Medicinal Plants: Their Role in Health and Biodiversity 9780812292633

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Medicinal Plants

Proceedings of an International Symposium Cosponsored by the Morris Arboretum of the University ofPennsylvania and the World Health Organization, Philadelphia, Pennsylvania, April1993

Medicinal Plants Their Role in Health and Biodiversity

Edited by Timothy R. Tomlinson and Olayiwola Akerele

PENN University of Pennsylvania Press Philadelphia

Copyright © I998 Morris Arboretum All rights reserved IO 9 8 7 6 5 4 3 2 I Published by University of Pennsylvania Press Philadelphia, Pennsylvania I9I04 Library of Congress Cataloging-in-Publication Data Medicinal plants : their role in health and biodiversity I edited by Timothy R. Tomlinson and OlayiwolaAkerele. p. em. "Proceedings of an international symposium cosponsored by the Morris Arboretum of the University of Pennsylvania and the World Health Organization, Philadelphia, Pennsylvania, Aprili993"- CIP t.p. verso. Includes bibliographical references and index. ISBN 0-8I22-343I-6 (cloth: alk. paper) I. Materia medica, Vegetable -Congresses. 2. Medicinal plantsCongresses. 3. Botany, Medical- Congresses. !. Tomlinson, Timothy R. II. Akerele, Olayiwola. RSI64.M373 I998 6I5'.32-dc2I 98-IOll3 CIP

Contents

Preface: Promoting the Worldwide Use of Medicinal Plants Symposium Co-Chair

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TIMOTHY R. TOMLINSON,

Acknowledgments

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Medicinal Plants, Scientific Progress, and Development 1. A Case History of Plant-Derived Drug Research: Phyllanthus and Hepatitis B Virus

3

BARUCH S. BLUMBERG, M.D.

2. An Expanded Program for Medicinal Plants Symposium Co-Chair

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OLAYIWOLA AKERELE, M.D.,

Medicinal Plants in the Socioeconomic Context

3. Exploiting Medicinal Plants: Why Do It the Hard Way?

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NATHAN SIVIN, PH.D.

4. Safety, Efficacy, and the Use of Medicinal Plants

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NORMAN R. FARNSWORTH, PH.D.

5. Economics and Medicinal Plants

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PETER P. PRINCIPE

6. The Medicinal Plant Marketplace ROBERT S. McCALEB

55

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Contents

Conservation: Issues and Future Prospects 7. Linking Ethnopharmacology and Tropical Forest: Conservation in Belize

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MICHAEL]. BALICK, PH.D.

8. Exploitation of Medicinal Plants

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AKHTAR HUSAIN, PH.D.

9. Agronomics and Medicinal Plants

103

DAN PALEVITCH, PH.D.

10. The Role of Botanical Gardens and Arboreta in Traditional Medicine: A Personal Reflection and Case Study

120

WILLIAM McKINLEY KLEIN,JR., PH.D.

Promising Practices in the Use of Medicinal Plants 11. The Legal Situation ofPhytomedicines in Germany

137

BARBARA STEINHOFF, PH.D.

12. Indonesia: The Utilization of Medicinal Plants for Primary Health Care

144

DJOKO HARGONO, PH.D.

13. Ethnopharmacological Surveys in Brazilian Extractive Reserves

149

ELAINE ELISABETSKY, PH.D.

14. Traditional Korean Medicine

156

CHONG-YUL KIM, PH.D.

15. Utilization and Conservation of Medicinal Plants in China with Special Reference to Atractylodes lancea

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HE, SHAN-AN

16. Medicinal Plants in the Philippines

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NELIA P. CORTES-MARAMBA, M.D.

17. Promising Practices in the Use of Medicinal Plants in the United States ARA H. DERMARDEROSIAN, PH.D.

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Contents

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Regulatory Issues 18. Medicinal Plants and Phytomedicines within the European Community

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HUBERTUS CRANZ, PH.D.

19. The Evolving Status of Herbals and Phytomedicines in the United States

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ROBERT G. PINCO, ESQ.

