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EXPERIMENTAL COMBINATION THERAPY WITH AMIODARONE AND LOW- DOSE BENZNIDAZOLE IN A MOUSE MODEL OF TRYPANOSOMA CRUZI ACUTE INFECTION
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Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Investigação Cardiovascular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Investigação Cardiovascular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Investigação Cardiovascular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Investigação Cardiovascular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Abstract
Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately 6
to 7 million people in Latin America, with cardiomyopathy being the clinical manifestation
most commonly associated with patient death during the acute phase. The etiological
treatment of CD is restricted to benznidazole (Bz) and nifurtimox (Nif), which involve long
periods of administration, frequent side effects, and low efficacy in the chronic phase.
Thus, combined therapies emerge as an important tool in the treatment of CD, allowing
the reduction of Bz dose and treatment duration. In this sense, amiodarone (AMD), the
most efficient antiarrhythmic drug currently available and prescribed to CD patients, is a
potential candidate for combined treatment due to its known trypanocidal activity.
However, the efficacy of AMD during the acute phase of CD and its interaction with Bz
or Nif are still unknown. In the present study, using a well-established murine model of
the acute phase of CD, we observed that the Bz/AMD combination was more effective in
reducing the peak parasitemia than both monotherapy treatments. Additionally, the Bz/
AMD combination reduced (i) interleukin-6 (IL-6) levels in cardiac tissue, (ii) P-wave duration,
and (iii) frequency of arrhythmia in infected animals and (iv) restored gap junction integrity
in cardiac tissue. Therefore, our study validates AMD as a promising candidate for
combined therapy with Bz, reinforcing the strategy of combined therapy for CD.
IMPORTANCE Chagas disease affects approximately 6 to 7 million people worldwide,
with cardiomyopathy being the clinical manifestation that most commonly leads to patient
death. The etiological treatment of Chagas disease is limited to drugs (benznidazole and
nifurtimox) with relatively high toxicity and therapeutic failures. In this sense, amiodarone,
the most effective currently available antiarrhythmic drug prescribed to patients with
Chagas disease, is a potential candidate for combined treatment due to its known trypanocidal
effect. In the present study, we show that combined treatment with benznidazole
and amiodarone improves the trypanocidal effect and reduces cardiac damage in
acutely T. cruzi-infected mice.
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