Natural Supplements 101Natural Supplements 101Introduction to Herbal MedicinesIntroduction to Herbal Medicines

R.L.Ogletree, Jr., Pharm.D.

HERBHERB

Any plant or plant part that is primarily used for medicinal purposes

Herbal vs. HomeopathyHerbal vs. HomeopathyUse a plant or part of a plant which can elicit desired

Use a compound which can cause the undesired condition.

response.Use enough of the plant or extract to get that response.

Use very small doses. For a greater response - use less.

PrevalencePrevalence

80% of the world’s population use plants as their

i f primary source of medicines52% of 200 patients surveyed have used supplements in last year. JABFP 7-8 1996

Projected MarketProjected Market

Natural product market in US$2.85 billion in 1994$6.5 billion in 1998$6.5 billion in 1998Approx $10 billion in 2001Approx $23 billion in 2007

Poorly Regulated MarketPoorly Regulated Market

RX and OTC drugs must be proven safe and effectiveHerbal products labeled as “Dietary Herbal products labeled as Dietary Supplements,” Dietary Supplement and Health Education Act of 1994

Dietary Supplement Health Dietary Supplement Health and Education Act of 1994and Education Act of 1994

Sold as dietary supplementsy ppCan make “structure or function” claims on labelCan not make health or therapeutic claims on label

DSHEA (continued)DSHEA (continued)

Can have accompanying literature if a “balanced view” is presentedBurden of proof for safety (or lack of) is Burden of proof for safety (or lack of) is on the FDADisclaimer

HERBAL LABELING

These statements have not been evaluatedby the FDA. This product is not intendedto diagnose, treat, cure, or prevent a disease, but rather is a dietary supplement intended solely for nutritional support.

Sold and recommended by lay publicMany preparations not standardizedSome complement standard therapy,

t l it

ConsiderationsConsiderations

not replace itSome treat conditions which have limited drug optionsProfessional literature of Europe and Asia abounds with efficacy and safety studies

German Commission EGerman Commission E

Established in 1978 to review and approve herbal t t ttreatmentsLooks at:

SafetyHistorical dataEfficacy studies

Natural = Safe?Natural = Safe?Natural = Safe?Natural = Safe?

Some potentially dangerous Some potentially dangerous herbsherbs

Ma Haungephedrineephedrineoften in combination with caffiene

Bitter Orangesynephrinephenylephrine

More potentially dangerous More potentially dangerous herbs:herbs:

Comfreyused topically on wounds and internally for gastric ulcersgcontains unsaturated pyrrolizodine alkaloids - hepatotoxic

Alfalfaused a a diuretic and antiasthmaticcan exacerbate or reactivate SLE

More potentially dangerous More potentially dangerous herbs:herbs:

5-HTP (5-hydroxytryptophan)precursor to serotonin (5-HT, 5-hydroxytryptamine)y y yp )used for depression, weight loss, insomniaorphan drug for postanoxic myoclonus (along with carbidopa)GI distressheart valve problems?

Therapeutically useful herbsTherapeutically useful herbsd l t td l t tand plant componentsand plant components

Procyanidolic OligomersProcyanidolic Oligomers

Also called pycnogenols, PCO’s OPC’s Used by Jacques Cartier 1534-35Major sources:Major sources:

Grape seedsPine bark

Highly bioavailable

Procyanidolic OligomersProcyanidolic OligomersAntioxidant

Inhibits XO scavenges hydroxyl radicals (initiation step of LPO) scavenges peroxyl radicals(propagation step)

Strengthen vascular systemantioxidantcollagen cross-linksinhibits proteolytic enzymes

PCO’s continuedPCO’s continued

Mast cell stablizationAnti-inflammatory activities

antioxidantantioxidantcyclo-oxygenase inhibition

Procyanidolic Oligomers Procyanidolic Oligomers --ApplicationsApplications

DiabeticsSmokersVascular problemsVascular problemsChronic pancreatitisSun worshippersHeavy drinkersExercisers

PCO’s PCO’s -- Other Possible Other Possible Applications Applications -- TheoreticalTheoretical

AllergyArthritis

RheumatoidRheumatoidOsteo-

ADHDAminoglycoside therapy

PCO’s/StudiesPCO’s/StudiesDecreased capillary resistance in hypertension/diabetes

controlled,double-blind, 25 patients150 mg/day PCO’s or placebo for 30 daysSignificant improvement in the PCO group

10

12

14

16

18

20

14.7

18

14.615.5

Cap

illar

y re

sist

ance

(mm

Hg)

Baseline 30 days

150 mg/day Placebo

Sem Hop (Paris) 1981;57:1399-1401

PCO’s/Studies PCO’s/Studies -- cont’dcont’dVeno-lymphatic insufficiency Phlebologie 1993;46:3134,729 female subjects on estrogen/ progestin or progestin only therapy showing s/s of venous 6

7

87.2

c a

l e

showing s/s of venous insufficiency (esp. feeling of leg heaviness)All subject on 150 mg/day PCO’sFive symptoms evaluated on a 0 (absent) to 3 (very important) scale2.4% adverse events - mostly GI

0

1

2

3

4

5

3.5

1.9

Baseline 45 days 90 days

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m p

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c

PCO’s vision studiesPCO’s vision studies

100 normal volunteers recieved 200 mg/day or placebo for 5 weeks. Sig. improvement of vision in low light or after glare in PCO group.J Fr Ophthmol 1988;11:453-460J Fr Ophthmol 1988;11:453 460

40 myoptic patients recieved 150 mg/day or placebo for 30 days. Ann Ott Clin Ocul 1988;114:85-93

85.7% of PCO vs 0% placebo group showed increase in visual acuity. 40% of PCO vs 0% placebo group showed improvement in electroretinograpical studies.

