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.

Curcumin Enhances the Anti-Trypanosoma cruzi Activity of Benznidazole-Based Chemotherapy in Acute Experimental Chagas Disease

“…However, high IgG1 levels are not always beneficial to the host, since IgG1 can block the activities of different isotypes of anti-T. cruzi antibodies through cross-linking with irrelevant antigens in the defense against the parasite, thus deflecting humoral immunity toward a nonspecific and ineffective response (37,43). According to previous investigations (26,44), the attenuation of the humoral response observed in this study is consistent with the best parasitological control and reduction of the parasite load induced by the cruzi and treated with benznidazole and curcumin. The treated animals received benznidazole (100 or 50 mg/kg) and curcumin (100 mg/kg).…”

Ergosterol biosynthesis and drug development for Chagas disease

“…UR-9825 is another potent fungal and protozoan CYP51 inhibitor with remarkable in vitro anti-T. cruzi activity (Urbina et al 2000). However, its very short half-life in the mouse (< 0.5 h) precluded in vivo studies in this animal model, but work in a canine model has demonstrated that the compound exhibits curative activity against established infections of the virulent Y strain of T. cruzi with very low toxicity, although drug resistance was encountered with the Berenice-78 strain (Guedes et al 2004). Finally, ravuconazole has also been shown to be very active against T. cruzi in vitro, but its in vivo activity in mice was limited, most likely due to inadequate pharmacokinetic properties in this animal model (terminal half-life of 4.5 h) (Urbina et al 2003b).…”

“…1), such as TAK-187 (Takeda Chemical Company) (Urbina et al 2003c, Corrales et al 2005, UR-9825 (Uriach & Company) (Urbina et al 2000, Guedes et al 2004) and ravuconazole (ER-30346, Eisai Co.; BMS 207,147; Bristol-Myers Squibb) (Urbina et al 2003b) also exhibit trypanocidal activity in vitro and in vivo. TAK-187 is a long-lasting triazole derivative with broad-spectrum antifungal activity, which also possesses very potent anti-T. cruzi activity in vitro and is capable of curing both acute and chronic infections in murine hosts even when the infecting strain is resistant to nitrofuran and nitroimidazole (Urbina et al 2003c).…”

Absence of CD4+T Lymphocytes, CD8+T Lymphocytes, or B Lymphocytes Has Different Effects on the Efficacy of Posaconazole and Benznidazole in Treatment of Experimental AcuteTrypanosoma cruziInfection

“…In addition, they possess pharmacokinetic properties particularly suited to the control of this disseminated intracellular infection. Several triazole derivatives have been experimentally tested, including D0870 (20), posaconazole (POS) (19,43), ravuconazole (44), albaconazole (15), and TAK-187 (42). In particular, POS (Schering-Plough Research Institute) was recently registered for the prophylaxis and treatment of invasive fungal infections in the European Union, Australia, and the United States.…”