Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Gabexate”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources
PubMed2006

Ulinastatin shows preventive effect on post-endoscopic retrograde cholangiopancreatography pancreatitis in a multicenter prospective randomized study.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) is a useful diagnostic and therapeutic procedure; however, ERCP occasionally causes post-ERCP pancreatitis. The administration of gabexate mesilate has been reported to be effective for the prevention for post-ERCP pancreatitis when given during and after the procedure. The aim of the present study was to investigate the preventive effect of the novel protease inhibitor ulinastatin on post-ERCP pancreatitis. METHODS: One hundred and thirty-nine patients who underwent the ERCP procedure were studied. These patients were randomly divided into three groups based on the agent and dose given during and following the ERCP procedure: gabexate mesilate (900 mg), high-dose ulinastatin (450 000 units) and low-dose ulinastatin (150 000 units). Serum amylase, interleukin (IL)-6 and IL-8 levels and plasma polymorphonuclear leukocyte elastase (PMN-E) activity were measured after ERCP. In addition, post-ERCP hyperamylasemia and post-ERCP pancreatitis were recorded. RESULTS: There were no significant differences in serum amylase, IL-6 and IL-8 levels and PMN-E activity after ERCP procedure between the three groups. Post-ERCP pancreatitis was observed in two (4.3%), three (6.5%) and four (8.5%) cases in the gabexate mesilate, high-dose ulinastatin and low-dose ulinastatin groups, respectively. Multiple logistic regression analysis showed that the addition of endoscopic sphincterotomy during the ERCP procedure was the only significant risk factor for the development of post-ERCP hyperamylasemia and post-ERCP pancreatitis (P = 0.03 and P = 0.04, respectively), but there was no significant difference in the occurrence of post-ERCP hyperamylasemia and post-ERCP pancreatitis between the three groups receiving different preventative treatments. CONCLUSION: The administration of low- and high-dose ulinastatin has similar effects to high-dose gabexate in the prevention of post-ERCP pancreatitis.

Aged↗
PubMed2003

Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis: the evidence-based medicine derived from a meta-analysis study.

Uncertainties still exist about the clinical benefit of pharmacological prevention of post-ERCP pancreatitis by either antisecretory drugs such as somatostatin and its long-acting analogue octreotide, or protease inhibitors such as gabexate mesilate. Recent, large-scale prospective studies have reported a fourfold reduction in acute pancreatitis as compared to a placebo with the prophylactic administration of either gabexate mesilate or somatostatin, whereas octreotide was found to be ineffective. An initial meta-analysis of all available controlled trials on this topic has confirmed these findings. The indiscriminate use of these drugs in all patients is unlikely to be cost-effective, but the selective use of prophylaxis for high-risk patients might be advocated. Moreover, inasmuch as 85% of complications developed within 4 to 6 hours of completing the ERCP, it would be reasonable to infuse drugs only for this limited length of time. A recent prospective trial, carried out on high-risk patients, has surprisingly documented a higher incidence, although a non-significant one, of pancreatitis in patients who received short-term prophylaxis with somatostatin or gabexate mesilate than those given a placebo: 11.5% and 8.1% vs. 6.5%, respectively. In order to explore this discrepancy, the original meta-analysis was updated by including data of this negative trial: heterogeneity among the trials was apparent. A careful scrutiny of the most recent studies has revealed differences in patient population, protocols of drug administration, technique and operator-related risk factors for complications among the trials, which could explain, by themselves, the contrasting results reported by the interventional studies. In conclusion, current literature does not support the prophylactic use of either somatostatin or gabexate mesilate for the prevention of ERCP-related pancreatic damage, even in patients deemed to be at high risk for complications. At present, post-ERCP complications (and pancreatitis) can be prevented efficaciously by appropriate selection of patients, mastering of the technique and operator competence.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed1992

Effect of synthetic protease inhibitors on superoxide (O2-), hydrogen peroxide (H2O2) and hydroxyl radical production by human polymorphonuclear leukocytes.

