title: Comparison of SCH 39304, fluconazole, and ketoconazole for treatment of systemic infections in mice.
abstract: SCH 39304 was compared with fluconazole and ketoconazole in a systemic Candida albicans infection in mice (10(6) CFU per mouse). Results were based on survival rates and CFU in kidneys following once-daily oral treatment of 2, 5, or 10 days duration. In normal mice, SCH 39304 (dose to reduce kidney counts by 4 log units, 0.5 mg/kg of body weight) was 3 and 200 times more active than fluconazole and ketoconazole, respectively. In immunocompromised mice (gamma irradiation, 600 rads), SCH 39304 (dose to reduce kidney counts by 4 log units, 1.3 mg/kg) was 35 and greater than 100 times more active than fluconazole and ketoconazole, respectively. In normal mice, when the infecting inoculum varied from 10(5) to 10(7) CFU, only a fivefold increase in the dose to reduce kidney counts by 4 log units was observed with SCH 39304. Excellent protection was also seen when mice were treated with a single oral dose of SCH 39304 up to 24 h prior to infection with C. albicans. Studies in a systemic C. albicans infection model indicated that SCH 39304 is equally efficacious following either oral or intravenous administration. In a systemic Aspergillus flavus infection, mice treated with SCH 39304 (5 mg/kg) survived twice as long (16 days) as those treated with fluconazole (50 mg/kg) or controls did.
authors.affiliation: Schering-Plough Research, Bloomfield, New Jersey 07003.
authors.forename: A
authors.initials: A
authors.lastname: Cacciapuoti
authors.forename: D
authors.initials: D
authors.lastname: Loebenberg
authors.forename: R
authors.initials: R
authors.lastname: Parmegiani
authors.forename: B
authors.initials: B
authors.lastname: Antonacci
authors.forename: C
authors.initials: C
authors.lastname: Norris
authors.forename: E L
authors.initials: EL
authors.lastname: Moss
authors.forename: F
authors.initials: F
authors.lastname: Menzel
authors.forename: T
authors.initials: T
authors.lastname: Yarosh-Tomaine
authors.forename: R S
authors.initials: RS
authors.lastname: Hare
authors.forename: G H
authors.initials: GH
authors.lastname: Miller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D002177:Candidiasis / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D015725:Fluconazole / Q000008:administration & dosage / Q000627:therapeutic use*; D007275:Injections, Intravenous; D007654:Ketoconazole / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000382:microbiology / Q000528:radiation effects; D008297:Male; D051379:Mice; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C056513:Sch 39304; D015725:Fluconazole; D007654:Ketoconazole