PROSEA, Introduction to Medicinals 1

Plant Resources of South-East Asia Introduction

List of species

Introduction

True to its title Prosea 12 is devoted to medicinal and poisonous plants used in South-East Asia. Following common practice in literature, the two categories of plants have been combined into one commodity group. This is because many poisonous plants are used medicinally; at lower doses their toxic constituents are often beneficial.

Systems of medicine

It is important to distinguish between three different types of medicine: traditional, herbal and pharmaceutical. A plant may be consumed as a medicinal tea by members of a community living in the area where the plant is indigenous, the same plant may be cultivated and processed in the country of origin into a formulation of a herbal medicine sold in western countries, and it may provide a lead compound for a pharmaceutical product. These systems of medicine are complementary in health care and can in no way substitute one another (Balick et al., 1996). In this volume, the role of the species in each of the three systems is distinguished whenever possible.

The importance of medicinal plants

Medicinal plants are of great economic importance. They are used as raw materials for the extraction of active constituents in pure form (e.g. quinine and quinidine from Cinchona bark), as precursors for synthetic vitamins (e.g. fixed oil for vitamin E) and steroids (e.g. Dioscorea and Smilax roots), and as preparations for herbal and indigenous medicines. Plants are not only the major source of energy-rich foods in most societies, but are also an indispensable source of vitamins and other substances promoting healthy growth. But note that though the consumption of certain plant parts may be prophylactic, e.g. scurvy is prevented by eating citrus fruits (in which vitamin C is the active factor), plant species with these properties are generally treated in other Prosea volumes, particularly Prosea 2: "Edible fruits and nuts" and Prosea 8: "Vegetables".

The present volume covers only those species of plants whose medicinal uses and properties are described in the literature. The discovery of important medicinal properties (e.g. oncolytic properties of the alkaloids in Catharanthus roseus (L.) G. Don) in the last 40 years has resulted in thousands of scientific reports on South-East Asian medicinal plants. The few existing handbooks on medicinal plants of South-East Asia (e.g. Perry, 1980) only give information on the plants' uses and properties, but the team of authors and editors responsible for this volume has combined the information in the reports and manuals with botanical and agronomic information.

Many plants used in medicine or as poison have other uses. In this volume, however, generally only those species with primarily medicinal or poisonous functions are dealt with.

This compilation of the published data will be especially useful to researchers developing new drugs. It is more efficient to screen plants used in traditional medicine, as these yield a much higher output of interesting substances than plants sampled at random. This is why many pharmaceutical companies incorporate ethnobotanical information into their research and development programmes. Much knowledge still only exists as oral tradition and many species still need to be investigated to find out their constituents and biological effects. Numerous plant species are used in traditional veterinary medicine. Most small farmers in South-East Asia rely on herbal medicines to treat their sick animals, since these are easily available and affordable. Written information on veterinary uses is scarce; most information is still transmitted orally.

Aromatic plants

Many kinds of aromatic plants are traditionally used medicinally, usually prepared as teas. The volatile components of essential oils are often present in the preparations and these are often thought to be responsible for the biological activity.

It was sometimes difficult to decide which species should be covered in Prosea 12: "Medicinal and poisonous plants", Prosea 19: "Essential-oil plants", and Prosea 13: "Spices" (the latter includes numerous aromatic plants). Wherever possible it is tried to avoid an overlap in the species treated in these 3 volumes, with the result that the final choice is somewhat subjective. Furthermore, though lower plants (fungi, algae, mosses, lichens and ferns) are sometimes also used medicinally, they have not been included in this volume, even when they have no other use; instead, they appear in Prosea 15: "Cryptogams". Several plant species used medicinally also produce dyes or tannins, and are treated in Prosea 3: "Dye and tannin-producing plants".

Poisonous plants used as medicine and pesticide

Only those poisonous plants used medicinally or as pesticides are dealt with in this volume. The pests that plant extracts can be used against are rodents, birds, insects, molluscs, nematodes, fungi, bacteria, algae, viruses and weeds. The preparations used to protect against these pests are known respectively as rodenticides, avicides, insecticides, molluscicides, nematicides, fungicides, bactericides, algaecides, virucides and herbicides. Though traditional applications of pesticides of plant origin were gradually ousted by chemical pesticides, there has recently been a resurgence of interest in plant-based pesticides. This is partly because chemical pesticides have been found to have disadvantages, including being health hazards to farmers and consumers. Furthermore, there is concern about the accumulation of residues in soil, groundwater and animals, and the build-up of resistance in pests. In contrast, plant-based pesticides are usually not accumulative, so are environmentally benign. Moreover, they are often highly selective, their toxicity to non-target mammals is usually low, and pests do not appear to develop resistance to them because these pesticides contain many active ingredients, even when derived from a single plant source (Chomchalow in Chomchalow & Henle, 1993). Examples of plant species used as a source of plant-based pesticides are neem (Azadirachta indica A.H.L. Juss.), derris (Derris elliptica (Wallich) Benth.), turmeric Curcuma longa L.) and citronella (Cymbopogon nardus Rendle). However, because plant-based pesticides are so biodegradable they are rather unstable, which means that they have a short shelf-life, must be used soon after preparation, and have low persistence after application. Many plant-based pesticides are made domestically and more cheaply than chemical pesticides. Since only crude extracts are used to make them, such pesticides are definitely much less effective than chemical pesticides that have been formulated and purified to a high concentration.

In 1996 a Prosea Task Force on Medicinal and Poisonous Plants was appointed to delineate the large commodity group and to propose how this group could best be dealt with in the Prosea handbook. The Task Force, which consisted of L.S. de Padua (University of the Philippines, chairwoman), R.H.M.J. Lemmens (Prosea Publication Office, the Netherlands, secretary), N. Wulijarni-Soetjipto (Prosea Network Office, Indonesia), N. Bunyapraphatsara (Mahidol University, Thailand), A.M. Latiff (Universiti Kebangsaan, Malaysia), Nguyen Tien Ban (Institute of Ecology and Biological Resources, Vietnam), Sjamsul Arifin Achmad (Institut Teknologi Bandung, Indonesia), R.P. Labadie (Utrecht University, the Netherlands) and D.K. Holdsworth (Norwich, United Kingdom) presented its report in March 1996.

It proposed that Prosea 12: "Medicinal and poisonous plants" should consist of three parts, published separately. The three parts would essentially reflect the importance accorded to the species: the most important species would be treated in part 1, the least important ones in part 3. In spite of its shortcomings, this approach has important advantages over alphabetical treatment: it enables important and well-known medicinal and poisonous plants to be dealt with in greater detail than unimportant and lesser-known ones, and allows for any omissions from the first two parts to be made good in the third part. Preliminary lists for the 3 parts were drawn up more or less subjectively, based on existing handbooks on medicinal or useful plants for South-East Asia like Burkill (1966), Dharma (1981), Heyne (1927), Holdsworth (1977), Nguyen Van Duong (1993) and Quisumbing (1978). The list was finalized after being critically reviewed by the members of the Task Force.

The plants in Prosea 12: "Medicinal and poisonous plants" are dealt with primarily by genus rather than by species. This is because the properties of different species within one genus and hence their uses are often similar. Furthermore, the genus approach reduces the large commodity group to manageable proportions. After each genus description, selected species are described briefly. If only one species of a genus is important in South-East Asia, however, it is dealt with as a species.

Since time immemorial people have used plants and other materials that were not part of their usual diet to treat illness. They arrived at these treatments by trial and error and accumulated tradition and experience. All cultures have long histories of the use of plants in folk medicine, recorded in ancient herbals from which most of the present-day pharmacopoeias have been derived. Archaeological evidence for the use of herbal remedies goes back 60 000 years: in a Neanderthal cave burial site, excavated in Iraq in 1960, pollen from 8 plant species was found around human bones. These plants were evidently intentionally collected and placed there; 7 of them are medicinal plants still used today. In the last 30 years there has been a resurgence of interest in the use of plants as medicines. However, although the world population is increasing and plant-rich habitats such as the tropical forests are dwindling steadily (Latiff, 1991) there appears to be no concerted effort in research and conservation. The renewed interest in medicinal plants is also clearly noticeable in South-East Asia and has resulted in research and development programmes in several countries, and also in joint efforts such as the Asian Network on Medicinal and Aromatic Plants (ANMAP).

Forests have long been regarded primarily as a source of timber, but now the value of non-wood forest products is becoming increasingly appreciated. Medicinal plants are important non-wood forest products and should therefore be a priority in forest protection measures. It is therefore gratifying that biodiversity prospecting and its policy implications for medicinal plants are now recognized as an important issue in conservation.

Traditional and modern medicine in South-East Asia

Below, the history, status and role of medicinal plants is described briefly for each country in South-East Asia; likely future developments are also noted. For practical reasons (the cross-border distribution of ethnic groups) the islands of Borneo and New Guinea are treated separately instead of under Malaysia, Brunei, Indonesia and Papua New Guinea.

Indonesia

The traditional use of plants for healing in Indonesia dates back to prehistoric times. The art and knowledge of the uses of plants as medicine have been handed down orally from generation to generation. Some plants still used in traditional medicine can be found depicted in reliefs on the walls of ancient temples in Java, such as those of Borobudur, Prambanan, Penataran and Sukuh. They include Aegle marmelos (L.) Correa, Antidesma bunius (L.) Sprengel, Borassus flabellifer L., Calophyllum inophyllum L., Datura metel L. and Syzygium cumini (L.) Skeels.

The earliest written references to the local uses of plants in Indonesia are in the early 16th Century reports of Portuguese explorers. The first endeavour to gather data on Java's medicinal plants was by Bontius (1658). His work includes some 60 plates of plants with descriptions of their healing powers and uses. Rumphius's work ("Herbarium Amboinense", 1741-1755), a special study of the flora of Ambon (Moluccas) was more important. It describes hundreds of plants, giving extensive details on their medicinal use and properties. Horsfield (1816) published one of the first monographs on the medicinal plants of Java.

Many publications on medicinal plants appeared in the 19th and early 20th Century. Of these, Greshoff's publications (in the period 1890-1914) focused mainly on poisons but also included plants with medicinal properties. Kloppenburg-Versteeg (1907, 1911) wrote books in Dutch, giving hints and advice on using Indonesian plants. The second edition of Heyne's book on the useful plants of Indonesia (1927) gave extensive information on the medicinal uses. Since then, numerous papers and books have been published on the medicinal plants of parts and islands of Indonesia, but these usually either relate to one or a few species, or summarize recorded traditional uses in a confined region (e.g. AvÉ) & Sunito (1990) for Siberut and Bell & van Houten (1993) for Central Seram). There have also been some books dealing summarily with larger numbers of medicinal plants from Indonesia, e.g. Kasahara & Hemmi (1995) and Syamsuhidayat & Hutapea (1991).

In rural areas, "dukuns", i.e. persons with putative expertise in medical matters and who use medicinal plants in their preparations, still play an important role in primary health care. So-called "jamus" - complex mixtures of herbs - are still widely and commonly used in Java. The ingredients are well pounded and mixed, and steeped in hot water. Alternatively, they may be dried, and then boiled when required, to yield a decoction for use. Jamus may be preserved in powder form, after drying over heat in an iron pan. Most jamus have a long history of traditional use and some have been tested empirically and shown to be effective. However, they are often not used as medicine for a given disease but to keep the body healthy, in a holistic approach. Sometimes they are used for cosmetic purposes. It is often recommended to take jamus regularly. The composition of a jamu used to treat a certain disease and having a certain standard name may vary, depending on the custom or view of the person preparing the mixture. Jamus are in general prepared and traded by women from Central Java, whose good healthy complexions advertise the efficacy of their products. Some jamus are given to livestock. It is estimated that 1000-1300 plant species are used in the preparation of jamus. Most of these are collected from the wild. Manufactured products are also widely available over the counter throughout Indonesia. Jamus produced industrially have also been exported from Indonesia for a number of years in the form of powders and tablets. The knowledge on medicinal plants and jamus has been kept in families in the form of hand-written records. The original manuscript on Javanese traditional medicine, called "serat kawruh bab jampi-jampi Jawi" and written around 1831 was kept in the library of the Surakarta Palace. It contains 1166 prescriptions, 922 of which are jamu preparations.

Research on medicinal plants has been conducted in Indonesia for more than 50 years. The studies have included the collection of samples, the inventory of genetic resources, ethnobotany, biotechnology, agronomy, chemical properties, pharmacological and toxicological screenings, product standardization, formulation and plant conservation. Several institutes working on medicinal plants have been established since 1950, as well as working groups and committees. Numerous scientific meetings have been organized on the subject.

Recent developments point to an increased interest in medicinal plants. A national working group on medicinal plants was established in 1990 as a follow-up to a national seminar. To promote the development and socialization of the use of medicinal plants, the Ministry of Health has issued lists of recommended medicinal species to be planted in family gardens. Gardens with medicinal plants have been established throughout the country. Various institutions have made a germplasm inventory of medicinal and aromatic plants (Wahid in Chomchalow & Henle, 1993).

