Preface to the Series The systematic study of herbal medicinal products and the investigation of the biologically active principles of phytomedicines, including their clinical applications, standardization, quality control, mode of action and potential drug interactions have emerged as one of the most exciting developments in modern therapeutics and medicine. Studies in phytomedicine have moved from purely descriptive analytical studies to conceptual inquiries on the pharmacodynamic advantages and limitations of plant medicines for the treatment of moderate or moderately severe diseases and prevention. Healthcare practitioners and medical scientists have come to accept herbal medicinal products as drugs that are different from the pharmacologically active molecules that they may contain. Several comparative clinical studies have been published to show that these plant medicines could have full therapeutic equivalence with chemotherapeutic agents, while retaining the simultaneous advantage of being devoid of serious adverse effects. Developments in molecular biology and information technology have now made it possible for us to begin to understand the mechanism of action of many herbal drugs and the associated phytomedicines, which differ in many respects from that of synthetic drugs or single chemical entities. Herbal medicinal products are now generally available in both industrialized countries and traditional societies. With the current lack of standardization and regulation of herbal products, it is important to develop common criteria for judging safety and efficacy of phytotherapeutic agents. This 'new' science demands different approaches to the classical methods of drug analysis, dosage formulations, manufacturing and claims substantiation. The therapeutic response observed with most herbs and phytomedicines are often not fully explainable using the currently available methods. Their activity usually characterized as polyvalent and interpreted as an aggregate or additive outcome of several constituents in the plant medicines are subject of intense pharmacological studies. In most cases, a rationale does not even exist for the observed pharmacodynamic effects of very low doses of phytomedicines after prolonged or long-term application. The public press is replete with lay information and claims about the use of herbal remedies, however, there is scarcity of scientifically accurate reviews and guides on the efficacy and safety of plant medicines. The time therefore seemed ripe to broaden the communication on the use and benefits of phytomedicines as safe and useful natural health care products aimed at the health professionals and scientists. It is also important to provide a broader dissemination of the extant scientific literature on phytomedicines, to enable the conventional medical community to fully appreciate the fact that plant extracts specifically, and natural products generally, offer valuable and needed benefits in the treatment and prevention of diseases, especially for conditions where there is no effective or generally acceptable drugs. viii Preface to the Series Although there are many papers published yearly on the use and analysis of plants as sources of biologically active molecules and some published materials on the use of plants as medicinal substances, volumes specifically addressing the needs of scientists and clinicians in the use of herbal products and standardized extracts as medicinal agents are far-in-between. We considered it therefore appropriate to fill this gap by producing an entirely new multi-volume series on the sourcing, selection, standardization, safety and clinical application of herbal medicinal products. As the name of the series implies, emphasis will be on those herbal medicinal products that are well characterized, standardized and substantiated as phytomedicines. The series will also provide timely reviews on the industrial production, regulatory and policy issues related to the use of phytomedicines. Although the literature in this field is evolving so rapidly that books on the subject become obsolete soon after they leave the press, the volumes in this series will aim at capturing the fundamental framework of each topic while remaining thoroughly up-to-date and comprehensive in scope. The aim of this series is to present to the scientists and clinicians the state of current knowledge in various fields of phytomedicine research, development and use. The approach is to provide the historical background to each topic, discuss methodological issues and illustrate current trends with case studies and critical examples, and when ever possible, the authors will indicate those plant medicines that are available for immediate use in clinical settings. The series is not intended to serve or replace the many excellent journals in this field but it will rather attempt to distill information from primary references and introduce elements of medicinal plants research and development that are in transition from speculative knowledge to standard practice. Advances ni Phytomedicine is also not meant to be a textbook of the various topics covered in the series. It will, however, provide a guide to specialized articles and books on the topics that are relevant to scientific research and development of plant medicines, as well as information on the regulatory issues, clinical trials and application of phytomedicines for healthcare. Advances ni Phytomedicine will therefore serve as a platform for reviewing recent developments in the use of herbal medicinal products. The coverage will include reviews of studies and use of all plant medicines, phytotherapeutic