Putting aside the excitement surrounding the human genome, in the near future we may well start to see the emergence of a new class of prescription medicine containing complex mixtures of plant extracts. This article discusses the important role that plants can play in the search for new medicines and effective therapies.

As technology advances, the pharmaceutical industry is increasingly focusing on the human genome as a source of the many unanswered questions relating to how disease is prevented, diagnosed and treated. It is easy to forget one of the other life forms that has contributed much to our current understanding of medicine and many effective therapies.

Plants are an abundant natural source of potential new medicines and as a pharmaceutical company seeks to achieve an optimally balanced R&D portfolio this potential should be kept in mind as a target for new or additional funding. In assessing the potential risks and benefits associated with such investment some insight into the following should contribute to decision making:

– historical evidence
– current research trends
– future opportunities
– development issues
– regulatory hurdles
– facilitative technologies
– market potential and competition

What contribution have plants made to medicine today?

Prior to the advances in synthetic chemistry and the discovery of antimicrobials in the late 19th early 20th centuries, plants provided the major source of medicines. Evidence of their use as long as 50,000 years ago comes from the Middle Eastern grave site of a Neanderthal man containing plant specimens, seven of which are still in use medicinally today by the local population (1).

The hugely diverse plant kingdom, consisting of some 250,000-300,000 species, continues to evolve and adapt to a multiplicity of environmental conditions and to protect from pathogens and predators. Whether by serendipity or design the human species appears, in contrast, to have stabilised its genetic code. Many characterised human endogenous receptors, important in physiological function, are activated by plant-derived chemicals; for example the opioid, and the more recently discovered cannabinoid, receptors. It is not unreasonable to hypothesise that many more structure-activity relationships, of physiological and pharmacological significance, involving plant molecules have yet to be characterised.

In excess of 20% of the ethical turnover of pharmaceutical companies today is generated from plantderived medicinal products. Some of these are the original natural product, others the synthetic equivalent or synthetic derivatives designed to improve efficacy or decrease associated side effects. The most important of these, representing historically accepted medical practice, yet still prescribed today, are listed in Table 1.

More recent new product introductions and some plant-derived products currently in development are included in Table 2.

Another area of interest in the West is herbal medicine, which has proved extremely popular in some continental European countries with many products licensed as medicines, and is growing in significance in the UK and the US as herbal remedies, nutraceuticals or functional foods. The application of herbal medicine goes back centuries in Traditional Chinese, Ayuverdic, Unani and other cultures in the developing world.

Thousands of plants are used as a basis for these traditional practices of medicine and while many in the West are sceptical of any therapeutic value, more and more beneficial effects are being demonstrated. A number of new companies have begun to focus on plant-derived medicines with a number of products, some new others derived from traditional medicine, already being investigated in clinical trials.

How can future opportunities be derived from traditional medicine?

The accumulated evidence derived from centuries of use in traditional medicine or from knowledge of how species of plants have evolved and adapted to their environment can substantially reduce the time to identify development candidates. Thousands of plantderived products have been prescribed for patients by practitioners of traditional medicine for centuries, providing supporting, although often only anecdotal, evidence of potential efficacy and lack of frank toxicity. These data are becoming more accessible in today’s world of advanced communication, information technology and improvements in global standards of education and welfare.

Scientists and clinicians in the Far East and Asia, many trained in the West, are applying Western clinical research and practice to traditional products and publishing their results in reputable, peer reviewed, journals. Further significant preclinical and clinical research is published in original language journals but is becoming more easily available from databases like Medline. Some of the newer companies involved in phytopharmaceuticals have specialist internal staff and/or have established links with companies, experts and academic institutions in the countries used to source materials. All these avenues can facilitate narrowing the search for potentially effective medicinal plants.

The demands and expectations of the increasingly knowledgeable, health conscious and environmentally aware consumers and patients of the Western world are placing increasing pressure on regulators, clinicians and politicians. A recent example of where this has made an impact, is in the pressure to recognise the medicinal qualities of the plant Cannabis sativa.

