Comparative studies of nafamostat mesilate and various serine protease inhibitors in vitro

Inhibitory effects of nafamostat mesilate (nafamostat) on various enzymes were investigated, and they were compared with those of gabexate mesilate (gabexate), leupeptin, aprotinin and urinastatin in vitro. Nafamostat inhibited trypsin, plasmin, thrombin, pancreatic kallikrein, Clr and Cls more potently than gabexate and leupeptin. Gabexate and leupeptin did not inhibit pancreatic kallikrein and thrombin, respectively. Aprotinin inhibited trypsin, plasmin, pancreatic kallikrein and chymotrypsin. Urinastatin inhibited trypsin and chymotrypsin. Nafamostat inhibited the complement-mediated hemolysis in diluted serum more potently than gabexate and leupeptin, but aprotinin and urinastatin did not. Nafamostat, furthermore, inhibited the complement-mediated hemolysis in undiluted serum, but gabexate did not. Unlike aprotinin and urinastatin, nafamostat and gabexate inhibited alpha 2-macroglobulin bound trypsin as well as free trypsin to the same extent. The inhibitory effect of gabexate toward trypsin was reduced more markedly than that of nafamostat after incubation with plasma at 37 degrees C. These results show that nafamostat is more useful than other inhibitors such as gabexate, leupeptin, aprotinin and urinastatin.     

Pharmacological studies on 6-amidino-2-naphthyl[4-(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethane sulfonate (FUT-187). I: Inhibitory activities on various kinds of enzymes in vitro and anticomplement activity in vivo.

FUT-187, a newly synthesized compound, was studied on its inhibitory activities mainly on proteolytic enzymes, in comparison with those of FUT-175 and FOY-305, known serine protease inhibitors. FUT-187, as well as FUT-175 and FOY-305, had selective inhibitory activities on serine proteases including Clr, Cls, kallikrein, trypsin, plasmin and thrombin; its activities on these enzymes except Clr and pancreatic kallikrein were relatively lower than those of FUT-175 and FOY-305. Further studies were conducted focusing on complement-mediated reactions. In spite of its lower activities against Clr and Cls, inhibitions by FUT-187 on the complement-mediated hemolysis in vitro and in vivo were only a little weaker than or equivalent to that of FUT-175. FOY-305 was ineffective in these tests. Forssman shock in guinea pigs is known to be initiated by the activation of the complement system. The protective effect of intravenous or oral FUT-187 against this shock was definitely superior to that of FUT-175. Furthermore, FUT-187 inhibited changes accompanied with Forssman shock, such as increase in lung weight, the decrease in platelet counts and CH50, and histopathological changes. These results suggested that FUT-187 should be a more potent oral therapeutic agent than FUT-175 for various inflammatory diseases attributed to the excessive activation of the complement system followed by platelet aggregation.     

Pharmacological studies of FUT-175, nafamstat mesilate. III. Anti-inflammatory activities of FUT-175

Anti-inflammatory effects of FUT-175 (nafamstat mesilate), a new synthetic serine protease inhibitor, on various types of experimental inflammation were investigated in vivo and in vitro, in comparison with non-steroidal anti-inflammatory drugs (NSAID). The in vivo studies showed that FUT-175 has the abilities to inhibit almost all types of inflammatory reactions employed in the present study. In particular, being evaluated on the basis of the effect of indomethacin, FUT-175 exhibited relatively higher potencies against some reactions such as zymosan-induced increase of vascular permeability, scald paw edema, zymosan-induced granuloma-pouch, the Arthus reaction and acetic acid-induced writhing in which the complement system or the kallikrein-kinin system are considered to play an important role. The in vitro studies showed that FUT-175 is quite different from NSAID, that is, FUT-175 had no effects on heat-induced erythrocyte-lysis and heat-induced denaturation of bovine serum albumin. FUT-175 also had no effect on chemotaxis of polymorphonuclear leucocytes, but inhibited the production of chemotactic factor by antigen-antibody reaction. These above results suggested that FUT-175 has a different mode of action from NSAID and that serine protease inhibiting activities of this compound might play an important role in its anti-inflammatory effect.     

Inhibitory effects of a novel synthetic protease inhibitor, FUT-175, on the paw edema in rats and zymosan-induced complement activation in vitro

FUT-175 inhibited the zymosan-induced rat paw edema in a dose-dependent manner, while indomethacin exhibited no significant activities in this model. FUT-175 also inhibited the decrease in hemolytic complement (CH50) induced by zymosan in vitro, and indomethacin was inactive. These results suggest that FUT-175 has potent in vitro and in vivo inhibitory activity against the activation of the complement system induced by zymosan.     

