Lexipafant fails to improve survival in severe necrotizing pancreatitis in rats

Abstract

Conclusion: Lexipafant administration fails to improve survival or lessen the disease severity in two experimental models of severe acute pancreatitis.

Background: The potent platelet activating factor antagonist Lexipafant has been shown to attenuate the biochemical and histologic changes associated with some animal models of acute pancreatitis, suggesting an important role for this cytokine in its pathogenesis. However, a survival advantage following Lexipafant administration has not been demonstrated. This study evaluates the effect of this platelet activating antagonist on survival in rat models of necrotizing and fulminant hemorrhagic pancreatitis.

Methods: Sprague-Dawley rats underwent induction of either acute necrotizing (n = 40) or hemorrhagic pancreatitis (n = 36) with a time- and pressure-controlled bile duct infusion of 10 mM glycodeoxycholic acid (GDOC) or enterokinase 15 U/mL, in combination with supramaximal cerulein stimulation (5 micrograms/kg/h). Immediately after pancreatitis induction, rats were randomly divided into three groups and received Lexipafant (1 mg or 10 mg) or saline as a continuous intravenous infusion over 9 h. Twenty-four-hour survival rates were determined and severity of pancreatitis was assessed by pancreatic histology scores.

Results: The survival rates for GDOC treated rats were 55% (saline), 50% (1 mg Lexipafant) and 50% (10 mg Lexipafant). As expected, all rats induced with enterokinase and treated with saline died with hemorrhagic pancreatitis within 24 h. The same was true of those treated with high- and low-dose Lexipafant, and there was no difference in survival time. Histology scores did not differ between Lexipafant-treated and control rats in either GDOC or enterokinase rats.