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At least 19 recordsLinked to original sources
PubMed1986

[Gabexate mesilate in the treatment of acute pancreatitis. Results of a Hannover multicenter double-blind study with 50 patients].

We investigated the effect of a new synthetic protease- and phospholipase A2-inhibitor gabexate mesilate (FOY) in a multicenter (6 hospitals in Hannover and vicinity) double-blind study on the clinical course of acute pancreatitis. 50 patients were randomized into two subgroups. One group was treated with 3 X 300 mgs of gabexate mesilate per day for 9 days as a continuous intravenous infusion, the control group received placebo. There was no difference in these two groups regarding age and sex, but there was a discrepancy concerning the severity (stage I-IV) of the acute pancreatitis at the onset of treatment. More of the patients in the gabexate mesilate-group had severe disease on admission to hospital. Of the 7 patients (14%) who died, 5 were in the gabexate mesilate-group whereas only 2 were in the placebo group. This difference in the mortality rate is not significant. There was, however, a significant difference at the 5% level between the verum-group and the control group concerning the decline in alpha-amylase activity in serum and the number of complications. The difference was greatest in alcohol induced acute pancreatitis. A non-parametric test showed a significant reduction in hospitalisation time in the gabexate mesilate-group. Due to the small number of patients and the inhomogeneous clinical course of the acute pancreatitis a definite conclusion concerning the effect of gabexate mesilate on the clinical course of acute pancreatitis is not possible. Further studies with a much greater number of patients and more homogeneous groups with respect to the severity of the acute pancreatitis at the onset of the therapy with gabexate mesilate or placebo are necessary.

Acute Disease↗
PubMed1990

Gabexate and camostat, synthetic proteinase inhibitors, as direct inducing factors of water and bicarbonate secretion in the isolated and blood-perfused dog pancreas.

The effects of proteinase inhibitors on the secretion of pancreatic juice were investigated in preparations of the isolated and blood-perfused dog pancreas as compared with those of secretin. Each drug tested was administered i.a. Graded doses of gabexate (1-10 mg) elicited dose-dependent biphasic responses for the secretory rates, bicarbonate concentrations and outputs of pancreatic juice, with maximum effects at approximately 5 mg, but had little effect on the protein concentrations. Camostat, at a high dose of 10 mg, caused significant increases in the secretory rate, bicarbonate concentration and output of pancreatic juice over their basal levels, but had little influence on the protein concentration. Secretin (0.03-0.3 U) usually produced similar to gabexate-induced results (1-5 mg). Both bicarbonate and protein concentrations of the juice obtained with gabexate or camostat were almost the same as those obtained with secretin at a similar secretory rate of pancreatic juice, suggesting the secretory action of gabexate or camostat might be similar to that of secretin. In addition, gabexate (3 mg) and camostat (10 mg) elicited more than the respective additive secretory responses in the presence of i.a. infusion of a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (12 micrograms/min) as well as secretin (0.1 U). These results indicate that gabexate and camostat induce water and bicarbonate secretion by acting directly on ductular cells of the dog pancreas, which might be mediated at least partially through cyclic AMP.

1-Methyl-3-isobutylxanthine↗
PubMed1989

In vitro inhibition of phospholipase A2 by gabexate mesilate, camostate, and aprotinine.

Gabexate mesilate (FOY, ethyl-p-(6-guanidino-hexanoyl-oxy)-benzoate-methansulfonate), camostate (N,N-dimethyl-carb-amoylmethyl-4-(guanidinobenzoyloxy)-phenyl-acet ate) methansulfonate and aprotinine (Trasylol) were tested for possible inhibition of phospholipase A2. Gabexate mesilate at a concentration of 5 x 10(-4) mol/l and camostate at a concentration of 10(-3) mol/l caused a 50% reduction in enzyme activity. There was almost no inhibition by aprotinine at clinical doses; 40 million KIU/l were necessary to reduce phospholipase A2 activity by 20%. From the therapeutic dose (4,000 mg/day per i.v. infusion) and the half-life of gabexate mesilate in blood circulation (1 min) it can be calculated that the in vitro concentration of gabexate mesilate is only 10(-6) to 10(-7) mol/l. Under these conditions gabexate mesilate cannot diminish the in vivo enzyme activity of phospholipase A2.

