Health Santé

Canada Canada

Adulteration/Contamination of Herbal Products, Ayurvedic & Chinese Medicines with Drugs and Heavy Metals: An Under- Recognized Threat

Harpal S. Buttar, D.V.M., M.Sc., Ph. D.

Senior Scientist and Adjunct Professor

Therapeutic Products Directorate,

Health Canada, Ottawa, Ontario

Intl. Conf. & CME On Pharmacovigilance, Lady Hardinge Medical College, New Delhi, Nov. 26-28, 2010

Health Santé

Canada Canada

Summary ofNew Canadian NHP Regulations

• Quality– GMPs– site licensing

• Safety – product licensing– adverse reaction

reporting– labelling requirements

• Efficacy– proof of claim

Potential Contaminants that Should be Taken Into account in the Quality Control of Herbal

Remedies

De Smet, P.A.G.M. (1999): Drug Information J. 33, 717-724

Type of contaminantor adulterant

Examples

Botanicals Atropa belladonna, Digitalis, Colchicum, Rauvolfia serpentina, pyrrolizidine-containing plants

Micro-organisms Staphylococcus aureus, Escherichia coli (certain strains), Salmonella, Shigella, Pseudomonas aeruginosa

Microbial toxins Bacterial endotoxins, aflatoxins

Pesticides Chlorinated pesticides (eg, DDT, DDE, HCH-isomers, HCB, aldrin, dieldrin, heptachlor), organic phosphates, carbamate insecticides and herbicides, dithiocarbamate fungicides, triazin herbicides

Potential Contaminants that should be taken into account in the Quality Control of Herbal

Remedies

De Smet, P.A.G.M. (1999): Drug Information J. 33, 717-724

Type of contaminantor adulterant

Examples

Fumigation agents Ethylene oxide, methyl bromide, phosphine

Radioactives Sr-90, Ru-103, I-131, Cs-134, Cs-137

Metals Lead, cadmium, mercury, arsenic

Synthetic drugs Analgesic and anti-inflammatory agents (e.g. aminophenazone, phenylbutazone, indomethacin), corticosteroids, hydrochlorothiazide, diazepam

Animal substances Thyroid hormones

Adulteration of phytomedicines and traditional Chinese medicines with

pharmaceuticals

Part I

Health Santé

Canada Canada

PC-SPES Products

• PC-SPES* is a complex mixture of extracts obtained from eight Chinese and American herbs (7 medicinal herbs plus saw palmetto)

• It was recommended by naturopathic healers for the treatment of prostate cancer, and was touted to induce castrate serum levels of testosterone and a reduction in prostate specific antigen (PSA).

• In 1996, PC-SPES gained tremendous popularity in USA as a herbal medicine for the treatment of prostate cancer. Clinical trials of the product were initiated at several health centres, some with federal funding from the NIH.

Saw palmetto *PC-SPES: PC = prostate cancer; SPES = Latin for hope Cont’d…

Adulteration of PC-SPES with Prescription and Non-Prescription Drugs

• Chemical analyses of PC-SPES and its related preparation SPES showed adulteration with pharmacological dosages of:– Diethylstilbestrol (DES, synthetic estrogen-like compound)– Warfarin (anticoagulant)– Indomethacin (analgesic)

• Serious adverse effects were experienced by PC-SPES users taking 6 to 9 x 320 mg capsules daily.

• ADRs included breast tenderness and/or enlargement, loss of libido and/or erectile dysfunction, deep vein thrombosis, pulmonary embolus, myocardial infraction, and ischemic heart disease. There were 2 case reports of severe bleeding.

Cont’d…

• In January 2002, PC-SPES was withdrawn from the market due to serious ADRs and alleged adulteration with warfarin, DES, or indomethacin.

1. Blumenthal M. (2002): Integrative Cancer Ther., 1, 266-70

2. Guns et al. (2002): Can. J. Urol., 9, 1684-88

3. Oh and Small (2002): Semi. Oncol., 29, 575-84

4. Sovak et al. (2002): J. Natl. Cancer Inst., 94, 1275-81

Adulteration of Herbal ED Products with PDE-5 Inhibitors

• Biovigora• Herbal Erotica• Herbal Viaphrodisiac

• Stamina-Rx*• Super-X*• Vip ViGa• Vuka Vuka

Of the 7 tested herbal products marketed via the internet or at health food stores for the treatment of male ED, 2 products were found adulterated with PDE-5 inhibitors. Stamina-Rx contained pharmacological amounts of tadalafil (19.8 mg/tablet), and Super-X

contained sildenafil (30.2 mg/capsule). Adulteration with vardenafil was not identified.