The effects of FUT-175 (nafamostat mesilate) on blood coagulation and experimental disseminated intravascular coagulation (DIC)

FUT-175 is a newly synthesized serine protease inhibitor. In the present study, we investigated the effects of FUT-175 on blood coagulation and experimental DIC. The effects on coagulation were examined in vitro by measuring the activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) of rat plasma in the presence of FUT-175. FUT-175 exhibited remarkable anticoagulative effects to prolong APTT at a plasma concentration of 3 x 10(-7) M, PT at 1 x 10(-5) M and TT at 3 x 10(-5) M. The anticoagulative effect of FUT-175 at 1 x 10(-6) M on APTT was almost similar to that of heparin at 0.3 U/ml or that of gabexate mesilate at 1 x 10(-3) M. Experimental DIC was induced by a four-hr sustained intravenous infusion of endotoxin. FUT-175 was administered intraperitoneally prior to the injection of endotoxin or infused intravenously with endotoxin. As a result, the prolongation of APTT and PT, the decreases of fibrinogen level, platelet counts and complement level, and the increase of FDP were remarkably improved by FUT-175. Furthermore, glomerular fibrin deposits were reduced by the infusion of FUT-175. These results indicate that FUT-175, having a potent inhibitory effect on blood coagulation, is clinically applicable to therapy for DIC.     

Inhibitory effect of nafamostat mesilate (FUT-175) on O2- production in rat polymorphonuclear leucocytes

Effect of nafamostat mesilate (FUT-175), a serine protease inhibitor, having anti-inflammatory effects was studied on superoxide (O2-) production in rat polymorphonuclear leucocytes (PMN) and compared with those of other serine protease inhibitors and typical anti-inflammatory agents. 1) O2- productions in rat PMN stimulated with concanavalin A (Con A) and cytochalasin B (Cyt B) were too weak to observe. With NADH, however, strong O2- production was induced by Con A and Cyt B. 2) FUT-175 at 10(-6) and 10(-5) M inhibited O2- production in rat PMN induced by Con A and Cyt B with NADH in a concentration-dependent manner. 3) The serine protease inhibitor L-tosylamido-2-phenylethyl-chloromethyl ketone (TPCK) and soybean trypsin inhibitor (SBTI) inhibited O2- production at 10(-5) M and 10(-4) M, respectively, while aprotinin, chymostatin and leupeptin did not. 4) Neither indomethacin nor dexamethasone, typical anti-inflammatory agents, inhibited O2- production. Mepacrine, a phospholipase A2 inhibitor, strongly inhibited it. 5) O2- production in PMN prepared from the rat administered FUT-175, 200 mg/kg, p.o., was significantly decreased in comparison with that of the control rat. 6) FUT-175 had no effect on O2- production by hypoxanthine-xanthine oxidase. These results showed FUT-175 had a strong inhibitory effect on O2- production in rat PMN which other typical anti-inflammatory agents did not have.     

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.

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 dehydrogenase (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 ONO3307 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.     

Effects of FUT-175, a novel synthetic protease inhibitor, on the development of adjuvant arthritis in rats and some biological reactions dependent on complement activation

1. The effects of FUT-175 on the development of adjuvant arthritis in rats were studied and compared with those of indomethacin. FUT-175 inhibited both primary and secondary paw lesions in the adjuvant arthritic rats when it was administered orally on a daily basis from the day before through 18th day after adjuvant injection. 2. In addition, FUT-175 inhibited the increase in hemolytic complement in adjuvant arthritic rats in a dose-dependent manner. 3. Indomethacin also showed an inhibitory effect on the development of arthritic lesion, but had no effect on the increase in hemolytic complement in the adjuvant arthritis in rats. 4. Furthermore, FUT-175 inhibited the activities of various proteases in vitro, and then strongly inhibited complement-mediated hemolysis via the classical and alternative pathways, while indomethacin had no effect on them. 5. These results suggest that the anti-inflammatory activity of FUT-175 may differ from indomethacin in the mechanisms of action and, at least in part, due to the anti-complement activity.     

