title: Benznidazole/Itraconazole Combination Treatment Enhances Anti-Trypanosoma cruzi Activity in Experimental Chagas Disease.
abstract: The nitroheterocyclic drugs nifurtimox and benznidazole are first-line drugs available to treat Chagas disease; however, they have limitations, including long treatment courses and toxicity. Strategies to overcome these limitations include the identification of new drugs with specific target profiles, re-dosing regimens for the current drugs, drug repositioning and combination therapy. In this work, we evaluated combination therapy as an approach for optimization of the current therapeutic regimen for Chagas disease. The curative action of benznidazole/itraconazole combinations was explored in an established infection of the mice model with the T. cruzi Y strain. The activities of the benznidazole/itraconazole combinations were compared with the results from those receiving the same dosage of each individual drug. The administration of benznidazole/itraconazole in combination eliminated parasites from the blood more efficiently than each drug alone. Here, there was a significant reduction of the number of treatment days (number of doses) necessary to induce parasitemia suppression with the benznidazole/itraconazole combination, as compared to each compound administered alone. These results clearly indicate the enhanced effects of these drugs in combination, particularly at the dose of 75 mg/kg, as the effects observed with the drug combinations were four times more effective than those of each drug used alone. Moreover, benznidazole/itraconazole treatment was shown to prevent or decrease the typical lesions associated with chronic experimental Chagas disease, as illustrated by similar levels of inflammatory cells and fibrosis in the cardiac muscle tissue of healthy and treated mice. These results emphasize the importance of exploring the potential of combination treatments with currently available compounds to specifically treat Chagas disease.
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Tassiane
authors.initials: T
authors.lastname: Assíria Fontes Martins
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil; Departamento de Patologia e Parasitologia, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil.
authors.forename: Lívia
authors.initials: L
authors.lastname: de Figueiredo Diniz
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Ana Lia
authors.initials: AL
authors.lastname: Mazzeti
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Álvaro Fernando
authors.initials: ÁF
authors.lastname: da Silva do Nascimento
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil; Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Sérgio
authors.initials: S
authors.lastname: Caldas
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil; Departamento de Patologia e Parasitologia, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil.
authors.forename: Ivo Santana
authors.initials: IS
authors.lastname: Caldas
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Isabel Mayer
authors.initials: IM
authors.lastname: de Andrade
authors.affiliation: Drugs for Neglected Disease initiative (DNDi), 1202 Geneva, Switzerland.
authors.forename: Isabela
authors.initials: I
authors.lastname: Ribeiro
authors.affiliation: Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Maria Terezinha
authors.initials: MT
authors.lastname: Bahia
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D014355:Chagas Disease / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009206:Myocardium / Q000473:pathology; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D059208:Parasite Load; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D007074:Immunoglobulin G; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D017964:Itraconazole; C009999:benzonidazole