DEVELOPMENT AND PRODUCTION OF STANDARDISED PHYTOMEDICINES

DEVELOPMENT AND PRODUCTION OF STANDARDISED PHYTOMEDICINES
By

Prof. Charles Wambebe
Chief Executive Officer
National Institute for Pharmaceutical
Research and Development, P.M.B. 21
Abuja, Nigeria

INTRODUCTION

In 1991, The Programme on Traditional Medicine of WHO published Guidelines for the Assessment of Herbal Medicines (WHO/TRM/91.4). The objective of these guidelines is to define basic criteria for the evaluation of quality, safety and efficacy of herbal medicines and thereby assist national regulatory authorities, scientific organizations, and manufacturers to undertake an assessment of the documentation/submission/dossiers in respect of such products. As a general rule, in this assessment, traditional experience means that long-term use as well as the medical, historical and ethnological background of herbal products shall be taken into account. Depending on the history of the country, the definition of long-term use may vary but would be at least several decades.

The World Health Organization, in recognition of the immense value of Herbal Medicine to Primary Health Care, has advocated for the proper identification, sensible exploitation, scientific development and appropriate utilisation of Herbal Medicines which provide safe and effective remedies in Medicare. In many countries, especially in Asia, Herbal Medicine has become an integral part of the health care delivery system on the same basis as Orthodox Medicine. However, in most countries in Africa, this is not yet the case. Even in the later situation, Herbal Medicine is recognised as an important component of the health care system especially among the rural dwellers who constitute about 70% of our population. Furthermore, in both rural and urban communities, many people depend partly on Herbal remedies for their Primary Health Care needs. Even in the developed countries, the popularity of crude herbal products is on the increase. In these technologically advanced societies, consumers' preference is shifting from purely synthetic to natural based drugs and this is dictating the basis for the resurgence in the utilisation of such products.

The world is already aware of Chinese Traditional Medicine (CTM). The Chinese government demonstrated unparalleled political will when CTM was included in the constitution. The Chinese government went further to commit substantial funds and resources for the research, development and commercial production of standardised CTM. In order to make African traditional medicine available to the world we have to appropriately adopt the Chinese model.

CURRENT STATUS
Ethnobotanical surveys have been conducted in different parts of Africa whereby relevant information on the traditional uses of medicinal plants for prevailing ailments has been obtained from herbalists, herb sellers in the open market and some indigenous people (Baba et al., 1982). For example, the Organization of African Unity's Scientific Technical and Research Commission (OAU/STRC) conducted ethnobotanical surveys in Western Nigeria, Uganda, Cameroon and Ghana (Adjanohoun et al., 1989, 1993 & 1997a & b).

Similarly, Agence de Cooperation Culturelle et Technique (ACCT) in Paris, supported ethnobotanical surveys in Central African Republic, Rwanda, Mali, Nigeria, Federal Islamic Republic of Comoros, Mauritius, Seychelles, Gabon, Dominica, Tunisia, Madagascar, Togo, Congo and Benin Republic. Databases (e.g. NAPRECA, NARISTAN etc.) have been produced based on such ethnobotanical data.

Screening of medicinal plants for the chemical constituents and biological properties has been conducted in various universities and research institutes in Africa and Europe. Since the early 60s NAPRALERT database for natural products in Chicago, Illinois (supported by WHO) has collated publications in this field. According to Sofowora, 1997 only 37 per cent of all the publications from 1988 to 1996 dealt with Bioassay guided isolation of plant constituents as well as their pharmacological and toxicological testing. This simply implies that the remaining 64% of the publications dealt with phytochemical research. Most of the screening activities relate to anti-malarial property, anti-microbial activity, molluscicidal effects anti-HIV, anti-inflammatory and toxicity assessment. Understandably, work on malaria has been sustained over the past 30 years. According to WHO 1996, malaria is still responsible for death of over one million young children under the age of five in Africa every year. Extracts of Phytolacca dedecandra, Swartizia madagascariensis and Tetrapleura tetraptera have shown potential against snail - the intermediate host of schistosomiasis (Hostettmann, 1989, Adewumi, 1991; Amusan et al 1995).

Various African collaborative networks in Research and Development on Medicinal Plants have been established and encouraged by some Agencies. For example, UNESCO supported the establishment of the Natural Products of East and Central Africa (NAPRECA) as well as the West African Network (NAPRWA) so as to boost inter-African collaborative efforts on medicinal plants. Furthermore, the International Organization for Chemistry in Development (IOCD) established the Network of Analytical and Bioassay Services in Africa (NABSA) with headquarters in the Department of Chemistry, University of Botswana and Dr. Abegaz as Co-ordinator. They offer the following services: NMR, MS, GC/MS, IR, UV-Visible GC, HPLC, Polarography, Anti-feedant, Larvicidal and Brine shrimp assays. The co-ordinator is expected to send all samples received to laboratories within the region where facilities exist for the specified tests.

In 1996, the Commonwealth Science Council established a Network for South African Plants Resource Exploration (SAPR-E) which was involved in the documentation and sustainable utilisation of plant resources in the sub-region. The co-ordinator is Dr. A. A. Gurib-Fakim of the Medical Research Council, Mauritius and the Department of Chemistry, University of Mauritius.

In March 1997, at the end of an African Workshop which was jointly sponsored by TCDC and the Federal Government of Nigeria, African Network for the Industrial Utilisation of Medicinal and Aromatic Plants (ANIUMAP) was established with the National Institute for Pharmaceutical Research and Development (NIPRD) as the Co-ordinating Centre and Prof. Charles Wambebe as the Co-ordinator. The objectives of African Network for Industrial Utilisation of Medicinal and Aromatic Plants (ANIUMAP) include:

- Dissemination of information on medicinal and aromatic plants to other focal centres in each African country.
- Training of personnel in the various aspects including R&D, industrial utilisation of medicinal and aromatic plants, clinical trials, commercial production and rational use of phytomedicine.

All these efforts at establishing sub-regional and regional network to link scientists, researchers; government bodies, universities and research institutes are expected to facilitate the research and development of medicinal and pharmaceutical raw materials from the abundant bio-diversity within the region. The outcome of these various efforts has not yet become obvious.

Endemic plant and animal species abound in Madagascar, Comoros, Mauritius, Sao Tome and Principe, Seychelles. Furthermore, the African continent is rich in forest species such as Cote d'Ivoire, Liberia, the lowland and mountain forests of Nigeria, Cameroon and Gabon, Western escarpment of Angola, the lowland and mountain forests of Zaire, Western Uganda and Rwanda, Coastal Kenya, Eastern Tanzania and wetland areas of river Niger Delta in Mali, flood plains of Central African Republic, Sudd Region of Sudan and arid land areas of Somalia, Ethiopia and Namibia, South Africa and Mediterranean region of North Africa .