Inhibitory effect of aprotinin and gabexate mesilate on human plasma kallikrein

Prekallikrein (PK) in human plasma was activated with kaolin in the presence of protease inhibitors aprotinin (Trasylol) and gabexate mesilate to investigate a difference in the inhibitory activity of plasma kallikrein (K) between these inhibitors. Benzoyl-prolyl-phenylalanyl arginine-p-nitroanilide (PPAN) cleavage of purified plasma K was markedly inhibited by aprotinin and gabexate mesilate, and acetyl-glycyl-l-lysine methyl ester hydrolysis of purified PK activator was slightly inhibited. PPAN cleavage of plasma K-alpha2 macroglobulin complex was hardly inhibited by aprotinin while PPAN cleavage of the complex was markedly inhibited by gabexate mesilate. The inhibitory activity of gabexate mesilate towards plasma K completely disappeared after 10 min incubation with plasma at 37 degrees C and also in 30 min on the experiment in which the time course of kaolin-induced PK activation was observed at 10 degrees C. On the other hand, the inhibitory activity of aprotinin towards plasma K never changed after 10 min incubation with plasma at 37 degrees C or 30 min incubation with plasma at 10 degrees C. From the results it is concluded that a predominant effect of aprotinin in human plasma is due to its stability in contrast to instability of gabexate mesilate.     

Aprotinin revisited: formulation,characterization, biodistribution and therapeutic potential of new aprotinin microemulsion in acute pancreatitis

The aim of this study was to develop aprotinin-loaded microemulsion (M_A) for intravenous administration and evaluate the biodistribution and therapeutic potential of developed formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify microemulsion region and the optimal microemulsion was evaluated for physicochemical properties and treatment effect in rats, and comparisons made with the solution of aprotinin (S_A). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was radiolabeled with ^99mTc radionuclide. Mild and severe acute pancreatitis was induced in rats by subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue myeloperoxidase activities were measured to evaluate the pancreatic damage. According to gamma scintigraphy and biodistribution studies, accumulation times and distribution of ^99mTc-M_A and S_A were different. While M_A was highly uptake by reticuloendothelial system, S_A was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis group, treatment with M_A significantly decreased the serum amylase activity and pancreas myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has therapeutic potential in acute pancreatitis. Finally, M_A may be suggested as a promising alternative for treatment of acute pancreatitis.     

Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

Acute, nontoxic cadmium exposure inhibits pancreatic protease activities in the mouse.

Toxic effects of cadmium on liver, kidney, lung, and testes have been well established in experimental animals and in cell model systems. However, little is known about the effect of cadmium on pancreas, though the pancreas has been reported to accumulate high concentrations of cadmium. Therefore, in this study we examined the effects of cadmium on the pancreas of mice. A single sc injection of 1 mg Cd/kg to mice had no obvious toxic effects on the liver, kidney, and pancreas at both 1 and 5 days after cadmium treatment. Within the pancreas, however, the activities of trypsin, chymotrypsin, and carboxypeptidase A were significantly decreased at 1 day after cadmium treatment, whereas the activity of carboxypeptidase B was not changed. All pancreatic enzyme activities returned to the control levels by 5 days after cadmium treatment. The concentrations of cadmium in pancreas were very similar at 1 and 5 days after cadmium treatment, indicating a stable deposition of the metal. The concentration of zinc in pancreas was markedly increased at 5 days after cadmium treatment. In order to more fully examine the inhibitory effects of cadmium on these protease activities in pancreas, the direct effects of cadmium on purified proteases were studied in vitro. Contrary to the results in vivo, cadmium increased the activity of purified trypsin in a concentration-dependent manner. Consistent with the in vivo results, the activity of purified carboxypeptidase A was decreased by cadmium treatment in a concentration-dependent fashion in vitro. The activities of chymotrypsin and carboxypeptidase B did not change by the cadmium exposure in vitro. The enhanced activity of trypsin by cadmium was returned to the control levels by subsequent treatment with EDTA, indicating that enhancement was reversible. In addition, the zinc normally contained in purified carboxypeptidase A and carboxypeptidase B was released by the cadmium treatment. These results indicate that cadmium inhibits protease activities within the pancreas in vivo at doses that do not induce overt hepatic, renal, or pancreatic toxicity. Based on in vitro study, the decreases seen in trypsin and chymotrypsin activities might be based on indirect effects of cadmium, whereas the decreases in carboxypeptidase A are probably due to the direct inhibition by the metal.     

