Benoxaprofen attenuation of lethal canine endotoxic shock

Our prior work demonstrated in a canine endotoxic shock model (LD100) that the cyclooxygenase inhibitor ibuprofen given 60 minutes after endotoxin administration could improve hemodynamics but not survival over control animals. The present study was designed to examine the effect of benoxaprofen, a dual lipoxygenase and cyclooxygenase inhibitor, in the same canine endotoxic model (LD100) and compare it to ibuprofen treatment. After thiopental anesthesia (25 mg/kg IV), animals were instrumented to measure various cardiovascular parameters. Endotoxic shock was induced by injecting Escherichia coli (0111:B4) endotoxin (1 mg/kg IV). Benoxaprofen (10 mg/kg IV; N = 13), ibuprofen (12.5 mg/kg; N = 6), or saline (N = 12) was injected 60 minutes after endotoxin administration. During the treatment period, both benoxaprofen and ibuprofen increased mean arterial pressure, heart rate, and vascular resistance to the same degree over the control animals. Benoxaprofen did increase dP/dtmax while ibuprofen did not. Twenty-four-hour survival was 0% for the control animals (N = 12), 0% for the ibuprofen group (N = 6), and 61.5% for the benoxaprofen group (N = 13). In an additional set of experiments, benoxaprofen (N = 8) was given 120 minutes after endotoxin administration and demonstrated similar improvements in hemodynamics and survival. These data demonstrate that benoxaprofen could improve survival in an otherwise lethal endotoxic model and suggest that the products of the lipoxygenase pathway may contribute to the lethality of an LD100 endotoxic shock model.