Animals↗
PubMed1990

[The protease inhibitor gabexate mesilate in experimentally-induced acute pancreatitis with early gram-negative infection in the Göttingen minipig: therapeutic efficacy and effects on blood coagulation and fibrinolysis].

Due to its biochemical properties, the newly developed low-molecular protease inhibitor gabexate mesilate is assumed to be efficient in the treatment of complicated acute pancreatitis. This thypothesis was tested using the model of the experimental taurocholate pancreatitis with early artificial E. coli infection in Göttingen mini pigs. Either gabexate mesilate or a placebo was given intravenously 150 min after induction of pancreatitis in a dosage of 2 mg/kg b.w. and h. Median survival time was 15 h in the gabexate mesilate treated animals (n = 7) as compared to 34 h in the placebo group (n = 7); this difference was not significant. The application of gabexate mesilate had no influence on the increased coagulation activity (decrease of prothrombin time, antithrombin III and platelet count) nor on the additional hyperfibrinolysis with concomitant decrease of plasminogen and antiplasmin. Prothrombin time and antithrombin III were less distinctly decreased in the placebo group; decrease of platelet count was more pronounced. On the basis of this study the hypothesis is not confirmed that treatment with gabexate mesilate for necrotizing experimental pancreatitis with additional gram-negative infection has a therapeutic efficiency.

Acute Disease↗
PubMed1986

Gabexate mesylate inhibition of serine proteases: thermodynamic and computer-graphics analysis.

The inhibitory effect of gabexate mesylate, which is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation, and as a regional anticoagulant agent for hemodialysis, has been measured on bovine factor Xa, bovine alpha-thrombin, human Lys77-plasmin, human urinary kallikrein, human urokinase, porcine pancreatic beta-kallikrein-B, and bovine beta-trypsin catalyzed hydrolysis of p-nitrophenyl esters of N-alpha-carbobenzoxy-L-arginine and N-alpha-carbobenzoxy-L-lysine. On the basis of enzyme:gabexate mesylate affinities, the serine proteases can be arranged as follows: human urinary kallikrein approximately porcine pancreatic beta-kallikrein-B much less than bovine beta-trypsin approximately bovine factor Xa approximately human Lys77-plasmin approximately human urokinase approximately bovine alpha-thrombin. The mode of binding of gabexate mesylate to the serine proteases conforms to the active-reactive site geometries observed in their complexes with natural and synthetic inhibitors. Differences in gabexate mesylate affinities for these proteases reflect structural differences at their primary specificity subsite, which have been investigated by comparative analysis of amino acid sequences and by computer-graphics techniques.

Animals↗
PubMed1989

Inhibition of porcine pancreas phospholipase A2 activation by gabexate mesilate.

We investigated the effect of gabexate mesilate on the catalytic activity of phospholipase A2 in homogenized porcine pancreatic tissue. Gabexate mesilate is a potent inhibitor of serine proteases. There is no direct inhibition of phospholipase A2 catalytic activity in concentrations up to 6 mmol/l. Preincubation of homogenized pancreatic tissue with gabexate mesilate leads to a reduction of phospholipase A2 activity even in concentrations as low as 6 mumol/l. The activation of purified porcine prophospholipase A2 added to pancreatic tissue can be completely inhibited. Thus gabexate mesilate might influence the activation of phospholipase A2 administered in therapeutic concentrations in inflamed pancreatic tissue.

Animals↗
PubMed1985

Inhibitory effect of gabexate mesilate on pancreatic phospholipase A2-mediated hydrolysis of ghost membranes.

Human erythrocyte ghost membranes were incubated with human pancreatic phospholipase A2 [EC 3.1.1.4] in the presence of gabexate mesilate (FOY, ethyl 4-(6-guanidinohexanoyloxy)-benzoate methanesulfonate) in Tris-buffered saline (10 mM Tris-HCl, 150 mM NaCl, 2 mM CaCl2, pH 7.4). Membrane phospholipids were extracted by chloroform-isopropanol, 7:11 (v/v), and separated by thin-layer chromatography. Gabexate mesilate at a concentration of 400 microM caused a 50% inhibition of the enzyme-mediated hydrolysis of membrane phospholipids. When phosphatidylcholine micelles were incubated with the enzyme in the presence of gabexate mesilate, the mode of inhibition of the enzyme action by the drug appeared to be noncompetitive and Ki of gabexate mesilate for phospholipase A2 was 0.77 mM.