The effects of clinically used protease inhibitors (aprotinin, nafamostat mesilate, gabexate mesilate) on the production of oxygen-derived free radicals (O2-, H2O2, .OH) by human polymorphonuclear leukocytes were examined. Nafamostat mesilate and gabexate mesilate markedly and dose-dependently inhibited zymosan-stimulated O2- production by human polymorphonuclear leukocytes. However, aprotinin had a slight scavenging effect on O2- produced by the xanthine-xanthine oxidase system. All the protease inhibitors inhibited H2O2 production, but had no significant scavenging effect on H2O2. Nafamostat mesilate and gabexate mesilate slightly inhibited .OH production. These results indicate that the synthetic protease inhibitors nafamostat mesilate and gabexate mesilate inhibit the production of various activated oxygen radicals by human polymorphonuclear leukocytes, and the differences in their inhibitory effects suggest that each synthetic protease inhibitor is specific for a particular oxygen-derived free radical.

Adult↗
PubMed1983

[Therapeutic effects of human urinary trypsin inhibitor on acute experimental pancreatitis].

Therapeutic effects of human urinary trypsin inhibitor (MTI) on acute pancreatitis were examined. MTI potently inhibited not only proteases such as trypsin or alpha-chymotrypsin, but also inhibited lipase or creatine phosphokinase which are considered to be related to pancreatitis. Although gabexate mesilate (gabexate) and aprotinin also strongly inhibited trypsin, their inhibition spectra against pancreatic enzymes were narrower and aprotinin also strongly inhibited trypsin, their inhibition against pancreatic enzymes were narrower than MTI. MTI inhibited proteases released from pancreatic slice by trypsin more potently than gabexate or aprotinin. The therapeutic effects of MTI on experimental acute trypsin-induced pancreatitis in dogs or rats were stronger than those of gabexate or aprotinin. These results suggest that MTI may suppress pathogenesis and development of pancreatitis in several ways, for example, by directly inhibiting trypsin and by inhibiting tissue-damaging enzymes released from the pancreas by stimulation with trypsin.

Acute Disease↗
PubMed1992

Protease inhibitors (gebexate mesylate and ulinastatin) stimulate intracellular chemiluminescence in human neutrophils.

The effect of protease inhibitors on the intracellular production of free radicals was investigated by measuring chemiluminescence (CL) elicited from phagocytosed luminol-bound microspheres (Lumispheres) in human neutrophils stimulated with formylmethionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL-8), phorbol 12-myristate 13-acetate, or diacylglycerol. Both gabexate mesylate (Foy) and ulinastatin (Miraclid), urinary trypsin inhibitor, increased intracellular CL in a dose dependent manner. Compared to control buffer without protease inhibitor, gabexate mesylate (322 micrograms/ml) caused about a 10-fold increase in intracellular CL in stimulated neutrophils, and ulinastatin (3100 U/ml) a twofold increase in neutrophils stimulated with fMLP or IL-8. When the protease inhibitors were added to the cell suspension after the phagocytosis of lumispheres, CL responses rapidly increased again to the level which was observed when both protease inhibitors and neutrophil stimulants were incubated simultaneously. In contrast, extracellular release of oxygen metabolites from stimulated neutrophils, assayed by a conventional measurement of luminol-dependent CL, was reduced by the protease inhibitors in a dose dependent fashion. When luminol-unbound microspheres were incubated with neutrophils stimulated by fMLP in luminol solution, extracellular CL was almost completely inhibited by gabexate mesylate. These results indicate that the protease inhibitors enhance the generation of intracellular CL and suppress the extracellular release of free radicals.

Dose-Response Relationship, Drug↗
PubMed2002

Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver.

BACKGROUND: Total clamping of the hepatic pedicle can induce profound hepatic ischemia/reperfusion (I/R) injury, which remains a potentially lethal problem after hepatectomy. STUDY DESIGN: The purpose of this study was to evaluate the efficacy of a protease inhibitor in ameliorating I/R injury of the human liver. In a prospective, randomized, clinical study, 66 patients who underwent liver resection under conditions of continuous inflow occlusion were randomly assigned to three groups: 25 patients were given a synthetic protease inhibitor (gabexate mesilate [GM], 2.0 mg/kg/hr) intravenously starting 24 hours before surgery until postoperative day 3 (preop GM group); 16 were similarly given GM at the beginning of surgery (intraop GM group); and 25 served as controls (without GM group). Laboratory data and intraoperative and postoperative variables were analyzed and plasma levels of cytokines--tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6)--were measured to determine the relationship between surgical stress and hepatic I/R injury. RESULTS: The three groups of patients were similar in terms of age, gender, preoperative assessments, hepatic inflow occlusion time (approximately 50 minutes), extent of resection (proportion of major and minor hepatectomy), and background liver conditions. Preoperative administration of gabexate mesilate (preop GM group) substantially ameliorated hepatic I/R injury as compared with the other patients (intraop and without GM groups); postoperative serum transaminase levels were notably decreased in association with marked suppression of IL-6 levels in blood circulation during liver surgery. This was accompanied by a lower rate of postoperative complications and no mortality. Gabexate mesilate pretreatment abrogated the positive correlation between postreperfusion hepatocyte injury and hepatic ischemia time. CONCLUSIONS: Preoperative administration of GM is useful for preventing I/R injury of the human liver, accompanied by suppression of the plasma proinflammatory cytokine IL-6.

