The Pharmaceutical Journal
Vol 268 No 7204 p921-923
29 June 2002

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Joint symposium

Plants are still an important source of pharmaceuticals

Opening the meeting, Professor Peter Houghton, professor of pharmacognosy, King's College London, told participants that several companies were involved with the commercialisation of bioactive compounds, mainly from higher plants, and plants were still an important source of pharmaceuticals.

Sweet potatoes

Professor Robert Nash, Molecular Nature Ltd (MNL), discussed carbohydrate analogues (aza-sugars) found in British plants as bioactive chemicals. Many interesting compounds were being isolated by MNL scientists from local temperate species — there was no need to go to the tropics, he said. Some of the first such compounds to be discovered were nojirimycin, a glucose analogue, and 1-deoxynojirimycin, a potent glucosidase inhibitor with antidiabetic activity, which is found in Morus spp. Anti-HIV and anticancer agents had also been isolated, including castanospermine (an indolizidine alkaloid which inhibits metastasis in mice) from a tropical plant found in New South Wales, Australia.

According to Professor Nash, it was becoming apparent that such compounds were extremely common. For example, a group of nortropane alkaloids known as calystegines were found in healthy tubers of the potato (Solanum tuberosum) and also in red peppers, aubergines and tomatoes. Castanospermine and swainsonine, a carbohydrate analogue found in small amounts in Stellaria media, were currently in development. Carbohydrate analogues were also found in the popular herbal medicine echinacea.

Plant creativity

Dr Angela Stafford, Galileo Laboratories Ltd, explained how plants have developed multiple systems to deal with environmental stresses, such as high levels of sunshine or shade, extreme temperatures, predators and so on. This "plant creativity" meant that many diverse chemicals, including those with antioxidant, antifungal and antibacterial activities, which were relevant to human conditions, were produced by plants.

According to Dr Stafford, investigating whole plants presented only a limited picture. Her company's approach was to use plant-cell culture to "coax" plant cells to adopt numerous diverse genetic and chemical expression states. A large plant-cell culture library had now been developed, which could be used, for example, to hunt for strategic biosynthetic genes. For example, the technology was now being applied to the discovery of novel therapeutics for redox failure, with potential applications in inflammation and ischaemia.

Cannabis as a POM?

The challenge discussed by Dr Brian Whittle, GW Pharmaceuticals, was how to make a respectable medicine out of something (cannabis) which had hitherto been considered a drug of abuse. Cannabis had not, however, always been considered so — it had been used medicinally "from antiquity".

Today, clinical trials involving patients with multiple sclerosis and pain resulting from spinal cord injury were ongoing and, in October 2001, the Home Secretary had expressed support for cannabis as a medicine, provided that evidence of efficacy from controlled clinical trials became available.

The development and commercialisation of any medicinal product involved risks, Dr Whittle said, such as establishing quality, safety and efficacy, and protecting intellectual property rights. With cannabis, the additional issues involved with unlocking its commercial value included security (because cannabis was a scheduled substance), the legislative climate, and patient and professional attitudes.

In order to overcome the problem of security for any potential prescription cannabis products, GW Pharmaceuticals was developing a specialist advanced dispensing system [see PJ, 22 June, p866]. This anti-diversionary unit was electronically controlled and comprised an enclosed cartridge, release device and docking component, which recharged the batteries and allowed data from the unit (eg, for monitoring purposes) to be sent to a central computer.

Dr Whittle said that they were probably "over-egging the pudding" with the complexity of the device, but the object of it was "to give comfort to legislators".

Prospecting with insects

Professor John Pickett, Institute of Arable Crops Research, Rothamsted, described how insect olfactory receptor systems are highly sensitive to specific molecular structures, even in the presence of similar compounds at much higher concentrations. The wide range of natural products to which insects respond could be used for commercial purposes, eg, to detect the onset of food deterioration, or for legal purposes, eg, to detect the illegal presence of natural products. His group was using honeybees in an odour-conditioned proboscis extension assay.

Traditional plant remedies

According to Dr Daryl Rees, Phytopharm Plc, the generation of intellectual property was key to developing novel pharmaceutical medicines from traditional plant remedies. Phytopharm's approach was to select traditional plant medicines with a long history of use and strong anecdotal evidence of clinical efficacy. Simple or complex phytochemical extracts from these plants were then taken into full pharmaceutical development, but this differed from the conventional approach in that early clinical work and studies investigating mode of action were done in parallel. Where novel modes of action were discovered, this could form the basis for "drug discovery platforms" where families of products, all with the same mode of action, could be developed. In turn, this could lead to the development of single chemical entities and, thus, the potential for further intellectual property.

Phytopharm had several drug discovery platforms in development.

P57 — Obesity and metabolic syndrome P57 was developed from a plant used by South African bushmen to satisfy hunger. It is the first true appetite suppressant and does not act on any previously known receptor. Clinical trials in overweight healthy volunteers have been carried out. P57 was licensed to Pfizer in 1998.

P58 — Age-related memory loss and dementia P58 was developed from a plant extract used traditionally as a "tonic" for the elderly. P58 protects against glutamate-induced neurotoxicity in neuronal cells in vitro, and reverses muscarinic receptor and cognitive function decline in rats. Phase I pharmacokinetic studies have been carried out, and results of a randomised, double-blind, placebo-controlled trial to assess safety, tolerance and pharmacokinetics in 30 individuals aged 55 years or more are expected in the third quarter of 2002.

Other drug platforms include P7v/P55, a three-plant extract for canine atopic dermatitis.

Fuzzy specifications?

Professor Peter Hylands, Oxford Natural Products Plc, described a new approach to the characterisation of plant extracts which aims to overcome the limitations of existing methodologies which rely on known active constituents. The approach involves the use of high-field hydrogen-1 nuclear magnetic resonance (NMR) spectroscopy to generate "data-rich" fingerprints, followed by statistical analysis to simplify the data. According to Professor Hylands, by using this approach it is possible to distinguish between feverfew samples from five different suppliers. It is also possible to differentiate between the target species and closely related species, and between samples of the target species grown in different areas. The process could also be used to distinguish between pure samples of a herb and those with contaminants at low concentrations (around 0.02 per cent).

Summing up, Professor Hylands said that central to this approach was the fact that it respected the principles of plurality and totality, ie, that several constituents of a plant are responsible for its activity.

Super natural products

Professor Peter Leadley, University of Cambridge, described how genes and enzymes which govern the biosynthesis of complex polyketides, such as erythromycin, can be manipulated to produce altered products and also libraries of "un-natural products", in a process termed "combinatorial biosynthesis". For example, combining genetic alterations in polyketide synthase with other changes in a particular biosynthetic pathway in a micro-organism, such as changing the starter unit or altering glycosylation patterns, could result in the production of new building blocks for drug leads, and could also help to provide a better understanding of the extent and diversity of secondary metabolites that could be produced by micro-organisms.