Peninsular Malaysia

Traditional medicine has been important to Malaysians of all ethnic groups for centuries. The influence of the cultures of China, India and Java is strong. For instance, almost all the medicinal products sold in the Chinese community are imported from China, and the influence of Javanese medicine is still important among the local Javanese communities in Selangor. The classic work by Burkill (1935) is still the standard reference for traditional medicine. Much of the knowledge on traditional medicine still dominant in the culture of various ethnic groups is unrecorded, and handed down from one generation to the next. The practitioners of traditional Malay medicine have vast knowledge about the identification and classification of plants, folk nomenclature and, above all, the medicinal properties. This knowledge has not yet been tapped systematically to develop medicines based on traditional remedies (Latiff, 1991). However, since 1981 researchers at the University Kebangsaan Malaysia have conducted many multidisciplinary projects on medicinal plants. Although the cultivation of medicinal plants was advocated to ensure a continuous and reliable supply of products for local consumption or export, no large companies have shown interest; small-scale cultivation for local consumption or sale has started, however (Latiff, 1991).

The approaches summarized by Latiff (1991) as being vital for future research in traditional medicine in Malaysia remain valid today. They are:

• An inventory and therapeutic classification of the medicinal plants used.
• The development of scientific criteria and methods for assessing the safety of medicinal plant products and their efficacy in the treatment of diseases.
• The introduction of national standards and specifications for identity, purity, strength and manufacturing practices.
• The designation of research and training centres for the study of medicinal plants.

Borneo

The original inhabitants of Borneo were probably the forest dwelling Punan people. Other groups, such as the Iban, immigrated over the centuries. In more recent history, Malay people have immigrated to coastal areas, followed by Chinese settlers later. The traditional medicine of these peoples of Borneo reflects their origins.

Many Chinese inhabitants of Borneo use imported dried herbs packaged in China, which have often been recorded as Chinese herbal medicine for several thousand years. These are supplemented to some extent by local plants. There are Chinese medicine shops in most coastal towns in Borneo. Malays recognize the similarities of the flora of Borneo and Peninsular Malaysia. Malay traditional medicine has only been recorded in this century.

Many of the non-Chinese people of Borneo have a tradition of a "bomor" or "shaman": persons who have accumulated the medicinal lore of their people, who are regarded as healers. These persons may still use incantations, invoke animistic spirits in trances and be well versed in local superstitions and native psychology. Above all, they use plants either from the rain forest or cultivated in their garden. In contrast to Chinese herbal medicine the plants used are invariably collected fresh and used externally or internally as decoctions. Though Malay medicine is similar in origin, it has been modified by the influence and teachings of Islam.

Until very recently, there have been few studies of the traditional medicine of the indigenous tribal peoples of Borneo. This still represents a challenge to botanists, pharmacologists, pharmacognosists, anthropologists and phytochemists. There were some studies of traditional medicine done by Dutch explorers when Indonesia was still a Dutch colony, but these were almost exclusively confined to the economically more important islands of Java and Sumatra. The difficulties of learning the languages of the people of Borneo contributed to the general lack of scientific studies. In the early 1990s, some inventories and bio-assay screening of medicinal plants used by the Kenyah Dayak people, under the auspices of World Wide Fund for Nature, resulted in a publication (Leaman et al., 1991).

The same might be said of British explorers in the former British colonies of North Borneo (present-day Sabah) and Sarawak. Traditional medicine was of little interest when western drugs and quinine could be imported. The establishment of the Sarawak Museum in Kuching led to an interest in ethnic cultures and in the medicinal properties of indigenous plants associated with these cultures. Recently some research has been done by the Sarawak Forest Department (unpublished), and a publication by Ahmad & Holdsworth (1994) is available. For Sabah, there are two recent publications by Ahmad & Holdsworth (1994, 1995). In Brunei some interest in publishing data on medicinal plants began in the early 1990s. There are several recent publications on the medicinal plants of Brunei (Holdsworth, 1991; Mohiddin, Wong Chin & Holdsworth, 1991, 1992). Recent studies by the staff of the Herbarium Bogoriense resulted in seminar reports on medicinal plants of Kalimantan in 1995. The increased cooperation of nations in the area should result in future joint studies of the medicinal plants and plant lore in different areas of Borneo.

New Guinea

There is a rich heritage of traditional knowledge on the use of plants as medicines in New Guinea. The first New Guineans, who possibly arrived from South-East Asia and settled some 60 000 years ago, may have brought medicinal plants with them, or the knowledge of how to use the familiar plants they found on arrival. This would have been followed over thousands of years by systematic trial and error experimentation in the coastal and highland areas. Plants that had effective medicinal properties would be used again, and in this way a local tribal pharmacopoeia would be built up.

A few scattered records of medicinal plants were made by explorers and botanists in Dutch, German and Australian New Guinea at the beginning of the 20th Century. The first collection of some importance was that of Father Futscher, a Catholic priest on New Britain in the 1950s. He collected about 80 plant species used as medicine, noted the local Kuanua language names and tried to identify the plants. The results were published in German in 1959. In the early 1970s many plants from Papua New Guinea were tested in the Chemistry Department of the University of Papua New Guinea (Port Moresby) for the presence of alkaloids. In 1973 it was decided to concentrate on testing traditional medicinal plants. It was shown that these plants - particularly those used internally to treat malaria and fevers - were more likely to contain alkaloids than plants chosen randomly. The medicinal plants collected were identified at the Papua New Guinea National Herbarium at Lae. In over 20 years of fieldwork, Holdsworth collected several thousand specimens of medicinal plants in many different areas of Papua New Guinea; their uses were noted, and the plants were identified, mainly at the PNG National Herbarium in Lae. To date, the survey has yielded over 600 species of medicinal plants. It is interesting to crosscheck the medicinal uses of the plants in different areas of New Guinea (with its numerous languages and consequently little exchange of information between tribal communities) and other tropical countries, by studying the available literature. A first survey was published in 1977 (Holdsworth, 1977), and a more complete overview is in preparation.

In New Guinea, fresh plant material is invariably used for medicinal applications. One plant is often used alone, and sap from its leaves or bark is drunk, or rubbed on the body. Decoctions of bark, twigs or fresh leaves are also drunk. Many traditional medicines have a strong or bitter taste, which suggests that they contain alkaloids, although other substances might account for this taste too. A healer may also choose plants for a treatment based on the Doctrine of Signatures, a practice favoured by many mediaeval physicians.

Traditional beliefs are strong in rural areas throughout New Guinea and healing methods that use medicinal plants are still widely practised. Most tribes have a traditional healer who has been trained by an elder close relative in the uses of certain effective and secret medicinal plants. Often the healer was regarded as a sorcerer and practitioner of traditional medical psychology. Papua New Guinea is currently experiencing rapid changes. Young men and women leave their villages to attend school and to seek employment in towns. They are not available to learn the traditions and medicinal knowledge of their relatives and ancestors, so many traditional customs and practices are disappearing in village communities or are being replaced. The demonstrative effectiveness of a shot of antibiotics and other modern medicines at the first aid post, health clinic or hospital has reduced reliance on plant medicines and is accelerating the disappearance of traditional medical practice in many areas. It is essential to record the traditional uses of medicinal plants before they are lost forever.

The Philippines

Plants have played an important role in traditional medicine in the Philippines since ancient times. When the Spaniards colonized the Philippines in 1521, they were suprised to find many medicinal plants. It is possible that Chinese traders who came to the Philippines before the Spaniards introduced their herbal medicines and traded them with the Filipinos for other goods. Several manuscripts written during the Spanish regime (1521-1898) survive; well known among these are Father Blanco's "Flora de Filipinas" (1737), and "Plantas Medicinales de Filipinas" by Trinidad Pardo de Tavera (1892). Much research on medicinal plants was conducted in the years of American occupation (1898-1935) at the University of the Philippines and at Government Laboratories, now the Department of Science and Technology. Guerrero led these scientific activities, and working with him were scientists such as Merrill, Brown, Elmer, Sulit, Valenzuela, Maranon, Santos, Concepcion and Quisumbing, all well known in the field of medicinal plants. It was during this period that Brown's "Useful plants of the Philippines" and Quisumbing's "Medicinal plants of the Philippines" were written, surveys were extended to unexplored regions and chemical analyses and clinical investigations were done. During the Second World War, Filipinos depended entirely on plants as sources of medicines, and came to realize not only that the Philippines abounds with a wide variety of medicinal plants, but also that research on these plants was still much needed.

Medicinal plants are part of the cultural heritage and the "herbolario" (herb doctor) is a respected member in his community. The "herbolario" and the "hilot" (midwife) are traditional practitioners who learn and pass down their craft from generation to generation. They use plants for the treatment of diseases and to relieve pain and physical suffering. Traditional practice was coupled with native beliefs and superstition. The common belief was that disease is due to the presence of evil spirits in the human body which could only be removed by using some bitter-tasting substances, usually derived from plants. Although the practice of the traditional practitioners was empirical in nature, most of the original information on drug-producing plants was derived from them and forms the basis for recent scientific studies and for the present research and development programmes on medicinal plants.

When modern western drugs became available, many Filipinos, especially those in the urban centres, lost touch with their herbal heritage. It became very difficult for herbalists and researchers on medicinal plants to attract interest and support for their work, particularly for the wide acceptance of the use of these plants. The persistence and dedication of Filipino scientists to the efforts of providing adequate health care to poorer sectors of the population through intensive research and dissemination of information have brought about major changes in attitudes and in the health care system. Many western-trained doctors now prescribe herbal medicines for their patients, and medicinal plants continue to provide basic and alternative health care to the Filipino people, particularly in remote areas and islands where the lack of medicines is critically felt. As in most developing countries, herbal medicines still play a major role, with more than 80% of the population using herbal remedies. Dosage forms such as tablets, capsules, syrups, ointments, liniments, tinctures, lozenges, lotions and herbal teas are available, and herbal soaps, shampoos and other body care products are popular. Some of these products are even exported. Remarkable progress and new developments have taken place in recent years, strengthened by the active participation of government and private agencies. Some pharmaceutical companies have expanded into herbal medicines and body care products, and the government has established 4 factories in different regions to manufacture herbal medicines. As a result of intensive research, several medicinal plants are being promoted for use and cultivation in the countryside. Dissemination of information about medicinal plants and herbal products is actively pursued through publications, presentations, seminars, training programmes, exhibitions and educational displays. Many publications are available on Philippine medicinal plants, e.g. "the National Formulary" by Concha (1978), "the Guidebook on the proper use of medicinal plants" by Maramba, and the four volumes of "the Handbook on Philippine medicinal plants" by de Padua, Lugod & Pancho. The population now has access to safe, effective and affordable herbal medicines, and meanwhile there is renewed and accelerating interest in the industrialization and exploitation of Philippine medicinal plants.

Thailand

Medicinal plants have constituted an important part of Thai traditional medicine since that system of medicine, which was adapted from the Ayurvedic system incorporating Thai culture and tradition, was introduced 700-1000 years ago. The earliest knowledge is not well documented, as only a few prescriptions survive. The system of traditional medicine was revised and compiled during the reigns of Kings Rama I and II of Ratanakosin in the 18th and early 19th Century. The prescriptions were recorded on the stone plaques and walls of the Wat Poh temple. Under King Rama V (1868-1910) the royal prescriptions were again compiled, revised and published, and this served as the basis for the Thai traditional medicine of today.

The use of medicinal plants fell sharply when western drugs became available. It is difficult to reverse the decline, because the texts on traditional medicine are too vague. Most of the texts contain the name of the plants, their indications and recipes, but lack detailed information on the preparation. This is probably because traditional doctors jealously guarded their knowledge. Most of the recipes are composed of many ingredients, and each ingredient is added for a specific purpose. At present, most doctors are trained in western medicine and the health care system relies almost totally on imported western drugs. This leads to the following problems:

• A large amount of foreign exchange is lost.
• The drugs are too expensive for people with low incomes.
• The ease of using modern medicines allows abuse.
• A shortage of drug supplies may arise in times of civil unrest.
• The government cannot provide equal health care between rural and urban areas, especially in terms of drug supply

These problems prompted the government to consider revitalizing the use of local medicinal plants. The first development plan was set up in 1982. Studies by the Faculty of Pharmacy of the Mahidol University suggested that medicinal plants should be developed for use in primary health care, for the pharmaceutical industry and for export. Of these, the development for primary health care has been most successful, with about 55 plant species being promoted for use. The use of single species of plants was investigated, to make it easier to determine or trace the cause of any adverse effect that might occur.

The plants were selected carefully, using the following criteria:

• Only species for which there is scientific evidence of beneficial activity are selected, and only those with pharmacologically confirmed efficacy are recommended for use in primary health care.
• The plants must have passed toxicity tests, including mutagenic and teratogenic tests, or must also be used as food.
• The plants are used to treat symptoms for which self-diagnosis is possible.
• The method of preparation is simple.
• The plants are locally available, so as to ensure year-round supply.

