Toxicological profile of praziquantel, a new drug against cestode and schistosome infections, as compared to some other schistosomicides.
2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one (praziquantel, EMBAY 8440, Biltricide), a new anthelminthic drug with activity against all species of schistosomes pathogenic to man, and against a wide range of cestodes, did not reveal any undesired pharmacodynamic effects. After oral administration praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a variety of metabolites predominantly via the kidneys by all species tested, including man. Its acute toxicity tested in rats, mice, rabbits and dogs is very low as compared with other schistosomicidal drugs. After repeated oral administration rats tolerated daily doses of up to 1000 mg/kg for four weeks, and dogs up to 180 mg/kg for thirteen weeks without any organ damage. In contrast to some other schistosomicidal drugs praziquantel did not disturb the whole reproductive process (up to F2-generation) in rats, nor did it reveal teratogenic effects in mice, rats and rabbits. In extensive mutagenicity trials performed in different European laboratories in a variety of test systems no induction of point mutations, nor of gene conversion, nor of DNA-repair, nor of sister chromatid exchanges (SCEs), nor of X-linked recessive lethals was detected. Besides, Salmonella tests with urines of praziquantel-treated mice, rats, healthy and Schistosoma-infected persons gave no indication of a mutagenic effect. In different in vivo mammalian assays praziquantel was not mutagenic either. In contrast to these findings other schistosomicidal drugs demonstrated mutagenic potential, in bacterial tests at least. According to the results available so far from carcinogenicity studies with oral doses of 100 and 250 mg praziquantel/kg, given once weekly to Syrian hamsters for 80 weeks and to rats for 104 weeks, there is no hint of a carcinogenic potential of praziquantel in small rodents, while hycanthone had cancerogenic effects in mice and niridazole was carcinogenic in mice, rats and Syrian hamsters.
D000818:Animals; D002273:Carcinogens; D002875:Chromosomes / Q000187:drug effects; D006224:Cricetinae; D004285:Dogs; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000633:toxicity*; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009153:Mutagens; D011223:Praziquantel / Q000378:metabolism / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D012556:Schistosomicides / Q000633:toxicity*
D002273:Carcinogens; D007546:Isoquinolines; D009153:Mutagens; D012556:Schistosomicides; D011223:Praziquantel