Protection by a New Synthetic Protease Inhibitor, ONO3307, of the Rat Exocrine Pancreas during Acute Edematous Pancreatitis Induced by a Supramaximal Dose of Caerulein in Comparison with FOY007

Abstract

The present study investigated the protective effects of the new potent synthetic protease inhibitors, ONO3307 (4-sulfamoyl phenyl-4-guanidinobenzoate methanesulfonate) and FOY007 (gabexate misilate), on the exocrine pancreas in rat caerulein-induced acute pancreatitis in both in vitro and in vivo experiments. These protease inhibitors prevented hyperamylasemia, pancreatic edema, congestion of amylase, redistribution of lysosomal enzyme in acinar cells, and lactic dehy-drogenase (LDH) discharge from dispersed acini. They also inhibited the cathepsin B leakage from the lysosomes in a dose-dependent manner in doses of 2–10 mg/kg·h of ONO-3307 and 20-50 mg/kg·h of FOY007. These results indicate that both ONO3307 and FOY007 exert protective effects against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases appear to be important in the pathogenesis and development of acute pancreatitis, and low-molecular-weight protease inhibitors may be of clinical use in the treatment of acute pancreatitis.

Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

“…Yoshikawa et al found a protective effect against endotoxin‐induced DIC in rats with 10 or 100 μg/kg/h of ONO‐3307 as measured by fibrin degradation products, number of renal glomeruli with fibrin deposition, and other effects . Likewise, Hirano and others observed beneficial effects of ONO‐3307 in rat acute pancreatitis …”

“…136 Due to the combined effect on thrombin (coagulation) and plasmin (fibrinolysis), ONO-3307 was tested as a treatment for DIC 137 and pancreatitis. [138][139][140] Yoshikawa et al found a protective effect against endotoxininduced DIC in rats with 10 or 100 μg/kg/h of ONO-3307 as measured by fibrin degradation products, number of renal glomeruli with fibrin deposition, and other effects. 137 Likewise, Hirano and others observed beneficial effects of ONO-3307 in rat acute pancreatitis.…”

“…137 Likewise, Hirano and others observed beneficial effects of ONO-3307 in rat acute pancreatitis. [138][139][140] Both nafamostat and gabexate have been approved for clinical use in Japan and Italy. Reports suggest that prophylactic intravenous nafamostat mesilate reduces the frequency of postendoscopic retrograde cholangiopancreatography pancreatitis.…”

“…Moreover, although not fully understood, TXA has been implicated in the treatment of melasma, prevention of UV-induced pigmentation, and the recovery of skin barrier. 270,271 Finally, nafamostat and gabexate have been found useful for complex pathologies such as DIC, 7,137,148 pancreatitis, [138][139][140][141][142][143][144] and liver diseases. 272…”

“…Likewise, the three inhibitors inhibited thromboplastin release from stimulated leukocytes at ∼10 μM dosage . Due to the combined effect on thrombin (coagulation) and plasmin (fibrinolysis), ONO‐3307 was tested as a treatment for DIC and pancreatitis . Yoshikawa et al found a protective effect against endotoxin‐induced DIC in rats with 10 or 100 μg/kg/h of ONO‐3307 as measured by fibrin degradation products, number of renal glomeruli with fibrin deposition, and other effects .…”