NPC-15669 REDUCES MORTALITY ASSOCIATED WITH SEPSIS IN RATS

,7-dimethylfluoren-9-ylmethoxy)carbonyl]-L-leucine (NPC 15669), a leuk ocyte recruitment inhibitor, was investigated for its ability to enhan ce survival in a rat model of sepsis, fecal peritonitis. Infusion of N PC 15669 (3 mg kg-1 hr 1 i.v.) for 19, 24 or 48 hr or three to four bo lus injections (1 0 mg/kg) at 2- or 6-hr intervals along with gentamic in effectively cured all animals (>2-week survival) relative to gentam icin-treated controls (28 +/- 1 hr survival), whereas infusion at a 10 -fold lower dose was ineffective. Unlike aspirin and dexamethasone, wh ich were inactive (< 36-hr survival), ibuprofen significantly increase d the survival time (66 +/- 1 hr) but did not cure septic rats. The ef ficacy of NPC 15669 on survival was associated with the reversal of le ukopenia and a marked inhibition of neutrophil infiltration into the s mall intestine. By contrast, i.v. bolus injection or infusion of a rel ated analog, N-[9H-fluoren-9-ylmethoxy)carbonyl] glycine, which does n ot inhibit leukocyte recruitment, failed to reduce the mortality rate associated with fecal peritonitis-induced sepsis. In addition, NPC 156 69 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 tre atment of septic shock.