Adult↗
PubMed1987

Abdominal aortic aneurysm complicated with chronic disseminated intravascular coagulopathy: a case of surgical treatment.

This article reports a case of an infrarenal abdominal aortic aneurysm complicated with chronic disseminated intravascular coagulopathy (DIC). The patient was a 68-year-old man; bleeding of 20 months' duration was reported. Physical examination indicated a pulsating mass in the abdomen. The diagnosis of DIC was made on the basis of standard coagulation studies. Indium 111-labeled platelet scintigraphy demonstrated an increased accumulation of radioactivity over the aneurysm. After preoperative control of the bleeding tendency was obtained by continuous intravenous infusion of gabexate mesilate (FOY), the aneurysm was successfully replaced with a prosthetic graft. Gabexate mesilate therapy is useful for DIC as is heparin therapy. If surgical intervention is required for an abdominal aortic aneurysm with concomitant DIC, preoperative control of bleeding with gabexate mesilate or heparin is recommended to lessen operative bleeding.

Aged↗
PubMed1996

Susceptibility of Helicobacter pylori to simethicone and other non-antibiotic drugs.

The antifoaming agent simethicone (Lefax), the protease inhibitor gabexate mesilate (FOY), the antimycotic ketoconazole, and the hydroxyl scavangers dimethylsulphoxide (DMSO) and allopurinol were investigated for growth inhibition of Helicobacter pylori and representative strains of other bacterial species. H. pylori were selectively inhibited by 64-128 mg/L of simethicone, 64-128 mg/L gabexate mesilate, and 16-64 mg/L ketoconazole. Dimethylsulphoxide and allopurinol showed no antibacterial effect at concentrations used therapeutically. It is concluded that gabexate mesilate, ketoconazole and, particularly, simethicone are candidates for treatment of H. pylori infection.

Antifoaming Agents↗
PubMed1987

Coagulability and fibrinolytic changes during veno-venous bypass in liver transplantation.

In clinical liver transplantation, a venous bypass that rechannels the blood flow from the inferior vena cava and portal vein to the superior vena cava has been used to maintain the venous return. However, the usage of mechanical shunt has given rise to derangements of blood coagulability and fibrinolysis. Therefore, changes of coagulability and fibrinolysis during the venous bypass were examined in dogs using a centrifugal pump (Bio-Pump), and the effect of gabexate mesilate for coagulation were studied. Venous bypass from the inferior vena cava and the portal vein to the external jugular vein was performed in mongrel dogs (group A: bypass without pump, group B: bypass with the Bio-Pump, group C: bypass with the Bio-Pump and the addition of gabexate mesilate). In group A, blood pressure gradually decreased, but in groups B and C it maintained the pre-bypass level. All results of coagulation parameters and fibrinolytic measurements of group B were not significantly different from those of group A; only partial thromboplastin time was prolonged in group B. However, this prolongation was effectively prevented by the addition of gabexate mesilate in group C.

Animals↗
PubMed2002

Biological phenotype determination with ex vivo model in gastric cancer for matrix-metalloproteinase inhibitor treatment.

Among the many biological characteristics of cancer, matrix-metalloproteinases (MMPs) are essential for tumor invasion and metastasis. To test the possibility of ex vivo model as a therapeutic guideline for MMP inhibitor (MMPI) treatment, we evaluated IC50 of the gabexate mesylate against MMP-9. Thirty-four paired normal and gastric cancer tissues were tested to measure the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. Both MMP-9 expression (p=0.04) and IC50 (p=0.02) were higher in cancer than normal tissues. IC50 of the cancer tissues was higher than paired normal tissues especially in cases with large tumor (> or =5 cm) (p=0.03), higher T-stage (p=0.04), lymph node metastasis (p=0.04) and advanced stage (p=0.04). In cancers extending beyond submucosa or in diffuse/mixed type, a tendency of higher IC50 was observed than tumors confined to submucosa or intestinal type cancer despite similar MMP-9 activity between the groups. Patients with high IC50 showed poorer prognosis than patients with low IC50 in curatively-resected group. In multivariate analysis, high IC50 was suggested as an independent prognostic factor. We were able to differentiate the high risk patients using IC50 of gabexate mesylate in ex vivo model. This model can be applied in detecting patients with poor prognosis and patients who may benefit from MMPI treatment.