Appendixes A. WHO Guidelines for the Assessment of Herbal Medicines

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B. A Recommendation for Governments around the World

212

List of Contributors

213

Index

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Preface: Promoting the Worldwide Use of Medicinal Plants Timothy R. Tomlinson

All cultures, from ancient times to the present, have used plants as a source of medicine. According to the World Health Organization (WHO), most of the world's population depend upon plants as an important element in primary health care systems. Nevertheless, a large number of plants have not yet been studied for their medicinal properties, and researchers around the world are turning increasingly to plants in the search for new medicines. In developing countries, governments are looking to plants as a way to extend health care benefits within a viable economic framework; in developed countries, consumers are seeking viable alternatives to modern medicine. Despite a rich history and powerful economic possibilities, medicinal plants' potential to contribute to the health of the world's people has not been fully tapped. For the last two decades, through the resolutions of its governing bodies and implemented by the WHO Traditional Medicine Program, WHO has promoted the use of traditional medicine in general, and the use of medicinal plants in particular, for primary health care. The program has promoted the use of medicinal plants through a series of international consultations, seminars, and symposia. The symposium on the utilization of medicinal plants held in Philadelphia, Pennsylvania, in April 1993 was part of a WHO international program strategy and had several specific objectives shared by the Morris Arboretum of the University of Pennsylvania: to increase awareness throughout the world of the use of plants as medicines; to promote the propagation and cultivation of medicinal plants;

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to promote the appropriate use of medicinal plants in primary health care systems; to promote conservation and preservation practices that extend to plants and to traditional cultural practices that hold the secret of ethnomedicinal uses of plants; and to promote new partnerships among international agencies, arboreta and botanical gardens, and the international pharmaceutical and herbal/botanical industries. The Philadelphia symposium was the most recent in a series of meetings that represented an effective vehicle for implementing WHO's Traditional Medicine Program goal of promoting the conservation and utilization of medicinal plants for primary health care. Conducted over the past two decades, four of these meetings have served as important defining moments that move us toward that goal. These include: Alma-Ata, USSR (1978), Chiang Mai, Thailand (1988), Munich, Germany (1991), and Philadelphia, U.S.A. (1993). WHO Assembly resolutions in the 1970s prompted the convening of an international meeting, the Conference on Primary Health Care, in AlmaAta (1978), attended by delegates and observers from more than 130 countries. The conference restructured the international health agenda. Participants provided an assessment of need, a philosophy for action, a blueprint of activities, and an assignment of resources and responsibilities. With the goal of health for all by the year 2000, it was clear that the promotion, development, and utilization of plants as medicine were essential elements of any international strategy. Policies regarding medicinal plants as an integral unit in traditional medicine systems moved from a passive recognition of the role of plants in providing medical care to an active promotion of their identification, conservation, and further exploitation. Through a network of regional committees, special consultancies, technical programs, collaborating centers, and cooperative activities with other international agencies of the United Nations and member states, WHO sought to provide direction for the following actions: 1. developing a realistic approach to the use of medicinal plants to ensure that this use will complement existing modern systems and is functionally integrated into the larger health system; 2. studying and evaluating medicinal plants in the context of scientific methodology; 3. promoting the integration of proven knowledge and procedures of medicinal plant use into the health care system; and 4. conserving the plant resources of the world.

