Combined therapy with Benznidazole and repurposed drugs Clofazimine and Benidipine for chronic Chagas disease

Abstract

Current treatment for Chagas disease is limited to Benznidazole andNifurtimox which present side effects and limited efficacy at the chronicstage of disease. This underscores the need for novel therapeuticapproaches particularly for individuals with long-lasting T. cruziinfection. In previous studies, Benidipine and Clofazimine wererepurposed as potential new drugs against Chagas disease using in silicomethodologies. In vitro assays and in vivo acute and chronic murinemodels of Chagas disease demonstrated their activity against T. cruzi.Here, we tested the performance of these repurposed compounds incombination with Benznidazole. In vitro assays against the intracellularamastigotes - the clinical relevant form- exhibited an overallsynergistic effect for both combinations in a wide range of drug doseswith different models of drug interaction. Then, we studied the combinedtherapy of these compounds with Benznidazol in low dose regime in amurine model of chronic infection. Mice at 90 dpi infection with amyotropic T. cruzi strain were treated for 30 days with Benznidazole(75mg/kg/day); Benznidazole (30mg/kg/day); Benznidazole plus Clofazimine(30mg/kg/day each); Benznidazole (30mg/kg/day) plus Benidipine(15mg/kg/day) or left untreated (vehicle). As determined by quantitativePCR, combined therapy reduced parasitic load in peripheral blood, butthis effect was non-significative in heart and skeletal muscles. However,histopathological studies showed a beneficial effect of combined therapyover Benznidazole monotherapy (75 mg/kg/day) on skeletal muscle damage asreflected by fewer tissue infiltrates and adipose replacement. Inperspective, these combined therapies could be an alternative strategy toreduce the dose and/or duration of conventional treatments and to enhancethe beneficial effect of monotherapy.