et al Does Borreliosis Activate the Coagulation System and is Coag Regulatory Protein Defect predispostional IDSA Oct 2003

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titers in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

74 Wahl SM Tranforming growth factor-beta innately bipolar Curr Opin Immunol 200719(1)55-62

References

88

75 Tanaka M Ozaki S Kawabata D v Potential preventive effects of follistatin-related proteinTSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis Int Immunol 200315(1)71-7

76 Alcayaga-Miranda F Cuenca J Khoury M Antimicrobial Activity of Mesenchymal Stem Cells Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies Front Immuno 20178(339)1-15

77 Oliveria-Bravo M Sanglorgi BB Schavinato S et al LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells Stem Cell Resch amp Ther 20167-189

78 Fuente-Nunez C Hancock Using anti-biofilm peptides to treat antibiotic-resistant bacterial Infections Postdoc J 20153(2)1-8

79 Eckard A Wood S In-Vitro Susceptibility of Different Morphological Forms of Borrelia burgdorferi to Common Lyme Antibiotics in Combination with Antimicrobial Peptides J Microb Exp 20163(4)1-19

80 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

81 Arking B Biology of Aging Observations and Principles 3rd Edition Oxford University Press 2006

82 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

83 Korkushko OV Khavinson VK Shatilo VB et al Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

84 Khavinson VK Bondarev IE Peptide Epitalon Induces Telomerase Activity and Elongation of Telomeres in Somatic Human Cells Ibid 20031356692-695

85 W E Wright and J W Shay Historical claims and current interpretations of replicative aging Ibid 2002207682-688

86 Anisimov V et al Mechanisms of Ageing and Development 2001

87 Dilman VM Anisimov VN Ostroumova MN et al Increase in lifespan of rats following polypeptide pineal extract treatment Exp Pathol 197917539-545

88 Anisimov VN V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

89 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

90 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

91 Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-Aug24(3-4)233-40

References

89

92 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-306

93 Kalaszcynska I Ferdyn K Whartonrsquos Jelly Derived Mesenchymal Stem Cells Future of Regenerative Medicine Recent Findings and Clinical Significance BioMed Res Int 20151-11

94 Hsieh J-Y Wang H-W Chang S-J et al (2013) Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection Neurogenesis and Angiogenesis PLoS One 20138(8)e72604

95 Blood Coagulation Fibrinolysis 2000 96 American Association of Clinical Chemistry 2003

97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new insights Immunology Today 199415(12)575-581

98 Chiu LL Reis LA Radisic M Controlled delivery of thymosin β4 for tissue engineering and cardiac regenerative medicine Ann N Y Acad Sci 201212691625

99 Ye L Shang P Duval S et al Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair Circulation 2013128S32-S41

100 Thymosin beta 4 reduces brain tissue damage improves brain function in rats Research paper RegeneRx Biopharmaceuticals Inc May 24 2010

101 Neurological Functional Recovery After Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis Int J Immunopharmac 199719(910)501-505

102 Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience 2009164(4)1887-93

103 Chopp M Ahang ZG Thymosin B4 as a restorativeregenerative therapy for neurological injury and neurodegenerative diseses Expert Opinion on Biological Therapy 201515(1)9-12

104 Ruff D Crockford D Girardi G A randomized placebo-controlled single and multiple dose study of intravenous thymosin beta4 in healthy volunteers Ann NY Acad Sci 20101194223-9

105 Chennupati SK Chiu AG Tamashiro E Effects of an LL-37ndashderived antimicrobial peptide in an animal model of biofilm Pseudomonas sinusitis Am J Rhinol Allergy 20092346-51

106 Sato H Feix JB Peptidendashmembrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides Biochim Biophys Acta 20061758(9)1245-56

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References

References

85

33 Schulof RS et al 1985 A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer J Biol Response Modif 4 147ndash158

34 Freeman KW Bowman BR Zetter BR Regenerative protein thymosin β-4 is a novel regulator of purinergic signaling The FASEB Journal 2011 Mar 125(3)907-15

35 Lee HR Yoon SY Song SB et alchopp Interleukin-18-mediated interferon-gamma secretion is regulated by thymosin beta 4 in human NK cells Immunobiology 2011 Oct 31216(10)1155-62

36 Kim S Kwon J Effect of thymosin beta 4 in the presence of up-regulation of the insulin-like growth factor-1 signaling pathway on high-glucose-exposed vascular endothelial cells Molecular and cellular endocrinology 2015 Feb 5401238-47