Adenocarcinoma↗
PubMed1986

Pharmacological studies of FUT-175, nafamostat mesilate. V. Effects on the pancreatic enzymes and experimental acute pancreatitis in rats.

Effects of FUT-175 on the pancreatic enzymes in vitro and in vivo in the enterokinase-induced experimental acute pancreatitis were investigated, and they were compared with those of gabexate and aprotinin. In in vitro experiments, FUT-175 inhibited the pancreatic protease activities 10 to 100 times more potently than gabexate. Furthermore, FUT-175 inhibited the enterokinase activity. Unlike aprotinin, FUT-175 inhibited alpha 2-macroglobulin bound trypsin activity as well as free trypsin. In in vivo experiments, at doses of 0.5-50 micrograms/kg/min, FUT-175 suppressed the elevated protease activities in the experimental acute pancreatitis more potently than gabexate. Differently from the action of aprotinin, FUT-175 suppressed trypsin activities both in the pancreas and in the plasma to the same extent. Furthermore, FUT-175 reduced the mortality of rats in the experimental acute pancreatitis in a dose-dependent manner. These data strongly support that FUT-175 is clinically useful in the therapy of acute pancreatitis.

Acute Disease↗
PubMed2003

Pharmacological prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis.

The incidence of clinically significant pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) ranges from 1-13.5%. It is more common after therapeutic procedures such as sphincterotomy or balloon dilatation of the sphincter, and diagnostic procedures such as biliary or pancreatic manometry. The severity of post-ERCP pancreatitis may vary from very mild to extremely severe disease with multiple organ failure and fatal outcome. Several factors including papillary oedema, injection of hyperosmolar contrast-material, introduction of previously activated enzymes during repeated cannulation, bacterial contamination and thermal injury from endoscopic sphincterotomy have been implicated as triggering factors that initiate the sequential cascade of pancreatic autodigestion and release of proinflammatory cytokines leading to acute pancreatitis. Recovery from post-ERCP pancreatitis is usually rapid when the injury is confined to the pancreas. However, systemic production of inflammatory mediators may lead to the development of more serious manifestations including multiorgan failure.A wide range of pharmacological agents has been tested in experimental and clinical trials, but the results have been largely disappointing. Several drugs are discussed in this review, but only somatostatin and gabexate (gabexate mesilate) have consistently shown a moderate beneficial effect. In clinical trials, both gabexate and somatostatin appear equally effective in reducing the incidence of pancreatitis by two-thirds compared with controls. However, both drugs need to be given by continuous infusion for about 12 hours and this makes them less cost-effective than conventional treatment. One potential strategy is to reserve these drugs for high-risk patients undergoing ERCP. Preliminary studies have shown encouraging results with nitroglycerin, antibacterials and heparin. However, these observations need to be corroborated in a rigorous fashion in large, randomised, double-blind, controlled trials. If these drugs are found to be effective in further trials, it may become cost-effective to use them routinely for the prevention of post-ERCP pancreatitis. Despite the theoretical benefits, interleukin-10 has not shown a consistent benefit in clinical trials. It is probable that other cytokine inhibitors or modulators may become available for future trials to prevent pancreatitis or more probably, to reduce the severity of pancreatitis. Further research also should focus on developing newer molecules or the use of a combination of currently available drugs to prevent pancreatitis in high-risk patients undergoing therapeutic ERCP procedures.

Acute Disease↗
PubMed2003

Pharmacological prevention of post-ERCP pancreatitis: which therapy is best?

