Plants have played a central role in the prevention and treatment of disease since prehistoric times. It seems, therefore, paradoxical that of the many hundreds of plant remedies described in the Papyrus of
Ebers, discovered in Egypt and written in about 1550 BC, only a handful of products currently appear among the accepted remedies in the United States Pharmacopoeia. But upon reflection, this disparity makes sense. The empiric process of identifying medicinal agents by trial and error is not an efficient one, and countless individuals no doubt have succumbed following treatments with plant products that were poisonous and/or ineffective. With the blossoming of scientific medicine in the 20th century, the discovery of new drugs has come to depend on the application of rational codified principles, providing an understanding of why some treatments are effective and others are not, and how we can tell the difference.
CONTRASTING CRITERIA
A significant number of the many potent modern drugs used today trace their origins to plants. But there is a fundamental difference between such drugs used in ‘‘alternative’’ medicine and bona fide drugs used in mainstream medicine: all drugs of the latter type, whether of plant origin or not, must meet federally decreed stringent requirements for purity, safety, and efficacy before they can be distributed to the public. These scientific criteria are not mandated for or met by most of the popular plant remedies used in alternative medicine. Although many plant agents have been used for centuries and are obviously ‘‘natural,’’ the popular perception that this attribute alone guarantees safety is as naı¨ve as are assumptions that time has proven their effectiveness. Almost no alternative treatments have been subjected to the exacting criteria mandated for conventional therapies. Many, if not most, plant products used in alternative medicine comprise multiple components that have not been rigorously characterized, are difficult to quantify, and vary qualitatively and quantitatively from plant to plant, in different plant parts, and according to stages of plant development and conditions of growth. These problems were recently addressed comprehensively in a symposium entitled ‘‘Botanicals: A Role in U.S. Health Care?’’
What, then, is responsible for the extraordinary explosion of interest in alternative medicines? In the 1960s, ‘‘green, organic, and natural’’ became buzzwords that attained maturity in the 1990s, when consumers increased their interest in self-care and in controlling their own destinies. Many turned to ‘‘holistic’’ medicine. People became tired of the high costs of treatment that was often impersonal, and with the difficulty in identifying compassionate and nurturing physicians. They also were disappointed by the failure of modern medicine to cure the increasingly prevalent chronic diseases, in contrast to its dramatic successes in treating acute illness.
This tide of popular dissatisfaction was seized upon by promoters of ‘‘health foods,’’ who engaged in relentless advertising. Soon, more than half of the U.S. population was consuming health foods, including huge quantities of vitamins that most people did not need. Politicians whose states were prominent suppliers to the health food industry pursued this trend. Thus, apparently well-intentioned efforts to enact new legislation concerning health foods and supplements—to protect the public’s health—were in part heavily motivated by commercial interests.
Moreover, perceptive and persuasive arguments presented by Beyerstein establish why, in many cases, bogus therapies can appear to be effective. These situations include, for example, fluctuations in the natural courses of many chronic diseases and the extraordinary effectiveness of placebos.Thus, the apparent successes of alternative strategies have strengthened the public’s resolve to try alternative medicines and have fueled an exceptionally vigorous industry that is growing at several times the rate of the overall economy.
To put the impact of these forces into an organized framework, we trace the major scientific milestones and the legislative framework that have made the many spectacular successes of modern therapeutics possible. We then describe how these hard-won and dramatic advances suffered a substantial setback by enactment of the Dietary Supplement Health and Education Act of 1994 (DSHEA), a measure that significantly weakened regulations designed to protect the health of the public. We conclude with a discussion of two illustrations of research on potentially important plant derived therapeutic or prophylactic agents (already present in some foods) that are being pursued through rigorous scientific methods. We emphasize the remarkably demanding, time-consuming, and expensive scientific efforts that are required to establish the safety and efficacy of such agents.
SCIENTIFIC DEVELOPMENT OF MODERN DRUGS
In the last 100 years, four major developments have played a critical role in the extraordinary achievements of modern therapeutics in the United States and throughout the world. These developments include the codification of the principles of (chemo)therapy; introduction of the controlled clinical trial; enactment of federal drug laws and regulations; and creation of the U.S. Food and Drug Administration (FDA) and similar bodies in other countries.