37 Philp D Kleinman HK Animal studies with thymosin β4 a multifunctional tissue repair and regeneration peptide Annals of the New York Academy of Sciences 2010 May 11194(1)81-6

38 Jeon BJ Yang Y Shim SK Yang HM Cho D Bang SI Thymosin beta-4 promotes mesenchymal stem cell proliferation via an interleukin-8-dependent mechanism Experimental cell research 2013 Oct 15319(17)2526-34

39 Stark C Taimen P Tarkia M et alTherapeutic potential of thymosin β4 in myocardial infarct and heart failure Annals of the New York Academy of Sciences 2012 Oct 11269(1)117-24

40 Ershler N Smart CA Risebro AA Melville K Moses RJ Schwartz KR Chien PR Riley et al Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization Nature 445 (2007) 177ndash182

41 AL Goldstein E Hannappel HK Kleinman et al Thymosin beta4 actin-sequestering protein moonlights to repair injured tissues Trends Molecul Med 11 (2005) 421ndash429

42 Wang L Chopp M Szalad A et al Thymosin β4 Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice Neurobiol Dis 201248(3) 546ndash555

43 Sikiric P Seiwerth S Rucman R et al Stable gastric pentadecapeptide BPC 157 novel therapy in gastrointestinal tract Curr Pharm Des 201117(16)1612-32

44 Boban-Blagaic A Vladimir Blagaic et al The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice The effect of NG -nitro-L-arginine methyl ester and L-arginine Med Sci Monit 2006 12(1) BR36-45

45 Wong GK Zhu XL Poon WS Beneficial effect of cerebrolysin on moderate and severe head injury patients result of a cohort study InIntracranial Pressure and Brain Monitoring XII 2005 (pp 59-60) Springer Vienna

References

86

46 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A 28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

47 Rockenstein E Torrance M Mante M Adame A Paulino A Rose JB Crews L Moessler H Masliah E Cerebrolysin decreases amyloid‐β production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimers disease Journal of neuroscience research 2006 May 1583(7)1252-61

48 Alvarez XA Cacabelos R Laredo M Couceiro V Sampedro C Varela M Corzo L Fernandez‐Novoa L Vargas M Aleixandre M Linares C A 24‐week double‐blind placebo‐controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimers disease European journal of neurology 2006 Jan 113(1)43-54

49 Ladurner G Kalvach P Moessler H Neuroprotective treatment with cerebrolysin in patients with acute stroke a randomised controlled trial Journal of neural transmission 2005 Mar 1112(3)415-28

50 Masliah E Armasolo F Veinbergs I Mallory M Samuel W Cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice Pharmacology Biochemistry and Behavior 1999 Feb 2862(2)239-45

51 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

52 Ojo-Amaize EA Conley EJ Peter JB Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome Clin Infect Dis 1994 Jan18 Suppl 1S157-9

53 Stricker RB Winger EE Decreased CD57 lymphocyte subset in patients with chronic Lyme disease Immunol Lett 2001 Feb 176(1)43-8

54 Lee SJ McPherron AC Regulation of myostatin activity and muscle growth Proc Nat Acad Sci 2001 98(16)9306-11

55 Kota J Handy CR Haidet AM et al Follistatin gene delivery enhances muscle growth and strength in nonhuman primates Sci Trans Med 2009 Nov 111(6)6ra15

56 Calvo RM Villuendas G Sancho J San Millaacuten JL Escobar-Morreale HF Role of the follistatin gene in women with polycystic ovary syndrome Fertility and sterility 2001 May 3175(5)1020-3

57 McPherron AC Lawler AM SJ L Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member Nature 199738783ndash90

58 Milan G Nora D Pagano C Changes in muscle myostatin expression in obese subjects after weight loss JCEM 2004 Jun89(6)2724-7

References

87

60 Berende A Oosting M Kullberg BJ et al Activation of innate host defense mechanisms by Borrelia Eur Cytokine Netw 201021(1)7ndash18

61 Cadavid D London˜o D Understanding tropismand immunopathological mechanisms of relapsing fever spirochaetes Clin Microbiol Infect 200915(May(5))415ndash21

62 Kraiczy P Hartman K Hellwage J Skerka C Kirschwink M Brade V et al Immunological characteristics of the complement regulation factor H binds CRASP and Erp proteins of Borrelia burgdorferi Int J Med Microbiol 2004293152ndash7

