Chapter Notes: Biological and geographical sources of drugs

Biological and geographical sources of drugs

Current estimates place the number of species of flowering plants (angiosperms) between about 200 000 and 250 000, distributed in roughly 300 families and 10 500 genera. Only a small fraction of these species has been examined chemically; therefore a large field remains open for phytochemical and pharmacological research.

Folk medicine and ethnobotany as starting points for drug discovery

Long before modern analytical methods existed, humans assembled a materia medica of plant remedies by trial and error. These folk medicines vary with local flora and climate and often reflect centuries of practical screening by communities. Ethnobotanical knowledge therefore offers a practical starting point in the search for new drugs: plants used in traditional systems have already been subjected to some degree of human selection for efficacy and tolerability.

Because traditional knowledge is being lost rapidly in some regions (for example parts of South America), ethnobotanists work urgently to record uses before they disappear. Successful discoveries from one region commonly prompt the investigation of related species elsewhere (for example, work with Hypericum and Taxus). Large, coordinated screening programmes (for example national cancer-screening efforts) combine botanical, phytochemical, pharmacological and clinical expertise to evaluate plant extracts for activities such as cytotoxic or antitumour effects.

Biological groups that yield pharmaceutical materials

Medicinal substances arise from diverse biological sources. The principal groups and their pharmaceutical significance are:

• Spermatophyta (seed plants): the dominant terrestrial source of medicinal plant products. Within Spermatophyta, the Gymnospermae provide resins, oils and some alkaloids (for example ephedrine), while the Angiospermae (flowering plants) - especially the dicotyledons - supply most of the classical plant drugs.
• Fungi: an important source of drugs (notably antibiotics) and metabolites used in pharmacy and biotechnology.
• Algae: give industrially important products such as agar and alginic acid; the full pharmacological potential of algae is still under investigation.
• Bryophytes and lichens: at present contribute little to mainstream medicine, although isolated active compounds exist.
• Pteridophytes (ferns and allies): known pharmaceutically for some taenicidal (anthelmintic) ferns and for lycopodium-derived compounds.
• Animals: provide materials such as gelatin, wool fat (lanolin), beeswax and cochineal, and are also sources of hormones, vitamins and sera.
• Bacteria (Bacteriophyta): produce antibiotics, catalyse useful chemical conversions, and play central roles in genetic engineering - for example, production of recombinant human insulin and the transformation of plant cells using bacterial vectors.

Examples of therapeutically important plant-derived compounds

• Quinine from Cinchona spp. (antimalarial).
• Vinblastine and vincristine from Catharanthus roseus (antineoplastic alkaloids).
• Reserpine from Rauwolfia serpentina (historically used as an antihypertensive and antipsychotic).
• Steroidal hormones and semi-synthetic steroids (many manufacture processes begin with plant sterols such as diosgenin).
• Artemisinin from Artemisia annua (antimalarial); also the subject of biotechnological efforts to produce precursors in microbes for semisynthetic supply.

Geographical sources and factors affecting them

The commercial and practical geographical sources of a drug depend mainly on two factors:

1. the suitability of the plant (or organism) to a particular environment, and
2. economic and political factors governing production, trade and processing.

Many medicinal plants grow well across different areas with similar climates, so cultivation or collection can shift geographically when economic conditions change. Examples of geographical shifts and their causes include:

• Cinnamon-traditionally produced in Sri Lanka but successfully introduced to other islands (for example the Seychelles) and grown elsewhere; local success has in some cases led to the plant becoming invasive.
• Cinchona (quinine)-native to the Andes; commercial cultivation was most successful when introduced to Indonesia (Java) and parts of India. War and political events (for example the fall of Java in 1942) caused shortages and stimulated synthetic antimalarial drug development. Later resistance to some synthetic antimalarials renewed the demand for quinine and other cinchona alkaloids; today bark production is significant in parts of Africa (for example Zaire) and Central America (for example Guatemala).
• Solanaceous medicinal plants (e.g., belladonna, stramonium, hyoscyamus) - commercial cultivation declined in some Western countries and raw material is often imported from Eastern Europe.
• Agar production expanded outside Japan during wartime (New Zealand, Australia, South Africa) but later market changes reduced dependence on these sources.
• Acacia gum shortages from Sudan prompted exploitation of Nigerian gum.
• Ginger-pharmacopoeial ginger was once mainly Jamaican; reduced Jamaican production and improved African and Chinese gingers led to wider use of those sources.
• Storax (Liquidambar)-limited Turkish supplies led to acceptance of American storax (Liquidambar styraciflua) in pharmacopeias.
• Ipecacuanha-shortages of Brazilian root led to use of varieties from Cartagena, Nicaragua and Panama; attempts to cultivate in other regions produced variable success.