Codification of Principles of (Chemo)therapy
In the early 1900s, Paul Ehrlich, the ‘‘father of chemotherapy,’’ formulated the basic principles that govern modern therapeutic discovery. He
1.demonstrated that drugs could be developed by deliberate and planned chemical synthesis and did not have to be of natural origin;
2.advocated systematic exploration of the relation of structure to biological activity to identify the structural features of molecules responsible for therapeutic activity and to distinguish them from the features responsible for toxicity;
3.emphasized the importance of achieving selective toxicity by maximizing the ratio of the dose required to produce toxicity in the host to that required to cure the disease; and
4.underscored the importance of developing animal models of diseases that provide quantitative measures of both therapeutic potency and toxicity.
The Controlled Clinical Trial
It is likely that the first randomized, placebo-controlled, blinded clinical trial was that devised in 1948 to evaluate the efficacy of streptomycin in the treatment of tuberculosis. Since that time, the controlled clinical trial has become the objective scientific standard for evaluating the efficacies of therapeutic procedures. The design of controlled trials has evolved to include randomization of research subjects to achieve uniformity of groups; inclusion of placebo controls; blinding (ideally double blinding) of subjects and researchers to the identity of the treatment group; statistical validation of results; and the requirement for informed consent by participating subjects, based on the compelling arguments advocated at the Nuremberg trials for ethical and humane treatment of participants in clinical trials.
Although controlled clinical trials are now commonplace, many advocates of alternative medicine neither follow these guidelines nor believe in their importance. Instead, they rely heavily—as does the population at large—on anecdotal reports of effectiveness of treatment. They subscribe to the notion that therapy must be individualized and that ultimately only the healer knows what is best for the individual patient. This belief is bolstered in part by the conviction that the controlled clinical trial is not capable of assessing mind–body interactions that alternative practitioners believe underlie much of human illness.
Federal Drug Laws
At the beginning of the 20th century, a plethora of medicines was available to the public to cure an extraordinary variety of real and imagined human afflictions. Moreover, extravagant testimonials and merciless advertising struck fear into the minds of the public about the prevalence of these diseases and offered improbable assurances of their curability by the countless nostrums that flooded the market. This state of affairs has been well described by Holbrook. The chemical or plant constituents of these patent medicines were not disclosed, even when the preparations contained narcotics or alcohol. Foods were also often adulterated and misleadingly described.
In 1906, in response to this chaotic state of affairs, Congress passed the first Pure Food and Drug Act, which was signed into law by Theodore Roosevelt. It was in essence a labeling law, requiring foods and drugs in interstate commerce to be labeled with truthful descriptions of their contents. It prohibited false or misleading labeling but exercised no control over safety or promotion of extravagant health claims. The law did not apply to imported products. Interestingly, the real pressure to pass this law had little to do with its unassailable logic. Rather, impetus for this measure stemmed from public outcry against the notoriously insanitary conditions in the Chicago stockyards, described by Upton Sinclair in his novel The Jungle; a series of articles by Samuel Hopkins Adams, ‘‘The Great American Fraud,’’ that appeared in Collier’s magazine in 1905 and attacked patent medicines; and the reports of Harvey W. Wiley, chief chemist of the Department of Agriculture, who found extraordinary contaminants in human foods. As described below, the major amendments to the 1906 law have also been propelled by public pressure resulting from a series of medical tragedies. The Federal Food, Drug, and Cosmetic Act of 1938 required, for the first time, that drugs be tested for safety. The manufacturer of a new drug would be required to submit to the FDA a New Drug Application (NDA) containing information about the composition, quality, labeling, and directions for administration of the drug, as well as evidence for its safety under the recommended conditions of use. In retrospect, it seems unbelievable that this rational, and even obvious, requirement that drugs be safe before permitting administration to humans was not mandated earlier.