63 de Taeye SW Kreuk L van Dam AP Hovius JW Schuijt TJ Complement evasion by Borrelia burgdorferi it takes 3 to tango Trends Parasitol 20101171ndash10

64 Kennedy M Lenhart TR Akins DR The role of Borrelia burgdorferi outer surface proteins Immunol Med Microbiol 2012661ndash26

65 Rui L Yu N Hong Let al Extending the time window of mammalian heart regeneration by thymosin beta 4 Journal of cellular and molecular medicine 2014 Dec 118(12)2417-24

66 Wei C Kumar S Kim IK Gupta S Thymosin beta 4 protects cardiomyocytes from oxidative stress by targeting anti-oxidative enzymes and anti-apoptotic genes PloS one 2012 Aug 37(8)e42586

67 Xiong Y Zhang Y Mahmood A et al Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours post injury following traumatic brain injury in rats Journal of neurosurgery 2012 May116(5)1081

68 Matarese G Moschos S Mantzoros CS Leptin in Immunology J of Immunology 2005174(6)3137-3142

69 Grier TM The Complexities of Lyme Disease A microbiology tutorial Part 1 Lyme Disease Survival manual LymeNet Europe

70 McDonald AB Borrelia Burdoferi group spirochetes detected in blood and cerebrospinal fluid in seronegative patients Current Research Discoveries May 2016 London England

71 Christ Berg et al Does Borreliosis Activate the Coagulation System and is Coag Regulatory Protein Defect predispostional IDSA Oct 2003

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titers in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

74 Wahl SM Tranforming growth factor-beta innately bipolar Curr Opin Immunol 200719(1)55-62

References

88

75 Tanaka M Ozaki S Kawabata D v Potential preventive effects of follistatin-related proteinTSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis Int Immunol 200315(1)71-7

76 Alcayaga-Miranda F Cuenca J Khoury M Antimicrobial Activity of Mesenchymal Stem Cells Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies Front Immuno 20178(339)1-15

77 Oliveria-Bravo M Sanglorgi BB Schavinato S et al LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells Stem Cell Resch amp Ther 20167-189

78 Fuente-Nunez C Hancock Using anti-biofilm peptides to treat antibiotic-resistant bacterial Infections Postdoc J 20153(2)1-8

79 Eckard A Wood S In-Vitro Susceptibility of Different Morphological Forms of Borrelia burgdorferi to Common Lyme Antibiotics in Combination with Antimicrobial Peptides J Microb Exp 20163(4)1-19

80 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

81 Arking B Biology of Aging Observations and Principles 3rd Edition Oxford University Press 2006

82 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

83 Korkushko OV Khavinson VK Shatilo VB et al Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

84 Khavinson VK Bondarev IE Peptide Epitalon Induces Telomerase Activity and Elongation of Telomeres in Somatic Human Cells Ibid 20031356692-695

85 W E Wright and J W Shay Historical claims and current interpretations of replicative aging Ibid 2002207682-688

86 Anisimov V et al Mechanisms of Ageing and Development 2001

87 Dilman VM Anisimov VN Ostroumova MN et al Increase in lifespan of rats following polypeptide pineal extract treatment Exp Pathol 197917539-545

88 Anisimov VN V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

89 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

90 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

91 Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-Aug24(3-4)233-40

References

89

92 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-306

93 Kalaszcynska I Ferdyn K Whartonrsquos Jelly Derived Mesenchymal Stem Cells Future of Regenerative Medicine Recent Findings and Clinical Significance BioMed Res Int 20151-11

94 Hsieh J-Y Wang H-W Chang S-J et al (2013) Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection Neurogenesis and Angiogenesis PLoS One 20138(8)e72604

95 Blood Coagulation Fibrinolysis 2000 96 American Association of Clinical Chemistry 2003

97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new insights Immunology Today 199415(12)575-581

98 Chiu LL Reis LA Radisic M Controlled delivery of thymosin β4 for tissue engineering and cardiac regenerative medicine Ann N Y Acad Sci 201212691625

99 Ye L Shang P Duval S et al Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair Circulation 2013128S32-S41

100 Thymosin beta 4 reduces brain tissue damage improves brain function in rats Research paper RegeneRx Biopharmaceuticals Inc May 24 2010

