MOLINA J, LIRA R, ROMANHA A, BRENER Z, URBINA JA; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 513.

Cent. Pesquisas Rene Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil

BACKGROUND: Specific chemotherapy of American Trypanosomiasis remains unsatisfactory as currently available drugs (nitroimidazoles) have limited efficacy against its causative agent, Trypanosoma cruzi and there are frequent toxic side effects. This parasite has a specific requirement of endogenous sterols for survival and growth. TAK-187 is an investigational triazole that inhibits sterol C14alpha demethylase in fungi and yeasts.METHODS: Susceptible (CL), partially drug-resistant (Y) and highly drug-resistant (Colombiana) strains of T. cruzi were used in the study. The epimastigote form of the parasite was grown in LIT medium at 28 degrees C. Lipids were extracted from parasites, purified and analyzed by gas-liquid chromatography coupled to mass spectrometry. For in vivo studies animals were infected with 10[4] bloodstream trypomastigotes, oral treatment started 4 days p.i. and given daily or every other day (e.o.d) for 20 days. Animals were followed by 60 days. Parasitological cures were verified using hemoculture and xenodiagnosis.RESULTS: The m.i.c. for TAK-187 against the epimastigote form was 0.1 micro-M. At the m.i.c. the endogenous parasite C4,14-desmethyl sterols were replaced by di- and tri-methylated sterols. In acutely infected mice TAK-187 at 5-20 mg/Kg.d induced 100% survival and complete suppression of parasitemia during the observation period. Evaluation of parasitological cures indicated that TAK-187 at 20 mg/Kg given daily (20 doses) or e.o.d. (10 doses) induce 60-100% parasitological cures, irrespective of the benznidazole resistance of the infecting strain.CONCLUSIONS: TAK-187 has a potent in vitro anti-T. cruzi activity and can eradicate both susceptible and benznidazole-resistant strains from acutely infected murine hosts. Supported by WHO/TDR/DDR 990201.KEYWORDS: Chagas disease; TAK-187; Trypanosoma cruzi

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Chagas Disease
• Cholestanol
• In Vitro
• Mice
• Nitroimidazoles
• Parasitemia
• Parasites
• Pharmaceutical Preparations
• Sterols
• TAK 187
• Triazoles
• Trypanosoma cruzi
• benzonidazole
• parasitology

Other ID:

• GWAIDS0010486

UI: 102247984

From Meeting Abstracts