J Altern Complement Med. 2001 ; 7 Suppl 1(): S73-82.

Demonstrating the validity of natural products as anti-infective drugs.

Schuster BG.

Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. [email protected]

This presentation reviews the synthetic or classical development pathway of drug development and contrasts it with developing natural products as drugs. Also presented is an example of a traditional medicine that has been developed from a natural product and has become a "new/old" antiparasitic drug used in the treatment of malaria. The classic paradigm of synthetic drug development breaks down into drug discovery, drug design, preclinical studies, and clinical studies. This paradigm, constructed to weed out failures, results in a drug-development process that is high risk, time consuming, and expensive. The process requires screening an average of 10,000 active compounds to find a single compound that successfully makes its way through validation to drug approval and the marketplace. Following this paradigm, researchers progress from identifying a chemical lead to testing the compound in humans. The World Health Organization (WHO) Guidelines for the Assessment of Herbal Medicines are based on the classical guidelines and follow the classical approach to validating quality, safety, and efficacy--with one major difference. The starting point is to look at the natural product in humans. By taking into account the traditional experience with the product, the validation standard for safety and efficacy of natural products allows for the prolonged and apparently uneventful use of a substance to offer testimony of its safety. The reliance, then, is on experience--or what Western regulatory agencies would call "anecdotal information." Since most phytomedicines are a combination of several active ingredients, the WHO guidelines cover two kinds of combination products: Combinations that are already used in traditional medicine are considered "old" combination products. "New" combination products are well-known substances that are now being used in combination. Artemisia annua, a pervasive weed, has been referred to in Chinese medicine for thousands of years as a treatment for fever. In 1971, an extraction of artemisia yielded activity against Plasmodium berghei, a mouse model for malaria. The isolated compound, artemisinin, is an example of a traditional medicine that started out in humans, but which then provided a lead structure for a standard drug-development paradigm. Today, artemisinin derivatives are being used widely in combination therapy, especially in areas of the world where there is multidrug-resistant malaria.