PCO dosingPCO dosing

Usually 150 to 300 mg/day in single or divided dosesSeparate from minerals - at least 2 hoursSeparate from minerals at least 2 hoursSome say 1 to 1.5 mg/pound for 2 weeks, then cut dose in halfLook for proanthocyanidin content

80-85% for pine bark90-95% for grape seed

EchinaceaEchinacea

Also known as purple cone flowerNative to the U.S.In the NF until the 1950’sCurrently, the most popular herb in U.S.

Echinacea PharmacologyEchinacea Pharmacology

Enhances non-specific immunityPromotes T-cell activationIncreases natural killer cell activityS i l h iStimulates macrophage recriutmentEnhances phagocytosisStimulates production of IL-1, interferons,

TNF-alpha, and properdinInhibits hyaluronidaseStimulates fibroblast production of hyaluronic acid

Echinacea UsesEchinacea Uses

Prevent or treat flu or common cold Prevent recurrent respiratory and UTIs Improve immune system suppressed by p y pp y

chemotherapy or radiation treatmentTopically for superficial woundsNot recommended for AIDS patients

Not enough knownTNF-alpha

Echinacea DosageEchinacea Dosage

900 mg/dayStart at the first sign of flu or coldContinous use should not exceed 8 weeks (a few days

should be plenty)should be plenty)Use product standardized to at least 4% phenolic

compoundIf using a liquid extract, it should cause the tongue to

tingle

Echinacea Echinacea –– Drug InteractionsDrug Interactions

Immunosuppressants – antagonizes effects (theoretical)

Ginger (Ginger (ZingiberZingiber OfficinaleOfficinale))

Useful part - the rhizome , sometmes called the rootPrimary Use is to prevent nausea and vomitingParticularly useful to prevent motion sickness A i i di “P i ” Active ingredient - “Pungent properties” or

oleoresin Works at level of the GI tractDoes not cause drowsiness or anticholinergic effects

Ginger Root Against Ginger Root Against Seasickness*Seasickness*

Randomized, double-blind, placebo controlled80 healthy naval cadets on training shippNone especially susceptible to motion sickness1 gram powdered ginger root Vs placeboscored symptoms of nausea, vertigo, vomiting and cold sweating

*Acta Otolaryngol 1988;105:45-49

Ginger / SeasicknessGinger / Seasickness

42

60

28

39

1930

40

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60

om S

core

p < 0.05

PlaceboGinger

Nausea Vertigo Vomiting ColdSweating

5

19

5

18

0

10

20

Sym

pt

Nausea Vertigo Vomiting ColdSweating

p

*5 subjects in placebo grp vomited 2 or more times, but none in the ginger grp vomited more than once

*

Ginger vs Dimenhydrinate vs Placebo Ginger vs Dimenhydrinate vs Placebo (Lancet, March 20,1982)(Lancet, March 20,1982)

Enrolled 36 undergraduate men and women who reported very high susceptibility to motion sicknessRandomized to ginger root (940mg), dimenhydrinate (100mg) or placebo(100mg) or placeboPlaced in rotating chair (4-17rpm)Vertical component to motion as wellRecorded symptoms every 15s. up to six minutesResults: mean times P-90s., D-216s., G-335s.

none of P or D gps able to stay in chair 6 minuteshalf subjects on ginger stayed full time(p<0.001)

Ginger in Hyperemisis gravidarum Ginger in Hyperemisis gravidarum -- Eur J Eur J Obstet Gynecol Reprod Biol 1991;38:19Obstet Gynecol Reprod Biol 1991;38:19--2424

Randomized, double-blind, controlled , crossover30 patients250 mg or placebo q.i.d. for four days, then switch to other group other group Decreased vomiting and number of vomiting attacks in ginger group70.4% of patients preferred ginger to placebo

Note: Safety of the use of ginger during pregnancy has not yet been determined

Ginger DosageGinger Dosage

Usually 2 to 4 grams/dayFor motion sickness - 1 gram 30 minutes prior to departure followed by 500 mg prior to departure followed by 500 mg q.i.d. Additional 500 mg at first sign of nauseaMany recommend a 1 gram daily maximum during pregnancy

Ginger Ginger –– Drug InteractionsDrug Interactions

Concern with antiplatelet activity?

