The Pharmaceutical Journal
Vol 277 (Supplement) F34-35
October 2006

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FIP Congress 2006

Natural products — their current importance and clinical developments

Introducing the session, Toshio Honda, professor of organic and medicinal chemistry in the faculty of pharmaceutical sciences at Hoshi University, Japan, said that throughout history the study of natural products has provided the impetus for great advances in drug development.

He cited the following examples of modern drugs derived from natural products:

• Digitoxin and digoxin have been historically obtained from Digitalis spp.

• Aspirin is based on salicin, a constituent of Salix alba.

• The analgesic morphine and the antitussive noscapine are both derived from Papaver somniferum.

• The antimalarial quinine is derived from Cinchona spp.

• The antiparkinson drug L-dopa is derived from Vicia faba.

• The plant Securinega suffruticosa yields an alkaloid that has been used in Russia as a central nervous system stimulating drug.

• Taxol, which plays a major role in the management of breast, ovarian and lung cancers, has its origins in the yew tree Taxus baccata.

Professor Honda said that the so-called “designer” drugs are derived by chemical modifications of natural structures and often give better bioavailability, effectiveness and safety than the original compounds. He explained that chemical modification of erythromycin, originally isolated from Streptomyces erythreus, has improved its stability. Many derivatives of the morphine molecule have been developed to fulfil different therapeutic requirements.

Professor Honda then outlined some recent work in which he and his colleagues looked for new drugs with antidiabetic properties based on naturally occurring anthrocyanins, and new analgesic agents based on isoquinolines.

Kurt Hostettmann, of the laboratory of pharmacognosy and phytochemistry in the school of pharmacy at the University of Geneva, Switzerland, also emphasised the importance of medicinal plants. He told the meeting that:

• 80 per cent of the world’s population use only medicinal plants

• In developed countries, about 35 per cent of prescribed drugs are of natural origin

• More than 40 per cent of over-the-counter drugs are derived from medicinal plants

• During the past decade, consumption of medicinal plants has doubled in western Europe

Dr Hostettmann then gave some examples of conditions that responded to plant-based medicines:

• Cancer therapy In the field of cancer therapy compounds developed from the Chinese plant Camptotheca acuminata are used to fight colon, ovarian and bronchial cancers.

• Alzheimer’s disease Galanthamine is a new drug used for the treatment of Alzheimer’s disease. Isolated in the mid 1950s from different Galanthus spp it is thought to inhibit acetylcholinesterase and improve cholinergic transmission. Huperzine A from the aerial parts of the Chinese club moss (Huperzia serrata) also has applications in treating Alzheimer’s disease. In Belgium and Germany Alzheimer’s disease is treated with Ginkgo biloba.

• Fatigue and stress Rosavin is the principal active constituent of Rhodiola rosea, a plant used in Russian traditional medicine, and in Scandinavia and Iceland, for improving physical endurance and altitude sickness, and for the treatment of fatigue, infections and central nervous system disorders. St John’s wort (Hypericum perforatum) is also used for stress and anxiety but has a number of potential interactions with orthodox medicines and can cause “light sickness” or photosensitivity. The latter property could have possible applications in photodynamic cancer therapy.

Although great progress has been made in the application of biotechnology, genetics and genomics in producing new and powerful drugs, the plant kingdom remains a hugely unexploited resource, said Dr Hostettmann. It has been estimated that over 300,000 plants have not yet been investigated. The selection of plants to be investigated, the preparation of extracts and their biological and chemical screening all need to be studied.

Combining techniques such as high pressure liquid chromatography with ultraviolet spectroscopy, mass spectroscopy and nuclear magnetic resonance is essential for the rapid identification of interesting compounds. Dr Hostettmann illustrated his comments with reference to the search for new antifungal agents against Candida albicans and new inhibitors of acetylcholinestrerase from masterwort (Peucedanum ostruthium), Gentiana campestris and various Lycopodium spp that could find application in the treatment of Alzheimer’s disease. He said that numerous plant constituents are not active but become active through metabolisation, adding that these “pro-drugs” offer an unexploited potential for new active compounds.

Regulatory changes

Freddie Ann Hoffman, of HeteroGeneity LLA, Washington DC, US, explained that recent changes in US regulatory policies have opened the door for classifying botanicals and other naturally heterogeneous health products previously considered to be foods and dietary supplements as “new” drugs.

A new drug is defined as “any drug that is not generally recognised as safe and effective under the conditions prescribed, recommended or suggested in the labeling”.

Dr Hoffman said the current method of classification of new drugs is based on a four-stage process aimed at “pulling out the actives”. This involves identifying, isolating and purifying the bioactive substances and then synthesising them. It is designed to satisfy the US regulatory authorities’ requirements that the compounds should be homogeneous, fully characterised and verified. It is also necessary to know the therapeutic targets of the drug.

Using garlic as an example, Dr Hoffman identified a number of difficulties with this approach. Over a hundred different products are currently identified as being garlic and there is a range of formulations and presentations. She said that many garlic products are standardised on allicin but benefits have been observed with products containing no allicin Furthermore, compounds other than allicin are responsible for some health benefits of garlic.

Dr Hoffman proposed a new paradigm based on considering complex, heterogeneous polymolecular products as a class of new drugs. This paradigm would allow new products to maintain the “whole is greater than the sum of the parts” idea consistent with phytotherapeutic beliefs.

It would also facilitate the development of multiple therapeutic targets (some of which may be initially unknown) and acknowledge the presence of unidentified active principles. The first botanical new drug to be considered and currently under review is green tea extract.

Clinical development

The clinical development of natural health products was discussed by Carmen Tamayo, R&D consultant at Flora Inc, Lyndon, Washington. She said that the goals of clinical development include the generation of data to support evidence-based patient care as well as to satisfy regulatory authorities’ requirements.

There are differences between the outcomes that could be claimed between the clinical benefit of modern drugs and the less specific benefit associated with dietary supplements. She outlined some of the issues involved in botanical drug development, which include:

• Good agricultural and field practice GAFP is necessary, from cultivation through to harvesting, to ensure the correct identity and quality of source material. Taxonomy and nomenclature are still changing, she said, and are not internationally harmonised, making it difficult to be certain that the correct plant is being used.

• Good manufacturing practice GMP is necessary to ensure quality and safety of the final product, There are some important differences between synthetic and botanical drugs in the ability to observe GMP, said Dr Tamayo. In botanicals batch-to-batch variability is likely and it is often difficult chemically to characterise active principles.

• Good clinical practice GCP must be associated with well-designed clinical studies and adequate postmarketing surveillance. Dr Tamayo said that although randomised clinical trials are often considered to be the gold standard for collecting evidence of efficacy by the scientific community they do have deficiencies. In particular, there is a considerable gap between methodological research and methodological practice as far as botanicals are concerned.

It is necessary to rely on available evidence for appropriate study design, intervention and population, and to use quality products with as little batch-to-batch variation as possible. Independent verification of botanical samples used in studies should be obtained at the start, halfway through and at the end of trials to ensure stability. The possibility of adverse reactions and interactions with orthodox medicines and other natural products should be carefully monitored.