c.1 A CHRISMAS CAROL: PRE-INTERMEDAITE (IE) DICKENS, C. c.2 A CHRISMAS CAROL: PRE-INTERMEDAITE (IE) CD-ROM DICKENS, C. A Christmas Carol : Preintermediate Charles Dickens A HACKER'S REVENGE: PASSWORD READERS Frances Hodgson A Little Princess African Adventure Celebration Chemical Secret Tim Vicary c.1 CITY MOUSE AND COUNTRY MOUSE c.2 CITY MOUSE AND COU
Pii: s0378-8741(00)00394-9Journal of Ethnopharmacology 75 (2001) 141 – 164 Should we be concerned about herbal remedies Department of Biology, Washington Uni6ersity, Box 1137, St. Louis, MO 63130-4899, USA Received 24 November 2000; received in revised form 5 December 2000; accepted 5 December 2000 Abstract
During the latter part of this century the practice of herbalism has become mainstream throughout the world. This is due in part to the recognition of the value of traditional medical systems, particularly of Asian origin, and the identification of medicinalplants from indigenous pharmacopeias that have been shown to have significant healing power, either in their natural state or asthe source of new pharmaceuticals. Generally these formulations are considered moderate in efficacy and thus less toxic than mostpharmaceutical agents. In the Western world, in particular, the developing concept that ‘natural’ is better than ‘chemical’ or‘synthetic’ has led to the evolution of Neo-Western herbalism that is the basis of an ever expanding industry. In the US, oftenguised as food, or food supplements, known as nutriceuticals, these formulations are readily available for those that wish toself-medicate. Within this system, in particular, are plants that lack ethnomedical verification of efficacy or safety. Unfortunatelythere is no universal regulatory system in place that insures that any of these plant remedies are what they say they are, do whatis claimed, or most importantly are safe. Data will be presented in this context, outlining how adulteration, inappropriateformulation, or lack of understanding of plant and drug interactions have led to adverse reactions that are sometimeslife-threatening or lethal. 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Herbal remedies; Evolving pharmacopeias; Surveillance and research databases; Adverse effects; Regulatory challenges 1. Introduction
worth of allopathic treatments, and the adverse effectsthat can be anticipated. They are seemingly unaware of During the latter part of the 20th century herbalism the potential problems associated with herbal use or the has become mainstream worldwide. This is due in part fact that their limited diagnostic skills, or of those to the recognition of the value of traditional and indige- prescribing treatment for them, may prevent the detec- nous pharmacopeias, the incorporation of some derived tion of serious underlying conditions like malignancies(Saxe, 1987; Youngkin and Israel, 1996; Donaldson, from these sources into pharmaceuticals (DeSmet et al., 1998; Winslow and Kroll, 1998; Shaw et al., 1999; 1992a; DeSmet, 1997; Winslow and Kroll, 1998), the need to make health care affordable for all, and the Most allopathic practitioners have traditionally con- perception that natural remedies are somehow safer sidered herbal treatments to be innocuous or alter- and more efficacious than remedies that are pharma- nately, potentially problematical. Three decades ago ceutically derived (Bateman et al., 1998; Murphy, only a few had any appreciation of the number of 1999). For a variety of reasons more individuals are remedies that had their origins in herbal medicine and nowadays preferring to take personal control over their most had a vague impression of what herbalism, or health, not only in the prevention of diseases but also other forms of alternate medicinal practices implied to treat them. This is particularly true for a wide variety (Lipp, 1996). There was still a great deal of carry-over of chronic or incurable diseases (cancer, diabetes, from the beginning of the 20th century when the intro- arthritis) or acute illnesses readily treated at home duction of wire services allowed for the dissemination (common cold etc.) (Kincheloe, 1997). In this respect of adverse effects of ‘snake-root’ concoctions and the many individuals have become disenchanted with the like. As early as 1906, misbranding and adulterationwere disallowed in the US Herbal remedies, not a part E-mail address: email@example.com (M. Elvin-Lewis).
of ‘The Dispensatory of the United States of America’, 0378-8741/01/$ - see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 8 - 8 7 4 1 ( 0 0 ) 0 0 3 9 4 - 9 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 were shunned as if the danger associated with one cacy that is frequently observed when single drugs are remedy was common to all much like the notion that if given over long periods of time (Borchers et al., 1997).
‘one mushroom is poisonous, all must be’ and by 1938, Nowadays such remedies can be still found in ethnic safety testing was mandated under the Federal Food, and health food stores, but are also available in phar- Drug and Cosmetic Act. By mid-century, pharmacog- macies and grocery stores. Unfortunately there is no nosy (study of plants affecting health) was a dying universal regulatory system that ensures that these science. Dicta of the day, as outlined in a 1962 law remedies are what they say they are, do what is (Kefauver – Harris Drug Amendments) required proof claimed, or most importantly, are safe (Angell and of safety and efficacy. This policy determined that only Kassirer, 1998; DeSmet, 1993; DeSmet et al., 1997).
chemically defined and clinically evaluated medicineshad value, and if pharmaceutically derived, must beprescribed by allopathic physicians. (Murphy, 1999).
2. Evolving pharmacopeias
Licensure to practice in the US was confined to allo-pathic clinicians and others in naturopathy and home- 2.1. Major types of herbal medicine opathy whose traditional use of herbs was well defined.
Some leeway was also given to practicing traditional Four general types of Herbal Medicine exist which healers within Asian and indigenous communities. On are Asian, European, Indigenous and Neo-Western.
the whole, other types of herbalists were not recognized Many like the Asian and European systems go back thousands of years, appear in pharmacopeia, and with Such was the case for decades, until the ‘age of such a tradition of use are better understood than those Aquarius’ arrived, and the ‘return to nature’ was the of indigenous origins that are often only orally or driving force of every ‘flower child’. In this wake, secondarily recorded (DeSmet et al., 1992a; DeSmet, self-medication became the rule as old European herbals and indigenous remedies were revisited, andwere used with impunity, without concern for adverse effects. In addition, hallucinogens, particularly fromAmerican indigenous cultures, became popular as many Indigenous medicinal systems are the most diverse trying to escape the reality of a war-torn and ‘hide- and are still practiced where such cultures are intact, bound’ world, experimented with ‘altered states’. Soon but are continuously evolving as contact with other ‘health food stores’ appeared, specializing in unrefined cultures continues. The knowledge may reside exclu- food, organic-grown vegetables, herbs and herbal sively with traditional healers, or be generally known.
preparations. With the opening up of Asian markets, Information regarding parameters of efficacy and toxic- other types of medicines were introduced, and were ity can vary since claims are primarily anecdotal. Usu- permitted since they were considered already ‘culturally ally regional variations to formulae exist, and plants acceptable’. A synthesis of all these types of herbal selected can be quite specific, generic, or inadvertently medicinal practices evolved into what can be called, adulterated. It usually follows that when a remedy is ‘Neo-Western’ herbalism. Formulae found in this sys- widespread in acceptance its efficacy and safety has a tem are based upon both ethnomedical worth or are sound therapeutic basis. It is these plants, in particular, simply serendipitous inventions of the formulator. A that can be found in Neo-Western herbalism.
belief of benefit over single-ingredient drugs is thecorner stone of this form of herbalism that subscribes to the notion that ‘primary active ingredients in herbsare synergized by secondary compounds, and secondary The most established types of herbalism are those of compounds mitigate the side effects caused by primary Asian origin, particularly from India (Aryuvedic, active ingredients’ (McPartland and Pruitt, 1999). Since it is possible for single taxa to contain a family of (Kampo), and today they still follow the ideas of related bioreactive compounds varying in potency, it is diagnosis and treatment known for millennia (Kanba et logical to presume that one or more of these will al., 1998; Wong et al., 1998; Vogel, 1991). Most of contribute to the totality of the effects observed (Lewis the remedies are mixtures of plants, sometimes also and Elvin-Lewis 1994; Elvin-Lewis and Lewis, 1995). It containing animal parts and minerals and are formu- would follow that when mixtures of several crude ex- lated to achieve expected therapeutic goals. They are tracts are used in formulations, enhancement of benefi- often referred to as ‘drugs’. In these remedies it is not cial effects (or greater toxicity) is expected through unusual to find more than one plant whose components either synergistic amplification or diminishment of pos- have complementary effects that seemingly work to- sible adverse side effects. It is also presumed that their gether to enhance the therapeutic value or other prop- combination could prevent the gradual decline in effi- erties of the mixture. This is also true for Indian dental M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 remedies containing berberine, additive or toxic effects (Elvin-Lewis, 1987, 1989). Under ideal conditions, due to undeclared pharmaceuticals like mefenamic care is taken by traditionally trained practitioners to acid and diazepam (Gertner et al., 1995), heavy metal carefully identify the ingredients, to harvest the plants adulterations (Schaumburg and Berger, 1992; Kew et at very specific times to insure appropriate levels of al., 1993; Sheerin et al., 1994), or when inadvertent bioreactivity, to prepare the remedies under strict adulterations with Podophyllum emodi instead of rules, and to prescribe them to achieve an appropriate londancao (Gentiana spp.) have elicited severe life- clinical response. In spite of the fact that parameters threatening events (Chan, 1997; Drew and Myers, of use may be known to the practitioner, including 1997). Highly concentrated alkaloid preparations like side effects that can be expected, packaging inserts tetrahydropalmatine, a potent neuroreactive, can be accompanying commercial products rarely cite these found in Jin Bu Huan. This Chinese patent medicine nor do they always accurately represent the contents.
used as a painkiller, has been associated with serious Also, there is a general acceptance in Asian countries, adverse reactions episodes in children and adults.
particularly India, for patients to seek concurrent Symptoms occurring in long-term users range from treatment through more than one Indian Medicinal acute toxicity, lethargy, muscle weakness, respiratory System as well as allopathy, or in Chinese herbalism compromise, bradycardia and coma, to ‘extreme fa- to fraudulently incorporate pharmaceuticals in some tigue’, fever, jaundice and hepatitis. These events were remedies. This only compounds issues related to reported in the Communicable Disease Center’s Mor- recognizing the source of potential side effects, and it bidity and Mortality Weekly Reports (Anonymous, is uncommon for them to be reported at all. More- 1993a,b), and by Horowitz et al. (1996).
over, without enforceable regulatory systems to gov- Ginseng preparations imported from China must al- ern the activities of practitioners and formulators, ways be suspect since not only can the content of the unexpected adverse reactions are always likely. In this ginsenosides vary (Consumer Reports, 1995), but respect, formulations may be inappropriately made, commercial formulations can be adulterated with po- prescribed, or taken. Formulation diversity, due to tent and dangerous plants like mandrake (Mandrogora advertent substitutions, can also exist in preparations officinarum) containing scopolamine and Rauwolfia with the same name. These changes are not always serpentina containing reserpine and stimulants like obvious. Examples can be found in Aryuvedic prepa- caffeine from Cola spp. (Drew and Myers, 1997). Cer- rations formulated in southern India, where tradi- tain Chinese remedies may be named the same but tional Himalayan plants are unavailable. Without are formulated differently depending upon the unique appropriate prescription labeling, adulterations are a condition of the patient; such is the case with Chinese particular problem in Asian medicines, and formula- herbal preparations called ‘Eternal Life’. Without ap- tions have been found to contain substitutions of propriate labeling of its ingredients it is almost impos- plant ingredients, dangerous levels of toxic plant com- sible to identify the source of any adverse effects ponents, unapproved ingredients like pharmaceuticals associated with its use (Sanders et al., 1995).
