Metabonomics research of gabex mesylate on septic-induced acute lung injury in rats / 中华急诊医学杂志

Objectve:To study the effect of gabexate mesylate (GM) on acute lung injury (ALI) in septic rats based on metabonomics.Methods:Fifty-seven SD rats were randomly(random number) divided into three groups: sham operation group (SC group), cecal ligation puncture induced septic ALI group (CLP group), and intraperitoneal administration of GM at 1 h after CLP (CLP-GM group). Twenty-four h after the experiment, the survival of rats in the SC, CLP and CLP-GM groups was observed, the lung tissue was collected for HE staining to observe the pathological changes, and the plasma was collected for metabonomics detection to analyze the characteristics of metabolites.Results:Compared with the SC group, the infiltration of inflammatory cells in the lung tissue of rats in the CLP groupincreased significantly, and the metabolic profile of plasma changed significantly. However, the pathological and metabonomic characteristics of the CLP-GM group showed that the above changes were reversed after the application of GM. Twelve major differential metabolites were found in plasma. The metabolic pathways involved in the disorder included biosynthesis of phenylalanine, tyrosine and tryptophan, phenylalanine metabolism and sphingolipid metabolism.Conclusions:GM may improve septic ALI by regulating amino acid metabolism, sphingolipid metabolism and other metabolic pathways.

Cost-effectiveness Analysis of 4 Kinds of Protease Inhibitor Preventing Hyperamylasemia and Pancreatitis after ERCP of Choledocholithiasis Patients / 中国药房

OBJECTIVE:To evaluate the economics of somatostatin,ulinastatin,octreotide and gabexate preventing hyperamy-lasemia and pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS:Medical records of 316 cho-ledocholithiasis patients underwent ERCP were selected from our hospital during Jul. 2008-Apr. 2016,and then divided into blank control group(58 cases),somatostatin group(64 cases),ulinastatin group(65 cases),octreotide group(68 cases)and gabexate group (61 cases) according to the use of protease inhibitor. Before ERCP,blank control group received routine treatment as fast-ing,parenteral nutrition support,acid suppression,etc. Based on it,other 4 drug groups received prophylactic drug use according to package inserts 6 h before ERCP. The incidence of hyperamylasemia and pancreatitis after ERCP,VAS scores 3,24,48 h after surgery and the occurrence of ADR were compared among 5 groups. The cost-effectiveness analysis was used to evaluate the eco-nomics of therapy plans in each group. RESULTS:Compared with blank control group,hospitalization time of somatostatin group, ulinastatin group,octreotide group and gabexate group were shortened significantly;the incidence of hyperamylasemia and pancre-atitis were significantly decreased;VAS score 3,24,48 h after surgery were significantly decreased,with statistical significance (P0.05). The cost-effectiveness ratio of somatostatin group was the lowest and has cost-effec-tiveness advantage. The results were supported by incremental cost-effectiveness and sensitivity analysis. CONCLUSIONS:Soma-tostatin,ulinastatin,octreotide and gabexate can significantly prevent the occurrence of hyperamylasemia and pancreatitis after ER-CP,and relieve pain with good safety. Somatostatin can achieve the best therapeutic efficacy at the lowest cost,so it is the best plan for hyperamylasemia and pancreatitis after ERCP.

A novel thermosensitive in-situ gel of gabexate mesilate for treatment of traumatic pancreatitis: An experimental study / 华中科技大学学报（医学）（英德文版）