Immunopharmacological actions of 6-amidino-2-naphthyl-4-guanidinobenzoate (FUT-175). 1. Effect of FUT-175 on immune response and host defense in mice

FUT-175 is a new synthetic protease inhibitor which strongly inhibits complement-mediated hemolysis via the classical and alternative pathways. The present study was undertaken to examine the effects of FUT-175 on antibody formation and host defense in mice since the complement system participates in both immunological responses and host defense against bacterial infection. FUT-175 did not suppress the primary IgM and IgG antibody responses to sheep red blood cells, although FUT-175 was given at 10 to 100 mg/kg/day p.o. for 3 days before or after immunization. On the other hand, the primary anti-DNP IgE antibody response to DNP-conjugated ovalbumin was slightly suppressed only by post-administration of FUT-175 in a dose of 100 mg/kg/day p.o. for 5 days. However, the results of the adoptive transfer experiments indicate that FUT-175 did not affect either T cells or B cells participating in the secondary anti-DNP IgE antibody formation. FUT-175 in a dose of 10(-4)M but not at 10(-6) to 10(-5)M significantly decreased the proliferation of spleen cells caused by concanavalin A, lipopolysaccharide or the one-way mixed lymphocytes culture reaction using 1000 R-irradiated spleen cells from BDF1 mice as stimulator cells and those from C57BL/6 mice as responder cells. FUT-175 had an inhibitory rather than an enhancing effect on host defense to infection with Escherichia coli when administered at 10 to 100 mg/kg/day p.o. for 3 days before or after infection. These results strongly suggest that FUT-175 does not affect antibody formation and host defense in mice.     

Potential effects of PKC or protease inhibitors on acute pancreatitis-induced tissue injury in rats

BACKGROUND: Acute pancreatitis (AP) is still one of the severe diseases, that cause the development of multiple organ dysfunction with a high mortality. Effective therapies for AP are still limited, mainly due to unclear mechanisms by which AP initiates both pancreatic and extrapancreatic organ injury. METHODS: Protease inhibitors (aprotinin, pefabloc, trypsin inhibitor) and PKC inhibitors (polymyxin B, staurosporine) were administrated 30 min before induction of AP in rats. To investigate the pancreatic, systemic and lung inflammatory response and injury, plasma IL-6 and IL-10, pancreatic and pulmonary myeloperoxidase (MPO) levels, pancreatic protease activity and phospholipase A(2) (PLA(2)) activity in ascites were measured 3 and 6 h after AP induction. RESULTS: Pretreatment with protease inhibitors significantly prevented from AP-increased plasma levels of IL-10, pancreatic and pulmonary levels of MPO, pancreatic protease activity and the catalytic activity of PLA(2) in ascites. PKC inhibitors significantly reduced pancreatic and pulmonary levels of MPO and pancreatic protease activity. CONCLUSION: Inhibition of proteases in AP may be helpful in ameliorating the inflammatory reaction in both pancreatic and extrapancreatic tissues, where neutrophil involvement may be regulated by PKC and proteases.     

Effects of E-3123, a new protease inhibitor, on several protease activities and on experimental acute pancreatitis

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.     

Inhibitory effect of human urinary trypsin inhibitor (urinastatin) on lysosomal thiol proteinases

Effects of human urinary trypsin inhibitor, urinastatin, a compound clinically prescribed for treatment of acute pancreatitis, on lysosomal thiol proteinases were studied. Urinastatin had inhibitory effect on the activities of cathepsins B and H in vitro. In the experimental acute pancreatitis induced by a closed duodenal loop, urinastatin prevented the enhancement of esterolytic activity and the activities of cathepsins B and H. Urinastatin also improved the activities of inhibitors of cathepsins B and H in the case of pancreatitis.     

Pathological events in experimental acute pancreatitis prevented by the bradykinin antagonist, Hoe 140.