and heavy metals in addition to other toxic and aller-genic substances (Anonymous, 1989; Chan et al., 1993; Chan, 1997; Drew and Myers, 1997; Ernst,1997; Ko, 1998). For example, although strictly not European Traditional Medicine has its roots mostly herbal remedies, lead has been found in a Laotian in antiquated Mediterranean civilizations and has over preparation known as Pay-loo-ah, a Korean remedy, the centuries evolved in its utilization of both Eu- hai ge fen, containing clam shell powder (Borins, ropean and plants from abroad. In the Middle Ages 1998) and in Indian traditional cosmetics used as eye- the color or shape of a plant denoted a cosmic clue to its medical usefulness, and hence the Doctrine of Chinese herbal medicines are typically unpalatable Signatures was a criterion by which many plants were and can induce nausea and vomiting. Most reported selected, e.g. heart-shaped leaf as a heart remedy, yel- adverse effects on the heart have been associated with low plant parts for treating hepatitis, etc. By the 19th Aconitum poisonings and certain topical skin prepara- tions that can also cause liver damage (Chan, 1997; become part of the pharmacopeias of allopathy, Drew and Myers, 1997; Ko, 1998; Armstrong and naturopathy and homeopathy, and their therapeutic Ernst, 1999). In addition, pain or asthma remedies basis investigated by medicinal chemists and pharma- containing Datura metel are recognized to cause anti- cognosists. Usually when compounds are isolated, and cholinergic effects leading to reduced visceral activity.
sometimes totally synthesized, their pharmaceutical Liquorice, by affecting the sodium/potassium balance, uses are more carefully regulated; aspirin, of course, can cause water retention. More serious are condi- being an early exception (DeSmet, 1993; DeSmet et tions like jaundice and brain damage due to neonatal M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 3. Regulatory challenges
In its totality European Traditional Medicine has matured along with American herbal introductions intoNeo-Western herbalism. In this system single plant Overall, the incidence of serious adverse reactions is preparations that have been either selected from formu- significantly lower with most of these therapeutic reme- lations found in ancient pharmacopeias or derived from dies when compared to pharmaceutically derived drugs.
medicinal plants valued in other cultures, including However, the need still exists to more closely monitor those of indigenous origin, are sold alone or as mix- tures in an assortment of combinations. For example, medicine, including those of Asian origin, so that one of the most popular plants in use in Europe today medicinal irregularities and unethical practices are re- is Echinacea with its origins in North American (Mid- duced. Also, Chinese herbal prescriptions are individu- western) indigenous medicine (Lewis and Elvin-Lewis, alized and when dispensed are not usually labeled, and 1977). Also, novel formulations can be devised without should adverse effects arise, identification of their con- ethnomedical data to support their merit, or represent a tents is difficult unless the patient has been provided a mixture of plants known to a variety of medicinal written copy of the formulation. Presuming that the systems (DeSmet, 1995a). To promote the sale of a formulation contains the plants described, verification particular product, examples exist where supporting may be impossible after processing has occurred.
ethnomedical data are purposely vague, obtuse, or con- Should traditional remedies be prepared in an Asian trived. While such mixtures may potentiate a remedy’s country, and imported, the task of insuring safety is medicinal value, it is also possible that these combina- even more difficult since the notion of incorporating tions could promote adverse effects not known when potentially toxic herbs or heavy metals may not beconsidered ‘harmful’ in the country of origin (Natori, individual plant components are used. Without tradi- 1980; Anonymous, 1989; Shaw et al., 1997).
tional parameters to guide the consumer, the benefits orrisks to these newly contrived formulations are cur- While most British, European and Asian herbalists Unfortunately, regulatory standards vary from coun- are formally trained within the context of known phar- try to country, and thus claims of content, efficacy, and macopeias or curricula, American herbalists can vary in safety of any herbal remedy cannot always be assured.
their instruction, some being self-taught, while others Germany is the leader in evolving rational regulatory undertake training in various types of apprenticeship policies (Benzi and Ceci, 1997). There, plant remedies programs. However, like allopathic clinicians, both are carefully delineated and registered in Commission E naturopathic and homeopathic clinicians undergo clas- Monographs with known risk/benefit/drug interactions sical training and in the US and Canada some schools cited, and consistency of bioreactive compounds chemi- of naturopathy also teach homeopathy as a sub-spe- cally defined as phytopharmaceuticals (Blumenthal et cialty. Both of these disciplines utilize specifically for- al., 1998). More detail is provided in the 50 mono- graphs published by the European Scientific Coopera- parameters of use. However, philosophies of diagnosis tive on Phytotherapy and 10 additional monographs and treatment differ. Naturopathy, based on hydrother- are underway (Blumenthal, 1999). While self-medica- apy and dietary treatment, currently prescribes formu- tion is the norm, prescriptions for some medications are lations containing plant extracts or phytochemicals at also mandated. Most European countries are evolving pharmacognostically determined levels of efficacy. The similar policies (Benzi and Ceci, 1997), although in the philosophy of treatment is two-fold and includes both United Kingdom only some herbal preparations fall curative and maintenance (normalization) aspects.
under such strict regulatory guidelines (Mills, 1995).
Homeopathic formulations (that contain plant extractsand other substances) are compounded under the phi- losophy that substances that cause specific toxic effectscan, at extremely dilute concentrations, reduce similar In the US regulatory mechanisms regarding herbal- effects elicited by disease states. While homeopathic ism were non-existent until only a few years ago, and remedies are often considered to only elicit placebo-like even then and now they still lack true enforcement actions, practitioners recognize their worth, and under- capability. FDA Commissioner Kessler voiced concerns stand that these remedies are not only bioreactive but regarding safety in 1993 and proposed removal of may also elicit minor adverse effects like rashes, nausea, herbal products without proven safety and efficacy. As vomiting, agitation, shaking and allergic reactions a reaction to this proposal the Dietary Supplement (Shaw et al., 1997; Glisson et al., 1999).
Health and Education Act (DSHEA) was inaugurated M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 in 1994. Under this act many botanical medicines graphs for herbal dietary supplements and dispensatory defined as ‘a vitamin, a mineral, an herb or other information (DI). They have already published 11 botanical (or) amino acid are now sold under the guise monographs and an additional 12 are under prepara- of food or dietary supplement (Brevoort, 1998; Mur- tion. In order to set standards to document the quality phy, 1999). As long as no medical claims are present on of herbal products, and outline the therapeutic parame- the label they are exempt from strict pharmaceutical ters for safe and effective use, publication of the WHO regulations. Any display literature must further claim Monographs on Selected Medicinal Plants is on-going that the product has not been reviewed by the FDA or (Akerele, 1993). Volume 1 (1999) contains 28 mono- is not intended for medication. Also in 1997, a Federal graphs on 31 plant species and Volume 2 to be pub- Commission on Dietary Supplements was established that recommended that manufacturers provide science- base evidence to consumers. To some physicians like Furthermore, the FDA is considering reviewing cer- Angell and Kassirer (1998), these guidelines, and vague tain botanicals via the IND/NDA (Investigational New or oblique claims related to the maintenance of good Drug/New Drug Application) process. Presently there health, still begs the issue regarding proven safety or are at least 50 botanicals or botanical formulas holding efficacy. They emphasize that since these herbal reme- active IND applications. Priority will be given to those dies are not classified as medications they are not under with a long-history of safety, particularly for short-term FDA scrutiny. Without being appropriately evaluated use since information is unlikely to be adequate to for content, safety or efficacy it is difficult to determine support claims of safety for long-term use. In some parameters of use. However, should adverse reactions cases issues related to accompanying chemistry and become apparent, the FDA could investigate and inter- toxicological data remain to be resolved (Murphy, vene to remove the product (Murphy, 1999). Moreover, 1999). Recently, a Federal Commission on Dietary the FTC (Federal Trade Commission) is active in defin- Supplements has been established (1997) recommends ing the regulatory framework for advertising claims for that manufacturers provide science-based evidence to dietary supplements. The legal and regulatory aspects consumers. Also to support evaluation of herbal of these US government agencies in overseeing the herb medicines and other non-traditional remedies the Na- and dietary supplement industry from the perspective tional Institutes of Health (Bethesda, MD) formed the of the Consumer Healthcare Products Association has Office of Alternative Medicine in 1992 that has recently been recently reviewed and is a useful reference to those been up-graded to the National Center for Complemen- requiring details of such aspects (Soller, 2000).
tary and Alternative Medicine (Murphy, 1999). Eventu- Attempts are being made to bring some sense out of ally, these initiatives and others evolving elsewhere, are this current regulatory chaos since it is in the best expected to provide needed information to validate this interest of everyone to do so. In this regard, pharma- type of therapy. To aid in this endeavor two searchable cognosists and natural products chemists have once databases generated by the US National Institutes of again become active in trying to understand the thera- Health on dietary supplements exist. The International peutic basis of herbal remedies and toxicologists are Bibliographic Information on Dietary Supplements addressing issues of the origins of potential adverse (IBIDS) can be accessed at the ODS website http:// effects as incidences of associated use or abuse become odp.od.nih.gov/ods. Currently, IBIDS contains 400 000 evident. As a complement to these efforts a number of citations and abstracts of published international, scien- organizations are preparing monographs to delineate tific literature on dietary supplements, including vita- details of herbs that are popularly used as phy- tomedicines and medicinal plant preparations so that quarterly. Scheduled to go online in 2001, CARDS their recognition as official medicines may result (Computer Access to Research on Dietary Supple- (McGuffin et al., 1997). The most ambitious is that of ments) will identify ongoing, federally funded research the American Herbal Pharmacopeia and Therapeutic on dietary supplements and individual nutrients (CAM, Compendium with plans to publish at least 2000 mono- 2000). Within this context clinical evaluation protocols graphs of this nature. Also, the herb trade in recogniz- should include those outlined in Table 1.
ing its responsibility to provide appropriate guidelines,has recently published through the American Products Herbal Association (AHPA) The Botanical SafetyHandbook, 2nd edition (1998). The FDA accepts this In Canada similar regulatory mechanisms are being organization’s Herbs of Commerce as the authoritative instituted and in March of 1999, an Office of Natural text for label nomenclature related to available herbal Health Products was created to assure that Canadian products. To aid pharmacists in understanding risks consumers have access to a full range of safe health and benefits of herbal products, the United States Phar- products. ‘‘The Office will undertake or coordinate all macopeia (USP) is also compiling standard mono- the regulatory functions within the life-cycle of natural M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 proposed that forms of herbal post marketing surveil- product licensing through licensing of establishments, lances be conducted to ‘detect serious adverse reactions, post-approval monitoring and the compliance and en- quantify their incidence and identify contributive and forcement tools appropriate with ensuring health pro- modifying factors’. Obviously, the success of such en- deavors depends on those willing to voluntarily and appropriate training standards of manufacturing and spontaneously report such events to appropriate health distribution establishments.’’ Within this context, crite- care officials, pharmocologists (http,//www.faseb.org/ ria to determine the applicability of efficacy as reflected aspet/H&MIG3.htm ctop), regulatory bodies (FDA in labeling claims will be established and information ‘MEDWATCH’ (http,//www.vmcfscan.fda.gov/ disseminated to allow the Canadian consumer to make aems.html)), and responsible parties in the herb trade informed self-care decisions. Accommodations will be industry itself, like the American Botanical Council made for aboriginal healers. Currently, Health Canada (http,//www.herbs.org), who are collating these data for policy allows an individual to import a 3 month supply public dissemination (Winslow and Kroll, 1998).
of a drug product for their own personal use that is not With the number of mixed plant formulations now subject to these evolving regulatory policies (Koryrskyj, marketed in the US alone, it is particularly important to refer to web sites that can provide on an on-goingbasis useful information on current adverse reactions.
