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Miltefosine and Benznidazole Combination Improve Anti-Trypanosoma cruzi In Vitro and In Vivo Efficacy

Authors :
Julián Ernesto Nicolás Gulin
Margarita María Catalina Bisio
Daniela Rocco
Jaime Altcheh
María Elisa Solana
Facundo García-Bournissen
Source :
Frontiers in Cellular and Infection Microbiology, Vol 12 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

Drug repurposing and combination therapy have been proposed as cost-effective strategies to improve Chagas disease treatment. Miltefosine (MLT), a synthetic alkylphospholipid initially developed for breast cancer and repositioned for leishmaniasis, is a promising candidate against Trypanosoma cruzi infection. This study evaluates the efficacy of MLT as a monodrug and combined with benznidazole (BZ) in both in vitro and in vivo models of infection with T. cruzi (VD strain, DTU TcVI). MLT exhibited in vitro activity on amastigotes and trypomastigotes with values of IC50 = 0.51 µM (0.48 µM; 0,55 µM) and LC50 = 31.17 µM (29.56 µM; 32.87 µM), respectively. Drug interaction was studied with the fixed-ration method. The sum of the fractional inhibitory concentrations (ΣFICs) resulted in ∑FIC= 0.45 for trypomastigotes and ∑FIC= 0.71 for amastigotes, suggesting in vitro synergistic and additive effects, respectively. No cytotoxic effects on host cells were observed. MLT efficacy was also evaluated in a murine model of acute infection alone or combined with BZ. Treatment was well tolerated with few adverse effects, and all treated animals displayed significantly lower mean peak parasitemia and mortality than infected non-treated controls (p

Details

Language :
English
ISSN :
22352988
Volume :
12
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cellular and Infection Microbiology
Publication Type :
Academic Journal
Accession number :
edsdoj.5e0cdc32c7e14717bfa3400ac03bf18c
Document Type :
article
Full Text :
https://doi.org/10.3389/fcimb.2022.855119