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(1998; 113 pages)
Discovery process and initial testing of praziquantel
At the beginning of the 1970s, the search for effective tranquilizers with few side effects was being actively pursued in the pharmaceutical industry. Scientists at E. Merck considered the pyrazinoisoquinoline substance group a promising possibility, but found that relatively high doses had to be used in order to achieve an effect comparable to that of established tranquilizers. As a result, the compounds in this group were not pursued further at E. Merck; according to an agreement between the two firms, the compounds were passed on to Bayer for veterinary screening (Groll, 1984). Using a step-by-step procedure, the most effective substance, praziquantel, was chosen from a total of approximately 400 compounds. This substance was found to be an effective anthelminthic against a broad spectrum of parasitic trematodes and cestodes (Andrews et al., 1983). The drug was first developed for veterinary use and later tested for the treatment of helminthic infections in humans.
The therapeutic potential of praziquantel for the treatment of S. mansoni infections was first explored by Andrews and Gönnert in 1977 at the Research Centre Wuppertal using the schistosoma/mouse model (Andrews et al., 1983). In wide-ranging preclinical studies in many animal species, they showed praziquantel to be highly effective experimentally and clinically against all species of schistosomes pathogenic to man and a wide range of cestodes (Davis, 1982). They obtained particularly good results in all of the S. mansoni strains (Wegner, 1979). An important observation was that the drug was also effective in the oral form. In addition, its acute toxicity was tested in rats, mice, rabbits, and dogs, and was shown to be very low compared to other schistosomicidal drugs.
Following promising results in animal experiments on toxicity and efficacy, therapeutic trials with healthy volunteers (Phase IA) were begun in 1978. In the Human Pharmacology Center at E. Merck, Leopold and co-workers performed a complex study involving 36 healthy volunteers in 1978 (Leopold et al., 1978). Tolerance and pharmacokinetics were tested for doses that were increased by steps to three doses of 25.0 mg/kg body weight each. No clinically relevant drug-related changes were detected by the extensive psychological, clinical, neurological, hematological and clinico-chemical examinations of the volunteers. The absence of toxic alterations of vital functions and organs in these pharmacokinetic studies in man confirmed the therapeutic potential of praziquantel (Wegner, 1979). Comprehensive toxicological studies, which employed a wide variety of test systems, were also carried out by WHO in collaboration with the International Agency for Research on Cancer. The tests found no mutagenic, carcinogenic, embryotoxic, or teratogenic activity of praziquantel (WHO, 1985).