Overall, the US is still a long way from the develop- 4. Surveillance of adverse effects through databases
ment of standardized herbal drugs, called phytophar-maceuticals, which have been formulated (in a fashion) Regardless of the type of herbalism being practiced to ensure a reproducible effect by undergoing suitable some adverse reactions are more easily recognizable means of identification and clinical evaluations to than others. Postulates have been proposed by Hughes achieve international approval. Obviously these are (1995) to define if adverse effects are linked to a drug needed steps if allopathic acceptance is to follow (An- use. According to Stewart (1990), DeSmet (1995b), gell and Kassirer, 1998). In the interim, information is events that are pharmacologically predictable are often accumulating that is providing appropriate ways to dose-dependant and thus preventable by dose reduc- understand herbal therapies and can be elicited from tion, or if allergenic, by elimination. However, in spite internet sources like the National Center for Comple- of the mode of application, individual differences in physiology may elicit a variety of idiosyncratic local or systemic reactions, including those that are life threat- (www.herbalgram.org), US Food and Drug Adminis- ening. Age may also be a factor and those remedies tration (www.fda.gov), and the US Pharmacopeia most frequently used by the elderly may elicit varying responses (Ernst, 1999). Similarly, long-term use canproduce predictable reactions or consist of delayedeffects such as carcinogenicity and teratogenicity. To 5. Bridging the gap between herbalism and allopathy
better understand the scope of these problems andbring them forward to the public DeSmet (1995b) Most importantly, it is now recognized that allo- pathic clinicians have little training in understandinghow various forms of herbalism and self-medications Table 1Proposed clinical evaluation protocol for the development of an are impacting on the health of their patients, who are often, also under prescriptive medication. However, asawareness of potential interactions with allopathic Confirm ethnomedical value in country of origin treatments and herbal remedies increases, many clini- Note all parameters of use particularly among children, the aged cians and hospitals are eliciting this information on Review traditional formulations to understand rationale of use admission questionnaires (Murphy, 1999). To ensure Know variations to standard formulations and reasons for that patients will be forthcoming with the information, it is recommended that such solicitations be carefully Conduct controlled clinical trial with formulation considered to worded so as not to be judgmental. This is essential since a patient’s response to treatment, particularly in a Identify bioreactive components to insure standardization of clinical trial, could be distorted when concurrent uses Conduct toxicological studies to understand safe parameters of with herbal remedies are not revealed (Kassler et al., 1991; Buchness, 1998; Donaldson, 1998).
Conduct placebo-based clinical trials following appropriate To increase the sensitivity of future practitioners, a guidelines for patient entry, evaluations of efficacy etc. to number of US medical schools are developing courses comply with regulations where product is to be sold in Complementary and Alternative Medicine, including M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 some exposure to herbal medicinal practices. At this (O’Hara et al., 1998). Infant deaths due to veno-occlu- point these curricula vary and are by no means univer- sive disease have been associated with the consumption sal. As a complement to this effort, the need to offer of pyrrolizidine alkaloid containing teas or cough reme- continuing education courses for physicians, nurses, dies during pregnancy (Roulet et al., 1988; Winship, pharmacists, nutritionists and the like should be pro- 1991). Since there is a risk of bleeding disorders being transmitted to the fetus or breast feeding infant hep-arin-containing herbs should also be avoided duringpregnancy or lactation (Ernst, 1997). Due to its do- 6. Pharmacokinetic behavior of plant-derived drugs
paminergic actions, the same is true for use of chaste-berry fruit (Vitex agnus-castus Boehnert, 1997). Birth Studies on plant-derived drugs primarily with quinine weights are also lower in women chewing the stimulant, and sparteine have provided a better understanding of khat (Catha edulis) during pregnancy (Ghani et al., factors affecting the pharmacokinetic behavior of drugs 1987). At parturition, blue cohosh (Caulophyllum thal- within human populations. It has been recognized, for ictroides), used to promote uterine contractions should instance, that age effects storage and clearance rates be avoided since a neonate developed acute myocardial just as the ability to metabolically oxidize certain com- infarction, associated with profound congestive heart pounds can be genetically determined and racially fo- failure and shock. The infant remained critically ill for cused. Diseases affecting the kidney and liver can alter several weeks but survived. This event was believed due the clearance rates of certain compounds or exacerbate to vasoactive glycosides, a toxic alkaloid, and sparteine underlying conditions. Infections like malaria can actu- found in the plant (Jones and Lawson, 1998).
ally raise the plasma levels of the medication (quinine) Also consumption by a mother of senna laxative, just as low protein diets can alter urine pH, which when with rhein, was reported as having elicited catharsis in alkaline, can slow its renal clearance. Smoking or cer- her nursing infant (Faber and Strenge-Hess, 1988).
tain drug interactions can also effect oral or metabolic Comfrey tea, now banned, contains a potentially harm- clearance rates. Normal ovarian function can be altered ful pyrrolizidine alkaloid, echimidine known to have by use of Vitex agnus castus (Cahill et al., 1994). All hepatotoxic, genotoxic and carcinogenic properties is these activities can impact either beneficial or adverse also excreted in breast milk (Winship, 1991). In one effect of drugs and/or herbal therapies (DeSmet and instance a veno-occlusive hepatic illness resembling Budd – Chiari syndrome was linked to the consumptionof a tea containing flowers of Tussilago farfara androots of Petasites officinalis (Radix petasitidis) (Roulet 7. Herbal drug transmission in utero or through
et al., 1988; Spang, 1989), and in another, senecionine, mother’s milk
a pyrrolizidine alkaloid present in an herbal coughremedy was responsible for this fatal illness (Fox et al., It is well known that transmission of particular drugs in utero to the fetus or through breast milk to an infantcan take place. Evidence is accumulating that this isalso true should mothers use certain herbal remedies 8. Allergic reactions
during pregnancy or while nursing their babies. Effectsmay be transient, grave, or fatal. The fetus is in partic- Allergic reactions that can occur with herbal use are ular jeopardy should herbs with teratogenic, carcino- manifested in a variety of forms (Rieder, 1994). Both genic, toxic or abortifacient properties be employed.
Type I immediate hypersensitivity reactions leading to For example, constituents like salicylates are potentially rhinitis, headache, dermatitis (hives), and/or anaphylac- teratogenic and embryocidal, even if applied externally tic shock are commonly induced by cross-reactions in Oil of Wintergreen. Ingestion of sassafras (Sassafras among Asteraceous (daisy family) plants taken inter- albidum), tea popular in the US for its flavor and use as nally, whereas delayed Type IV, contact dermatitis is a diuretic (D’Arcy, 1993), might also pose problems to more prevalent when topical applications are used the fetus. This is suggested by studies in mice where (Gordon, 1999). Within this family, wide cross-reac- transplacental carcinogenesis has been found to occur tions are known and a major sensitizing plant in the US following treatment with sassafras and is possibly is ragweed (Ambrosia spp.), it follows that patients with caused by its major carcinogenic component, safrole known sensitivity to ragweed should avoid Asteraceous (DeSmet, 1992b). Neonatal jaundice has been traced to herbal teas like chamomile (Chamaemelum nobile) the use of goldenseal and barberry and its hydrastine (Lewis, 1992b) or other remedies containing flower content. Also, since feverfew (Tanacetum parthenium) is heads and pollen, and particularly in concentrated a traditional inducer of menses, its use to treat forms such as bee pollen (propolis) preparations. When used as a vulnerary agent, rare allergic reactions and M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 contact irritation have been reported; and it is espe- implicated in contact allergies (Paulsen et al., 1993) and cially to be avoided in ocular preparations (O’Hara et cheilitis induced by use of toothpaste (Hausen, 1984).
al., 1998). Also royal jelly, a thick mixture of honey and In another study when patch testing (Standard Eu- pollen naturally contaminated with pollen allergens has ropean Series) was used to test 20 patients with apht- been repeatedly linked to cases of severe bronchospasm hous stomatitis, a positive reaction to a number of food (Perharic et al., 1993). In Europe, where ragweed is substances were also considered clinically relevant and unknown or uncommon, chamomile was once consid- avoidance of the offending allergens recommend ered safe for use as a tea or in a variety of medications, unless of course one is allergic to the wormwoods It is also possible that inhalation of some of the (Artemisia) of Spain and elsewhere (Subiza et al., 1989) essential oils including lavender, jasmine and rosewood or other Asteraceae (Hausen, 1981, 1996). Recently a used in perfumes or as an ingredient in aromatherapy number of reports from throughout Europe suggest can elicit similar allergic reactions in the nasal passages that sensitization can take place and allergic reactions and respiratory tract, (Schaller and Korting, 1995; Sel- may be manifest systemically (Rodriguez-Serna et al., vaag et al., 1995a; Sugiura et al., 2000). Aromathera- 1998) as dermatitis (Subiza et al., 1989; Paulsen et al., pists may also be at risk of developing dermatitis from 1993; Bossuyt and Dooms-Goossens, 1994; Pereira et continued contact with these oils (Selvaag et al., 1995b).
al., 1997; Foti et al., 2000; Giordano-Labadie et al., Dermatological conditions associated with contact of 2000), or when used in an enema during labor, as fatal allergenic plants and their products have been recently anaphylaxis (Jensen-Jarolim et al., 1998). Recently two reports from Australia regarding Echinacea-inducedanaphylaxis (Mullins, 1998; Myer and Wohlmuth 1998)elicit further concerns regarding the use of asteraceous 9. Dental products
plants in complementary medicine. In this context,contact with feverfew (Tanacetum parthenium) may Adverse effects of dental products containing plant elicit contact dermatitis (Hausen, 1981) and in herbal components are rare, but are worthwhile considering preparations can be contraindicative to those allergic to (Ocasio et al., 1999). These formulations often include other members of the Asteraceae. For example, should, natural sources of calcium carbonate that can vary in a sensitized patient use a feverfew preparation to treat abrasivity, and when derived from seashells may con- headache their condition could be amplified rather than tain high amounts of mercury. It is not unusual for reduced (O’Hara et al., 1998). Also yohimbine has been Asian herbal dentifrices to be packaged in lead tubing reported as causing a lupus-like syndrome (Sandler and and it is unclear how many are still being sold in this Aronson, 1993). Recently a number of adverse reports have been associated with flavonoids used in European Aside from hypersensitivity reactions to flavoring herbal preparations (Ernst, 1998), e.g. cyanidanol elicit- agents that are primarily essential oils, or myrrh that is ing hemolytic anemia (Gandolfo et al., 1992), cirkan often used as a breathe freshener, long-term exposure causing chronic diarrhea (Maechel, 1992), sciadopitysin to other components may elicit more serious effects causing severe nephropathy (Lin and Ho, 1994) and (Elvin-Lewis, 1987, 1989; Elvin-Lewis and Lewis, 1995).
colitis from a phlebotonic French drug, cyclo-3 fort For example, American and Canadian dental products containing Ruscus aculeatus, hersperidin methyl chal- containing blood-root (Sanguinaria canadensis) extract, cone, ascorbic acid (Beaugerie et al., 1994).
