The WHO program was terminated shortly thereafter. Perhaps the first company in the United States to investigate KU-0063794 plants strictly through the ethnomedical approach was Shaman Pharmaceuticals in South San Francisco, California. Their approach was to send botanist/physician teams to tropical areas to assess firsthand the use of plants by traditional healers and to collect interesting plants and assess them for validity in the Shaman laboratories. Initial interest was directed toward antifungal and antiviral agents, several active compounds were discovered but were either toxic or failed in the clinic. Efforts were then directed toward antidiarrheal activity. SP 303, an oligomeric proanthocyanidin, was shown to be clinically efficacious and is currently marketed as a dietary supplement for diarrhea.
In addition, a major effort was directed toward discovery of novel antidiabetic agents, which resulted in the discovery of several patented compounds: cryptolepine, maprouneacin, Danusertib 3,30 dihydroxylupen 20 en 2 one, harunganin, vismin, and quinones SP18904 and SP18905. The most interesting discovery was nordihydroguaiaretic acid which, besides being active orally in db/db diabetic mice, also lowered cholesterol levels. In 1999 Shaman terminated their research in drug discovery. In 1985 we proposed an approach, based on ethnomedical information, to experimentally pursue plants as a source of drugs. The approach was designed primarily for implementation by developing countries, where lack of hard currency often prevents sophisticated types of research from being conducted.
The possibility of drug development in the form of stable, standardized crude extracts and eventual development of the active principles from these plants was envisioned. Some examples of drugs from plants that served as models for the next generation of drugs are exemplified as follows: Khellin was used as a bronchodilator in the United States until it was shown to produce nausea and vomiting after prolonged use. In 1955 a group of chemists in England set about to synthesize khellin analogs as potential bronchodilators with fewer side effects. This eventually led to the discovery of chromolyn, which stabilized cell membranes in the lungs to prevent the allergeninduced release of the substance ultimately causing bronchoconstriction in allergic asthma patients. Further studies elsewhere led to the synthesis of amiodarone, a useful antiarrythmia agent.
The structural relationship can be seen in Figure 4. Papaverine, useful as a smooth muscle relaxant, provided the basic structure for verapamil, a drug used to treat hypertension. Galegine was isolated as an active antihyperglycemic agent from the plant Galega officinalis L. This plant was used ethnomedically for the treatment of diabetes. Galegine provided the template for the synthesis of metformin and opened up interest in the synthesis of other biguanidine type antidiabetic drugs. It is extremely difficult to assess the value of any approach to the use of higher plants to develop new drugs.