Gabexate mesilate (GM) is a trypsin inhibitor, and mainly used for treatment of various acute pancreatitis, including traumatic pancreatitis (TP), edematous pancreatitis, and acute necrotizing pancreatitis. However, due to the characteristics of pharmacokinetics, the clinical application of GM still needs frequently intravenous administration to keep the blood drug concentration, which is difficult to manage. Specially, when the blood supply of pancreas is directly damaged, intravenous administration is difficult to exert the optimum therapy effect. To address it, a novel thermosensitive in-situ gel of gabexate mesilate (GMTI) was developed, and the optimum formulation of GMTI containing 20.6% (w/w) P-407 and 5.79% (w/w) P188 with different concentrations of GM was used as a gelling solvent. The effective drug concentration on trypsin inhibition was examined after treatment with different concentrations of GMTI in vitro, and GM served as a positive control. The security of GMTI was evaluated by hematoxylin-eosin (HE) staining, and its curative effect on grade II pancreas injury was also evaluated by testing amylase (AMS), C-reactive protein (CRP) and trypsinogen activation peptide (TAP), and pathological analysis of the pancreas. The trypsin activity was slightly inhibited at 1.0 and 5.0 mg/mL in GM group and GMTI group, respectively (P<0.05 vs. P-407), and completely inhibited at 10.0 and 20.0 mg/mL (P<0.01 vs. P-407). After local injection of 10 mg/mL GMTI to rat leg muscular tissue, muscle fiber texture was normal, and there were no obvious red blood cells and infiltration of inflammatory cells. Furthermore, the expression of AMS, CRP and TAP was significantly increased in TP group as compared with control group (P<0.01), and significantly decreased in GM group as compared with TP group (P<0.01), and also slightly inhibited after 1.0 and 5.0 mg/mL GMTI treatment as compared with TP group (P<0.05), and significantly inhibited after 10.0 and 20.0 mg/mL GMTI treatment as compared with TP group (P<0.01). HE staining results demonstrated that pancreas cells were uniformly distributed in control group, and they were loosely arranged, partially dissolved, with deeply stained nuclei in TP group. Expectedly, after gradient GMTI treatment, pancreas cells were gradually restored to tight distribution, with slightly stained nuclei. This preliminary study indicated that GMTI could effectively inhibit pancreatic enzymes, and alleviate the severity of trauma-induced pancreatitis, and had a potential drug developing and clinic application value.

Preparation and quality evaluation of gabexate mesilate thermosensitive in-situ hydrogels / 国际药学研究杂志

Objective To prepare thermosensitive in situ hydrogels (ISG) of gabexate mesilate and establish quality control method.Methods ISGs were prepared using PF127 and PF68 as matrix, evaluated by gelling temperature , gelling time, gelling ca-pacity in vitro, and determinated by HPLC.Results The gelling time of ISG was (1.8 ±0.2)min, with gelling temperature at 31℃. When the gel temperature rose to 31℃, the viscosity of ISG increased dramatically .The linear range of HPLC determination curve was 10-350 μg/ml, with an average recovery of 99.63%( RSD=0.88%) .Conclusion Preparation of the gel with controllable quality is simple and easy .The determination method is reliable for gabexate mesilate thermosensitive in situ hydrogels .

Preparation and quality evaluation of gabexate mesilate thermosensitive in-situ hydrogels / 国际药学研究杂志

Objective To prepare thermosensitive in sitt hydrogels (ISG) of gabexate mesilate and establish quality control method. Methods ISGs were prepared using PF127 and PF68 as matrix, evaluated by gelling temperature, gelling time, gelling capacity in vitro, and determinated by HPLC. Results The gelling time of ISG was (1. 8 ±0. 2) min, with gelling temperature at 317. When the gel temperature rose to 31 7, the viscosity of ISG increased dramatically. The linear range of HPLC determination curve was 10 -350 μg/ml, with an average recovery of 99. 63% (RSD =0. 88%). Conclusion Preparation of the gel with controllable quality is simple and easy. The determination method is reliable for gabexate mesilate thermosensitive m sitt hydrogels.

The Use of Gabexate Mesylate and Ulinastatin for the Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

BACKGROUND/AIMS: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP). Only a few pharmacologic agents have been shown to have potential efficacy for the prophylactic treatment of post-ERCP pancreatitis (PEP). The aim of this study was to determine whether prophylactic gabexate and ulinastatin can decrease the incidence of PEP. METHODS: From January 2005 to April 2010, 1,679 patients undergoing ERCP treatment were consecutively enrolled in the study. After selective exclusion, a total of 1,480 patients were included in the analysis. The patients were separated into 3 groups according to the prophylactic administration of gabexate (593 patients), ulinastatin (229 patients), or saline solution (658 patients) and analyzed retrospectively. The primary outcome measurements were the incidence of pancreatitis and hyperamylasemia. RESULTS: PEP occurred in 21 of the 593 (3.5%) patients who received gabexate, 16 of the 229 (7.0%) patients who received ulinastatin, and 48 of the 658 (7.3%) patients who received a saline solution. The incidence of PEP was significantly different between the gabexate and ulinastatin or saline solution groups (p<0.05). CONCLUSIONS: Gabexate prophylaxis is effective in preventing PEP. However, there is no difference in the beneficial effects of the prophylactic administration of ulinastatin and a saline solution.