The 1938 law contained no requirement that drugs be effective. They could be without activity (and many were), provided they were appropriately labeled and complied with safety requirements. A drug would be automatically approved in 60 days if the FDA filed no objection. Some control over advertising was vested in the Federal Trade Commission, and drugs already marketed were exempted as being Generally Recognized as Safe (GRAS). Again, the public played an important role in pushing for the introduction of a safety requirement as a result of a human tragedy, in which a pediatric ‘‘elixir of sulfanilamide’’ was marketed as a cherry flavored solution in ethylene glycol. Tragically, the glycol was toxic and 107 children died. The government was able to seize and stop distribution of the ‘‘elixir’’ for mislabeling, because an elixir by definition is a solution in alcohol, in which sulfanilamide is not sufficiently soluble. Another 24 years elapsed before the enactment of the Harris–Kefauver amendments (1962) to the Federal Food, Drug, and Cosmetic Act. The interesting history leading up the adoption of this legislation can be found in two monographs: The Real Voice,6 by Richard Harris, published in 1964, and In a Few Hands: Monopoly Power in America,7 by Estes Kefauver (published posthumously in 1965). These rational advances in drug legislation required, for the very first time, proof that drugs were effective for their intended uses. The law mandated, also for the first time in history, stringent adherence to scientific guidelines for testing of drugs. Preclinical toxicity studies and evidence of efficacy were both required to precede strictly phased controlled clinical trials, thus assuring maximization of information while minimizing hazards to human participants. Clinical evaluations had to be carried out by individuals who were specially qualified by training and experience, based on the concept that not all physicians were equally competent to develop such information.
The strictly formalized regulations for evaluating effectiveness for intended use also included a requirement for filing an Investigational New Drug (IND) application prior to initiating clinical studies, and if approval was given by the FDA, subsequently submitting a New Drug Application (NDA). Other major requirements were full disclosure of information about effectiveness, contraindications to use, and side effects. Most important, careful keeping of records of adverse reactions to new drugs and their reporting to the FDA were mandated. Approval of prescription drug advertising was vested in the FDA. The FDA was also assigned the massive task of reviewing retrospectively the efficacies of all drugs marketed between 1938 and 1962. When this daunting task was finally completed, many of these entities did not survive.
These laws and the ensuing regulations defined the ‘‘gold standard’’ for the world on how drugs should be developed scientifically to provide reasonable assurances that marketed medications were both safe and effective. Passage of the 1962 amendments was fought with acrimony by special-interest groups who predicted that their enactment would result in the demise of therapeutic innovation and of the pharmaceutical industry. However, public furor over the tragic consequences of the use in Europe of thalidomide, the notorious teratogen that caused the birth of more than 10,000 children with phocomelia (‘‘seal limbs’’), provided the impetus for passage of the amendments. Contrary to predictions, the pharmaceutical industry has never been stronger. Indeed, by setting high scientific standards for the development of new agents, these regulations were largely responsible for the rapid growth and spectacular achievements of the ethical pharmaceutical industry in the last 35 years.
These major, and now widely accepted, four principles (purity, truth in labeling, safety, and effectiveness) are at the heart of modern therapeutics. They are responsible for the usefulness of most modern drugs administered for the treatment of many serious diseases, and the amelioration of much suffering. We believe that the merits of alternative forms of treatment can and must be rigorously assessed according to the same fundamental principles if we are to avoid public tragedies similar to those described above. And yet, we are in danger of losing some of this hard-won scientific therapeutic rationalism with the recent passage of the Dietary Supplement Health and Education Act (DSHEA).
THE DIETARY SUPPLEMENT HEALTH AND EDUCATION ACT
In 1994, the U.S. Congress enacted legislation defining a new class of products that were classified as ‘‘dietary supplements,’’ based on the belief that they provided health benefits. These products were legally neither foods nor drugs. They were defined as containing one or more of the following types of substances: a vitamin; a mineral; an herb or other botanical; an amino acid; or a concentrate, metabolite, extract, or combination of any of these ingredients. These products, intended to be ingested in pill, capsule, tablet, or
liquid form, were required to be labeled as dietary supplements. The categories of agents classified by law as dietary supplements are enormously diverse, and include many substances that were already being advocated, sold, and perceived to provide health benefits. They were not a rational compilation of materials meeting specific health or medical needs.