frequently promoted by dentists, have recently been Essential oil delayed-hypersensitivity can be related shown to induce a sanguinaria-associated leukoplakia to episodes of aphthous stomatitis (canker sores), when syndrome (hyperorthokeratosis, epithelial atrophy, and other predisposing factors like atopy and stress are in epithelial atypia/mild dysplasia) that in one instance place. In a preliminary study of eight patients with was also contiguous to a squamous cell sarcoma aphthous stomatitis, of 34 essential oils or their compo- (Damm et al., 1999). Although these observations have nents tested, 30 of these substances proved to elicit been vigorously defended as being spurious (Munro et some reactivity in one or more patients, whereas four al., 1999) the fact remains that sanguinaria extract has control patients were unreactive. Using lymphoblastic recently been removed from the Viadent formulation! transformation to test hypersensitivity, a major exciting The flat structure of the alkaloids (sanguinarine and agent was found to be eugenol found in spices (oil of cherylethrine) and their ability to intercalate with DNA cloves), herbs, foods (artichokes), flavorings, cosmetics, were known at the time of formulation 15 years ago fragnances and medicinals. Walnut, anise, dill, pepper- and were predictive of potential carcinogenicity (Cul- mint, caraway, and lavender were also significant elici- venor, 1983a,b). The concern of pyrrolizidine alkaloid tors (Elvin-Lewis et al., 1985) in addition to cashew nut mutagenicity (Yamanaka et al., 1979; Takanashi et al., and its urushiol (Lewis and Elvin-Lewis, 1977). L-car- 1980) was provided to the company but since results of vone in many mint and peppermint oils has also been Ames and other mutagenicity tests were reported as M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 equivocal, the sale of the formulation was allowed. The mice (Rosenkranz and Klopman, 1995; Awasthy et al., company and its ‘Expert Panel’ of advisors (as related 1999). Neem oil, bark and leaf extracts are particularly to me) considered the tingling or irritating sensation bioreactive and are currently being evaluated for a wide reported by some users to be associated with the flavor- range of medicinal uses (Van der Nat et al., 1991), ing agent. They did not consider, as relevant, the fact including hypoglycemic action (Chakraborty and Pod- that users of an African chewing stick, Fagara xan- der, 1984), and because of immunomodulatory effects, thoxyloides containing related alkaloids, also reported also for contraceptive and abortifacient activities similar effects (El-Said et al., 1971). (How this type of (Mukherhee et al., 1996; Talwar et al., 1997a,b). Leaf chronic irritation predisposed to the precancerous le- extracts have also been shown to adversely affect thy- sions is unknown.) While many pharmacognosists, and roid function in mice, (Panda and Kar, 2000). If the myself, continued to be concerned about accumulative ideal neem dentifrice is to be formulated then com- carcinogenic effects, a few considered the amount of the pounds that promote dental health should be retained compounds in the formulations to be of little conse- and others that could potentially elicit adverse effects quence. To date, almost 100 cases of leukoplakia have been reported in long-term users. This has resulted in arecent reformulation of the product and the removal ofthe offending alkaloids. Little is known about the con- 10. Problems associated with long-term use
sequences of use elsewhere in the body, but these arehighly bioreactive alkaloids. It is recognized that dental Today, many herbal remedies are being used prophy- products are swallowed during oral hygiene and that, at lactically to maintain or enhance good health or pre- least with fluoride; they can be absorbed beneficially vent certain conditions from occurring. Since many of into the bones and teeth. It is important to also empha- these herbal medications are popular and promoted as size that there was no ethnodental validation to support both safe and efficacious, it is not always possible for the development of the product in the first place, in the long-term user to understand why this practice spite of claims to the contrary, unless of course one could be harmful. Symptoms can vary from trivial to were to rely on anecdotal information from one horse severe and are particularly disconcerting when they trainer that used blood-root to remove plaque from effect the heart, blood pressure, liver, gastrointestinal tract and nervous or endocrine systems (Table 2). Note- Adverse effects of other popular herbal dental prod- worthy are effects associated with ginseng, golden seal, ucts are unknown. It is prudent to read the labels and milk thistle, cassia, saw-palmetto, valerian, and a vari- be aware of the plant products that they contain since ety of stimulants (D’Arcy, 1993; Anonymous, 1995a; many, especially if claimed to be of Ayurvedic origin, Ernst, 1998; O’Hara et al., 1998) including those that are mixtures of numerous substances with quantities of contain caffeine, like guarana (Paullinia cupana) or each ingredient unrevealed. However, such products mate (Ilex paraguariensis). The latter beverage has also should be avoided if information regarding their ability been implicated in inducing oral cancers (Victora et al., to be locally irritating (a possible predisposing factor 1990), but clear correlative evidence has yet to be for cancer), evoke contact dermatitis, or systemically forthcoming. Another herbal stimulant, Ma Huang, bioreactive is brought forward. This is a concern with containing ephedrine, has been reported to cause hallu- Tea Tree Oil, (Melaleuca alternifolia) found in herbal cinations and paranoia (Anonymous, 1996; Doyle and dental products. It is antiseptic but the oil can be Kargin, 1996). Also anthranoid laxatives such as aloe, locally irritating and elicits contact dermatitis (Knight cascara, rhubarb, and senna, commonly considered as and Hausen, 1994; Blushan and Beck, 1997; Greig et safe, may be a risk factor for colorectal cancer if used al., 1999), vulvovaginitis (Varma et al., 2000), and if on a long-term basis (Siegers et al., 1992). Similarly, ingested is toxic to the central nervous system (Rubel et abuse of these laxatives can increase the loss of serum al., 1998; Bruynzeel, 1999). Neem (Azadirachta indica) K, thereby potentiating the effects of cardiac glycosides used a chewing-stick or as an oil-extract in dental and antiarrhythmic agents (Blumenthal, 2000). The use products might also potentially elicit problems. Neem is of astragulus root (Astragulus membranaceus), a major valued for its antimicrobial and anti-inflammatory ef- immunostimulating herb of Chinese medicine, may be fects and for its ability to ameliorate gingivitis (Elvin- contraindicative when patients are undergoing im- Lewis, in press). However, little is known regarding the munosuppressive therapy (DeSmet and D’Arcy, 1996).
exact nature of the neem components it contains such Also, black cohosh (Cimicifuga racemosa) used for as the highly regarded insecticide and anti-feedent, gynecologic disorders (Liske, 1998) and to treat azadirachtin. Although early Ames tests have been rheumatism, can when taken in large doses or for reported as negative, its structure suggests it may be prolonged periods cause nausea, vomiting and gas- potentially carcinogenic. It is known to elicit disruptive troenteritis (Saxe, 1987). Similar conditions have also changes in metaphase chromosomes in both insects and been reported for blue cohosh (Caulophyllum thalic- M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Table 3Hepatotoxicity related to herbal remedies Senecio, Crotalaria, Symphytum, Winship, 1991; Hill et al., 1951; Bras et al., 1954; Fox et al., 1978; Lyford et al., Mentha puleguim, Hedeoma pulegoides Sullivan et al., 1979; Anderson et al., 1996 Larrey et al., 1992; World Health Organization, 1992; D’Arcy, 1993 Anonymous, 1993a,b; Horowitz et al., 1996 Georgiou et al., 1988; Stickel et al., 2000; Hamouda et al., 2000 Segelman et al., 1976; Liu et al., 1999; Burkey et al., 2000 Nordihydroguair- Larrea tridentata (chaparral) Anonymous, 1992; Sheikh et al., 1997; Batchelor et al., 1995 troides) (Saxe, 1987), in addition to adverse effects to heinous are particularly harmful to the liver and lungs, the newborn when used to promote labor (Jones and causing veno-occlusive disease (Winship, 1991). While the disease is relatively rare in the US and is usuallyrelated to the consumption of herbal remedies (Sprang,1989) mass human poisonings have occurred elsewhere 11. Effects on internal organs
from ingestion of seeds with these alkaloids contami-nating cereal crops (Chauvin et al., 1994; Drew and Detoxification and clearance of poisonous substances Myers, 1997). Abdominal pain, vomiting, and the de- from the body are primarily a function of the liver and velopment of ascites characterize this condition. Pa- kidneys and they are often the first to be affected by tients may recover if the alkaloid intake is discontinued toxic herbs (Larrey, 1994; DeSmet et al., 1996; Kaplow- and the liver damage not too severe, otherwise death itz, 1997; Nortier et al., 1999; Stickel et al., 2000).
can follow. In Jamaica, for example, endemic veno-oc- Sometimes the causes are more obtuse, as when kava clusive disease, has been linked to the consumption of user developed a necrotizing hepatitis (Strahl et al., Senecio or Crotalaria spp. as ‘ bush teas’ (Hill et al., 1998), but not the usual ‘kava dermatology’ of yellow 1951; Bras et al., 1954). Comfrey teas have now been and scaling skin associated with long-term use (Ruze, banned in the US due to this serious side effect (Ridker, 1990). Equally perplexing are the number of cases of 1989). Some, like chaparral tea for example, should be acute hepatitis following the use of greater celadine avoided during cancer treatments or when underlying (Chelidonium majus) for treating biliary and gastric diseases of the liver are known. A retrospective study disorders (Benninger et al., 1999), or the one case of on adverse effects of herbal medicines by the National necrotizing hepatitis possibly associated with use of Poisons Unit (London) led the authors (Perharic et al., ‘lesser or common celidine’ (Strahl et al., 1998). Simi- 1994) to recommend that routine liver function tests be larly, May apple (Podophyllum peltatum) used as a liver done on individuals using Chinese herbal remedies.
tonic has been found to cause nausea, vomiting, inflam- This is important since so many cases of liver damage mation and edema of the bowel, diarrhea, elevated liver leading to acute liver failure have been associated with enzymes and hematologic abnormalities (Saxe, 1987).
the use of Chinese herbal remedies for the treatment of Table 3 lists some of these or other herbs most prob- skin disorders (Shaw et al., 1997; Armstrong and Ernst, Over 100 hepatotoxic pyrrolizidine alkaloids are Care should also be taken when using herbal medica- found within species of the Asteraceae, Borginaceae, tions to treat cardiovascular problems (Mashour et al., and Fabaceae. Such plants are consumed as food, for 1998). While some may be worthwhile, many contain medicinal purposes, or as contaminants of other agri- natural cardiac glycosides, blood thinners, or affect cultural crops (FDA/CFSAN AEMS Search Results, blood pressure and are not only bioreactive on their 2000). Pyrrolizidine alkaloids and others, equally own but can work with prescribed medications to po- M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 tentiate or diminish their action (Catania, 1998). For These events are more likely due to adulterants in the example, ginger contains a potent inhibitor of throm- formulations, to unknown interactions in complex mix- boxan synthetase (Backon, 1986) that prolongs bleeding tures, as a result of undisclosed pharmaceutical interac- time. According to Miller (1998) its use could result in tions, to inappropriate dosage or use, or to underlying adverse implications for pregnant patients or those on factors associated with the specific patient (O’Hara et al., 1998; FDA/CFSAN AEMS Search Results, 2000).
nonetheless, that ginger is still a favored remedy to A variety of serious reactions due to use alone, with treat nausea from morning or motion sickness. Fever- other herbal medications, or with pharmaceutical drugs few (Tanacetum parthenium) has the potential of poten- have been recorded and include effects on coagulation tiating platelet inhibitors and its use as a headache by feverfew (Murphy, 1999), garlic ginger, and ginkgo remedy should be avoided during therapy with blood- and antagonistic effects of ephedra. Noteworthy is the thinning agents (O’Hara et al., 1998). It is also recom- immunosuppression that can be induced by long-term mended that heparin-like herbs not be taken during Echinacea used for immune stimulation. Photosensitiv- pregnancy or lactation, since cranial bleeding or other ity that is associated with St. John’s wort (Hypericum associated effects could be induced in the fetus or perforatum) and Psoralea corylifolia (an ingredient in several Chinese herbal formulations) (Maurice and Ratanasir, 1992; Pansatinkul and McKnanee, 1993). A Cream, 1989) is considered rare (Blumenthal et al., number of cases of allergy and anaphylactic shock 1998). However, according to one herbalist that has (Jaspersen-Schib et al., 1996) and one case of hepatic observed this reaction in a number of St John’s wort injury (Takegoshi et al., 1986) have been associated users (Cathy Crandall, personal communication) this with the use of horse chestnut species to treat chronic phenomenon may be under-reported. Also, St John’s venous insufficiency (Ernst, 1999) (Table 4).