About 70 per cent of the 300,000 plant species so far identified in the world are found in Africa and other parts of the Tropics. About 80 per cent of the population of Africa live in the rural areas where they rely on the bio-diversity in their vicinity for food, medicine and shelter. One fifth of the total 120,000 (including 30,000 undescribed species) seed plants found in the tropical moist forests reside in Africa (Farnsworth & Soejarto, 1991). All over the world, and especially in Africa, factors which cause forest depletion include direct human pressure as well as indirect factors: Commercial logging in the forest, fuel wood consumption, cattle ranching, forest farming and forest fires. Also, environmental factors such as desert encroachment, pollution, acid rain, green house effect and erosion are other factors causing loss of forests.

Africa faces the most serious problems of population growth. With economic stagnation over most of the continent except Uganda, reduced mortality but little or no reduction in fertility, it may grow from its current 600 million to 1.4 to 1.6 billion by the year 2025, and still be expanding at annual rates of above 2 per cent (McNeely, 1996).

As Africa's population grows, demand for traditional medicines will increase, and pressure on the medicinal plant resources will become greater than ever. While loss of habitat is the major factor contributing to the depletion of natural resources in Africa, collection of wild plants for traditional medical use is extremely detrimental to certain species (Sofowora, 1997).

Since most of the medicinal plants are not cultivated in Africa, many of these plants have become endangered due to uncontrolled usage without replacement. According to Cunningham (1993 a & b) indigenous forests cover only 0.3 per cent of South Africa but are a source of over 130 commercially exploited medicinal plants. Furthermore, over 400 indigenous species and 70 exotic species are commercially sold to Zulu people as herbal medicines. Slow-growing forest species are particularly vulnerable to this over exploitation. More than 500 medicinal plant species are traded in the Johannesburg area of South Africa alone. Over 500 medicinal plants species are sold in Johannesburg alone (Williams, 1996).

Mauritius and Rodriguez have two of the most threatened floras in the world. Over 150 species of plants on these African islands are threatened with extinction, out of which at least 30 species are known from less than 10 individuals (Owadally et al., 1991).

According to Kokwaro (1991), high and medium potential land in Kenya constitute about 17% of the country and these support 90% of the population which is mostly rural. The plant community in such potential areas are usually the most threatened by over utilisation. The depletion rates of the forest resources which include medicinal plants are very high. For example, Kakamega, North and South Mandi forests which occur in high potential areas are said to be cleared at the rate of 245,295 and 490 ha per year respectively (Kokwaro, 1991). Regina (1996) indicated that the major threats to medicinal plants leading to extinction in Kenya include over-exploitation and poor harvesting techniques. The same factors may also apply in most African countries. Recently, a medicinal plant conservation project has been established in Kenya within the East African Herbarium. The broad objectives are to collate information on plant used in ethnomedicine in Kenya, parts used, modes of harvest and assess potential threats plus factors affecting potential for sustainable utilisation. The project will form a basis for focusing the limited available resource towards conservation of heavily exploited species. The projected out-put includes a database on species used in ethnomedicine, case studies on those that are utilised heavily, regional surveys in districts whose communities still rely on herbal medicine, ex-situ conservation collections of heavily exploited species and market study reports on species and plant parts in trade (Regina & Simiyu, 1996).

In Uganda the Rukararwe Partnership Workshop for Rural Development actively supports the herbalists to cultivate medicinal plants in their gardens so as to preserve the remaining forests. A seedbed at the project centre supplies up to 100,000 seedlings regularly to farmers and herbalists (Bitahwa, 1996). Although legislation is a useful tool, this practical approach is commendable. This approach is included in the Guidelines on Conservation of Medicinal Plants recommended by WHO/IUCN/WWF (1993).

In Nigeria, the total land area is 923,768,000 ha. Of this amount, forests account for only 9.61%, grasslands 48.53%, fresh water and wetlands 20.33%, mangroves 1.05% and farmlands 20.33% (see figure 2). Within 1980-1992, an estimated 43.48% of the total forest ecosystem was lost through human activities (such as shifting cultivation), erosion, flooding and desertification. The in-situ and ex-situ conservation of gene resources abound all over Nigeria covering 9,651,800 ha. which represent 10.3% of the total land area. However, many of these forest reserves have very porous borders and illegal felling of timber and game hunting still continues.

According to Okafor (1993) the basic scientific criteria for successful conservation and restoration of bio-diversity in Nigeria. These include studies of ecology, phenology and taxonomy of species of interest, identification of parameters to be used in species selection procedure, propagation techniques and procedures, dissemination of information on the species and extensive research into utilisation. Similar criteria are currently used by Project TRAFFIC in Southern and Eastern Africa.

In Nigeria, in situ and ex situ conservation measures are being undertaken by the State Forestry Services, Forestry Research Institute of Nigeria (FRIN), World Wide Fund for Nature (WWF), Man and Biosphere Programme and the Nigerian Conservation Foundation, for in situ conservation. FRIN, Forestry Development and Investigation Branch (FDIB), the National Centre for Genetic Resources Conservation, National Institute for Horticulture Research and some other organizations undertake ex situ conservation (Gbile 1996; Isichei, 1995). FDIB has successfully developed vegetative propagation techniques (by bud grafting and stem cuttings) for about 20 indigenous woody plant species. Suitable germination techniques were also developed for Dacryoides edulis, Irvingia gabonensis, Treculia africana, among others (Okafor, 1993). But there are many wild growing medicinal plants that are hardly cultivated. Dioscoreophyllum comminsii, Landolphia spp, Piper guineense, Gnetum spp, Tetracarpidium canphorum, all of which are climbers are usually the first to be eliminated during forest clearing and are thus very vulnerable medicinal plants. Shrubs and small trees such as Synsepalum dulcificum are also fast disappearing in Nigeria (Gbile 1992, 1996; Isichei, 1995).

According to Cunningham (1996), five major steps to be taken to identify the "Top 50" medicinal plant species for conservation action are:

1.) Identify major sale sites
2.) Identify the medicinal plants in the trade
3.) Prepare a short list of species in trade, which are destructively harvested or other wise threatened
4.) Short-list these further on the basis of commonness or rarity
5.) Within the resulting short-list, set priorities on the basis of phylogenetic distinctness.