The effectiveness of the pharmacological prevention of post-ERCP pancreatitis can be established only from large controlled randomized studies. Over the last decade, fifteen studies dealt with these characteristics and a cumulative series of about 3,000 non-selected patients were evaluated. Cumulating the data of the placebo groups, the median incidence of post-ERCP pancreatitis was 8.7% (mean 9.3%), the range varied from 1.6 to 17.7% likely due to case mix and/or different criteria defining acute pancreatitis. These variables, other than differences in the modalities of the administration of the drugs, could explain their contrasting effectiveness between the studies. Somatostatin and octreotide were the prophylactic drugs more frequently experimented (8 studies) followed by corticosteroids such as hydrocortisone, prednisone or methylprednisolone (four studies) and gabexate (three studies). While octreotide was confirmed to be ineffective, somatostatin and gabexate seem to be the best for the prevention of post-ERCP pancreatitis, but both can present some limits such as unreported sample size calculation in the statistical analysis for somatostatin studies and lack of widespread commercial availability for gabexate. Pharmacoeconomic studies are lacking in English language literature. On this point of view, it seems reasonable and preferable a selective as opposed to universal pharmacological prophylaxis but, actually, the experimented pre-treatments in high-risk patients are ineffective.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed1993

Multivariate analysis of risk factors for thrombus formation in University of Tokyo ventricular assist device.

Of 77 University of Tokyo ventricular assist devices used in a total of 70 patients at 21 institutions, 13 pumps were found to have macroscopic thrombus formations. Because 19 devices that were used for less than 24 hours showed no thrombus deposition, they were considered not to have been sufficiently exposed to the thrombogenic environment for macroscopic thrombus deposition and were removed from the subsequent multivariate study. A total of eight potential risk factors were assessed in relation to thrombosis. Prevalences of thrombus formation were compared between two groups with or without each of the risk factors. In a univariate analysis, the following categoric variables were demonstrated to be significantly associated with complications, in descending order of significance: use of gabexate mesilate (protease inhibitor) as an anticoagulant (p = 0.005), normal platelet count (p = 0.010), duration of support (p = 0.038), leukocytosis (p = 0.042), and minimum pumping flow (p = 0.042). Use of heparin and the consequent increase in activated clotting time showed no relationship. Multivariate discriminant analysis, which was done to identify risk factors rejecting cross correlation between each variable, demonstrated platelet count (p = 0.006), use of gabexate mesilate (p = 0.007), and minimum flow (p = 0.008) to have significant and independent risks. These results indicate the importance of maintaining pumping flow above a certain minimum level, addition of antiplatelet drugs to the antithrombogenic regimen, and nonuse of gabexate mesitate.

Adolescent↗
PubMed1999

Effect of protease inhibitor on ischemia-reperfusion injury to rat liver.

Liver failure due to ischemia-reperfusion injury, believed to be closely related to the generation of oxygen-free radicals, is a serious problem during liver surgery. Gabexate mesilate, a synthetic protease inhibitor, suppresses the extracellular release of oxygen-free radicals in the microvascular endothelium. To determine its effects on ischemia-reperfusion injury to the liver, we performed experiments with rats. We divided the animals into two ischemia-reperfusion groups: an experimental group, which underwent ischemic injury for 30 minutes, along with the infusion of gabexate mesilate, and a control group, which underwent injury only. Each group was then divided into four subgroups: ischemic injury only and 60-, 120-, and 180-minute reperfusion injury. The test parameters were tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) in serum and superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) in liver and lung tissues. The experimental group had a significantly higher liver SOD and catalase levels and a significantly lower level of liver and lung MDA than the control groups. TNFalpha levels in the experimental groups were significantly lower during the early phase, but a comparison of IL-6 levels between the two groups yielded no differences. Levels of lung catalase and SOD were not significantly different between the two groups. We concluded that protease inhibitor suppressed liver ischemia-reperfusion injury, and that it was due to an increase of antioxidant or suppression of oxygen-free radicals. The roles of TNFalpha and IL-6 in liver reperfusion injury were not clear, though TNFalpha might have had an effect during the early phase. With liver ischemia-reperfusion injury, the mechanism of lung involvement might be different from that of liver involvement.

Animals↗
PubMedDate not supplied

Protective effect of CR 1409 (cholecystokinin antagonist) on experimental pancreatitis in rats and mice.