wort interacts with some anesthetic agents and resultsin eliciting mild monamine oxidase inhibition (MAOI),or selectively inhibits serotonin uptake (SSRI) (Mur- 12. Effects under predisposing conditions
phy, 1999). Ginseng, while considered GRAS, has alsobeen reported to elicit a wide range of adverse condi- Patients taking herbs for various purposes may also tions, and should be avoided with other stimulants and predispose themselves to unwanted conditions prior to particularly it should not be used by patients with surgery, when pregnant, if atopic, or under treatment cardiovascular disease due to its effect on blood pres- for other conditions, including those that require psy- sure and heartbeat (chronotrophic effect), and its abil- choactive medications. Deaths due to medication of generally recognized ‘as safe’ herbs are extremely rare.
hypertensive effects and can potentiate the activity of Table 4Cardiovascular herbal treatments, adverse reactions Jaspersen-Schib et al., 1996; Takegoshi et al., Headache, nausea, hiccups, diminished efficacy of other cardiovascular drugs including diltiazemand propranolol Potentiates digitalis activity, increases coronary ESCOP, 1997, 1999; Upton, 1999; Tyler, 1994; dilatation effects of theophylline, caffeine, papaverine, sodium nitrate, adenosine andepinephrine, increase barbituate induced sleepingtimes Sedation, inability to complete tasks, mental depression, nasal congeston, increased gastric Chan et al., 1995; Izzat et al., 1998; Yu et al., Hypotension in cancer patients in treatment M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 digitalis and thiazide diuretics (Cugini et al., 1983; renal fibrotic syndrome (Vanherweghem et al., 1993). In Blumenthal, 2000; Olukoga and Donaldson, 2000; Shi- some cases Aristolochia fangchi was incriminated. The bata, 2000). Influences on thyroid function can vary; same type of renal failure was associated with 12 Chi- for example, kelp used for weight loss can induce nese in Taiwan using a variety of traditional Chinese hyperthyroidism (DeSmet et al., 1990) whereas, use of herbal preparations (Yang et al., 2000) and two others horseradish remedies can result in hypothyroidism in the UK (Lord et al., 1999). In two cases in Japan, (D’Arcy, 1993). Valerian (Valeriana officinalis) is Fanconi syndrome involved the use of the Chinese known to potentiate the sedation or excitation effects of medicine, Kanmokutsu containing A. manshuriensis certain sedatives or anxiolytics, respectively (Miller, (Tanaka et al., 2000). This syndrome may also be 1998; Murphy, 1999). While considered GRAS, vale- associated with the development of overt transitional rian has also been reported in rare cases to elicit cell carcinoma (TCC) (Cosyns et al., 1999). In Taiwan, headache, palpitations, insomnia (O’Hara et al., 1998), bronciolitis obliterans (rapidly progressive respiratory pruritis, anorexia, hepatitis and intoxication (FDA/CF- distress) was related to the consumption of uncooked SAN AEMS Search Results, 2000). Use of Devil’s Claw vegetable juice of Sauropus androgynus in guava or (Harpagophytum procumbens) for anorexia, dyspepsia pineapple juice (Lai et al., 1996). Used in a weight and degenerative disorders of the locomotor system are control formulation for 10 weeks, 23 individuals were contraindicated in individuals with gastric and duode- nal ulcers or with individuals with gallstones (Blumen-thal et al., 1998). Arsenic has been found to anadulterant in a variety of herbal formulations (FDA/ 14. Drug and herbal interactions
CFSAN AEMS Search Results, 2000) and in kelp hasbeen reported to cause autoimmune thrombocytopenia Numerous examples exist of drug and herbal interac- tions. These effects may potentiate or antagonize drugabsorption or metabolism, the patient’s metabolism, orcause unwanted side-reactions such as hypersensitivity 13. Effects of slimming agents
(Brinker, 1997; Cupp, 1999; Blumenthal, 2000). Sucheffects may also impinge on pharmaceutical product Natural slimming agents can also be problematical as interactions occurring concurrently with those elicited has been found for guar gum that has elicited severe by herbal use (Aslam and Stockley, 1979; Jankel and adverse obstructions of the bowel and esophagus, par- Speedie, 1990). Care should be taken to understand ticularly among those with esophageal abnormalities effects of foods (Williams et al., 1993; Kane and Lip- (Opper et al., 1990; Seidner et al., 1990) that in one sky, 2000) or herbal remedies during anti-coagulant instance was fatal (Lewis, 1992a). The presence of therapy, in the treatment of diabetes, depression, pain, sparteine in a variety of herbal remedies used for slim- asthma, the heart, blood pressure, and for slimming. By ming and diabetes has been reported to cause circula- way of illustration, the high content of vitamin K in a tory collapse, respiratory arrest (Galloway et al., 1992) variety of green vegetables, particularly broccoli and and classic anticholinergic effects (Tsiodras et al., other Brassicaceae, can in large amounts, be antagonist 1999). Also, because of its oxytoxic effects sparteine- to the effects of anti-coagulant therapy (D’Arcy, 1993).
containing herbals would be contraindicative for use in In addition, grapefruit juice, can lead to the elevation pregnancy (Bensousan and Meyers, 1996). Blossoms of of serum concentrations of a variety of medications like germander (Teucrium chamaedrys) in herbal teas or cyclosporine, some 1,4-dihydropyridine calcium antago- capsules to treat obesity have been shown to cause nists, and some 3-hydroxy-3-methyglutaryl coenzyme A acute hepatitis (Larrey et al., 1992). A patient taking reductase inhibitors (Kane and Lipsky, 2000). Also, warfarin and using papaya extract (containing papain) unwanted side-effects like gynaecomastia can occur for slimming was shown to have an increased interna- with ginseng and rauwolfia with a variety of medica- tions, hallucinations with cinnamon and tetracycline, prothrombin time was only restored to normal follow- sedative effects with valerian or passion flower and ing withdrawal of both substances (Shaw et al., 1997).
anti-histamines, elevated blood pressure with thizidine Aristolochia species have been responsible for disorders diuretic and Ginkgo biloba and seizures may even be referred to as Chinese herb nephropathy (CHN) (Van- increased if evening primrose is taken in addition to haelen et al., 1994) or Fanconi syndrome in Japan, and phenothiazines (Newall et al., 1996; Shaw et al., 1997).
Tanaka et al. (2000) suggests that differences in clinical Similarly, the Ayurvedic remedy ‘Sankhapushpi’ con- presentation may be due to the amount or type of taining Centella asisatica, Con6ol6ulus pluricaum, Nar- aristolochic acids ingested. For example, in Belgium, a dostachys jatamansi, Nepeta ellipica, Nepeta hindostana variety of Chinese herbal remedies use for slimming and Onosma bracteatum reduced plasma levels of purposes were linked to a rapidly progressive interstitial phenytoin, given concurrently, and resulted in the loss M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 McDermott, 1989; McDermott andRidker, 1990 of seizure control (Dandekar et al., 1992) (Table 5). In where, can be life-threatening or fatal (Chauvin et al., addition, when St John’s wort (Hypericum perforatum) 1994; Drew and Myers, 1997). While adulterations re- is used simultaneously with a wide variety of drugs that lated to Asian medicines have already been reviewed, it use CYPEA4 as a substrate, activity is lowered since is noteworthy that misidentification of plants has re- this herb is considered to increase the activity of the sulted in a number of other serious events primarily due isoenzyme CYPEA4 (Blumenthal, 2000). Salicin-con- to poisonings with digitalis (often mistaken for com- taining oils and herbal medications have been known to frey), belladonna and skullcap (Table 6).
elicit adverse conditions. For example, accidental inges-tion by an infant of oils of wintergreen, camphor andeucalyptus caused generalized seizures (Malik et al.,1994) and use of an herbal medication, massive hemol- 16. Conclusion
ysis (Baker and Thomas, 1987). Theoretically salicincontaining herbs and salicylates, like aspirin, could Overall, when compounded and prescribed appropri- interact and potentiate their activity, although no re- ately the safety of traditional herbal medications is port has yet to appear in the literature (Blumenthal, high. It is generally recognized that life-threatening 2000). Also patients undertaking anti-coagulant therapy events are rare, compared to the hundreds of thousands should be warned against eating large amounts of green reported for pharmaceutical products each year. This is vegetables like broccoli and others high in vitamin K due, in part, to the moderate bioreactivity that is im- parted by most herbal preparations and the knowledgethat is known regarding parameters of use. Althoughlinkage to some adverse effects may not be discovered,since problems are likely to be under reported, it is 15. Adulterations
reasonable to assume that there is a wide margin ofsafety for many popular remedies. There are always Adulterations in herbal remedies are particularly dis- risks when appropriate regulations do not mandate the concerting since they occur so unexpectedly. Usually appropriate formulation of the remedies, or when self- they remain undetected unless they can be linked to an medication fosters abuse. While it is assumed that most outbreak or epidemic. In this respect veno-occlusive practitioners of herbalism conduct their activities in a disease due to pyrrolizidine alkaloids, discussed else- conscientious and ethical manner, it is difficult to know M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 if their skills can match the challenge of dealing with the problem at hand. Moreover, it must be appreciated that most allopathic practitioners have little knowledge Be informed, seek out unbiased, scientific sources of the fundamental premises of herbalism or how its practice might impact on their diagnostic decisions and Inform your allopathic physician of self-medication regimens treatments. Clearly promoting appropriate education at Be aware that an allopathic physician’s knowledge of herbal medical schools and through continuing education Know benefits and risks and potential side effects courses can remedy this situation. Hopefully this will Read labels carefully, do not exceed recommended dose ranges generate respect for aspects of healing utilizing certain plant remedies that are not generally apart of allopathic Take care when giving to childrenTake care when giving to the elderly However, to aid in the identification of potential adverse effects, allopathic clinicians should always question their patients about their alternative medicinal Know your source, formulator or manufacturer practices, including herbal use. This should be done in Select standardized formulationsUnderstand that batch-to-batch variations of the formula may the context of understanding its meaning to the patient and the implications that it might have to his or her To avoid misidentification, do not collect plants yourself total well-being. Eisenberg (1997) has recommended Make sure packaging is appropriately labeled with contents that this strategy include ‘a formal discussion of pa- Make sure that labeling includes scientific namesStore appropriately to prevent loss of potency tient’s preferences and expectations, the maintenance ofsymptom diaries, and follow-up visits to monitor forpotentially harmful situations’. This is important since law is very restrictive regarding what can be put on a a national survey conducted by him and others (Eisen- label and because of the description of the use that is berg et al., 1998; Barrett et al., 1999) on trends in implied, can often be misleading. Also, when authors of alternative medicine in the United States between 1990 booklets, pamphlets or package-inserts, or personnel and 1997 was particularly revealing. It showed that at selling the products lack appropriate credentials one least a third of patients used unconventional therapy, has to be wary of claims that are being made. In these and the majority of these did so for chronic conditions.
instances it is always possible that fact and misinforma- These same patients also sought treatment from allo- tion are being mixed together for other than altruistic pathic practitioners, but were unlikely to inform their reasons. Further, perspective herbal users must be con- medical doctor of other treatments they were undertak- scious that these medicines are usually formulated from ing. In this context, the following guidelines related to raw materials and as such contain a wide range of temporal associations of herbal use may be useful when substances that can vary both in pharmacokinetic and adverse effects are suspected (Table 7). It is essential pharmacognostic capabilities. It is important to empha- that anyone considering taking herbal medications size that some well known foods can also potentiate or must be well informed and not rely on unfounded antagonize pharmaceutical treatments and thus their claims found in other than scientific literature. It should use should be restricted under certain conditions (Per- be emphasized that even within the context of medical haric et al., 1993, 1994). The notion that ‘natural is journals, observations reported as ‘Letters to the Edi- safe’ has little meaning in reality unless, of course, one tor’ are likely to be perpetuated as fact until proven puts into the same context the idea that ‘pharmaceuti- otherwise by subsequent clinical evaluations (Anderson cally derived’ is not always totally beneficial. Table 8 et al., 1998; Goodwin and Tangum, 1998). Current US illustrates guidelines for rational herb use and followsmany of those recommendations of Murphy (1999), Practitioners may recognize acute symptoms of toxicity but are References
unlikely to link effects associated with hepatotoxicity,teratogenicity or carcinogenicity to use Akerele, O., 1993. Summary of WHO guidelines for the assessment of Temporal association between exposure and effect herbal medicines. Herbalgram 26, 13 – 20.