What prompted the development of this new legislation? Since it was, and is, a top priority of the federal government to improve the public’s health status, and scientific studies have documented the importance of nutrients and dietary supplements to health promotion and disease prevention, the act ostensibly was designed to ensure that safe and appropriately labeled products remain or become available to the public. Although this was a worthy goal, it seems likely that pressure from the public, and particularly from the health food industry, played a major role in the enactment of the DSHEA. Many individuals believe that they are entitled to choose their own preventive health care programs, and that the government should not impose unreasonable regulatory barriers to slow the flow of safe products to consumers (although it should act quickly against unsafe or adulterated products). Moreover, consumers were already relying increasingly on nontraditional and unusual health practices to provide a more ‘‘holistic’’ approach to treatment and to avoid costly traditional medical care, which was often perceived as impersonal. Indeed, almost half of the U.S. population had been consuming supplements of vitamins, minerals, or herbs in the belief that these substances improve nutrition and health. Such supplements are usually considered to be safe within a broad range of intakes. Perhaps one of the most compelling reasons for enactment of the DSHEA was that the United States was spending about 12% of its gross national product (GNP) on health care and that the nutritional supplement industry had become an integral part of the U.S. economy, showing a consistently positive trade balance and enormous annual sales. In our view, DSHEA is a form of deregulation, and it is by no means clear that it has led to safer ‘‘dietary supplements’’ being made available to the public.
Why has this situation occurred? There are two overriding reasons: First, despite requirements for precise information about specific ingredients, most of the herbal preparations now marketed contain numerous components that defy chemical characterization. Second, whereas the manufacturer of conventional drugs must provide proof of safety, the manufacturer of ‘‘natural’’ dietary supplements is not required to establish product safety. Instead, the burden of safety has been placed on the FDA, which depends on information supplied by customers or their advocates. In order to withdraw a marketed dietary supplement, the Secretary of Health and Human Services must determine that the product poses an imminent hazard to public health or safety under recommended conditions of use, or that it is adulterated. It is difficult for the Secretary to comply with these requirements because reporting of adverse effects of dietary supplements is not mandated. The dietary supplement product label must carry the disclaimer: ‘‘This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’’ Nevertheless, surveys have shown that the public assumes, from mention of the Food and Drug Administration on the label, that the opposite is true, and that the FDA has condoned marketing and use of the supplement. Furthermore, although the DSHEA does not permit health claims unless there is convincing clinical evidence, claims for maintenance of healthy or normal ‘‘structure and function’’ are allowable.
Thus, a label may state that a product ‘‘maintains normal cardiovascular function and a healthy circulatory system’’ but not that it ‘‘reduces blood pressure’’ (unless there is proof that it does so). It may claim that it ‘‘maintains a healthy cholesterol level’’ but not that it ‘‘lowers cholesterol,’’ unless the FDA accepts proof that it does. As a consequence of these claims promoting health maintenance, the dietary supplement industry is booming and herbal remedies are being combined with other over-the-counter preparations
such as vitamins, many of which also qualify as dietary supplements.
DANGERS OF MANY DIETARY SUPPLEMENTS
Concerns over the toxicity of many herbal preparations and plant-derived products contained in dietary supplements are ever-present issues, especially now that the alternative medicine movement is relying increasingly on ‘‘natural’’ supplements, and their regulation under DSHEA has been loosened. In a recent review, Ernst cites allergic reactions, toxic reactions, possible mutagenic effects, drug interactions, drug
contaminations, and mistaken plant identities in his attempt to classify the scope of adverse reactions induced by botanical medications in common use in the Western world. These issues have become of such importance that the FDA has voiced its concerns through efforts to educate health professionals and notify dietary supplement manufacturers. The reader is referred to a 1993 FDA review document entitled ‘‘Unsubstantiated Claims and Documented Health Hazards in the Dietary Supplement Marketplace,’’
especially the section, ‘‘Illnesses and Injuries Associated with the Use of Selected Dietary Supplements.’’ The following examples focus on some toxicities reported since 1992 and probably represent only a small fraction of their incidence, because many remain unrecognized and/or unreported.
1. Jane Brody, writing in The New York Times, remarks that ‘‘under the new law, entitled the Dietary Supplement Health and Education Act, it is up to the FDA to take products off the market only after they have proved dangerous to people taking them. Only when a new ingredient is introduced is the company obliged to provide the drug agency with documentation of its presumed safety.’’
2. Dr. Lori Love of the FDA states that ‘‘there are currently no federal regulations that establish specific criteria for purity, identification, and manufacturing procedures of dietary supplements.’’ The drug agency researchers have pointed out that there are no requirements to maintain pharmaceutical standards, and that there are no requirements for mandatory reporting to the FDA of adverse events by the manufacturer or distributor of these products. Rather, it is up to the agency and physicians to detect and report them.