101 Neurological Functional Recovery After Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis Int J Immunopharmac 199719(910)501-505

102 Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience 2009164(4)1887-93

103 Chopp M Ahang ZG Thymosin B4 as a restorativeregenerative therapy for neurological injury and neurodegenerative diseses Expert Opinion on Biological Therapy 201515(1)9-12

104 Ruff D Crockford D Girardi G A randomized placebo-controlled single and multiple dose study of intravenous thymosin beta4 in healthy volunteers Ann NY Acad Sci 20101194223-9

105 Chennupati SK Chiu AG Tamashiro E Effects of an LL-37ndashderived antimicrobial peptide in an animal model of biofilm Pseudomonas sinusitis Am J Rhinol Allergy 20092346-51

106 Sato H Feix JB Peptidendashmembrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides Biochim Biophys Acta 20061758(9)1245-56

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References

References

86

46 Ruether E Husmann R Kinzler E Diabl E Klingler D Spatt J Ritter R Schmidt R Taneri Z Winterer W Koper D A 28-week double-blind placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimers disease International clinical psychopharmacology 2001 Sep 116(5)253-63

47 Rockenstein E Torrance M Mante M Adame A Paulino A Rose JB Crews L Moessler H Masliah E Cerebrolysin decreases amyloid‐β production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimers disease Journal of neuroscience research 2006 May 1583(7)1252-61

48 Alvarez XA Cacabelos R Laredo M Couceiro V Sampedro C Varela M Corzo L Fernandez‐Novoa L Vargas M Aleixandre M Linares C A 24‐week double‐blind placebo‐controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimers disease European journal of neurology 2006 Jan 113(1)43-54

49 Ladurner G Kalvach P Moessler H Neuroprotective treatment with cerebrolysin in patients with acute stroke a randomised controlled trial Journal of neural transmission 2005 Mar 1112(3)415-28

50 Masliah E Armasolo F Veinbergs I Mallory M Samuel W Cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice Pharmacology Biochemistry and Behavior 1999 Feb 2862(2)239-45

51 Panisset M Gauthier S Moessler H Windisch M Cerebrolysin Study Group Cerebrolysin in Alzheimers disease a randomized double-blind placebo-controlled trial with a neurotrophic agent Journal of neural transmission 2002 109(7-8) 1089-104

52 Ojo-Amaize EA Conley EJ Peter JB Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome Clin Infect Dis 1994 Jan18 Suppl 1S157-9

53 Stricker RB Winger EE Decreased CD57 lymphocyte subset in patients with chronic Lyme disease Immunol Lett 2001 Feb 176(1)43-8

54 Lee SJ McPherron AC Regulation of myostatin activity and muscle growth Proc Nat Acad Sci 2001 98(16)9306-11

55 Kota J Handy CR Haidet AM et al Follistatin gene delivery enhances muscle growth and strength in nonhuman primates Sci Trans Med 2009 Nov 111(6)6ra15

56 Calvo RM Villuendas G Sancho J San Millaacuten JL Escobar-Morreale HF Role of the follistatin gene in women with polycystic ovary syndrome Fertility and sterility 2001 May 3175(5)1020-3

57 McPherron AC Lawler AM SJ L Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member Nature 199738783ndash90

58 Milan G Nora D Pagano C Changes in muscle myostatin expression in obese subjects after weight loss JCEM 2004 Jun89(6)2724-7

References

87

60 Berende A Oosting M Kullberg BJ et al Activation of innate host defense mechanisms by Borrelia Eur Cytokine Netw 201021(1)7ndash18

61 Cadavid D London˜o D Understanding tropismand immunopathological mechanisms of relapsing fever spirochaetes Clin Microbiol Infect 200915(May(5))415ndash21

62 Kraiczy P Hartman K Hellwage J Skerka C Kirschwink M Brade V et al Immunological characteristics of the complement regulation factor H binds CRASP and Erp proteins of Borrelia burgdorferi Int J Med Microbiol 2004293152ndash7

63 de Taeye SW Kreuk L van Dam AP Hovius JW Schuijt TJ Complement evasion by Borrelia burgdorferi it takes 3 to tango Trends Parasitol 20101171ndash10

64 Kennedy M Lenhart TR Akins DR The role of Borrelia burgdorferi outer surface proteins Immunol Med Microbiol 2012661ndash26

