In vitro and in vivo characterization of novel 8-methoxy derivatives of chlortetracycline.

Abstract

The in vitro activities of three new 8-methoxychlortetracyclines, Sch 36969, 33256 and 34164 were compared to tetracycline, minocycline and doxycycline. Against aerobic Gramnegative rods Sch 36969 had a geometric mean MIC (GMM)of 4.2^g/ml, about 8-fold more potent than Sch 33256, and similar to all the other compounds. Sch 36969 also had good activity against methicillin-resistant (GMM, 0.21^g/ml) and -susceptible Staphylococci (GMM, 0.14 A*g/ml), Streptococci (GMM, 0.06^g/ml), and most anaerobic bacteria (GMM, <0.5 jug/ml). In general, Sch 36969 was similar to, or more potent than, all the other compounds tested.Serum levels of Sch 36969 in squirrel monkeys were 4-fold lower (AUC, 4.5 /ug>hours/ml) than those of chlortetracycline (AUC, 16.1^g-hours/ml). In mouse protection tests (PD50s) against various strains of bacteria, Sch 36969 was similar in activity to tetracycline, but up to 6-fold less active than chlortetracycline.The structure activity relationships for these new chlortetracyclines are described.

Current and Emerging Azole Antifungal Agents

“…A complete response was achieved in 34 patients (27%), 45 (36%) improved, 20 (15%) were unchanged, and 26 (21%) worsened. However, if the response rates were based on only patients who received at least 2 weeks of treatment, the corresponding percentages are 30,39,16, and 14% and are better than the 39% rate of complete or partial response achieved in 30 of 76 patients treated in an earlier study by the NIAID-MSG (53). Moreover, in the present analysis, a complete response or improvement was observed in 72% of 11 patients who received bone marrow transplants (55).…”

“…SCH 56592 has demonstrated therapeutic efficacy in a number of animal models of fungal infections, including systemic, gastrointestinal, and vaginal candidiasis; systemic and pulmonary aspergillosis; cryptococcal meningitis; histoplasmosis; disseminated coccidioidomycosis; and topical dermatophyte infection with Trichophyton mentagrophytes. SCH 56592 was effective in preventing infection in murine models of systemic candidiasis and pulmonary aspergillosis (30,31). A dose of 50 mg of SCH 56592 per kg administered 1.5 to 24 h prior to infection with C. albicans provided 100% protection, as did a dose of 100 mg/kg administered 72 h prior to infection with A. fumigatus or A. flavus.…”

“…A dose of 50 mg of SCH 56592 per kg administered 1.5 to 24 h prior to infection with C. albicans provided 100% protection, as did a dose of 100 mg/kg administered 72 h prior to infection with A. fumigatus or A. flavus. It was found that if therapy was delayed, higher doses of SCH 56592 were needed to provide the same degree of efficacy (30). For example, in mice infected with A. flavus, treatment with 20 mg of SCH 56592 per kg given once daily for 4 days starting on day 1 or 2 postinfection was as effective as treatment with 80 mg/kg starting on day 2 or 3 postinfection.…”