title: Evaluation of water-soluble pneumocandin analogs L-733560, L-705589, and L-731373 with mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.
abstract: The activities of the water-soluble pneumocandin derivatives L-733560, L-705589, and L-731373 were evaluated in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis and were compared with those of commercially available antifungal agents. Pneumocandins are inhibitors of 1,3-beta-D-glucan synthesis. In the aspergillosis model, L-733560 and L-705589 significantly prolonged the survival of DBA/2N mice challenged intravenously with Aspergillus fumigatus conidia. L-733560 and L-705589 exhibited efficacies comparable to that of amphotericin B (AMB) with 90% effective doses of 0.48, 0.12, and 0.36 mg/kg of body weight, respectively. Two mouse models of disseminated candidiasis were used to evaluate these compounds. In both models, mice were challenged intravenously with Candida albicans. In a C. albicans survival model with DBA/2N and CD-1 mice, the efficacy of L-733560 was comparable to that of AMB, while L-731373 and L-705589 were somewhat less active. In a previously described C. albicans target organ kidney assay, the pneumocandin analogs and AMB at doses of > or = 0.09 mg/kg were effective in sterilizing kidneys, while fluconazole and ketoconazole were considerably less active and did not sterilize kidneys when they were used at concentrations of < or = 100 mg/kg. Although orally administered L-733560 showed activity in both candidiasis models, its efficacy was reduced compared with that of parenterally administered drug. In a disseminated cryptococcosis mouse model that measures the number of CFU of Cryptococcus neoformans per gram of brain and spleen, L-733560 at 10 mg/kg was ineffective in reducing the counts in organs, while AMB at 0.31 mg/kg sterilized the organs. These results indicate that the pneumocandins may be beneficial as potent parenterally administered therapeutic agents for disseminated aspergillosis and candidiasis.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
authors.forename: G K
authors.initials: GK
authors.lastname: Abruzzo
authors.forename: A M
authors.initials: AM
authors.lastname: Flattery
authors.forename: C J
authors.initials: CJ
authors.lastname: Gill
authors.forename: L
authors.initials: L
authors.lastname: Kong
authors.forename: J G
authors.initials: JG
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Krupa
authors.forename: V B
authors.initials: VB
authors.lastname: Pikounis
authors.forename: H
authors.initials: H
authors.lastname: Kropp
authors.forename: K
authors.initials: K
authors.lastname: Bartizal
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D051379:Mice; D008811:Mice, Inbred DBA; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; C094855:L 705589; C094857:L 731373; C089367:L 733560; D010455:Peptides; D010456:Peptides, Cyclic