Author | Silva, Francisca Hildemagna Guedes da | |
Author | Batista, Denise da Gama Jaén | |
Author | Silva, Cristiane França da | |
Author | Pavão, Beatriz Philot | |
Author | Batista, Marcos Meuser | |
Author | Moreira, Otacílio Cruz | |
Author | Souza, Letícia Rocha Quintino | |
Author | Britto, Constança | |
Author | Rachakonda, Girish | |
Author | Villalta, Fernando | |
Author | Lepesheva, Galina I. | |
Author | Soeiro, Maria de Nazaré C. | |
Access date | 2019-09-17T14:54:53Z | |
Available date | 2019-09-17T14:54:53Z | |
Document date | 2019 | |
Citation | SILVA, Francisca Hildemagna Guedes da et al. Successful Aspects of the Coadministration of Sterol 14α- Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi. ACS Infectious Diseases, v. 5, p. 365-371, 2019. | pt_BR |
ISSN | 2373-8227 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/35638 | |
Language | eng | pt_BR |
Publisher | American Chemical Society | pt_BR |
Rights | restricted access | pt_BR |
Subject in Portuguese | Trypanosoma cruzi | pt_BR |
Subject in Portuguese | Doença de Chagas | pt_BR |
Subject in Portuguese | Benznidazole | pt_BR |
Subject in Portuguese | Linhagem Colombiana | pt_BR |
Subject in Portuguese | Co-Administração | pt_BR |
Title | Successful Aspects of the Coadministration of Sterol 14α-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi | pt_BR |
Type | Article | pt_BR |
DOI | 10.1021/acsinfecdis.8b00253 | |
Abstract | Up to now, no vaccines are available for Chagas disease, and the current therapy is largely unsatisfactory. Novel imidazole-based scaffolds of protozoan sterol 14α-demethylase (CYP51) inhibitors have demonstrated potent antiparasitic activity with no acute toxicity. Presently our aim was to investigate the effectiveness of the experimental 14α-demethylase inhibitor VFV in the mouse models of Trypanosoma cruzi infection using a naturally drug-resistant Colombiana strain, under monotherapy and in association with the reference drug, benznidazole (Bz). The treatment with VFV resulted in complete parasitemia suppression and 100% animal survival when administered orally (given in 10% DMSO plus 5% Arabic gum) at 25 mg/kg (bid) for 60 days. However, as parasite relapse was found using VFV alone under this treatment scheme, the coadministration of VFV with Bz was assayed giving simultaneously (for 60 days, bid) by oral route, under two different drug vehicles (10% DMSO plus 5% Gum Arabic with or without 3% Tween 80). All tested mice groups resulted in >99.9% of parasitemia decrease and 100% animal survival. qPCR analysis performed on cyclophosphamide immunosuppressed mice revealed that, although presenting lack of cure, VFV given as monotherapy was 14-fold more active than Bz, and the coadministration of Bz plus VFV (given simultaneously, using 10% DMSO plus 5% Gum Arabic as vehicle) resulted in 106-fold lower blood parasitism as compared to the monotherapy of Bz. Another interesting finding was the parasitological cure in 70% of the animals treated with Bz and VFV when the coadministration was given using the VFV suspension in 10% DMSO + Arabic gum + Tween 80 (a formulation that we have found to provide a better pharmacokinetics), even after immunosuppression using cyclophosphamide cycles, supporting the promising aspect of the drug coadministration in improving the efficacy of therapeutic arsenal against T. cruzi. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Meharry Medical College. Department of Microbiology and Immunology and Physiology. Nashville, Tennessee, USA. | pt_BR |
Affilliation | Meharry Medical College. Department of Microbiology and Immunology and Physiology. Nashville, Tennessee, USA. | pt_BR |
Affilliation | Vanderbilt University. Institute for Global Health. School of Medicine. Department of Biochemistry. Nashville, Tennessee, USA. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Subject | Coadministration | pt_BR |
Subject | Benznidazole | pt_BR |
Subject | VFV | pt_BR |
Subject | VNI | pt_BR |
Subject | Colombiana strain | pt_BR |
Subject | Trypanosoma cruzi | pt_BR |
Subject | Chagas disease | pt_BR |
Embargo date | 2022-01-01 | |