65 Rui L Yu N Hong Let al Extending the time window of mammalian heart regeneration by thymosin beta 4 Journal of cellular and molecular medicine 2014 Dec 118(12)2417-24

66 Wei C Kumar S Kim IK Gupta S Thymosin beta 4 protects cardiomyocytes from oxidative stress by targeting anti-oxidative enzymes and anti-apoptotic genes PloS one 2012 Aug 37(8)e42586

67 Xiong Y Zhang Y Mahmood A et al Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours post injury following traumatic brain injury in rats Journal of neurosurgery 2012 May116(5)1081

68 Matarese G Moschos S Mantzoros CS Leptin in Immunology J of Immunology 2005174(6)3137-3142

69 Grier TM The Complexities of Lyme Disease A microbiology tutorial Part 1 Lyme Disease Survival manual LymeNet Europe

70 McDonald AB Borrelia Burdoferi group spirochetes detected in blood and cerebrospinal fluid in seronegative patients Current Research Discoveries May 2016 London England

71 Christ Berg et al Does Borreliosis Activate the Coagulation System and is Coag Regulatory Protein Defect predispostional IDSA Oct 2003

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titers in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

74 Wahl SM Tranforming growth factor-beta innately bipolar Curr Opin Immunol 200719(1)55-62

References

88

75 Tanaka M Ozaki S Kawabata D v Potential preventive effects of follistatin-related proteinTSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis Int Immunol 200315(1)71-7

76 Alcayaga-Miranda F Cuenca J Khoury M Antimicrobial Activity of Mesenchymal Stem Cells Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies Front Immuno 20178(339)1-15

77 Oliveria-Bravo M Sanglorgi BB Schavinato S et al LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells Stem Cell Resch amp Ther 20167-189

78 Fuente-Nunez C Hancock Using anti-biofilm peptides to treat antibiotic-resistant bacterial Infections Postdoc J 20153(2)1-8

79 Eckard A Wood S In-Vitro Susceptibility of Different Morphological Forms of Borrelia burgdorferi to Common Lyme Antibiotics in Combination with Antimicrobial Peptides J Microb Exp 20163(4)1-19

80 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

81 Arking B Biology of Aging Observations and Principles 3rd Edition Oxford University Press 2006

82 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

83 Korkushko OV Khavinson VK Shatilo VB et al Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

84 Khavinson VK Bondarev IE Peptide Epitalon Induces Telomerase Activity and Elongation of Telomeres in Somatic Human Cells Ibid 20031356692-695

85 W E Wright and J W Shay Historical claims and current interpretations of replicative aging Ibid 2002207682-688

86 Anisimov V et al Mechanisms of Ageing and Development 2001

87 Dilman VM Anisimov VN Ostroumova MN et al Increase in lifespan of rats following polypeptide pineal extract treatment Exp Pathol 197917539-545

88 Anisimov VN V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

89 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

90 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

91 Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-Aug24(3-4)233-40

References

89

92 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-306

93 Kalaszcynska I Ferdyn K Whartonrsquos Jelly Derived Mesenchymal Stem Cells Future of Regenerative Medicine Recent Findings and Clinical Significance BioMed Res Int 20151-11

94 Hsieh J-Y Wang H-W Chang S-J et al (2013) Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection Neurogenesis and Angiogenesis PLoS One 20138(8)e72604

95 Blood Coagulation Fibrinolysis 2000 96 American Association of Clinical Chemistry 2003

97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new insights Immunology Today 199415(12)575-581

98 Chiu LL Reis LA Radisic M Controlled delivery of thymosin β4 for tissue engineering and cardiac regenerative medicine Ann N Y Acad Sci 201212691625

99 Ye L Shang P Duval S et al Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair Circulation 2013128S32-S41

100 Thymosin beta 4 reduces brain tissue damage improves brain function in rats Research paper RegeneRx Biopharmaceuticals Inc May 24 2010

101 Neurological Functional Recovery After Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis Int J Immunopharmac 199719(910)501-505

102 Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience 2009164(4)1887-93

103 Chopp M Ahang ZG Thymosin B4 as a restorativeregenerative therapy for neurological injury and neurodegenerative diseses Expert Opinion on Biological Therapy 201515(1)9-12

104 Ruff D Crockford D Girardi G A randomized placebo-controlled single and multiple dose study of intravenous thymosin beta4 in healthy volunteers Ann NY Acad Sci 20101194223-9

