title: Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease.
abstract: Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.
authors.affiliation: Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, and Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Mónica Cristina
authors.initials: MC
authors.lastname: García
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, and Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Nicolás Eric
authors.initials: NE
authors.lastname: Ponce
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, and Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Liliana Maria
authors.initials: LM
authors.lastname: Sanmarco
authors.affiliation: Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, and Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Rubén Hilario
authors.initials: RH
authors.lastname: Manzo
authors.affiliation: Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, and Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Alvaro Federico
authors.initials: AF
authors.lastname: Jimenez-Kairuz
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, and Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina paoki@fcq.unc.edu.ar.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Aoki
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002997:Clomipramine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000494:pharmacology*; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D016896:Treatment Outcome; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity
chemical_list: D004338:Drug Combinations; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D002997:Clomipramine; C009999:benzonidazole