Could Nafamostat or Gabexate Prevent the Post Endoscopic Retrograde Cholangiopancreatography Pancreatitis? / 대한소화기학회지

BACKGROUND/AIMS: ERCP is the most common procedure for the diagnosis and treatment of bile duct and pancreatic disease, but Post-ERCP pancreatitis makes poor outcome in some cases. The protease inhibitors, nafamostat and gabexate, have been used to prevent pancreatitis related to ERCP, but there is some debate. We tried to evaluate the efficacy of gabexate and nafamostat for the prevention of post-ERCP pancreatitis. METHODS: Two hundred forty two patients (73 patients in the gabexate group, 88 patients in the nafamostat group and 81 patients in the placebo group) were included in the study after selective exclusion. The incidence of pancreatitis after ERCP was compared among groups. RESULTS: The incidence of pancreatitis were 6.8% in the gabexate group, 5.7% in the nafamostat group and 6.2% in the placebo group (p=0.954). CONCLUSIONS: There was no meaningful difference among the gabexate, nafamostat and placebo group.

Gabexate combined with Xuebijing after local infusion in treatment of severe acute pancreatitis / 国际外科学杂志

ObjectiveTo observe the treatment effect of seveve acute pancreatitis (SAP) with gabexate combined with Xuebijing after local infusion. MethodsForty-four patients with SAP were randomly divided into receiving intravenous gabexate or Xuebijing alone (control group) group and receiving local infusion with gabexate combined with Xuebijing( experimental group) group. At 1,7,14 days of testing in diamine oxidase (DAO), lipopolysaccharide, IL-18, TNF-α, APACHE- Ⅱ score, T lymphocyte subpopulation and monocyte HLA-DR expression and single change in the number of nuclear cells were tested. ResultsBetween two patients groups at 1,7,14 days diamine oxidase, lipopolysaccharide, IL-18, TNF-α, APACHE-Ⅱ score showed a downward trend; T suppressor cells (Ts) reduced in their percentage; total T lymphocytes, T helper cell (Th), monocyte HLA-DR expression (percentage) and mononuclear cells showed an upward trend in the experimental group than control group, the differences being statistically significant (P ＜ 0.05). In the experimental group and control group, the pain relief time, intestinal function recovery time, the withdrawal of ventilator time, the incidence of sepsis, the rate of conversion to open surgery were statistically significant different (P ＜ 0.05 ). Conclusions Compared with intravenous drug use alone the implementation of gabexate combined with Xuebijing local infusion can reduce the early course of SAP patients intestinal permeability and reduce endotoxin translocation, protect intestinal barrier function of patients with SAP, improve the patients' immune function, symptoms, signs and reduce the rate of sepsis and transit operations.

Nafamostat for Prophylaxis against Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis Compared with Gabexate

BACKGROUND/AIMS: The protease inhibitors, nafamostat and gabexate, have been used to prevent pancreatitis related to endoscopic retrograde cholangiopancreatography (ERCP). In vitro, nafamostat inhibits the pancreatic protease activities 10-100 times more potently than gabexate. We evaluated the efficacy of nafamostat for prophylaxis against post-ERCP pancreatitis in comparison with gabexate. METHODS: Five hundred patients (208 patients in the nafamostat-treated group and 292 in the gabexate-treated group) were analyzed retrospectively after selective exclusion. The incidences of pancreatitis and hyperamylasemia after the ERCP were compared between the nafamostat and gabexate groups. RESULTS: The incidences of acute pancreatitis and hyperamylasemia were 9.1% and 40.9%, respectively, in the nafamostat-treated group, and 8.6% and 39.4% in the gabexate-treated group. The frequencies of post-ERCP pancreatitis and hyperamylasemia did not differ significantly between the two groups, Post-ERCP pancreatitis in two group did not vary according to the different ERCP procedures. The mean serum amylase level at 6 h after ERCP was significantly lower in the nafamostat-treated group than in the gabexate-treated group (p=0.020). However, the difference in serum amylase level did not persist at 18 h and 36 h post-ERCP. CONCLUSIONS: Administration of nafamostat before ERCP was not inferior to gabexate in protecting against the development of pancreatitis.

