Abstract

N-[9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl]-L-leucine (NPC 15669), a leukocyte recruitment inhibitor, was investigated for its ability to enhance survival in a rat model of sepsis, fecal peritonitis. Infusion of NPC 15669 (3 mg kg-1 hr-1 i.v.) for 19, 24 or 48 hr or three to four bolus injections (10 mg/kg) at 2- or 6-hr intervals along with gentamicin effectively cured all animals (> 2-week survival) relative to gentamicin-treated controls (28 +/- 1 hr survival), whereas infusion at a 10-fold lower dose was ineffective. Unlike aspirin and dexamethasone, which were inactive (< 36-hr survival), ibuprofen significantly increased the survival time (66 +/- 1 hr) but did not cure septic rats. The efficacy of NPC 15669 on survival was associated with the reversal of leukopenia and a marked inhibition of neutrophil infiltration into the small intestine. By contrast, i.v. bolus injection or infusion of a related analog, N-[9H-fluoren-9-ylmethoxy)carbonyl]glycine, which does not inhibit leukocyte recruitment, failed to reduce the mortality rate associated with fecal peritonitis-induced sepsis. In addition, NPC 15669 was efficacious therapeutically, even when administered as late as 6 hr after the induction of sepsis (14 of 16 animals survived > 5 days). Together, these data suggest that NPC 15669 may be useful in the treatment of septic shock.