CR 1409, a glutaramic acid derivative with competitive cholecystokinin-antagonistic activity, was administered IP and evaluated in comparison with proglumide (the model CCK-receptor antagonist), gabexate (protease inhibitor) and PGE2 (cytoprotective) on two different models of experimental pancreatitis. Acute pancreatitis was induced in mice by six IP injections of 50 micrograms/kg caerulein at hourly intervals. The drugs were administered 30 minutes before each caerulein administration. Blood samples and pancreata were collected 3 hours after the last caerulein injection. In the second experiment, pancreatitis was induced in rats by injecting 0.3 ml 6% sodium taurocholate interstitially into the pancreas. The drugs were administered twice, 30 minutes before and 3 hours after taurocholate. The animals were killed 6 hours after laparotomy and blood samples and pancreata were collected. CR 1409 exhibited on both pancreatitis models a protective effect in a dose range of 0.3-10 mg/kg. Proglumide exhibited a protective activity at higher doses (200-400 mg/kg). Gabexate and PGE2 were effective only in pancreatitis induced by taurocholate in a dose range of 30-60 mg/kg and 60-130 micrograms/kg respectively. These results, showing a high protective effect of CR 1409 on different models of acute pancreatitis, suggest an important role of CCK in the pathogenesis of pancreatitis.

Acute Disease↗
PubMed1997

Effects of protease inhibitors on postischemic recovery of the heart.

It is well known that activation of proteases in the lysosomes and cytosol is one of the mechanisms of ischemic injury. It might thus be beneficial to determine whether the addition of several clinically available protease inhibitors to a cardioplegic solution can improve its protective ability. Using an isolated working rat heart preparation, the effects of several protease inhibitors (serine protease inhibitors; nafamostat mesilate and gabexate mesilate, a thiol-protease inhibitor; NCO-700; and a urinary trypsin inhibitor, urinastatin) on the postischemic recovery of function and enzyme leakage were investigated in this study. These protease inhibitors were added to either the cardioplegic solution or reperfusion solution. The addition of each of the protease inhibitors, except urinastatin, to the cardioplegic solution improved the postischemic recovery of function and reduced enzyme leakage. The dose-response characteristics of these three protease inhibitors were bell shaped, and the optimal concentrations of nafamostat mesilate, gabexate mesilate, and NCO-700 were 5 microM, 100 microM, and 20 microM, respectively. In contrast to the results of the preischemic treatment study, the addition of any of the protease inhibitors to the perfusion medium during Langendorff reperfusion failed to improve the postischemic recovery of function and to reduce enzyme leakage. Surprisingly, the addition of NCO-700 to the reperfusion solution at a concentration of 5 microM or higher had rather harmful effects on both functional recovery and enzyme leakage. These findings suggest that serine and thiol proteases may play an important role in myocardial injury during ischemia, but not necessarily during reperfusion.

Animals↗
PubMed2001

Regional effects of nafamostat, a novel potent protease and complement inhibitor, on severe necrotizing pancreatitis.

BACKGROUND: We evaluated the effect of the novel protease inhibitor nafamostat on rat necrotizing pancreatitis through different routes of administration. METHODS: Three hours after the induction of severe pancreatitis, the rats received intravenous gabexate or intravenous or local mesenteric intra-arterial nafamostat. At 9 hours, ascites and bronchoalveolar lavage fluid were collected for the evaluation of capillary leakage (Evans blue extravasation). Pancreas and lung were excised for histologic features, myeloperoxidase, and trypsinogen activation peptide. Twenty-four hour survival was evaluated. RESULTS: Only the intravenous infusion of nafamostat significantly reduced myeloperoxidase (11.7 +/- 2.3 vs 18.3 +/- 1.8 mU/mg; P <.05) and capillary leakage in lungs (Evans blue dye, 1.6 +/- 0.3 vs 2.6 +/- 0.3; P <.05). Only intra-arterial infusion of nafamostat significantly diminished capillary peritoneal leakage (Evans blue dye, 3.6 +/- 0.9 vs 9.4 +/- 0.4; P <.01). Typsinogen activation peptide levels were significantly reduced in all groups, but only intra-arterial infusion did so to baseline. Histologic inflammation in the pancreas was most significantly reduced after intra-arterial infusion (0.92 +/- 0.08 vs 2.91 +/- 0.06; P <.05). No form of protease inhibition reduced mortality rates. CONCLUSIONS: The effects of protease inhibition depend on the route of administration. Nafamostat has maximal effects on the pancreas and peritoneal capillary leakage when delivered by way of local intra-arterial infusion, and shows a greater reduction of lung leukocyte infiltration and capillary leakage by the intravenous route. Nafamostat is more effective than gabexate.

Animals↗