The protective effect of Gabexate mesilate on D-galactosamine-lipopolysaccharide-induced acute liver failure in rats / 中华急诊医学杂志

Objective To investigate the protective effect of Gabexate mesilate(GM)on D-galactosamine- lipopolysaccharide-indneed acute liver failure in rats.Methods The model of acute liver failure in rats was produced by injection of D-galactosamine(D-GalN)and lipopolysaccharide(LPS).The alanine aminotransferase(ALT),aspartate aminotransferase(AST)in serum and malondiadehyde(MDA)content,superoxide dismutase(SOD)and glutathione peroxidase(GSH-PX)activities in liver homogenate were assayed by spectrophotometry.The levels of turnout necrosis factor-?(TNF-?),interleukin-?(IL-?)and interleukin-6(IL-6)were determined by ELISA method.Hepatic pathological examination was observed.Results 25 mg?kg~(-1),50mg?kg~(1),100 mg?kg~(-1) of GM significantly decreased the serum transaminase activities,the infiltration of inflammatory cells,and MDA content,hut didn't reduce SOD and GSH- PX activities in liver homogenate.GM significantly reduced TNF-?,IL-1?and IL-6 levels in serum.Conclusions GM showed significant protective effects on acute liver failure in rats.

Risk Factors for Post-ERCP Pancreatitis after Needle Knife Sphincterotomy following Repeated Probing / 대한소화기내시경학회지

BACKGROUND/AIMS: Needle knife sphincterotomy (NKS) following repeated probing due to difficult cannulation during ERCP increase the risk of post-ERCP pancreatitis. However, the risk factors for post-ERCP pancreatitis are not well-known. The aim of this study is to investigate the incidence and risk factors of post-ERCP pancreatitis in patients who underwent NKS. We also evaluated the effect of gabexate on the prevention of post-ERCP pancreatitis. METHODS: Medical records from a total of 200 patients who underwent NKS following repeated probing during ERCP were reviewed retrospectively. The potential risk factors for post-ERCP pancreatitis were investigated. The effect of gabexate infusion after ERCP procedure on the incidence of post-ERCP pancreatitis was also evaluated. RESULTS: A total of 13 (6.5%) patients out of 200 patients developed post-ERCP pancreatitis. Gender, age, the presence of pancreatitis at procedure, underlyng disease, direction of sphincterotomy, success or failure of cannulation, diameter of CBD, pancreatic duct status and the presence of acinar filling were proved unrelated with pancreatitis. Post-ERCP pancreatitis developed in 9 out of 38 (23.7%) when gabexate was given, while 4 out of 160 (2.5%) experienced pancreatitis without administration of gabexate. CONCLUSIONS: We couldn't determine any risk factor for pancreatitis in patients who underwent NKS following repeated probing during ERCP. The gabexate infusion after ERCP procedure might be associated with the increased risk of pancreatitis.

Effects of Gabexate Mesilate (Foy(R)) on Endotoxin-Induced Acute Lung Injury in Rabbit / 대한마취과학회지

BACKGROUND: This study was to clarify the effects of gabexate mesilate (Foy(R)), a synthetic protease inhibitor, on endotoxin induced acute lung injury in rabbit. METHODS: Animals were randomly assigned to one of four groups: saline only (n = 7), saline and Escherichia coli endotoxin 5 mg/kg over 30 mins (n = 7), Foy(R) 1 mg/kg bolus, followed by infusion of Foy(R) at 1 mg/kg/h and endotoxin (n = 7), Foy(R) 2 mg/kg bolus, followed by infusion of Foy(R) at 2 mg/kg/h and endotoxin (n = 7). Infusion of saline or Foy(R) was started 0.5 hour before the start of infusion of saline or endotoxin and continued for 6.5 hours. At the end infusion animals were sacrificed, and the wet to dry (W/D) weight ratio of lung, lung injury score and leukocyte counts, percentage of polymorphonuclear leukocyte (PMNL), and concentrations of albumin and interleukin-8 (IL-8) in bronchoalveolar lavage fluid (BALF) were evaluated. RESULTS: Endotoxin decreased the PaO2 and peripheral blood leukocyte and platelet counts. And it increased the W/D weight ratio of lung, lung injury score and leukocyte counts, percentage of PMNL, and concentrations of albumin and IL-8 in BALF. Foy(R) attenuated all these changes except the decreased peripheral blood leukocyte count. CONCLUSIONS: These findings suggest that Foy(R) attenuates endotoxin-induced acute lung injury in rabbit by inhibiting neutrophil, IL-8 and platelet responses which may play a central role in sepsis related lung injury.

