Jarir At ThobariJarir At ThobariDepartment of PharmacologyDepartment of Pharmacology

Faculty of Medicine GMUFaculty of Medicine GMU

EBM of Herbal Medicine & Phytopharmaca

(safety and efficacy)

COMPLEMENTARY &ALTERNATIVE MEDICINE

• “While some scientific evidence exists regarding some CAM therapies, for most there are key questions that are yet to be answered through well-designed scientific studies.” - NCCAM

• “A group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine.”

Are they safe? Do they work?

Alternative medicine - used in place of conventional medicine. A special diet to treat

cancer instead of undergoing surgery, radiation, or chemotherapy recommended by a

conventional doctor.

Complementary medicine - used together with conventional medicine. Aromatherapy to help lessen a patient's discomfort following surgery

COMPLEMENTARY &ALTERNATIVE MEDICINE

5 MAIN TYPES OF CAM• Alternative medical systems

– Homeopathy, Naturopathy

• Mind-body interventions – hypnosis, imagery, support groups

• Biologically-based treatments – Herbal, dietary treatment,

• Manipulative and body-based methods – chiropractic, acupressure, osteopathy

• Energy therapies – magnets, therapeutic touch

THE USE OF HERBS

81% US adults take 1+

med/week 7 of 10 US adults regularly take

vitamin, mineral, herb or supplement

Rates and numbers of meds increase with age

• 14% percent of the population takes at least 1 herbal/supplement each week*

• 16% of prescription drug users also use 1+herbal/supplement

• $17.8 BILLION on dietary supplements• $4.2 Billion for Herbal products**

*JAMA Jan 16, 2002

**NEJM Dec 19, 2002

THE USE OF HERBS

YET - only 38% told their doctor

WHY DO PEOPLE TAKE HERBS?

Health/good for you 16%Arthritis 7%

Memory Improvement 6%

Energy 5%Immune Booster 5%

Joints 4%

Supplement diet 4%Sleep aid 3%Prostate 3%

Don’t know/no reason 2%

All other reasons 45%

JAMA Jan 16, 2002

• 60% of US physicians recommended CAM at least once

• 47% of physicians reported using alternative therapies themselves

WHY DO PEOPLE TAKE HERBS?

PROBLEMS OF HERBAL

Herbs have pharmacological properties

including side effects & interactionsSuggestive evidence

exists on efficacy

Many ‘drugs’ came from plants. So, why shouldn’t there be

potential for efficacy of herbs?

• WHO 65%-80% of the world's population use traditional medicine as their primary form of health care.

• dominant in developing countries, increasing in developed countries

• safety and efficacy are an important issue for the health professions.

• Potential adverse drug reactions (ADRs).

PROBLEMS OF HERBAL

PROBLEMS: REGULATORY ISSUE

• 1906 Food and Drug Act - Accurate labeling, purity required

• 1962 Kefauver-Harris Amendment - ‘Safe & Effective’ required

• 1994 Dietary Supplement Health and Education Act– FDA lost authority over Herbs, Vitamins

unless proven to be unsafe– Became ‘Nutritionals’

• Unmonitored, uncontrolled, non-uniform products• No standards of bioequivalence between brands,

or between lots• Ingredients not required to be completely listed• Producers do not need to prove safety or efficacy• Adulteration has commonly been described

PROBLEMS: REGULATORY ISSUE

Many touted for prevention - hard to evaluate

Placebo effect is strong

Quality of science varies

Much of the research is not in English

PROBLEMS WITH HERBAL MEDICINE

• It is widely perceived that "natural" products are safe, the evidence suggests that CAM use is not without risk.

• Of 90 patients with rheumatoid arthritis,– 82% had tried more than one form of

alternative medicine or therapy, including dietary modification

– 31% of these patients had experienced at least one adverse effect

PROBLEMS WITH HERBAL MEDICINE

CLASSIFICATION ADE• Intrinsic effects

– Intrinsic effects are those of the herb itself and are characterized, as for pharmaceuticals

– type A (predictable, dose dependent)– type B (unpredictable, idiosyncratic)

reactions– overdose or accidental poisoning and

interactions with pharmaceuticals.

CLASSIFICATION ADE• Extrinsic effects

• manufacture or extemporaneous compounding.

• Good Manufacturing Practice

Misidentification Lack of standardization

SubstitutionContamination

AdulterationIncorret dosage/preparation

Inappropriate labelling/adv

MISIDENTIFICATION

• It is difficult to track and identify adverse effects of herbal ingredients, as the plants can be named in four different ways – the common English name,– the transliterated name, – the Latinized pharmaceutical name, – the scientific name

• Plant material can be misidentified at the time of the manufacturer's bulk purchase or when wild plants are picked

STANDARDIZATION

• Therapeutic/toxic components– ripeness, geographic area where the plant is grown,

and storage conditions.

• Batch-to-batch reproducibility of plant material should be assessed in the production of marketed products product variation

• Ginsenoside (glycosylated steroid) 50 commercial brands of ginseng sold in 11 countries.– 44 product 1.9% to 9% – 6 no ginsenoside– one of these six contained large amounts of ephedrine

(for which athlete was accused of doping)

CONTAMINATION

• Growth, storage, crude plant material can become contaminated by pesticide residues, microorganisms, aflatoxins, radioactive substances and heavy metal (lead, cadmium, mercury, arsenic and thallium) 6%-60%

SUBSTITUTION

• A report of nine cases of rapidly progressive interstitial nephritis in young women taking a Belgian slimming treatment

• Aristolochia fangchi, containing the nephrotoxic component aristolochic acid

• Eighty cases have now been identified and more than half of these patients developed terminal renal failure

ADULTERATION

• Product contains/mix with chemical drugs – Unethical herbal compund– Mefenamic acid and diazepam – acute interstitial nephritis, reversible renal failure,

loss of blood pressure control and peptic ulceration – a Chinese herbalist was prosecuted for adding a

steroid cream to a herbal preparation, which produced severe facial erythema in a patient

PREPARATION AND LABELLING

• The processing of crude plant material carried out by a manufacturer, practitioner or the patient is a major determinant of the pharmacological activity of the finished product.

