Molecular Modifications of Imidazole Compounds: Studies of Activity and Synergy in Vitro and of Pharmacology and Therapy of Blastomycosis in a Mouse Model
Three orally administered imidazoles (R34,000, R40,500, and R41,400) were tested in vitro for activity against Blastomyces dermatitidis and in vivo in a mouse model of pulmonary blastomycosis; results of these tests were compared with those of tests with miconazole and amphotericin B. All of these drugs were inhibitory in vitro, and fungicidal activity was demonstrated. The imidazoles had promising pharmacokinetics, with peak blood concentrations that greatly exceeded the MICs and prolonged potentially therapeutic concentrations in serum; all three drugs appeared to be well tolerated. In vivo, however, they prolonged life temporarily but were not curative. After challenge with a sublethal inoculum of B. dermatitidis, R41,400 (ketoconazole) produced clinical cure but not sterilization of the lung. The three drugs were comparable to miconazole in efficacy in the mouse model but were inferior to parenterally administered amphotericin B. In vitro, results of synergy studies with several other orally administered drugs did not suggest that combined therapy is a promising avenue for improved results. The versatility and reproducibility of the mouse model permits study of antifungal drugs in several settings. Ketoconazole appears to be the most promising of the “second generation” of imidazoles, and ketoconazole therapy of longer duration might produce results in this model comparable to those seen in other studies.