title: Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains.
abstract: We investigated the activity of TAK-187, an experimental antifungal triazole with a long terminal half-life in several experimental animals, against Trypanosoma cruzi. In vitro studies showed that the minimal inhibitory concentration (MIC) against the (extracellular) epimastigote form was 0.3-1 microM, while the corresponding concentration against clinically relevant intracellular amastigotes was 1 nM. At the MIC the endogenous epimastigote C4,14-desmethyl sterols were replaced by di- and tri-methylated sterols, supporting the notion that the primary target of TAK-187 is the parasite's sterol C14alpha demethylase. We investigated the in vivo activity of the compound in a murine model of acute Chagas disease, using T. cruzi strains with different susceptibilities to the drugs currently used clinically (nitrofurans and nitroimidazoles). It was found that TAK-187 given orally at 20 mg/kg induced complete protection against death and high levels (60-100%) of parasitological cures, independently of the infecting strain and even when administered every other day (e.o.d.), consistent with its long terminal half-life in mice. Other experiments, using longer treatment periods were carried out in both acute and chronic models of the disease and showed that TAK-187 given at 10-20 mg/kg e.o.d. induced 80-100% survival with 80-100% of parasitological cures of survivors in both models. No toxic side effects were observed in any of the experimental protocols. TAK-187 is a potent anti-T. cruzi compound with trypanocidal activity in vivo and should be considered for further studies as a potential specific treatment of human Chagas disease.
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: Judith
authors.initials: J
authors.lastname: Molina
authors.forename: Renee
authors.initials: R
authors.lastname: Lira
authors.forename: Zigman
authors.initials: Z
authors.lastname: Brener
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Romanha
mesh_terms: D000208:Acute Disease; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D051379:Mice; D014230:Triazoles / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D005466:Fluorocarbons
chemical_list: D014230:Triazoles; D014344:Trypanocidal Agents; C105227:TAK 187; D005466:Fluorocarbons