TREATMENT OF PANCREATITIS WITH AN ORALLY AVAILABLE ELASTASE INHIBITOR

Abstract

Introduction: Circulating serum levels of neutrophil-elastase (PMN-elastase) are known to correlate with the severity of clinical pancreatitis and are closely associated with the extent of leukocyte transmigration into inflamed tissue. We tested whether prophylactic administration of a novel, orally available peptidyl-trifluoromethyl-ketone inhibitor of PMN-elastase (ZD-0892), with cross-specificity for pancreatic elastase, can ameliorate experimental pancreatitis. Methods: Male Wistar rats (250-300 gr) received gavage tube feeding of ZD-0892 (at a dose of 240 mg/kg per day) at 3h and 1h before the induction of acute caerulein pancreatitis for 4 and 12 hrs. Pancreatic and lung tissue as well as serum was collected for further analysis of clinical and morphological severity markers. Inhibitor specificity and capacity was tested in vitro. Isolated pancreatic acini were incubated with ZD-0892 and protease activity after supramaximal caerulein stimulation was monitored employing specific fluorogenic substrates for trypsin, elastase, cathepsin B and cathepsin L. Results: Oral administration of the elastase inhibitor ZD-0892 significantly reduced the serum level of amylase, the extent of pancreatic edema, as well as leukocyte infiltration in the pancreas and lungs during caerulein-induced pancreatitis. Incubation of isolated pancreatic acini with ZD-0892 and subsequent supramaximal CCK stimulation reduced pancreatic elastase activity to below 10%, whereas neither trypsin, nor cathepsin B nor cathepsin L activity were affected. Moreover, inhibiting pancreatic elastase reduced the rate of acinar cell necrosis to below 50%. Conclusion: Prophylactic administration of a novel, orally available PMN-elastase inhibitor with cross-specificity for pancreatic elastase improves the severity of acute experimental pancreatitis. ZD-0892 therefore represents the first orally active drug with treatment potential for patients at risk of developing pancreatitis such as those before ERCP, those with exogenous risk factors (e.g. ethanol abuse) and those with inherited predispositions.