While the psychotropic properties of cannabis are well recognised and the therapeutic effect of its major component 9-tetrahydrocannabinol in alleviating nausea and vomiting caused by chemotherapy has been proven, evidence of efficacy in other diseases like multiple sclerosis, while compelling is mainly anecdotal. There now exists, however, a vast database of research on cannabis, its individual components and synthetic derivatives.

Relatively recently, endogenous cannabinoid receptors were identified in man and animals, opening up a new field of research into cannabinoid receptor agonists and antagonists (2). Compounds synthesised by companies in the past, shelved or abandoned because of the associated stigma, may well be resurrected or utilised to refine the search for more specific targeted candidates.

While the stigma of abuse is not associated with traditional ethnic medicines an element of quackery is sometimes applied to it by the so-called educated West. It should not be forgotten, however, that much of our current understanding of medicine is based on the discovery of the medical application of plantderived substances like opium, curare, atropine and ephedrine. More credence today is being given to the activity of herbs like St John’s Wort, Saw Palmetto and Gingko biloba. Table 3 lists some of the current most popular medicinal herbs.

Increasing use of some of these active agents is leading to a greater incidence of adverse events, often due to interactions with prescription drugs. Clinical awareness of the potential for these types of interactions has led to a number of studies which have recently been published (3), prompting regulatory authorities to issue guidance on the use of some products. While this could be viewed negatively for herbal products it does, however, serve to show that many herbs can produce significant pharmacological effects and supports the developing view that their use requires improved regulation and control.

During the 1990s some futurists and more recently pharmaceutical scientists, including Dr George Poste (4), have predicted that one of the major advances in the next couple of decades will be the individualisation of therapy. This proposal has been linked mainly to the advances in genomics. For many hundreds if not thousands of years, however, some ethnic cultures have been individualising treatments for patients.

Two important examples utilising plant-derived medicines, come from China – Traditional Chinese Medicine, and India – Ayuverdic Medicine. Thousands of herbs have been associated with beneficial effects that are often given in multiple combinations designed by practitioners for each individual patient’s total well-being.

More recently academic researchers have investigated pharmacological activity for many of the more widely used herbs, utilising methods accepted by Western cultures. For example, many herbal products available in China for the treatment of benign prostatic hypertrophy are now being screened for their activity in mice with testosterone-induced hyperplasia, a classic test for alpha reductase inhibition (5). An extract of the plant Serenoa repens has been shown to be more effective and associated with fewer side effects than finasteride (6).

This has contributed to a growing interest in the use of and developing herbs as potential new medicines in the Western world. A significant example of this is the development of a Chinese herbal mixture for the treatment of eczema by Phytopharm Plc, based on the observation that a patient receiving treatment from a TCM practitioner in London was showing unexpected signs of significant improvement. Some examples of the many INDs currently with the FDA are listed in Table 4 (7).

How can plant-derived medicines shift the balance of emphasis for R&D?

R&D programmes to develop a new drug by de novo synthesis can typically take up to 20 years: establish a new research programme; define the target; synthesise and screen the activity of potential leads; select the optimal few and further define their pharmacological and safety profile. Optimistically, one or two candidates make it into development. If clinical efficacy and safety are demonstrated to achieve product licence approval, a period of product exclusivity will follow. The return on investment will be related to the effectiveness of a company’s patent strategy and product life cycle management.

Advances in technology have been designed to reduce the time to identify candidate new drugs; for example, high throughput screening, combinatorial chemistry and most recently genomics and proteomics. The evidence to date of these increasing the chances of success is limited but that is not to say that in the near future these significant investments will not come to fruition.

These technologies, in addition to others like cell culture and cloning, can also be applied to plantderived substances. When embarking on a programme to identify therapeutically active plant components or mixtures one can often have a head start in the race due to prior knowledge about potential activity associated with a particular species or genus. By reducing serendipity, the time, cost and complexity of de novo synthesis, one can substantially reduce the time to reach the market and increase the chances of success.

It is relevant here to add that evidence of clinical exposure, and thus safety, can often be documented for traditional herbal medicines. Such products can be evaluated in small, well-designed and controlled, clinical studies to test ‘proof of concept’ negating the need for significant investment in preclinical safety prior to having confidence that one has a potential product.

