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PRECLINICAL EVALUATION OF COMBINED THERAPY WITH AMIODARONE AND LOW-DOSE BENZNIDAZOLE IN A MOUSE MODEL OF CHRONIC TRYPANOSOMA CRUZI INFECTION
Benznidazole
Amiodarone
Combination therapy
Trypanosoma cruzi
Produção científica do Laboratório de Biologia das Interações.
Produção científica do Laboratório de Fisiopatologia Clínica e Experimental.
Produção científica do Laboratório de Ultraestrutura Celular.
Produção científica do Laboratório de Virologia e Parasitologia Molecular.
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Resumen en ingles
Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.
Palabras clave en ingles
Chagasic chronic cardiomyopathyBenznidazole
Amiodarone
Combination therapy
Trypanosoma cruzi
Editor
Elsevier
Referencia
BARBOSA, Juliana Magalhães Chaves et al. Preclinical evaluation of combined therapy with amiodarone and low-dose benznidazole in a mouse model of chronic Trypanosoma cruzi infection. Biomedicine and Pharmacotherapy, v. 175, p. 1-22, June 2024.DOI
10.1016/j.biopha.2024.116742ISSN
0753-3322Notas
Produção científica do Laboratório de Biologia Celular.Produção científica do Laboratório de Biologia das Interações.
Produção científica do Laboratório de Fisiopatologia Clínica e Experimental.
Produção científica do Laboratório de Ultraestrutura Celular.
Produção científica do Laboratório de Virologia e Parasitologia Molecular.
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