Effects of co-administration of benznidazole in animal model chronic Chagas disease

SBARAGLINI, ML; CARRILLO C.; GELPI, B.; ARECO, Y; KELLY J.; ALBA SOTO, CD; BELLERA, CL; BUCHHOLZ R.; TALEVI, A

Dundee

Congreso; Setting our Sights on Infectious Diseases.; 2019

Wellcome Centre for Anti-Infectives Research at the University of Dundee

Only two drugs are currently available to treat Chagas disease, namely, benznidazole and nifurtimox. Both require long treatments, display severe side effects and have controversial efficacy in adults in chronic stage. Therefore, safe and efficacious treatment alternatives are required. Through computer-aided drug repurposing, our group has identified two drugs of clinical use with trypanocidal activity: benidipine and clofazimine. Both of them showed promising results in vitro and in vivo, including murine model of acute and chronic Chagas. In this study we tested the combinations of clofazimine or benidipine with benznidazole in a murine model of chronic infection, using the myotropic strain of T. cruzi K98. We studied the effects of the treatments in electrical activity of the heart, skeletal and cardiac muscle inflammation and parasite load in blood. We compared combinations of a low dose benznidazole (30mg/kg/d) with clofazimine (30 mg/kg/d) or benidipine (15 mg/kg/d) versus the reference drug benznidazole (75 mg/kg/d or 30 mg/kg/d). Non-treated animals were used as controls. All treatments showed a reduction in parasitic load in peripheral blood vs untreated control. Moreover, the clofazimine combination achieve lower parasitic burden than de monotherapy with benznidazole 30mg/kg/d. None of the treatments achieved sterile cure. Combination therapies showed no significant differences in heart rate, length of RR, QT and RP intervals between groups. At the histopathological level, they showed a beneficial effect over benznidazole 75 mg/kg/day in terms of inflammation markers. All treatments seem to improve inflammation markers in cardiac muscle compare to the untreated group. Thus, with the help of computational tools, we have found new trypanocidal compounds with potential against American trypanosomiasis, with a minimal investment of time and resources. Co-administration of benidipine or clofazimine with benznidazole diminishes parasitic load in blood tissue and improves inflammation markers in muscle. Combination treatment displayed some advantages, and it could be an alternative strategy to reduce the dose and/or duration of conventional treatments, possibly enhancing the beneficial effect of monotherapy.