Health workers were trained in the proper use of medicinal plants and their cultivation, and are responsible for encouraging their use at village level. The programme of developing medicinal plants for primary health care was successful in rural areas where there is no easy access to drugstores and hospitals. At present the government is preparing to add some medicinal plants to the national list of essential drugs. It is also drawing up good manufacturing practices for the factories preparing traditional medicine, to improve the quality of herbal drugs.

Development for export is progressing slowly, because there is no large-scale cultivation technology and also because of the rapid change in world demand. Medicinal plants are recommended as catch crops. Many of them can be grown in areas where the more common commercial crops cannot be cultivated, and they can play a role in forest conservation.

Vietnam

Up until the 18th Century the history of the Vietnamese traditional medicine, which goes back more than 2000 years, is interlarded with the names of famous physicians such as Tue Tinh (14th Century). Only two books from this period have survived: "Nam Duoc Than Hieu" ("The miraculous effect of traditional medicine"), which includes 580 ingredients of traditional medicine, and "Hong Nghia Giac Tu Y Thu" ("Hong Nghia's summary of using traditional medicine"), which covers 600 ingredients. In the 18th Century, Le Huu Trac added another 330 ingredients to the former book, and published it as "Linh Nam Ban Thao" ("Linh Nam's traditional medicine book"). This formed the basis for traditional medicine in Vietnam. Since the beginning of the 19th Century there have been many publications on Vietnamese medicinal plants.

Since the mid-1950s, the Vietnamese government has stimulated research on medicinal plant resources for use in primary health care. From 1960 to date, over 200 species of medicinal plants have been commercialized. The plants are collected from natural resources or from cultivation in quantities in excess of 100 000 t/year. Most of them are used in traditional medicine forms such as pastes, powders, pills and liquids, but some plant compounds are extracted industrially, the total quantity being over 2000 t/year. The number of research and development institutes dealing with traditional medicine is increasing, as is their input, and the availability of experienced physicians is further helping increase the popularity of traditional medicine. The Vietnamese system of traditional medicine has contributed greatly to community health care.

Production and trade

Statistics on international trade usually refer to commodity groups. Exact figures for individual plant drugs can be obtained for only a few cases. Often it is not even possible to distinguish between medicinal plants used in the pharmaceutical industry and plant species used in other industries. Medicinal and aromatic applications are lumped together (e.g. Piper nigrum L., Zingiber officinale Roscoe). According to trade figures of the United Nations Conference on Trade and Development, the international trade in plant-based drugs has a value of US$ 800 million annually, on average. China is by far the leading country: between 1992 and 1995, its average annual exports were more than 120 000 t, with a value of over US$ 250 million. India followed (33 000 t, US$ 46 million), and then Germany (14 000 t, US$ 68 million). Singapore exports the largest amount of plant-based drugs of the South-East Asian countries: 13 200 t annually with a value of US$ 54 million in the period between 1992 and 1995. Thailand is also amongst the top 12 countries in the world: its annual exports are 3300 t, with a value of US$ 7 million (Lange & Schippmann, 1997). The export value of Indonesian medicinal plants amounted to just US$ 2 million in 1991, whereas the internal market was worth US$ 45 million. The major countries importing plant-based drugs are Hong Kong (China) with 77 000 t worth US$ 134 million annually between 1992 and 1995, Japan (43 000 t, US$ 114 million) and Germany (43 000 t, US$ 96 million). Singapore is market leader in South-East Asia with an average annual import of 7300 t and a value of US$ 36 million.

However, the trade in medicinal plants is vast and largely unmonitored. Moreover, most people in developing countries depend on the direct use of plants for their health care, and thus the total trade in plant-based medicines may be a hundred times more than the volume of the international trade.

Phytochemistry deals with the chemistry of plant metabolites and their derivatives. The metabolic system of a plant may be regarded as being constituted of regulated processes within which biochemical conversions and mass transfer take place. Our understanding in this field has advanced to a stage in which definite metabolic processes, biosynthetic pathways and their interconnection are distinguished and studied in the context of their function and genetic control.

The metabolic performance of living organisms can be distinguished into primary metabolism and secondary metabolism. Primary metabolism is associated with fundamental life processes common to all plants. It comprises processes such as photosynthesis, pentose cycle, glycolysis, the citric acid cycle, electron transport, phosphorylation and energy regulation and management. Primary metabolites are produced and converted molecular entities, that are needed in anabolic pathways to build, maintain and reproduce the living cell. In catabolic pathways, primary metabolites (and food products) provide the chemical energy and precursors for biosynthesis.

Primary and secondary metabolism are interconnected in the sense that the biosynthesis of accumulating secondary metabolites can be traced back to ubiquitous primary metabolites. However, in contrast to primary metabolites, secondary metabolites represent features that can be expressed in terms of ecological, taxonomic and biochemical differentiation and diversity. The biosynthesis and accumulation of secondary metabolites provide a basis for biochemical systematics and chemosystematics. In addition, the wide molecular diversity of secondary metabolites throughout the plant kingdom represents an extremely rich biogenic resource for the discovery of novel drugs and for developing innovative drugs. Not only do plant species yield raw material for useful compounds; the molecular biology and biochemistry provide pointers for rational drug development.

Primary and secondary metabolites can be classified on the basis of their chemical structure into much the same categories of chemical compounds: carbohydrates, lipids, amino acids, peptides, proteins, enzymes, purine and pyrimidine derivatives. Within such compound classes, secondary metabolites generally show greater individuality and diversity in their molecular structure than primary metabolites. On the other hand, certain compound classes appear to be extraordinarily rich in secondary metabolites. Examples are the structurally diverse groups of alkaloids, phenolics, acetogenins and terpenoids. Ubiquitary primary metabolites belonging to these compound classes seem to be restricted to only a limited number of key compounds functioning as biosynthetic precursors.

Most of the plant compounds that have been found to be medicinally useful and interesting tend to be secondary metabolites. Nonetheless, the discussion of compound classes that follows has been arranged according to chemical structure classes usually clustered as such.

Carbohydrates

The first products plants produce by photosynthesis are carbohydrates. They are formed from water and carbon dioxide and can be grouped into sugars and polysaccharides. The sugars are either monosaccharides such as glucose and fructose, or oligosaccharides containing up to 5 or 6 monosaccharide units. Monosaccharides are classified according to the number of carbon atoms they contain; thus, trioses, tetroses, pentoses, hexoses and heptoses are C compounds. The polysaccharides are macromolecules, containing a large number of monosaccharide residues.

Carbohydrates constitute a large portion of plant biomass, e.g. cellulose as part of the cellular framework, and starch as a food reserve.

Sugars can unite with a wide variety of compounds to form glycosides, increasing the water solubility of the compounds. Glycosides vary in chemical stucture and pharmacological activity due to their aglycone component.

In addition to their use as bulking agents in pharmaceuticals, carbohydrates have recently been recognized to have useful pharmacological properties. Several polysaccharides exhibit immunomodulatory, antitumour, anticoagulant (e.g. heparin), hypoglycaemic or antiviral activities. The various carbohydrate products traded include fibre, cellulose and its derivatives, starch (glucose polymers) and its derivatives, dextrins, fructans (fructose polymers; e.g. inulin), algenic acids, agar and gums.

Lipids

Vegetable oils

Vegetable oils are major sources of β-sitosterol, which is a steroid drug precursor. One vegetable oil, obtained from groundnut, yields lecithins, which are used to enhance food digestibility. Lecithins are also used in pharmaceutical formulations. Recently, some vegetable oils have been found to be rich in γ-linolenic acid (see Figure 1), which is the precursor of prostaglandins, leukotrienes and thromboxanes. All these compounds are involved in platelet aggregation and inflammatory processes. Only members of Onagraceae, Saxifragaceae and Boraginaceae contain γ-linolenic acid.

Vegetable oils are significant in both the food and pharmaceutical industries. Some are used as solvents for lipid-soluble drugs such as vitamins and antibiotics. Others, e.g. almond oil and olive oil, are used in cosmetics. Castor oil is well known for its purgative activity, but has fallen out of favour because of its unpleasant taste.

Acetogenins

Acetogenins are long-chain aliphatic compounds with 35-39 carbon atoms, ending with a γ-lactone, most often unsaturated and cyclized into one or two tetrahydrofuran rings that may or may not be adjacent. They are characteristic of Annonaceae (e.g. Annona, Goniothalamus, Rollinia and Uvaria). The potential application of acetogenins is linked to their antitumour (e.g. asimicin, bullatacine), antibacterial (e.g. cherimolin) and insecticidal (e.g. asimicin, annonin, annonacin) properties. See Figure 2 for the structure of annonacin, as an example of an acetogenin.

Amino acids and their derivatives

Amino acids are constituents of peptides, proteins and enzymes, but also the precursors of a large variety of secondary metabolites including alkaloids and phenolic compounds, which are both discussed separately.

Amino acids

The function of amino acids is not only for protein synthesis; they are also considered to be a form of nitrogen storage (e.g. cannovanine, hemoarginine) and a germination inhibitor. The few studies of the pharmacological activities of amino acids include reports of curcubitine being used as taeniacide. Many toxic amino acids have been identified; examples include β-(γ-L-glutamylamino)proprionitrile and γ-N-oxalyl-L-α,β-diaminoproapionic acid which are responsible for the toxicity of grass pea (Lathyrus sativus L.) that brings about osteolathyrism and neurolathyrism in livestock, and mimosine from Leucaena inhibiting protein and nucleic acid synthesis which results in livestock losing appetite and weight, and their growth being inhibited.

Cyanogenic glycosides

Cyanogenic glycosides are compounds derived from amino acids. Hydrolysis of these compounds by enzymes or acids yields hydrocyanic acid, a toxic principle. Biosynthetically, the aglycones of cyanogenic glycosides are derived from L-amino acids. Cyanogenic glycosides are prevalent in the families Rosaceae, Leguminosae, Gramineae, Araceae, Euphorbiaceae and Passifloraceae. Examples are linamarin, amygdalin and prunasin.

Sulphur-containing compounds

The sulphur-containing compounds of pharmaceutical significance are allein, allicin, ajoene and other related compounds isolated from garlic. Allicin and ajoene (the latter is a condensation product of allicin) exhibit many biological activities, including antihypercholesterolaemic, antiplatelet aggregation, antihypertensive, fibrinolytic and antifungal activities. Recently, diallyl cysteine, an odourless active ingredient of garlic, was found to be biosynthesizable.

Lectins

Lectins are proteins or glycoproteins that are able to bind with the carbohydrate moiety on cell membranes in a specific and reversible fashion, without displaying enzymatic activity. Most lectins in higher plants are located in seeds. They are commonly found in legumes such as groundnut, soya bean and common bean. Some lectins have the ability to agglutinate red blood cells of a specific blood group. These lectins are referred as phytohaemagglutinin. The haemagglutination activity is important in immunological studies. Some lectins are toxic, e.g. ricin from castor (Ricinus communis L.) seeds and abrin from jequirity bean (Abrus precatorius L.) seeds.

Enzymes

Plant-derived enzymes used as drugs include papain and bromelein. Both are proteolytic enzymes useful as an anti-inflammatory drug. Ficin has similar properties.

Alkaloids

It is not easy to define the term "alkaloid" precisely, since there is no sharp border between alkaloids and naturally occurring complex amines. At present, the term is used for plant-derived compounds containing one or more nitrogen atoms (usually in a heterocyclic ring), and usually having a marked physiological action on humans or animals. The term "proto-alkaloids" or "pseudo-alkaloids" is sometimes applied to compounds that lack one or more of the properties of the typical alkaloids, e.g. the nitrogen in a heterocyclic ring system; examples include mescaline and ephedrine. To avoid problems with this common definition of alkaloids, some authors propose a more narrow definition: an alkaloid is a cyclic organic compound containing nitrogen in a negative oxidation state, which has limited distribution in living organisms.

Based on their chemical structures, alkaloids are divided into several sub-groups: non-heterocyclic alkaloids, and heterocyclic alkaloids which are again divided into 12 major groups according to their basic ring structure. Figure 3 shows some examples; mescaline is an example of a non-heterocyclic or pseudo-alkaloid, tetrandrine of a bisbenzylisoquinoline alkaloid and solasodine of a triterpene alkaloid. Free alkaloids are soluble in organic solvents such as ether or chloroform. Alkaloids will furthermore react with acids to form water-soluble salts. There are a few exceptions to this general rule. In certain alkaloids, e.g. in ricinine, the lone pair of electrons on the nitrogen atom can be protonated. Another example is berberine, a quaternary ammonium alkaloid; the free base is already water-soluble. Physically, most alkaloids exist in solid form, but some are liquid, e.g. nicotine.

Alkaloids in plants are believed to be waste products and a nitrogen source. They are thought to play a role in plant protection and germination, and to be plant growth stimulants. Alkaloids are more common in dicotyledons than in monocotyledons; families rich in them are Amaryllidaceae, Liliaceae s.l., Apocynaceae, Berberidaceae, Leguminosae, Papaveraceae, Ranunculaceae, Rubiaceae and Solanaceae.

Many alkaloids are pharmaceutically significant, e.g. morphine as a narcotic analgesic, codeine in the treatment of coughs, colchicine in the treatment of gout, quinine as an antimalarial, quinidine as an anti-arrythmic and L-hyoscyamine (in the form of its racemic mixture known as atropine) as antispasmodic and for pupil dilation.