Although herbal products are marketed as devoid of adverse effects, their adulteration with PDE-5 inhibitors can cause potentially fatal drug interactions in patients taking nitrates.

Fleshner et al. (2005): J. Urology, 174, 636-641

Pharmaceuticals in Asian Patent Medicines• Asian patent medicines comprise multiple products,

including herbs, plants, animal parts, and minerals, which are formulated into tablets, pills, or liquids for ease of use.

• Of 260 Asian patent medicines collected from California retail herbal stores, 14 had labels that declared pharmaceutical ingredients, and 3 had insufficient sample amounts. At least 83 (32%) contained undeclared pharmaceuticals or heavy metals, and 23 had more than one adulterant.

• Of the remaining 243 products, 17 (7.0%) contained undeclared pharmaceuticals. The most common undeclared ingredients were ephedrine, chlorpheniramine, methyltestosterone, and phenacetin.

Ko, RJ. (1998): New Eng. J. Med. 339, 847

How Natural Are 'Natural Herbal Remedies'? A Saudi Perspective

In Saudi Arabia, 247 herbal remedies and related preparations were analysed for heavy metals, synthetic drugs, bacterial contamination or the presence of toxic natural substances.

Of 123 samples examined, the indication for use was not specified.

Other preparations were indicated for the treatment of: - Leukemia and other cancers (n=22); obesity (n=18);

diabetes mellitus (n=14); rheumatic disorders (n=14); skin pigmentation problems (n= 11); or to enhance male sexual activity (n=9).

Eight preparations contained undeclared synthetic drugs: - benzodiazepines; tricyclic antidepressants; cyproheptadine, ibuprofen; and dipyrone.

Cont’d…

How Natural Are 'Natural Herbal Remedies'? A Saudi Perspective

– Micro-organisms (E. coli, S. aureus and other pathogens) contamination was noted in 18 samples, while dangerous and toxic natural compounds were present in 14 preparations used for the treatment of skin conditions or indigestion .

– Strikingly high amounts of heavy metals were identified in 39 samples. The levels of arsenic ranged from 522 to 161, 600 ppm in remedies used for treating leukemia, and the content of mercury ranged from 5,700 to 126,000 ppm in creams used for skin whitening. High lead concentration (> 1.5%) was also found in few samples.

– The authors concluded that an urgent action is required to control the production, importing and selling of herbal preparations in the Kingdom of Saudi Arabia.

Bogusz et al. (2002): Adv. Drug React. Toxicol. Rev. 2 (4), 219 - 29.

Undeclared pharmaceuticals found in traditional Chinese medicines

• Caffeine• Chlorzoxazone• Dexamethasone• Diclofenac• Fenfluramine• Glibenclamide

• Aminopyrine• Carbamazepine• Clobetasol propionate• Diazepam• Ethoxybenzamide• Fluocinolone acetonide

Cont’d…

• Hydrochlorothiazide• Indometacin• Methylsalicylate• Phenacetin• Phyenytoin

• Hydrocortisone• Mefenamic acid• Paracetamol• Phenylbutazone• Valproate

Ernst E. (2005): The Pharmaceutical Journal, 275, 167-168

Two cases of severe adverse effects were reported from South Africa after the ingestion of herbal remedies adulterated with an anti-epileptic drug (trimethadione), an anti-inflammatory agent (diclofenac), and an anesthetic (propofol).

Snyman et al. (2005): Ther Drug Monit. 27, 86-89

Adulterants found in Chinese Herbal Products

The following six undeclared adulterants were found in herbal weight-reducing dietary supplements

marketed in China and exported abroad.

Wang J. et al. (2008): Food Additives & Contaminants, 25 ; 822-30.

N-di-desmethyl sibutramine

N-mono-desmethyl sibutramineSibutramine

OrlistatPhenolphthaleinFenfluramine

Cont’d…

Fenfluramine was removed from the market in 1997 by the US FDA because of its serious side effects.

Phenolphthalein has been used as a laxative for over a century, but now its use is discouraged due to carcinogenicity risk.

N-mono-desmethyl sibutramine and N-di-desmethyl sibutramine are metabolites of sibutramine.

In 2004, USFDA sent warning letters to 16 Chinese manufacturers asking them to stop making false claims for weight loss, and requested 23 companies to stop distributing dietary supplements containing androstenedione.

