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plants as a source of new medicines 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

Photograph courtesy of Macfarlan Smith Ltd plant extracts. This article discusses the important role that plants Galanthus woronowiis (daffodil); source of galanthamine can play in the search for new medicines and effective therapies.

By Jennie Gwynn s technology advances, the pharmaceutical 20th centuries, plants provided the major source of and Peter J Hylands industry is increasingly focusing on the medicines. Evidence of their use as long as 50,000 Ahuman genome as a source of the many unan- years ago comes from the Middle Eastern grave site swered questions relating to how disease is prevented, of a Neanderthal man containing plant specimens, diagnosed and treated. It is easy to forget one of the seven of which are still in use medicinally today by other life forms that has contributed much to our cur- the local population1. rent understanding of medicine and many effective The hugely diverse plant kingdom, consisting of therapies. Plants are an abundant natural source of some 250,000-300,000 species, continues to evolve potential new medicines and as a pharmaceutical com- and adapt to a multiplicity of environmental condi- pany seeks to achieve an optimally balanced R&D tions and to protect from pathogens and predators. portfolio this potential should be kept in mind as a Whether by serendipity or design the human species target for new or additional funding. In assessing the appears, in contrast, to have stabilised its genetic potential risks and benefits associated with such code. Many characterised human endogenous recep- investment some insight into the following should tors, important in physiological function, are activat- contribute to decision making: ed by plant-derived chemicals; for example the opioid, and the more recently discovered cannabinoid, recep- G historical evidence tors. It is not unreasonable to hypothesise that many G current research trends more structure-activity relationships, of physiological G future opportunities and pharmacological significance, involving plant G development issues molecules have yet to be characterised. G regulatory hurdles In excess of 20% of the ethical turnover of phar- G facilitative technologies maceutical companies today is generated from plant- G market potential and competition derived medicinal products. Some of these are the original natural product, others the synthetic equiva- What contribution have plants made to lent or synthetic derivatives designed to improve effi- medicine today? cacy or decrease associated . The most Prior to the advances in synthetic chemistry and the important of these, representing historically accepted discovery of antimicrobials in the late 19th early medical practice, yet still prescribed today, are listed in

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Artemisia annua; source of artemisinin htgahcuts fHg au otclueLtd Horticulture Value High of courtesy Photograph

Table 1. More recent new product introductions and tion technology and improvements in global standards some plant-derived products currently in development of education and welfare. are included in Table 2. Scientists and clinicians in the Far East and Asia, Another area of interest in the West is herbal medi- many trained in the West, are applying Western clin- cine, which has proved extremely popular in some con- ical research and practice to traditional products and tinental European countries with many products publishing their results in reputable, peer reviewed, licensed as medicines, and is growing in significance in journals. Further significant preclinical and clinical the UK and the US as herbal remedies, nutraceuticals research is published in original language journals or functional foods. The application of herbal medi- but is becoming more easily available from databas- cine goes back centuries in Traditional Chinese, es like Medline. Some of the newer companies Ayuverdic, Unani and other cultures in the developing involved in phytopharmaceuticals have specialist world. Thousands of plants are used as a basis for internal staff and/or have established links with com- Manufacturing plant recently these traditional practices of medicine and while many panies, experts and academic institutions in the commissioned at Macfarlan in the West are sceptical of any therapeutic value, more countries used to source materials. All these avenues Smith to process and extract and more beneficial effects are being demonstrated. A can facilitate narrowing the search for potentially galanthamine from Galanthus number of new companies have begun to focus on effective medicinal plants. woronowiis 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 iden- tify development candidates. Thousands of plant- derived 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 toxic- ity. These data are becoming more accessible in today’s world of advanced communication, informa- Photograph courtesy of Macfarlan Smith Ltd, manufacturers of and fine chemicals

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Ta bl e 2 Some more recent new products and drugs in development