The Effect of Gabexate Mesylate in vivo Model of Intimal Hyperplasia on the Activity of Matrix Metalloproteinase and Proliferation of Smooth Muscle Cell

PURPOSE: Migration and proliferation of vascular smooth muscle cells (VSMCs) are important for neointimal formation after arterial injury. Migration of VSMCs requires the degradation of basement membrane and extracellular matrix surrounding the cell. There is increasing evidence that VSMCs produce extracellular matrix-degradating proteinases, such as matrix metalloproteinases (MMPs) after arterial injury. METHOD: To assess the effect of gabexate mesylate, an MMP inhibitor, in VSMCs proliferation, migration and intimal thickening, the gelatinolytic activity of MMPs and the expression of VSMC alpha-actin mRNA were analyzed in the balloon-injured rat aorta model. Forty male Sprague-Dawley rats, weighing of 250 to 300 g, underwent aortic intimal denudation with a 2 F balloon catheter. The rats were divided into two groups: the control group (n=20: no medication), and the treatment group (n=20: daily intraperitoneal injection of gabexate mesylate (5.0 mg/kg)). The aorta was harvested at various time intervals, 1, 5, 7, and 21 days after the injury. MMP expression was analyzed by using gelatin zymography, the VSMC alpha-actin mRNA expression was analyzed by RT-PCR, and the intima to media area ratio (IMAR) were evaluated microscopically. RESULT: The treatment group showed significant suppression of intimal hyperplasia compared to the control group on day 21 (P<0.05). Mean IMAR on day 21 were 1.18+/-0.2 in the control group and 0.61+/-0.06 in the treatment group. The gelatinolytic activity of MMP-9 on day 1 after injury was significantly lower in the treatment group compared to the control group (P<0.05). The gelatinolytic activity of activated MMP-2 on days 5, 7, and 21 after injury, decreased significantly in the treatment group compared to the control group (P<0.05). The expression of VSMC alpha-actin mRNA increased on days 7 and 21 after injury. Although the expression of VSMC alpha-actin mRNA was lower in the treatment group, it was not statistically significant. CONCLUSION: These results suggest that gabexate mesylate suppresses intimal hyperplasia formation after arterial injury by decreasing activation of MMP.

Effects of protease inhibitor gabexate mesilate on motility of human Oddi's sphincter / 中华消化杂志

0.05).②Gabexate mesilate significantly reduced the frequency of contraction (P0.05).③High dose gabexate mesilate could markedly reduce the motility index ( P

The Effects of Gabexate Mesilate on the Ishemia-Reperfusion Injury in the Rabbit Liver

PURPOSE: Ischemia-reperfusion is an important pathologic process that leads to impairment of the liver after major surgery. Ischmia-reperfusion injury includes both hypoxia and an inflammatory response associated with reperfusion; the former is caused by the lack of microvascular perfusion and the latter is mediated by cytyokines and oxygen free radicals. In addition to inhibiting thrombin, plasmin, kalikrein, trypsin, and neutrophil elastase, gabexate mesilate also plays an important role in inhibiting cytokines and oxygen free radical production. The purpose of this study was to investigate the effects of gabexate mesilate on ischemia- reperfusion injury in the liver. METHODS: Twenty-four New Zealand white rabbits were divided into three groups. Clamping was not done in group A (n=8), although it was done in group B (n=8) and group C (n=8). Group C received intravenous infusion of gabexate mesilate (10 mg/kg/hr) continuously during the process of clamping. Serum alanine aminotrasferase (ALT) and purine nucleoside phophorylase (PNP) were measured immediately before clamping, following 30-minute ischemia, and after 60-minute reperfusion. Hepatic tissue adenosine triphophate (ATP), xanthine oxidase, and malondialdehyde (MDA) plus 4-hydroxyalcenals (4HA) were measured after reperfusion. RESULTS: Compared with group A, group B and group C demonstrated a significant increase in ALT and PNP levels following ischemia and reperfusion, as well as in xanthine oxidase and MDA plus 4HA levels following reperfusion. However, ATP levels showed no significant differences among the three groups. ALT levels were significantly lower in group C than in group B following reperfusion (P<0.01),although there was no significant differences in PNP levels between them. Xanthine oxidase and MDA plus 4HA levels were significantly lower in group C than in group B (P<0.05). The results suggest that gabexate mesilate inhibits an increase in ALT, xanthine oxidase, and MDA plus 4HA levels. CONCLUSION: Gabexate mesilate inhibits oxygen free radical production of xanthine oxidase, and results in a reduction of hepatic ischemia-reperfusion injury.