Phenols and phenolic glycosides

Phenols probably constitute the largest group of secondary plant metabolites. They range from simple structures with one aromatic ring to complex polymers such as tannins and lignins. Examples of phenolic classes of pharmaceutical interest are (1) simple phenolic compounds, (2) tannins, (3) coumarins and their glycosides, (4) quinones, (5) flavonoids, (6) anthocyanins, (7) phloroglucinols, and (8) lignans and related compounds. These phenolic compounds are biosynthesized via the shikimic acid or acetate pathways.

Simple phenolic compounds

Compounds in this group have a monocyclic aromatic ring with an alcoholic, aldehydic or carboxylic group. They may have a short hydrocarbon chain. Figure 4 shows some examples; capsaicin is a vanillyl amide of isodecenoic acid. Eugenol is widely used in dentistry due to its antibacterial, anti-inflammatory and local anaesthetic activities. Vanillin is commonly used as a food flavouring. For salicylic acid anti- inflammatory properties have been reported. Capsaicin, a compound isolated from Capsicum, is now marketed as an analgesic.

Tannins

The chemistry of tannins is complex. The distinction made in the literature between hydrolysable tannins and condensed tannins is based on whether acids or enzymes can hydrolyse the components or whether they condense the components to polymers. Although not watertight, this distinction largely corresponds to groups based on gallic acid and those based on flavane-related components. Numerous vegetable tannins have been discovered, but only the major tanning constituents of the most important groups of tannins are listed here, i.e. the group of gallotannins and ellagitannins, and the group of proanthocyanidins. Gallotannins and ellagitannins are esters of gallic acid or its dimers digallic acid and ellagic acid with glucose and other polyols. Proanthocyanidins are oligomers of 3-flavanols (catechins) and 3,4-flavandiols (leucoanthocyanidins); see Figure 5 in which R = H or OH. Tannins are able to react with proteins. On being treated with a tannin, a hide absorbs the stain and is protected against putrefaction, thereby being converted into leather. For more information, see Prosea 3: "Dye and tannin-producing plants".

Though tannins are widespread in plants, their role in plants is still unclear. They may be an effective defence against herbivores, but it is likely that their major role in evolution has been to protect plants against fungal and bacterial attack. The high concentrations of tannins in the non-living cells of many trees (heartwood, bark), which would otherwise readily succumb to saprophytes, have been cited in support of this hypothesis. Some authorities consider tannins to be waste products, and it has also been suggested that leaf tannins are active metabolites used in the growing tissues. However, tannins in different plant species probably have different functions.

Tannins are used against diarrhoea and as antidotes in poisoning by heavy metals. Their use declined after the discovery of the hepatotoxic effect of absorbed tannic acid. Recent studies have reported that tannins have anti-cancer and anti-HIV activities.

Coumarins and their glycosides

Coumarins are benzo-α-pyrone derivatives that are common in plants both in a free state and as glycosides. They give a characteristic odour of new-mown hay and occur, for instance, in many Leguminosae. They are biosynthetically derived via the shikimic acid pathway. Figure 6 shows the structure of coumarin. Common derivatives are umbelliferone, herniarin, aesculetin, scopoletin, fraxin and chicorin.

The biological activities reported are spasmolytic, cytostatic, molluscicidal, antihistaminic and antifertility.

Quinones

Quinones are oxygen-containing compounds that are oxidized homologues of aromatic derivatives and are characterized by a 1,4-diketo-cyclohexa-2,5-diene pattern (paraquinones) or by a 1,2-diketo-cyclohexa-3,5-diene pattern (orthoquinones). In naturally occurring quinones, the dione is conjugated to an aromatic nucleus (benzoquinones) or to a condensed polycyclic aromatic system: naphthalene (naphthoquinones), anthracene (anthraquinones), 1,2-benzanthacene (anthracyclinones), naphthodianthrene (naphthodianthrone), pyrelene, phenanthrene and abietane-quinone. See Figure 7. Naphthoquinones and anthraquinones have some importance medicinally; see below.

Naphthoquinones

Naphthoquinones are yellow or orange pigments from plants. Most are 1,4-naphthoquinones; 1,2-naphthoquinones are rarely found. Hydroxyl and methyl substitutions at C-2 are common. Biosynthetically, the naphtoquinones are almost exclusively derived via the shikimic acid pathway. The occurrence of naphthoquinones is limited in fungi and sporadic in Angiosperms. They are found in species of the families Bignoniaceae, Ebenaceae, Droseraceae, Juglandaceae, Plumbaginaceae, Boraginaceae, Lythraceae, Proteaceae and Verbenaceae.

The pharmaceutical significance of this group of quinones is limited. Plumbagin exhibits antibacterial and cytotoxic activities. Lawsone from henna (Lawsonia inermis L.) is a powerful fungicide and hair colourant.

Anthraquinones

Anthraquinones are characterized by the presence of phenolic and glycoside moieties, derived from anthracene, and have a variable degree of oxidation. They have a common double hydroxylation in the positions 1 and 8 (see Figure 7). The glycosidic linkage may be C- or O-bonding. The anthraquinones are mostly biosynthesized via the acetate pathway, although some examples may be derived via the shikimic acid pathway. Anthraquinones are found in species of the families Rubiaceae, Leguminosae, Polygonaceae, Rhamnaceae, Ericaceae, Euphorbiaceae, Lythraceae, Saxifragaceae, Scrophulariaceae and Verbenaceae. In monocotyledons, they are found only in Liliaceae s.l.

Anthraquinones isolated from plants with laxative activity include sennosides, aloins and emodin. The therapeutic use of anthraquinones as laxatives is very well recognized. The products are sold commercially. Common medicinal plants which contain anthraquinones are Senna and Aloe species.

Flavonoids

Flavonoids are the compounds responsible for the colour of flowers, fruits and sometimes leaves. Some, such as chalcones and flavonols, are yellow. The name refers to the Latin word "flavus", which means yellow. Some may contribute to the colour by acting as co-pigment. Flavonoids protect the plant from UV-damaging effects and play a role in pollination by attracting animals by their colours.

The basic structure of flavonoids is 2-phenyl chromane or an Ar-C₃-Ar skeleton. Biosynthetically they are derived from a combination of the shikimic acid and acetate pathways. Small differences in basic substitution patterns give rise to several sub-groups; in the plant flavonoids can either occur as aglycones or as O- or C-glycosides. See Figure 8 for basic structures.

Recently, flavonoids have attracted interest due to the discovery of their pharmacological activities as anti-inflammatory, analgesic, antitumour, anti-HIV, antidiarrhoeal, antihepatotoxic, antifungal, antilipolytic, anti-oxidant, vasodilator, immunostimulant and anti-ulcerogenic. Examples of biologically active flavonoids are hesperidin and rutin for decreasing capillary fragility, and quercetin as antidiarrhoeal.

Anthocyanins

Anthocyanins are the compounds responsible for the red, pink, mauve, purple, blue or violet colours of most flowers and fruits. These water-soluble pigments occur as glycosides (anthocyanins sensu stricto) and their aglycone (anthocyanidins). They are derived from the 2-phenyl benzopyrylium cation, more commonly referred to as the flavylium cation. Cyanin (see Figure 9) is an example of an anthocyanin.

Anthocyanins are found in all Angiosperms, except for most species of the order Caryophyllales: only species of the families Caryophyllaceae and Molluginaceae contain them; in other families (e.g. Chenopodiaceae, Cactaceae), the pigmentation is due to betalains.

The application of anthocyanins is as food additive, e.g. in beverages, jams and confectionary products. The pharmacological activities are similar to flavonoids; for instance for decreasing capillary permeability and fragility, and as anti-oedema.

Phloroglucinols

Phloroglucinols are derivatives of 1,3,5-trihydroxybenzene, which e.g. are found in Cannabis sativa L., a well-known stimulant of the central nervous system.

Tetrahydrocannabinol and its derivatives influence behaviour, inducing euphoria and relaxation at low doses, but at higher doses, they may induce anxiety, sometimes to panic proportions. Sometimes hallucination and tinitus are observed. Other effects are bronchodilation and a lowering of intra-ocular pressure.

Lignans and related compounds

Lignans and related compounds are derived from condensation of phenylpropane units. Formerly, the term referred to compounds whose skeleton results from bonding between β-carbons of the side chain of two units derived from 1-phenylpropane (8-8' bond). Neolignans are also condensation products of phenylpropanoid units, but the actual bond varies and involves no more than one β-carbon (8-3', 8-1', 3-3', 8-0-4' for example). The term "oligomers" is incorrect; designated lignans or neolignans result from the condensation of 2-5 phenylpropanoid units (e.g. sesquilignans and dilignans, lithospermic acid). Norlignans are probably specific to gymnosperms and have a Cskeleton. Lignins are substances deposited at the end of the formation of the primary and secondary cell walls. Chemically, they are polymers arising from copolymerization of alcohol with a p-hydroxycinnamic structure (p-hydroxycinnamyl, coniferyl or sinapyl alcohol). Lignins are always combined with polysaccharides.

The pharmacological activity of lignans is antitumour. Kadsurenone, a neolignan, exhibits anti-allergic and antirheumatic activity. The major application of lignins is as a precursor of vanillin, which is widely used in the food industry.

Terpenoids and steroids

Terpenoids and steroids are derived from isoprene (a 5-carbon unit), which is biosynthesized from acetate via mevalonic acid.

Monoterpenes

Monoterpenes are the most simple constituents in the terpene series and are C compounds. They arise from the head to tail coupling of two isoprene units. They are commonly found in essential oils. Iridoids and pyrethrins are included in this group. Examples of monoterpenes found in essential oils are shown in Figure 10.

Iridoids are monoterpenes characterized by a cyclopenta [C] pyranoid skeleton, also known as the iridane skeleton (cis-2-oxo-bicyclo-[4,3,0]-nonane). Secoiridoids, which arise from iridoids by cleavage of the 7,8-bond of the cyclopentane ring, are also included in the iridoids. Examples of secoiridoids are the bitter constituents of gentian, e.g. gentiopicroside, amarogentin and esters of sweroside and swertiamarin.

Pyrethrins are irregular monoterpenes arising from the non-classic coupling of isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Some are found in essential oils. Figure 11 gives the basic structures of iridoids and secoiridoids and an example of pyrethrins.

The pharmacological properties of iridoids are quite limited: the iridoid-containing drugs currently used do not yield any major active principle. However, there are reports on analgesic and anti-inflammatory activities of some iridoids, e.g. harpagoside. Pyrethrins are toxic for coldblooded animals such as fish, amphibians and insects. They are widely used as insecticides.

Sesquiterpenes

Sesquiterpenes are also constituents of essential oils of many plants, e.g. bisabolol, humulene and caryophyllene. Figure 12 shows two examples of sesquiterpenes. Sesquiterpenoid lactones are well known as bitter principles. They occur in fungi, bryophytes and angiosperms (especially common in Compositae). Sesquiterpenes possess a broad range of biological activities due to the α-methylene-γ-lactone moiety and epoxides. Their pharmacological activities are antibacterial, antifungal, anthelmintic, antimalarial and molluscicidal. Examples are santonin used as an anthelmintic and artemisinin as an antimalarial.

Diterpenes

Diterpenes constitute a vast group of C₂₀ compounds arising from the metabolism of 2E,6E,10E-geranylgeranyl pyrophosphate. They are present in some animals and plants; they are particularly abundant in the orders Lamiales and Asterales.

Diterpenes have some therapeutic applications. For instance, taxol (see Figure 13) and its derivatives from are anti-cancer drugs. Other examples are forskolin, with antihypertensive activity, zoapatanol, as an abortifacient, and stevioside, as a sweetening agent.

Triterpenes and steroids

Triterpenes are C₃₀ compounds arising from the cyclization of 3S-2,3-epoxy,2,3-squalene. The basic skeletons are shown in Figure 14: oleanane is an example of a pentacyclic triterpene, quassin of a tetracyclic triterpene and testosterone of a steroid. Tetracyclic triterpenes and steroids have similar structures, but their biosynthetic pathway is different. Steroids contain a ring system of three 6-membered and one 5-membered ring; because of the profound biological activities encountered, many natural steroids together with a considerable number of synthetic and semi-synthetic steroidal compounds are employed in medicine (e.g. steroidal saponins, cardioactive glycosides, corticosteroid hormones, mammalian sex hormones).

The pharmaceutical applications of triterpenes and steroids are considerable. Cardiac glycosides have been used in medicine without replacement by synthetic drugs. Saponins from ginseng and liquorice exhibit many therapeutic effects.

Saponins

Saponins constitute a vast group of glycosides which occur in many plants. They are characterized by their surfactant properties; they dissolve in water and, when shaken, form a foamy solution. Saponins are classified by their aglycone structure into triterpenoid and steroid saponins; most triterpenoid saponins are derivatives of one of the triterpenes oleanane, ursane and lupane, while steroid saponins generally possess the typical steroid skeleton enlarged with 2 extra rings E, a furan structure and F, a pyran structure, respectively. Examples of 2 aglycones are shown in Figure 15. In saponins, sugar and/or uronic acid residues are attached to the aglycones via the C-3 hydroxyl group.