105 Chennupati SK Chiu AG Tamashiro E Effects of an LL-37ndashderived antimicrobial peptide in an animal model of biofilm Pseudomonas sinusitis Am J Rhinol Allergy 20092346-51

106 Sato H Feix JB Peptidendashmembrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides Biochim Biophys Acta 20061758(9)1245-56

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References

References

87

60 Berende A Oosting M Kullberg BJ et al Activation of innate host defense mechanisms by Borrelia Eur Cytokine Netw 201021(1)7ndash18

61 Cadavid D London˜o D Understanding tropismand immunopathological mechanisms of relapsing fever spirochaetes Clin Microbiol Infect 200915(May(5))415ndash21

62 Kraiczy P Hartman K Hellwage J Skerka C Kirschwink M Brade V et al Immunological characteristics of the complement regulation factor H binds CRASP and Erp proteins of Borrelia burgdorferi Int J Med Microbiol 2004293152ndash7

63 de Taeye SW Kreuk L van Dam AP Hovius JW Schuijt TJ Complement evasion by Borrelia burgdorferi it takes 3 to tango Trends Parasitol 20101171ndash10

64 Kennedy M Lenhart TR Akins DR The role of Borrelia burgdorferi outer surface proteins Immunol Med Microbiol 2012661ndash26

65 Rui L Yu N Hong Let al Extending the time window of mammalian heart regeneration by thymosin beta 4 Journal of cellular and molecular medicine 2014 Dec 118(12)2417-24

66 Wei C Kumar S Kim IK Gupta S Thymosin beta 4 protects cardiomyocytes from oxidative stress by targeting anti-oxidative enzymes and anti-apoptotic genes PloS one 2012 Aug 37(8)e42586

67 Xiong Y Zhang Y Mahmood A et al Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours post injury following traumatic brain injury in rats Journal of neurosurgery 2012 May116(5)1081

68 Matarese G Moschos S Mantzoros CS Leptin in Immunology J of Immunology 2005174(6)3137-3142

69 Grier TM The Complexities of Lyme Disease A microbiology tutorial Part 1 Lyme Disease Survival manual LymeNet Europe

70 McDonald AB Borrelia Burdoferi group spirochetes detected in blood and cerebrospinal fluid in seronegative patients Current Research Discoveries May 2016 London England

71 Christ Berg et al Does Borreliosis Activate the Coagulation System and is Coag Regulatory Protein Defect predispostional IDSA Oct 2003

72 Consolini R Legitimo A Calleri A et al Distribution of age-related thymulin titers in normal subjects through the course of life Clin Exp Immunol 2000 121444-447

73 Gui J Mustachio LM Su DM et al Thymus Size and Age-related Thymic Involution Early Programming Sexual Dimorphism Progenitors and Stroma Aging Dis 20123(3)280-90

74 Wahl SM Tranforming growth factor-beta innately bipolar Curr Opin Immunol 200719(1)55-62

References

88

75 Tanaka M Ozaki S Kawabata D v Potential preventive effects of follistatin-related proteinTSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis Int Immunol 200315(1)71-7

76 Alcayaga-Miranda F Cuenca J Khoury M Antimicrobial Activity of Mesenchymal Stem Cells Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies Front Immuno 20178(339)1-15

77 Oliveria-Bravo M Sanglorgi BB Schavinato S et al LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells Stem Cell Resch amp Ther 20167-189

78 Fuente-Nunez C Hancock Using anti-biofilm peptides to treat antibiotic-resistant bacterial Infections Postdoc J 20153(2)1-8

79 Eckard A Wood S In-Vitro Susceptibility of Different Morphological Forms of Borrelia burgdorferi to Common Lyme Antibiotics in Combination with Antimicrobial Peptides J Microb Exp 20163(4)1-19

80 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

81 Arking B Biology of Aging Observations and Principles 3rd Edition Oxford University Press 2006

82 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

83 Korkushko OV Khavinson VK Shatilo VB et al Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

84 Khavinson VK Bondarev IE Peptide Epitalon Induces Telomerase Activity and Elongation of Telomeres in Somatic Human Cells Ibid 20031356692-695

85 W E Wright and J W Shay Historical claims and current interpretations of replicative aging Ibid 2002207682-688

86 Anisimov V et al Mechanisms of Ageing and Development 2001

87 Dilman VM Anisimov VN Ostroumova MN et al Increase in lifespan of rats following polypeptide pineal extract treatment Exp Pathol 197917539-545

