title: In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease.
abstract: Ravuconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in humans. In this work, we investigated the in vitro and in vivo activities of this compound against Trypanosoma cruzi. Ravuconazole showed very potent in vitro anti-T. cruzi activity with minimal inhibitory concentrations (MIC) of 300 and 1 nM against the extracellular epimastigote and intracellular amastigote forms, respectively. As with other azole derivatives, ravuconazole at the MIC led to an essentially complete depletion of the epimastigotes' endogenous C4,14-desmethyl sterols and their replacement by di- and tri-methylated sterols. In murine acute models of acute Chagas disease, it was found that ravuconazole treatment led to high levels of parasitological cures, but only when given twice a day (b.i.d.), consistent with its short terminal half-life in mice (4 h). Furthermore, it was found that this curative activity was restricted towards nitrofuran/nitroimidazole-susceptible (CL) and partially drug-resistant (Y) strains of T. cruzi, with no curative activity in animals infected with the fully drug-resistant Colombiana strain. No curative activity occurred in a chronic model of the disease. No toxic side effects were observed resulting from treatment with the triazole. Ravuconazole is a very potent and specific anti-T. cruzi agent in vitro but its in vivo activity in mice is limited, probably due to its unfavourable pharmacokinetic properties in this animal model. However, these results do not necessarily rule out the potential utility of ravuconazole in the treatment of human T. cruzi infections.
authors.affiliation: Laboratorio de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Apartado 21827, Caracas 1020A, Venezuela. jurbina@ivic.ve
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Gilberto
authors.initials: G
authors.lastname: Payares
authors.forename: Cristina
authors.initials: C
authors.lastname: Sanoja
authors.forename: Renee
authors.initials: R
authors.lastname: Lira
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Romanha
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D051379:Mice; D013844:Thiazoles / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D013844:Thiazoles; D014230:Triazoles; D014344:Trypanocidal Agents; C104066:ER 30346