• The alkaloid composition and plant's toxicity• Products claim a certain unproven effect

GINGER ROOT

• Traditional use: stimulant, diuretic, antiemetic, dyspepsia, prevention of motion sickness

• Evidence: RCTs– > placebo in postop nausea, similar to metoclopramide– > placebo in seasickness

• Safety:– low toxicity; no side effects;– platelet changes;– not recommended during pregnancy

HORSE CHESTNUT SEED EXCTRACT

• Traditional use: arthritis/rheumatism; congestion (leaves)

• Evidence: Numerous RCTs, systematic review– superior to placebo, reduced edema, leg circumference;– better compliance than compression hose;– improved pain, fatigue, itching, leg tension (observational)

• Safety:– No Contraindications; mild and – rare adverse effect – (occais. pruritis, nausea, GI c/o); – no restrictions in pregnancy;– whole seed is toxic.

VALERIAN ROOT

• Traditional use: sedatives, insomnia, Restlessness, sleeping disorders based on nervous conditions

• Evidence: RCTs– Improvement in sleep latency, quality– REM maintained– Releases GABA in brain; weak affinity

for benzodiaz. receptors

• Safety:– No known side effects, interactions,

contraindications, non addictive

BLACK COHOSH

• May relieve menopausal symptoms (mood, flushes, sleep)

• No evidence of other protection benefits of estrogen

• Safe – – no drug-herb interactions– Possible interaction with

tamoxifen

FEVERFEW• Prevention of migraines• Cochrane review, 2003:

– 3 of 4 trial suggest beneficial effect;– 1 showed no difference vs.. placebo– Conclusion: Suggestive, but efficacy not established

beyond a doubt

• Avoid:– In pregnancy,– W/antiplatelet agents

ECHINACEA• Wide variability in products,

adulteration• Positive and negative results

have been reported:– Poor evidence for prevention of

URI’s, flu– Possible mild decrease in

length/severity

• Appears generally safe• Avoid in HIV, immuno-

compromised pts, longer then 8-10 weeks

GARLIC

• Evidences: – Insufficient data on clinical CV outcomes

(claudication and MI)– Possible small, positive, short-term effects on lipids– Inconsistent reductions in blood pressure– Promising but inconclusive on antithrombotic

activity.– Use < 3 to 5 years not associated with decreased

risks of breast, lung, gastric, colon, or rectal cancer.

• Cautions: – Problems with standardization– Watch in combination with anti-platelet agents

GINSENG

• Use: For fortification; fatigue; improve capacity for work, concentration; colds and flu; diabetes; immune support; herpes; general well being; stress; male sexual function; sports performance

• COCHRANE (2003): “efficacy is not established for any outcomes”

• Concerns:– Adulteration is common– Expensive– Anti-platelet properties– Insomnia, diarrhea, vaginal bleeding, SJ syndr

TURMERIC

Evidence grade B1

Evidence grade B1

Evidence grade B2

Evidence grade B2

Evidence grade B2

Evidence grade B2

Evidence grade C

Evidence grade C

Evidence grade C

Evidence grade D

Evidence grade D

Anti-inflammatory

Dyspepsia

Billiary dyskinesia

Gallstone prevention

Osteoarthritis

HIV

Peptic ulcers

Rheumatid arthritis

Uveitis

Cancer prevention

Hyperlipidemia

LEVEL OF EVIDENCE

NO EVIDENCE YET

• Cochrane Review :– No firm evidence of efficacy for any

medicinal herbs for Hepatitis C infection

– Some herbs may work in Chronic Hep B, but evidence is too weak to recommend any

HERBS-DRUGS INTERACTION

• Aspirin• Warfarin

• Garlic• Ginger• Ginko• Ginseng• Feverfew• Clove oil

PRACTICE POINTS

• Ask every patient about herbs and supplements

• Address– “natural doe not mean safe”– “If it sounds too good to be true, it probably is…”

• Avoid preparations with >1 herb• Avoid switching brands frequently• Buy packaged products with

– name/address of manufacturer, batch/lot number common and scientific name, standardization when possible dosing guidelines, side effects

RESOURCES

• American Botanical Council: http://www.herbalgram.org • NIH National Center for Complementary and Alternative

Medicine: http://nccam.nih.gov/ • Sloan Kettering Cancer Cntr “Information About Herbs”

www.mskcc.org/aboutherbs • MEDLINEplus http://medlineplus.gov/ then search “Herbs”• Office of Dietary Supplements (NIH) http://ods.od.nih.gov/ • iHerb www.iherb.com/health.html , then use “The Natural

Pharmacy” and “Commission E Monographs”• ClinicalTrials.gov http://clinicaltrials.gov/ then type in “Herbs”• FDA Safety and Adverse Reporting Program

http://www.fda.gov/medwatch For warnings on dietary supplement see also http://www.cfsan.fda.gov/%7Edms/ds-warn.html

Herbs & Natural Supplements

An Evidence-based Guide

Second Edition