Most saponins have haemolytic properties and are toxic to coldblooded animals, especially fish. The steroidal saponins are important precursors for steroid drugs, including anti-inflammatory agents, androgens, oestrogens and progestins. Well-known steroid sapogenins are diosgenin from Dioscorea hecogenin from and smilagenin from Smilax.

Triterpene saponins exhibit various pharmacological activities: anti-inflammatory, molluscicidal, antitussive, expectorant, analgesic and cytotoxic. Examples include the ginsenosides, which are responsible for some of the pharmacological activity of ginseng, and the active triterpenoid saponins from liquorice.

Cardiac glycosides

The aglycone part of cardiac glycosides is a tetracyclic steroid with an attached unsaturated lactone ring that may have 5 or 6 members. Cardiac glycosides are classified into two groups according to the lactone ring: the C₂₃ cardenolides with an α,β-unsaturated d-γ- lactone (= butenolide), and the C₂₄ bufadienolides with a di-unsaturated γ-lactone (= pentadienolide). The sugar moiety is normally attached via de C-3 hydroxyl group of the aglycone. The majority of the saccharides found in cardiac glycosides are highly specific. They are 2,6-dideoxyhexoses, such as D-digitoxose, L-oleandrose or D-diginose. These sugars give a positive reaction with the Keller-killiani reagent.

Cardiac glycosides have been used as drugs for the treatment of cardiac insufficiency. An example is digitoxin from Digitalis, where the sugar moiety is attached to the aglycone digitoxigenin (see Figure 16) via the C-3 hydroxyl group.

Carotenoids

Carotenoids contain 8 isoprene (C₄₀) units that are responsible for the yellow or orange colour of some vegetables and fruits. Among these compounds, the hydrocarbons are collectively referred to as carotenes and the hydroxylated derivatives as xanthophylls. Carotenoids are either acyclic (e.g. lycopene) or comprise one or two pentacyclic or hexacyclic rings at one end or the other (e.g. β,ψ,-carotene), or at both ends (e.g. β,β-carotene).

Carotenoids became interesting agents after the discovery of a negative correlation between the plasma concentration of β-carotene and the prevalence of certain forms of cancer. Some doctors prescribe β-carotene for cancer patients. Furthermore, in the intestine β-carotenes are converted to retinol (vitamin A). They can be used for the treatment of photosensitization, retinal disease and glaucoma. Carotenoids are also safe colouring agents for food and cosmetics.

Among the many classical examples of biological action of plant material in man are the different tastes (sweet, bitter, sour, astringent), sensations (irritating, itchy, pungent, acrid) and the types of euphoria and hallucinations. However, only recently biological activity is understood in terms of molecular interactions. Plants and plant constituents have a key position in the advancement of modern studies and knowledge on biological activity of substances. There are several reasons for this. Firstly, plant species, whether traditionally used or not, continue to be important sources of food, medicines and supplementary health products. Secondly, the bioactive plant compounds are themselves products (or derived products) of metabolism, and hence function in life processes in a similar way to compounds that operate in humans and animals. Researchers hoping to develop drugs from plants need to understand the basics of such functions and mechanisms in relation to the bioactive molecular entities. Thirdly, plants also yield products which are auxiliaries in medicine and pharmacy and sustain or condition pharmacological activity and therapeutic efficacy. In addition, a series of these auxiliary substances are used in biomedical research and in clinical tests.

Testing the biological activity of medicinal or potentially medicinal plant material demands a special approach. Investigations may be focused on understanding the bioactivity of a compounded plant extract or simply directed at isolating a single bioactive chemical compound. In the latter case, results often lead to oversimplification or wrong explanations of the bioactivity of extract preparations. On the other hand, thorough studies on single bioactive constituents provide important information for plant drug research. However, the much more complex array of molecular interactions and bioactivity mechanisms that arises from plant extracts represents a much greater and more fascinating challenge to science.

Factors affecting biological activity

Various aspects of bioactivity apply to any chemical, whether of natural or synthetic origin. These aspects will now be described briefly. They fall into three categories (Gringauz, 1997; Gubernator & Böhm, 1998; Krogsgaard-Larsen & Bundgaard, 1991):

• Physicochemical properties such as solubility, partition coefficients and ionization.
• Chemical parameters such as resonance, inductive effects, oxidation-reduction potentials, types of bonding and isosterism.
• Spatial considerations such as molecular dimensions, interatomic distances and stereochemistry.

Physicochemical properties

These relate to the transport of the bioactive compound to its site of action, usually a receptor or other biomacromolecule at cellular or subcellular level. Under experimental (in vivo or clinical) or real life conditions the extent to which a drug passes through semipermeable membranes before reaching its site of action depends on its solubility. Under in vitro conditions many of these barriers are absent. In vitro bioactivity therefore represents only a stage in the basic assessment of pharmacological effects. In plant drug research, the solubility of active constituents may be revealed from extraction procedures. Extraction programmes separate lipophilic constituents from water-soluble compounds. Further fractionation of an extract may lead to further refinement of physicochemical properties. After the bioactive molecular entity has been identified, detailed data on solubility, partition coefficients and the electrolytic behaviour can be determined. Solubility characters are closely related to drug absorption, and the degree of absorption is an important determinant of drug action. Many bioactive plant constituents are weak acids and bases, and their degree of ionization, when dissolved, is of great importance to their bioactivity. As a rule, the ionic form is more water-soluble.

These factors are important when bioactivity is regarded in the context of drug distribution between intestine and plasma, between kidney tubules and urine, and between plasma and other body compartments. Generally, but simplified, one may say that only the lipid-soluble and undissociated forms of a bioactive molecule will pass through membranes. However, at the site of action, bioactive compounds may generate their action by binding to a receptor on the cell membrane.

Chemical parameters

The structural features of a compound can be related to its pharmacological properties, either qualitatively or quantitatively. The principles, concepts and numerical rules governing qualitative and quantitative relationships between structure and activity help explain the pharmacological activity of a new compound, which is why it is important to elucidate the structure of a newly isolated plant compound. The basic aspects of molecular structures involved in bioactivity include:

• Resonance. This is the phenomenon that a molecule can be represented by two or more structures that differ only in their electron, but not atomic, arrangement. So, electron density and electron distribution patterns help explain the molecule's reactivity and hence its molecular interaction and bioactivity.
• Inductive effects. These are measurable electrostatic phenomena caused by actual electron shifts or displacements along chemical bonds. Either negative or positive inductive effects may lead to changes in bioactivity.
• Oxidation-reduction potential. This phenomenon represents the tendency of a compound to lose electrons (oxidation) or gain electrons (reduction). Without electron transfers, various systems in the living cell would not function. Through the nature of their chemical structure, bioactive compounds may affect these systems. Note that bioactive compounds derived from plant sources function in enzyme systems in the plant which are similar to those in the humans or animals treated.
• Types of bonding. Basically the phenomenon of biological activity is concerned with covalent and noncovalent molecular interactions. Firstly, covalent bonds (single, double and triple bonds) are common to all biomolecules. Under the physiological conditions of living organisms, covalent bonds form enzymatically. As a rule, however, further biochemical functionality of biomolecules proceeds through noncovalent interactions. Hydrogen bonds, ionic forces, hydrophobic (or lipophilic) bonding, and charge-transfer interactions, all representing noncovalent interactions, are also common to functional life processes. Thus bioactivity as encountered when a given compound, whether biogenic or xenobiotic, comes in contact with a living system (in vitro, in vivo, clinically, or unintentionally) interferes with ongoing life processes. However, the molecular interactions will still be in terms of covalent or noncovalent principles. Agents that affect physiological functions by forming irreversible covalent bonds with target biomacromolecules are usually very toxic at cellular level, and would be difficult to control clinically and medically. So in plant drug research, constituents that exert their activity through much weaker and reversible bonding processes are much more desirable. Noncovalent and reversible covalent binding of target molecules are preferable and, moreover, are characterized by equilibrium thermodynamics (Gubernator & Böhm, 1998). Association constants can be determined and are reproducible. In the case of high-molecular weight ligands (e.g. a large bioactive plant molecule) the association rate of these ligands with the target biomolecule slows down and it becomes unpractical to determine an equilibrium. In cases of reversible covalent interactions, measurable activity constants (e.g. IC₅₀ values = concentration giving 50% inhibition) are very dependent on experimental conditions such as the concentration of constituents, incubation time, temperature, acidity, etc. The systematic search for desirable plant ligands not only strives for bioactivity through reversible covalent or noncovalent interactions, but also for selectivity. The latter conditions the specificity of action, and reduces toxicity and side-effects. From the vast number of studies of biological and pharmacological activity and its molecular basis, it is clear that it is still a long way to total understanding and sufficient explanations.

Spatial considerations

It appears important to have good steric and electronic complementarity between ligand and target biomolecule (Gubernator & Böhm, 1998). A bioactive compound interacting with DNA, a receptor molecule or an enzyme fits sterically into a binding pocket, the space sterically provided by these targets. The molecular dimensions, interatomic distances, arrangements of electrons and the stereochemical properties of both ligand and target are decisive. In other words, a molecular "docking" mechanism is at the basis of biological and pharmacological activity. This is illustrated by an example.

(-)-Huperzine A is a potent and reversible inhibitor of acetylcholinesterase. However, this plant compound does not show muscarinic effects. The lack of these undesirable side-effects suggests that (-)-huperzine A has potential for treating "cholinergic insufficiency" disorders, such as Alzheimer's disease. This compound has been isolated from the club moss Huperzia serrata (Thunb. ex Murray) Trevisan (synonym: Lycopodium serratum Thunb. ex Murray), which is used medicinally (Raves et al., 1997). See Figure 17 for the structure diagram. The (-) isomer of this chiral molecule has a more potent bioactivity than either the (+) isomer or the racemic mixture.

Such detailed molecular orientation and interaction data are not available for most known bioactive plant ligands. However, the target biomolecule of many other plant compounds is known, and, if not, the pharmacological effects have been studied (Bierhaus et al., 1997; Colegate & Molyneux, 1993; Hassig et al., 1997; Hung et al., 1996; Raves et al., 1997). Table 1 gives examples of plant ligands whose target biomolecules are known.

Bio-assaying

Requirements for screening medicinal plant material

The biological and pharmacological effects caused by ligand-target interactions can be studied and assessed in specifically designed bio-assays. The huge range of bio-assay literature cannot be covered within the scope of this brief treatise, but a few essential remarks are in place here. When searching for plant ligands that are not only effective but also selective, specific and reversible in their interactions, bio-assays should meet certain requirements.

Firstly, one or more appropriate assays should be selected or developed for initial screening of extracts. "Appropriate" means rapid and simple to perform, and functional and specific in their goal. The functions of the biochemical factors involved under physiological and pathophysiological conditions must be clear. In other words, bio-assaying is a way to relate bioactivity to factors and conditions relevant to disorders and homeostasis. As a result, bio-assaying should result in a closer understanding of a biological or pharmacological effect of a single compound. By giving an integral picture of interactions and effects, bio-assaying elucidates the pharmacological actions of plant extracts and their ethnomedical uses.

In the initial stage, in vitro testing should have priority over in vivo studies using laboratory animal models. Such a decision can be based on purely scientific as well as economic and ethical reasons. In vivo studies may be preferable at later stages of research, but this depends on the amount and nature of evidence of bioactivity already collected by means of in vitro studies, and the quest for additional information under life conditions. A bioactive plant compound and a bioactive plant preparation that are candidates for therapeutic application will still have to undergo extensive clinical and toxicological screening programmes before they can be registered as medicines.

Medicinal plant material is screened for bioactive compounds for many different considerations and using a variety of approaches ranging from selecting plant sources randomly to more systematic approaches. Some background features of screening approaches are listed below (Bierer et al., 1996; Colegate & Molyneux, 1993; Sills, 1996):

• Phytochemistry directed screening approaches. The typical feature of such approaches is that isolation and structure elucidation studies always precede work on biological activity as two unconnected experimental stages. The focus may be on a specific class of compounds (e.g. alkaloids), or a specific subgroup of compounds, or even a subgroup within a certain plant family or genus. Such approaches may have been inspired by pharmacological data on related substances or by ethnomedical data, but usually there is no direct correlation with the research approach.
• Ethnomedicine and ethnobotany directed screening approaches. These follow up clues on bioactivity that have been derived from evaluative studies on traditional medicine and folkloric practices. In the set-up, the choices made for bio-assaying are strongly influenced by pharmaceutical, medical, health and cultural considerations.
• Randomized screening approaches. The most characteristic feature of these approaches is the absence of any clues. The plant material is simply a carrier of potential bioactive substances. Randomly selected and collected plant samples are extracted according to general protocols, and subjected to specialized bio-assays.
• Integral screening approach. Basically the bioactivity of a plant ligand should be seen and explored within the full context of its phenomenal existence, i.e. its biology, biochemistry, molecular biology, chemistry and biophysics. The approach is based on all life-science aspects and on the biocultural empirical experience with a plant source. A disease, a medical indication or an illness is usually the starting-point for the bio-assay. From the pathophysiology of a disease the relevant in vitro bio-assays and in vivo models are derived and refined. Furthermore, the experimental part of the bio-assay involves bioactivity-guided fractionation and isolation. This method represents a very appropriate and rational link between the detection of bioactivity and phytochemical methods.

