CLINICAL STUDY OF PLANT DERIVED MEDICINE

Guidance by – Dr. A.U. Tatiya Sir .Presented by –Vishvanath N. Vaidya .DEPARTMENT OF PHARMACOGNOSY,RCPIPER , SHIRPUR.

IntroductionTypes of clinical Trial Types of Phases used in Clinical trial Protocol for clinical trial in Herbal medicines Examples of plant derived medicines Limitations of Herbal drugs in clinical trials

CONTNTS

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical trial.   A clinical trial is a prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (vaccines, drugs, treatments, devices, or new ways of using known drugs, treatments, or devices).

INTRODUCTION

Clinical trials can be classified in to :1. Treatment trials2. Screening trials3. Prevention trials4. Supportive care trials

TYPES OF CLINICAL TRIALS

1. Treatment trials : It refers to trials which involves test on new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.

2. Screening trials : It refers to trials which test the best way to detect certain diseases or health conditions.

3. Prevention trials : These are those trials which intend to find better ways to prevent disease in people who never had the disease or to prevent a disease from returning .These approaches may include vaccines, minerals,vitamins,medicines etc.

4.Supportive care trials : Explore ways to improve comfort and the quality of life for individuals with a chronic illness.

TYPES OF CLINICA TRIALS

Phase 1• Phase 2

Phase 3• phase4

THE EFFICIENCY AND EFFECTIVENESS AND COST OF A CLINICAL TRIAL DEPEND ON:response to each treatmentinfluence of other factors such as age, gender or life style number of patients how patients are selected for the trialhow patients are allocated to treatments type of trial: parallel or crossover compliance of patients to treatments how data are recorded, analysed and interpreted

RISKS There are risks to clinical trials.•There may be unpleasant, serious or even life-threatening side effects to experimental treatment.•The experimental treatment may not be effective for the participant. SIDE EFFECTS AND ADVERSE REACTIONS : •Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems.

•Experimental treatments must be evaluated for both immediate and long-term side effects.

•Side effects are any undesired actions or effects of the experimental drug or treatment.

THE CRITICAL PATH OF CLINICAL TRIAL

Planning

Protocol . CRFRegulatory and Ethical Approval

Trial Documents . Materials

Select investigators Initial Visits

Site Assessments

Patient Recruitment Periodic

Monitoring Study Termination

Data Data Statistical Final entry clean-up analysis Report

• START • END

GCP. IND

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REGULATORY REQUIREMENTS FOR THE CONDUCT OF CLINICAL TRIALS ON HERBAL MEDICINES-• Traditional medicines are governed by the Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945.• In 1959, the Government of India amended the Drugs and Cosmetics Act to include drugs which are derived from traditional Indian medicine. • In 1993, the guidelines for the safety and efficacy of herbal medicines developed by an expert committee. • No new herbal medicines other than those authorized by the licensing authorities be allowed to be manufactured or marketed, except for those mentioned in ancient scriptures.

Plants remain an important source of new drugs, new drug leads and new chemical entities. The plant based drug discovery resulted mainly in the development of anticancer and anti-infectious agents and continues to contribute to the new leads in clinical trials. For many centuries plants have been the main source of crude drugs used to cure or alleviate human sickness. In today’s era of medicine engineering also, plants play an equally important role in drug discovery and development.

PLANT-DERIVED NATURAL PRODUCTS IN CLINICAL TRIALS

Sr . No Parameter Garlic1 Synonym Garlic ,allium2 Botanical source bulbs of plant known as Allium sativum.Family : Liliaceae.3 Chemical

constituents•29 % carbohydrate•56 % of proteins•0.1 % of fat•mucilage•0.06 to 0.1 % of volatile oil•Volatile oil of the drug is the chief constituent and contains allyl propyl

1.GARLIC

CLINICAL STUDIES OF GARLIC EXTRACTS :

Powdered garlic preparations tested in clinical studies include Kwai, Pure Gar as well as unbranded or generic dried garlic. Kwai is manufactured by Lichtwer Pharma AG in Germany and distributed in the United states by Litchwer Pharma US. The tablets contain a preparation known as LI 111 that is standardized to contain 600 mcg allicin in 100 mg garlic powder. Garlic preparation studied clinically for reduction in risk for atherosclerosis heart disease include dried garlic, aged garlic , garlic oil , and raw garlic. The end points of those trials include elevated serum cholesterol, hypertension , blood clotting factors and lipid oxidation. most number of studies has been conducted on the ability of dried garlic essentially Kwai , to reduce elevated levels of plasma lipids , especially cholesterol.