Erythrocyte Membrane↗
PubMed1985

Gabexate mesilate and camostate: new inhibitors of phospholipase A2 and their influence on the alpha-amylase activity in serum of patients with acute pancreatitis.

The new synthetic polyvalent protease inhibitors gabexate mesilate (ethyl-p[6-guanidinohexanoyloxy]-benzoate methansulfonate) and camostate (N,N-dimethylcarbamoylmethyl-4-[4-guanidinobenzoyloxy]-phenylacetate methansulfonate) were tested for possible inhibition of phospholipase A2 activity. In a pilot study, we treated 17 patients suffering from acute pancreatitis with continuous intravenous administration of gabexate mesilate, 450 mg/d. The results were compared with a placebo group (same standard therapy) of 21 patients suffering from acute pancreatitis. In vitro experiments showed that, at concentrations between 10(-4) and 5 X 10(-4) mol/L (depending on the enzyme assay employed) for gabexate mesilate and between 10(-3) and 5 X 10(-4) mol/L for camostate, a 50% reduction in phospholipase A2 activity was effected. Comparing the two groups of acute pancreatitis patients after 6 days of treatment with gabexate mesilate, we observed a statistically significantly lower alpha-amylase activity in the serum of treated patients compared with the placebo group.

Acute Disease↗
PubMed1988

Gabexate as a therapy for disseminated intravascular coagulation.

The effects of gabexate mesilate on disseminated intravascular coagulation (DIC) accompanying neoplastic diseases or severe infections in ten patients were investigated and compared with those of heparin therapy in ten other patients with DIC. Of 11 patients with DIC (control) who did not receive any anticoagulation therapy for DIC, ten died of pneumonia, DIC secondary to the underlying diseases, or pulmonary edema. Heparin therapy was effective in five patients (50%), while treatment with gabexate was successful in seven patients (70%). Although the therapeutic efficacy of gabexate was not significantly different from that of heparin, in patients in whom bleeding tendencies were observed at the start of the therapy, the former was successful in four (80%) of five patients, while the latter was effective in only one (25%) of four patients treated. The results of this preliminary and nonrandomized study suggest that gabexate is as effective as heparin for the treatment of DIC, and that it may be more successful than heparin in the treatment of DIC accompanied by bleeding diathesis.

Anticoagulants↗
PubMed1989

Effect on hemodynamics of therapeutic infusion of gabexate mesilate (FOY) in experimental acute pancreatitis.

Acute pancreatitis was induced in ten anesthetized dogs by retrograde injection for bile mixed with trypsin into the pancreatic duct. Five animals were treated with i.v. infusion of gabexate mesilate in a dose of 1 mg/kg per hour. Hemodynamic data were regulary monitored during a 10-h observation period. Cardiac output (CO), mean arterial pressure (MAP), and left ventricular stroke volume (LVSV) decreased rapidly in untreated animals. An increase of systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) was observed in dogs without treatment. Gabexate mesilate given as a therapy significantly improved the hemodynamic parameters. The study demonstrates an advantageous influence of synthetic antiprotease gabexate mesilate on the course of acute experimental pancreatitis.

Acute Disease↗
PubMed1990

Improvement in wound healing by epidermal growth factor (EGF) ointment. I. Effect of nafamostat, gabexate, or gelatin on stabilization and efficacy of EGF.

The healing effect of human epidermal growth factor (hEGF) on open wounds was studied in rats. No improvement in wound healing was found by topical application of EGF alone to open wound sites. We found an ointment containing EGF and a protease inhibitor, nafamostat mesilate or gabexate mesilate, or gelatin accelerated the healing rate of open wounds. Significant increases in the dry weight of the wound site granulation tissue, uronic acid (as an index of acid mucopolysaccharide) and hydroxyproline (as an index of collagen) were observed by treatment with EGF ointment containing nafamostat compared with the controls. The effects of the protease inhibitor on wound healing were dose dependent. Nafamostat was more efficient than gabexate or gelatin on wound healing. The degradation of 125I-EGF in wound tissue homogenate was significantly decreased in the presence of a protease inhibitor, such as nafamostat or gabexate, or gelatin. These findings indicate that the stabilization of EGF at the wound site is an important factor in permitting the expression of its healing effects and suggest that the ointment containing EGF and a stabilizing agent would be a suitable dosage form for acceleration of wound repair.

