Ketoconazole inhibition of intracellular multiplication of Trypanosoma cruzi and protection of mice against lethal infection with the organism

Abstract

The effects of ketoconazole against infection with Trypanosoma cruzi both in vivo and in vitro were examined. In vivo, ketoconazole significantly protected mice infected with lethal inocula of the Y strain of T. cruzi even when treatment was initiated seven days after infection; protection was also demonstrated for three other strains. Although mice had demonstrable parasitemia after completion of therapy, tissue sections of treated mice revealed a complete absence of organisms. Concentrations of ketoconazole as low as 0.001 microgram/ml inhibited in vitro replication of intracellular organisms, whereas concentrations of ketoconazole that prevented replication of intracellular amastigotes had no effect on extracellular organisms. This finding and the observation that inhibition of replication of amastigotes occurred in macrophages exposed to ketoconazole before infection suggests that the inhibitory effect depends on interaction of the drug with host cells. Thus ketoconazole should be tested as a therapeutic agent for Chagas' disease in humans.