Clomipramine and Benznidazole act synergistically and ameliorate the outcome of experimental Chagas disease: In vivo and in vitro assessments

GARCÍA, MC; PONCE, NE; SANMARCO, LM; MANZO, R; JIMENEZ KAIRUZ, A; AOKI, MP

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2016 vol. 60

0066-4804

Chagas disease is animportant public health problem in Latin America, and its treatment by chemotherapywith benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to designnew alternative strategies to improve the current etiological treatments, inthe present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effect of clomipramine(CMP, a parasite-trypanothione reductase-specific inhibitor) combined with BZ.In vitro studies, carried out by checkerboard technique on trypomastigotes(Tulahuen strain), revealed a combination index (CI) of 0.375, indicative of a synergisticeffect of the drug combination. This result was correlated with the dataobtained in infected BALB/c mice. We observed that, during the acute phase (15days post-infection -dpi-), BZ at 25 mg/kg/d alone decreased the levels ofparasitemia compared with the control group, but when BZ was administered withCMP, the drug combination completely suppressed the parasitemia due to theobserved synergistic effect. Furthermore, in the chronic phase (90 dpi), micetreated with both drugs showed less heart damage assessed by thehistopathological analysis, index of myocardial inflammation, and levels ofheart injury biochemical markers, than mice treated with BZ alone at the referencedose (100 mg/kg/d). Collectively, these data support the notion that CMPcombined with low doses of BZ diminishes cardiac damage and inflammation duringthe chronic phase of cardiomyopathy.The synergisticactivity of BZ-CMP clearly suggests a potential drug combination for Chagasdisease treatment, which would allow a reduction of the effective dose of BZand an increase in the therapeutic safety.