At the Third Conference of the Parties under the Convention on Bio-diversity (COP-3) (Buenos Aires, November, 1996), governments adopted two formal decisions that reflect, in particular, their new emphasis on the need to demonstrate and achieve measurable progress in implementing the Convention. Other developments outside the COP process also show a growing interest in the need to demonstrate and achieve measurable progress in CBD implementation. Two overarching categories are capacity and performance targets (Stas Burgiel, 1997). In this respect, AMCEN for regional level in Africa as well as appropriate agencies at country level should decide on a minimum X funding level to be allocated to medicinal plant conservation; X% of priority degraded areas to be restored before the next reporting date of first national reports on implementation which should be submitted by Parties by 1 January 1998 in readiness for COP4 (Sofowora, 1997).

UNIDO has undertaken various missions to Burkina Faso, Burundi, Cape Verde, Ethiopia, Ghana, Kenya, Madagascar, Mauritius, Niger, Nigeria, Rwanda, Tanzania, Guinea, Senegal, Sierra Leone, Zambia and Zimbabwe. In spite of these missions to Africa, process technology form the commercial utilisation of medicinal and aromatic plants has not been successful. Except for Egypt, Algeria, Ethiopia, Ghana and South Africa, most of the countries in the region depend either wholly or 80% on the importation of finished medicinal or pharmaceutical raw materials. According to Sofowora 1991, the capacity utilisation of pharmaceutical industry in Africa was about 50%. Some African countries like Botswana, Madagascar and Cameroon have now diversified to produce simple extracts from medicinal plants thereby enhancing the unutilised capacity. Prof. Sofowora also estimated that production of simple extract from medicinal plant increases the value added by ten times compared with exporting such plant raw materials. It is abnormal that US spent about $8 billion US dollars on plant derived drugs annually and consume herbal drugs or natural products up to 20% yearly. Most African countries only use 5% of plant derived drugs. This situation is better appreciated when the economic analysis and health benefit of plant derived drugs are compared to one another. The African Pharmacopoeia published monographs for 100 medicinal plants for which industrial production can commence. In 1991, WHO released the Guidelines for the Assessment of Herbal Medicine. UNECA 1989 released their financial assessment, which show within one year or financial recovery will be accomplished for ginger oil while clove oil is two years. In 1989, UNECA published data which shows that recovery of investment in ginger oil and clove oil was one and two years respectively.

3. MAIN CONSTRAINTS

3.1 Conservation and Cultivation

In order to sustain the sensible utilisation of medicinal and aromatic plants, conservation has to be kept as the central focus. In conducting research and development activities, the plant parts from which the extracts are obtained have to be such that will not destroy the plant. Furthermore, the methods of harvesting the desired plant parts should take cognisance of the conservation of the plant. Ex situ cultivation of the desired medicinal and aromatic plants would be necessary so as to obtain raw plant materials grown under the same conditions of climate, ecology etc. The acquisition of large scales of land required for ex situ cultivation from government agencies can be a serious obstacle.

3.2 Lack of Research and Development Equipment

The economies of most African countries are subjected to immense and diverse pressures with varied competing interests. Science and Technology is usually the sacrificial lamb in view of the general notion that such investments do not yield immediate tangible results. Generally, therefore, the funds allocated for research equipment are indeed insignificant.

3.3 Patenting

The cost of patenting of any new process or drugs or use of plant materials in Patent Licensing Office which has the resources to protect the patent information is relatively high for most African Scientists and Institutions. In some cases, the patent experts to advise on the various processes are not available. Furthermore, it is also known that plant materials cannot be patented in their native form.

3.4 International Market

The various markets available in the Western World for plant part and extract are not usually available to the Institutions in Africa. Furthermore, the quality requirement of standardised plant extracts are generally not met by most researchers in Africa due to inadequate facilities and resources. Furthermore, the regular supplies of the plant raw materials in adequate quantities on a long-term basis cannot be guaranteed.

3.5 Pilot Plant

Since most African countries have not established pilot plants (except Nigeria, Rwanda, South Africa, Zimbabwe etc.) it is not possible to establish the process technology required for upgrading the R&D findings to semi industrial scale. Of course, no serious industrialist will accept R&D data without scaling up appropriately. It would be too risky.

Until the war in Rwanda, it was the only country that was noted to be producing plant derived drugs as a viable activity. Most investors will easily remember the failure encountered in the cinchona plantation in Guinea and Cameroon. The NIPRD, Abuja, Nigeria has had a functional polyvalent multipurpose pilot plant facility since 1997. It is too early to assess the success of this new plant.

3.6 Funding

Most entrepreneurs are sceptical about funding in this sector of the economy. They prefer investment in areas that will yield quick turnover. Foreign investors also consider the political situation in Africa, which they believe, is not favourable for serious investment.

3.7 Lack of Basic Infrastructure

Infrastructural facilities like water, electricity, telephone, transport, communication etc. which are easily taken for granted in developed countries are serious problems in various part of Africa. This situation hampers R&D activities to varying degrees in different African Countries.

3.8 Bureaucracy

When government is to implement any project that is capital intensive, the processes are generally lengthy. Similarly, grants from either UNIDO or UNDP have to pass through various stages of evaluation. Furthermore, continuity could be a problem since government officials are regularly transferred from their various positions.



3.9 Political Instability

The fact that civil unrest and change of government takes place often in Africa has affected progress in the industrialisation of medicinal and aromatic plants in Africa. The cases of Rwanda and Guinea have been cited as examples. The recent civil war in Rwanda has seriously affected personnel and the productivity of the model pilot extraction plant in Butane while the political change in Guinea has resulted in the closure of the company which was established to produce drugs from plants.

3.10 The political will

The political will of the government to develop traditional medicine and medicinal plants is paramount. Lack of government policy to develop medicinal plants industrially has been advanced as the reason for inactivity in some countries. Appropriate legislation and machinery to implement the provisions of the law are responsibilities of the government. Registration of TMP, establishment of curricular, laws to regulate traditional medicine practice, setting up of governing boards fall within the premise of government.

4.0 SUGGESTIONS TO OVERCOME THE MAIN CONSTRAINTS
4.1 Conservation and Cultivation of Medicinal and Aromatic Plants

From the Atlantic shore to the most northern parts of Africa, there is a marked climatic change embracing humid coastal lowlands, sub-humid uplands and semi-arid zones. Some plants are adapted to specific ecological zones. Some plants are adapted to specific ecological zones while others are ubiquitous. It is therefore not surprising that the African region has one of the richest biological diversities in both flora and fauna in the world. However, the annual bush burning for game, deforestation, increased land utilisation for industrial development and farming as well as dessertification are threatening the very survival of many medicinal plants found in the diverse ecological nitches of Africa (Wambebe, 1994).
A major bottleneck in commercialisation of herbal drugs is availability of an adequate quantity of plant material of requisite quality. Many plants are collected from the wild. Proper botanical authentication should be followed by development of agricultural practices and post-harvest technology. Research inputs are needed to evolve better (high yielding, pest resistant, etc.) strains and to identify alternative sources. Cultivation usually involves a homogenous strain of the plant thus reducing the risks of adulteration.