Black Black CohoshCohosh((CimicifugaCimicifuga racemosaracemosa ))

Uses alternative to HRT for menopausal symptomsdysmenorrheadyspepsia, rheumatism, sore throat, insect repellant

Black Cohosh Black Cohosh Chemical ComponentsChemical Components

triterpene glycosides (actein)27-deoxyacteine is used in Remifemin27-deoxyacteine is used in Remifemin

formononetin (an isoflavone)cinnamic acid esters

Black CohoshBlack CohoshMechanism

May bind estrogen receptors; “estriol-like” and may affect vaginal lining (not associated with greater risk of breast ovarian endometrial CA)greater risk of breast, ovarian, endometrial CA)“Formononetin” may suppress LH Contains salicylic acid

Black Cohosh Black Cohosh SafetySafety

FDA: “Herb of undefined safety”Likely safe if used in low doses; possibly unsafe when used > 6 months (G C i i E)(German Commission E)Contraindicated in pregnancy/lactationGI distressRare reports of liver toxicityBreast cancer aggression?

Black Cohosh Black Cohosh -- EfficacyEfficacyPossible effectiveness for menopausal symptoms, (Menopausal Index, Ham-A)

Hot flushesInsomnia

hNight sweatsAlso menstrual discomfortStudies have used the product Remifenin20 mg bid

Black CohoshBlack CohoshAdverse Effects

GI, visual, decreased BP/HR, perspiration (1 case report of seizures); increased vaginal epitheliumg pInsufficient information on salicylate content

Black CohoshBlack CohoshDrug Interactions

Additive with BP meds?Estrogenic substances? – not recommended concomitantlyconcomitantlyInsufficient info on salicylate content to produce interactions

Evening Primrose OilEvening Primrose Oil

High in Gamma-Linolenic AcidDecreases cholesterolHas been helpful in arthritisHas been helpful in arthritisHas been helpful in PMSHelpful in atopic dermatitisHelpful in diabetic neuropathy

EPO EPO -- Diabetic neuropathyDiabetic neuropathyImprovements seen in:

Nerve conduction velocityHot and cold thresholdsSensationsTendon reflexesMuscle strength

Pain was not assessedKeen, et al. Diabetes Care 1993;16(1):8-15Jamal, et al. Lancet May 10,1986:1098Boulton, et al. Diabetologia 1997;40 Suppl1:A32 (abstr)

Evening Primrose OilEvening Primrose Oil

Daily Dose 4 grams EPOEPO ~ 9% GLADaily Dose 360 mg GLADaily Dose 360 mg GLAOther sources of GLA

Borage Oil ~ 20 - 26% GLABlack Currant Oil ~ 6 - 19 % GLA

Caution with seizure disorder?

EPO EPO –– Drug InteractionsDrug Interactions

Phenothiazine – precipitate seizures?

Ginseng (Ginseng (PanaxPanax))

AdaptogenGinsenosidesRb1 and Rg1Rb1 and Rg1

increase brain protein synthesisdecrease 5-HT levelincreases ACTHincreases ACh release (Rb1)

GinsengGinseng

Rg1increases BPCNS stimulantCNS stimulant

Rb1decreases BPCNS depressant

Ginseng Ginseng -- activitiesactivities

Anti-stressImprovement and facilitation of memory and learning - esp reactions, memory and learning esp. reactions, abstract thinking, and mental arithmeticModulation of cellular metabolic processes on CHO, fats, and proteinPromotes hematopoesisFree radical scavenger

Ginseng Ginseng -- Flu vaccineFlu vaccine

227 volunteers

Scalgione, et al. Drugs Exp Clin Res 1996;22:65

227 volunteersRandomized to Ginseng 200 mg/day or placeboAfter 4 weeks - flu vaccineLooked at incidence of flu, antibody titers and natural killer cell activity

Ginseng Ginseng -- Flu vaccine cont’dFlu vaccine cont’d

4050

Placebo

42

Ginseng

15

0102030

In c ide nc e o f F lu

Ginseng Ginseng -- Flu vaccine cont’dFlu vaccine cont’d

0

2 0 0

4 0 0Placebo

171

Ginseng

272

0

A b t i t e r s

Natural killer cell activity nearly twice as high in ginseng group

Ginseng in diabetesGinseng in diabetes

36 newly diagnosed Type II diabeticsRandomized to Ginseng 100 mg 200

Sotaniemi, et al. Diabetes Care 1996;18:1373

Randomized to Ginseng 100 mg, 200 mg or placebo for 8 weeksAll were educated for dietary modifications

Ginseng in diabetes, cont’dGinseng in diabetes, cont’d

Decreased HbA1C (200 mg group)Decreased FBGImprovedImproved

moodwell-being (200 mg)vigorphysical activity (200 mg)

Ginseng in Chronic Ginseng in Chronic BronchitisBronchitis

Randomized, open-label, placebo-controlled75 patients (38 placebo, 37 ginseng)

acute attacks of chronic bronchitisAugmentin® 875 bid for 9 daysginseng G-115 100 mg or placebo bid for 9 days

