Of Better Drugs Author: Tianhan Xue
The scientific merits of traditional and herbal remedies have been a topic of great controversy. Critics, including many scientists, have questioned whether claimed effects of such alternative therapies can stand up to rigorous tests that apply to conventional medicine, and even whether they are science at all. Yet, as is evidenced by an examination of Chinese herbal medicine (CHM), the therapeutic effects of some herbal remedies have been scientifically proven, and they represent a significant source of new pharmaceuticals. However, regulatory hurdles, along with other factors, have impeded the development of herb-derived drugs in the United States. It is time now to take measures that encourage scientific research on herbal remedies as an alternative approach to the discovery of new and better therapies.
CHM is an organized system of medical knowledge, passed down from one generation to another in both written and unwritten form, that has evolved since the beginning of civilization. CHM has its unique theories and practice, using mainly plant extracts (plus some minerals and animal parts) for treating disease.
Recent studies indicate that CHM has worked effectively in some instances in which conventional Western therapies failed or proved to be insufficient. For example, a randomized, controlled clinical trial conducted in Japan showed that sho-saiko-to, an extract of seven Chinese herbs, helps prevent liver cancer in patients with cirrhosis (H. Oka et al., Cancer, 76:743-9, 1995). This is the first treatment in any medical system that offers such benefits. In another study-a controlled, double-blind British clinical trial-a formula of 10 herbs produced impressive responses in treating severe atopic eczema, a widespread skin disease that was resistant to conventional Western therapies (M.P. Sheehan, D.J. Atherton, British Journal of Dermatology, 126:179-84, 1992). These studies suggest that further research on CHM may produce new and improved therapies, especially in the area of chronic diseases.
There are two basic approaches to drug discovery: rational drug design and the traditional method of random screening. Rational design-engineering new drug molecules from scratch with the help of computers and molecular biology-requires knowledge of the drug target (such as a receptor or an enzyme). So far, it has had only limited payoffs, although it has promising potential. In random screening, many synthetic chemicals or natural products are indiscriminately tested for biological activity. Because this method is both costly and time-consuming, there has been a great need for better efficiency in strategic R&D planning for pharmaceutical corporations.
The strategy of developing new drugs based on leads from Chinese herbs has an advantage over random screening, since it is guided by experience from a long history of clinical practice. According to a recent survey (P. Xiao, ed., A Pictorial Encyclopaedia of Chinese Medicine, vols.1-10, Hong Kong, Commercial Press, 1988-90), almost 7,300 plants have been used in CHM, and about 60 new herb-derived drugs have been developed by Chinese scientists over the last four decades.
The story of artemisinin (qinghaosu) is illustrative (D.L. Klayman, Science, 228:1049-55, 1985). Chemical studies on many species of Artemisia (including A. annua) have been conducted ouside China since the 1930s, but the Chinese were the first to discover its antimalarial activity.
Artemisinin possesses a novel bioactive peroxide group that distinguishes it from the old generation of antimalarial drugs. It is effective in treating chloroquine-resistant and severe cases without side effects. A Chinese medical book written 2,000 years ago described the herb Artemisia annua as a remedy for malaria. Following this indication, Chinese researchers started to evaluate various extracts of the plant during the late 1960s. After initial failure, bioactivity-directed isolation finally yielded this new antimalarial drug in 1972.
In the U.S., several new drugs originated from Chinese herbs have recently undergone development. One of them is Paluther, a synthetic analog of artemisinin, from Collegeville, Pa.-based Rh™ne-Poulenc Rorer. The anti-HIV drug trichosanthin (GLQ 223) works by a mechanism different from that of AZT, the most widely used AIDS medicine. A Phase II clinical trial of the drug was conducted by GeneLabs Technologies, based in Redwood City, Calif.
Huperzine A, an alkaloid from leaves of a Chinese herb, holds promise for improving memory and learning ability in Alzheimer's patients (S. Borman, Chemical and Engineering News, Sept. 20, 1993, page 35-6). Clinical data from China and preclinical tests in the U.S. indicate that huperzine A is much more potent and less toxic than tacrine, the only drug approved in the U.S. for the treatment of Alzheimer's disease. Interneuron Pharmaceuticals, based in Lexington, Mass., was granted a patent on the composition of huperzine A and began efforts to develop the drug in 1992. Although it is not certain that any of these drugs will finally make its way to the U.S. market, their novel structures or new mechanisms of action have provided scientists with valuable guidance in the search for new drugs.
A number of other drug leads have also resulted from CHM research. The bitter melon plant has been used in China as a treatment for common infections, tumors, and immune disorders. In Asia and in the U.S., there has been community interest in the use of the plant as an alternative therapy for AIDS. The Bitter Melon Therapy Group, based in Los Angeles, has been organizing tests on AIDS patients and recently claimed encouraging results.
