Additive effects of a bradykinin antagonist, NPC 17761, and a leumedin, NPC 15669, on survival in animal models of sepsis.

The effects of coadministration of NPC 17761 (D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Hype (transthiophenyl)-Oic-Arg), a potent bradykinin antagonist, and NPC 15669 (N-[9H-(2,7-dimethylfluoren-9-yl-methoxy)carbonyl]-L-leucine), a leukocyte recruitment inhibitor, were examined in rodent models of experimental shock. In mice, ED50 doses of NPC 17761 (0.12 mg/kg) and NPC 15669 (4 mg/kg), administered together, increased survival (83%) and inhibited leukopenia (60% at 4 h) in response to a lethal dose of endotoxin. In rats, independent administration of NPC 15669 (10 mg/kg, i.v. bolus) or NPC 17761 (0.1 mg/kg/h, 4 h) did not significantly increase survival (36 +/- 4 and 46 +/- 9 h, respectively) versus controls (27 +/- 1 h). However, co-treatment essentially "cured" (survival > 1 week) all septic animals, suggesting synergistic effects of the two agents.