sm-8668 and Agranulocytosis

To investigate the potential use of SCH-39304 for the prevention and treatment of disseminated candidiasis in granulocytopenic patients, we studied its in vivo antifungal activity as preventive, early, and late treatments in three models (acute, subacute, and chronic) of disseminated candidiasis in persistently granulocytopenic rabbits. SCH-39304 was an effective as amphotericin B alone and fluconazole alone for the prevention of disseminated candidiasis. SCH-39304 alone and fluconazole alone were as effective as amphotericin B plus flucytosine for early treatment of subacute disseminated candidiasis. When treatment was delayed for 5 days to establish chronic disseminated candidiasis, SCH-39304 was less effective than amphotericin B plus flucytosine. In comparison with different treatment regimens, SCH-39304 was more effective in early and preventive treatment. Thus, SCH-39304 was comparable to treatment control regimens in prevention and early treatment of subacute disseminated candidiasis. SCH-39304 also was most effective in granulocytopenic rabbits with disseminated candidiasis when used for prevention or early treatment.

Topics: Agranulocytosis; Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Female; Fluconazole; Immunosuppression Therapy; Rabbits; Triazoles

We studied the plasma pharmacokinetics and tissue penetration of Sch 39304 (SCH), a new antifungal triazole, in granulocytopenic [G(+)] and nongranulocytopenic [G(-)] rabbits. Five female New Zealand White G(-) rabbits were given a single oral dose of 2 mg of SCH per kg of body weight. Levels in plasma, determined by gas-liquid chromatography-electron capture, were obtained for 6 days. This procedure was repeated 2 weeks later with the same rabbits, which were induced and maintained G(+) with cytosine arabinoside. There were no significant differences between the pharmacokinetic parameters of G(+) and G(-) rabbits. Among all animals studied, the maximum concentration of the drug in plasma was 1.4 +/- 0.11 micrograms/ml at 4 +/- 0.5 h, the half-life was 25 +/- 1.4 h, the volume of distribution at steady state was 3.8 +/- 0.3 liters, and the area under the concentration-time curve was 44 +/- 3.4 micrograms.h/ml. SCH was detectable in plasma up to day 6. Levels of SCH in tissue were studied at steady state in six G(+) and six G(-) rabbits receiving 2 mg of the drug orally per kg per day for experimental disseminated candidiasis. Tissue SCH levels equalled or exceeded those in plasma (at steady state) at all sites examined, and these ratios were similar in both G(+) and G(-) rabbits. Thus, plasma pharmacokinetics of orally administered SCH were similar for G(+) and G(-) rabbits, and SCH achieved high levels of penetration into multiple tissues, including the liver and the central nervous system.

Topics: Agranulocytosis; Animals; Antifungal Agents; Chromatography, Gas; Half-Life; Male; Rabbits; Tissue Distribution; Triazoles