Changes in market demand, quality considerations and production costs also influence source countries. China has emerged as a major producer of many medicinal plant products (for example: coumarin, menthol, eucalyptus oil, peppermint and spearmint oils, sassafras oil, and valerian preparations). Other market examples include high-quality Australian coriander being accepted in European markets, Guatemala as an important cardamom producer, and Podophyllum emodi being produced in China.

Economic and political influences on sources

National policies and political events strongly influence supply chains:

• Government export controls can redirect trade. For example the restriction of crude rauwolfia root exports by one producing country led buyers to obtain supplies from Thailand.
• Nationalisation of natural-product production can raise prices and prompt manufacturers to seek alternative starting materials. For example, after nationalisation of diosgenin production in Mexico (a key intermediate for steroid manufacture) manufacturers turned to alternative plant sterols (hecogenin from sisal, solasodine from Solanum spp.), microbiological conversions of cholesterol, and other sterols (stigmasterol, sitosterol) and even petroleum-derived processes. The later emergence of new suppliers (for example China) altered the market again.
• Legal cultivation and controls on crops (for example opium poppy cultivation) shift production locations; political pressure may curtail or encourage cultivation in particular regions (for example large-scale poppy cultivation in Tasmania in recent decades, subject to regulatory change).

Conservation, regulations and sustainable supply

Restrictions on wild collection and international trade have also altered sources. The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) lists many species to control overexploitation. Sudden listings can cause market disruptions-for example, several Aloe species (except Aloe vera) were placed on protected lists, affecting the supply of commercial aloes. Other medicinal plants given trade protection include Hydrastis canadensis (goldenseal) and Prunus africana.

Pressure from trade restrictions, scarcity and market demand has increased interest in:

• clonal propagation and selection of high-yielding cultivars,
• plant tissue culture and organ culture to produce valuable metabolites in vitro, and
• microbial and chemical routes to produce or modify natural products.

Modern biotechnological approaches

Biotechnology complements traditional collection and cultivation by:

• using plant cell, tissue and organ culture to produce secondary metabolites under controlled conditions;
• applying cloning and selection to develop uniform high-yielding strains for cultivation;
• engineering microorganisms to produce precursors or complete natural products, reducing dependence on crop harvests.

An example of microbial engineering is the development, reported in the mid-2000s, of genetically engineered microbes that produce a precursor of the antimalarial artemisinin; that precursor can be chemically converted into a bioequivalent drug. Researchers reported plans to move such semisynthetic supply systems towards distribution (report by K. Purcell, 2006). Such approaches aim to ease shortages and reduce costs of plant-derived medicines.

Research strategies for selecting plants to study

Because so few plant species have been chemically and pharmacologically characterised, researchers use pragmatic strategies to choose species for study:

• prioritise plants with recorded traditional medicinal use (ethnobotanical leads);
• survey related species once activity is found in a genus (chemotaxonomic approach);
• conduct broad random screening of plant extracts for specific biological activities (for example cytotoxicity, antimicrobial or cardiovascular effects);
• foster interdisciplinary collaboration among botanists, phytochemists, pharmacologists and clinicians to progress promising leads from collection to clinical evaluation.

Practical considerations in production and quality

Even when a plant grows successfully in new localities, the quantity and quality of active constituents may vary with genotype, altitude, soil, climate, harvest time and post-harvest handling. For example, cinchona trees grown at different altitudes or in different soils may produce differing alkaloid profiles. As a result, source substitution requires careful chemical and pharmacological standardisation.

Summary

Biological and geographical sources of drugs include a wide range of organisms - seed plants, fungi, algae, bacteria and animals - each contributing important pharmaceutical substances. Ethnobotanical knowledge remains a valuable guide to discovery, but modern screening, phytochemical analysis and biotechnology greatly expand the capacity to find, develop and supply useful drugs. Economic, political and conservation factors strongly influence where medicinal raw materials are produced and traded; these forces drive cultivation, tissue culture, synthetic and semisynthetic production, and microbial engineering as strategies to secure sustainable and affordable supplies.

Further reading

Journal of Ethnopharmacology, special issue 1996, 51(1-3): Intellectual property rights, naturally-derived bioactive compounds and resource conservation.