SOURCE PLANT PLANT PRODUCT* DERIVATIVE* INDICATIONS MODE OF ACTION

Galanthus woronowiis galanthamine Alzheimer’s reversible cholinesterase (Shire/Johnson & Johnson) inhibitor Podophyllum peltatum podophyllotoxin etoposide anti-cancer topoisomerase II (Bristol Myers Squibb/Novartis) anti-viral inhibitor Camptotheca acuminata camptothecin topotecan (SmithKline Beecham) anti-cancer topoisomerase I irinotecan (Pharmacia/ Aventis) inhibitor Artemisia annua artemisinin artemether (Aventis) malaria schizontocide Taxus brevifolia taxol (Bristol Myers Squibb) docetaxel (Aventis) anti-cancer microtubule disaggregation inhibitor Tricosanthes kirilowii tricosanthin anti-cancer reverse transcriptase anti-viral inhibitor Coleus forskolii forskolin glaucoma adenylate cyclase stimulator impotence Cannabis sativa ⌬9-tetrahydrocannabinol nabilone (Eli Lilly) antiemetic in chemotherapy analgesic (Unimed) ⌬9-tetrahydrocannabinol sedative cannabadiol hemisuccinate appetite stimulation muscle relaxant multiple sclerosis spasticity pain management Silybum marianum silymarin (Madaus) hepatic disorders free radical scavenger amanita poisoning

* = company affiliation denotes marketed product. Source: various, see additional source material

has made an impact, is in the pressure to recognise the Ta bl e 1 medicinal qualities of the plant Cannabis sativa. Significant plant-derived pharmaceutical products While the psychotropic properties of cannabis are well recognised and the therapeutic effect of its major com- ⌬9 SOURCE PLANT DRUG INDICATION ponent -tetrahydrocannabinol in alleviating nausea and vomiting caused by chemotherapy has been Salix spp aspirin analgesic proven, evidence of efficacy in other diseases like mul- anti-pyretic tiple sclerosis, while compelling is mainly anecdotal. cardiovascular There now exists, however, a vast database of research Atropa belladonna atropine anti-cholinergic on cannabis, its individual components and synthetic pupil dilation Digitalis lanata digoxin cardiotonic derivatives. Relatively recently, endogenous cannabi- Mucuna deeringiana (L)-dopa anti-parkinsonism noid receptors were identified in man and animals, Dioscorea deltoidea diosgenin anti-fertility opening up a new field of research into cannabinoid analgesic and antitussive receptor agonists and antagonists2. Compounds syn- thesised by companies in the past, shelved or aban- Colchicum autumnale colchicine anti-tumour anti-gout doned because of the associated stigma, may well be Cinchona ledgeriana quinine anti-malarial resurrected or utilised to refine the search for more Catharanthus roseus vincristine anti-tumour specific targeted candidates. vinblastine While the stigma of abuse is not associated with tra- ditional ethnic medicines an element of quackery is Source: various, see additional source material sometimes applied to it by the so-called educated West. It should not be forgotten, however, that much The demands and expectations of the increasingly of our current understanding of medicine is based on knowledgeable, health conscious and environmentally the discovery of the medical application of plant- aware consumers and patients of the Western world derived substances like , curare, atropine and are placing increasing pressure on regulators, clini- ephedrine. More credence today is being given to the cians and politicians. A recent example of where this activity of herbs like St John’s Wort, Saw Palmetto and

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Papaver somniferum (opium ); source of morphine and codeine htgahcuts fMcalnSihLtd Smith Macfarlan of courtesy Photograph

