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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↗

PubMed1983

Inhibitory effect of aprotinin and gabexate mesilate on human plasma kallikrein.

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

Adult↗

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↗

PubMed1983

Effects of antiproteases (aprotinin and gabexate-mesilate) on the postischemic vascular response of the kidney.

Both under physiologic conditions and after short-term ischemia (1-3 min) kallikrein and locally synthesized prostaglandins contribute to control renal blood flow. In the present experiment the antiproteases aprotinin and gabexate-mesilate were administered to rabbits in an attempt to show whether the hemodynamic changes produced by 60 min of normothermic ischemia, i.e., postischemic hyperemia and reduction of vascular resistance, were equally mediated by kallikrein. Vascular responses were evaluated by determining renal cortical blood flow using radioactively labelled microspheres, by calculating vascular resistances, and by measuring the diameters of renal medullary vessles. Kidneys exposed to normothermic ischemia and sham-operated control organs of animals treated with aprotinin (2 X 40,000 KIU/kg body weight) and gabexate-mesilate (2 X 7 mg/kg body weight) were compared with those of rabbits which were analogously operated, but did not receive any drugs. As the antiproteases used did not significantly affect the hyperemia and the reduction of renal cortical vascular resistance seen after 60 min of normothermic ischemia, these phenomena are apparently not mediated by kallikrein. Renal medullary vasodilatation (arteriolae rectae) was significantly lower under aprotinin than in untreated ischemic kidneys, and was not longer demonstrable in gabexate-mesilate-treated animals. Thus, the effect of gabexate-mesilate was superior to that of aprotinin. Whether the antiprotease action is due to an unspecific membrane-stabilizing, to a general enzyme-inhibiting, or to a specific kallikrein-inhibiting effect, is still unclear.

Animals↗

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↗

PubMed1983

Influence of aprotinin and gabexate mesilate on arachidonic acid release by the Ca-ionophore A 23187 in the lung.

In a model of isolated, ventilated rabbit lungs, perfused with Krebs-Henseleit albumin buffer in a recirculating system, increased availability of free AA (arachidonic acid) results in an increase in pulmonary vascular resistance and permeability. The former can be ascribed to cyclooxygenase products of AA, among which thromboxane A2 is mainly responsible. The increase of vascular permeability is, at least partly, due to lipoxygenase products of AA. Availability of free AA for the different oxygenation pathways can be achieved either by direct application of free AA to the perfusion fluid or by stimulation of AA release from the membrane phospholipid pool by the Ca-ionophore A 23187. The serine proteinase inhibitor gebaxate mesilate in a concentration range between 1 microM and 10 microM and aprotinin in a concentration range between 8 and 200 KIE/ml dose-dependently reduce the increase in vascular resistance after stimulation with A 23187. Correspondingly the increase in vascular permeability due to A 23187 is significantly reduced by gabexate mesilate (5 microM) to 52% and by aprotinin (200 KIE/ml) to 73%. On the contrary the increase in pulmonary vascular resistance and permeability after direct application of free AA to the perfusion fluid is not affected by gabexate mesilate and aprotinin. AA metabolism by cyclooxygenase from ram vesicular gland microsomes is inhibited in vitro by gabexate mesilate and by aprotinin only in very high concentrations (greater than 1mM respectively greater than 2130 KIE/ml). Measurements with porcine pancreas and bee venom phospholipase A2 reveal no influence of aprotinin on these enzymes. Gabexate mesilate inhibits pancreas phospholipase A2 in concentrations more than 10-fold higher than those necessary in the isolated lungs (IC50 = 430 microM), bee venom phospholipase A2 not being affected at all. It is thus apparent that the release of AA from the membrane phospholipid pool rather than any particular step in its oxygenation metabolism is the site of action of these proteinase inhibitors in the pulmonary vascular bed. The possible involvement of an intracellular proteinase is discussed.

Animals↗

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↗

PubMed1984

Influence of the anti-inflammatory serine esterase inhibitor gabexate mesilate (Foy) on aggregation, locomotion and adhesion of polymorphonuclear leukocytes.

The effects of the anti-inflammatory serine esterase inhibitor, gabexate mesilate (Foy) were studied, on locomotion, autoaggregation and adhesion of polymorphonuclear leukocytes stimulated with the complement peptide C5a-desArg. The drug inhibited aggregation as well as spontaneous and directed migration of human leukocytes at concentrations of about 10(-3) M. Adhesion of peritoneal guinea-pig leukocytes to autologous aortic strips was reduced at about 20 times lower drug concentrations. The inhibitory drug effects were highly time- and temperature-dependent. Experiments with the two major drug metabolites, pHB and epsilon GC, indicate that gabexate mesilate is not active by itself but rather by its hydrolytic aromatic metabolite pHB. The results further suggest that the inhibitory effects on leukocyte activities observed are not related to the anti-inflammatory effects of gabexate mesilate.

Animals↗

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↗

PubMed1984

Effects of the serine protease inhibitor gabexate mesilate on purified pancreatic phospholipase A2.

The catalytic activity of purified porcine pancreatic phospholipase A2 is competitively inhibited by the cationic amphiphilic serine protease inhibitor gabexate mesilate (ethyl 4-(6-guanidinohexanoyloxy) benzoate methanesulfonate). A Ki of 1.3 X 10(-4)M was found when 1,2-dioctanoyl-sn-glycero-3-phosphorylcholine was used as a substrate. The main metabolites of this drug, 6-guanidinocaproic acid and ethyl p-hydroxy-benzoate, had no effect in concentrations up to 10(-2)M. From the high gabexate mesilate concentrations required to reduce phospholipase A2 activity and from the considerably lower drug concentrations sufficient to cause beneficial effects in acute pancreatitis it is concluded that direct inhibition of pancreatic phospholipase A2 cannot be the cause of the therapeutic results, improvement of the symptoms and prognosis of acute pancreatitis.

Animals↗