title: New semisynthetic pneumocandins with improved efficacies against Pneumocystis carinii in the rat.
abstract: A new series of semisynthetic, water-soluble pneumocandin analogs has been found to be extremely potent against Pneumocystis carinii in an immunocompromised-rat model. These compounds are 5 to 10 times more potent than the parent natural product, pneumocandin B0 (L-688,786) (R. E. Schwartz et al., J. Antibiot. 45:1853-1866, 1992), and > 100 times more potent than cilofungin. One compound in particular, L-733,560, had a 90% effective dose against P. carinii cysts of 0.01 mg/kg of body weight when delivered parenterally (subcutaneously, twice daily for 4 days). This compound was also effective when given orally for the treatment and prevention of P. carinii pneumonia. For treating acute P. carinii pneumonia, oral doses of 2.2 mg/kg twice daily for 4 days were required to eliminate 90% of the cysts. A once-daily oral prophylactic dose of 2.2 mg/kg prevented cyst development, and a dose of 6.2 mg/kg prevented any development of P. carinii organisms (cysts and trophozoites), as determined through the use of a P. carinii-specific DNA probe (P. A. Liberator et al., J. Clin. Microbiol. 30:2968-2974, 1992). These results demonstrate that the antipneumocystis activities of the pneumocandins can be significantly improved through synthetic modification. Several of these compounds are also extremely effective against candidiasis (K. Bartizal et al., Antimicrob. Agents Chemother. 39:1070-1076, 1995) and aspergillosis (G. K. Abruzzo et al., Antimicrob. Agents Chemother. 39:860-894, 1995) in murine models, making them attractive as broad-spectrum antifungal agents.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Schmatz
authors.forename: M A
authors.initials: MA
authors.lastname: Powles
authors.forename: D
authors.initials: D
authors.lastname: McFadden
authors.forename: K
authors.initials: K
authors.lastname: Nollstadt
authors.forename: F A
authors.initials: FA
authors.lastname: Bouffard
authors.forename: J F
authors.initials: JF
authors.lastname: Dropinski
authors.forename: P
authors.initials: P
authors.lastname: Liberator
authors.forename: J
authors.initials: J
authors.lastname: Andersen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D054714:Echinocandins; D005936:Glucans / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008826:Microbial Sensitivity Tests; D010455:Peptides; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D011010:Pneumocystis / Q000187:drug effects / Q000378:metabolism; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D051381:Rats
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D005936:Glucans; C094855:L 705589; C094857:L 731373; C089367:L 733560; D010455:Peptides; D010456:Peptides, Cyclic; C079465:pneumocandin B(0); C077459:L 693989; D003907:Dexamethasone