Wang J. et al. (2008): Food Additives & Contaminants, 25 ; 822-30.

A baby was hospitalized in 2008 after consuming melamine-tainted milk

In 2010, 20 children’s jewelry items were recalled after Health Canada found that jewelry pieces imported from China were made of almost pure lead.(Canadian permissible limit of Pb = 0.06%)

In April 2010, many pediatric Tylenol products were recalled in USA and Canada due to lack of regulatory standards.

McNeil company recalled approx. 136 million bottles of children’s liquid Tylenol and other pediatric products because they contained > labelled dose of active drug ingredient, metal particles or inactive ingredients that failed quality tests.

Since 1995, half of the 21 drugs pulled from the US & Canadian market for safety reasons involved heart complications. Average recall time was 8 yrs. after approval.

• Posicor (antihypertensive) was withdrawn in 1998 because it caused irregular heart rhythm and the risk of potential muscle injury.

• Hismanal (antihistaminic) was withdrawn in 1999 because it produced serious arrhythmias, allergic reactions and interactions with other drugs.

• Vioxx (antiarthritic) was recalled in 2006 due to the risk of heart attacks.

• Meridia (sibutramine), the diet-pill or weight-loss drug was tied to 16% higher risk of heart attack or stroke. The manufacturer voluntarily removed this drug from the Canadian and US markets in Oct. 2010.

• Avandia (antidiabetic) has been linked to 43% higher risk of heart attacks. Health Canada, FDA and European regulators are considering new labelling restrictions or complete withdrawal from market.

Doctors of Chinese medicine across Canada join forces to fight Federal Government's Bill C-51.

– Federal Health Minister Tony Clement contends that "the bill,...will allow the Federal government to continuously monitor the safety of products even after they have been approved."

– Some "Critics believe Bill C-51 will outlaw up to 60 percent of NHPs currently sold in Canada, and penalize parents who give herbs or supplements to their children. They also argue that the government could designate any NHP a prescription drug, making it available by prescription only, forcing smaller companies out of the market."

DIA Communications: July 21, 2008 Cont’d…

Doctors of Chinese medicine across Canada join forces to fight Federal Government's Bill C-51.

• CBC News (18 July 2008) reported:

– "Doctors of Chinese medicine across Canada have joined forces to fight the federal government's controversial Bill C-51 -- a proposed law that critics say will make many NHPs unavailable, including Chinese herbs."

– If the bill is "approved, the Federal bill would treat NHPs like herbs, vitamins, and minerals as drugs, making it harder to import, sell, or dispense them.“

– The doctors "say their herbs would have to pass Western-style clinical trials under Bill C-51."

DIA Communications: July 21, 2008

Advice for patients regarding the use of herbal medicines

K Herbal remedies should be considered medicines by all parties concerned.

K Recommended dosage regimens must be followed.

K Long-term therapy should be discouraged.

K Discussion with conventional health care providers should be encouraged.

K The possibility of herb-drug interactions should be considered.

Cont’d…

K Reputable suppliers should be chosen.

K The possibility of contamination and adulteration with prescription and OTC drugs should be considered.

K When experiencing adverse effects, herbal medicines must be discontinued and a health care professional should be consulted.

K Extra caution is advised for pregnant or breast-feeding women, young children or the elderly.

Ernst E. (2005): The Pharmaceutical Journal, 275, 167-168

Adulteration, by definition, is fraudulent. Some manufacturers evidently include synthetic drugs in their products with the aim of rendering them more clinically effective and presumably to boost sales.

An effective strategy of minimizing these risks should follow several avenues. The consumer should be informed that natural does not necessarily mean free from risk.

Patients and pharmacists should be encouraged to talk openly about the use of Asian herbal medicines and the possibility of interactions of herbal medicines with prescription drugs.

The implications of adulteration of herbal medicines with pharmaceuticals highlight the necessity for regulatory bodies to establish more stringent regulations for efficacy and safety assessment, quality assurance, and standardization of natural health products and dietary supplements.

Conclusions

Heavy metals adulteration or contamination of Ayurvedic remedies,

traditional Chinese medicines, and other plant products

Part II

Ayuverda is the most commonly practised form of non-allopathic medicine in India, especially in rural areas, where 70% of the population lives.

The system comprises a wide range of therapeutic approaches which include diet, herbs, metals, minerals, sea shells, precious gems (e.g. diamond, pearls), and their combinations as well as exercise and lifestyle modifications.

Ayurvedic theory of healing emphasizes important therapeutic roles of metals such as gold, silver, copper, iron, zinc, arsenic, mercury and lead.

