Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts

Abstract

Albaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas' disease.

FIG. 1.

Chemical structure of albaconazole (UR-9825).

FIG. 2.

T. cruzi-specific immunoglobulin G antibodies in the sera of dogs in the infected control group and dogs treated with 1.5 mg of albaconazole (UR-9825) per kg of body weight for 60 (A) or 90 (B) days or with 7 mg of benznidazole per kg divided into two daily doses for 60 days. IC, infected nontreated controls; BzT−, dogs treated with benznidazole with negative hemoculture and PCR test results; ALB+, dogs treated with albaconazole with positive hemoculture and PCR test results; ALB−, dogs treated with albaconazole with negative hemoculture and PCR test results. Data represent means ± standard deviations.

FIG. 3.

In vitro stimulation of PBMCs with trypomastigote antigen before, during, and 6 months after treatment from dogs infected with the Y and the Berenice-78 T. cruzi strains for the control group and dogs treated with 1.5 mg of albaconazole per kg of body weight for 60 (A) and 90 (B) days or 7 mg of benznidazole per kg divided into two daily doses for 60 days. IC, infected nontreated controls; UC, uninfected controls; BzT−, dogs treated with benznidazole with negative hemoculture and PCR test results; ALB+, dogs treated with albaconazole with positive hemoculture and PCR test results; ALB−, treated with albaconazole with negative hemoculture and PCR test results. Data represent means ± standard deviations.

FIG. 4.

Comparative analysis between the immunological profiles determined by ELISA (A) and the proliferative assay (B) 6 months posttreatment with blood from dogs infected with the Y or the Berenice-78 T. cruzi strain for the infected control group and dogs treated with 1.5 mg of albaconazole (UR-9825) per kg of body weight or 7 mg of benznidazole per kg divided into two daily doses for 60 days. IC, infected nontreated controls; ALB+, dogs treated with albaconazole with positive hemoculture and PCR test results; ALB−, dogs treated with albaconazole with negative hemoculture and PCR test results; BZT−, dogs treated with benznidazole with negative hemoculture and PCR test results; UC, uninfected controls. The symbols represent individual observations for each group.