Experimental Pre-Clinical Index of Anti-Fungal Activity.
Summary rept. 1 Feb 82-31 Jan 83,
CALIFORNIA UNIV OAKLAND NAVAL BIOSCIENCES LAB
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A three-phase animal model system has been used in efficacy comparisons of orally-administered imidazole and triazole drugs for deep mycotic disease. The test organism was 30-80 arthrospores of coccidioides immitis introduced intranasally into mice LD20-LD95. In Phase-I studies, treatment was initiated on the 4th day after infection with an LD90 dose of arthrospores, after the onset of pulmonary disease but prior to the development of extensive extrathoracic disease. In Phase-II studies, treatment was withheld until the onset of moribundity or pre-moribundity, at which time massive disseminated fungal involvement of the organs of the peritoneal cavity was demonstrated. In Phase-III, treatment for 120 days was given to survivors of an acute LD30 dose of arthrospores. Indices of efficacy were based upon survival rates, pathologic sequelae and the frequency and extent of continuing infection during and after treatment. Ketoconazole among eight azole derivatives, was markedly therapeutic mortality was prevented completely in Phase-II evaluations, and the infection was well-controlled in a chronic disease syndrome, which occurs in Phase-III studies, and which ordinarily leads to death.