Parasitological Cure of Acute and Chronic Experimental Chagas Disease Using the Long-Acting Experimental Triazole TAK-187. Activity Against Drug-Resistant Trypanosoma Cruzi Strains

Int J Antimicrob Agents. 2003 Jan;21(1):39-48. doi: 10.1016/s0924-8579(02)00274-1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Chagas Disease / drug therapy*
  • Chagas Disease / parasitology
  • Chronic Disease
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Female
  • Mice
  • Triazoles / therapeutic use*
  • Trypanocidal Agents / therapeutic use*

Substances

  • Triazoles
  • Trypanocidal Agents
  • TAK 187