Gingko biloba. Table 3 lists some of the current most classic test for alpha reductase inhibition5. An extract popular medicinal herbs. Increasing use of some of of the plant Serenoa repens has been shown to be these active agents is leading to a greater incidence of more effective and associated with fewer side effects adverse events, often due to interactions with pre- than finasteride6. This has contributed to a growing scription drugs. Clinical awareness of the potential for interest in the use of and developing herbs as potential these types of interactions has led to a number of stud- new medicines in the Western world. A significant ies which have recently been published3, prompting example of this is the development of a Chinese herbal regulatory authorities to issue guidance on the use of mixture for the treatment of eczema by Phytopharm some products. While this could be viewed negatively Plc, based on the observation that a patient receiving for herbal products it does, however, serve to show treatment from a TCM practitioner in London was that many herbs can produce significant pharmaco- showing unexpected signs of significant improvement. logical effects and supports the developing view that Some examples of the many INDs currently with the their use requires improved regulation and control. FDA are listed in Table 47. During the 1990s some futurists and more recently pharmaceutical scientists, including Dr George Poste4, Ta bl e 3 have predicted that one of the major advances in the Some of the current most popular next couple of decades will be the individualisation of botanical medicines therapy. This proposal has been linked mainly to the advances in genomics. For many hundreds if not thou- sands of years, however, some ethnic cultures have LATIN NAME COMMON ACTIVITY been individualising treatments for patients. Two NAME important examples utilising plant-derived medicines, Gingko biloba gingko stimulation of peripheral come from China – Traditional Chinese Medicine, and circulation India – Ayuverdic Medicine. Thousands of herbs have Echinacea spp coneflower immunostimulant been associated with beneficial effects that are often Allium sativum garlic cholesterol reducing given in multiple combinations designed by practi- Serenoa repens saw palmetto alleviation of symptoms of BPH tioners for each individual patient’s total well-being. Panax ginseng ginseng ‘tonic’ Tanacetum parthenium feverfew migraine prophylaxis More recently academic researchers have investigat- Hypericum perforatum St John’sWort anti-depressant ed pharmacological activity for many of the more Crataegus spp hawthorn cardiotonic, hypotensive widely used herbs, utilising methods accepted by Ephedra spp ma huang CNS stimulant, appetite Western cultures. For example, many herbal products suppressant available in China for the treatment of benign prosta- Valeriana officinalis valerian calmative, sleep inducing tic hypertrophy are now being screened for their activ- Source: ten Kate, K and Laird, SA 1999 ity in mice with testosterone-induced hyperplasia, a

