title: Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection.
abstract: The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD.
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: F H
authors.initials: FH
authors.lastname: Guedes-da-Silva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: D G J
authors.initials: DG
authors.lastname: Batista
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: C F
authors.initials: CF
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: M B
authors.initials: MB
authors.lastname: Meuser
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: M R
authors.initials: MR
authors.lastname: Simões-Silva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: J S
authors.initials: JS
authors.lastname: de Araújo
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: C G
authors.initials: CG
authors.lastname: Ferreira
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: O C
authors.initials: OC
authors.lastname: Moreira
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Britto
authors.affiliation: Department of Biochemistry, Institute for Global Health, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: G I
authors.initials: GI
authors.lastname: Lepesheva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil soeiro@ioc.fiocruz.br.
authors.forename: Maria de Nazaré C
authors.initials: Mde N
authors.lastname: Soeiro
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology*; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D018512:Parasitemia / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D012737:Sex Factors; D016896:Treatment Outcome; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D058888:14-alpha Demethylase Inhibitors; C509352:CYP51 protein, Trypanosoma cruzi; D007093:Imidazoles; D007166:Immunosuppressive Agents; D009593:Nitroimidazoles; D010069:Oxadiazoles; D014344:Trypanocidal Agents; C578921:VNI compound; D003577:Cytochrome P-450 Enzyme System; C009999:benzonidazole