Regulatory issues for licensing of plant-derived medicines and how are they are evolving?
This is not to say that the development of plantderived medicines is without complication. The key issues for development programmes, where it proves difficult or for other reasons not desirable to synthesise the active plant component(s), relate to identification, standardisation and consistency of material.

Fears of adulteration or even contamination of plant material by potentially toxic materials are not unfounded and serve to substantiate the long standing attitude of regulators towards combination products and a frank ‘adverse reaction’ to complex mixtures like herbal extracts. As a result many companies have shied away from this potentially fruitful area of R&D.

It is reassuring for those interested in developing plant-derived medicines that the anticancer taxol has been so therapeutically, and commercially, successful. The recent first European approval of galanthamine for Alzheimer’s disease in Sweden further supports the premise that plants are a source of new medicines.

Major initiatives have been under way in Europe and the US for some time to address the regulation of herbal medicines. This is mainly in recognition of a lack of continuity of, or complete absence of regulation, for herbal products used as medicines, nutraceuticals and functional foods and of consumers’ desire for access to such products. In the US the final rule relating to the DSHEA regulations has recently been published (Federal Register, 6th January 2000).

This relates to statements that can be made about the effects of dietary supplements on bodily structure or function and is of major significance to manufacturers of herbal products targeted at the general consumer. Europe is not as advanced in this specific area of regulation but the European Agency for the Evaluation of Medicinal Products has made significant progress towards achieving a European-wide assessment of herbal medicinal products including evaluation of monographs for well recognised herbs.

While regulatory approval of some of the more widely known medicinal herbs is potentially being made easier, that of new chemical entities remains as stringent as ever. New plant-derived chemicals, extracts and their derivatives fall within the latter category. Some phytopharmaceutical companies are focusing their efforts on single molecules or plant extracts with the aim of simplifying the regulatory process by avoiding complex mixtures and combinations. Others are looking to the future success of their new technologies to facilitate approval.

How will new technologies facilitate product licence approval?

To overcome the major regulatory concern related to quality of plant-derived material, a few companies specialising in phytopharmaceuticals, including PharmaPrint, CV Technologies and Oxford Natural Products, are independently developing and patenting new technologies. Some of these technologies are addressing the agricultural process and practice leading to raw materials of consistent source, quality and yield; essentially to facilitate Good Agricultural Practice.

It is worth noting in this context that the ability of developing countries and the emerging nations to pay for expensive new medicines is in part influenced by their infrastructure and economic growth. Sourcing of plant materials from their natural habitat, grown under controlled conditions, can contribute to local economies and to provision of better quality lower priced medicines. In addition this can contribute to the conservation of rare species and to the obligations laid down by The Convention on Biological Diversity.

Others of these new technologies are combining advanced chemical and biological assays that will enable the raw material to be identified and standardised in order to meet the stringent regulatory requirements for quality. It is of relevance to note that PharmaPrint Inc has recently been granted a US patent for the application of its PharmaPrint process technology for saw palmetto, a product that they are investigating under an IND for benign prostatic hypertrophy.

These new technologies, if ultimately successful in their application, will not only facilitate regulatory approval of a new generation of safe and effective products containing unique, ‘fingerprinted’ plant extracts but also afford a greater degree of product exclusivity and protection of both intellectual property and investment. Where can acquisitions to add to the R&D portfolio be found?

Many herbal product companies are taking advantage of the new DSHEA regulations in the US for nutraceuticals and exploiting ways of suggesting that the quality of their products is better than their competitors. Some of the multinational pharmaceutical companies, with a major interest in consumer products, are establishing links with herbal product companies and capitalising on the growing consumer interest in herbal remedies and their environmentally friendly or ‘green’ association. This is a significant and growing market but is still dwarfed by prescription pharmaceuticals.

Some of the multinationals have natural product R&D programmes that have been in existence for a considerable number of years where the focus is broader than plants or has actually moved away from plants as a source of new medicines in recent years. Where large screening programmes are in place there is the opportunity to adapt and take advantage of the increasing database of information on plants. Many companies today, however, are streamlining their internal R&D organisations and seeking licensing opportunities from outside.