agents, nutraceuticals, plant cosmetics and therapeutically important molecules derived from these plant medicines. The first volume in this series has been devoted to exploring the ethnomedical approaches to drug discovery. It is indeed a very important starting point in addressing the relationship between plants and human health. Subsequent volumes will deal with other aspects of the use of herbal medicinal products. Selection of subjects will be through consultations with experts in the various fields of interest. We shall be guided by the principles of the so-called 6S, that is, herb selection, sourcing, structure, standardization, safety and substantiation. Acknowledged experts and authorities in the various aspects of phytomedicine will be invited to assemble and edit specific volumes in the series. The series is the outcome of extensive consultations among several biomedical scientists and clinicians who participated in the workshops and conferences organized by the Bioresources Development and Conservation program (BDCP) on related subjects. I am immensely grateful to these colleagues for their support in Preface to the Series xi developing the original concept. Many thanks go also to Ms Kim Briggs and Ms Joke Zwetsloot of Elsevier Science for their suggestions and help in producing this series. I am indebted to my colleagues at BDCP and the International Centre for Ethnomedicine and Drug Development for their contribution; and to my wife, Kate for her love and support. I acknowledge the International Cooperative Biodiversity Group (ICBG) of the Fogarty International Centre, United States National Institutes of Health for providing financial support to my research group at the Walter Reed Army Institute of Research and BDCP. Maurice M. Iwu M.Pharm., Ph.D. S6ries Editor Preface The first book in the series, Advances in Phytomedicine, provides an interface between ethnomedical approaches to new drug discovery and advances in biotechnology, molecular and clinical sciences that have made it increasingly feasible to transform traditional medicines into modern drugs. The contributions are drawn primarily from an international conference with the same title, Ethnomedicine and Drug Discovery, held in Silver Spring, Maryland, USA, November 3-5, 1999. Speakers and delegates attended from 71 different countries, spanning 5 continents. Different systems of traditional medicine were represented: African, North American Indian, South American, Ayurvedic, Chinese, and the European Eclectics. This book, however, is not a conference proceedings. Not all speakers from the conference contributed papers, and some additional papers were specifically commissioned to ensure full coverage of all aspects of the topic. This volume represents a rare collection of contributions from eminent scholars and experts in this field. Professor Iwu's introduction, Therapeutic Agents from Ethnomedicine, unpacks the conceptual ambiguities underlying ethnomedical and ethnobotanical research. Herbs contain pharmacodynamic compounds that can be standardized and incorporated into modern Western phytomedicines or nutraceuticals, based on the drug model of isolating a single active ingredient. This is a standard approach to new drug design, but quite different from the whole herb or multi-component herbal traditions from which the natural products derive, where the components are known to act synergistically and often non-specifically. Such herbal traditions are neither unscientific nor static but are based on systematic experimentation and, particularly in the Asian systems, careful documentation. Iwu also draws an important distinction between an eclectic approach to integrative medicine that allows pragmatic borrowing between conceptually distinct systems and recognition of the parallel development of both traditional systems of medicine and modern western medicine as different and largely incompatible. Most of the following papers can be seen to fall into one of the two approaches. Cragg (Chapter )1 sets the scene with a rich history of drugs developed from nature by successfully isolating the main active ingredient. While so much of the world's biodiversity remains unexplored the potential for future drug development is enormous. Harvey's paper (Chapter 2) discusses a way to make the process more efficient with high-throughput screening, while Carlson (Chapter )3 suggests multidisciplinary teams of researchers. Chapter 71 on Garcinia kola by Iwu et al. provides a case study for discussing many of the sensitive issues involved in developing a modern ethnobotanical product. Screening of plants for development into pharmaceuticals is usually based on local community knowledge. This raises a host of legal and ethical issues surrounding intellectual property rights. Moran (Chapter )61 provides an overview of the xii ecaferP Convention on Biological Diversity. The underlying issues are discussed by Lettington, Gollin, and Guerin-MacManus et al. (Chapter ,7 18-19). The situation is compounded by problems of sustainability and how to restore populations of medicinal plants, Cech (Chapter .)8 Gericke ( Chapter )31 gives a Southern African perspective on the failure of authorities to validate local knowledge. Schuster in Chapter 41 outlines the development of antimalarial agents based on leads from traditional medicine. The paper by Balick et al. (Chapter 23) describes the ongoing Belize ethnobotany project that was started in 1988 and encompasses all the interwoven issues of conservation, declining local knowledge, and benefit sharing. A further case study of the collaboration between the Buganda Traditional