Preface

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These goals and issues formed a WHO agenda in the decade that followed Alma-Ata. WHO's activity increased significantly in 1988 with an International Consultation on the Conservation of Medicinal Plants, held in Chiang Mai, Thailand. The meeting agenda was framed by the initiation of the Global Medium-Term Program of traditional medicine that established priorities for action for the period 1990-1995. The principles of this Medium-Term Program were articulated by a small group coordinated by Dr. Olayiwola Akerele, at that time the manager ofWHO's Traditional Medicine Program. Dr. Akerele observed that the therapeutic value of medicinal plants was no longer open to question. There were, however, other issues to debate: safety and efficacy, the integration of traditional medicine/medicinal plant use into the larger health care system, and the economic value/importance of medicinal plants. Safety and efficacy were important considerations to many participants at Chiang Mai. Indeed, some indicated that safety should be the overriding criterion in the selection of medicinal plants for use in national health care systems. As was the case in Alma-Ata, the deliberations at Chiang Mai provided a focus, a further delineation of the blueprint for "Health for All in the Year 2000." The Munich Consultation, convened in 1991, carried the work further, giving birth to the Munich Guidelines for the Assessment of Herbal Medicines, an important international statement on medicinal plants that covers pharmaceutical assessment, safety assessment, assessment of efficacy and intended use, combination products, product information for the consumer, and promotion (see Appendix A). The guidelines were presented to and recommended for wider use in 1991 by the Sixth International Congress of Drug Regulatory Authorities, held in Ottawa, Canada. The Philadelphia symposium in 1993 continued the work begun in Alma-Ata, addressing issues of international collaboration and redefining them in the context of conservation, economics, health care reform, legislation, and new partnerships. In addition to reaffirming the work begun at the previous meetings, this symposium brought to the discussion a new partner whose interests have for centuries played an important role in the promotion, utilization, preservation, and conservation of plants throughout the world: botanical gardens and arboreta. In addition to promoting and fostering the economic viability of local vegetation, botanical gardens and arboreta attempt to foster a greater understanding of the degree to which all life depends on maintaining a species-rich environment, and to discover and promote indigenous management techniques that seek coexistence with nature rather than domination and destruction.

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The first botanical gardens in the Western scientific tradition were medicinal and herbal gardens attached to faculties of medicine: Pisa, Padua, Florence, Oxford, and Cambridge. As centers for the scientific study of plants, botanical gardens and arboreta are institutions for conservation and development. In the past, their work focused on the discovery of new plant species and the protection of endangered plant species. Recently, this focus has widened to include responsibility and appreciation for the potential value of all plants. This shift in focus is due in part to the work of botanists such as Peter Raven (Missouri Botanical Garden) and ethnobotanists such as Richard Schultes (Harvard), Michael Balick (New York Botanical Garden), and D. D. Soejarto (University of Illinois at Chicago). The Philadelphia symposium gathered 139 participants from twentyfour countries and twenty-six states in the United States. Featured speakers included Nobel laureate Baruch Blumberg and Dr. Joseph Jacobs, the former director of the Office of Alternative Medicine, United States National Institutes of Health. Continuity with the Chiang Mai proceedings was maintained by the participation of Olayiwola Akerele (WHO), He, Shan-An (Nanjing Botanical Gardens), Norman Farnsworth (University oflllinois at Chicago), Akhtar Husain (Lucknow), Peter Principe (United States Environmental Protection Agency), and Dan Palevitch (Volcani Institute, Israel). Two ideas dominated the Philadelphia symposium: the importance of medicinal plants to global health care reform and the importance of forging new relationships and partnerships. The symposium participants recognized and endorsed the potential role of arboreta and botanical gardens in balancing these interests. Indeed, the participants recognized that these and other related institutions could be at the center of regional, national, and international strategies. This role would be a reprise of the historic role these institutions played as centers for the study of plants and for the study of plants as medicine. Following the import of the defining moments of Alma-Ata, Chiang Mai, and Munich, the Philadelphia symposium participants proposed for the coming decades that new partnerships be established, partnerships that link university arboreta with WHO policies and programs, with governmental and intergovernmental agencies in developing and developed countries, with indigenous populations and their practices, and with pharmaceutical research interest (see Appendix B). The partnerships should be ones in which all partners have a stake, a role, a voice. The chapters in this book speak eloquently to promising practices in medicinal plant usage and to worldwide opportunities and challenges for the twenty-first century.

Acknowledgments

The editors wish to acknowledge the support of the Organizing Committee for the International Symposium on the Utilization of Medicinal Plants, held in Philadelphia, Pennsylvania, Aprill993. Many of the members of this committee contributed essays to this book. We wish also to thank William Learnard, Jerome Reinstein, Hubertus Cranz, and Rick Lewandowski for meeting with us in Philadelphia, London, Munich, and Geneva. These meetings provided the orientation and focus for this publication. We appreciate the editorial and organizational efforts of Mary Brooks Mullahy, Christine Pape, and the Princeton Group. The transformation from rough manuscript to finished copy would not have happened without their skill and dedication. Rick Lewandowski and Ara DerMarderosian made important contributions to taxonomic nomenclature. We are indebted also to He, Shan-An and the staff of the Nanjing Botanical Garden for the line art illustrations. The efforts and dedication of these persons added greatly to the quality of this book. We wish to acknowledge the financial support of the McLean Contributionship, and particularly the sustained interest in the project by William McLean III andJohn Buhsmer. We appreciate also the support of the Traditional Medicine Program of the World Health Organization and the Barra Foundation, Wyndmoor, Pennsylvania. We thank also the World Federation of Proprietary Medicine Manufacturers, the European Proprietary Medicine Manufacturers Association, the 1957 Charity Trust, and private donors. Timothy R. Tomlinson Olayiwola Akerele