PREPARATION OF GARLIC EXTRACT :•Garlic extract is prepared by storing sliced garlic in 15 to 20 % aqueous ethanol for 18 to 20 months.•After this , the liquid is filtered and concentrated.•Most of the sulphur compounds responsible for the characteristic garlic odor are removed during processing.• few allicin or alliin derived compounds obtained. The sulphur compound measured for quality purposes is S – allylcycteine.•Garlic extract is available in both liquid as well as dry forms.•The liquid form contains 10 % ethanol.•The trials were much higher than those suggested in available product.

Sr . No. Parameters Information1 Manufacturer : Lichtwer Pharma AG , company2 US distributer : Lichtwer Pharma U.S.3 Botanical ingredient : Garlic clove powder4 Extract name : LI 1115 Quantity : 100 mg concentrated dry garlic, equivalent to 300 mg fresh garlic.6 Processing : Garlic cloves are cut in to slices and carefully dried in 50 – 60 ̊c air for several hours. The dried slices are ground in to powder and sieved.7 Standardization : 600 mcg alliicin per tablet8 Formulation : Tablet9 Level of evidence : I10 Therapeutic benefit Yes

TRIAL DESIGN : PARALLELDetail Type

Study duration 4 months

Dose 4 tablets daily (800 mg garlic powder)

Route of administration Oral

Randomized Yes

Randomized adequate Yes

Blinding Double blind

Placebo Yes

Drug comparison No

Site description 30 general practices

No. of subjects enrolled 261

No. of subjects completed 219

Sex Male and Female

Age 4 7- 71 years (mean 59) 1 8

CRITERIA :Inclusion criteria: Total serum cholesterol values of 200 to 300 mg / dl and triglyceride values of 200 to 300 mg / dl End points : Total cholesterol and triglyceride levels , as well as supine and diastolic blood pressure , were measured. Results : After four months ,mean cholesterol levels dropped in the garlic group by 12 % (266 to 235 mg /dl) and triglyceride levels by 17 % (226 to 188 mg / dl). The difference between the garlic and placebo was highly significant. analysis showed that patient with initial total cholesterol levels between 250 to 300 mg / dl showed the most improvement compared with placebo.

Side effects :Mild garlic smell in 2 percent of garlic and 9 % of placebo groups.Also minor gastrointestinal upset.Recommended dose: Take two tablets three times daily with liquid ,ideally with meals.Cholesterol lowering results observed after 1 weeks of usage.Caution :If a disease or health related condition requires the lowering of cholesterol , consult a doctor.

Uses :1. As carminative, aphrodisiac , expectorant, stimulant and disinfectant in the treatment of pulmonary condition.2. It is highly used as condiment.3. Oil of garlic is used as anthelmintic and rubefacient .4. Allicin is antibacterial.5. Garlic oil is used in high blood pressure and atherosclerosis . 6. Fresh garlic is prophylactic against amoebic dysentery.

Sr . No Parameter Ginger

1 Synonym Zingiber , Zingiberis

2 Botanical source Rhizomes of Zingiber officinaleZingiberaceae

3 Chemical constituents Volatile oil (1 – 4 %)Starch (40 – 60 %)Fat (10 %)Fibre (5 %)Inorganic material (6 %)

GINGER

Sr . No. Parameters Information1 Manufacturer : Dalidar Pharma Ltd. Israel2 Botanical ingredient : Ginger root3 Extract name : Zintona4 Quantity : 250 mg5 Processing : Dried root powder6 Standardization : pungent phenolic compounds7 Formulation : capsule Formulation : capsule8 Indication : Motion sickness9 Level of evidence : II10 Therapeutic benefit : yes

Zintona-Produt profile

A. Several studies used generic preparations of powdered ginger root and rhizome.B. Most studies described the product as powdered ginger and gave the dose.C. None of the studies mentioned profiling the ginger for quantities of gingerols.D. Ginger products have been tested in clinical studies of effectiveness in reducing nausea and vomoting due to administration of chemotherapy,emergence from general anesthesia.E. Morning sickness associated with pregnancy and most commonly for motion sickness , vertigo, nausea, vomiting ,cold sweat. F. Here Zintona was studied clinically and three studies with Zintona demonstrated a benefit for this ginger product on motion sickness.

TRIAL DESIGN : PARALLEL Subjects received one of the seven substances frequently used to prevent seasickness and matching placebo of another substance in a double method.Nobody received only placebo.The comparison medications were Touristil (cinnarazine 20 mg,domperidone 15 mg ),marzine (cyclizine 50 mg ),Dramamine (dimenhydrinate 50 mg , caffeine 50 mg ).In most cases, subjects took the medication two hours prior to departure.For Touristil and Zintona an additional dose was administered four hours later.