3. Many, and perhaps most, people who take over-the counter dietary supplements never report untoward events to their physicians. Even if they suffer such adverse reactions, they often are embarrassed to tell their doctors what they have been taking. Thus, physicians mistakenly may attribute supplement-caused adverse effects to the illness or to conventional treatment that has been prescribed, which in turn can result in unwarranted and hazardous changes in the patient’s medical care (e.g., withdrawal of an effective or even essential drug).
4. These problems are clearly illustrated in a recent article concerning the contamination of botanical dietary supplements by Digitalis latana, in which the case histories are described of two women who were brought to the emergency room and diagnosed as having heart block. This condition was subsequently attributed to the toxicity of cardiac glycosides, although neither patient was known to be taking these substances. Instead, both patients had taken an oral regimen of dietary supplements for ‘‘internal cleansing.’’ The supplements were marketed as a ‘‘program,’’ which, according to the label and accompanying materials, consisted of 37 ingredients, including 14 different herbs and six species of bacteria. Analysis revealed that the ‘‘cleansing’’ material contained cardiac glycosides, which were then traced to plantain contaminated with Digitalis lanata. The plantain in question was part of a 6,000-pound shipment imported into the United States over about two years that had been received by more than 150 manufacturers, distributors, and retailers. Extensive efforts were then made to inform all of these groups. The authors of the report cite several reasons for the widespread and protracted distribution of a potentially lethal product.
We also cite here a few more examples of the potentially life-threatening hazards of herbal products that may be contaminated with powerful toxins.
One of the most graphic and devastating examples of the toxic potential of plant preparations concerns the development of renal failure and epithelial cancers of the urinary tract in humans who consumed certain Chinese herbs. The recognition of this association illustrates the extraordinary vigilance and detective work that was required to make this association. This still-unfolding story began almost ten years ago in a Belgian clinic that offered a weight-reduction regimen that included two Chinese herbs as well as appetite suppressants and other components. Rapidly progressive renal failure, necessitating dialysis and ultimately leading to a number of kidney transplants, was observed in a large number of young women. Deft detective work revealed a strong association of these cases of renal failure with the inclusion of certain Chinese herbs in the weight-reduction program. The condition became known as ‘‘Chinese herb nephropathy,’’ and in Great Britain two cases of end-stage renal failure requiring dialysis were attributed to a Chinese herbal eczema remedy that contained known nephrotoxins.
In the case of the Belgian clinic, there seems to have been some confusion over similarities of herbs and their Chinese names.Apparently one of the Chinese herbs (Aristolochia fangchi) contains known nephrotoxins (aristolochic acids: nitrophenanthrene carboxylic acids). These compounds were also well recognized carcinogens in laboratory animals. It was therefore not surprising that cancers of the urinary tract were reported to occur in individuals who consumed the aforementioned herbs. Urothelial neoplastic lesions were detected in the urinary tracts of patients undergoing renal transplantation for Chinese herb nephropathy. A number of these patients were offered the option of prophylactic nephrectomy of the remaining kidney. Among the 39 who accepted the surgical procedure, 18 were found to have urothelial carcinoma (17 cases of carcinoma of the ureter or of the renal pelvis, or both, and one case of carcinoma of the bladder). In an editorial commenting on this report, David A. Kessler, a former Commissioner of the FDA, wrote, ‘‘Congress has shown little interest in protecting consumers from the hazards of dietary supplements, let alone from the fraudulent claims that are made, since its members apparently believe that few of these products place people in real danger. Nor does the public understand how potentially
dangerous these products can be.’’
5. Other examples of contamination of nonprescription medicines include Asian patent medicines collected from retail herbal stores in California that were found to be contaminated with dangerously high levels of heavy metals. For example, of 251 products analyzed, 35 contained from 22.4 to 5,070 ppm of mercury. The U.S. Pharmacopoeia limits heavy metals to 30 ppm, and even lower levels for lead, arsenic, and mercury.