Ayuveda experts estimate that 35 – 40% of the approx. 6,000 medicines in the Ayurvedic formulary intentionally contain at least one heavy metal, and about 20 – 25% of formulations contain more than one heavy metal.

Gogtay et al. (2002): Drug Safety, 25, 1005 – 19.

Contamination of traditional Indian medicines with heavy metals

Ernst E. (2005): Pharmaceut. J., 275, 167-68

Ayurvedic HMPs containing lead, mercury, and/or arsenic

Saper et al. (2004): JAMA, 292, 2868 - 73.

ND= not detectedConcentration of Arsenic in liquid product (Safi) was expressed as µg/mL* Label specifically recommended pediatric use

Heavy Metal Content of Ayurvedic HMPs

Of 70 Ayurvedic herbal medicine products (HMPs) sold in the Boston-area retail stores, a total of 14 (20%) products contained heavy metals such as: Lead (n = 13) median concentration 40 µg/g Mercury (n = 6) median concentration 20,225 µg/g Arsenic (n = 6) median concentration 430 µg/g

If taken as recommended by the manufacturers, each of these 14 products could result in heavy metal intakes above the daily regulatory standards published by the US Pharmacopoeia and the US Environment Protection Agency.

Users of Ayurvedic HMPs may be at risk for heavy metal toxicity. Physicians should consider Ayurvedic HMP intake in the differential diagnosis of unexplained heavy metal toxicity.

Saper et al. (2004): JAMA, 292, 2868 - 73.

Gair R (2008): BC Medical Journal, 50 ;105

Ayurvedic medicine used to increase vigor. Each tablet contained about 28 mg Pb, 0.7 mg Hg, and 0.11 mg As

Herb used to manage diabetes, contained 179.5 mg lead per 5 g

Heavy Metal Poisoning From Ayurvedic MedicinesHeavy Metal Poisoning From Ayurvedic Medicines

Results of a recently published study showed that about 21% of both US- and Indian-manufactured Ayurvedic medicines purchased via the internet contained high levels of lead , mercury, or arsenic.

Rasa shastra (herbs with metals) compared with non-rasa shastra (herbal-only) medicines had markedly greater prevalence of metals (40.6% vs. 17.1%; P= 0.007) and higher median concentrations of lead (11.5 µg/g vs. 7.0 µg/g; P =0.03) and mercury (20,800 µg/g vs. 34.5 µg/g; P=0.04).

Among the metal-containing products, 95% were sold by US Web sites and 75% claimed Good Manufacturing Practices. However, all metal-containing products exceeded one or more standards for acceptable daily intake of toxic metals.

Heavy metals in US- and Indian-manufactured Ayurvedic medicines sold via the internet

Cont’d…

Saper et al (2008): JAMA, 300, 915-23

Several rasa shastra medicines exceeded US-EPA limits of Pb and Hg ingestions by 3 to 4 orders of magnitude.

Since 1978, more than 80 cases of lead poisoning associated with Ayurvedic medicine use have been reported worldwide, according to the study.

Based on their findings, the study's authors are calling for tougher regulations for dietary supplements: "We suggest strictly enforced, government-mandated daily dose limits for toxic metals in all dietary supplements and requirements that all manufacturers demonstrate compliance through independent third-party testing."

• Of 251 products collected from California retail herbal stores, 24 contained at least 10 ppm of lead; 36 products contained arsenic ranging from 20.4 to 114,000 ppm; and 35 products contained mercury ranging from 22.4 to 5,070 ppm.

• The US Pharmacopoeia limits heavy metals in most oral pharmaceuticals to 30 ppm, with lower limits for lead, arsenic, and mercury.

Heavy Metals Found in Asian Patent MedicinesHeavy Metals Found in Asian Patent Medicines

Ko, RJ. (1998): New Eng. J. Med. 339, 847

In Brazil, cadmium, mercury, and lead were detected in medicinal herbal products such as celastraceae, cascara buckthorn, horse chestnut, and chlorella.

Chronic exposure to cadmium can cause nephrotoxicity in humans. Lead and mercury can cause adverse effects on the renal and nervous systems of adults and the developing fetus.

Caldas & Machado. (2004): Food and Chem. Toxicol. 42, 599-603

Symptoms of Pb poisoning include abdominal pain, loss of appetite, vomiting, weakness, anemia, hypertension, and convulsions, sometimes leading to permanent brain damage or even death.

