Am. J. Trop. Med. Hyg., 32(6), 1983, pp. 1242-1250
Copyright © 1983 by The American Society of Tropical Medicine and Hygiene
Trypanosoma Cruzi: Efficacy of the 2-Substituted, 5-Nitroimidazoles, MK-436 and L634,549, in Tissue Culture and Mice
P. K. Murray,
M. C. Habbersett AND
R. D. Meurer
Department of Immunoparasitology, Merck Sharp & Dohme Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065
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 µg/ml and L634,549 a dihydroxy metabolite of MK-436 showed activity 2 µg/ml. Neither compound caused morphological damage to the host cells at levels tested (250 µg/ml). By contrast, nifurtimox, which was active at 2 µg/ml, caused significant host cell damage at 100 µg/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.
Accepted for publication May 27, 1983.
Copyright © 1983 by the American Society of Tropical Medicine and Hygiene.