The raw material for extraction of pure products or destinated to phytopharmaceutical preparations can be obtained from medicinal plants collected in the wild or from medicinal plants grown in farms. The medicinal plants harvested in the wild are subject to the risks of incorrect botanical identification, of adulteration or active principles in wild growing plants vary considerably according to the area and the time of harvest. To obtain homogenous results several batches of wild harvested plants must be combined. The harvesting of wild medicinal plants also may result in endangering certain species. Furthermore, contamination due to yeast and pathogenic bacteria can be reduced to permissible limits. It is more appropriate to follow post-harvest procedures which consequently reduces unnecessary losses due to storage or improper drying.
It is therefore urgent for us to ensure that policies and practices necessary to conserve plants and animals which save lives are put in place (Akerele, 1988). Systematic campaigns are necessary at all levels and co-operation of traditional rulers and government officials is essential for success. Adequate penalties may be evoked to ensure compliance with the regulations on this important issue.

Federal, State and Local governments as well as private organizations and individuals should be encouraged to establish botanical gardens for the cultivation and conservation of such plants. The institute is collaborating with the Federal Ministry of Agriculture and Natural Resources on this matter. The Institute, in our research and development efforts, is very conscious of the parts of plants used such that the plants do not eventually become extinct especially when both the economic and medicinal significance of such plants become apparent to the farmers and plant collectors.

4.2 Funding of Research and Development

Development of drugs is an expensive venture. It is now generally believed that a multinational Pharmaceutical company needs about 600 million US dollars for the development of a drug. In Africa, we don not have that kind of money and in fact, we do not need such an amount to develop one drug. Labour is relatively cheap while the knowledge of Traditional Medicine offers a unique advantage. In most cases, we are involved with "Reverse Pharmacology" since the recipes have been used clinically for many centuries before they are subjected to scientific validation. In spite of this pleasant situation, scientists have to patiently seek adequate and sustained funding from their governments. Selection of the disease to be targeted is crucial. It should be a disease that presents a serious national problem for which there is no safe effective and cheap remedy. Efforts should also be made to reach all levels of government via-a-vis relevance and justification of adequate and sustained funding of R & D activities. In addition to national funding, researchers should endeavour to seek for grants from bilateral, multilateral bodies as well as NGOs.

4.3 Patent

All those involved in R & D of herbal medicines should take cognisance of patent right requirements in their countries, Africa and the world. This is important in view of the varied requirements of different Patent Licensing Offices. Although, it is true that plant materials cannot be patented in their natural form, efforts should be made to protect the processes involved in the development of herbal medicine as well as the novel uses of the product. It should however be noted that processing a Patent Application can be relatively expensive. Nonetheless, it is a worthwhile venture. Such application should include the establishment, researchers and traditional medicine practitioners who initially gave the recipe of the product.

4.4 Pilot Plant

The establishment of a good functional pilot plant costs over $200,000 (US dollars). It is relatively expensive for most institutions and researchers involved in R & D of herbal medicine in Africa. It may therefore be necessary to initiate and encourage establishment of pilot plant facilities at sub-regional levels. UNIDO has designed a polyvalent multi-purpose pilot plant that can be used for both distillation of essential oils and extraction of potential active principles from medicinal plants. There used to be a functional pilot plant facility in Rwanda before the civil war. A new one was commissioned in 1997 at the National Institute for Pharmaceutical Research and Development (NIPRD), Abuja, Nigeria. Such facilities where they exist should be made available to other scientists within the sub region. Such facilities can also be used for training purposes, especially process technology and product formulation. Most entrepreneurs will not invest in phytomedicines vis-�-vis large-scale production, commercialisation and marketing until such products have been appropriately scaled up to pilot stage.

4.5 Political Factor

It is important that researchers interact positively with civil servants, politicians and other policy makers. Sometimes, scientists take certain things for granted vis-�-vis the long term benefit of research and development to the economy of the country, health, productivity and well being of the citizens (Wambebe, 1996). It is true that there are demanding pressures for the limited resources in our various countries. However, if we persist in enlightening our colleagues in the civil service, our proposals would receive more objective and favourable appraisal. As scientists, we should not be discouraged when our efforts do not yield immediate results. What is also important to the government is that any funds disbursed for R & D purposes should be judiciously utilised.

4.6 Traditional Medicine Practitioners (TMP)

TMP should be given due recognition and support in the development of herbal medicines. Their trust is critical especially in the development of phytomedicines based on their recipes. They need to be convinced about our purpose and willingness to share with them the future benefits of any new phytomedicine under development, if it finally scales through the clinical trial and registration processes. Training programmes should be organised for TMP so as to expose them to various ways of improving their formulations and practice as well as their limitations. In many African countries, there are different TMP Associations. In most cases, these associations do not agree with one another. In such cases, sustained efforts should be made to form an umbrella national organization.
4.7 Legislation

Although, in most African countries about 80% of the population rely on traditional medicine for their primary health care needs, the governments have not yet promulgated edicts or decrees vis-�-vis regulation and recognition of the practice of traditional medicine. Even in the countries where there is an apparent recognition, appropriate budgeting to facilitate the function of the Traditional Medicine Board is usually inadequate or totally lacking. I am aware that WHO, Africa, Regional Office in Congo Brazzaville prepared a model decree for adoption by member countries. Furthermore, various workshops and seminars have been organised by WHO and OAU/STRC on this topic. Scientists in various African countries should bring to the attention of their governments relevant documents, which would facilitate the formulation and subsequent promulgation of appropriate decrees on the development and recognition of this important cultural heritage.

5. PRIORITY ISSUES RELATED TO THE DEVELOPMENT OF STANDARDISED PHYTOMEDICINES
5.1 Botanical Standardisation

The safety and efficacy of phytomedicines depend on several factors including quality of plant material, extraction process, formulation, quality assurance, etc. The botanical definition including the genus, species and authorities should be supplied and authenticated by indigenous national authorities so as to facilitate the correct identification of the plant. This is very important because of similarities between the physical characteristics of many plants. Both macroscopy and microscopy of the plant parts used for formulating the herbal medicine should be established. Furthermore, a description of the part of the plant that is used for preparing the herbal medicines should be indicated. For example, fresh or dry plant parts like leave, flower, root, stem, fruit, etc. The season, ecological characteristics and time of the day of collection should be noted, since these factors affect the chemistry and pharmacology of plant extracts. It is advised that a qualified botanist should appropriately authenticate the voucher specimen representing each lot of the plant material which has been processed, and the specimen should be stored for at least ten years. A lot number should be assigned which should appear on the product level.