1. In a previous investigation, Hoe 140, a specific and potent bradykinin B2 receptor antagonist, prevented the pancreatic oedema and the hypotension observed during acute experimental pancreatitis; however, it augmented the associated rises in the serum activities of pancreatic enzymes. Therefore, we have now investigated the consequences of the pancreatic oedema for the fate of activated enzymes released into the tissue during the course of acute pancreatitis. 2. Acute oedematous pancreatitis was induced in rats, pretreated with captopril (50 mumol kg-1, i.p.), by hyperstimulation of the exocrine function of the pancreas with the cholecystokinin analogue, caerulein (4 nmol kg-1 h-1, i.v.), for up to 120 min. 3. Pancreatic oedema began to develop 10 min after the start of the caerulein infusion, reached a maximum within about 45 min, and then declined slightly. The development of the oedema parallelled the second phase of the caerulein-induced fall in blood pressure found in earlier experiments. No further extravasation of plasma proteins occurred during the 2nd hour of the caerulein infusion. The oedema formation was completely blocked in animals pretreated with the bradykinin receptor antagonist, Hoe 140 (100 nmol kg-1, s.c.). Pretreatment with aprotinin or soy bean trypsin inhibitor did not result in a significant inhibition of the oedema. 4. The haematocrit of animals with experimental pancreatitis showed a pronounced increase which started 10 min after the start of the caerulein infusion and reached maximal values at 60 min. The changes in haematocrit showed a reduction in total blood volume of 28% due to a 48% loss of plasma. This effect was completely blocked by Hoe 140.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blockade of bradykinin B(2) receptor suppresses acute pancreatitis induced by obstruction of the pancreaticobiliary duct in rats.

1. The involvement of bradykinin (BK) B(2) receptor in acute pancreatitis induced by pancreaticobiliary duct ligation was investigated in rats. 2. The activities of amylase and lipase in the serum, the water content of the pancreas, and vacuolization of the acinar cells were significantly increased 2 h after obstruction of the duct in Sprague-Dawley rats. 3. Elevated serum amylase activity, increased pancreatic oedema, and damage of the pancreatic tissue were significantly less marked in plasma kininogen-deficient, B/N-Katholiek rats than in the normal strain, B/N-Kitasato rats 2 h after the ligation. 4. Obstruction of the pancreaticobiliary duct augmented the level of (1-5)-BK (Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)), a stable BK metabolite, in the blood from 73.0+/-21.7 pg ml(-1) at 0 h to 149.8+/-38.0 pg ml(-1) at 2 h after the induction of pancreatitis in SD rats. 5. Administration of a BK B(2) receptor antagonist, FR173657 (100 mg kg(-1), p.o.) or Hoe140 (100 nmol kg(-1), s.c.), reduced the elevation of amylase and lipase activities in the serum and of pancreatic water content in a dose-dependent manner. The effective attenuation of oedema formation and vacuolization by the antagonists was also confirmed light-microscopically. In contrast, treatment with gabexate mesilate or indomethacin did not cause significant suppression of the pancreatitis. 6. These findings suggest a possible involvement of kinin B(2) receptor in the present pancreatitis model. Furthermore, they point to the potential usefulness of the B(2) receptor in clinical acute pancreatitis.     

Antimetastatic activity of a synthetic serine protease inhibitor, FOY-305 (Foypan)

Metastasis is one of the major causes of mortality in cancer. It is well known that the activities of cell surface serine proteases are especially enhanced in malignant tumors. Proteolytic degradation of the extracellular matrix and basal membrane is a crucial event for tumor cell invasion and metastasis formation. FOY-305 (Foypan), a remedy for tumor pancreatitis, is a broad spectrum synthetic serine protease inhibitor which inhibits enzymatic activities including trypsin, thrombin, kallikrein and plasmin. Using Lewis lung carcinoma cell, we found that FOY-305 inhibited both spontaneous and experimental pulmonary metastasis. Furthermore, the combined treatment of FOY-305 and a traditional anti-cancer drug, 5-FU or bleomycin, resulted in marked enhancement of anti-pulmonary metastatic activity.     

Sesamol attenuates oxidative stress-mediated experimental acute pancreatitis in rats

Acute pancreatitis is a potentially fatal disease with no known cure. The initial events in acute pancreatitis may occur within the acinar cells. We examined the effect of sesamol on (i) a cerulein-induced pancreatic acinar cancer cell line, AR42J, and (ii) cerulein-induced experimental acute pancreatitis in rats. Sesamol inhibited amylase activity and increased cell survival. It also inhibited medium lipid peroxidation and 8-hydroxydeoxyguanosine in AR42J cells compared with the cerulein-alone groups. In addition, in cerulein-treated rats, sesamol inhibited serum amylase and lipase levels, pancreatic edema, and lipid peroxidation, but it increased pancreatic glutathione and nitric oxide levels. Thus, we hypothesize that sesamol attenuates cerulein-induced experimental acute pancreatitis by inhibiting the pancreatic acinar cell death associated with oxidative stress in rats.