Disappearance of effect after product discontinued Almeida, J.C., Grimsley, E.W., 1996. Coma from the health food Reappearance of effect when product re-introduced store, interaction between kava and alprazolam. Annals of Inter- Association of product use and interactions with medicines Occupational chemicals, and recreational drugs Anderson, I.B., Mullen, W.H., Meeker, J.E., Khojasteh-Bakht, C., Association with underlying disease states considered Oishi, S., Nelson, S.D., Blanc, P., 1996. Pennyroyal toxicity, Association of exposure and effects known in scientific literature measurement of toxic metabolite levels in two cases and review ofthe literature. Annals of Internal Medicine 124, 726 – 734.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Anderson, I.B., Mullen, W.H., Meeker, J.E., Khojasteh-Bakht, S.C., Bensousan A., Meyers, S.P., 1996. Towards a safer choice. The Oishi, S., Nelson, S.D., Angell, M., Kassirer, J.P., 1998. Alterna- practice of traditional Chinese medicine in Australia, Department tive medicine — the risks of untested and unregulated remedies.
The New England Journal of Medicine 339, 839 – 841.
Benzi, G., Ceci, A., 1997. Herbal medicines in European regulation.
Angell, M., Kassirer, J.P., 1998. Alternative medicine — the risks of Pharmaceutical Research 33, 355 – 362.
untested and unregulated remedies. The New England Journal of Blumenthal, M., Busse, W.R., Goldberg, A., Gruenwald, J., Hall, T., Medicine 339, 839 – 841 Editorial.
Riggins, C.W., Rister, R.S., (eds.) Klein, S., Rister, R.S., (trans), Anonymous, 1989. Epidemiologic notes and reports cadmium and 1998. The Complete German Commission E Monographs, Thera- lead exposure associated with pharmaceutical imported from Asia peutic Guide to Herbal Medicines. Klein S., Rister R.S., transla- — Texas. Morbidity and Mortality Weekly Reports 38, 612 – 614.
Anonymous, 1992. Chaparral-induced toxic hepatitis — California American Botanical Council, Boston (MA).
and Texas. Morbidity and Mortality Weekly Reports 41, 812 – Blumenthal, M., 1999. Monograph update, WHO publishes herbal monographs; ABC, AHP, ESCOP and USP continue monograph Anonymous, 1993a. Jin Bu Huan toxicity in Adults — Los Angelos publication. Herbalgram 47, 40 – 45.
Morbidity and Mortality Weekly Reports 42, 920 – 922.
Blumenthal, M., 2000. Interactions between herbs and conventional Anonymous, 1993b. Epidemiologic notes and reports Jin Bu Huan drugs, introductory considerations. Herbalgram 49, 52 – 63.
toxicity in children — Colorado. Morbidity and Mortality Blushan, M., Beck, M.H., 1997. Allergic contact dermatitis from tea tree oil in a wart paint. Contact Dermatitis 36, 117 – 118.
Anonymous, 1995a. Self-treatment with herbal and other plant- Boehnert, K.J., 1997. The use of Vitex agnus – castus for hyperpro- derived remedies — rural Mississippi, 1993. Morbidity and Mor- lactinemia. In: Brown, D.J. (Ed.), Quarterly Review Natural tality Weekly Reports 44, 204 – 207.
Medicine. Seattle (WA) Natural Product Research Consultants, Anonymous, 1995b. Anticholinergic poisoning associated with an herbal tea — New York City, 1994. Morbidity and Mortality Borchers, A.T., Hackman, R.M., Keen, C.L., Stern, J.S., Gershwin, M.E., 1997. Complementary medicine, a review of immunomodu-latory effects of Chinese herbal medicines. American Journal of Anonymous, 1996. Adverse events associated with ephedrine-contain- Clinical Nutrition 66, 1302 – 1312.
ing products — Texas, December 1993 – September 1995. Morbid- Borins, M., 1998. The dangers of using herbs. Postgraduate Medicine ity and Mortality Weekly Reports 45, 689 – 692.
Armstrong, N.C., Ernst, E., 1999. The treatment of eczema with Bossuyt, L., Dooms-Goossens, A., 1994. Contact sensitivity to nettles Chinese herbs, a systematic review of randomized clinical trials.
and camomile in ‘alternative’ remedies. Contact Dermatitis 31, British Journal of Clinical Pharmacology 48, 262 – 264.
Aslam, M., Stockley, I.H., 1979. Interaction between curry ingredient Bras, G., Jelliffe, D.B., Stuart, K.L., 1954. Veno-occlusive disease of (karela) and drug (chlorpropamide). Lancet 1, 607 Letter.
liver with nonportal type of cirrhosis, occurring in Jamaica.
Atal, C.K., Dubey, R.K., Singh, J., 1985. Biochemical basis of Archives of Pathology 57, 285 – 300.
enhanced drug bioavailability by piperine, evidence that piperine Brevoort, P., 1998. The booming US botanical market, a new is a potent inhibitor of drug metabolism. Journal Pharmacology overview. Herbalgram 44, 33 – 446.
and Experimental Therapeutics 232, 258 – 262.
Brinker, F. 1997. Herb Contraindications and Drug Interactions.
Awasthy, K.S., Chaurasia, O.P., Sinha, S.P., 1999. Prolonged murine genotoxic effects of crude extracted from neem. Phytotherapy Brunton, L.L., 1996. Agents affecting gastrointestinal water flux, emesis and antiemetics, bile acids and pancreatic enzymes. In: Bach, N., Thung, S.N., Schaffner, F., 89. Comfrey herb tea-induced Hardman, J.G., Limbird, L.E., Monlnoff, P.B., et al. (Eds.), hepatic veno-occlusive disease. American Journal of Medicine Goodman and Gilman’s The Pharmaceutical Basis of Therapeu- tics, 9th. McGraw-Hill Book Company, New York, NY, pp.
Backon, J., 1986. Ginger, inhibition of thromboxane synthetase and stimulation of prostacyclin, relevance for medicine and psychiatry.
Bruynzeel, D.P., 1999. Contact dermatitis due to tea tree oil. Tropical Medicine and International Health 4, 630.
Bano, G., Raina, R.K., Zutshi, U., Bedi, K.L., Johri, R.K., Sarma, Buchness, M.R., 1998. Alternative medicine and dermatology. Semi- S.C., 1991. Effect of piperine on bioavailability and pharmacoki- nars in Cutaneous Medical Surgery 17, 284 – 290.
netics of propranolol and theophylline in healthy volunteers.
Burkey, J.L., Sauer, J., McQueen, C.A., Glenn Sipes, I., 2000.
European Journal of Clinical Pharmacology 41, 615 – 617.
Cytotoxicity and genotoxicity of methyleugenol and related con- Barrett, B., Kiefer, D., Rabago, D., 1999. Assessing the risks and geners — a mechanism of activation for methyleugenol. Mutata- benefits of herbal medicine, an overview of scientific evidence.
Alternative Therapies in Health and Medicine 5, 40 – 49.
Cahill, D.J., Fox, R., Wardle, P.G., Harlow, C.R., 1994. Multiple Baskaran, K., Kizar Ahamath, B., Radha Shanmugasundaram, K., follicular development associated with herbal medicine. Human Shanmugasundaram, E.R., 1990. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependant dia- Caldwell, S.H., Feeley, J.W., Wieboldt, T.F., Featherston, P.L., betes mellitus patients. Journal Ethnopharmacology 30, 295 – 305.
Dickson, P.C., 1994. Acute hepatitis with use of over-the-counter Batchelor, W.B., Heathcote, J., Wanless, I.R., 1995. Chaparral-in- herbal remedies. Virginia Medical Quarterly 121, 21 – 33.
duced hepatic injury. American Journal of Gastroenterology 90, CAM (Complementary and Alternative Medicine at NIH), 2000.
Bateman, J., Chapman, R.D., Simpson, D., 1998. Possible toxicity of Catania, P.N., 1998. Problems with herbal remedies in anticoagulated herbal remedies. Scottish Medical Journal 43, 7 – 15.
home care patients. Home Care Provider 3, 253 – 255.
Beaugerie, L., Luboinski, J., Brusse, N., 1994. Drug induced Chan, Y.K., 1997. Monitoring the safety of herbal medicines. Drug lymphocytic colitis. Gut 35, 426 – 428.
Benninger, J., Schneider, H.T., Schuppan, D., Kirchner, T., Hahn, Chan, Y.K., Chan, J.C.N., Tomlinson, B., Critchley, J.A.J.H., 1993.
E.G., 1999. Acute hepatitis induced by greater celandine (Chelido- Chinese herbal medicines revisited, a Hong Kong perspective.
nium majus). Gastroenterology 117, 1234 – 1237.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Chan, K., Lo, A.C., Yeung, J.H., Woo, K.S., 1995. The effects of DeSmet, P.A.G.M., D’Arcy, P.F., 1996. Drug interactions with Dansen (Sal6ia, miltiorrhiza) on warfarin enantiomers in rats.
herbal and other non-orthodox remedies. In: D’Arcy, P., McEl- Journal of Pharmacy and Pharmacology 47, 402 – 406.
nay, J.C., Welling, P.G. (Eds.), Mechanisms of Drug Interactions.
Chakraborty, T., Podder, G., 1984. Herbal drugs in diabetes – Part Springer-Verlag, New York, pp. 327 – 352.
1: Hypoglycemic activity of indigenous plants in Streptozotocin DeSmet, P.A.G.M., Stricker, B.H.C., Wilderink, F., Wiersinga, (STZ) induced diabetic rats. Journal of the Institute of Chemists W.M., 1990. Hyperthyreoı¨dı¨e tijdens her gebruik van kelpt- abletten. Nederlands Tijdschrift voor Geneeskunde 134, 1058 – Chauvin, P., Dillon, J.C., Moren, A., 1994. An outbreak of He- liotrope food poisoning, Tadjikistan, November 1992 – March DeSmet, P.A.G.M., Keller, K., Hansel, R., Chandler, R.F., 1992a.
Adverse Effects of Herbal Drugs I and II. Springer-Verlag.
Cheng, T.O., 2000. Interaction of herbal medicine with Coumadin.
DeSmet, P.A., Keller, K., Hansel, R., Chandler, R.F., 1996. In: Journal of Emergency Medicine 18, 122.
Pharmaceutical of the World Health Organization, R (eds.), Ad- Commission E Monographs — Therapeutic Guide to Herbal verse Effects of Herbal Drugs, Volume 3, Springer-Verlag, New Medicines. Austin, TX. American Botanical Council, Boston, MA, Integrative Medicine Communications.
DeSmet, P.A.G.M., Van den Eertwegh, A.J., Lesterhui, W., Stricker, Consumer Reports, 1995. Herbal roulette. November, 698 – 705.
B.H., 1997. Hepatotoxicity associated with herbal tablets. British Cosyns, J.P., Jadoul, M., Squifflet, J.P., Wese, F.X., van Ypersele de Strihou, C., 1999. Urothelial lesions in Chinese-herb nephropathy.
Donaldson, K., 1998. Introduction to the healing herbs. ORL Head American Journal of Kidney Diseases 33, 1011 – 1017.
Cugini, P., Gentile, R., Zard, A., Rocchi, G., 1983. Hypertension in Doyle, H., Kargin, M., 1996. Herbal stimulant containing ephedrine licorice abuse. A case report. Giornale Italiano di Cardiologia 13, has also caused psychosis. British Medical Journal 313, 756.
