ici-195739 and Disease-Models--Animal

We have incorporated several inhibitors of sterol biosynthesis into long-circulating polyethyleneglycol-polylactide (PEG-PLA) nanospheres in order to improve the bioavailability of these poorly soluble compounds. Mice infected with CL and Y strains of Trypanosoma cruzi and treated for 30 consecutive days with DO870-loaded nanospheres at doses of 3 mg/kg/day, by the intravenous route, showed a significant cure rate (60-90%) for both strains. The activity was dose dependent and significant activity was observed for doses > or = 0.75 mg/kg/day. No cure was observed in mice treated with unloaded nanoparticles. Ketoconazole and itraconazole failed to induce cure against the Y strain even in the entrapped form.

Topics: Animals; Chagas Disease; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Female; Mice; Microspheres; Polyesters; Polyethylene Glycols; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

We report the effects of ketoconazole and the bistriazole ICI 195,739 acting alone or in combination with the allylamine terbinafine (Lamisil) on murine models of Chagas' disease. Mice infected with 10(5) Trypanosoma (Schizotrypanum) cruzi blood trypomastigotes and treated orally with 30 mg of ketoconazole per kg of body weight per day for 7 days, starting at 24 h postinoculation, had 100% survival after 35 days, while controls (untreated) or animals that received 15 mg of ketoconazole or 100 mg of terbinafine per kg/day by the same route had 0% survival after the same period of time. However, all mice receiving the combination of 15 mg of ketoconazole plus 100 mg of terbinafine per kg/day survived for 35 days after infection; it was shown that the survival of the animals treated with this combination was statistically greater than that obtained with either drug acting alone and was indistinguishable from that observed with the high doses of ketoconazole, indicating a synergistic action of the drugs in vivo. However, most animals that survived after the 7-day treatments were not cured, as indicated by a delayed but persistent parasitemia. When the treatment was extended to 14 days, 100% survival was obtained 10 weeks after inoculation for mice treated with 30 mg of ketoconazole per kg/day and the combination of 15 mg of ketoconazole per kg/day plus 100 mg of terbinafine per kg/day, while two-thirds of the mice treated with 15 mg of ketoconazole per kg/day alone were alive after the 14-day treatment; controls or animals that received 100 mg of terbinafine per kg/day did not survive after 25 days. Parasitemia in all surviving mice was negative after 55 days but parasitological cure, as assessed by subinoculation of organs in naive animals, was predominant only in animals that received the combined drug treatment. We also investigated the bistriazole ICI 195,739 and found, as reported previously, that just 1 mg of the compound per kg/day administered orally for 5 days was enough to protect most mice from death 30 days after inoculation, but no parasitological cures were observed. However, in the protocol used in the present study, the protective activity of ICI 195,739 at suboptimal doses (0.5 mg/kg/day) could be enhanced when it was used in combination with terbinafine at doses of the allylamine that by themselves induced no significant protection. Survival of the mice was inversely correlated with the levels of parasitemia in all cases. Extension of the tr

Topics: Animals; Antifungal Agents; Chagas Disease; Disease Models, Animal; Ergosterol; Female; Ketoconazole; Mice; Naphthalenes; Terbinafine; Triazoles; Trypanocidal Agents

ICI 195,739 shows superior potency to other azoles in eliminating vaginal candidosis or dermatophyte infections in animal models of infection by both oral dosing and topical application; effective doses are in the range of 0.5-5.0 mg/kg/day or 0.01-0.30% in a topical formulation. ICI 195,739 is likewise effective in models of systemic fungal infection; 1, 10, 25 mg/kg/day will protect animals given a lethal inoculum of C. albicans, C. neoformans, or A. fumigatus, respectively, as long as dosing is continued, showing activity in this respect superior to that of other azoles tested. ICI 195,739 will suppress infections in mice with T. cruzi and prevent mortality with five daily doses of 1 mg/kg; cure rather than suppression of patent infections has been achieved with 35 daily doses of 10 mg/kg.

Topics: Animals; Antifungal Agents; Antiprotozoal Agents; Candidiasis, Vulvovaginal; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Malaria; Mice; Rats; Structure-Activity Relationship; Tinea; Triazoles; Trypanosomiasis