Common pharmacological screening methods

There are many types of pharmacological screens, most of which have to be carried out in a well-equipped laboratory. There are screens for specific bacteria, fungi, protozoa, intestinal worms, viruses and spirochaetes. The efficacy of compounds against specific health problems such as cancer and inflammation is also often probed, and the effect on various physiological and anatomical systems such as reproduction, digestion and circulation can be judged. The brine shrimp screen, the antibacterial screen, the brewers' yeast screen and the Hippocratic screen are commonly applied simple techniques.

Brine shrimps are small aquatic animals that can be grown in solutions resembling seawater. In order to test the potential toxicity of a plant - and thus its probability of containing an anti-cancer agent - measured amounts of plant extract are added to containers holding known numbers of brine shrimps. The surviving brine shrimps are counted after 6 hours and 24 hours, and the acute and chronic LD values are calculated, respectively; this corresponds to the concentration of the compound in solution that kills 50% of the brine shrimps.

Bacteria can be grown on agar medium in Petri dishes. When measured amounts of a plant extract are placed on paper disks set on the surface of the bacteria-inoculated agar under sterile conditions, after 18-24 hours bacteria-free circles can be observed around some of the paper disks, indicating that the extract has inhibited the microbes. Plant extracts can be tested for phototoxic and fungicidal activity against brewers' yeast (Saccharomyces cerevisiae).

These tests yield much less information than the sophisticated assays that are done in fully equipped laboratories, and can only detect a limited range of biological activities (Martin, 1995).

Hippocratic screening is a simple observational technique. Only crude plant material is used. Dried plant material is chopped and run through a mill. The resulting powder is suspended by trituration in a sterile 0.25% agar solution in double-distilled water, and injected intraperitoneally into rats. Only rats can be used for Hippocratic screening of crude natural products because they effectively resist both infection and peritonitis. A log-dose series of injections is made, ranging from 1 g/kg downwards, and the presence or absence of a large number of symptoms is recorded within certain intervals. The result is a unique pharmacological "fingerprint" for each class of drug. Virtually all known drug types can be detected as active by the Hippocratic screen conducted in rats, with the exception of the various chemotherapeutic drugs such as antibiotics (Malone, 1981).

Surveys of bioactivity, pharmacological and therapeutic categories

There is a need for comprehensive surveys to cope with the enormous expansion of information on diverse types of bioactivity and novel bioactive structures. There are published surveys on ligand-target interactions, in pharmacological categories and at the level of pharmacotherapeutical grouping. Examples of ligand-target categories are: inhibitors of HIV-1 reverse transcriptase, inhibitors of acetylcholinesterase, inhibitors of protein kinases and inhibitors of glycosidases. Examples of pharmacological categories are: agents acting at synaptic and neuroeffector junctional sites, agents acting on the central nervous system, agents affecting renal and cardiovascular function and agents interfering with inflammatory processes. Examples of pharmacotherapeutic groups are: emetics, analgesics, anti-inflammatories, anaesthetics, anti-cancer drugs, psychoactive drugs and anti-AIDS drugs. Table 2 lists some plant compounds with their bioactivity categories.

Future developments in research on bioactivity

Future advances in plant drug research will provide information on bioactivity in terms of molecular interactions with target biopolymers on a broad scale, all this within the context of homeostasis and pathophysiological conditions. Developments in the fields of genetics, molecular biology, bioinformatics and techniques used in determining the steric structure of plant metabolites and target macromolecules appear important today. In addition, fundamental understanding of molecular biodiversity seems important in the process of using plants as resources for drug development. Some animal models will be replaced by testing on cell cultures, because new techniques of culturing cells and tissues have become available. These new testing methods require smaller amounts of test compounds and will provide information at cellular level. This will lead to extensive studies on medicinal plants.

Plants used in medicine

The World Health Organization has compiled a list of more than 21 000 plant species purportedly used globally in medicine. It is estimated that 2000-3000 species are used for medicinal purposes in South-East Asia. The number of medicinal plants in Indonesia is estimated at 1000, out of a total flora of 28 000 species. In Malaysia, approximately 1200 trees, shrubs and herbs of the about 12 000 species have been reported to have traditional medicinal properties (Soepadmo, 1991). The number of medicinal plant species in Philippine handbooks (e.g. Quisumbing, 1978) is about 850, out of a total number of higher plant species in the Philippines roughly estimated as 8000. It is estimated that there are more than 10 000 plant species in Thailand, of which about 1800 are listed as medicinal in the Thai Traditional Materia Medica. However, only 1100 of these are botanically identified. Over 1800 plant species have been identified in Vietnam as useful for medicinal purposes. Medicinal plants are also numerous in adjacent regions. In India, the number of plant species used in traditional medical systems is estimated at 1100-1500, and about 700 species of medicinal plants grow wild in Nepal. An estimated 300 plant species are used in traditional medicine in Pakistan, and about 550 flowering plants in Sri Lanka.

Weedy and forest species

Approximately half (125 000) of the world's flowering plant species live in tropical forests. The tropical rain forests continue to support a vast reservoir of potential drug species. They can provide natural product chemists with invaluable compounds or starting points for developing new drugs. Less than 1% (Balick et al., 1996) of tropical species have been studied for their pharmaceutical potential; this proportion is even lower for species confined to the tropical rain forest. To date, about 50 major drugs have come from tropical plants. The existence of undiscovered pharmaceuticals for modern medicine has often been cited as one of the most important reasons for protecting tropical forests, so the high annual extinction rate of an estimated 3000 plant species is a matter of great concern.

It is notable that the more important medicinal and poisonous plants include many weedy species. It seems most likely that this is because these species are so widely ditributed and common that they are the most obvious plants to be tried for medicinal purposes. Also, their toxic effects manifest comparatively easily because of the presence of livestock. The weeds include species that are pantropical or even cosmopolitan (e.g. Achillea millefolium L.), and that therefore occur in regions where research on medicinal plants is more common than in South-East Asia (e.g. in India, China and Europe). There is thus much literature on these species and they are more highly valued.

More advanced defence mechanisms by secondary metabolites to prevent browsing by livestock might also account for the high proportion of weedy species among the more important medicinal plants.

Chemotaxonomy

The medicinal and poisonous plants in South-East Asia form an extremely diverse group taxonomically. Some families are, however, comparatively rich in species used medicinally, usually because of the common occurrence of certain types or classes of chemical compounds. Examples are Apocynaceae and Menispermaceae with their alkaloids, and Compositae and Umbelliferae that contain essential oils.

The great diversity in the taxonomy of medicinal and poisonous plants is also reflected in the growth forms, which range from small herbs to large trees, and in life cycles, ranging from annuals (e.g. Artemisia annua L.) to slow-growing trees (e.g. Cinchona spp.).

No study of medicinal plants can be started without a proper botanical identification of the species. As there is a relationship between taxonomy and the chemical profile, taxonomic botany is important when attempts are made to find a species that yields a desired substance. A certain compound (or a compound close to it) is more likely to be present in a species related to a species known to contain this compound. Taxonomic studies can therefore help predict the presence of active substances in certain groups of plants (Hedberg in Leeuwenberg, 1987). Constraints are the lack of herbaria and qualified botanists in many tropical countries.

It is essential to use the correct scientific name of medicinal plants. Vernacular names are often very confusing. Erroneous namings are quite common. It should be compulsory for a voucher specimen to be deposited in a public herbarium accompanying a scientific publication on medicinal plants or their compounds.

Plants to be evaluated for medicinal properties (e.g. for anti-cancer activity, as has been done for a long time by the National Cancer Institute, United States) should cover a wide taxonomic range as this will provide a great diversity of types of chemical structures, thereby increasing the likelihood of finding active compounds.

Temperature, rainfall, photoperiod and altitude are factors of great importance for the development of plants. The day length may considerably influence the growth and yield of constituents. Mentha ×piperita L., for instance, does not grow well under short-day conditions. Most medicinal plants in cultivation need plenty of sun to be of high quality. Most aromatic herbs do not tolerate more than half-day shade, and for these plants the sunniest sites should be chosen in somewhat cool and cloudy climates, though a shady site is acceptable in sunnier climates. Altitude may have a definite effect on growth and on yield of constituents. For example, Cinchona, grows slowly at altitudes above 2000 m, and the quinine yield is low when cultivated at altitudes below 800 m. A number of medicinal plants thrive best at high altitudes, and some species only flower at higher elevations and never in the lowland.

Many medicinal plants are easy to grow because they are tolerant of and adaptable to poor conditions. However, unfavourable climatic conditions can cause the synthesis and accumulation of excessive levels of undesirable compounds and/or low levels of desirable compounds. In oil-yielding plants, for instance, poor oil quality may result. Alkaloid yields are affected by environmental factors such as altitude, temperature, moisture, light, soil type, together with handling after harvest and genetic factors. In many alkaloid-yielding plants (e.g. Datura metel L.), the alkaloid content peaks in the dry season and is lowest in the rainy season.

The soil requirements vary with the species. Certain species, like most Zingiberaceae, prefer loose, moist and humus-rich soils with a pH of 6-7.5, while others e.g. most Labiatae, thrive best in dry, well-drained and sandy soils enriched with organic matter. Most medicinal plants are intolerant of waterlogging. In general, alluvial and clayey soils that are slightly acid and have a good water-retaining capacity are suitable for growing medicinal plants in regions with not too much rain.

Production systems

Medicinal plants are often collected from the wild. Many medicinal plants, especially the aromatic herbs, are grown in home gardens but some are cultivated as field crops, either in sole cropping or in intercropping systems, and rarely as plantation crops.

Collection of medicinal plants from the wild

In most countries, the collection of medicinal plants from wild sources is still the rule. Although the natural flora has been used as the major source of medicinal plants throughout history, it is neither possible nor desirable to base a medium-scale industry on it. Attempts to do this have caused depletion of species and even eradication. Furthermore, the quality of raw material obtained from spontaneous growth may vary considerably with respect to their constituents. It is possible to use the wild flora in a way that enhances and preserves the plant resources, but this requires strict regulations and control. Such use must be preceded by an evaluation of the abundance of selected species within a large area, resulting in recommendations about how much raw material may be harvested in a certain area. Local people often transplant and cultivate wild medicinal plants in and around their homes and villages.

Cultivation of medicinal and poisonous plants

Several countries in South-East Asia including Indonesia, the Philippines, Vietnam and Thailand grow medicinal crops for domestic use and for export. The number of medicinal crops grown varies from country to country. Although cropping of medicinal and poisonous plants is common practice, it is usually on a small scale. Large-scale cultivation is dictated by the requirements of the pharmaceutical industry, the main user of the raw material. The demand for medicinal plant material is fickle; large-scale cultivation often brings down the price, and the market situation often changes drastically when the industry's search for cheaper alternative source materials for drugs is successful. The great variation in the demand and supply have acted as a damper to developing efficient crop production systems. Moreover, many medicinal plants are labour-intensive in propagation, husbandry, harvesting, post-harvest processing and packing. On the other hand, pharmaceuticals are often commodities of high value and low bulk, which makes them attractive crops for small-holder farmers in communities where transport constraints restrict bulky cash crops.

South-East Asia has a long practice of traditional farming systems, but these have not been developed to include medicinal and poisonous crops. Commercial cultivation of medicinal crops has to be based on a sound scientific footing. However, research carried out on cropping systems including medicinal crops is rather limited in South-East Asia, whereas very little scientific information is available on the medicinal crops themselves. Farmers in India have long grown complementary crops to derive maximum benefits of existing soil moisture and nutrients. In cropping systems based on opium poppy in India, groundnut and black gram proved a profitable combination which is recommended to the growers. The results of trials with Rauvolfia serpentina (L.) Benth. ex Kurz in India showed that the yield was highest when grown as a sole crop and that intercropping often depressed yields considerably. However, it is reported that vegetable crops, soya bean, garlic and onion have little effect on root yields of Rauvolfia and add to the overall economy of the system.

There is extensive experience with the cultivation of Cinchona in Indonesia, although this crop has declined in importance since the Second World War. The cropping system practised is a long-term one, with a cutting cycle of 7-8 years, leaving a coppice to produce new shoots. Leguminous cover crops are sometimes planted in between the Cinchona rows or on the contour to prevent erosion, but Cinchona may also be cultivated under the shade of spared rain forest trees.

The success of a new crop in a cropping system depends upon its growing period, soil nutrient and irrigation requirements, disease and pest tolerance or resistance, and its yield. For example, mint (Mentha spp.) and opium poppy (Papaver somniferum L.) make heavy demands on irrigation and fertilizers, whereas psyllium (Plantago spp.) and periwinkle (Catharanthus roseus (L.) G. Don) need light irrigation and less fertilizer. Cinchona produces an economic yield from 7 years after planting onward, whereas jasmine (Jasminum), also a perennial crop, starts yielding already from the second year onward, and Rauvolfia after 18 months. Some species are grown as annual crops, e.g. opium poppy, mint and psyllium. These annuals may rather easily fit into existing crop rotations and modes of cultivation.

