CHEMOTHERAPEUTIC AND TOXIC ACTIVITY OF ANTIFUNGAL AGENT X-5079C IN EXPERIMENTAL MYCOSES

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Abstract
A new antifungal agent, X-5079C (a polypeptide isolated from Streptomyces nov. sp. X-5079C), has an unusual spread between a minimal effective antimycotic dosage and maximal tolerated dosage. Its LD50 in acute toxicity tests in 16-g mice varied from 650 mg/kg in early lots to more than 3300 mg/kg in 18-g mice in lots prepared recently. The most toxic lot tested was given in daily intraperitoneal injections of 240 mg/kg for one month without clinical evidence of toxicity. Survivors of a 625-mg/kg dosage of Lot No. 16 and mice on long-term therapy at high dosages of that lot did not show histologic evidence of permanent tissue damage. The agent is effective in preventing death in mice with otherwise overwhelming experimental histoplasmosis even when given at the dosage level of 5 mg/kg for as short a time as 7 days. This dosage does not clear tissues of Histoplasma. At the level of 2.7 mg/kg given in 20 treatments over a period of 28 days, Lot No. 41 of X-5079C protected 9 of 10 mice from death, and 10.8 mgAg sterilized tissues. This therapeutic activity was achieved in an experiment in which the median day of death of 30 control mice was day 10. The substance is effective against experimental histoplasmosis, partially effective against blastomycosis and coccidioido-mycosis, and has no effect upon the course of experimental cryptococcosis.