Healers Association and Shaman Pharmaceuticals, si provided by Nelson-Harrison et al. (Chapter 24). Some researchers from developing countries call for raising the profile of their contribution to drug development by increased training and expertise in medicinal chemistry, Efange (Chapter ,)5 or by using methods of bioprospecting for economic development, Onugu (Chapter .)8 One example of an herbal drug developed in Nigeria used for sickle cell anemia and derived from ethnomedicine si discussed by Okogun. In contrast, No6 (Chapter )01 celebrates the traditional healing systems that incorporate spiritual and cosmological belief systems. Such whole systems cannot be incorporated into the framework of modern western medicine. The conference incorporated a Festival of Living Culture with a celebration of plants, music, dance, and incantations reminding delegates that science, spirit, art, dance and ritual are integral to the world's main healing traditions. Borrowing of traditions cuts both ways. Obijiofor (Chapter )6 develops a model for integrating the best of western biomedicine and traditional ethnomedicine in South-eastern Nigeria. Integrative approaches to modern medicine usually involve a distinction between pharmaceutical drugs and dietary supplements and how to regulate them. Gruenwald (Chapter 20) provides an explanation of the regulatory situation in Europe; In Chapter 21, Osuide discusses the regulatory system in Nigeria; and Srinivasan (Chapter 22) provides the US perspective. Wootton (Chapter 4) presents the HerbMed database that gives access to neutral categorized scientific data on which regulatory and drug development decisions are based. The ultimate goal should be to obtain therapeutic agents from ethnomedicines that are safe, consistent, and effective remedies based on whole herbs, and standardized methods of cultivation and preparation. Meserole (Chapter )51 elaborates on the concept using the example of health foods in anti-aging therapy while Elisabetsky (Chapter )11 proposes ways to develop truly innovative paradigms in drug usage and development using psychotropic drug actions as a model. Finally, Iwu in the concluding chapter, weighs up the strengths and limitations of an ethnobotanical approach to drug discovery. We were privileged to have Representative, John Edward Porter, give the opening keynote address at a meeting on Capitol Hill. Mr Porter, since retired from office, has been a great champion of science funding and was a key driving force behind the International Cooperative Biodiversity Group grant program in the United States. Special thanks are due to the staff of the Bioresources Development and ecaferP iiix Conservation program (BDCP), in particular Dr Magnus Azuine, the conference assistant, who worked indefatigably to ensure the conference ran smoothly. The team were able to combine a cheerful, relaxed atmosphere with sharp academic rigor and efficient organization. It was a great pleasure to be involved in all aspects of the conference organization, the conference sessions and exhibits, and as joint editors of this volume. We would like to pay tribute to the many individuals and groups who have made this volume and the preceding event possible: Chris Okunji, Angela Duncan Diop, Chioma Obijiofor, Tony Onugu, Sam Iwu, Baljit Wadhwa and to other members of the organizing committee: Alice Clark, Ph.D.; University of Mississippi; James Miller, Ph.D., Missouri Botanical Garden; Katy Moran, the Healing Forest Conservancy; and to Mendy Marsh, the editorial assistant who collected, collated and copy-edited all the papers for this volume. We are grateful to Kim Briggs, Joke Zwetsloot and Anthony Prukar of Elsevier Science for their invaluable assistance and hard work in producing the book. We are indebted to the Ford Foundation, whose generous financial support of the International Conference on Ethnomedicine and Drug Discovery made this volume possible. Jacqueline Wootton Maurice M. Iwu uwI dna Wootton (eds.), enicidemonhtE dna Drug yrevocsiD (cid:14)9 2002 Elsevier ecneicS B.V. llA rights .devreser Introduction" therapeutic agents from ethnomedicine MAURICE M Iwu Abstract Ethnomedicine covers healthcare systems that include beliefs and practices relating to diseases and health, which are products of indigenous cultural development and are not explicitly derived from a conceptual framework of modern medicine. Ingredients used in the preparation of ethnomedical remedies provide attractive templates for the development of new pharmaceutical products. They contain compounds with pharmacological activities, which could be transformed into modern therapeutic agents and personal care products. Herbal medicinal plants used in ethnomedical practice are much more than vessels that contain lead compounds for drug development. They are medicinal agents in their own right, even as crude unprocessed materials. They are also considered in some settings as possessing vital healing energy that exceeds the measurable effects of their physical properties. Furthermore, they can be developed into dietary supplements, nutraceuticals and phytomedicines with precisely defined characteristics and consistent quality but with pharmacodynamic properties that are different from those of pharmaceuticals containing isolated single chemical compounds. The ultimate objective in drug discovery and development should be the production of safe and effective remedies, not the introduction of elegant molecular entities into medicine often without discernible therapeutic advantages over the traditional formulations. :sdrowyeK ethnomedicine, healing remedies, drug discovery, phytomedicines