Medicinal Plants, Scientific Progress, and Development

Chapter 1

A Case History of Plant-Derived Drug Research Phyllanthus and Hepatitis B Virus Baruch S. Blumberg

Introduction There is a paradox in the current approach to the discovery of medications derived from natural sources. On the one hand, there are many successful medications in current use that have been derived from natural materials, particularly plants. In addition to the drugs derived directly from plants, there are many others, introduced as plant-derived materials, originally used for a particular purpose but whose molecules have subsequently been greatly altered by the ingenuity of synthetic chemists and which now serve other purposes. Many of these plant-derived medications came from indigenous medical systems in the Western tradition or were identified because of their folk use. On the other hand, there is a suspicion of folk medicine by practitioners of scientific medicine and among scientists whose responsibility is to discover drugs. This is, in large part, due to the nonscientific process by which folk systems traditionally operate. Folk therapies are often based on faith. Some may be derived from a system of medicine with a rationale radically different from the principles that guide scientific medicine. These include, for example, the ayurvedicmedicine of Hinduism or the unani practices of Islam. (Interestingly, unani is based on the Greek medical tradition preserved and enhanced by Islam.) Other folk medications are based not on a comprehensive logic but on empirical wisdom accumulated over many years and often arrived at through trial and error. The use of these medications may be associated with what Western scientists might construe as irrelevant, magical, or incantatory practices.

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Hence, any questioning of the effectiveness of the treatment could be construed as a lack offaith in the underlying religious practice. Scientific medicine is built on skepticism; any theory or practice must be subjected to unbiased trial. And it is the responsibility of the scientist to continue to question as new data on effectiveness and disadvantage emerge. Where then do ethnobotanical concepts fit into the scientific process? Science can be viewed as inductive or deductive. In the inductive phase, data are first collected and a hypothesis is then derived from the data. In the deductive phase, the hypothesis is stated first and then the data are collected to test it. Ethnobotany is useful in the inductive phase, that is, to obtain ideas on what may be a successful treatment. In the subsequent deductive phase, critical scientific method is used to test effectiveness. Scientific medicine and the pharmaceutical industry appear to have a cyclic interest in drugs derived from natural sources, with periods of intense interest alternating with a refractory attitude. We appear to be going through a relatively upbeat period at present, which has been sustained by several interesting and important recent successes; for example, the yew tree-derived taxol, which has shown promising results in cancer therapy. I would like to discuss some of the pitfalls and cautions associated with drug discovery from natural products.

Folk Medicine and Scientific Progress One of the basic tenets of scientific medicine is that one should seek a single cause for a disease; identify a single or small number of biochemical, physiological, immunologic, or other abnormalities; and then administer a single medication to set it right. (This reductionist approach is often not observed, and patients with even straightforward diagnoses may require many medications.) Folk medicines often use the whole plant, many plants, or extracts of them, all of which contain many chemical compounds. The folk tradition may emphasize the importance of the mixture, but it is difficult to evaluate complex mixtures using conventional scientific methodology. The contribution of each element of a mixture may be difficult to determine, as there can be a very large number of combinations of the separate components as well as different doses. Also, treatment is often individualized. Testing each of these mixtures may be prohibitively complex. An important and often insurmountable problem is the difficulty of determining whether any preparations of the mixtures are the same. Modern therapeutic trials are often based on the assumption that the drug to be tested is consistent. One of the major contributions of the pharmaceutical industry is to produce pills that are identical in chemical com-

