title: In vitro and in vivo antifungal activities of BMY-28864, a water-soluble pradimicin derivative.
abstract: BMY-28864, a water-soluble pradimicin derivative, had potent in vitro activity against a wide variety of fungi, including those associated with deep-seated mycosis; it inhibited the growth of standard strains and clinical isolates at concentrations of 12.5 micrograms/ml or less. At the MIC or higher concentrations, BMY-28864 was fungicidal for Candida albicans under both growing and nongrowing conditions. BMY-28864 expressed fungicidal activity only in the presence of Ca2+, and its activity was totally diminished when ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), a Ca2+ chelator, was added to the test medium. The effectiveness of intravenously administered BMY-28864 in vivo was examined and compared with that of amphotericin B in mouse models of fungal infections. Both normal and cyclophosphamide-treated immunosuppressed mice infected with C. albicans, Cryptococcus neoformans, or Aspergillus fumigatus responded to therapy with BMY-28864 (50% protective doses of 17, 18, and 37 mg/kg of body weight in normal mice and of 32, 35, and 51 mg/kg in cyclophosphamide-treated mice, respectively). Lethal lung infections were also established with C. albicans or A. fumigatus in cyclophosphamide-treated mice. The 50% protective doses of BMY-28864 were 15 and 23 mg/kg per dose against C. albicans and A. fumigatus, respectively. The immunosuppression induced by intraperitoneal administration of 200 mg of cyclophosphamide per kg lasted for 5 days, and total recovery was observed by day 7.
authors.affiliation: Bristol-Myers Squibb Research Institute, Bristol-Myers Squibb Kabushiki Kaisha, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kakushima
authors.forename: S
authors.initials: S
authors.lastname: Masuyoshi
authors.forename: M
authors.initials: M
authors.lastname: Hirano
authors.forename: M
authors.initials: M
authors.lastname: Shinoda
authors.forename: A
authors.initials: A
authors.lastname: Ohta
authors.forename: H
authors.initials: H
authors.lastname: Kamei
authors.forename: T
authors.initials: T
authors.lastname: Oki
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000502:physiology; D003470:Culture Media; D004533:Egtazic Acid / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects*; D007165:Immunosuppression Therapy; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000935:Antifungal Agents; D003470:Culture Media; C067714:N,N-dimethylpradimicin FA-2; D004533:Egtazic Acid; D000666:Amphotericin B; D002118:Calcium