Type DetailsStudy duration 1 dayDose 500 mg 2 hours prior to departure

and after 4 hoursRoute of administration OralRandomized YesRandomized adequate YesBlinding Double blindPlacebo NoDrug comparison YesDrug name Touristil, Marzine, Dramamine,

Peremesin, stugeron, Scopoderm TTS

Site description ShipNo. of subjects enrolled 1741No. of subjects completed 1475Sex Male and Female Age 16 – 65 years

CRITERIA : INCLUSION CRITERIA : •Tourists participating in a whale watching tour in Norway between the ages of 16 and 65 years old. EXCLUSION CRITERIA : •Pregnant or nursing women, persons who had used antiemetic or anti allergic drugs within the past 48 hours, patients with glaucoma and persons with a history of adverse reactions to any of the substances to be tested. End points : •The outcome measures were vomiting ,malaise and subjective reports of adverse events.•The information was collected via a questionnaire gathered at the end of the trip.

Results :1. Questionnaires were completed by 85.5 percent of volunteers(n = 1489)2. Those who tried to avoid seasickness by fixing their eyes on the horizon, by putting cotton in their ears, or by wearing a “ sea band ” on the wrist were excluded from analysis.3. None of the study medications offered complete protection from seasickness.4. All had similar rates of efficacy compared to an earlier trip without prophylaxis when 80 % got sick.5. No statistical difference was seen between treatments.6. In each treatment group 4.1 to 10.2 percent experienced vomiting and 16.4 to 23.5 percent experienced malaise .

SIDE EFFECTS :•No serious adverse reactions reported.•Sleepiness and tiredness were reported generally for all seven agents. Dose :•For motion sickness : adults and children over six years•0.5 g, 2 – 4 times daily •1 g ginger 30 to 60 minutes before travel CAUTION :•WHO suggests that it is not recommended for children less than six years of age.•USP suggests that patients with an increased risk of hemorrhage or those taking anticoagulants should use ginger with caution.

USES: A.Used as stomachic, an aromatic, a carminative, stimulant and flavouring agent.B.Ginger oil is used in mouth washes, ginger beverages and liquors.C.Ginger powder is effective in motion sickness.D.It ha s been suggested that adsorbent, aromatic and carminative properties of ginger on GI tract cause adsorption of toxins and acid enhanced gastric motility.E.These may have probably blocking effects of GI reactions and nausea.

•Green tea is derived from Camellia sinensis •Family : Theaceae Chemical constitutes:•A cup of green tea usually contains 300 to 400 mg polyphenols•.•Polyphenols are a large class of mildly acidic compounds with anti oxidant properties.

GREEN TEA

•Polyphenols can be divided in to many subclasses, including catechins , an example of which is epigallocatechin gallate. PREPARATION OF GREEN TEA:•Heating the freshly picked leaves shortly after harvesting process produces green tea.•This process inactivates the enzymes.

Sr. No Parameter Information1 Manufacturer: Thomas J. Lipton Co., North America2 Botanical ingredient : Green tea leaf extract3 Processing : Lyophilized (Freeze dried) tea solids4 Indication: Cardiovascular risk factor5 Level of indication : III

LIPTON RESEARCH BLEND CLINICAL STUDY OF GREEN TEA PRODUCTS

TRIAL DESIGN:Parallel

After a two week pretrial period in which all subjects consumed 900 ml (6 cups ) of water per day, they were divided in to three groups and given 900 ml (6 cups) of either water, green tea, black tea (0.5 g black tea extract per cup) daily.

Type DurationStudy duration 1 month

Dose 6 (0.5 g tea extract in 150 ml) cups daily

Route of administration Oral

Randomized No

Randomized adequate No

Placebo No

Drug comparison No

Site description Single center

Sex Male and female

Age 20 – 61 groups

TRIAL DESIGN

CRITERIA:Inclusion criteria:Ages 18 to 65 years, healthy, non smoking,not using vitamin C, vitamin E, carotenoid, selenium,or zinc supplements or consuming a medically or weight loss diet, and a stable weight for atleast one month before the start of the day.Exclusion criteria :Pragnant or lactating women.END POINTS :Blood samples were obtained before and after experiments period.

Serum lipid concentrations, plasma and low density lipoprotein (LDL) antioxidant status,resistance of LDL to oxidation and plasma malodialdehyde and LDL – hydro peroxide concentration were measured.

RESULTS :•Consumption of green tea or black tea did not affect serum lipid concentrations, resistance of LDL to oxidation ex vivo,or markers of oxidative damage to lipids in vivo.

•However ,consumption of green tea slightly increased total antioxidant activity of plasma .SIDE EFFECTS: Not mentioned.•Daily consumption of 900 ml green tea per day for four weeks had no effect on serum lipid concentrations or resistance of LDL to oxidation ex vivo.•Future research should focus on mechanisms by which tea flavonoids may reduce the risk of cardiovascular disease other than by increasing the intrinsic antioxidant status of LDL.