Propagation

Several species are mostly propagated by seed. Examples are found amongst commercially important crops like hemp (Cannabis sativa L.), coca (Erythroxylum novogranatense (Morris) Hieron.) and opium poppy (Papaver somniferum L.). Disadvantages of this method of propagation may be the great genetic diversity of the progeny and the rapid decrease in seed viability that sometimes occurs. Some species, e.g. Mentha arvensis L. and Erythroxylum coca Lamk, are commonly propagated by cuttings. Rooting can be stimulated by application of growth regulators. Bryophyllum pinnatum (Lamk) Oken is propagated from foliar embryos. Although in vitro propagation techniques are commonly used for ornamentals, they are still rarely used for medicinal crops, though they may be very advantageous in providing homogeneous plant material.

Husbandry

Most medicinal crops are grown in gardens, but sometimes they are grown in pots. Certain cropping techniques can considerably influence the yield of both dry matter and pharmacologically active constituents. The quantity and quality of chemical fertilizers, for instance, may influence the content of secondary metabolites in plants. For example in Datura stramonium L., where the alkaloid biosynthesis is increased by replacing part of the NO₃ in fertilizer by NH₄ (Demeyer & Dejaegere, 1993).

Fertilizers and pesticides may contaminate crops. Therefore, manure should preferably be applied before planting short-duration crops, because harvested plant material may be contaminated with bacteria if it is applied later. Chemical fertilizers are usually not used when growing medicinal crops, because plants usually take up too much sodium and potassium, resulting in excessive concentrations of these elements in decoctions. Very often, compost is used. Biological pest control by companion planting (e.g. with Tagetes) is often practised.

Harvesting

Medicinal plants, especially those growing in the wild, are often harvested by hand. Even when cultivated, manual harvesting is often more practical, e.g. for harvesting bark and fruits that do not mature simultaneously (e.g. Senna spp.). Leafy plant material is often labour-intensive to harvest; it is easier to harvest it from cultivated plants, as the individual plants are in approximately the same stage of development and grow close together in smaller areas. The amount of a constituent is usually not constant throughout the life cycle of a plant. Therefore, the stage at which a plant is harvested is very important for the yield of the desired constituent. There may be seasonal variations, but in perennial plants the age may also be important. It is generally assumed that the best time for harvesting is when the organ in question has reached its optimal state of development. Roots and rhizomes are usually collected at the end of the growing period, bark often at the beginning of the growing season, when it is easier to strip because of the abundance of soft cells near the cambium, leaves before flowering, flowers at anthesis, and fruits and seeds when fully ripe.

Uncontrolled stripping of bark will easily destroy trees, and in several cases has seriously threatened the diversity and abundance of species. It is therefore important, but not easy, to harvest bark in a sustainable non-destructive fashion.

Drying and cleaning

After harvest and cleaning, usually by washing, some plant materials have to be dried in the sun, others in the shade. Flowers are usually dried immediately after picking, in the shade; they are regularly turned over to prevent browning. Drying is the most common method of preserving plant material. Rapid removal of moisture largely prevents degradation of the constituents, since enzymatic processes require the presence of water. Drying also lessens the risk of external attack, e.g. by moulds (Samuelsson, 1992). In some extreme cases, soaking in ethanol is required to deactivate the enzyme. The desired constituents are often damaged by heat, so it is often advantageous to dry at moderate temperatures (45-50 °C). The best method of drying depends on the plant material, and uncontrolled drying may cause severe loss of quality. Irradiation is sometimes practised in manufacturing to avoid contamination by bacteria and fungi. The most efficient drying is achieved in large driers of the tunnel type. The material is spread out on trays placed on mobile racks and transported into a tunnel where they meet a stream of air. However, most often plant material is simply dried in the open. Mechanical driers are used for bulk operation. Sizeable losses still occur in drying and subsequent post-harvest handling.

Most materials have to be crushed or ground, coarsely or finely, before they can be loaded into an extractor or distillation vessel. Most extracts will be dried by distillation under vacuum or spray drying. Freeze-drying (lyophilization) is an adequate method for drying water extracts containing heat-sensitive substances such as antibiotics and proteins, but it requires relatively complicated and expensive apparatus.

Storage conditions

Raw material in the form of dried plant material can be stored only for a limited period of time and provided certain requirements are met. Storage time can be minimized when the processing is planned in such a way that the harvested raw material is used as soon as possible. Preparation of material for distillation varies with the properties of the material. Some materials like flowers should be distilled immediately after harvesting, whereas others such as foliage parts are best stored for some days before distilling. Some materials can be stored indefinitely before distillation.

There are great differences in the stability of crude drugs. Drugs containing glycosides, esters and essential oils are usually less stable than those containing alkaloids and tannins (Samuelsson, 1992). Optimal storage conditions must be employed to prevent deterioration. The enzymes able to break down constituents are rendered inactive in properly dried plant material, but they may become active again if not well protected from moisture during storage. Humidity should therefore be controlled, and wilted leafy plant material should be kept dry and cool to prevent fermentation or mould growth. A concrete floor under shade is often used. The moisture content of the material should stay under 10%. To avoid insect and fungal attacks, the material is often redried in the sun. In order to reduce undesirable microbial contamination and to prevent the development of other organisms, some plant materials are sterilized before storage. Ethylene oxide or methyl chloride may be used, and drugs so treated should comply with an acceptable limit for toxic residues.

The storage of end products such as extracts, also requires care. Storage vessels should be well cleaned prior to being filled. Sometimes it is necessary to fill the vessel to capacity to prevent oxidation, and to run an inert gas over the top to eliminate traces of oxygen. Post-processing oxidation of essential oils is a common problem to be avoided by exclusion of air, trace metals and sunlight. Light-sensitive products such as essential oils are stored in vessels in the dark. Under suitable conditions, however, most essential oils can be stored for long periods. Larger quantities are stored in metal drums lined with polyethylene. It is important that the essential oil is not in contact with rubber or plastic because chemical contamination may occur.

Extraction methods

Active constituents can be extracted from the plant material by maceration, percolation or continuous extraction. Extraction is the first step in isolating the desired constituents from plant material, using a solvent. Sometimes it is sufficient to achieve an equilibrium of concentration between drug components and the solution within set limits, as in the case of tinctures, tisanes, decoctions and teas. In other cases the drug is extracted to exhaustion, i.e. until all solvent extractables are removed by the solvent. The latter method is mostly used in industry.

In all industrial procedures the raw material is pretreated with solvent outside the extractor, preventing sudden changes in bulk and accelerating the penetration of the solvent through the cell walls to release the extractables. To facilitate extraction, the solvent should diffuse inside the cell and the desired substance must be sufficiently soluble in the solvent. The ideal solvent for extraction is one in which the extractive is most soluble and selective, so that the desired constituent will be extracted with minimum impurities. Alcohol is often used, but because of its great extractive power it is often the least selective in that it extracts all soluble constituents. The ratio of alcohol and water used varies, depending on the polarity of the active compounds. Most alkaloids can easily be extracted with organic solvent after the powdered drug has been mixed with water and alkali. The alkali will liberate the alkaloid from its salts. However, some volatile alkaloids, protoalkaloids and quaternary ammonium alkaloids should not be extracted by this method. Even though the alkaloids are soluble in acids, the use of acids is not appropriate for industry because of the large volumes required for exhaustive extraction. Some herbs are extracted with volatile organic solvents to produce oleoresins.

The equipment used for extraction with solvents comprises the following components (Wijesekera in Chomchalow & Henle, 1993):

• An extraction vessel with a heating jacket for steam heating or fitted with electrical devices.
• A condenser in a reflux position.
• A solvent reservoir.
• A facility to convert to reboiler position or a separate reboiler.
• A short column for solvent recovery.

There are 3 basic types of essential oil distillation:

• Water distillation (hydrodistillation).
• Wet steam (water and steam) distillation.
• Dry steam (steam) distillation.

Stills of the first type are the simplest and are used by small producers. The plant material is immersed in boiling water. Steam distillation is an improved method to avoid prolonged contact of the material with heat. The still contains a grid which keeps the plant material above the water level (wet steam distillation) or steam is provided from a separate boiler (dry steam distillation). Stills should be insulated to reduce heat losses.

The passage of steam through plant material causes volatile oil to distil over with the steam. The compounds can be distilled out of the plant material at around 100 °C. When the condensate cools through a condenser, the oil, dispersed in water, separates from the aqueous phase, forming two layers which can then be separated easily. It is important that the separator has a large volume to minimize turbulence, because significant amounts of oil can be lost with the distillate water if the oil is not allowed to separate completely. The best material for stills, condensers and separators is stainless steel. The method of distillation chosen must be suited to the particular essential oil, and has to be determined experimentally.

Hydrodiffusion is another, more recent process in which low-temperature, low-pressure steam is used to extract the essential oils. Essential oils from the more fragile flower material can be obtained by enfleurage, a process in which successive batches of freshly picked flowers are exposed to layers of grease coated on stacked glass plates, and finally the resulting pomade is extracted, usually with alcohol, to obtain absolute. This is an almost superseded method practised in the perfume industry, for flowers that continue to produce aroma compounds for several days after they have been picked. At present it is only used for the most expensive perfumes. See Prosea 19: "Essential-oil plants" for more detailed information on essential oil distillation.

New industrial standards

The practice in industry is to judge plants according to their content of important constituents, but the extent to which the desired secondary metabolites are technically and biologically exploitable is also a governing consideration. Tissue culture techniques have much to offer. They can produce more homogeneous plant material and are also of interest for the industrial production of plant-derived natural substances, including drugs. The main reason why plant tissue and cell cultures have not yet become important for the production of pharmacologically active natural products is the high cost of producing the desired substances by this method. The breakthrough will depend on basic research in molecular biology to clarify how the plants regulate the formation of secondary metabolites and how this is connected with the development of organs (Samuelsson, 1992). Often, high-yielding cell lines are selected, taking advantage of the somaclonal variation. This requires rapid and sensitive methods for analysing the desired metabolites.

Standards are available for several herbal products and guidelines specifying the requirements have been formulated by individual countries, the World Health Organization (WHO) and United Nations Industrial Development Organization (UNIDO). One of the key points on which the medicinal plant-based industry differs from any other agro-industry is the requirement of sophisticated facilities for chemical analyses at all stages. Quality control and assessment are needed, and analytical research has to go hand in hand with plant breeding. A range of quick, reliable and acceptable methods is available, and the institutions dealing with medicinal plants need to have a well-equipped laboratory.

For the quality control of crude drugs the identity of the crude drug must be known, and also the content of active constituents and impurities. Descriptions of the macro- and micromorphology of crude drugs are given in pharmacopoeias and handbooks. A laboratory carrying out the quality assurance of crude drugs should have a well-documented collection of reference materials.

Household preparation

In some countries of South-East Asia, standard pharmaceutical methods have been modified to enable herbal medicines to be made without sophisticated and expensive laboratory equipment. The materials employed in the procedures are those found in rural kitchens. In the Philippines, for instance, these methods of preparation, referred to as "kitchen technologies", are being taught nationwide and are part of the health care system. The most common preparations made are infusions or teas, decoctions, syrups, liniments, ointments, pills, herbal soaps and lozenges.

The following general guidelines are given for household preparations of medicinal plants in the Philippines:

• Be sure of the identity of the plant.
• Use only one plant drug at a time.
• Use only the recommended plant parts.
• Collect only those plant parts that look healthy: no insect damage, discolouration or other signs of abnormality.
• Follow the recommended methods of preparation.
• When using dried drugs, use only half the amount prescribed for fresh plant drugs.
• Infusions and decoctions should be freshly prepared. A dose for one day may be prepared and kept in a thermos flask.
• Use containers made of inert materials; for cooking: earthenware pots, enamel-lined, pyrex, not metallic utensils.
• Sterilization of medicine bottles is very important. This may be done by heating the bottles, caps or bottled products in a double boiler for at least 20 minutes.
• Observe care and cleanliness at all times.

An example of "kitchen technology" as described in the Philippines is a sweetened preparation from the leaves of Vitex negundo L. called lagundi syrup, and is indicated below:

• Materials: cooking pot, ladle, cup, stove, strainer, medicine bottles, labels, lagundi leaves, sugar/honey, water.
• Proportion: 1 cup chopped lagundi leaves to 2 cups water.
• Procedure: (1) Prepare a decoction by boiling the leaves in water in an uncovered pot for 20 minutes or until the water has decreased to half of the original volume. (2) Cool and strain. (3) Measure the amount of decoction produced. One-third of this volume is the amount of sugar/honey to be added. (4) Add the sweetener, stirring gently. The mixture can be put back on the stove, on low heat, until all the sweetener is dissolved/blended with the mixture. This is the syrup. (5) Transfer the syrup to the sterilized medicine bottles. Seal and label properly. (6) Store the bottled syrup in a clean, cool, dry place away from light.