5.2 Chemical Standardisation

The chemical studies should determine the importance of using the extracts that correlate to the way in which the original recipe is utilised as a reference material in all specimen studies. For example, if the plant part is soaked in ethanol before it is used then the total ethanol extract will be used as a reference specimen- while if the plant material is boiled in water, then water extract would be the appropriate reference material. However, in each of such cases, the solvent should be removed from the material prior to use. The ultimate goal of the chemical evaluation is to identify and characterise the structure of the pharmacologically active constituents. While such studies are progressing, if other evaluation data indicate that the phyto-pharmaceutical is effective and safe for the disease in question, pharmaceutical formulation and initial clinical trials can commence after the product has been standardised (Wambebe, 1996). In such a situation, it would be important to characterise substances or mixture of substances through chromatographic fingerprinting to ensure consistent quality of the products. HPLC can also be utilised for chemical standardisation (Sharma et. l., 1992 a, b; Sharma et al, 1993), 1992; 1993; Fomi, 1980; Wagner, 1984). The chemical evaluation should endeavour to identify all the characteristic constituents and also define their acceptable limits. Ideally, the component used for clinical standardisation should possess the desired pharmacological activity.

5.3 Microbiological Standardisation

If the primary use of the herbal medicine is to combat microbes then the anti-microbial potential of the preparation should be determined. In such a situation, like other screening procedures, standard anti-microbial screening protocols for the specified disease should be used. The anti-microbial screening data should be interpreted along with the pharmaceutical and toxicological data which will then suggest whether further scientific evaluation is necessary. When the herbal medicine is not intended to be used primarily as an anti-microbial agent, its microbial load should be determined and limit established following the broad WHO guidelines on purity.

5.4 Pharmacological Standardisation

Both intensive and extensive pharmacological studies should be conducted using all the fractions including the total crude ethanol or water extracts. The intensive studies should embrace use of appropriate animal models, tissue, cell lines and other in vitro techniques for the particular disease for which the herbal medicine is eventually intended for use. The extensive studies will be necessary so as to identify possible side effects of the herbal medicine (Wambebe, 1996). Where there are no existing laboratory models for the disease, it would be important to develop a suitable model as part of the project (Dhawan, 1995).

5.5. Toxicological Evaluation

It has been stated by WHO that the most critical assessment of herbal medicine is safety evaluation. Although Farnsworth indicated that phyto-toxicity is very low, nonetheless, from scientific, professional and moral viewpoints toxicological assessment must be conducted on all herbal medicines intended for either veterinary or human use. Most herbal medicines are obtained from genuine practitioners have been used in ethno-medicine for many centuries. Thus, it can be assumed that only the safe herbal medicines have withstood the test of time. Nonetheless, standard toxicological protocols should be employed for acute, sub-chronic and chronic toxicity tests. Such data is mandatory for the registration of the product with National Health Authorities. It would also enhance the confidence of Health Professionals in the use of herbal medicines.

5.6 Carcinogenic and Mutagenic Evaluation

Since some of the herbal medicines are needed for the management of chronic diseases, long-term use may evoke carcinogenicity and or mutagenicitity. There is also the fact that herbal medicine used in its native form may contain both carcinogenic and anti-carcinogenic constituents. For example, Zingiber officianale contains both carcinogenic and anti-carcinogenic constituents. However, chemical purification leading to separation of individual constituents will result in removal of any native antagonist in the preparation. It is therefore of vital importance that these tests are conducted on all crude, semi-purified and purified samples.

5.7 Pharmaceutical Standardisation

The procedures regarding processing and formulation of herbal medicine should be in accordance with Good Manufacturing Practice (GMP).

Plant preparations include comminuted or powdered plant materials, extracts, tinctures, fatty acids or essential oils, expressed juices and preparations whose production involves a fractionation, purification or concentration process. If any other substance is added during the manufacture to adjust the plant preparation to a certain level of active or characteristic constituents or for any other purpose, the added substances should be mentioned in the procedure.

The manufacturing procedure and formula including the amount of excipients should be described in detail. A finished product specification should be defined. A method of identification, and where possible quantification of the plant material in the finished product should be defined. If the identification of an active principle is not possible, it should be sufficient to identify a characteristic substance or mixture of substances (e.g. "chromatographic fingerprint") to ensure consistent quality of the product. The finished product should comply with general requirements for particular dosage forms.

As many herbal remedies consist of a combination of several active ingredients, and as experience on the use of traditional remedies is often based on combination products, the assessment should differentiate between old and new combination products.

The labelling of the products and the package insert should be understandable to the consumer/patient. The package information should cover all necessary information on the appropriate use of the product.

5.8 Quality Standardisation of Raw Material

The quality of the raw materials is a significant determinant of the quality of the finished product. Some of the components of the standardisation of the raw materials are indicated below:

Authentication: The correct, properly identified plant material is collected from an appropriate location, time of the day and stage of growth is authenticated by a taxonomist.

Foreign Matter: Plant parts other than what constitutes the drug are considered as foreign matter. Medicinal plant material should be entirely free from soil, stones, dust, insects, animal excreta, etc.

Organoleptic Evaluation: Organoleptic examination involves organs of sense and includes the macroscopic appearance of the drug, its odour and taste, occasionally the sound or "snap" of its fracture and the feel of the drug to the touch.

Microscopic Examination: Microscopic examination of the plant is not only essential to the study of adulterants but it is also indispensable in the correct identification of the material. Diagnostic microscopic features are of immense value in standardisation. Quantitative microscopy like stomata number, stomata index and palisade ratio is useful in differentiating closely allied species.

Volatile Matter: The volatile matter is determined by steam distillation of the plant and analysed using GLC.
Ash Value: The presence of ash in medicinal plant materials is determined as total ash, acid insoluble ash and sulphated ash. When vegetable drugs are incinerated, they leave an inorganic ash that in the case of many drugs varies within fairly wide limits and these values are of significance for the purpose of evaluation of the raw material.
Extractive Value: The determination of extractable matter refers to the amount of constituents in a given amount of medicinal plant material extracted with solvents. Such extractive values provide an indication of the extent of polar, medium polar and non-polar components present in the medicinal plant material.

