[PubMed] [Google Scholar] 23

[PubMed] [Google Scholar] 23. two of five animals infected with the Y and Berenice-78 strains, respectively. All ravuconazole-treated dogs consistently had negative serological test results during and until 30 days after treatment, regardless of the therapeutic scheme used. However, after the end of treatment, an increase in specific antibody levels was observed in all treated animals, although the antibody levels were always significantly lower than those of the nontreated control dogs. Despite being unable to induce a parasitological cure, ravuconazole treatment led to significant Amotosalen hydrochloride reductions in the levels of gamma interferon expression and lesions in cardiac tissues in animals infected with the Y strain, while the level of interleukin-10 mRNA expression increased. We conclude that ravuconazole has potent suppressive but not curative activity in the canine model of acute Chagas’ disease, probably due to its unfavorable Amotosalen hydrochloride pharmacokinetic properties (half-life, 8.8 h). The longer half-life of ravuconazole in humans (4 to 8 days) makes it a promising drug for assessment for use as chemotherapy in human Chagas’ disease. Chagas’ disease, a century after its discovery, remains an important health problem, being broadly dispersed in South and Central America (9). About 15 million people are currently estimated to be infected with in Mexico and in Central American and South American countries, while 28 million remain at risk of infection (30). Due to international migration, a significant number of infected individuals now reside in countries where the disease is not endemic (9). Recently, the success of programs to control the domiciliary vector has led to a decrease in the incidence and prevalence of Chagas’ disease in some regions of the continent (20). However, despite the substantial advances in the control Amotosalen hydrochloride of the vectorial transmission of agents, as this parasite has an essential requirement for endogenous sterols for survival and proliferation and cannot use the abundant supply of cholesterol available in its mammalian hosts (23). Several steps in the sterol biosynthesis pathway in have been investigated as potential chemotherapeutic targets, both and in experimental infections (4, 23, 25, 26) The most advanced EBIs are azole compounds, comprising imidazole and triazole derivatives, which inhibit the C-14 demethylation of lanosterol. Novel triazole compounds, posaconazole (Schering Plough), ravuconazole (RAV; Eisai Co. Ltd., Tokyo, Japan), TAK 187 (Takeda Chemical Company), and albaconazole (Uriach), have MIC values against the clinically relevant intracellular amastigotes in the range of low nanomolar levels, being 30- to 100-fold lower than those of ketoconazole and itraconazole (24, 27). Studies performed in murine or dog models indicate that posaconazole, TAK-187, and albaconazole induced 50 to 100% parasitological cure rates in the acute phase and 50 to 60% in the chronic phase, even if the infecting Mouse monoclonal to SND1/P100 strains were partially or fully resistant to benznidazole (11, 19, 23). Although ravuconazole has very potent anti-activity in this animal model. In the present study, we made a head-to-head comparison of the anti-activities of ravuconazole and benznidazole in a dog model of acute Chagas’ disease described previously (11, 14), using strains susceptible and resistant to EBIs (11). The effect of drug treatment on the immune response of the infected animals was also assessed. MATERIALS AND METHODS stocks. In this study, two strains were used: the Y strain (strains. Five age-matched noninfected dogs were used as negative controls. Drugs. Ravuconazole ([strain were divided into three experimental groups: (i) five dogs were treated with ravuconazole at 12 mg/kg twice a day (b.i.d.; i.e., every 12 h [q12h]) for 90 days; (ii) five dogs were treated with benznidazole, the reference drug, at 7.0 mg/kg b.i.d. (q12h) for 60 days; and (iii) five dogs were maintained as nontreated controls. Another five animals were maintained as a noninfected and nontreated control group. The treatment schemes were previously described by Guedes et al. (11, 14). In all therapeutic schemes, oral treatment was started 12 to 22 days postinfection, immediately after the appearance of parasitemia, detected by fresh blood examination. Assessment of.