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Regulatory issues for licensing of Ta bl e 4 plant-derived medicines and how are Some examples of herbal-based INDs they are evolving? currently with the FDA This is not to say that the development of plant- derived medicines is without complication. The key issues for development programmes, where it proves HERB INDICATION difficult or for other reasons not desirable to synthe- sise the active plant component(s), relate to identifi- St John’s Wort depression Gingko biloba cognitive impairment cation, standardisation and consistency of material. Saw Palmetto benign prostatic hypertrophy Fears of adulteration or even contamination of plant Green Tea cancer material by potentially toxic materials are not Chinese Herb Formula menopausal hot flushes unfounded and serve to substantiate the long stand- Chinese Herb Formula plantar warts ing attitude of regulators towards combination prod- Chinese Herb Formula eczema ucts and a frank ‘adverse reaction’ to complex mix- Source: Proceedings of Herbal Extracts 2000; citation: FDC Reports, May 1998 tures like herbal extracts. As a result many compa- nies have shied away from this potentially fruitful area of R&D. References How can plant-derived medicines shift It is reassuring for those interested in developing 1 Fowler, MW. Plants, the balance of emphasis for R&D? plant-derived medicines that the anticancer taxol Pharmaceuticals and Plant Cell R&D programmes to develop a new drug by de novo has been so therapeutically, and commercially, suc- Culture – A Perspective, In: synthesis can typically take up to 20 years: establish a cessful. The recent first European approval of Recontrés Europeane de Phytochemie. Actes du new research programme; define the target; synthesise galanthamine for Alzheimer’s disease in Sweden Colloque (eds Brunetton, J and and screen the activity of potential leads; select the further supports the premise that plants are a Guinandeau, H) Angers, optimal few and further define their pharmacological source of new medicines. France, 124-133, 1993. and safety profile. Optimistically, one or two candi- Major initiatives have been under way in Europe 2 Pertwee, RG. dates make it into development. If clinical efficacy and and the US for some time to address the regulation of Neuropharmacology and therapeutic potential of safety are demonstrated to achieve product licence herbal medicines. This is mainly in recognition of a cannabinoids. Addiction approval, a period of product exclusivity will follow. lack of continuity of, or complete absence of regula- Biology 5, 37-46, 2000. The return on investment will be related to the effec- tion, for herbal products used as medicines, 3 Fugh-Berman, A. Herb-drug tiveness of a company’s patent strategy and product nutraceuticals and functional foods and of con- interactions. Lancet, 355, 134- life cycle management. sumers’ desire for access to such products. In the US 38, 2000. 4 Poste, G. The right treatment Advances in technology have been designed to reduce the final rule relating to the DSHEA regulations has for the right patient. Scrip the time to identify candidate new drugs; for example, recently been published (Federal Register, 6th Magazine, January 2000, Issue high throughput screening, combinatorial chemistry and January 2000). This relates to statements that can be 86, PJB Publications Ltd, UK, most recently genomics and proteomics. The evidence to made about the effects of dietary supplements on 2000. date of these increasing the chances of success is limited bodily structure or function and is of major signifi- 5 Yu, H. Personal communication. Oxford but that is not to say that in the near future these signif- cance to manufacturers of herbal products targeted Natural Products plc. March 2, icant investments will not come to fruition. at the general consumer. Europe is not as advanced 2000. These technologies, in addition to others like cell in this specific area of regulation but the European 6 Champault, G, Patel, JC and culture and cloning, can also be applied to plant- Agency for the Evaluation of Medicinal Products has Bonnard, AM. A double-blind derived substances. When embarking on a programme made significant progress towards achieving a trial of an extract of the plant Serenoa repens in benign to identify therapeutically active plant components or European-wide assessment of herbal medicinal prod- prostatic hyperplasia. British mixtures one can often have a head start in the race ucts including evaluation of monographs for well Journal of Clinical due to prior knowledge about potential activity asso- recognised herbs. Pharmacology, 18, 461-462, ciated with a particular species or genus. By reducing While regulatory approval of some of the more 1984. serendipity, the time, cost and complexity of de novo widely known medicinal herbs is potentially being 7 Proceedings from Herbal Extracts 2000 Feb 24-25, synthesis, one can substantially reduce the time to made easier, that of new chemical entities remains as London. IBC Global reach the market and increase the chances of success. stringent as ever. New plant-derived chemicals, Conferences Ltd. It is relevant here to add that evidence of clinical extracts and their derivatives fall within the latter cat- Continued on page 59 exposure, and thus safety, can often be documented egory. Some phytopharmaceutical companies are for traditional herbal medicines. Such products can be focusing their efforts on single molecules or plant evaluated in small, well-designed and controlled, clin- extracts with the aim of simplifying the regulatory ical studies to test ‘proof of concept’ negating the need process by avoiding complex mixtures and combina- for significant investment in preclinical safety prior to tions. Others are looking to the future success of their having confidence that one has a potential product. new technologies to facilitate approval.