I. Healing and traditional knowledge Ethnomedicine encompasses the use of several health-promoting cultural practices and/or the use of minimally processed naturally occurring products for the prevention and treatment of diseases, as well as for the maintenance of optimal physical and emotional health. These indigenous or culturally based forms of medicine have their origin in antiquity, but they are not ancient medicine, so the use of the term 'traditional' to describe ethnomedicine may be misleading. As has been noted by Barsh, 1 the term 'traditional' may erroneously imply the repetition, from generation to generation, of a fixed body of data, or the gradual, unsystematic accumulation of new data. This is hardly the situation in ethnomedicine. On the contrary, ethnomedicine is based on careful observation by healers in a given generation of indigenous people. It is the healers' duty to compare their personal 2 Ethnomedicine and drug discovery experiences with what they have been told by their teachers and neighbors, conduct experiments to test the reliability of their knowledge, and exchange their findings. As Barsh 1 remarked, 'All "tradition" in actuality is continually undergoing revision. What is "traditional" about traditional knowledge is not its antiquity but the way in which it is acquired and used, which in turn is unique to each indigenous culture. Much of the knowledge is actually quite new, but it has a social meaning and legal character, entirely unlike the knowledge indigenous peoples acquire from settlers and industrialized societies.' The use of the term 'traditional medicine' to describe ethnomedicine in this volume should be understood to denote merely the historical and cultural context of the origin of the healing systems. Ethnomedicine covers a very wide spectrum, which may be classified into two types, the personalistic systems, where supernatural causes ascribed to angry deities, ghosts, ancestors and witches predominate, and the naturalistic systems, where illness is explained in impersonal, systemic terms. 2 The personalistic system appears to predominate (although not to the exclusion of the naturalistic explanations) in the traditional medical systems of native America, parts of China, South Asia, Latin America and most of the communities in Africa. Naturalistic explanations (also not to the exclusion of personalistic causation) predominate in Ayurveda, Unani, Khampo (Japan) and traditional Chinese medicine. In the later types, part of the belief is that intrusion of heat or cold into, or their loss from, the body upsets its basic equilibrium; that is, the balance of humors, or of the dosha of Ayurveda, or the yin and yang of Chinese medicine, and these must be restored if the patient is to recover. In the personalistic system, as exemplified by the traditional African system of medicine, healing is concerned with the utilization of human energy, the environment, and the cosmic balance of natural forces as tools in healing. In the African world, the natural environment is a living entity, whose components, the land, sea, atmosphere, and the faunas and floras, are bound to man in an intrinsic manner. Plants therefore play a participatory role in healing. A healer's power is not determined by the number of efficacious herbs they know, but by the magnitude of their understanding of the natural laws. The ability of the healer to utilize these natural laws for the benefit of his patient and the whole community is the ultimate measure of his success. Treatment therefore is not limited to the sterile use of different leaves, roots, fruits, barks, grasses and various objects like minerals, dead insects bones, feathers, shells, eggs, powders, and the smoke from different burning objects for the cure and prevention of diseases. If a sick person is given a leaf infusion to drink, they drink it believing not only in the organic properties of the plant but also in the magical or spiritual force imbibed by nature in all living things and also the role of his ancestors, spirits and gods in the healing processes. The patient also believes in the powers of the incantation recited by the healer and assists them in the designation of the ingredients of the remedies given, from mere objects into healing tools. The patient is also an active participant in the art of healing, not a passive subject of therapy. According to the World Health Organization, a large segment of human population still depends on traditional medicine, or the so-called alternative medicine, as the preferred form of healthcare, even with improved access to modern citueparehT agents from enicidemonhte 3 hospital medicine and the spectacular advances in molecular biology and physiological chemistry that have greatly enhanced our understanding and treatment of diseases. Traditional medical systems such as meditation, acupuncture, relaxation, training, hypnosis, and energy healing are becoming increasingly popular as alternative or complementary techniques to Western scientific medicine. Herbal- based therapies, once used only in traditional medical systems are now recommended for the treatment of several degenerative disorders and chronic conditions where modern pharmaceutical agents have proved inadequate. The acceptance of these techniques as standard healthcare options has posed serious conceptual problems in the development of public-health programs that are responsive to the real needs of the population, with a tremendous impact in the cost of healthcare interventions, preventive medicine and self-healing. With globalization, major changes are occurring in the practice of traditional medicine