title: [Effects of E-3123, a new protease inhibitor, on several protease activities and on experimental acute pancreatitis].
abstract: 4-(2-Succinimidoethylthio) phenyl 4-guanidinobenzoate (E-3123) potently inhibited trypsin, plasmin and thrombin with IC50 values of 3.9 x 10(-8) M, 9.5 x 10(-7) M and 1.9 x 10(-6) M, respectively. Experimental acute pancreatitis was induced by injection of a mixture of trypsin and taurocholate into the pancreas in rats and rabbits or by an application of a closed duodenal loop in dogs. Intravenous infusion of E-3123 at 0.03-0.3 mg/kg in rats or at 0.3-3.0 mg/kg in rabbits reduced mortality after the induction of pancreatitis in a dose-dependent manner. Light microscopy of the pancreas in the E-3123-treated rabbits revealed marked decrease in cell necrosis and acinar cell vacuolation. Increase in plasma lipase activities associated with the progression of pancreatitis in rabbits was also reduced by the infusion of E-3123. In dogs with pancreatitis, increases in serum trypsin and lipase activities were significantly reduced by infusion of E-3123 at 1.0 and 3.0 mg/kg. The efficacies of E-3123 in the in vivo experiments were higher than those of nafamostat mesilate. These results show that E-3123 may possess suppressing effects on pathogenesis and development of acute pancreatitis.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
authors.forename: I
authors.initials: I
authors.lastname: Hishinuma
authors.forename: J
authors.initials: J
authors.lastname: Nagakawa
authors.forename: N
authors.initials: N
authors.lastname: Nagaoka
authors.forename: T
authors.initials: T
authors.lastname: Yamanaka
authors.forename: T
authors.initials: T
authors.lastname: Wakabayashi
mesh_terms: D000208:Acute Disease; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D008049:Lipase / Q000037:antagonists & inhibitors; D008297:Male; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014361:Trypsin Inhibitors
chemical_list: D006146:Guanidines; D011480:Protease Inhibitors; D014361:Trypsin Inhibitors; C057059:4-(2-succinimidoethylthio)phenyl 4-guanidinobenzoate; D008049:Lipase