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 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.

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 .

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.

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 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 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

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.

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.

The Effects of Proteolytic Agent on the Lung Injured by Endotoxemia

The authors studied the lung injury induced by endotoxemia and the effects of proteolytic agent on the lung changed by endotoxemia. Sprague-Dawley rats were intraperitoneally administrated with a single dose of endotoxin (4 mg/kg, E. coli 025 : B6 lipopolysaccharide) or with endotoxin and gabexate mesilate (200 mg/kg), a proteolytic agent, concomitantly. Rats of each group were scarificed at 9, 18, and 27 hours after injection. Light and electron microscopic examination were done. The results obtained were summarized as follows: Light microscopic exmination revealed congested capillaries and neutrophilic infiltration in both groups. Electron microscopic findings were interstitial and alveolar neutrophilic infiltration, endothelial swelling with increased pinocytotic vesicles and cytoplasmic process formation, and interstitial edema. Decrease of osmiophilic bodies in the type II pneumocytes had appeared at 9 hours after endotoxin injection. These changes were increased in severity at 18 hours and 27 hours after endotoxin injection. In the group of concomitant treatment of gabexate mesilated and endotoxin, there was no edema at 9 hours after injection. After 18 hours welling of endothelial cell and interstitial edema had appeared. However, the severity of the edema was markedly decreased. Type II pneumocytes showed well preserved osmiophilic bodies. According to these results, it is considered that administration of gabexate mesilate can significantly redeced the lung injury induced by endotoxemia.