HEALTHY WEIGHT LOSS BENEFITS OF GREEN TEA 

A. Healthy diet weight loss can be significantly aided by the use of   green tea extract.  

B. Research confirms that the active ingredients of green tea promote increase in metabolic rate and burning of fat.

C. There are many  varieties of green tea available  and all of them are greatly beneficial.

D. A study that appeared in American Journal of Clinical Nutrition found that 4% increase in overall energy expenditure in 24 hours was attributed to green tea extract.

E. The findings further specified that the extra expenditure took place during the day and concluded that the 4% increase due to green tea extract actually translated into thirty five to 43% increase in daytime thermo genesis. (Thermo genesis is the body’s rate of burning calories.)

GINSENG

oBiological source : Dried roots of various species of Panax , like P.ginseng(Koreanginseng) P. japonica (Japaneseginseng) P. notoginseng (Chineseginseng) P. quinquefolium (American ginseng)oFamily : Araliaceae

CHEMICAL CONSTITUTES :•Contains a mixture of several saponin glycosides, belonging to triterpenoids group.They are grouped as follows :•Ginsenosides•Panaxosides•Chikusetsusaponin•Ginsenosides contain aglycone dammarol while panaxosides have oleanolic acid as aglycone.•Panaxosides give oleanolic acid, Panaxadiol and panaxatriol on decomposition.

The root of Ginseng is mainly used in the traditional medicine.Commercially supplied roots are graded according to their source, age, part of root, and the method of preparation.The root can be used fresh, or prepared as white ginseng (peeled and dried) or red ginseng (steamed and dried).The fresh root is often sliced thinly and taken with or without honey, or it can be boiled in soup.White or red ginseng can be powdered, extracted, or made in to a tea.The trials reviewed in test ginseng for its effects on physical performance,well being, cognitive performance, the immune system, and diabetes.It indicates that the use of ginseng may reduce the risk of cancer.

Sr. No. Parameters Information1 Manufacturer : Pharmaton S.A ., Switzerland2 Botanical ingredient : Ginseng root extract3 Extract name : G 1154 Quantity : 100 mg extract (equivalent to 500 mg root)5 Processing : no information6 Standardization : 4 % ginsenosides7 Formulation : Capsule8 Indication : Physical performance in healthy athletes9 Therapeutic benefits : Yes

PRODUCT PROFILE : GINSANA

Type DetailStudy duration 9 weeksDose 2 (100 mg G 115)capsules daily

Route of administration OralRandomized YesRandomized adequate No Bliding Double blindPlacebo YesDrug comparison NoSite description Not describedNo. of subjects enrolled 28No.of subjects completed 28Sex MaleAge 21 – 29 years

Trial design : parallel

CRITERIA : Inclusion criteria :Healthy male athletes whose training program consisted of at least ten hours per week with their trainer. End points :Performance capacity was measured before treatment, at the end of 9 weeks, and 1, 3, 7 and 11 weeks following the treatment.Oxygen uptake was measured at rest and during exercise with a cyclic ergometer.Pulmonary functions and heart rate were monitored, as well as reaction times to visual signals.

RESULTS :Following 9 weeks, the ginsana group had an increase in maximum oxygen uptake of 17 % and a lowering of the maximum exercise heart rate by 10 %.The oxygen pulse, oxygen uptake divided by heart rate, increased by 26 %.Serum lactate levels decreased by 40 %.There was an increase in parameters of pulmonary function, i.e. forced expiratory one second volume and forced vital capacity, as well as a shortning of reaction time to visual stimuli.These changes persisted for three weeks following treatment.

DOSE :Two capsules with water in the morning or one capsule in the morning and one in the afternoon.Optimal results have been shown with four weeks continuous use, when taken as directed.PRECAUTION :Diabetic patients should consult a physician to taking ginseng root, since it may slightly reduce blood glucose levels.

USES :An important immunomodulatory drug.Increases the natural resistance and enhances the power to overcome the illness or exhaustion.Has both stimulant and sedative properties.Used as aphrodisiac, demulcent and in gastritis and anemia.Useful in adrenal and thyroid dysfunctioning.Used for curing the giddiness and prolonging life of elderly and diabetic persons.

1. Barrett Marilyn , Ph D Editor, The Handbook of Clinically Tested Herbal Remedies , Vol II,CBS publishers and Distributors, New Delhi, India, page No. – 787, 789, 796, 799 -802, 1175,1197,4.93-508,673-691,403-429.2. Tripathi KD , Essentials of MEDICL PHARMACOLOLOGY , Seventh Edition, Jaypee Brothers Medical Publishers PVT . Ltd. New Delhi ,Page No.-073-813. Kokate, C .K. Purohit, A .P. Gokhale, S .B.2010.PHARMACOGNOSY, forty fifth edition, Nirali Prakashan,Pune ,Page No.-1.103,1.156.11 4. www.wikipedia .net5. www.Gogle images .com

REFERENCES

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