Trypanosoma cruzi: efficacy of the 2-substituted, 5-nitroimidazoles, MK-436 and L634,549, in tissue culture and mice.
Experimental studies were undertaken in tissue culture and mice infected with a cloned derivative of Trypanosoma cruzi, Y strain to determine the efficacy of two 2-substituted 5-nitroimidazole compounds, MK-436 and L634,549. The use of an X-irradiated myoblast culture system proved better than a conventional fibroblast culture for assaying the activity of compounds against intracellular parasite stages. MK-436 showed activity against amastigotes at a level of 25 micrograms/ml and L634,549 a dihydroxy metabolite of MK-436 showed activity 2 micrograms/ml. Neither compound caused morphological damage to the host cells at levels tested (250 micrograms/ml). By contrast, nifurtimox, which was active at 2 micrograms/ml, caused significant host cell damage at 100 micrograms/ml. In mice, studies in the chronic infection showed that MK-436 was curative at a level of 30 mg/kg if given daily for 20 days. Neither nifurtimox nor benznidazole were fully curative when given at a level of 100 mg/kg daily for 20 days. These studies showed that administration of MK-436 with a suitable solvent, PEG 400, enhanced its efficacy fourfold, and that efficacy was also enhanced by increasing the treatment interval. Since MK-436 showed better efficacy in chronic rodent infections than either nifurtimox or benznidazole, such compounds should be evaluated for efficacy in human Chagas' disease.
D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009132:Muscles; D009547:Nifurtimox / Q000627:therapeutic use; D009593:Nitroimidazoles / Q000627:therapeutic use*; D051381:Rats; D014349:Trypanosoma cruzi / Q000187:drug effects*
D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D009593:Nitroimidazoles; C022191:MK 436; D009547:Nifurtimox