Looking at clearance of bacteria from lungs daily samplesScaglione, et al. Clin Drug Invest 2001;21:41-45

Ginseng in Chronic BronchitisGinseng in Chronic Bronchitiscont’dcont’d

Chronic bronchitis - productive cough on most days at least 3 consecutive months for at least 2 yearsAcute exacerbation rapid onset of Acute exacerbation - rapid onset of cough w/purulent sputum & dyspnea, tachypnea, wheezing, and/or fever (>38° C)44 evaluable patients - 31 dropouts

22 missing bacterial counts at least 1 point9 withdrew

Ginseng in Chronic BronchitisGinseng in Chronic BronchitisResultsResults

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120

Bacterial Counts (% of baseline)

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Baseline Day 4 Day 5 Day 6 Day 7 Day 8

ABX onlyABX + Ginseng

Ginseng in Chronic BronchitisGinseng in Chronic BronchitisResultsResults

Statistically sig. at days 4, 5, 6, and 7Time to undetectable bacterial count

ABX only median - 7 daysABX only median - 7 daysmean - 6.7 days

ABX + ginseng median - 6 daysmean - 5.9 days

Both statistically sig.

Ginseng Ginseng -- DosingDosing

Use roots from 4 to 6 year old plantsAt least 4% ginsenosidesRb1 to Rg1 ratio of 2:1Rb1 to Rg1 ratio of 2:1Usually 200 to 400 mg/dayOften 2 months on, 1 month offSiberian ginseng is not the same

Ginseng Ginseng –– Drug InteractionsDrug InteractionsDiuretics (furosemide) - decreases diuretic activityMAOI’s – increases CNS side effectsInsulin sulfonylureas – increases Insulin, sulfonylureas – increases hypoglycemic effectsWarfarin – increases bleeding riskCYP3A4 inhibitor

Increased levels of nifedipineCase report of imatinib (Tykerb) hepatotoxicity

Ginkgo bilobaGinkgo biloba

Trees can live up to 1000 yearsVery resistant to bacteria, pollution, and insectsinsectsA ginkgo tree survived the Hiroshima bombMost widely used herb in EuropeOne of the most widely prescribed drugs in Germany

Ginkgo Ginkgo Flavone glycosides, terpene lactonesEffects: antioxidant, vascular protectant, inhibit platelet aggregation, PAF antagonist, neuroprotectant neuroprotectant

Primary uses: Conditions resulting from decreased cerebral or peripheral circulation (Senile dementia, vertigo, sudden deafness, intermittent claudication, vascular impotence)

Also useful: Antioxidant, antiallergy, radiation induced injury

Ginkgo / StudiesGinkgo / Studies

Many good double-blinded studies. Most in German literatureMeta-analysis of 40 studies found Ginkgo to be useful in improving such symptoms as difficulty in concentration or memory, confusion, dizziness, tinnitis, headaches, depressed mood, etc. Br J Clin Pharmacol 1992;34:352-385Nine double-blind, randomized clinical trials with ginkgo in intermittent claudication: increased distance of pain-free walking by 75-110%, maximum walkling distance by 52.6-119% and improved blood flow on doppler ultrasound Am J Nat Med 1995, 2(1):10

Ginkgo Ginkgo -- Antidepressant Antidepressant Induced Sexual DysfunctionInduced Sexual Dysfunction

Open-label63 patients (30 men, 33 women)Taking antidepressantsTaking antidepressantsReporting sexual dysfunction

libido (76%)erectile dysfunction (19%)delayed or inhibited orgasm (54%)

Cohen, et al. J Sex & Marital Ther. 1998 24:139-143

Ginkgo Ginkgo -- Antidepressant Antidepressant Induced Sexual DysfunctionInduced Sexual Dysfunction

Most had used other drugs to alleviate (cyproheptadine, yohimbine, amantadine, buspirone, or , p ,antidepressant dose)Dose: 40 -60 mg bid up to 120 mg bidAvg. daily dose = 207 mg

Ginkgo Ginkgo -- Antidepressant Antidepressant Induced Sexual DysfunctionInduced Sexual Dysfunction

ResultsResults84% positive effect

91% women76% n76% men

Helped all 4 phasesdesireexcitement (erection, lubrication)orgasmresolution (afterglow)

Ginkgo Ginkgo -- DosingDosing

Usual dose 60 - 240 mg/day (usually in divided doses)Be sure to use a standardized extract

50:1 concentration24% flavone glycosides6% terpene lactones

Side Effects: rare; gastric upset, headachesGive it time to work

Ginkgo Ginkgo –– Drug InteractionsDrug Interactions

Induces CYP2C19 – lowers levels of omeprazole, valproic acid, phenytoinTrazodone – comaTrazodone comaAnti-platelet activity – increases bleeding risk of warfarin and NSAIDs

St. John’s wort (Hypericum peforatum)St. John’s wort (Hypericum peforatum)

Named for John the BaptistWort - Olde English for plantActive ingredients:

H i iHypericinPseudohypericinHyperforin

Inhibits monoamine oxidaseInhibits reuptake of dopamine, serotonin and norepinephrineEffects: antiretroviral, antidepressant

St. John’s Wort / UsesSt. John’s Wort / Uses

Liscensed in Germany for: Depression, anxiety, sleep disordersas effective as standard antidepressantsfewer and milder side effectsMost widely prescribed antidepressant in Germany

30%-50% of antidepressant Rx’s - around 3 million yearly

St. John’s WortSt. John’s Wort(Scientific Evidence)*(Scientific Evidence)*

Recent review and meta-analysis publishedRandomized trials involving 1757 outpatients with mild to moderate depression: superior to placeboAs effective as amitriptyline imipramine As effective as amitriptyline, imipramine, maprotilinePooling studies of different preparations of herb problematic23 randomized, controlled studies identified between 1983-1994. NONE in the English language!

*BMJ 1996;313:253

St. John’s wortSt. John’s wort

Dose: Commission E recommends 1 mg hypericin content dailyMost studies used 2.7 mg hypericin content/day (0.9 mg tid)mg tid)Some studies now using 3 - 6% hyperforinSide effects: GI, photosensitivity?, MAOI?

0 - 25% in studiesone study 3250 patients - 2.4%

2 to 4 weeks may be needed to see results Fair skinned patients may have problem with UV-A

St. John’s Wort St. John’s Wort --Drug InteractionsDrug Interactions

MAO inhibitors SSRI’s - serotonin syndromeTriptans – serotonin syndrome (theoretical)Di i l di l lDigoxin - lowers dig. levelsIndinavir, nevirapine, lamivudine - lowers levelsCyclosporin, tacrolimus - lowers levelsSimvastatin, atorvastatin – lowers levelsOral Contraceptives??

Saw Palmetto (Serenoa repens)Saw Palmetto (Serenoa repens)Also called sabalNative to the Southeastern U.S.Liposterolic extract is usedAntiandrogenic, antiestrogenic, antiinflammatoryg , g , yInhibits 5 alpha reductaseAlpha-1 antagonistUse: benign prostatic hypertrophy

Can decrease prostate sizeCan help with symptoms within 1 monthStudies have not shown an effect on PSA

BPH BPH -- MetaMeta--AnalysesAnalyses

Saw Palmetto18 trials2939 pts

Alpha-1 blockers25 trials6840 ptsp p

Wilt, et al. JAMA

1998;280:1604

Djavan, et al. Eur Urol

1999;36:1

BPH BPH -- MetaMeta--AnalysesAnalysesSaw Palmetto

Urinary tract sx: 28% abs vs placeboMax flow: + 1.93 ml/s (24%) abs vs

Alpha-1 blockersUrinary tract sx: 10 to 20% abs vs placeboMax flow: + 5 to 15% abs vs placebo/ ( )

placeboADR’s: 0.8% vs placebo Dropouts: 2.1% vs placebo

abs vs placeboADR’s: 5-10% vs placebo for terazosin & doxazosin (5% for tamsulosin & alfuzosinDropouts: 4-10% vs placebo (Ter & Dox)

Saw Palmetto MetaSaw Palmetto Meta--AnalysisAnalysis

Mean flow: +2.22 ml/s (28% vs placebo)Residual volume: -22.05 ml (43% vs placebo)placebo)

Saw Palmetto DosageSaw Palmetto Dosage160 mg twice a dayBe sure it is standardized to 85 - 95% fatty acids and sterolsfatty acids and sterolsWell tolerated, but a few GI effects

LicoriceLicoriceGlycyrhizin - mimics aldosterone

Usesliver disorderschronic fatigue

Precautionssodium retentionpotassium loss

Deglycyrrhized licorice (DGL) - GI disorders (activity probably due to flavonoids)

DGLDGL

More helpful in ulcersIncreased gastric prostaglandinsIncreased mucus secretionIncreased mucus secretionUsually chewable tablets300 mg - 400 mg 20 min before meals

Milk Thistle (Silybrum Milk Thistle (Silybrum marianum)marianum)

Active component - silymarin (a bioflavanoid complex)

Hepatoprotective: antioxidantantioxidantmembrane stabilizerstimulation of hepatocyte regeneration

Staple in European emergency departmentsUses: alcoholic liver disease, hepatitis (acute, chronic, infectious, chemical), Amanita mushroom poisoning

Randomized Controlled Trial of SilymarinRandomized Controlled Trial of Silymarinin Patients with Cirrhosis of the Liver*in Patients with Cirrhosis of the Liver*

Double- blind, prospective randomized 170 patients with cirrhosis (91 alcoholic; 79 non-alcoholic)Silymarin: 140mg TIDSeverity: Child A:89 B:69 C:12yMean observation period 41 months4-year survival rate: 58% silymarin ; 39% placebo (p=0.036%)Sub-group analysis: Treatment effective in patients with alcoholic cirrhosis (p=0.01) and patients rated Child A (p=0.03)

*J Hepatology 1989;9:105-113

Milk Thistle DosageMilk Thistle Dosage200 mg three times a dayCan change to twice daily after improvementBe sure product is standardized to provide p p

70% silymarin (140 mg in a 200 mg capsule)

May cause transient loose stools

Valerian Valerian (Valeriana officinalis)(Valeriana officinalis)

Name from Valere - to be in health Used in WWI for “overwrought

” d i tillnerves” during artillerybombardment

Over 50 tons sold yearly in FranceActive ingredients:

Volatile oil ?Valepotriates ?