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How will new technologies facilitate considerable number of years where the focus is Continued from page 58 product licence approval? broader than plants or has actually moved away from To overcome the major regulatory concern related to plants as a source of new medicines in recent years. Additional source quality of plant-derived material, a few companies Where large screening programmes are in place there material – Clark, AM. Natural Products specialising in phytopharmaceuticals, including is the opportunity to adapt and take advantage of the as a Resource for New Drugs. PharmaPrint, CV Technologies and Oxford Natural increasing database of information on plants. Many Pharmaceutical Research, 13 Products, are independently developing and patenting companies today, however, are streamlining their (8), 1133 – 1141, 1996. new technologies. Some of these technologies are internal R&D organisations and seeking licensing – Grabley, S and Thiericke, R. addressing the agricultural process and practice lead- opportunities from outside. It would seem prudent, Bioactive agents from Natural Sources: Trends in Discovery ing to raw materials of consistent source, quality and therefore, to maintain a watching brief on the prolif- and Application, Advances in yield; essentially to facilitate Good Agricultural erating number of small companies specialising in Biochemical Practice. It is worth noting in this context that the plant-derived medicines. Not only do these compa- Engineering/Biotechnology, 64, ability of developing countries and the emerging nies have the relevant internal expertise to identify 101 – 154, 1999. nations to pay for expensive new medicines is in part significant leads; they recognise and understand the – Harvey, AL. Medicines from nature: Are natural products influenced by their infrastructure and economic issues associated with developing plant-derived med- still relevant to drug growth. Sourcing of plant materials from their natural icines. Access to their new technologies should discovery? Trends in habitat, grown under controlled conditions, can con- enable, in the shorter term, development of safe and Pharmacological Sciences, 20 tribute to local economies and to provision of better effective plant-derived medicines of high and consis- (5), 196 – 198, 1999. quality lower priced medicines. In addition this can tent quality. – ten Kate, K and Laird, SA. The Commercial Use of contribute to the conservation of rare species and to In the near future, we may well start to see the Biodiversity: Access to genetic the obligations laid down by The Convention on emergence of a new class of prescription medicine, resources and benefit sharing. Biological Diversity. containing complex mixtures of plant extracts Earthscan Publications Ltd, Others of these new technologies are combining designed, or inherently containing the active synergis- 1999. advanced chemical and biological assays that will tic components, to cure disease, treat associated symp- – Xu, G. Chinese Herbal Medicine, A practical guide to enable the raw material to be identified and standard- toms and prevent recurrence. DDW the healing power of herbs. ised in order to meet the stringent regulatory require- Vermilion, UK, 1996. ments for quality. It is of relevance to note that Jennie Gwynn MSc PhD MRPharmS is Development – Cannabis: The Scientific and PharmaPrint Inc has recently been granted a US patent Director at Oxford Natural Products plc in Medical Evidence, 1998, Select for the application of its PharmaPrint process technol- Oxfordshire. Following a period with the Medicines Committee on Science and Technology, House of Lords, ogy for saw palmetto, a product that they are investi- Control Agency as a preclinical assessor, she joined Session 1997-98, 9th Report. gating under an IND for benign prostatic hypertro- the in 1980. Her broad London: The Stationery Office. phy. These new technologies, if ultimately successful drug development experience has been gained from a – Botanical Medicine: Efficacy, in their application, will not only facilitate regulatory range of responsibilities in R&D, medical affairs, Quality Assurance, and approval of a new generation of safe and effective project management and strategic planning depart- Regulation. Eskinazi, D (ed), Mary Ann Liebert, Inc, USA, products containing unique, ‘fingerprinted’ plant ments of SB, Roche, Sigma Tau, Pharmacia & 1999. extracts but also afford a greater degree of product Upjohn, and as an advisor to the Pharmaceutical – Martindale: The complete exclusivity and protection of both intellectual proper- Industry Group of Coopers & Lybrand Management drug reference, 32nd edition. ty and investment. Consultancy Division. Kathleen Parfitt (ed). The Pharmaceutical Press, 1999. Where can acquisitions to add to the Peter J Hylands PhD CChem FRSC is Chief Scientific Websites R&D portfolio be found? Officer at Oxford Natural Products plc in Oxfordshire. www.herbtech.com (CV Many herbal product companies are taking advan- He is a pharmaceutical chemist with a 15-year academ- Technologies Inc) tage of the new DSHEA regulations in the US for ic career at the University of London focusing on www.oxfordnaturalproducts.com nutraceuticals and exploiting ways of suggesting that research into the use of plants as medicines. He joined www.paracelsian.com the quality of their products is better than their com- Xenova in 1988 as founding Director of Chemistry www.pharmaprint.com www.phytera.com petitors. Some of the multinational pharmaceutical and then as Research Director to www.phytopharm.co.uk companies, with a major interest in consumer prod- PHYTOpharmaceuticals, Inc, both companies dedicat- ucts, are establishing links with herbal product com- ed to the discovery and commercialisation of pharma- panies and capitalising on the growing consumer ceuticals derived from natural products. He has acted as interest in herbal remedies and their environmentally a consultant to the United Nations and Commonwealth friendly or ‘green’ association. This is a significant Science Council and is well connected in every conti- and growing market but is still dwarfed by prescrip- nent with regard to natural product research and devel- tion pharmaceuticals. opment. A visiting Professor in the Department of Some of the multinationals have natural product , Kings College, London, he also serves on a R&D programmes that have been in existence for a number of boards and advisory boards.

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