Chromatographic Profile and Marker Component: Of the many chromatography (TLC) has become widely adopted for the rapid and positive analysis of plants since the time required for the demonstration of most of the characteristic constituents by TLC is very short. In addition to qualitative detection, TLC also provides semi-quantitative information on the main constituents of the plant and thus enables an assessment of drug quality. Furthermore, TLC provides chromatographic fingerprint (Fomi, 1980). It is therefore, suitable for monitoring the identity and purity of drugs, and for detection of adulteration and substitution. TLC-densitometer scanner has been used for obtaining fingerprint profile of extracts of many drugs introduced into clinical trials. High Pressure Liquid Chromatography (HPLC) has also been employed in standardising hepatoprotective and anti-asthmatic herbal medicines (Sharma et al, 1993).

Pesticide Residue: The use of pesticides has greatly reduced the presence of insects, fungi and moulds in food. Medicinal plants are therefore liable to be affected by pesticide residues which accumulate from agricultural practices of spraying soils during cultivation and through the administration of fumigants during storage. Since many medicinal plant preparations are taken over long periods of time, limits for pesticide residues should be established following the recommendations of the Food and Agricultural Organization (FAO) and the WHO.

Determination of Heavy Metals: Contamination of medicinal plant materials with arsenic and heavy metals (like cadmium and lead) can be attributed to many causes such as environmental pollution and traces of pesticides. The limits (parts per million) of such heavy metals in metals in medicinal plants should remain within official specifications.

Microbial Contamination: Medicinal plant materials normally carry a great number of bacteria and moulds, often of soil origin. Aerobic spore forming bacteria frequently predominate. Current practices of harvesting, handling and production often cause additional contamination and microbial growth. The determination of E. coli and aflatoxin is recommended.
Radioactive Contamination: Irradiation, may have been used as a procedure for microbial decontamination and sterilisation of plant materials (after harvest), packaging materials, intermediate products, bulk materials and finished products. WHO, guidelines can be used for this assessment.

5.9 Quality Standardisation of Herbal Medicines

Quality of phyto-pharmaceuticals must be as high as that of other medicinal products. It may not be possible to evaluate the specific chemical entity when the pharmacologically active moiety is not known. In most cases, as a general procedure, chemical analyses are not conducted for medicinal plant materials even when the active ingredients are known. For example, much of the ginseng or valerian is bought and sold on the basis of its sensory characteristics, rather like tea. For medicinal purposes, ginseng should be assayed for its ginsenoside content and valerian for its valepotriates.

Standardisation problem arises from the complex composition of drugs that are used in the form of whole plant, parts of the plant(s) and of plant extracts. Though these inert accompanying components may not directly influence the therapeutic value of the product, it is recommended to use the complex mixture because these inert components might influence bio-availability and excretion of the active component. Furthermore, inert plant components may enhance the stability of the active component, minimise the side effects, and manifest additive or potential effect on the active moiety.

The analytical protocol of vegetable drugs must take account of the fact that the material to be examined has a complex and inconsistent composition. Therefore, the analytical limits cannot be so precise as for the pure chemical compounds. Vegetable drugs are inevitably inconsistent because their composition and hence their evaluation may be influenced by several factors such as age and origin, harvesting period, method of drying, etc. In order to reduce the causes of these inconsistencies, cultivated rather than wild plants that are often heterogeneous in respect to the above factors and consequently in their content of active principles should be used. The purpose of standardising medicinal plant products is obviously to ensure consistent therapeutic efficacy.

GENERAL PROTOCOL FOR STANDARDISED PRODUCTION OF PHYTOMEDICINES (SHARMA, 1993)

6.0 QUALITY CONTROL AND QUALITY ASSURANCE OF PHYTOMEDICINES

Although the terms quality control and quality assurance often are used interchangeably, there is a continuing trend to separate and define their functional responsibilities (Nasipuri, 1997).

Quality control can be defined broadly as the day-to-day control of quality within an organization, staffed with scientists and technicians responsible for the acceptance or rejection of incoming raw materials and packaging components, for the myriad of in-process tests and inspections, to assure that systems are being controlled and monitored and finally, for the approval or rejection of the final products.

Quality control, therefore, includes not only the analytical testing of the finished product, but also the assessment of all operations beginning with the receipt of raw materials and continuing throughout the production and packaging operations, finished product testing and documentation.

Quality assurance, on the other hand, may be defined as the responsibility of an organization to determine that systems, facilities and written procedures all are adequate and followed in order to assure that products are controlled and will meet, in the final dosage form, all the applicable specifications. Quality assurance naturally then becomes an oversight function, often auditing all operations to determine that procedures and all systems including the environmental control system are suitable.

The main purpose of a quality assurance programme is to devise and implement systems and procedures that provide a high probability that each dose or package of a herbal medicinal product will have homogenous characteristics and properties (within reasonable acceptable limits) to insure both clinical safety and efficacy of the formulation. A broad stability testing plan is an essential and pertinent expansion of the quality assurance programme. The assigned expiration date is a direct application and interpretation of the knowledge gained from the stability study.

It readily becomes apparent that quality must be built into the product and that it cannot be inspected or tested into a product and such quality in order to be meaningful, must be maintained throughout the storage and handling procedures necessary in the production process.

In the manufacturing industry, whether it is for the conventional medicines or for the phytomedicines, there are many sources of error. The five 'M's which constitute the variations and errors in production and therefore in the final products, are Material, Method, Machinery, Men and Milean. If these five 'M's are properly taken care of and carefully controlled, it would be possible to build quality into the final product. For most of the plant based products, quality has to be built beginning from the use of good quality authentic raw materials followed by good post harvest treatment, control of all processes and equipment involved in the production and proper packaging and storage to avoid contamination and loss of quality.

Raw materials must be properly standardised and monographs are to be prepared to include description, colour, odour, taste, identification test/s, macroscopy, microscopy, loss on drying, water-soluble extractives, alcohol-soluble extractives, total ash, acid-insoluble ash, sulphated ash, foreign organic matter etc.

For phytomedicines it is also necessary to standardise the extracts, the monographs for which should include description, identification, moisture content, loss on drying, solubility, pH of aqueous extract, water-soluble and alcohol soluble extractives, total sulphate and acid-insoluble ash, contents of heavy metals and pesticide residues, microbial load, TLC and spectroscopic fingerprints etc.

Similarly, the quality of the final products must be assessed in terms of its therapeutic activity using biological or micro biological fingerprint as well as TLC and/or spectroscopic fingerprint, its toxicity, stability and, if possible, bio-availability. Besides these, all physical standard must also be assessed, depending on the type of the dosage from, including weight uniformity, disintegration time, dissolution rate, pH, weight per ml, colour, alcohol content, odour and taste etc. On the basis of the accelerated stability testing results, its shelf life should also be determined.