Smells like old socks - Excites cats

ValerianValerian

Actions:Enhances activity of GABAAntagonizes hypnotic effect of alcohol, but

Z ZZ

g yp ,not impaired judgement or reaction times

UsesInsomniaAnxiety includingtraffic stress and performance anxiety

HypnosedativesHypnosedatives

Common Treatments of InsomniaBenzodiazepinesDiphenhydramineDiphenhydramine

Disadvantages of Hypnosedativesextended sedationimpaired cognition and motor activitydecreased REM sleepanticholinergic side effectsdependence

Valerian DosageValerian DosageAnxiety: 100 - 200 mg per doseInsomnia: 200 - 500 mg

Take 30 to 40 minutes prior to bedtimeDose may need to be increased in patients used to anxiolytics or hypnoticsLarge doses (>900 mg ) could cause

hangoverDo not abruptly stop benzodiazepines

NONNON--BOTANICAL BOTANICAL NATURAL PRODUCTS NATURAL PRODUCTS

AND THEIR AND THEIR AND THEIR AND THEIR IMPACT ON HEALTHIMPACT ON HEALTH

Coenzyme Q 10Coenzyme Q 10

Also known as ubiquinone or ubidecarenoneEndogenous lipid soluble anti-oxidantEndogenous lipid soluble anti oxidantFound mostly inside mitochondriaImportant as an electron carrier for respiratory energy transportSynthesized from mevalonate

Coenzyme Q 10 Coenzyme Q 10 --Dilated cardiomyopathyDilated cardiomyopathy

Ma, et al. Blood Press Suppl

19963:53 5561 patientsMitochondrial membrane phospholipid (MMP) injury3 groups: placebo, captopril, CoQ10

19963:53-55

Coenzyme Q 10 Coenzyme Q 10 -- Dilated Dilated cardiomyopathy, cont’dcardiomyopathy, cont’d

At 12 weeks sig. MMP repair in captopril and CoQ10 groups2 year survival improvement

placebo: 24.7%captopril: 64.0%CoQ10: 72.7%

Coenzyme Q 10 Coenzyme Q 10 --CardiomyopathyCardiomyopathy

143 patients

Int J Tissue React 1990 12:169

143 patients chronic stable non-hypertrophic cardiomyopathy98% NYHA class III or IVfollowed for 6 years

Coenzyme Q 10 Coenzyme Q 10 --Cardiomyopathy, cont’dCardiomyopathy, cont’dsig improvement in ejection fraction in 84% (from 44% EF to 60% in 6 months)( )85% improved 1 to 2 NYHA classesMortality:

12 month 11.1%24 month 17.8%

New York Heart AssocNew York Heart AssocClassificationClassification

I Well compensated, no physical limitations no sx at normal activity

II Sl. limitation of physical activity, sl. p y y,increase in of sx at normal activity

III Comfortable only at rest. Sx with less than normal activity

IV Sx at rest

Coenzyme Q 10 in AMICoenzyme Q 10 in AMI

Randomized, double-blind, placebo control144 patients 144 patients

73 - Co Q 10 120 mg/day X 28 days71 - placebo X 28 days

Started within 3 days of symptom onset

Singh, et al. Cardiovasc Drugs Ther 1998;12:347-353

Co Q 10 in AMI (cont’d)Co Q 10 in AMI (cont’d)CoQ10 Placebo

angina 9.5% 28.1% arrhythmias 9.5% 25.3%poor left vent.f ti 8 2% 22 5%function 8.2% 22.5%total cardiacevents (fatal &nonfatal) 15.0% 30.9%increased Vits. A, E, C, beta-carotene intx group

Coenzyme Q 10 in Coenzyme Q 10 in Isolated Systolic HypertensionIsolated Systolic Hypertension

Randomized, double-blind, placebo control80 patients 80 patients

32 - Co Q 10 60 mg bid X 12 wks (additional 9 normotensive)39 - placebo X 12 wks

SBP 150 -170; DBP<90Burke, et al. Souther Medical Journal 2001;94(11):1112-1117

Coenzyme Q 10 in ISH (cont’ed)Coenzyme Q 10 in ISH (cont’ed)

10 day washoutSBP > 175 once or > 170 x 3 consec.visits excluded ptexcluded pt.Same for DBP > 115Co Q10 levels baseline and after tx

Coenzyme Q 10 in ISH resultsCoenzyme Q 10 in ISH results

Co Q10 pts 55% responders (> 4 mmHg decrease in SBP))(43% > 7 MmHg) 45% non-responders