Effects of Gabexate Mesilate for the Prevention of Pancreatic Damage Related to ERCP / 대한소화기내시경학회지

BACKGROUND/AIMS: Recent studies reported that 1g of gabexate mesilate (GM) was effective in preventing endoscopic retrograde cholangiopancreatography (ERCP)-related pancreatic damage. The aim of this study was to evaluate the effectiveness of low dose GM for the prevention of ERCP-related pancreatic damage. METHODS: This study was performed prospectively with 102 consecutive patients (68 for the GM group, 34 for the placebo group) who were scheduled for ERCP. Infusion of GM (500 mg) was started 30 minutes before ERCP and continued for 12 hours afterward. The serum amylase and lipase were measured before ERCP and 4, 8, and 24 houps after ERCP. RESULTS: The incidence of hyperenzymemia was 45.6% in the GM group and 55.9% in the control group (p=0.40). Acute pancreatitis was developed in only one patient who was given the placebo. Although difficult cannulation, visualization of the pancreatic duct, performance of therapeutic procedures, and longer total procedure time were associated with an increased incidence of hyperenzymemia, the incidence of pancreatic damage was not affected by the GM treatment in these conditions. CONCLUSIONS: Prophylactic treatment with 500 mg of GM has no advantage for the prevention of ERCP-related pancreatic damage. Considering the cost effectiveness, further studies are necessary to identify the patients at greatest risk fot acute pancreatitis.

Gabexate for the Prevention of Pancreatic Complications Following Endoscopic Retrograde Cholangiopancreatography / 대한소화기내시경학회지

BACKGROUND/AIMS: Gabexate, a protease inhibitor, has been known to prevent pancreatic damage following ERCP. We conducted a prospective and randomized study to assess the preventive effect of gabexate. Methods: Of the 96 patients enrolled, 46 were treated with gabexate and 50 with placebo. The groups were similar with regard to sex, age, body-mass index, and the final diagnosis of ERCP. RESULTS: 24 patients (25.0%) had elevated pancreatic-enzyme levels; the frequency was similar in the two groups (P=0.48). Mean serum amylase value at 4 hours after ERCP was similar in patients with elevated basal level (220.5+/-43.2 U/L) and those with normal basal level (170.4+/-31.2 U/L). After the procedures, serum amylase values were lower in the gabexate group (137.1+/-19.8 U/L) than in the placebo group (212.0+/-50.4 U/L). The differences were not significant in the mean levels of amylase between the groups for any of imaging of the pancreatic ducts (pancreatic-duct imaging, 201.5+/-49.4 U/L, bile-duct imaging, 153.7+/-30.0 U/L). But in the patients with pancreatic duct imaging, serum amylase values were significantly higher in the placebo group (295.0+/-97.6 U/L) than in the gabexate group (112.0+/-10.6 U/L)(p<0.05). CONCLUSIONS: Prophylactic treatment with gabexate does not reduce pancreatic damage related to ERCP, but only in the patients with pancreatic duct imaging there were the significant differences between in the gabexate group and in the placebo group.

Application of Gabexate Mesylate IC against MMP - 9 Using ex vivo Model in Gastric Cancer: Prognostic Factor and Selection Criteria for Anti - MMP Treatment / 대한암학회지

PURPOSE: Among the many biological characteristics of cancer, matrix metalloproteinases(MMPs) are essential for tumor invasion and metastasis. The correction of the imbalance between MMPs and tissue inhibitors of matrix metalloproteinase (TIMP) has been suggested as a possible goal for the control of invasive phenotype of the cancer. To test the possible inhibition of MMP-9 in ex vivo model and the selection of the patients who are sensitive to MMP inhibitory (MMPI) treatment, we evaluated IC50 of the gabexate mesylate (Foy) against MMP-9 and compared them to the clinical parameters and patients survivals. MATERIALS AND METHODS: Thirty-four paired normal and gastric cancer tissues were tested for the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. RESULTS: MMP-9 expression (percent of sample band density to control band) (p=0.04) and IC50 (p=0.02) of cancer tissues were significantly higher than those of normal tissues. Cancer tissue IC50 was higher than that of normal tissues in cases when the tumor mass diameter was longer than 5 cm (p=0.03) as well as in higher T-stage (p=0.04), lymph node metastasis (p=0.04) and in advanced stages (p=0.04). There was a tendency of increased IC50 of diffuse and mixed type than that of intestinal type (diffuse & mixed: 11.0+-20.8 mg/ml, intestinal: 2.7+-3.9 mg/ml; p 0.07), in spite of no difference in MMP-9 expression (diffuse & mixed: 40.3+49.2%, intestinal: 51.0+-58.0%). In early gastric cancer (EGC), there was no difference in IC50 between normal and cancer tissues whereas cancer tissue IC50 was higher than that of normal tissue in advanced gastric cancer (p 0.02). There was a tendency of increment of ICo in cancer tissues of advanced gastric cancer than that of EGC whereas no difference was found in MMP-9 expression between these types of cancers. Poor prognosis was found in high IC50 patients in curatively resected patients (p=0.04). In multivariate analysis, high IC50 was suggested as a possible independent prognostic factor. CONCLUSION: We could 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 can have a possible benefit with MMPI treatment.

