Effect of IS-741 (a new synthetic antiinflammatory agent) on acute necrotizing pancreatitis in dogs

IS-741, a new synthetic anti-inflammatory agent, is known to have some inhibitory effect on cytosolic phospholipase A₂ (cPLA₂), an enzyme which hydrolyzes cellular phospholipids, liberating fatty acids and lysophospholipids and providing the precursor substrates for the biosynthesis of eicosanoids and platelet-activating factor. cPLA₂ is therefore an attractive target for the development of novel therapies. During infusion of lactated Ringer's solution at a rate of 10 ml/kg/h, acute pancreatitis was induced in dogs by injecting autologous gallbladder bile into the main pancreatic duct. The dogs were then divided into two groups: group A (nontreatment), no treatment during the experiment, and group B (IS-741), intravenously injected with IS-741 at 6 and 30 h after induction of acute pancreatitis. As a result, the survival rate was significantly higher in group B than in group A. Mean arterial pressure and PaO₂ were well maintained in group B as compared with group A. The NAG index, which is known to be markedly increased in renal tubular damage, was significantly lower in group B than in group A. Histological examination of the pancreas, lung, and kidney in group B showed milder changes than in group A. cPLA₂ activity in the pancreas, lung and renal cortex was much lower in group B than in group A, but sPLA₂ activity in these tissues did not differ significantly between the two groups. In conclusion, IS-741 exerts a potentially therapeutic effect on experimental acute pancreatitis by mitigating the degree of damage in the pancreas, lung, and kidney. The inhibitory effect of IS-741 on cPLA₂ may contribute to one of the antiinflammatory mechanisms of actions of this agent.