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

BELLERA CL; CARRILLO C; GELPI R; QUARROZ BRAGHINI JUAN; CRISTIAN MIRANDA; BRUNO BUCHHOLZ; CATALINA ALBA SOTO; SBARAGLINI ML; YÉSICA ARECO; JAZMÍN KELLY; ALAN TALEVI

EUROPEAN JOURNAL OF MEDICAL CHEMISTRY

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Lugar: Paris; Año: 2019 vol. 184 p. 1 - 7

0223-5234

Current treatment for Chagas disease is limited to Benznidazole and Nifurtimox which present side effects and limited efficacy at the chronic stage of disease. This underscores the need for novel therapeutic approaches particularly for individuals with long-lasting T. cruzi infection. In previous studies, Benidipine and Clofazimine were  repurposed as potential new drugs against Chagas disease using in silico methodologies. In vitro assays and in vivo acute and chronic murine models of Chagas disease demonstrated their activity against T. cruzi.Here, we tested the performance of these repurposed compounds in combination with Benznidazole. In vitro assays against the intracellular amastigotes - the clinical relevant form- exhibited an overall synergistic effect for both combinations in a wide range of drug doseswith different models of drug interaction. Then, we studied the combined therapy of these compounds with Benznidazol in low dose regime in a  murine model of chronic infection. Mice at 90 dpi infection with a myotropic 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 quantitative PCR, combined therapy reduced parasitic load in peripheral blood, but this effect was non-significative in heart and skeletal muscles. However,histopathological studies showed a beneficial effect of combined therapy over Benznidazole monotherapy (75 mg/kg/day) on skeletal muscle damage as reflected by fewer tissue infiltrates and adipose replacement. In perspective, these combined therapies could be an alternative strategy to reduce the dose and/or duration of conventional treatments and to enhance the beneficial effect of monotherapy.