A Study on the Effect of Combination Therapy with Anti - Thrombin III and Gabexate Mesilate in Premature Infants for Disseminated Intravascular Coagulation

PURPOSE: Both antithrombin III(ATIII) and Gabexate mesilate(Foy) are effective for the treatment of disseminated intravascular coagulation(DIC). However, their mechanisms of action are slightly different, and combined effect of ATIII and Foy in premature infant with DIC has not been studied. We evaluated therapeutic efficacy of treatments with either ATIII or Foy alone or both in combination. METHODS: We studied 23 premature infants of gestational ages between 30 and 36 weeks with DIC. Group A(n=10) was treated by ATIII only, Group B(n=7) by Foy only and Group C(n=6) by both ATIII and Foy. Three groups were compared for volume of blood sampling and transfusion and hematologic data. RESULTS: Improvement of hematologic data(platelet, PT, aPTT, fibrinogen, FDP) was not significantly different among 3 groups. The mean volume of blood sampling during 5 days of treatment was 30 mL, 22.5 mL, and 30 mL, respectively. The mean volume of packed RBC transfusion was 12.8 mL, 9 mL, and 2.5 mL, respectively: and mean volume of platelet transfusion was 25.9 mL, 10 mL, and 0 mL, respectively, showing no significant statistical difference. But the mean volume of FFP transfusion was 141 mL only in group B, significantly higher compared to other groups. CONCLUSION: The combination therapy of ATIII and Foy significantly decreased the volume of FFP transfusion and may be more effective than monotherapy with ATIII or Foy alone in DIC of premature infant.

Effect of Protease Inhibitor on the Ischemia-reperfusion Injury to the Rat Liver

BACKGROUND: Liver failure due to ischemia-reperfusion injury is a serious problem in liver transplantation and radical wide resection of the liver. This injury is believed to be closely related to the generation of oxygen free radicals. Gabexate mesilate, a synthetic protease inhibitor, has an effect on the suppression of extracellular release of oxygen free radicals in the microvascular endothelium, as well as on protease inhibition. In order to understand the effects of gabexate mesilate on ischemia-reperfusion injury to the liver, we performed animal experiment with rats. METHODS: We divided the rats into two ischemia-reperfusion groups:the experimental group which received a 30 minutes ischemic injury along with the infusion of gabexate mesilate and a control group which received only the injury. Each group was subdivided into 4 sub-groups:ischemic injury only and ischemic injury plus 60, 120 or 180 minutes reperfusion injury. The test parameters were TNF-a and IL-6 in the serum, and superoxide dismutase(SOD), catalase, and malondialdehyde(MDA) in liver and lung tissues. RESULTS: The group receiving gabexate mesilate had a significantly higher level of liver SOD and liver catalase and a significantly lower level of liver MDA and lung MDA than the control groups. The TNF-a levels in the gabexate mesilate groups were significantly lower in the early phase, and a comparison of the IL-6 levels between two main groups yielded no significant results. The levels of lung catalase and SOD showed no significant difference between the two main groups. CONCLUSIONS: Protease inhibitor has the beneficial effect of liver ischemia-reperfusion injury suppression due to an increase in antioxidants or oxygen-free-radical suppression. The roles of TNF-a and IL-6 in liver reperfusion injury was not clear in our investigation. However, TNF-a might have an effect in the early phase. The mechanism of reperfusion injury to the lung in liver ischemia-reperfusion injury might be different from that to the liver.