Coenzyme Q 10 in ISH Coenzyme Q 10 in ISH resultsresults

Avg reduction in SBP For CO Q10 was 17.8 mmHg(+7 3)

160

165

170

7.3)

Avg reduction in responders was 25.9mm Hg (+ 25.9)

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Co

Q10

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ebo

BeforeAfter

Coenzyme Q 10 in peridontal Coenzyme Q 10 in peridontal dzdzPatients w/ peridontal dz often have CoQ10 (around 80% of normal)The deficiency has been measured in serum and local tissueStudies using CoQ10 replacement have shown improvement in 5 to 7 daysUse with physiotherapy not instead of it

Coenzyme Q10 and Coenzyme Q10 and Breast CancerBreast Cancer

32 high risk pts. (spread to axillary nodes)Co-Q10 (90 mg) and other antioxidants for 18 months

Lockwood, et al. Molec Aspects Med 1994;15:S231

Coenzyme Q10 and Coenzyme Q10 and Breast Cancer FindingsBreast Cancer Findings

No deaths (4 expected)No weight lossI d QOLImproved QOLReduced analgesic usage6 partial remission - 2 in full remission after 24 months (dose increased to 300 -390 mg)

Lockwood, et al. Molec Aspects Med 1994;15:S231

Coenzyme Q10 and Coenzyme Q10 and CardiotoxicityCardiotoxicity

Children (3 - 15 y/o) w/acute lymphoblastic leukemia & Non-Hodgkins lymphomaHodgkins lymphomaOn anthracyclines10 Co-Q 10; 10 placeboCumulative anthracycline doses 210 -270 mg/m2

Iarussi, et al. Molec Aspects Med 1994;15:S207

Coenzyme Q10 and Coenzyme Q10 and CardiotoxicityCardiotoxicity

Less left ventricular fractional shortening in Co-Q 10 groupDecrease in intraventricular septum Decrease in intraventricular septum wall thickening only in placebo groupFewer wall motion abnormalities in Co-Q 10 group

Iarussi, et al. Molec Aspects Med 1994;15:S207

Coenzyme Q 10 Coenzyme Q 10 -- dosingdosing

Breast Cancer - 390 mg/dayCHF - at least 200 mg/dayPeriodontal dz 100 Periodontal dz - 100 “Statin” pts. - 100 mg/dayFat soluble, so fatty form best

Q-gelpeanut butter

Coenzyme Q 10 Coenzyme Q 10 –– Drug InteractionsDrug Interactions

Warfarin – inconsistentCoQ10 – vit K like molecule that can antagonize effects of warfaringMay decrease INR

Chemotherapy – decreases effectiveness due to antioxidant activity (theoretical)

Glucosamine and ChondroitinGlucosamine and Chondroitin

Glycosaminoglycans - components of cartilage matrixChondrotin attracts fluids and nutrients Chondrotin attracts fluids and nutrients into proteoglycan moleculesGlucosamine stimulates chondrocyte activityUsually used in osteoarthritis

Chondroitin vs DiclofenacChondroitin vs Diclofenac

Randomized, double-blind 146 patients with knee osteoarthritis

Morreale, et al. J Rheum 1996;23:1385

Diclofenac 50 mg t.i.d or chondroitin 400 mg t.i.d.Diclofenac worked faster, but chondroitin worked better and lasted longer and cessation of tx

Glucosamine vs IbuprofenGlucosamine vs Ibuprofen

Double-blind40 outpatients

Vaz. Curr Med Res Opin 1982;8:145

pRandomized to Ibuprofen 400 mg t.i.d or Glucosamine 500 mg t.i.d.At 2 weeks, ibuprofen was betterAt 8 weeks, Glucosamine was betterSide effect: Ibu-25% Gluc-11%

Glucosamine vs IbuprofenGlucosamine vs Ibuprofen

Double-blind178 outpatients - knee OA

∗Qui, et al. Arzneim-Forsch 1998;48:469

pRandomized to Ibuprofen 400 mg t.i.d or Glucosamine 500 mg t.i.d.At 2 weeks, and 4 weeks knee pain scores and knee swelling scores

Qui, et al studyQui, et al study

789

Knee Pain Score

0123456

Pre-TX 4weeks

GSIbu

Qui, et al studyQui, et al study

Knee Swelling Score

11.21.41.6

00.20.40.60.8

1

Pre-TX 4weeks

GSIbu

Glucosamine vs IbuprofenGlucosamine vs Ibuprofen

Adverse effects due to drugsGS - 6%

∗Qui, et al. Arzneim-Forsch 1998;48:469

Ibu - 16%Drug related drop-outs

GS - 0%Ibu - 10%

Both statistically significant

Glucosamine 3 Year StudyGlucosamine 3 Year Study

212 patients106 glucosamine 1500 mg qd106 placebo qd106 placebo qd

OA of knee Symptoms - WOMAC scale - every 4 monthsDx progression - X-ray - joint space width - baseline, 1 yr & 3 yr

Reginster, et al. Arthritis and Rheumatism 1999;9:S400(abstr)