The need for a comprehensive inventory of medicinal plants is felt in countries where such plants are starting to play a role in the primary health care system. In most countries in South-East Asia the extent of genetic erosion is being inventoried, but this is not being done as well as it should be, because of the huge cost involved.

Plant diversity and conservation

Several species occurring in primary forest are rare and endangered because of large-scale forest destruction and/or over-collecting. Forest destruction may easily endanger species with a narrow area of distribution and may result in genetic erosion. The discovery and use of plants by the herbal and pharmaceutical industries often lead to degradation of the resources. Often both habitat loss and over-harvesting reinforce each other as synergetic factors contributing to the species's overall endangered status. However, in only a few cases is it known whether certain medicinal plants are already or potentially endangered (Lange & Schippmann, 1997). It has been necessary to protect some species, e.g. Rauvolfia serpentina (L.) Benth. ex Kurz and spp., by including them in the Appendices of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Several species with a large area of distribution (e.g. Acorus calamus L.) need not be considered as at risk from genetic erosion; others have a remarkable capacity to regenerate.

Although medicinal plants have been cultivated for centuries, their germplasm collection has been very limited. There are no germplasm collections for most species and very little effort has been made towards conserving the genetic variation. Gene banks are a way of conserving genetic diversity, but they generally cover major food crops and include hardly any medicinal plants. Gene banks of medicinal and poisonous plants with limited collections (up to 500 accessions) are listed for most of the countries in the region, but the coverage of the geographical and botanical diversity is far from complete. In situ conservation of valuable species in natural parks and reserves and in botanical gardens is too little focused on medicinal plants. In the few important medicinal plant gardens in South-East Asia, the diversity of species has mostly decreased in the last 30 years.

Breeding

Unlike other commercial crops, medicinal crops continue to be cultivated in the same way as they were hundreds or sometimes thousands of years ago, with few exceptions. Very little has been done to genetically improve these crops, despite their long history of domestication. There seems to be great potential for improving the yield and quality of medicinal crops. Breeding work on medicinal crops whose wild forms have great genetic variability often leads to spectacular successes, even in the first few cycles of selection. Therapeutic value and yield are important criteria for selection and breeding. For industrial-scale production of raw material it is vital to select cultivars with the required characteristics.

Research on breeding of medicinal crops thus lags far behind that of food crops and other commodities. The objectives of breeding in medicinal crops are to obtain a high yield of active constituents, to improve adaptability and quality, and also to obtain resistance to diseases and pests and stress tolerance. The trend in several countries towards using plants in primary health care increases the need for improvement of crops through breeding. However, for many species there is still no information available.

Examples of existing breeding programmes include:

• The development of genotypes of Rauvolfia with a short maturation period and a high root yield for the production of reserpine and ajmalicine.
• The development of genotypes of Catharanthus roseus (L.) G. Don with a high root yield and total alkaloid content.

Biotechnology, plant cell culture and molecular techniques are important for the improvement of medicinal plants. For many medicinal species, complete plants have been regenerated from callus cultures, excised plant organs and isolated protoplasts, whereas selections have been made for cell lines with high alkaloid content. Natural or artificially induced mutations have been used to develop plants that produce desired types of alkaloids (e.g. in Datura and Papaver). Sophisticated hybridization techniques have been applied to several plants of pharmaceutical interest, for the purpose of combining certain desirable characteristics or for producing entirely new characteristics not found in either parent. Gene transfer is possible from related wild species to cultivated plants.

The most profitable system for the synthesis of secondary metabolites is plant cell suspension culture, but the yields of medicinally important alkaloids are lower than in whole plants grown in the field. Hairy root cultures are promising, but quite expensive. Genetic transformation may lead to better in vitro production of secondary metabolites.

Main research topics

Research priorities in South-East Asia for medicinal and poisonous plants are:

• Ethnobotanical research on traditionally used plants.
• Agronomy and commercialization of traditional medicinal plants.
• Medical, biological, microbiological and biochemical screening and standardization.
• Issues related to the use, conservation and socio-economic aspects of traditionally used medicinal plants.
• Legislation and management locally, regionally, nationally and internationally.

Main institutions

The main institutes and universities conducting research on medicinal and poisonous plants in the respective countries in South-East Asia are:

Indonesia

• Agency for Development and Application of Technology (Badan Pengkajian dan Penerapan Teknologi), Serpong
• Central Institute for Research and Development of Agrobased Industry (Balai Besar Penelitian dan Pengembangan Industri Hasil Pertanian), Bogor
• Research and Development Centre for Biology (Pusat Penelitian dan Pengembangan Biologi), Bogor
• Research and Development Centre for Industrial Crops (Pusat Penelitian dan Pengembangan Tanaman Industri), Bogor
• Research and Development Centre for Pharmacy (Pusat Penelitian dan Pengembangan Farmasi), Jakarta
• Research Institute for Spices and Medicinal Crops (RISMRC), Bogor (including 14 experimental gardens)
• Research Institute for Veterinary Medicine, Bogor
• Tawangmangu Research Institute for Medicinal Crops (Balai Penelitian Tanaman Obat Tawangmanggu), Surakarta
• various academic institutions throughout Indonesia including Institut Teknologi Bandung, Universitas Airlangga (Surabaya), Universitas Gadjah Mada (Yogyakarta), Universitas Jenderal Sudirman (Purwokerto), Universitas Udayana (Denpasar).

Malaysia

• Forest Research Institute Malaysia (FRIM), Kepong
• Malaysian Agricultural Research and Development Institute (MARDI), Serdang
• Universiti Putra Malaysia (UPM), Serdang
• University of Malaya (UM), Kuala Lumpur
• Universiti Kebangsaan Malaysia (UKM), Bangi
• Universiti Sains Malaysia (USM), Penang

Papua New Guinea

• Wau Ecology Institite, Wau
• University of Papua New Guinea, Port Moresby

The Philippines

• University of the Philippines System: various institutes, colleges and departments at UP Los BaÉ9 os, UP Manila and UP Diliman, Quezon City
• Department of Science and Technology: Philippine Council for Health Research and Development (PCHRD), Philippine Council on Agriculture and Foresty Resources Research and Development (PCARRD), Integrated Technology Development Institute (ITDI), Forest Products Research and Development Institute (FPRDI), Food and Nutrition Research Institute (FNRI), National Research Council of the Philippines (NRCP)
• Department of Health: Traditional Medicine Unit (TRADMED), Philippine Institute for Traditional and Alternative Health Care (PITAHC), Bureau of Food and Drugs (BFAD), Institute of Tropical Health (ITM)
• various academic institutions including University of Santo Tomas and De la Salle University in Manila, Philippine Institute for Pure and Applied Chemistry and Ateneo de Manila University in Quezon City

Thailand

• Department of Agriculture: research stations at Chiang Rai, Chiang Mai, Chanthaburi, Chumphon, Ubon Ratchathani, Chai Nat, Suphan Buri
• Department of Medical Sciences: botanical garden at Chanthaburi
• Royal Forestry Department: Phu Khae Botanic Gardens and various National Parks
• Thailand Institute of Scientific and Technological Research (TISTR), Bangkok
• various academic institutions, in particular Mahidol University, Faculty of Pharmacy, Bangkok

Vietnam

• Institute Materia Medica, Hanoi
• Institute of Natural Products Chemistry, Hanoi
• Institute of Chemistry, Ho Chi Minh City - Ministry of Health, Hanoi
• Science Production Centre of Vietnamese Ginseng, Ho Chi Minh City
• Institute of Tropical Biology, Ho Chi Minh City

Since the 1950s, the pharmaceutical industry has relied primarily on new synthesized compounds, with the exception of most antibiotics which are derived from micro-organisms. There was almost no interest in using plants for drug development, but in the last few years that situation has changed slowly.

Plants are still an overwhelming source of novel chemical structures, and substances within plants widely used by humans are less likely to be seriously toxic than synthetic chemical compounds. There is renewed recognition that traditional systems of medicine are appropriate starting points for the development of modern medicines. Another reason for a shift from synthetics to plant-derived products is the increased interest of the public in using medicines from plant sources.

When one or more active constituents have been isolated, studies are performed in animal species (rodents, other mammals) to investigate the mechanism of action. Acute and chronic toxicity studies are required, to ensure the safety of the drug. The most suitable preparation must be determined, i.e. one that provides the proper dose of the drug and is stable enough to be launched on the market. Then clinical studies are carried out. The first clinical phase deals with a small group of healthy subjects, to observe the efficacy and possible side-effects. In the second clinical phase the drug is tested on a small group of patients, and finally a complete clinical study is carried out. All this involves much time and money.

Drug discovery programmes have become less efficient, and the costs involved in developing a drug have escalated rapidly with the increasing requirements associated with the demonstration of the safety and efficacy of a compound. The minimum costs are US$ 100 million (Horrobin & Lapinskas in Prendergast et al., 1998), but may amount to US$ 2000 million. The high costs discourage companies from entering a drug development programme unless there is a fair chance that the returns will eventually be much higher and there is protection of intellectual property.

Although the patenting of new pharmaceutical uses of known compounds is now possible in many countries, new plant-source drugs often cannot be patent-protected. They may arise from traditional sources or from scientific publications, and in such cases marketing protection may be necessary to make the necessary investment attractive for companies to take the drug through the approval process. This is often in the form of a market monopoly for a period up to 10 years.

Important issues to be addressed to develop a plant source successfully as a pharmaceutical are:

• A chemical substance must be shown to be safe and to have a reasonable prospect of being effective. A problem arises because in many cases, the activity of isolated compounds is equated with the efficacy of the preparation without considering the possibly important modifying action of other drug constituents.
• A financial assessment should be made to compare the costs for developing the drug with the revenue expected from sale of the product.
• Where possible, it is usually preferable to prepare the compound concerned at reasonable cost synthetically. Where this is not possible, plants should be comparatively easy to cultivate and the plant should contain a reasonable amount of the compound, preferably in easily harvested parts such as leaves or seeds.

The South-East Asian region abounds with medicinal and poisonous plants, many providing drugs for various therapeutic categories and having revolutionized medical science over the years. Accounts of positive effects of herbal preparations are no longer just folklore; they are backed by extensive scientific research, and many modern-day medicines have been derived from medicinal plants. More significant cures for major health problems remain to be discovered.

The sharing of benefits is at present a sensitive issue for the cooperation between drug-resource countries and drug-producing countries. Standard regulations should be set up by resource countries to gain benefit from commercial production of drugs from plant resources.

To harness the full potentials of medicinal plants research should focus not only on the validation of safety and efficacy, combined with development and conservation efforts, but also on chemistry, biological activity, formulation of drugs, clinical trials and cultivation technology. The need for state-of-the-art facilities, adequate funding for research and training of medical researchers are issues to be addressed. Concerted efforts along these lines are critical if long-term objectives are to improve the health of man and provide good health care to all.

There is worldwide concern about the side-effects produced by purified compounds and synthetic drugs. Dangerous side-effects of medicinal plants tend to be limited, but are often concentration-dependent. The long-continued use of numerous medicinal plants with apparent positive effects and no evidence of detrimental side-effects validates their safety and efficacy and supports their position in the medical practice today. Furthermore, some optically active asymmetrical compounds cannot be synthesized chemically. Many plants are used as pesticides in farms, gardens and homes. People concerned with maintaining ecological balances prefer pesticides from plant products over synthetic formulations.

This implies that the prospects for medicinal and poisonous plants are promising. In fact, there is already a trend in South-East Asia towards a revaluation of the use of medicinal plants in primary health care. In some countries, there are already initiatives to promote their use and to disseminate information on proper applications. In other countries, the recent economic crisis is forcing governments to seriously consider the use of medicinal plants. Sometimes regulations have to be modified to make it easier to register locally produced herbal drugs. At the same time, appropriate manufacturing practices should be introduced to assure the quality of such drugs.

It is envisaged that certain medicinal plants may become commercial crops. However, the demand for medicinal plant products is often not as large as expected and can change rapidly. Oversupply must be avoided by attuning supply to demand in and between countries.

It has been estimated that the higher plants in the world's tropical forests contain about 375 potential pharmaceuticals of which about 50 have already been discovered. It has been suggested that the complete collection and screening of all tropical forest species may cost about US$ 3-4 billion to a private pharmaceutical company, and as much as US$ 147 billion to society as a whole (Mendelsohn & Balick, 1995). The potential value of undiscovered drugs is an additional incentive to conserve species-rich tropical forests.

L.S. de Padua, N. Bunyapraphatsara & R.H.M.J. Lemmens

with contributions from D.K. Holdsworth (traditional and modern medicine in South-East Asia: Borneo, New Guinea), R.P. Labadie (phytochemistry (introductory part), biological and pharmacological activity and therapeutic applications), Nguyen Tien Ban (traditional and modern medicine in South-East Asia: Vietnam), N. Wulijarni-Soetjipto (traditional and modern medicine in South-East Asia: Indonesia) & J.L.C.H. van Valkenburg (definitions, botany, research and development)