Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease.

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dc.contributor.authorBahia, Maria Terezinha
dc.contributor.authorNascimento, Álvaro Fernando da Silva do
dc.contributor.authorMazzeti, Ana Lia
dc.contributor.authorMarques, Luiz F.
dc.contributor.authorGonçalves, Karolina Ribeiro
dc.contributor.authorMota, Ludmilla Walter Reis
dc.contributor.authorDiniz, Lívia de Figueiredo
dc.contributor.authorCaldas, Ivo Santana
dc.contributor.authorSilva, André Talvani Pedrosa da
dc.contributor.authorShackleford, David M.
dc.contributor.authorKoltun, Maria
dc.contributor.authorSaunders, Jessica
dc.contributor.authorWhite, Karen L.
dc.contributor.authorScandale, Ivan
dc.contributor.authorCharman, Susan A.
dc.contributor.authorChatelain, Eric
dc.date.accessioned2017-05-02T14:40:25Z
dc.date.available2017-05-02T14:40:25Z
dc.date.issued2014
dc.description.abstractThis study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole- treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.pt_BR
dc.identifier.citationBAHIA, M. T. et al. Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. Antimicrobial Agents and Chemotherapy, v 58, p. 4362-4370, 2014. Disponível em: <http://aac.asm.org/content/58/8/4362>. Acesso em: 19 fev. 2017.pt_BR
dc.identifier.doihttps://doi.org/10.1128/AAC.02754-13
dc.identifier.issn1098-6596
dc.identifier.urihttp://www.repositorio.ufop.br/handle/123456789/7654
dc.identifier.uri2https://aac.asm.org/content/58/8/4362
dc.language.isoen_USpt_BR
dc.rightsrestritopt_BR
dc.titleAntitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease.pt_BR
dc.typeArtigo publicado em periodicopt_BR
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