Case History of Plant-Derived Drug Research

5

position and in dose. The outcome variables, that is, therapeutic effects or detrimental side effects, can then be objectively evaluated. With plant mixtures, there are too many constituents that may vary from one dose to the next. Even if a single plant is used, the concentration of the active principle may vary because of the location in which the plant was grown, the pH of the soil, agricultural methods used, and many other variables that are difficult to quantify. Possibly because of this, controlled trials of folk treatments are not often successfully completed, and when they are, the results of different trials using different preparations can vary greatly. Despite this, well-controlled studies of indigenous treatments are reported. See, for example, the Sheehan et al. (1992) report on the efficacy of traditional Chinese herbal therapy in adult atopic dermatitis. The present emphasis in drug discovery is on rational drug design based on the enormous increase in knowledge made possible by molecular biology. The molecular explanation of the dysfunction caused by a disease is determined, and then an effort is made to design the exact chemical grouping needed to set the mischief right. The methods that served in the past were based on developing appropriate biochemical, tissue culture, animal, and other screens for pharmaceutical activity. The source of the chemicals to be tested included extracts of natural products, active chemicals isolated from the natural products, synthetically modified molecules, de novo synthesized chemicals, and recombinant products. Even with a certain amount of function-structure knowledge in the design of the chemicals, the process often had a hit-or-miss quality. Rational drug design now promises a more logical and scientific approach; the next few years will reveal how successful this can be. In the next section, I will describe one of the studies in which we have been involved in an attempt to find a plant-derived antiviral that would be effective against hepatitis B virus (HBV). We have, so far, been unsuccessful in identifying a useful treatment, but the discussion of the process will, I hope, illustrate some of the promises and problems inherent in this approach.

Hepatitis B Virus: Search for Plant-Derived Antiviral HBV is one of the most common chronic human viral infections. There are about 350 million chronic carriers of HBV in the world, most of them in Asia, sub-Saharan Africa, and the Pacific region. Many of these carriers are at high risk of developing chronic liver disease, which can be lifeshortening, and primary cancer of the liver, which has a low survival rate and is very difficult to treat. Because of the morbidity associated with HBV infection, there are now universal childhood vaccination programs in more than forty countries. These are based on vaccines derived from

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the original vaccine Dr. Irving Millman and I invented more than twenty years ago. These programs have had a significant effect on the incidence of chronic infection in the young, but there are still an enormous number of carriers in the world. It is thought that eliminating the virus from the carrier or, if that is not possible, decreasing its replication and pathogenesis, will significantly decrease the risk of developing the deadly late consequences of infection. In order to identify a plant from which we might extract an HBV antiviral, we used an ethnobotanical-guided approach. We prepared a list of plants that had been used in indigenous medical systems for the treatment ofjaundice. The rationale behind this was that hepatitis B is and has been the cause of much of the jaundice in the world. We reasoned that this list might give a rough indication of plants used to treat HBV infection and that some of them might have antiviral capabilities. A total of 1,887 species were identified in a search of 557 references. The databank included information on common name, location where the plant was used, the part of the plant said to be effective, and other information on local usage. We then sorted the species alphabetically and identified species in which the same species or species in the same genus had been used in three or more continents or major geographic regions. This resulted in a short list of about 150 species. Plant exploration trips were then organized to collect sufficient amounts of the short-list plants to test the possible efficacy of the plants and to obtain voucher specimens to validate identification. This required the establishment of the Fox Chase Cancer Center Herbarium to maintain an orderly collection of the voucher specimens. Among the locations where field tests were conducted are Australia, England, Nepal, Trinidad, the Western Ghats in Karnataka, India, and the United States (California, Hawaii, Pennsylvania, South Carolina, and Texas). I am indebted to the many systemic botanists who helped in the identification and classification of the plants collected on these trips.

Laboratory Screening Two laboratory screens were used to reduce the number of plants to be considered for further investigation. These tests were introduced before the detailed knowledge of the molecular biology of HBV was known and are relatively unsophisticated. With the recent advances in the understanding of the replication and pathogenesis of HBV, several more tests have been introduced and will considerably broaden the scope of HBV antiviral research. A major lesson we derived from this project is the central role of the screening tests. The development of a wide variety of tests that can give an indication of potential clinical efficacy and can be

