Experimental Combination Therapy with Amiodarone and Low-Dose Benznidazole in a Mouse Model of Trypanosoma cruzi Acute Infection

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)...

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Published in:	Microbiology spectrum Vol. 10; no. 1; p. e0185221
Main Authors:	Barbosa, Juliana Magalhães Chaves, Pedra Rezende, Yasmin, de Melo, Tatiana Galvão, de Oliveira, Gabriel, Cascabulho, Cynthia Machado, Pereira, Evelyn Nunes Goulart da Silva, Daliry, Anissa, Salem, Kelly Salomão
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 23-02-2022
Subjects:	amiodarone Amiodarone - adverse effects Amiodarone - pharmacology Amiodarone - therapeutic use Animals Antimicrobial Chemotherapy benznidazole cardiac function Chagas disease Chagas Disease - drug therapy Disease Models, Animal Drug Therapy, Combination - methods Heart - drug effects Heart Diseases - chemically induced Heart Diseases - pathology Heart Function Tests Humans Male Mice Nitroimidazoles - adverse effects Nitroimidazoles - pharmacology Nitroimidazoles - therapeutic use Parasitemia - drug therapy Research Article Trypanosoma cruzi Trypanosoma cruzi - drug effects Chagas disease cardiac function amiodarone benznidazole Trypanosoma cruzi
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Summary:	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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors declare no conflict of interest.
ISSN:	2165-0497 2165-0497
DOI:	10.1128/spectrum.01852-21