In 1990, a research team led by Sylvia Lee-Huang of New York University School of Medicine, Hao-Chia Chen at the National Institutes of Health, and Hsiang-fu Kung at National Cancer Institute isolated a protein, MAP 30, from bitter melon and found it has multiple functions that are responsible for its anti-HIV activity. Last year, they reported the finding that the MAP protein is able to inhibit HIV-1 integrase, an enzyme essential for gene expression of the virus (S. Lee-Huang et al., Proceedings of the National Academy of Sciences, 92:8818-22, 1995). This type of activity is novel among anti-HIV agents. William Paul, director of AIDS research at NIH, has pointed out in an article that the development of integrase inhibitors "must be vigorously pursued" (W. Paul, Science, 267:633-6, 1995).
The root of a vine, Radix pucrariae, has been used in CHM for hundreds of years to treat patients who abuse alcohol. Recently, Wing-Ming Keung and coworkers at Harvard Medical School demonstrated that daidzin, a substance isolated from the herb, suppresses alcohol drinking in animal models (W.M. Keugn et al., PNAS, 92:8990-3, 1995). These findings bring hope for better drugs to treat human alcohol abuse. Current drugs on the market produce a range of side effects. On the other hand, the herb used in the Harvard study has been known to be nontoxic and is consumed as food in China.
Investigations into CHM conducted with theories and methods of modern science may also enrich Western medicine through the introduction of new ideas and concepts. For example, an important feature of CHM is the preference for composite prescriptions (combinations of herbs) over single active substances. The belief behind this practice is that the multiple ingredients interact with each other to produce synergistic therapeutic effects. This ancient concept is not readily compatible with modern medical theories.
For most modern drugs, each has only a single active ingredient with defined pharmacological effects, while herbal formulas contain many chemicals whose amounts vary with a range of factors. Nonetheless, some studies have shown that certain composite formulas have better efficacy and less toxicity than single ingredients. The Japanese researchers who investigated sho-saiko-to, for example, noted that it is difficult to explain its benefits as the effect of a single ingredient.
With the complex and variable nature of herbal formulas comes the challenge of developing new methodologies and techniques that are suitable for probing such systems. One success in this area is the application of "fuzzy logic" (a new approach to analysis of vaguely defined systems with uncertainties that are not amenable to precise measurement) to standardize amounts of ingredients in herbal preparations. These analyses provide novel protocols for quality control of herbal products.
In the face of skyrocketing drug-development costs, American pharmaceutical firms have paid attention to CHM as an alternative source of potential drugs. During the 1980s, Whitehouse Station, N.J.-based Merck and Co. Inc. and Kalamazoo, Mich.-based Upjohn Co. had extensive collaborative efforts with Chinese institutions to evaluate Chinese herbs. A number of bioactive natural products were discovered as a result of these joint studies. Last year, New York-based Pfizer Inc. and the Academy of Traditional Chinese Medicine in Beijing entered a three-year agreement to study CHM.
The majority of U.S. drug companies, however, are not actively pursuing research on Chinese herbs. This lack of interest is partly attributable to differences in culture and tradition, but it also reflects concerns over regulatory difficulties.
The stance of the U.S. Food and Drug Administration (FDA) has been that all drugs, whether they are synthetic chemicals, of an herbal origin, or herbal preparations long in use, must meet the same set of strict FDA criteria to be marketed. This attitude has created an unfavorable atmosphere for the development of herb-derived drugs. The reason is that it is difficult, though not impossible, to secure patent protection for natural products. Since a patent is a condition of profitability, drug companies would not take the risk of investing in herbal medicines without it. As one of the consequences, in the U.S. herbal medicines are sold as dietary supplements, which receive little regulation and pose more quality and safety problems than drugs.
Since a large portion of the drug-development cost falls on tests that are required for gaining regulatory approval, an obvious solution to this problem would be to reform regulations governing herb-derived drugs. Varro Tyler of Purdue University's School of Pharmacy has suggested that Europe's experience might be helpful in this regard. In Germany, if an herbal drug (plant or its extracts) has proven safety, the regulatory agency requires only "reasonable certainty" of its efficacy for marketing approval. In Britain and France, traditional use of herbal drugs is usually considered to be sufficient proof of safety and efficacy.
How can the U.S. improve its approval process? For herb-derived drugs with reasonable proof of safety and efficacy from their history of use, one option FDA may consider is to set up a special program that significantly reduces filing documentation as compared with that required for a synthetic compound. If FDA can properly use its regulatory power to reduce the cost of developing herb-derived drugs-thus encouraging industrial research on herbal medicines-it will eventually benefit the American public, especially people with currently untreatable diseases.
Although admittedly irrational concepts are present in Chinese herbal medicine (such as the intentional use of toxic heavy metals based on the belief that "toxin cures"), a growing amount of research data has suggested that a scientific basis lies behind it. The tasks of sorting out useful information from this wealth of knowledge and of integrating it into conventional medicine, though difficult and painstaking, are justified by the potential rewards.
Tianhan Xue is a consultant in pharmaceutical chemistry based in Santa Barbara, Calif. He has an M.S. in medical chemistry from the Chinese Academy of Medical Sciences and a Ph.D. in organic chemistry from Texas A&M University.