It is imperative that the processed products must comply with both national and international specifications, although production of phytomedicines for local use may not require such stringent conformity since what is produced will be a much more improved version of the already produced medicines using traditional methods. However, strict quality control procedures have to be introduced to ensure that standard dosage of medicines which are non-toxic, stable and safe and which will ensure therapeutic efficacy are produced.

Associated with quality management is the compliance with good manufacturing practices (GMP) since without GMP, products cannot be expected to be of required standard and quality.

Like the quality control of materials, control of production processes, equipment used for the production and personnel engaged in the system are similarly necessary if quality is to be built into the product and maintained. Production processes must conform the standard operating procedures (SOPs) for each production process. Any deviation to a SOP must be investigated, recorded and approved prior to final product acceptance. Similarly significant in-process steps are to be identified and appropriate sampling and testing must be done.

Equipment must be designed, constructed, of adequate size, suitably located and able to be maintained in order to be considered suitable for its intended use. Safety requirements, with respect to buildings, machinery and staff must be introduced.

Along with many other advances in the total control of quality is the growing recognition that the environment and the systems used for its control can have a significant effect on the finished product quality. Stringent requirements, with respect to microbiological monitoring, dust control, particularly during the harmattan season is this part of the world and other things should be introduced to safeguard the immediate environment of the production place.

WHO has also issued guidelines for quality control method for medicinal plant materials in 1992, which include detailed procedures of test on:


- Sampling - Microscopy

- Foreign matter - TLC profile

- Ash content - Extractable matter

- Volatile matter - Bitterness value

- Haemolytic activity - Tannins

- Swelling index - Foaming index

- Heavy metals - Microbial load

These guidelines should be followed as strictly as possible during the development of phytomedicines to build the quality of such medicines.

7. R & D COLLABORATION

Multidisciplinary approach is mandatory in the R&D of phytomedicines. Such multidisciplinary collaboration should take cognisance of all the disciplines relevant to the development of Phytomedicines. In addition to the classical fields of chemistry, botany, microbiology, economics, pharmacology, toxicology, pharmaceutical technology and statistics, new fields of computer science and genetic engineering should be considered for such collaboration. It is important for all the parties involved in the collaborative efforts to be fully aware of their varied responsibilities. In such a situation, a written legal document would be necessary. The agreement should contain in addition to the responsibilities of all the parties involved, the privilege, financial implications and penalties in case of default. International corporation involving short term training, grants, Consultancy services etc is also essential to facilitate the R&D of phytomedicines from medicinal plants. In this case the researchers should take cognisance of the specific emphases of the donor countries or organizations. In many cases, appropriate nodal government ministries must be consulted for recommendation before the multilateral and bilateral agreements are reached. Processes involved in developing international co-operation by their very nature are time consuming. Patience is a very valuable virtue in this situation. Needless to state that the varied requirements of the organizations may change any stage in the processing of the proposal. The researchers should be flexible so that his proposal can be modified prior to approval and implementation. The researchers need to conduct regular surveys regarding the various bilateral agreements and multilateral bodies which are favourably disposed to the funding of R&D of phytomedicines.

It is remarkable that Inter African Co-operation yielded the compilation of African Pharmacopoeia Volumes I & II under the auspices of the OAU/STRC in 1985 _ 1986. The OAU/STRC has also awarded fellowships to young African Scientists to Cairo University, Obefemi Awolowo University, University of Ibadan, Makerere University and Addis Ababa University. Other funding agencies like DAAD, UNESCO and IFS have also supported African Scientists for specific research projects in various African Universities. South South Co-operation has been encouraged by TCDC. For example, in March 1997, TCDC (New York) sponsored an African Regional Workshop on Cultivation, Conservation and Processing of Medicinal and Aromatic Plants in Abuja, Nigeria. Definitely, more of such TCDC modalities will enhance R&D on medicinal and aromatic plants, especially in view of the economic consideration and the practical training received during such activities. Another area of Inter-African Co-operation is ethnobotanical surveys. This is important because medicinal plants are not distributed in accordance with geopolitical boundaries.

8. CONCLUSION

Sustained efforts are required in ethnobotanical surveys, Inter-African trade and training of taxonomists to ensure appropriate documentation of valuable medicinal plants. The Natural Forestry Reserves and Parks should be adequately monitored so as to assist in the conservation of endangered and valuable plant species. Cultivation of medicinal and aromatic plants on large-scale basis is encouraged. It is gladdening to know that Egypt, Rwanda and Mali are already involved in this practice. Training should be organised for herbal sellers and herbalists vis-�-vis conservation efforts, rational use of medicinal plants and limitations of traditional medicine.

In 1997, the African Network for Industrial Utilisation of Medicinal and Aromatic Plants (ANIUMAP) was established at Abuja, Nigeria during a regional workshop organised by TCDC. The network should be adequately supported so that it can carry out its mandatory responsibilities. OAU/STRC organised a successful workshop in Nairobi in 1997 on Intellectual Property Rights as they relate to medicinal plants. Efforts should be made to ensure that the resolutions of that workshop are adopted and implemented by all member countries. Funding of R&D has been a major constraint in most African countries. The researchers should not relax in their efforts to convince their various governments to adequately and continuously fund R&D activities.


International donor agencies should also be approached. Production of standardised phytomedicines requires specialised expertise and pilot plant facility. International organizations should be requested to assist in setting up such facilities in various African sub-regions. The pharmaceutical potentials of African medicinal plants are immense. The world is already aware of Chinese traditional medicines. I hope, in the next millennium, the world will be able to use African Traditional Medicine (ATM) thereby according ATM its proper recognition The challenge to produce standardised phytomedicines for Africa and the world from our immense bio-diversity is enormous. However, through multidisciplinary approach, commitment by scientists and governments and International support, we shall be able to achieve such a laudable goal which will enhance the health status of our fellow human beings. It is possible that many chronic ailments that are presently untreatable by orthodox drugs can be cured using African traditional medicine. We must work together to give the world standardised African traditional medicines.


9.REFERENCES

1. Akerele, O (1988): Conservation of Medicinal Plants, edited by Akerele, O.

2. Dhawan, B.N. (1995): Evaluation of the efficacy and safety of herbal medicines and development of new plant-based drugs. Presented at the WHO/UNIDO Expert Group Meeting on the Promotion and Development of the Industrial Utilisation of Medicinal Plants in Africa, Brazzaville, Congo, 20-23 Nov. 1995 (Plenary Lecture).

3. Farnsworth, N.R. & Soejarto, D.D. (1989): Global Importance of Medicinal Plants. In: Conservation of Medicinal Plants ed. Olayiwola Akerele, pp 25- 40.

