Treatment of paracoccidioidomycosis with itraconazole in a murine model.
A new triazole, itraconazole, was studied as oral therapy of paracoccidioidomycosis in a murine model. The Paracoccidioides brasiliensis isolate, susceptible to itraconazole in vitro, was given by intranasal challenge, producing acute pulmonary and disseminated disease. Therapy was given twice daily over 4 weeks, and animals observed over 2 months. The infection was lethal for 70-80% of controls (untreated or polyethylene glycol diluent), whereas all treated animals, given 10-200 mg kg-1 day-1, survived. Itraconazole was ineffective in eradicating lung disease in survivors, though effective in treatment of disseminated sites. Since the highest doses did not give a better response than the lower doses, pharmacokinetic studies were performed. These showed irregular curves and small increases in peak serum concentrations and total area under the serum concentration-time curves, which were not proportional to the dose. This non-linearity appears to be best explained by poor absorption. Itraconazole, from these studies, appears to have promise for the therapy of human paracoccidioidomycosis but possibly with a different formulation.
D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000627:therapeutic use*; D017964:Itraconazole; D007654:Ketoconazole / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010229:Paracoccidioidomycosis / Q000188:drug therapy*
D000935:Antifungal Agents; D017964:Itraconazole; D007654:Ketoconazole