Culvenor, C.C.J., 1983a. Estimated intakes of pyrrolizidine alkaloids Drew, A.K., Myers, S.P., 1997. Safety issues in herbal medicine, by humans. A comparison with dose rates causing tumors in rats.
implication for the health professions. Medical Journal of Aus- Journal of Toxicology and Environmental Health 11, 625 – 635.
Culvenor, C.C.J., 1983b. Estimated intakes of pyrrolizidine alkaloids Eisenberg, D.M., 1997. Advising patients who seek alternative medi- by humans. A comparison with dose rates causing tumors in rats.
cal therapies. Annals of Internal Medicine 127, 61 – 69.
Journal of Toxicology and Environmental Health 11, 625 – 635.
Eisenberg, D.M., Davis, R.B., Ettner, S.L., Wilkey, S., Van Rompay, Cupp, M.J., 1999. Herbal remedies, adverse effects and drug interac- M., Kessler, R.C., 1998. Trends in alternative medicine use in the tions. American Family Physician 59, 1239 – 1245.
United States, 1990 – 1997, results of a follow-up national survey.
D’Arcy, P.F., 1991. Adverse reactions and interactions with herbal Journal of the American Medical Association 280, 1569 – 1575.
medicines, I, adverse reactions. Adverse Drug Reaction and Toxi- El-Said, M., Fadulu, S.O., Juye, J.O., Sofowara, E.-A., 1971. Native cures in Nigeria. II The antimicrobial properties of buffered D’Arcy, P.F., 1993. Adverse reactions and interactions with herbal extracts of chewing sticks. Lloydia 34, 172 – 174.
medicines. Part 2 — drug interactions adverse drug reactions and Elvin-Lewis, M., I n Press. Neem, From ethnodentistry to dental toxicological reviews 12, 147 – 162.
products, A review of its antiodontopathic potential. Proceedings Dalen, J.E., 1998. ‘Conventional’ and ‘Unconventional’ Medicine.
Archives of Internal Medicine 158, 2179 – 2218.
Elvin-Lewis, M., 1987. Medicinal plants in dentistry, keynote address.
Dalvi, S.S., Nayak, V.K., Pohujani, S.M., Desai, N.K., Kshirsagar, In: Saxena, R.C., Gupta, T.K. (Eds.), Proceedings of the Interna- N.A., Gupta, K.C., 1994. Effect of gugulipid on bioavailability of tionational Seminar on Clinical Pharmacology in Developing diltazem and propranolol. Journal of the Association of Physi- Elvin-Lewis, M., 1989. Development of phytochemicals for dental Damm, D.D., Curran, A., White, D.K., Drummond, J.F., 1999.
use. in Proceedings 1st Congress of the Asian Federation of Leukoplakia of the maxillary vestibule — an association with Clinical Pharmacognisists (1988). Asian Federation Clinical Phar- Viadent? Oral Surgery, Oral Medicine, Oral Pathology, Oral macologists, Process and Production, Lucknow, pp. 66 – 70.
Radiology, Endodontics 87, 61 – 66.
Elvin-Lewis, M., Lewis, W.H., 1995. New concepts and medical and Dandekar, U.P., Chandra, R.S., Dalvi, S.S., Joshi, M.V., Gokhale, dental ethnobotany. In: Schultes, R, Von Reis, S. (Eds.), Ethnob- P.C., Sharma, A.V., Shah, P.U., Kshirsagar, N.A., 1992. Analysis otany, evolution of a discipline. Dioscordes Press, Portland, pp.
of a clinically important interaction between phenytoin and Shankhapushpi, an ayurvedic preparation. Journal of Ethnophar- Elvin-Lewis, M., Hamiolos, D., El-Najdawi, E., Wedner, H.J., 1985.
Essential oil hypersensitivity in apththous stomatitis patients.
Datta, D.V., Khuroo, M.S., Mattocks, A.R., Aikat, B.K., Chhuttani, P.N., 1978. Herbal medicines and veno-occlusive disease in India.
Ernst, E., 1998. Harmless herbs? A review of the recent literature.
Postgraduate Medical Journal 54, 511 – 515.
The American Journal of Medicine 104, 170 – 178.
DeSmet, P.A.G.M., 1992b. Drugs used in non-orthodox medicine. In: Ernst, E., 1999. Herbal medications for common ailments in the Dukes, M.N.G. (Ed.), Side Effects of Drugs, 12th. Elsevier, elderly. Drugs Aging 15, 423 – 428.
ESCOP, European Scientific Cooperative on Phytotherapy. ESCOP DeSmet, P.A.G.M., 1993. An introduction to herbal pharmacoepi- monographs on the medicinal uses of plant drugs. Exeter, UK, demiology. Journal of Ethnopharmacology 38, 197 – 208.
DeSmet, P.A.G.M., 1995a. Health risks of herbal remedies. 1995 ESCOP, European Scientific Cooperative on Phytotherapy. ESCOP monographs on the medicinal uses of plant drugs. Exeter, UK, DeSmet, P.A.G.M., 1995b. An introduction to herbal pharacoepi- demiology. Journal of Ethnopharmacology 38, 197 – 208.
Faber, P., Strenge-Hess, A., 1988. Relevance of rhein excretion into DeSmet, P.A.G.M., 1997. The role of plant-derived drugs and herbal breast milk. Pharmacology 1 (36), 212 – 220 Supplement.
medicines in healthcare. Drugs 54, 801 – 840.
FDA/CFSAN AEMS Search Results, US Food and Drug Adminis- DeSmet, P.A.G.M., Brouwers, J.R.B.J., 1997. Pharmacokinetic eval- tration, Center for Food Safety and Applied Nutrition, Office of uation of herbal remedies. Clinical Pharacokinetics 32, 427 – 436.
Special Nutritionals, October, 2000.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Foti, C., Nettis, E., Panebianco, R., Cassano, N., Diaferio, A., Pia, Jaspersen-Schib, R., Theus, L., Guirguis-Oeschger, M., Gossweiler, D.P., 2000. Contact urticaria from Matricaria chamomilla. 2000 B., Meie Abt, P.J., 1996. Schweizerische medizinische wochen- schrift. Journal Suisse de Medecine 126, 1085 – 1098.
Fox, D.W., Hart, M.C., Bergeson, P.S., Jarret, P.B., Stillman, A.E., Jensen-Jarolim, E., Reider, N., Fritsch, R., Breiteneder, H., 1998.
Huxtable, R.J., 1978. Pyrrolizidine (Senecio) intoxication mimick- Fatal outcome of anaphylaxis to camomile-containing enema ing Reye syndrome. Journal of Pediatrics 90, 980 – 982.
during labor: a case study. Journal of Allergy Clinical Immunol- Galloway, J.H., Farmer, K., Weeks, G.R., Marsh, I.D., Forrest, A.R., 1992. Potentially hazardous compound in a herbal slimming Jones, T.K., Lawson, B.M., 1998. Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal Gandolfo, G.M., Girrelli, G., Conti, L., 1992. Hemolytic anemia and medication. Journal of Pediatrics 132, 550 – 552.
thrombocytopenia induced by cyanidanol. Acta Haematologica Kanba, S., Yamada, K., Mizushima, H., Asai, M., 1998. Use of herbal medicine for treating psychiatric disorders in Japan. Psy- Georgiou, M., Sianidou, L., Hatzis, T., Papadatos, J., Koutselinis, chiatry and Clinical Neurosciences 52, S331 – S333 Suppl.
A., 1988. Hepatotoxicity due to Atractylis gummifera-L. Journal Kane, G.C., Lipsky, J.J., 2000. Drug-grapefruit juice interactions.
of Toxicology and Clinical Toxicology 26, 487 – 493.
Mayo Clinic Proceedings 75, 933 – 942 Review.
Gertner, E., Marshall, P.S., Filandrinos, D., Potek, A.S., Smith, Kaplowitz, N., 1997. Hepatotoxicity of herbal remedies, insights into T.M., 1995. Complications resulting from the use of Chinese the intricacies of plant – animal warfare and cell death. Gastroen- herbal medications containing undeclared prescription drugs.
Arthritis and Rheumitism 38, 614 – 617.
Kassler, W.J., Blanc, P., Greenblatt, R., 1991. The use of medicinal Ghani, A., Eriksson, M., Kristiannsson, B., Qirbi, A., 1987. The influence of khat-chewing on birth-weight in full-term infants.
Archives of Internal Medicine 151, 2281 – 2288.
Social Science and Medicine 24, 625 – 627.
Kew, J., Morris, C., Aihie, A., Fysh, R., Jones, S., Brooks, D., 1993.
Giordano-Labadie, F., Schwarze, H.P., Bazex, J., 2000. Allergic Arsenic and mercury intoxication due to Indian ethnic remedies.
contact dermatitis from amomile used in phytotherapy. Contact British Medical Journal 306, 506 – 507.
Kim, J.Y., Kim, K.R., 2000. Dietary iodine intake and urinary iodine Glisson, J., Crawford, R., Street, S., 1999. Review, critique, and excretion in patients with thyroid diseases. Yonsei Medical Jour-nal 41, 22 – 28.
guidelines for the use of herbs and homeopathy. Nurse Practi- Kincheloe, L., 1997. Herbal medicines can reduce costs in HMO.
tioner 24, 44 – 46, 53, 60 passim, quiz 68 – 69.
Goodwin, J.S., Tangum, M.R., 1998. Battling quakery, attitudes Knight, T.E., Hausen, B.M., 1994. Melaleuca oil (tea tree oil) der- about micronutrient supplements in American academic medicine.
matitis. Journal American Academy of Dermatology 30, 423 – 427.
Archives of Internal Medicine 158, 2187 – 2191.
Ko, R.J., 1998. Adulterants in Asian patent medicines. New England Gonzalez-Seijo, J.C., Ramos, Y.M., Lastra, I., 1995. Manic episode and ginseng, a report of a possible case. Journal of Clinical Koryrskyj, A., 1977. Herbal products in Canada. How safe are they? 1977 Canadian Family Physician 43, 697 – 702.
Gordon, L.A., 1999. Compositae dermatitis. Australian Journal of Lai, R.S., Chaing, A.A., Wu, M.T., Wang, J.S., Lai, N.S., Lu, J.Y., Ger, L.P., Roggli, V., 1996. Outbreak of bronchiolitis obilterans Greig, J.E., Thoo, S.L., Carson, C.F., Riley, T.V., 1999. Allergic associated with consumption of Sauropus androgynus in Taiwan.
contact dermatitis following use of a tea tree oil hand-wash not due to tea tree oil. Contact Dermatitis 41, 354 – 355.
Larrey, D., 1994. Liver involvement in the course of phytotherapy.
Hamouda, C., Amamou, M., Thabet, H., Yacoub, M., Hedhili, A., Bescharnia, F., Ben Salah, N., Zhioua, M., Abdelmoumen, S., El Larrey, D., Vial, T., Pauwels, A., Castot, A., Biour, M., David, M., Mekki Ben Brahim, N., 2000. Plant poisonings from herbal medication admitted to a Tunisian toxicologic unit, 1983 – 1998.
chamaedrys) administration, another instance of herbal medicine Veterinary and Human Toxicology 53, 885 – 892.
hepatotoxicity. Annals of Internal Medicine 117, 129 – 132.
Hausen, B.M., 1981. Occupational contact allergy to feverfew Lewis, J.H., 1992a. Esophageal and small bowel obstruction from Tanacetum parthenium (L.) Schult Asteraceae. Derm Beruf guar-containing diet pills, analysis of 26 cases reported to the FDA. American Journal of Gastroenterology 87, 1424 – 1428.
Hausen, B.M., 1984. Toothpaste allergy. Deutsche Medizinische Lewis, W.H., 1992b. Allergenic potential of commercial chamomile, Chamaemelum nobile (Asteraceae). Economic Botany 46, 426 – Hausen, B.M., 1996. A 6-year experience with compositae mix.