4. Fomi, G. P. (1980): Thin Layer Chromatography and High Pressure Liquid Chromatography in the Analysis of Extracts. Fitoterapia 51, 13-34.

5. Sharma A. Lal K. and Handa S.S. (1992). Herbal Drug Standardisation: HPLC Determination of Vasicine in Polyherbal Formulations. Int. Nat. J. Pharmacog., 30, 205-208.

6. Sharma AL. Lal K. and Handa, S.S. (1992). Standardisation of Indian Crude Drug Kalmegh by High Pressure Liquid Chromatographic Determination of andrographolide, Phytochemical Analysis, 3,129 _ 131.

7. Sharma A; Singh R.T. & Handa, S.S. (1993). Estimation of Phyllanthin, Hypophyllanthin by High Pressure Liquid Chromatography in Phyllanthus amarus. Phytochemical Analysis, 4, 226-29.

8. Wagner H., Bladt S. Zgainski 1984., Plant Drug Analysis _ A Thin Layer Chromatography Atlas, Springer _ Verlag, Berlin.

9. Wambebe, C. (1993). Governmental Policies on Traditional Medicine in West Africa. Scientific Session of the West African College of Pharmacists, Gambia (Plenary Lecture).

10. Wambebe C. (1994): Research and Development in the Pharmaceutical Industry. Plenary lecture at the 2nd National Symposium on Pharmaceutical Technology, University of Ibadan, Nigeria.

11. Wambebe C. (1996). Research and Development of Drugs from Medicinal Plants. Presented at the OAU/STRC Symposium on African Traditional Medicines and Medicinal Plants, Kampala, Uganda, 13-17 May, 1996 (Plenary Lecture).

12. WHO (1991) Guidelines for the Assessment of Herbal Medicines. WHO/TRM/91.4.

13. WHO, (1992). Quality Control Methods for Medicinal Plant Materials WHO/PHARMA/92.559.

14. Aalbersberg, B. (1996). Medicinal Plant Conversation and Development in Fiji. Bulletin of the Working Group on Traditional Resource Rights. No.3, pp13.

15. Adjanohoun, E. et al. (1989). Contribution aux Etudes Ethnobotaniques et Floristiques en Republique du Benin. ACCT, Paris.

16. Adjanohoun, E. et al. (1993). Traditional Medicine and Pharmacopoeia: Contribution to Ethnobotanical and Floristic Studies of Uganda. OAU/STRC, Lagos.

17. Adjanohoun, E. et al. (1997a). Traditional Medicine and Pharmacopoeia: Contribution to Ethnobotanical and Floristic Studies of Cameroon. OAU/STRC, Lagos (In Press).

18. Adjanohoun, E. et al. (1997b). Traditional Medicine and Pharmacopoeia: Contribution to Ethnobotanical and Floristic Studies of Ghana. OAU/STRC, Lagos (In Press).

19. Baba S., Akerele O. and Kawaguchi Y. (Eds.) (1992). Natural Resources and Human Health. Tokyo: Elsevier.

20. Sofowora A. (1997). Cultivation, Conservation and Processing of Medicinal and Aromatic Plants _ A Situation Report on Africa Proceedings of the African Regional Workshop on Cultivation, Conservation and Processing of Medicinal and Aromatic Plants, Abuja, Nigeria.

21. Bitahwa, N. Malaria Treatment with Local Herbs at Rukararwe Partnership Workshop for Rural Development. Journal of Alternative and Complementary Medicine, 2(3), 419.

22. Cunningham, A.B. (1993a). Ethics, Ethnobiological Research and Bio-diversity. Gland: WWF.

23. Cunningham, A. B. (1993b). African Medicinal Plants. Setting Priorities at the Interface Between Conservation and Primary Healthcare. People and Plants Working Paper 1. Paris: UNESCO.

24. Cunningham, A. B. (1996). Working Towards a "Top 50" Listing. Medicinal Plant Conservation, Vol. 2, 4-6.

25. Farnsworth N. R. (1997). Database Search on NAPRALERT for Publications on African Medicinal Plants up to and including 1996.

26. Farnsworth N. R. and Soerjarto D. D. (1991) 'Global importance of medicinal plants'. In: Conservation of Medicinal Plants. Akerele, O., Heywood, N., Synge, H. (Eds.). Cambridge University Press.

27. Gbile Z. O. (1992). Status of Forest Conservation for Maintainance of Bio-diversity in Nigeria. In: Conservation of Plant Genes. Academic Press, Ibadan. Pp293-310.

28. Gbile Z. O. (1996). Nigerian Medicinal Plants and Danger of Extinction. Unpubliched Works (Personal Communication).

29. Isichei, A. O. (1995). Omo Biosphere reserve, Current Status, Utilisation of biological Resources and Sustainable Management. Working Paper No. 11 In: South South Co- operation Programme on Environmentally Sound Socio-Economic Development in the Humid Tropics, Pub: UNESCO, Paris.

30. Kokwaro J. O. (1991). 'Conservation of Medicinal Plants in Kenya'. In: Conservation of Medicinal Plants. Akerele, O., Heywood, V. & Synge, H. (Eds.), Cambridge: Cambridge University Press, Pages 315-319.

31. McNeely, J. A. (1996). Conservation and the Future: Trends and Options Toward the year 2025. A discussion Paper. IUCN Council Paper for November, 1996. Congress Document No. CGR/1/96/8. Page 16. IUCN-The World Conservation Union, Gland, Switzerland.

32. Okafor J. C. (1993). Lost Crops of Nigeria: An Overview. In: Okogie, J.A. and Okali, D. U. U. (eds.). Lost Crops of Nigeria. Implications for Food Security, PP 2-32.

33. Okigbo, B. N. (1994). The Convention on Biological Diversity: Issues of Relevance to Africa. United Nations Environmental Programme Document No. UNEP/AMCEN/RCU 7/1(A).

34. Nasipuri, N. (1997) Process Technology of Herbal Medicine. Proceedings of National Workshop on Regulation and Standardisation of Herbal Medicine, Abuja, Nigeria.

35. Regina A. and Simiyu S. (1996). The Medicinal Plant Conservation Project, E.A. Herbarium. Book of Abstracts: Plants for Food and Medicine. Society for Economic Botany and International Society for Ethnobiology, July 1-5. Page 34.

36. Sofowora (1991). Establishment of a Medicinal Natural Products Development and Production Centre for the East and Southern African Sub-region. Technical Report, UNIDO, Vienna.

37. WHO, IUCN & WWF (1993). Guidelines on the Conservation of Medicinal Plants. IUCN, Gland.

Reply

Delete

Show all messages in this topic