It would seem prudent, therefore, to maintain a watching brief on the proliferating number of small companies specialising in plant-derived medicines. Not only do these companies have the relevant internal expertise to identify significant leads; they recognise and understand the issues associated with developing plant-derived medicines. Access to their new technologies should enable, in the shorter term, development of safe and effective plant-derived medicines of high and consistent quality.

In the near future, we may well start to see the emergence of a new class of prescription medicine, containing complex mixtures of plant extracts designed, or inherently containing the active synergistic components, to cure disease, treat associated symptoms and prevent recurrence.

DDW

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This article originally featured in the DDW Summer 2000 Issue

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Jennie Gwynn MSc PhD MRPharmS is Development Director at Oxford Natural Products plc in Oxfordshire. Following a period with the Medicines Control Agency as a preclinical assessor, she joined the pharmaceutical industry in 1980. Her broad drug development experience has been gained from a range of responsibilities in R&D, medical affairs, project management and strategic planning departments of SB, Roche, Sigma Tau, Pharmacia & Upjohn, and as an advisor to the Pharmaceutical Industry Group of Coopers & Lybrand Management Consultancy Division.

Peter J Hylands PhD CChem FRSC is Chief Scientific Officer at Oxford Natural Products plc in Oxfordshire. He is a pharmaceutical chemist with a 15-year academic career at the University of London focusing on research into the use of plants as medicines. He joined Xenova in 1988 as founding Director of Chemistry and then as Research Director to PHYTOpharmaceuticals, Inc, both companies dedicated to the discovery and commercialisation of pharmaceuticals derived from natural products. He has acted as a consultant to the United Nations and Commonwealth Science Council and is well connected in every continent with regard to natural product research and development. A visiting Professor in the Department of Pharmacy, Kings College, London, he also serves on a number of boards and advisory boards.

References
1 Fowler, MW. Plants, Pharmaceuticals and Plant Cell Culture – A Perspective, In: Recontrés Europeane de Phytochemie. Actes du Colloque (eds Brunetton, J and Guinandeau, H) Angers, France, 124-133, 1993.

2 Pertwee, RG. Neuropharmacology and therapeutic potential of cannabinoids. Addiction Biology 5, 37-46, 2000.

3 Fugh-Berman, A. Herb-drug interactions. Lancet, 355, 134- 38, 2000.

4 Poste, G. The right treatment for the right patient. Scrip Magazine, January 2000, Issue 86, PJB Publications Ltd, UK, 2000.

5 Yu, H. Personal communication. Oxford Natural Products plc. March 2, 2000.

6 Champault, G, Patel, JC and Bonnard, AM. A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. British Journal of Clinical Pharmacology, 18, 461-462, 1984.

7 Proceedings from Herbal Extracts 2000 Feb 24-25, London. IBC Global Conferences Ltd.

Additional source material
– Clark, AM. Natural Products as a Resource for New Drugs. Pharmaceutical Research, 13 (8), 1133 – 1141, 1996.

– Grabley, S and Thiericke, R. Bioactive agents from Natural Sources: Trends in Discovery and Application, Advances in Biochemical Engineering/Biotechnology, 64, 101 – 154, 1999.

– Harvey, AL. Medicines from nature: Are natural products still relevant to drug discovery? Trends in Pharmacological Sciences, 20 (5), 196 – 198, 1999.

– ten Kate, K and Laird, SA. The Commercial Use of Biodiversity: Access to genetic resources and benefit sharing. Earthscan Publications Ltd, 1999.

– Xu, G. Chinese Herbal Medicine, A practical guide to the healing power of herbs. Vermilion, UK, 1996.

– Cannabis: The Scientific and Medical Evidence, 1998, Select Committee on Science and Technology, House of Lords, Session 1997-98, 9th Report. London: The Stationery Office.

– Botanical Medicine: Efficacy, Quality Assurance, and Regulation. Eskinazi, D (ed), Mary Ann Liebert, Inc, USA, 1999.

– Martindale: The complete drug reference, 32nd edition. Kathleen Parfitt (ed). The Pharmaceutical Press, 1999.

Websites
www.herbtech.com (CV Technologies Inc)
www.oxfordnaturalproducts.com
www.paracelsian.com
www.pharmaprint.com
www.phytera.com
www.phytopharm.co.uk