A combination of benznidazole and ketoconazole enhances efficacy of chemotherapy of experimental Chagas' disease

Despite the large number of patients infected with Trypanosoma cruzi, there are no commercial drugs available with high efficacy for use in the clinical treatment of Chagas' disease (American trypanosomiasis). As the prospects of the introduction of new compounds by the pharmaceutical industry are poor, alternative strategies are being designed to identify candidates among drugs already available on the market that could be used in combination to provide a synergic effect and improve the efficacy of chemotherapy. In this paper we investigated a possible synergic effect of drugs in mice inoculated with isolates of T. cruzi susceptible (CL), moderately resistant (Y) and naturally resistant (Colombiana) to benznidazole and nifurtimox. Our data demonstrated that the combination of benznidazole with ketoconazole induced a synergic effect in mice infected with the CL and Y isolate of T. cruzi. No differences were observed, however, in animals infected with the Colombiana isolate, suggesting that the synergic effect of benznidazole and ketoconazole is influenced by the isolate of parasite and that this could be important in further studies searching for useful combinations of drugs. Moreover, we observed that early treatment with ketoconazole could increase the cure rate in animals infected with the Y isolate. No positive effect, in relation to cure rate, was observed with the combination of benznidazole and ofloxacin. Our results re-emphasize the importance of identifying those compounds already on the market with synergic effects able to enhance the cure of T. cruzi infection.