6. In 1990, the U.S. Centers for Disease Control summarized information about 1,536 cases of eosinophilia–myalgia syndrome reported to them from all parts of the United States, with 27 deaths at that time. These illnesses were associated with the consumption of L-tryptophan-containing dietary supplements advocated to improve sleep. Eosinophilia–myalgia is a serious connective tissue disease characterized by severe muscle pain, elevated white blood cell counts, and a variety of neuromuscular and skin abnormalities. The number of contaminating impurities found in these tryptophan preparations was very large. While the precise identity of the agent(s) causing the syndrome was unclear in the absence of a suitable animal model, tryptophan itself or a condensation product of two molecules of tryptophan with acetaldehyde may have been the major culprit. The contaminants arose during the production of tryptophan by microbial fermentation and/ or subsequent processing. Since the surveillance definition for reporting eosinophilia–myalgia required not only severe debilitating myalgia but also a massive eosinophilia, it seems highly likely that many more individuals were affected with less severe forms of the syndrome.
7. Ephedrine alkaloids, derived from ephedra herbs, sometimes called ma huang, are amphetamine-like compounds with powerful stimulant effects on the nervous system and heart. Between 1994 and 1997, the FDA investigated more than 800 reports of adverse events associated with the use of ephedra products, most of which occurred in young to middle-aged adults who were otherwise healthy. These adverse events included high blood pressure, irregular heart rate, insomnia, nervousness, tremors and seizures, paranoid psychoses, heart attacks, strokes, and death. In 1997, the FDA proposed limiting the daily intake of ephedra alkaloids to 24 mg and required labels that warned consumers not to take ephedra products for more than seven days and that taking more than the recommended dosage could result in heart attack, stroke, seizure, and death. Following a strong lobbying effort by the dietary supplement industry (annual sales of ephedra-containing products last year exceeded $1 billion), the FDA was requested to provide ‘‘stronger evidence’’ of the relationship between ingestion of ephedra-containing food supplements and their reported adverse effects. Meanwhile, in the absence of an official FDA safety warning, in thousands of Internet postings, users continue to praise ephedra for raising their energy, helping them lose weight, and sharpening their muscle tone.
8. St. John’s wort (Hypericum perforatum), an over-the counter herbal extract, is being widely used for the treatment of clinical depression, although its effectiveness has not been demonstrated in controlled clinical trials. As with most other folk remedies, little information is available regarding the basic pharmacology of this herbal. It contains many biologically active components, of which the hypericins may be responsible for effects on the central nervous system. Recently, a routine pharmacokinetic study in human volunteers showed that addition of St. John’s wort to several therapeutic regimens reduced markedly the blood levels of indinavir, a protease inhibitor used in the treatment of AIDS, and of cyclosporin, a drug used to prevent transplant rejection. Following these reports, the FDA issued a public health advisory warning that St. John’s wort appears to induce cytochrome P-450 enzymes—a key pathway for the metabolism of prescription drugs, including many of those used to treat heart disease, depression, seizures, and certain cancers, or to prevent transplant rejection or pregnancy (oral contraceptives). These important drugs, often prescribed for life-threatening conditions, can lose their therapeutic effects when given concomitantly with St. John’s wort. A review of the effects of St. John’s wort in decreasing the effectiveness or increasing the toxicity of conventional drugs recently appeared in the Medical Letter. Thus, a routine pharmacokinetic study (one required for drugs subject to FDA approval, but not for herbal remedies), revealed the potentially serious consequences associated with the co-administration of a supposedly harmless natural product. All herbals contain many chemical components, some of which induce drug-metabolizing enzymes, and many more drug interactions with herbal remedies are likely to surface in the future.
9. Even normally safe products can be harmful if they are consumed together with certain conventional drugs prescribed for specific medical conditions. Thus, plant estrogens in herbal preparations used for treatment of prostate cancer were present at sufficiently high levels to affect patients who were already prescribed estrogenic steroids. In a recent issue of The New England Journal of Medicine, the Editors called for vigorous testing of all products, stating, ‘‘It is time for the scientific community to stop giving alternative medicine a free ride.’’ This request was echoed by articles in JAMA and other responsible publications. The loosening of regulatory requirements by the DSHEA has been a bonanza for the already wildly successful health food industry, and has deprived the FDA of its ability—and reversed its statutory responsibility—to guard the health of the public. Unfortunately, it is likely that sooner or later another public health crisis will force Congress to reexamine and reformulate the provisions of the DSHEA.
