title: Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.
abstract: The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.
authors.affiliation: Antibiotic Discovery and Development, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. george_abruzzo@merck.com
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: V B
authors.initials: VB
authors.lastname: Pikounis
authors.forename: J M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: A F
authors.initials: AF
authors.lastname: Bouffard
authors.forename: J F
authors.initials: JF
authors.lastname: Dropinski
authors.forename: H
authors.initials: H
authors.lastname: Rosen
authors.forename: H
authors.initials: H
authors.lastname: Kropp
authors.forename: K
authors.initials: K
authors.lastname: Bartizal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D002177:Candidiasis / Q000188:drug therapy*; D000077336:Caspofungin; D003453:Cryptococcosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D054714:Echinocandins; D005260:Female; D007274:Injections, Intraperitoneal; D007674:Kidney Diseases / Q000188:drug therapy; D055666:Lipopeptides; D051379:Mice; D008811:Mice, Inbred DBA; D010455:Peptides; D010456:Peptides, Cyclic
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D000077336:Caspofungin