88 Anisimov VN V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

89 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

90 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

91 Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-Aug24(3-4)233-40

References

89

92 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-306

93 Kalaszcynska I Ferdyn K Whartonrsquos Jelly Derived Mesenchymal Stem Cells Future of Regenerative Medicine Recent Findings and Clinical Significance BioMed Res Int 20151-11

94 Hsieh J-Y Wang H-W Chang S-J et al (2013) Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection Neurogenesis and Angiogenesis PLoS One 20138(8)e72604

95 Blood Coagulation Fibrinolysis 2000 96 American Association of Clinical Chemistry 2003

97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new insights Immunology Today 199415(12)575-581

98 Chiu LL Reis LA Radisic M Controlled delivery of thymosin β4 for tissue engineering and cardiac regenerative medicine Ann N Y Acad Sci 201212691625

99 Ye L Shang P Duval S et al Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair Circulation 2013128S32-S41

100 Thymosin beta 4 reduces brain tissue damage improves brain function in rats Research paper RegeneRx Biopharmaceuticals Inc May 24 2010

101 Neurological Functional Recovery After Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis Int J Immunopharmac 199719(910)501-505

102 Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience 2009164(4)1887-93

103 Chopp M Ahang ZG Thymosin B4 as a restorativeregenerative therapy for neurological injury and neurodegenerative diseses Expert Opinion on Biological Therapy 201515(1)9-12

104 Ruff D Crockford D Girardi G A randomized placebo-controlled single and multiple dose study of intravenous thymosin beta4 in healthy volunteers Ann NY Acad Sci 20101194223-9

105 Chennupati SK Chiu AG Tamashiro E Effects of an LL-37ndashderived antimicrobial peptide in an animal model of biofilm Pseudomonas sinusitis Am J Rhinol Allergy 20092346-51

106 Sato H Feix JB Peptidendashmembrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides Biochim Biophys Acta 20061758(9)1245-56

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References

References

88

75 Tanaka M Ozaki S Kawabata D v Potential preventive effects of follistatin-related proteinTSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis Int Immunol 200315(1)71-7

76 Alcayaga-Miranda F Cuenca J Khoury M Antimicrobial Activity of Mesenchymal Stem Cells Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies Front Immuno 20178(339)1-15

77 Oliveria-Bravo M Sanglorgi BB Schavinato S et al LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells Stem Cell Resch amp Ther 20167-189

78 Fuente-Nunez C Hancock Using anti-biofilm peptides to treat antibiotic-resistant bacterial Infections Postdoc J 20153(2)1-8

79 Eckard A Wood S In-Vitro Susceptibility of Different Morphological Forms of Borrelia burgdorferi to Common Lyme Antibiotics in Combination with Antimicrobial Peptides J Microb Exp 20163(4)1-19

80 Korkushko O et al Bulletin of Experimental Biology and Medicine 2004

81 Arking B Biology of Aging Observations and Principles 3rd Edition Oxford University Press 2006

82 Khavinson V Malinin V Gerontological aspects of genome peptide regulation Karger 2005

83 Korkushko OV Khavinson VK Shatilo VB et al Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People Results of 15-Year Follow-Up Bulletin of Experimental Biology and Medicine Vol 151 No 3 July 2011

84 Khavinson VK Bondarev IE Peptide Epitalon Induces Telomerase Activity and Elongation of Telomeres in Somatic Human Cells Ibid 20031356692-695

85 W E Wright and J W Shay Historical claims and current interpretations of replicative aging Ibid 2002207682-688

86 Anisimov V et al Mechanisms of Ageing and Development 2001

87 Dilman VM Anisimov VN Ostroumova MN et al Increase in lifespan of rats following polypeptide pineal extract treatment Exp Pathol 197917539-545

88 Anisimov VN V Kh Khavinson M Provinciali et al Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2neu transgenic mice Int J Cancer 200210117-10

89 Khavinson V Peptides and ageing Neuroendocrinology Letters 200223(3)11-144

90 Anisimo VNN et al Effect of synthetic thymic and pineal peptide on biomarkers of ageing survival and spontaneous tumor incidence of female CBAmice Mech Ageing Dev 2001122(1)41-68