Animals↗
PubMed1992

The effect of somatostatin, gabexate mesilate and dextran 40 on the microcirculation in sodium taurocholate-induced pancreatitis.

In vivo microscopy was performed to assess the effect of dextran 40, gabexate mesilate and somatostatin on the microcirculation in sodium taurocholate-induced pancreatitis in rats. Intraductal infusion of 0.4 ml of a 4% solution of sodium taurocholate decreased capillary blood flow, induced capillary stasis and increased vascular permeability in the head of the pancreas. Dextran 40, gabexate mesilate and somatostatin improved capillary blood flow in the initial phase of acute pancreatitis significantly and prevented stasis in 5 of 9, 3 of 8 and 7 of 10 (p < 0.05) cases. Only dextran 40 reduced the increase of vascular permeability. Decrease of capillary blood flow, capillary stasis and vascular permeability changes are important factors contributing to the pathogenesis of sodium taurocholate-induced pancreatitis. Dextran 40, gabexate mesilate and somatostatin exert a beneficial effect on the microcirculatory changes in this model of acute pancreatitis.

Animals↗
PubMed1988

Microcirculatory disturbances in endotoxin-induced disseminated intravascular coagulation. The effects of heparin and gabexate mesilate on locomotive and metabolic changes of neutrophils.

Neutrophil-mediated oxidative stress on the rat mesenteric microcirculation was studied in the experimental model of endotoxin-induced disseminated intravascular coagulation (DIC) by using an intravital fluorescent technique and luminol-dependent chemiluminescence (ChL) analysis. Leukocytes sticking to the venules were visualized by the injection of acridine orange, a fluorochrome tracer which shows high affinity to white cells. Endotoxin (E coli, O-111B4, Difco, USA) was infused intravenously at a dose of 2 mg/kg/hr. After starting the infusion of endotoxin, the number of sticking cells were gradually increased on the venular endothelium followed by a transient neutropenia. In order to investigate the distribution of infused endotoxin in the microvasculature, FITC-labeled endotoxin (Sigma, USA) was used. After administration of FITC-endotoxin, multiple patches of fluorescence along the venular walls were observed, while no fluorescent conjugates were found at the sticking neutrophils and along the arteriolar walls. ChL activities of neutrophils were also dramatically elevated, which may reflect the enhanced ability to generate oxyradical species. To investigate the inhibitory effects of heparin sodium and gabexate mesilate which was a synthetic protease inhibitor on locomotive and metabolic changes of neutrophils induced by endotoxemia, both agents were administered prior to endotoxin infusion. Gabexate mesilate attenuated these changes, but heparin sodium did not show any improving effects. It was concluded that endotoxin primarily affects the venular endothelial cells, resulting in the activation of neutrophils. Gabexate mesilate was more likely to attenuate neutrophil-mediated oxidative stress on microvasculature in endotoxin-induced DIC than heparin sodium.

Animals↗
PubMed1989

The effect of gabexate mesilate on the outcome of acute hemorrhagic pancreatitis in pigs.

The effects of gabexate mesilate (GM) on hemodynamics and phospholipase A2 activities (PLA2) during acute hemorrhagic pancreatitis (AHP) were studied in 17 piglets which were randomly divided into three groups: The control group (CG) received only the fluid replacement, whereas the pretreatment group (PG) was given an infusion of GM (20 mg/kg/5h), which was started 30 min before and in the treatment group (TG) 30 min after the induction of AHP. AHP was induced by infusing a mixture of trypsin and sodiumtaurocholate (1 ml/kg) into the pancreatic duct, and the animals were followed up for 5h. Two animals of the CG died, but no mortality was observed in the other groups. Histologically, acute hemorrhagic pancreatitis was detected in all animals, but no significant differences were observed between the groups. PLA2 activity in the serum increased rapidly after the induction of AHP in the CG, and it was significantly (P less than 0.05) higher 5h after the induction in the CG than in TG or PG. No significant differences developed between the groups in cardiac indices or hemodynamic pressure parameters during the 5h of surveillance, but the volume of secreted exudate into the peritoneal cavity was significantly (P less than 0.05) smaller in the PG than in the CG. In conclusion, GM treatment and pretreatment reduced mortality and the amount of the secreted ascitic fluid during AHP. Moreover, the activity of circulating PLA2 was inhibited in the groups receiving GM.

