title: Antipneumocystis activity of water-soluble lipopeptide L-693,989 in rats.
abstract: Water-soluble lipopeptide L-693,989 was evaluated for its antipneumocystis activity in rats. Rats from colonies with latent Pneumocystis carinii infections were immunosuppressed with dexamethasone for 6 weeks to facilitate the development of acute P. carinii pneumonia (PCP). After 6 weeks, the rats were maintained on dexamethasone and were treated twice daily for 4 days with various concentrations of L-693,989. At a dose of 0.15 mg/kg of body weight, the compound effectively eliminated 90% of the cysts in 4 days. Trophozoite forms of P. carinii were still present in these animals, as determined by using a P. carinii-specific DNA probe. A 3-week therapy study showed that the trophozoite load did not expand during treatment and that the trophozoites already present at the initiation of therapy appeared to persist. This may be a consequence of the stage specificity of the compound for cyst development and the severe immunosuppressive effects of dexamethasone on rats. When evaluated as a daily parenteral prophylactic agent, L-693,989 was effective in preventing the development of both P. carinii cysts and trophozoites, demonstrating its potential for use in prophylaxis and implying that the cyst stage of P. carinii is an obligatory step in trophozoite multiplication. The foamy exudate commonly associated with P. carinii infections was absent in the lungs of rats on prophylaxis. The compound was also evaluated via oral administration and was found to have a 90% effective dose of 32 mg/kg for therapy of acute infections and 5 mg/kg for daily prophylaxis.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065-0900.
authors.forename: D M
authors.initials: DM
authors.lastname: Schmatz
authors.forename: M A
authors.initials: MA
authors.lastname: Powles
authors.forename: D C
authors.initials: DC
authors.lastname: McFadden
authors.forename: L
authors.initials: L
authors.lastname: Pittarelli
authors.forename: J
authors.initials: J
authors.lastname: Balkovec
authors.forename: M
authors.initials: M
authors.lastname: Hammond
authors.forename: R
authors.initials: R
authors.lastname: Zambias
authors.forename: P
authors.initials: P
authors.lastname: Liberator
authors.forename: J
authors.initials: J
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011010:Pneumocystis / Q000187:drug effects; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy* / Q000382:microbiology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010456:Peptides, Cyclic; C077459:L 693989; D015662:Trimethoprim, Sulfamethoxazole Drug Combination