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performed rapidly and with good reproducibility is essential for drug discovery. The tests initially used were: 1. Interference with the reaction between the surface antigen ofHBV (HBsAg) and its equivalent antibody, anti-HBs. This reaction was thought to indicate an effect on pathogenesis, since the reactions of viral antigens with the hosts' immune responses play a major role in pathogenesis. At the time, it was also thought to be related to the binding site of HBV, a view that has not been supported by recent research. 2. Inhibition of the DNA polymerase (DNAp) of HBV. HBV produces its own DNAp, which is essential to the replication process of the virus. Chemicals that inhibit this reaction could be inferred to have ambivalent properties. We collected about thirty-five of the species on our short list; of these, about twelve passed the screening tests. We conducted a rough experiment to determine whether the folk use of a plant for the treatment ofjaundice predicted the ability of the extracts of the plants to inhibit HBV DNAp. During field trips in India and the United States, we collected fifteen plants that were on our short list and eleven controls that were not. Eleven (73%) of the short list plants but only three (27%) of the controls inhibited DNAp. This supported our decision to use the ethnobotanical guide for plant selection, but also indicated that it was not a precise technique. Deciding which of these plants to select for investigation was made on a different basis than originally planned. Dr. Venkateswaren, the natural products chemist working in our group, had started an investigation on Phyllanthus amarus (at that time identified as P niruri), which had been sent to him from India. Phyllanthus has been used for many centuries for the treatment of jaundice and is still widely used in the non-Western medical pharmacopoeia in modern India. (Typical of many folk remedies, it is used for many purposes in addition to the treatment of jaundice.) We subsequently noted that Phyllanthus was on our short list of plants that had been used for the treatment ofjaundice in three or more continents, and that it showed significant inhibition ofDNAp and interfered with the HBsAg/ anti-HBs reaction. We selected this as our lead plant and proceeded on several paths (Blumberg et al. 1990a, 1990b): 1. Agronomy, that is, developing Phyllanthus as a crop plant. These studies were directed by David Unander. We also compared different species of the genus Phyllanthus (Unander and Blumberg 1991; Unander, Webster, and Blumberg 1990, 1991, 1992). 2. Testing extracts in the laboratory and in woodchucks. Dr. Irving Millman, who played a prominent role in the project, was responsible for these studies. 3. Testing extracts in clinical trials (Thyagarajan et al. 1988). 4. Isolation of active principles using DNAp inhibition as a guide. The

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plants grown from seed in an experimental agricultural plot in southern Florida did not differ greatly in respect to the DNAp inhibition from the plants collected in the wild. Optimal growing conditions were determined, and several crops were raised in the Florida location and used for extraction and isolation studies. We did find significant variation depending on the geographic location in which different collections of the same species were taken. This suggested that there is genetic variability for the DNAp inhibition trait. There was only a small effect due to pH variation, but increased temperature increased the titer of DNAp inhibition. We also found that roots were significantly more active than shoots, but that the roots accounted for only 10 percent of the dry weight of the plant. We concluded that, based on the DNAp inhibition trait, Phyllanthus could be harvested as an agricultural crop and used for further studies. Experiments were also conducted by Unander on callus induction and growth. Callus was grown successfully, but extracts from field-grown plants were more active than the extracts of the calli and this line of investigation was not carried further (Unander 1991). There are some seven hundred species in the Phyllanthus genus organized in nine subgenera. Unander et al. surveyed the ethnobotanical literature and determined which plants were used for the treatment of liver disease. They clustered in only three of the subgenera. This provides a rough priority guide as to which of the many species of the genus should be investigated.

Laboratory and Woodchuck Tests Our initial strategy was to test water and organic extracts to determine if there was an effect in vitro and in vivo. This work has been presented elsewhere and will be briefly summarized here (Blumberg et al. 1990a). Phyllanthus extracts inhibited HBV-DNAp relatively more strongly than DNAp from bacterial and mammalian sources. They also inhibited the HBsAg/anti-HBs reaction. Woodchucks (Marmota monax) caught in the wild in certain geographic regions are often infected with a virus, woodchuck hepatitis virus (WHV), which is remarkably similar to HBV. WHV, as does HBV, causes a chronic carrier state, often leading to chronic hepatitis. Animals chronically infected for an extended time have a nearly 100 percent probability of developing primary cancer of the liver. It is a remarkable example of a model in a wild animal of an infectious agent and a mechanism of pathogenesis very similar to that found in humans. Long-term treatment of the animals with extract of P amarus led to the loss or a decrease in the quantity of the virus. These initial studies, which showed the most striking results, had been performed with plants col-

