title: Combination Chemotherapy with Suboptimal Doses of Benznidazole and Pentoxifylline Sustains Partial Reversion of Experimental Chagas' Heart Disease.
abstract: Chronic chagasic cardiomyopathy (CCC) progresses with parasite persistence, fibrosis, and electrical alterations associated with an unbalanced immune response such as high plasma levels of tumor necrosis factor (TNF) and nitric oxide (NO). Presently, the available treatments only mitigate the symptoms of CCC. To improve CCC prognosis, we interfered with the parasite load and unbalanced immune response using the trypanocidal drug benznidazole (Bz) and the immunoregulator pentoxifylline (PTX). C57BL/6 mice chronically infected with the Colombian strain of Trypanosoma cruzi and with signs of CCC were treated for 30 days with a suboptimal dose of Bz (25 mg/kg of body weight), PTX (20 mg/kg), or their combination (Bz plus PTX) and analyzed for electrocardiographic, histopathological, and immunological changes. Bz (76%) and Bz-plus-PTX (79%) therapies decreased parasite loads. Although the three therapies reduced myocarditis and fibrosis and ameliorated electrical alterations, only Bz plus PTX restored normal heart rate-corrected QT (QTc) intervals. Bz-plus-PTX-treated mice presented complementary effects of Bz and PTX, which reduced TNF expression (37%) in heart tissue and restored normal TNF receptor 1 expression on CD8(+) T cells, respectively. Bz (85%) and PTX (70%) therapies reduced the expression of inducible nitric oxide synthase (iNOS/NOS2) in heart tissue, but only Bz (58%) reduced NO levels in serum. These effects were more pronounced after Bz-plus-PTX therapy. Moreover, 30 to 50 days after treatment cessation, reductions of the prolonged QTc and QRS intervals were sustained in Bz-plus-PTX-treated mice. Our findings support the importance of interfering with the etiological agent and immunological abnormalities to improve CCC prognosis, opening an opportunity for a better quality of life for Chagas' disease (CD) patients.
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Glaucia
authors.initials: G
authors.lastname: Vilar-Pereira
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Isabela
authors.initials: I
authors.lastname: Resende Pereira
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Leonardo Alexandre
authors.initials: LA
authors.lastname: de Souza Ruivo
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Otacilio
authors.initials: O
authors.lastname: Cruz Moreira
authors.affiliation: Departamento de Patologia, Faculdade de Medicina, Universidade Federal Fluminense, Niterói, RJ, Brazil.
authors.forename: Andrea Alice
authors.initials: AA
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Constança
authors.initials: C
authors.lastname: Britto
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, RJ, Brazil lannes@ioc.fiocruz.br.
authors.forename: Joseli
authors.initials: J
authors.lastname: Lannes-Vieira
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D005260:Female; D005434:Flow Cytometry; D006331:Heart Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009593:Nitroimidazoles / Q000627:therapeutic use*; D010431:Pentoxifylline / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D010431:Pentoxifylline; C009999:benzonidazole