Acute Disease↗
PubMed1988

Influence of a small molecular weight proteinase inhibitor, gabexate mesilate (FOY), on insulin receptor function in vitro.

The effects of the low molecular weight serine proteinase inhibitor FOY (gabexate mesilate) upon insulin action was studied in three different experimental systems. Placenta membranes containing insulin receptors preincubated with FOY (10 microM) showed a reduction of insulin-stimulated tyrosine kinase activity (p less than 0.01). However, FOY (0.1-100 microM) did not affect the insulin-stimulated tyrosine kinase activity in a preparation of solubilized and partially purified insulin receptors from placental membranes. Isolated adipocytes were used to study the effect of FOY on intact cells. FOY neither altered the insulin induced inhibition of the catecholamine-stimulated lipolysis nor (at the low concentration of 0.1 mM) the stimulation of glucose transport by the hormone. High concentrations (0.5 mM) of FOY decreased the effect of insulin on the hexose transport.

Adipose Tissue↗
PubMed1991

Clinical trial with a protease inhibitor gabexate mesilate in acute pancreatitis.

To evaluate whether early administration of protease inhibitors could improve mortality and morbidity in acute pancreatitis (AP), we made a retrospective analysis of 23 patients with severe AP and 88 with mild to moderate AP who were treated in our institute and four affiliated medical centers during the 10-y period from 1980 to 1990. Intravenous infusion of a protease inhibitor, Gabexate Mesilate (FOY), was started within 24 h from onset of AP (early administration) in 17 patients with severe AP and 51 with mild to moderate AP. The remaining patients were put on FOY later than 24 h from onset of AP (late administration). Comparison of the mortality and morbidity between the two groups, early vs late administration of FOY, led to the following conclusions: (1) Early administration of FOY significantly improved mortality (29.4 vs 83.3%) in severe AP, although the improvement in mortality was not directly proportional to the shortening of the time lag between the onset of AP and the start of FOY, and (2) earlier administration of FOY brought about significantly earlier recovery of abdominal pain, hyperamylasemia, and leucocytosis in mild to moderate AP.

Acute Disease↗
PubMed1991

Protective effects of gabexate mesilate (FOY) against impaired pancreatic energy metabolism in rat acute pancreatitis induced by caerulein.

A supramaximal dose of caerulein (5 micrograms/kg.hr for 3.5 hours) caused edematous acute pancreatitis in rats, characterized by portal hyperamylasemia (32 +/- 3 U/ml) and pancreatic edema (pancreatic water content, 86 +/- 2%) [control group: amylase, 8 +/- 1 U/ml; water content, 74 +/- 2%]. In this model, increased portal levels of malate dehydrogenase (148 +/- 25 U/ml), increased mitochondrial fragility and impaired pancreatic energy charge level (0.77 +/- 0.05) were also observed [control group: malate dehydrogenase, 54 +/- 11 U/ml; energy charge level, 0.94 +/- 0.03]. Administration of gabexate mesilate, FOY, in a dose of 50 mg/kg.hr for 2 hours before and during the caerulein infusion had a significant protective effect against these pancreatic injuries (portal amylase level, 11 +/- 2 U/ml; MDH level, 72 +/- 19 U/ml; E.C., 0.89 +/- 0.02; water content, 76 +/- 2%). FOY in a dose of 20 mg/kg.hr was partially protective. These results indicate that subcellular organelle fragility and malfunction are closely related to the pathogenesis of acute pancreatitis and suggest the usefulness of FOY in the treatment of this disease.

Acute Disease↗
PubMed1986

Hemodialysis using gabexate mesilate (FOY) in patients with a high bleeding risk.

The efficacy of gabexate mesilate (FOY), a synthetic serine proteinase inhibitor, was compared with that of heparin in preventing the acceleration of bleeding after hemodialysis. Transfused blood volume (TBV) was measured 24 h before and after 24 dialyses in 14 bleeding patients with impaired hemostatic function. The predialysis TBV did not differ significantly between heparin and FOY groups; however, TBV was significantly (p less than .05) larger after heparin dialysis than after FOY dialysis. After dialysis, TBV was increased in eight of nine heparin patients, compared to only three of 15 FOY subjects (p less than .01). FOY is an effective agent and may decrease postdialysis bleeding complications in certain high-risk patients.

Acute Kidney Injury↗