PROGRESS IN SCIENTIFIC DEVELOPMENT OF DRUGS FROM PLANTS
While stressing the dangers of inadequately regulated herbal remedies, we should not forget that plants have provided a multitude of life-saving drugs. List 1 provides examples of plants and other sources producing important drugs that have been in use for centuries. Fourteen of the drugs in current use for cancer chemotherapy occur naturally, and of these, five originate from plants. Nevertheless, the long and arduous scientific journey from the discovery of the pharmacologic activity of a plant or tissue extract to the development of a useful drug of proven efficacy and safety is not widely appreciated by the many individuals who seek ‘‘cures’’ for their ailments or wish to ‘‘buy insurance’’ against becoming ill.
Two Case Studies
To illustrate the scientific development of a proven drug from plants, we have selected two representative examples of phytochemicals that are currently being developed as potential therapeutic and/or disease-protective agents. These are curcumin, an ancient spice, which continues to occupy a place in our diet and to be widely used in Asian medicine for a variety of medical conditions; and sulforaphane and its glucosinolate precursor, which were recently isolated from broccoli and other cruciferous vegetables in a search for chemoprotective agents that reduce the risk of developing cancer.
Curcumin. Curcumin is a spice that is widely used as a bright yellow coloring and flavoring agent. It is the major yellow pigment obtained from turmeric, the powdered rhizome of Curcuma longa, a Southeast Asian member of the ginger family. References to the healing power of C. longa are found in early Asian texts, in which the component of this plant was known by a variety of names, the most common of which is the Sanskrit term, haridra. In the West, where it is used as a constituent of curry, the more familiar name is turmeric. In Chinese medicine, it is one of the herbs that ‘‘invigorate’’ the blood and stimulate the Qi, which vitalizes the body, propels, and warms. All texts describe its bitter taste and astringent and antiseptic properties. The Materia Medica of Tibetan Medicine describes haridra as ‘‘hot in potency, ununctuous and promoter of the complexion of the body.’’ It is claimed not only that haridra eliminates waste products from the body, but that it also cures poisoning, itches, kustha (obstinate skin diseases, including leprosy), chronic rhinitis, and anorexia. As late as 1931, the Vegetable Materia Medica of India and Ceylon attributed a host of curative properties to turmeric from C. longa, including: ‘‘astringent and antiseptic—topically effective for wounds, boils, ulcers, eczema, and psoriasis; when mixed with olive oil—relieves measles, chicken pox, small pox, and prevents spread of disease; used internally—stomachic, carminative, cholagogue, relief of liver congestion, febrifuge and expectorant, valuable in bronchitis, and pneumonia, and beneficial in diabetes; used externally—a treatment for bites of snakes and other animals.’’ Although this suspiciously long list of curative properties resembles those of some bogus nostrums of the 19th century, curcumin has been extensively investigated over the past 20 years by modern scientific methods. These studies have demonstrated unequivocally its remarkable and potent antioxidant, anti-inflammatory, antiangiogenic, and antitumor properties in a variety of experimental systems. The chemistry of the active principles of turmeric is now well understood: it consists largely (about 80%) of curcumin, with the remainder comprising two curcuminoids lacking one (demethoxycurcumin) or two (bisdemethoxycurcumin) methoxyl groups. Curcumins block carcinogen-induced tumor formation in a variety of animal models, and appear to affect both the initiation and promotion phases in two-stage models of carcinogenesis. Curcumin is antimutagenic, scavenges free radicals, reduces carcinogen–DNA adduct formation, and decreases the expression of several oncogenes. Curcumin has been under development as an anticancer agent by the Chemoprevention Branch of the National Cancer Institute since 1988. Extensive preclinical toxicity studies have been completed, and based on knowledge of its pharmacokinetics, the planning and implementation of efficacy studies in humans are in progress. It has taken more than 12 years of intense, systematic, planned effort to reach this stage in the development of curcumin as a potential protective/therapeutic agent. Its development serves as an example of the extraordinary length of time and effort that may be required to produce a safe and effective treatment based on sound scientific principles from a herb that has been widely used for centuries. Preclinical efficacy, pharmacology, and toxicology must all be completed before Phase I studies in human volunteers can be undertaken. At that point, the issue of identifying surrogate markers for the protected state has to be resolved. If all of these are compatible with safety, and there are sufficient indications of efficacy, consideration can be given to intervention trials in populations that are at high risk for the development of cancer.