Children of mothers who are exposed to lead during pregnancy may show signs of mental retardation.

Organic and inorganic Hg compounds are highly toxic to the CNS and kidney. In adults, harmful effects may consist of irritability, tremors, insomnia, memory loss, concentration problems, and nephrotoxicity.

The developing nervous system of the fetus is more vulnerable to methylmercury than that of the adult. The baby’s brain can be severely damaged if the mother is exposed to Hg.

Toxic effects of As may include skin and lung cancers, diabetes mellitus and goiter, heart, kidney, and liver damage.

Plausible explanations for heavy metal adulterants or contaminants

• There are several plausible explanations for the presence of heavy metals in Asian herbal medicines.

• Heavy metals could be included intentionally for alleged medicinal properties. Traditional Indian schools of medicine (Ayurvedic, Sidha, Unani) emphasize the importance of metals like lead, copper, gold, iron, mercury, silver, tin and zinc for the proper functioning of the human body.

• Ayurvedic texts acknowledge the toxicity of heavy metals and recommend special physico-chemical procedures that allegedly “detoxify” them.

• In traditional Chinese medicines (TCMs), mercury is part of some preparations. For example, cinnabaris (mercury sulphide), calomel (mercury chloride), or hydrargyri oxydum rubrum (mercury oxide).

Cont’d…

• Lead is used as “Mi Tuo Seng” (Lithargyrum) and arsenic as “Xiong Huang” (Realgar) in the manufacture of several TCMs.

• The presence of heavy metals may be the result of contamination during manufacture from grinding weights, use of lead-increasing containers or other manufacturing utensils.

• Asian herbal medicines can contain heavy metals when plants are grown in heavily polluted soil, such as near roadways or metal mining or smeltering operations.

• High metal levels can be found when agricultural expedients are used, including cadmium-containing fertilizers, organic mercury or lead-based pesticides, and contaminated irrigation water.

• TCMs can also contain animal and mineral products and these, too, can be contaminated with heavy metals.

Ernst E. (2005): The Pharmaceutical Journal, 275, 167-168

Heavy metals are not the only possible toxins in herbal remedies. Contamination with herbicides, pesticides, micro-organisms or mycotoxins, or insects also occurs.

High levels of mycotoxins and microbes have been detected in herbal tea and polyherbal products, resulting in serious gastrointestinal and neurological disorders.

CONCLUSIONS

• In England, 30% of Ayurvedic HMPs sampled contained lead, mercury, or arsenic in excess of the permissible limits.

• In America, 20% of Ayurvedic HMPs sampled contained lead, mercury, or arsenic in amounts exceeding the legal standards.

• Of 22 Ayurvedic HMPs marketed in India, 64% contained lead and mercury, while 41% contained arsenic exceeding the permissible amounts.

• Traditional medicines from China, Malaysia, Mexico, Africa, and the Middle East have been shown to contain potentially harmful levels of heavy metals.

• If taken as recommended by the manufacturers, Ayurvedic HMPs, TCMs, and other herbal remedies would result in heavy metal intakes above the daily regulatory standards published by the US Pharmacopeia and the US Environment Protection Agency.

Cont’d…

• Since users of Ayurvedic HMPs, TCMs, and other phytomedicines are at a greater risk for heavy metal toxicity, physicians should consider the intake of these alternate remedies in the differential diagnosis of unexplained heavy metal toxicity.

• Deliberate adulteration or unintended contamination of Ayurvedic HMPs, TCMs, and herbal products with heavy metals and numerous reports of associated toxicity have serious public health implications.

• In most Western countries, these products are marketed as dietary supplements, which does not require proof of safety and efficacy.

• Strict regulations for mandatory testing of Ayurvedic, Chinese, herbal medicines and dietary supplements for toxic heavy metals are needed.

Bulwark of Pharmacology and Toxicology

“All substances are poisons, there is none which is not a poison.

The right dose differentiates a poison

from a remedy.”

Paracelsus (1493-1541)

In April 2010, many pediatric Tylenol products were recalled in USA and Canada due to lack of regulatory standards.

Toxic spill in Hungary from an industrial reservoir. The spill caused chemical burns due to NaOH used to extract alumina from bauxite ore. The spill also contained toxic heavy metals like lead, mercury, arsenic and cadmium. Several rivers were polluted with the spill in Oct. 2010.

Summary ofNew Canadian NHP Regulations

• Quality– GMPs– site licensing

• Safety – product licensing– adverse reaction

reporting– labelling requirements

• Efficacy– proof of claim