American Journal of Contact Dermatitis 7, 94 – 99.
Lewis, W.H., Elvin-Lewis, M., 1994. Basic quantitative and experi- Hill, K.R., Rohdes, K., Stafford, J.L., Aub, R., 1951. Liver disease in mental research phases of future ethnobotany with reference to Jamaican children (serous hepatosis). West Indian Medical Jour- the medicinal plants of South America. In: Chadwick, J., Marsh, J. (Eds.), Ethnobotany and the Search for New Drugs. John Horowitz, R.S., Feldhaus, K., Dart, R.C., Stermitz, F.R., Beck, J.J., Wiley and Sons, New York, pp. 60 – 76.
1996. The clinical spectrum of Jin Bu Huan Toxicity. Archives Lewis, W.H., Elvin-Lewis, M., 1977. Medical Botany, Plants Affect- ing Mans Health. John Wiley Interscience, NY.
Hughes, W.T., 1995. Postulates for the evaluation of adverse reac- Lin, J.L., Ho, Y.S., 1994. Flavonoid-induced acute nephropathy.
tions to drugs. Clinical Infectious Disease 20, 179 – 182.
American Journal of Kidney Disease 23, 433 – 440.
Izzat, M.B., Yim, A.P., El-Zufari, M.H., 1998. A taste of Chinese Lipp, F.J., 1996. The efficacy, history and politics of medicinal plants.
medicine. Annuals of Thoracic Surgery 66, 941 – 942.
Alternative Therapy and Health Medicine 2, 36 – 41.
Jamieson, D.D., Duffield, P.H., 1990. Positive interaction of ethanol Liske, E., 1998. Therapeutic efficacy and safety of Cimicifuga and kava resin in mice. Clinical Experimental Pharmacology and racemosa for gynecologic disorders. Advances in Therapy 15, Jankel, C.A., Speedie, S.M., 1990. Detecting drug interactions, a Liu, T.Y., Chen, C.C., Chen, C.L., Chi, C.W., 1999. Safrole-induced review of the literature. DICP, The Annals of Pharmacotherapy oxidative damage in the liver of Sprague – Dawley rats. Food and Chemical Toxicology 37, 697 – 702.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Lord, G.M., Tagore, R., Cook, T., Gower, P., Pusey, C.D., 1999.
Olukoga, A., Donaldson, D., 2000. Liquorice and its health implica- Nepthropathy caused by Chinese herbs in the UK. Lancet 354, tions. Journal of the Royal Society of Health 120, 83 – 89 Review.
Opper, F.H., Isaacs, K.L., Warshauer, D.M., 1990. Esophageal ob- Lyford, C.L., Vergara, G.G., Moeller, D.D., 1976. Hepatic veno-oc- struction with a dietary fiber product designed for weight reduc- clusive disease originating in Ecuador. Gastroenterology 70, 105 – tion. Journal Clinical Gastroenterology 12, 667 – 669.
Panda, S., Kar, A., 2000. How safe is neem extract with respect to Maechel, H., 1992. Diarrh( chronique secondaire au Cirkan, [Letter].
thyroid function in male mice? Pharmacological Research 41, Gastroenterologie Clinique et Biologique 16, 373.
Malik, A.S., Zabidi, M.H., Noor, A.R., 1994. Acute salicylism due to Pansatinkul, B.J., McKnanee, R., 1993. Dicoumarol content in alco- accidental ingestions of a traditional medicine. Singapore Medical holic her elixirs. South Asian Journal Tropical Medicine and Public Health 24 (1), 201 – 203 Suppl.
Mashour, N.H., Lin, G.I., Frishman, W.H., 1998. Herbal medicine Pansatiankul, B.J., Ratanasir, B., 1992. Acquired prothrombin com- for the treatment of cardiovascular disease, clinical consider- plex deficiency syndrome. Bulletin Department Medical Service ations. Archives of Internal Medicine 158, 2225 – 2234.
Maurice, P.D.L., Cream, J.J., 1989. The dangers of herbalism. British Paulsen, E., Andersen, K.E., Carlsen, L., Egsgaard, H., 1993. Car- Mawrey, D.B., 1993. Herbal Tonic Therapies. Keats Publishing Inc., sesquiterpene lactones? Contact Dermatitis 29, 138 – 143.
Pereira, F., Santos, R., Pereira, A., 1997. Contact dermatitis from McDermott, V.W., Ridker, P.M., 1990. The Budd – Chiari syndrome camomile tea. Contact Dermatitis 36, 307.
and hepatic veno-occlusive disease. Recognition and treatment.
Perharic, L., Shaw, D., Murray, V., 1993. Toxic effects of herbal Archives of Surgery 125, 525 – 527.
medicine and food supplements. Lancet 342, 180 – 181.
McGuffin, M., Hobbs, C., Upton, R., Goldber, A., 1997. Introduc- Perharic, L., Shaw, D., Colbridge, M., House, I., Leon, C., Murray, tion, American Herbal Products Association’s Botanical Safety V., 1994. Toxicological problems resulting from exposure to tradi- tional remedies and food supplements. Drug Safety 11, 284 – 294.
McPartland, J.M., Pruitt, P.L., 1999. Side effects of pharmaceuticals Pye, K.G., Kelsey, S.M., House, I.M., Newland, A.C., 1992. Severe not elicited by comparable herbal medicines, the case of tetrahy- dyserthyropiesis and autoimmune thrombocytopenia associated drocannabinol and marijuana. Alternative Therapy Health and with ingestion of kelp supplement. [Letter]. Lancet 339, 1540.
Ridker, P.M., McDermott, V.W., 1989. Comfrey herb tea and hepatic Miller, L.G., 1998. Herbal medicinals. Selected clinical considerations veno-occlusive disease. Lancet 1 (8639), 657 – 658.
focusing on known or potential drug – herb interactions. Archives Rieder, M.J., 1994. Mechanisms of unpredictable adverse drug reac- of Internal Medicine 158, 2200 – 2211.
Mills, S.Y., 1995. European pilot studies are under way. British Rodriguez-Serna, M., Sanchez-Motilla, J.M., Ramon, R., Aliaga, A., 1998. Allergic and systemic contact dermatitis from Matricaria Moum, B., Aukrust, P., Schrumpf, E., Mørk, T., Mathisen, Ø., Elgjo, chamomilla tea. Contact Dermatitis 39, 192 – 193.
K., 1992. Naturmidler kan fora˚rsaje geksesjader. Tidsskrift for Rosenblatt, M., Mindel, J., 1997. Spontaneous hyphema associated den Norske Laegeforening 112, 1308 – 1311.
with ingestion of Ginkgo biloba extract. [Letter]. New England Mukherhee, S., Lohiya, N.K., Pal, R., Sharma, M.G., Talwar, G.P., 1996. Purified neem (Azadirachta indica) seed extracts (Praneem) Rosenkranz, H.S., Klopman, G., 1995. An examination of the poten- abrogate pregnancy in primates. Contraception 53, 375 – 378.
tial genotoxic carcinogenicity of a biopesticide derived from the Mullins, R.J., 1998. Echinacea-associated anaphylaxis. Medical Jour- neem tree. Environmental and Molecular Mutagenesis 26, 255 – Munro, I.C., Delzell, E.S., Nestmann, E.R., Lynch, B.S., 1999.
Viadent usage and oral leukopakia, a spurious association. Regu- Roulet, M., Ricardo, L., Rivier, L., Calame, A., 1988. Hepatic latory Toxicology and Pharmacology 30, 182 – 196.
veno-occlusive disease in newborn infant of a woman drinking Murphy, J.M., 1999. Preoperative considerations with herbal herbal tea. Journal of Pediatrics 112, 433 – 439.
medicines. American Organization of Registered Nurses Journal Rubel, D.M., Freeeman, S., Southwell, I.A., 1998. Tea tree oil allergy, what is the offending agent? Report of three cases of tea Myer, S.P., Wohlmuth, H., 1998. Echinacea-associated anaphylaxis.
tree oil allergy and review of the literature. Australian Journal of Medical Journal of Australia 168, 583 – 584.
Natori, S., 1980. Application of herbal drugs to health care in Japan.
Ruze, P., 1990. Kava-induced dermopathy, a niacin deficiency? Journal of Ethnopharmacology 2, 65 – 70.
Neurauer, R.A., 1961. A plant protease for potentiation of and Sanders, D.M., Kennedy, N., McKendrick, M.W., 1995. Monitoring possible replacement of antibiotics. Experiment Medical Surgery the safety of herbal remedies. British Medical Journal 311, 1569.
Sandler, B., Aronson, P., 1993. Yohimbine-induced cutaneous drug Newall, C.A., Anderson, L.A., Phillipson, J.D., 1996. Herbal eruption, progressive renal failure, and lupus-like syndrome. Urol- medicines a guide for health care professionals. The Pharmaceuti- Sassevile, D., 1999. Phytodermatitis. Journal Cutaneous Medical Nolan, A., Lamey, P.J., Milligan, K.A., Forsyth, A., 1991. Recurrent aphthous ulceration and food sensitivity. Journal Oral Pathology Saxe, T.G., 1987. Toxicity of medicinal herbal preparations. Ameri- can Family Physician 35, 135 – 142.
Nortier, J., Depierreux, M., Vanherwehem, J.L., 1999. Herbal reme- Schaller, M., Korting, H.C., 1995. Clinical Experimental Dermatol- dies and nephrotoxicity. Revue Medicale de Bruxelles 20, 9 – 14.
Ocasio, N.A., Salomowitz, B.H., Sher, M.R., 1999. Natural remedies Schaumburg, H.H., Berger, A., 1992. Alopecia and sensory polyneu- recommended for the management of oral health. New York ropathy from thallium in a Chinese herbal medications. [letter].
Journal of the American Medical Association 268, 3430 – 3431.
O’Hara, M., Kiefer, D., Farrell, K., Kemper, K., 1998. A review of Segelman, A.B., Segelman, F.P., Karlinger, J., Sofia, R.D., 1976.
12 commonly used medicinal herbs. Archives Family Medicine 7, Sassafras and herb tea. potential health hazards. Journal Ameri- M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Seidner, D.L., Roberts, I.M., Smith, M.S., 1990. Esophageal obstruc- Sugiura, M., Hayakawa, R., Kato, Y., Sugiura, K., Hashimoto, R., tion after ingestion of a fiber-containing die pill. Gastroenterology 2000. Results of patch testing with lavender oil in Japan. Contact Selvaag, E., Holm, J.O., Thune, P., 1995a. Contact allergy to essen- Sullivan, J.B., Jr., Rumack, B.H., Thomas, H., Jr., Peterson, R.G., tial oils. Tidsskr Nor Laegeforen 115, 3369 – 3370.
Bryson, P., 1979. Pennyroyal oil poisoning and hepatotoxicity.
Selvaag, E., Holm, J.O., Thune, P., 1995b. Allergic contact dermatitis Journal American Medical Association 242, 2873 – 2874.
in an aroma therapist with multiple sensitization to essential oils.
Sunter, W.H., 1991. Warfarin and garlic. [Letter]. Pharmacology Shaw, D., Leon, C., Kolev, S., Murray, V., 1997. Traditional reme-
11° GRAND PRIX IUTA 2013 di ULTRAMARATONA Segnalare eventuali errori CLASSIFICA GENERALE FEMMINILE - FINALE e/o omissioni a: Aggiornamento Soci Iuta al 30\11\2013 SOCIETA' Migliori 9 ris. BELLATO Maria Applerun Team GARGANO Angela ASD Barletta Sportiva VERZELETTI Rossella ASD Runners Bergamo RAVANI Laura ASD Runners Bergamo PIASTRA Lorena