Sulforaphane. The isolation and identification of sulforaphane as an anticancer agent illustrates the strategy of surveying plants for a desired biological activity by means of bioassays specifically developed for this purpose. The logic of this strategy was based on the demonstration that the elevation (induction) of phase 2 detoxification enzymes in animals reduced their susceptibility to the neoplastic effects of certain carcinogens. A simple bioassay was developed for measuring the potency of inducers of phase 2 enzymes; this involved measurement of the activities of a quinone reductase in animal cells grown in microtiter plates. A systematic survey of the inducer activities of a wide variety of edible plants identified cruciferous vegetables (broccoli, Brussels sprouts, cabbage, cauliflower, kale) as particularly rich sources of this type of inducer activity. The isothiocyanate sulforaphane was isolated from one variety of broccoli as the principal and extremely potent inducer of phase 2 enzymes. Sulforaphane was then shown to reduce the incidence, multiplicity, size, and rate of growth of mammary tumors when administered to rats treated with the potent carcinogen, dimethylbenz(a)anthracene, thereby confirming the validity of the inducer bioassay-based isolation strategy. The enormous variability of the inducer activities of commercially
available broccoli samples prompted a systematic search for sources of higher and more consistent inducer activity.
Certain cultivars of three-day-old broccoli sprouts were demonstrated to contain 20- to-50-fold higher levels of the glucosinolate of sulforaphane than an average mature broccoli. Active studies are now under way to establish the safety and efficacy in humans of broccoli sprout extracts containing sulforaphane and glucoraphanin, its naturally occurring glucosinolate precursor.38 Although many individuals consume substantial quantities of broccoli, the establishment of safety and tolerance must be completed, and effects on biomarkers for chemoprotective efficacy established, before chemoprotection trials in human populations with high cancer susceptibility can be organized. These accounts of two compounds, curcumin and sulforaphane, which appear to be safe natural products that have been widely consumed for centuries, provide examples of the stringent scientific testing that must be undertaken to develop pharmacologic agents with proven safety and efficacy. They illustrate the types of rigorous evaluations that should be applied to alternative medicines.
CONCLUSION
Although many valuable drugs in current widespread use originate from plant sources or exist as chemically modified forms of naturally occurring phytochemicals, there is no reason to believe that a drug for every disease exists in nature. There is, however, every reason to require that all plant products used as drugs be evaluated for safety and efficacy by methods identical to those used for novel synthetic entities, according to widely (and wisely) accepted principles and procedures. These practices include evaluation of preclinical safety and efficacy; controlled phased clinical trials (placebocontrolled, randomized, double-blind, statistically validated) on research participants who have given informed consent; and a requirement that such trials be conducted in compliance with federally mandated regulations.
We also recommend that every physician, physician’s assistant, nurse, or other health provider be required to interrogate every patient with respect to his or her intake of ‘‘dietary supplements.’’ We believe that the DSHEA, which places on the FDA not the burden of approval, but only the obligation to order their withdrawal when the Secretary of the Department of Health and Human Services perceives an imminent danger, has substantially weakened the authority of the FDA with respect to ensuring the safety of dietary supplements. In our view, the DSHEA is a disaster waiting to happen. All previous major legislation relating to drug safety resulted from public health catastrophes (e.g., those caused by insanitary stockyards, elixir of sulfanilamide, and thalidomide). Unfortunately, attempts to strengthen current legislation will be opposed by special interests. We must always remember that Calvin Coolidge reputedly said ‘‘Idealism is America’s ideal,’’ but supposedly also added ‘‘Business is America’s business.’’ Note added in proof. Recently Haller and Benowitz reviewed 140 reports received by the FDA of adverse cardiovascular and central nervous system events in subjects taking dietary supplement preparations containing ephedra alkaloids during a 22-month period. They concluded that 31% of the events were definitely or probably related to ephedra intake, and among these there were ten deaths and 13 permanent disabilities. Commenting editorially, Fleming was understandably cautious in inferring that there was proof of associative risk in this study. However, he concluded that by passing the Dietary Supplement Health and Education Act (DSHEA) Congress had created a loophole: ‘‘This act allows inadequately tested drugs to be marketed as ‘dietary supplements’ —an innocuous and even holistic sounding term. . . . A compound containing ephedra alkaloids should not be called a dietary supplement; it is a drug.’’ This view is strengthened by the recent FDA order to withdraw phenylpropanolamine (an alpha-adrenergic agonist closely related to ephedrine)
from over-the-counter cold remedies and weight loss aids because of an increased risk of hemorrhagic stroke in women.
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