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

SBARAGLINI, MARIA LAURA; BELLERA, CAROLINA; ARECO, YESICA; CARRILLO, CAROLINA; BUCHHOLZ, BRUNO; KELLY, JAZMIN; GELPI, RICARDO; TALEVI, ALAN; ALBA SOTO CATALINA D.

Dundee

Congreso; Setting our Sights on Infectious Diseases; 2019

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

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 inchronic 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 murinemodel of acute and chronic Chagas.In this study we tested the combinations of clofazimine or benidipine with benznidazole in a murinemodel of chronic infection, using the myotropic strain of T. cruzi K98. We studied the effects of thetreatments in electrical activity of the heart, skeletal and cardiac muscle inflammation and parasite loadin blood. We compared combinations of a low dose benznidazole (30mg/kg/d) with clofazimine (30mg/kg/d) or benidipine (15 mg/kg/d) versus the reference drug benznidazole (75 mg/kg/d or 30mg/kg/d). Non-treated animals were used as controls. All treatments showed a reduction in parasiticload in peripheral blood vs untreated control. Moreover, the clofazimine combination achieve lowerparasitic burden than de monotherapy with benznidazole 30mg/kg/d. None of the treatments achievedsterile cure. Combination therapies showed no significant differences in heart rate, length of RR, QT andRP intervals between groups. At the histopathological level, they showed a beneficial effect overbenznidazole 75 mg/kg/day in terms of inflammation markers. All treatments seem to improveinflammation markers in cardiac muscle compare to the untreated group.Thus, with the help of computational tools, we have found new trypanocidal compounds with potentialagainst American trypanosomiasis, with a minimal investment of time and resources. Co-administrationof benidipine or clofazimine with benznidazole diminishes parasitic load in blood tissue and improvesinflammation markers in muscle. Combination treatment displayed some advantages, and it could be analternative strategy to reduce the dose and/or duration of conventional treatments, possibly enhancingthe beneficial effect of monotherapy.