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lected in the wild near Madras, India. Subsequent woodchuck studies with P. amarus collected in the same place but at a different time, or the same species collected elsewhere, gave results in the same direction, but less striking than the original observations. Hence, our original observations were very encouraging, but the subsequent ones less so. This difference in effect we presumed to be due to a difference in the activity in the plants collected for the later studies. Yeh and his colleagues in Taiwan (1993) have studied the effects of extracts of P. amarus on human hepatoma cell lines transfected with tandemly arranged HBV DNA. They found that cellular proliferation was inhibited and HBsAg production decreased. There was no effect on HBeAg, a measure of viral replication. They also found that HBsAg gene expression at the mRNA level was suppressed. A decrease of the production of duck hepatitis B virus in duck cell cultures has also been observed, but the extracts do not affect the production of virus in infected ducks. Clinical Studies As noted above, P. amarus has been used for many years in the treat-

ment of jaundice in India. Professor Thyagarajan from the University of Madras conducted a controlled trial using powdered whole plant collected in the Madras region. We participated in the study design and also confirmed some of the tests for the detection of HBV in the serum specimens collected from treated and untreated carrier patients. Twenty-two of thirty-seven carriers treated with the plant powder lost the surface antigen, while only one of twenty-three controls did so. These remarkable results encouraged others to conduct similar clinical trials. However, studies in Thailand and in the Netherlands failed to confirm the Madras observations. I am not aware of any clinical studies that were consistent with the original Indian results. Hence, the earlier studies on the extracts and whole plant, although very encouraging, were followed by later, ambiguous results. They illustrate the difficulty of dealing with chemically undefined substances and the inconsistencies that can occur in natural products. We have now focused our attention on isolated and characterized chemical constituents of the extracts, including ellagic acid, geraniin, and others. These are now under test to determine if they contain antiviral activity.

Conclusion The search for new medical treatments is long and difficult. There are many hazards on the road to discovery, and we have encountered our

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share of them. Workers in this field have every reason to be encouraged by the frequent success in the quest. Combining this ancient method of drug discovery with the new possibilities of rational drug design will, it is hoped, continue to provide new medications to combat old diseases and new ones not previously encountered. Scientific process must be rigidly adhered to in determining the efficacy of plant-derived drugs. This is difficult to do when using whole plants or combinations of plants, but appropriate methods can be developed that will allow us to test the current validity of the wisdom of indigenous practices that have been handed down to us. References

Blumberg, B. S., I. Millman, P. S. Venkateswaran, and S. P. Thyagarajan. 1990a. Hepatitis B virus and primary hepatocellular carcinoma: Treatment of HBV carriers with Phyllanthus amarus. Vaccine 8:S86-S92. - - . 1990b. Hepatitis B virus and hepatocellular carcinoma: Treatment ofHBV carriers with Phyllanthus amarus. A SEANJ Clin. Sci. Monograph 11:35-4 7. Sheehan, M.P., M. H. A. Rustin, D.J. Atherton, C. Buckley, D.J. Harris,]. Brostoff, L. Ostlere, and A. Dawson. 1992. Efficacy of traditional Chinese herbal therapy in adult atopic dermatitis. Lancet 340:13-17. Thyagarajan, S. P., S. Subramanian, T. Thirunalasundari, P. S. Venkateswaran, and B.S. Blumberg. 1988. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 2:764-766. Unander, D. W. 1991. Callus induction in Phyllanthus species and inhibition of viral DNA polymerase and reverse transcriptase by callus extracts. Plant Cell Reports 10:461-466. Unander, D. W., and B.S. Blumberg. 1991. In vitro activity of Phyllanthus (Euphorbiaceae) species against the DNA polymerase of hepatitis viruses: Effects of growing environment and inter- and intra-specific differences. Economic Botany 45:225-242. Unander, D. W., G. L. Webster, and B. S. Blumberg. 1990. Records of usage or assays in Phyllanthus (Euphorbiaceae) I. Subgenera