Glucosamine Glucosamine -- resultsresultsWOMAC scoresWOMAC scores

1000

1200

Per Protocol ITT

0

200

400

600

800

Placebo Placebo

Baseline3 Years

Glucosamine Glucosamine -- resultsresultsWOMAC score changeWOMAC score change

5

10

Per Protocol ITT

-25

-20

-15

-10

-5

0

Placebo Placebo

% change

Glucosamine Glucosamine -- results results Joint Space Width (mm)Joint Space Width (mm)

5 455.5

Per Protocol ITT

4.955

5.055.1

5.155.2

5.255.3

5.355.4

5.45

Placebo Gluosamine

Baseline3 Years

Glucosamine Glucosamine -- resultsresultsJoint Space Narrowing (mm)Joint Space Narrowing (mm)

0 30.35

Per Protocol ITT

-0.15-0.1

-0.050

0.050.1

0.150.2

0.250.3

Placebo Placebo

mm change

Glucosamine /ChondroitinGlucosamine /Chondroitin

More “antireactive” than anti-inflammatoryChondroprotectiveChondroprotectiveOsteoarthritis is degenerative more than inflammatoryGlucosamine is more bioavailable than chondroitin

Glucosamine /ChondroitinGlucosamine /Chondroitin

Glucosamine 500 mg po t.i.dChondroitin 400 mg po t.i.d.Often available in comboOften available in comboMay want to give NSAIDS for first 2 to 4 weeks

Glucosamine Glucosamine –– Drug InteractionsDrug Interactions

Theoretical concern that may increase insulin resistance

May require increased dose of insulin or y qsulfonylurea – not likely

MSMMSM

Methyl sufonyl methaneDimethylsulfoneSulfur containing productSulfur containing productDehydrating agentFacilitates attachment of flu viruses to cellsNo published human evidence in arthritis

SAMeSAMeS-adenosylmethionineSulfur containing amino acidMetabolized to homocysteineStudied inStudied in

depressionfibromyalgiaosteoarthritiscirrhosis

Expensive

SAMeSAMe

Osteoarthritis - compared topiroxicamnaproxennaproxenibuprofenindomethacin

Generally - as affective, less side effectsExpensive ~ $150.00/month

SAMe SAMe -- MetaMeta--analysisanalysisMore effective than placeboDepression - compared to

amoxapinemaprotalinemaprotalinetrazadoneimipramine

Generally - as affective, less side effectsExpensive ~ $250.00/monthBressa. Acta Neurol Scand. 1994;Suppl 154:7-14

SAMeSAMe –– Drug InteractionsDrug Interactions

Serotonin syndrome?

ChromiumChromium

Not an herb - a mineralGlucose tolerance factorIncreases insulin efficiencyIncreases insulin efficiencyDecreases triglyceridesIncreases HDL

Chromium study (China)Chromium study (China)

180 patients (60 in each group)Type II diabeticsOn other diabetes treatments (insulin On other diabetes treatments (insulin, sulfonylureas,metformin, chinese herbs)Placebo , 200 mcg/day, or 1000 mcg/day divided into 2 doses for 4 months

Anderson, et al. Diabetes. 1997;46(11):1786-91.

Chromium study Chromium study -- resultsresultsH e m o g l o b i n A 1 C

6789

1 0 9 .18 .5

9 .4

7 .5

9 .4

6 .6

Both chromium groups show sig. lower HbA1c at 4 months

56

B a s e l in e 4 m o n t h sP la c e b o 2 0 0 m c g 1 0 0 0 m c g

Chromium study Chromium study -- resultsresults

177160

177

129

100

150

200

Baseline

4 Months

Fasting Blood Glucose

0

50

Placebo 1000 mcg

Chromium Chromium –– Drug InteractionsDrug Interactions

Insulin, sulfonylureas – enhances hypoglycemic effectsLevothyroxine – lowers levelsLevothyroxine lowers levels

Take levothyroxine 30 min before or 4 hrs after chromium

NSAIDs – increase chromium levels

Patient ConsiderationsPatient ConsiderationsUse a reliable sourceInterpret extravagant claims in light of scientific evidenceThere could be side effectsHormonal systems have multiple feedback mechanismsSome could interact with other drugsVery little information about use in children, pregnant, or lactating women

Recommended Web SitesRecommended Web Siteshttp://www.consumerlab.com

$19.95/yr

Memorial Sloan-Kettering Cancer Center http://www.mskcc.org/mskcc/html/11570.cfm

Recommeded Reference Recommeded Reference SourcesSources

☺ Pharmacists Letter/Prescriber’s Letter Guide to Natural Products, 2002 $100

☺ The Lawrence Review of Natural Products, ( thl d t ) $60/

NATURALPRODUCTS

(monthly update) $60/yr☺ Facts and Comparison’s Guide to Popular Natural

Products, 2002, $30☺ Herbs of Choice, 1994 , Tyler,V $25/$13☺ Physicians & Pharmacists Guide to the Top Ten

Scientifically Proven Natural Products, Ogletree, RL & Fischer,RG 1997