91 Morozov VG Peptides of pineal gland and thymus prolong human life Neuro Endocrinol Lett 2003 Jun-Aug24(3-4)233-40

References

89

92 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-306

93 Kalaszcynska I Ferdyn K Whartonrsquos Jelly Derived Mesenchymal Stem Cells Future of Regenerative Medicine Recent Findings and Clinical Significance BioMed Res Int 20151-11

94 Hsieh J-Y Wang H-W Chang S-J et al (2013) Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection Neurogenesis and Angiogenesis PLoS One 20138(8)e72604

95 Blood Coagulation Fibrinolysis 2000 96 American Association of Clinical Chemistry 2003

97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new insights Immunology Today 199415(12)575-581

98 Chiu LL Reis LA Radisic M Controlled delivery of thymosin β4 for tissue engineering and cardiac regenerative medicine Ann N Y Acad Sci 201212691625

99 Ye L Shang P Duval S et al Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair Circulation 2013128S32-S41

100 Thymosin beta 4 reduces brain tissue damage improves brain function in rats Research paper RegeneRx Biopharmaceuticals Inc May 24 2010

101 Neurological Functional Recovery After Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis Int J Immunopharmac 199719(910)501-505

102 Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience 2009164(4)1887-93

103 Chopp M Ahang ZG Thymosin B4 as a restorativeregenerative therapy for neurological injury and neurodegenerative diseses Expert Opinion on Biological Therapy 201515(1)9-12

104 Ruff D Crockford D Girardi G A randomized placebo-controlled single and multiple dose study of intravenous thymosin beta4 in healthy volunteers Ann NY Acad Sci 20101194223-9

105 Chennupati SK Chiu AG Tamashiro E Effects of an LL-37ndashderived antimicrobial peptide in an animal model of biofilm Pseudomonas sinusitis Am J Rhinol Allergy 20092346-51

106 Sato H Feix JB Peptidendashmembrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides Biochim Biophys Acta 20061758(9)1245-56

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References

References

89

92 Khavinson VKh Morozov VG Anisimov VN Experimental studies of the pineal gland preparation Epithalamin The Pineal Gland and Cancer Neuroimmunoendocrine Mechanisms in Malignancy 2001294-306

93 Kalaszcynska I Ferdyn K Whartonrsquos Jelly Derived Mesenchymal Stem Cells Future of Regenerative Medicine Recent Findings and Clinical Significance BioMed Res Int 20151-11

94 Hsieh J-Y Wang H-W Chang S-J et al (2013) Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection Neurogenesis and Angiogenesis PLoS One 20138(8)e72604

95 Blood Coagulation Fibrinolysis 2000 96 American Association of Clinical Chemistry 2003

97 Clerici M Shearer GM The Th1-Th2 hypothesis of HIV infection new insights Immunology Today 199415(12)575-581

98 Chiu LL Reis LA Radisic M Controlled delivery of thymosin β4 for tissue engineering and cardiac regenerative medicine Ann N Y Acad Sci 201212691625

99 Ye L Shang P Duval S et al Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair Circulation 2013128S32-S41

100 Thymosin beta 4 reduces brain tissue damage improves brain function in rats Research paper RegeneRx Biopharmaceuticals Inc May 24 2010

101 Neurological Functional Recovery After Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis Int J Immunopharmac 199719(910)501-505

102 Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience 2009164(4)1887-93

103 Chopp M Ahang ZG Thymosin B4 as a restorativeregenerative therapy for neurological injury and neurodegenerative diseses Expert Opinion on Biological Therapy 201515(1)9-12

104 Ruff D Crockford D Girardi G A randomized placebo-controlled single and multiple dose study of intravenous thymosin beta4 in healthy volunteers Ann NY Acad Sci 20101194223-9

105 Chennupati SK Chiu AG Tamashiro E Effects of an LL-37ndashderived antimicrobial peptide in an animal model of biofilm Pseudomonas sinusitis Am J Rhinol Allergy 20092346-51

106 Sato H Feix JB Peptidendashmembrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides Biochim Biophys Acta 20061758(9)1245-56

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References

90

107 Saiman L Tabibi S Starner TD et al Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis Antimicrob Agents amp Chemo 200145(10)2838-44

108 M Wang Y Yang D Yang et al The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro Immunology 2009126(2)220ndash32

109 Nell MJ Tjabringa GS Wafelman AR et al Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application Peptides 200627(4)649-60

110 Giuliani A Pirri G Rinaldi AC Antimicrobial peptides the LPS connection Methods Mol Biol 2010618137-54

References