Aerosolized L-693,989 for Pneumocystis carinii prophylaxis in rats.
Water-soluble pneumocandin L-693,989, a potent antipneumocystis agent in the rat model for Pneumocystis carinii pneumonia (PCP), inhibits P. carinii cyst development and effectively prevents the development of PCP when used as a prophylactic agent (D. M. Schmatz, M. A. Powles, D. C. McFadden, L. Pittarelli, J. Balkovec, M. Hammond, R. Zambias, P. Liberator, and J. Anderson, Antimicrob. Agents Chemother. 36:1964-1970, 1992). However, because of limited oral bioavailability, this compound would likely be restricted to parenteral use in humans. As an alternative, the aerosol delivery of L-693,989 was explored to determine the dosing regimen required to prevent the onset of PCP. Rats with latent P. carinii infections were immunosuppressed continuously with dexamethasone to promote the onset of PCP. During the 6-week immunosuppression period, L-693,989 was delivered to rats as a nebulized solution (volume median diameter of 3.8 microns) via a nose exposure inhalation chamber. The efficiency of aerosol delivery to the lungs and the rate of clearance were determined by using radiolabelled compound. It was found that a daily dose of 0.7 micrograms of L-693,989 per lung or a weekly dose of 77.9 micrograms/lung effectively prevented the development of P. carinii cysts and trophozoites as well as the associated pneumonia commonly seen in rats with acute P. carinii infections. These results demonstrate that L-693,989 is potentially useful as an aerosol prophylactic agent for PCP.
Powles
M A
MA
Merck Research Laboratories, Rahway, New Jersey 07065.
McFadden
D C
DC
Liberator
P A
PA
Anderson
J W
JW
Vadas
E B
EB
Meisner
D
D
Schmatz
D M
DM
D000336:Aerosols; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011020:Pneumonia, Pneumocystis / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000336:Aerosols; D000935:Antifungal Agents; D010456:Peptides, Cyclic; C077459:L 693989