Download Contamination of Herbal Medicines

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
Summary of
New 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
Type of
contaminant
or 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, HCHisomers, HCB, aldrin, dieldrin, heptachlor),
organic phosphates, carbamate insecticides and
herbicides, dithiocarbamate fungicides, triazin
herbicides
De Smet, P.A.G.M. (1999): Drug Information J. 33, 717-724
Potential Contaminants that should be taken into
account in the Quality Control of Herbal Remedies
Type of contaminant
or 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
De Smet, P.A.G.M. (1999): Drug Information J. 33, 717-724
Health
Santé
Canada Canada
Part I
Adulteration of phytomedicines and
traditional Chinese medicines with
pharmaceuticals
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
•
•
•
•
•
•
Aminopyrine
Carbamazepine
Clobetasol propionate
Diazepam
Ethoxybenzamide
Fluocinolone acetonide
•
•
•
•
•
•
Caffeine
Chlorzoxazone
Dexamethasone
Diclofenac
Fenfluramine
Glibenclamide
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 antiepileptic drug (trimethadione), an antiinflammatory 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.
Fenfluramine
Phenolphthalein
Orlistat
Sibutramine
N-mono-desmethyl sibutramine
N-di-desmethyl sibutramine
Wang J. et al. (2008): Food Additives & Contaminants, 25 ; 822-30.
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
Conclusions
 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.
Part II
Heavy metals adulteration or
contamination of Ayurvedic remedies,
traditional Chinese medicines, and other
plant products
 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
ND= not detected
Concentration of Arsenic in liquid product (Safi) was expressed as µg/mL
* Label specifically recommended pediatric use
Saper et al. (2004): JAMA, 292, 2868 - 73.
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.
Heavy Metal Poisoning From Ayurvedic Medicines
Herb used to manage diabetes,
contained 179.5 mg lead per 5 g
Ayurvedic medicine used to increase vigor.
Each tablet contained about 28 mg Pb, 0.7 mg
Hg, and 0.11 mg As
Gair R (2008): BC Medical Journal, 50 ;105
Heavy metals in US- and Indian-manufactured
Ayurvedic medicines sold via the internet
 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.
Cont’d…
 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."
Saper et al (2008): JAMA, 300, 915-23
Heavy Metals Found in Asian Patent Medicines
• 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.
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 of
New Canadian NHP Regulations
• Quality
– GMPs
– site licensing
• Safety
– product licensing
– adverse reaction
reporting
– labelling requirements
• Efficacy
– proof of claim