and the role of related therapeutic agents in healthcare delivery. It is changing from a highly personalized form of healing to generic health intervention systems often administered outside its cultural base and for conditions that were neither intended or envisaged by the healers. There is also a shift from dealing with a 'patient' to catering for faceless 'consumers'-often through layers or chains of commercial intermediaries. With an ever-increasing clientele, practitioners of traditional medicine and interested scholars must format a strategy that will make traditional medicine available to a wider population while preserving the cultural bases of the healing systems. This challenge is being met by two approaches: one is the development of integrated approaches, in which elements of the two systems are adopted in an eclectic manner, and the other is the parallel recognition of both traditional medicine and modern Western medicine as legitimate but different types of healthcare. The ingredients used in traditional medicine, therefore, must be recognized and used in modern medicine, not only as therapeutic agents with verifiable pharmacodynamic properties, but as agents of healing with beneficial effects, even when the precise mode of activity has not been properly understood. II. Traditional medicine and spiritual healing One aspect of traditional medicine that has remained difficult to understand by conventional Western medicine is spiritual healing. This is due to the differences in the fundamental concepts of health, diseases and healing between Western societies and traditional cultures. This aspect of traditional medicine deals with healing in which intangible energy is used to restore health. The healing ritual, whether pharmacological or spiritual, only reflects a recognition or identification of the part of the multi-layered matrix of human life and existence that is diseased and where the treatment is being targeted. 3 Proponents of ethnomedicine argue that while pharmacologically active herbs do possess beneficial effects in the treatment of several physical components of existence, they are hardly useful in disorders that involve the core of a person's innermost being and reality, or when the non-tangible 4 Ethnomedicine and drug discovery self si in disequilibrium, or when a person loses the rapture of being alive and merely exists with their spirit long receded. Traditional healers insist that unless this aspect of healing is acknowledged (even if not accepted), our understanding of traditional medicine will remain flawed because of the inherent limitation in our very method of inquiry. In a limited Western sense, spiritual healing could be described as a method of treating patients by positive mental intentions only. 4 This form of treatment si not limited by time and space, therefore, personal contact si no prerequisite for therapy, and healing sessions are known to have occurred over large distances. Although spiritual healing si practised in nearly all human communities, the subject still remains a complicated undertaking because of the very nature of spirituality and healing. As has been noted, 5 the very process of describing it will inevitably be reductionist, since healing and the response to healing are often 'state-of-mind'- dependent and are not readily accessible to outside observers. It si generally accepted that evaluation of spiritual healing does not fit readily into the usual methodologies used in either laboratory medicine or clinical research. 6 There is a growing body of evidence to suggest that although it si difficult to know when healing is effective (beyond the determination of obvious physiological differences), it si possible to determine clinical outcomes and even undertake randomized clinical studies to establish the effect of spiritual healing practices. 9-7'4 A recent controlled study of patients treated by spiritual healing concluded that chronically ill patients who want to be treated by distant healing and know that they are treated show a statistical improvement in their quality of life. 4 The study reported by German investigators, Wesendanger, Reuter, and Walach has been described as providing an example of a realistic balance between scientific rigor and clinical relevance, by retaining the essential features of proper experimental comparison (random allocation to treatment and good inferential analysis) and, at the same time, staying close to the actual practice situation. 7 III. Integration and complementarity Many practitioners of evidence-based medicine view the increasing recognition for traditional health systems as a failure by modern medicine to satisfy the healthcare needs of the society. Some practitioners of biomedicine even feel threatened by a system, which they view as unscientific and beyond rational categorization. Traditional medicine, they argue, si steeped in spiritual and magical practices based on ritual, whereas biomedicine si derived from the belief in materialism and mechanism anchored on experiments and verifiable theories. By this logic, the two forms of healthcare are seen as direct opposites, systems that cannot collaborate in any meaningful way for the greater interest of the population. The issues are often reduced into two intractable questions: should healthcare providers permit the introduction of healing ceremonies, charms, music, incantations into modern healthcare clinics to free the sick persons from demons and ghosts who have possessed them? Is it ethical to allow costumed medicinemen and medicinewomen with their elaborate rituals, feathers, pipes, drums, beads and egg-shells to further