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PubMed1995

[Antioxidant action of gabexate mesilate (Foy) in an experimental model of endotoxic shock].

BACKGROUND: Circulatory shock, especially endotoxin shock, is characterized by the release of a large number of mediators, among which proteases play a key role. The production of oxygen free radicals into the extracellular space and the increase of capillary permeability is one of the most important consequences of that phenomenon. In order to evaluate the efficacy of gabexate mesilate (Foy) in preventing such increase of microvascular permeability, an experimental model of endotoxin shock was used. MATERIALS AND METHODS: Experiments were performed on the mesocecum of male Wistars rats, fluorescent labeled bovine albumine was injected intrarterially to evaluate the capillary permeability and the mesocecum microcirculation was observed by fluorescent light. The control group received saline i.v.; the II group received a DL 100 of E. coli endotoxin (DIFCO 0111: B4); the III and the IV group received a continuous infusion or topical application of gabexate mesilate respectively, before the administration of endotoxin. To evaluate capillary permeability and to quantify the degree of extravasion by counting the number of leaky sites, fluorescent labelled bovine albumin was injected i.v. and mesocecum was observed with fluorescent microscopy for 2 hours. RESULTS AND CONCLUSIONS: Capillary permeability did not increase in control rats; it largely increased in rats receiving endotoxin i.v. but it did not almost increased in rats receiving gabexate mesilate (Foy) that prevents the increase of capillary permeability that was observed in the group treated with endotoxin alone.

Animals↗
PubMed1998

Effects of loxiglumide on experimental acute pancreatitis in comparison with gabexate mesilate.

Loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N- pentylglutaramic acid, CAS 107097-80-3, CR 1505) is a cholecystokinin-A (CCK-A) receptor antagonist. In this report, the effects of loxiglumide and gabexate mesilate were studied on three experimental acute pancreatitis models induced by caerulein, sodium taurocholate + caerulein and closed duodenal loop. The intravenous injection of loxiglumide at 3 and 10 mg/kg (6 times at hourly intervals) significantly inhibited an increase in serum amylase activity induced by the intraperitoneal injection of caerulein (50 micrograms/kg i.p., 6 times at hourly intervals) in mice. But gabexate mesilate at 10, 30 and 60 mg/kg did not. The intravenous infusion of loxiglumide at 18 and 60 mg/kg/h showed a life prolonging effect in the lethal necrotizing pancreatitis, induced by the subcutaneous injection of caerulein (50 micrograms/kg s.c., 4 times at 2 h intervals) after the injection of sodium taurocholate (10%, 0.1 ml/body) into the common bile duct, cumulative survival rates being 86 and 90%, respectively. Gabexate mesilate at 180 mg/kg/h showed the prolonging effect (cumulative survival rates 75%). The intravenous injection of loxiglumide at 6, 18 and 60 mg/kg/h significantly inhibited an increase in total ascitic lipase activity, and plasma amylase and lipase activity of rats with closed duodenal loop. These results suggest that CCK plays an important role in the progression of acute pancreatitis, and that loxiglumide may have a therapeutic potential for pancreatitis.

Acute Disease↗
PubMed1997

Competitive inhibition of swine kidney copper amine oxidase by drugs: amiloride, clonidine, and gabexate mesylate.

Competitive inhibition of swine kidney copper amine oxidase by diuretic, antihypertensive, and anticoagulant drugs, amiloride, clonidine, and gabexate mesylate, respectively, is reported. The affinity of these compounds for swine kidney copper amine oxidase is similar to that observed for inhibitor binding to nitric oxide synthase and trypsin-like serine proteinases. This finding suggests that amiloride, clonidine, and gabexate mesylate should be administrated under careful control, since enzyme cross-inhibition may occur also in vivo.

Agmatine↗
PubMed1995

Effectiveness of gabexate mesilate in acute pancreatitis. A metaanalysis.

Since the effectiveness of gabexate mesilate in patients with acute pancreatitis is controversial, a metaanalysis of the published literature was conducted to address this problem. Five randomized trials were identified by our literature search. Three end points (mortality, complications, and complications requiring surgery) were evaluated. The results of our metaanalysis indicate that the treatment with gabexate mesilate does not affect mortality at 90 days (P = 0.27), but significantly reduces the incidence of complications requiring surgery (odds ratio = 0.61, 95% CI: 0.41-0.89; P < 0.05) and of complications in general (odds ratio = 0.69, 95% CI: 0.54-0.89; P < 0.05). Because the drug proves to be beneficial only to a low proportion of the treated patients, its clinical impact seems to be small. A pharmacoeconomic evaluation shows that its use in all patients with acute pancreatitis would imply a very high cost for preventing each complication. The administration of the drug to select patients who are at higher risk of complications could have a better cost-effectiveness ratio. However, specific studies on this point are still lacking.

Acute Disease↗
PubMed1993

Gabexate mesilate vs aprotinin in human acute pancreatitis (GA.ME.P.A.). A prospective, randomized, double-blind multicenter study.

The authors report the results of a randomized, double-blind multicenter clinical trial on the use of gabexate mesilate vs aprotinin in the therapy of acute pancreatitis. The size of the study sample and the end points chosen for evaluation of the early systemic complications of the pancreatitis--carefully selected targets for reliable assessment of the efficacy of any protease inhibitor--lead to the conclusion that gabexate mesilate is more efficacious than aprotinin in reducing the early complications of necrotizing acute pancreatitis, if administered within 72 h of onset of symptoms. Its good tolerability means that it can be used safely even at the dose of 3 g/24 h.

Acute Disease↗
PubMed2006

Effects of gabexate mesilate on ischemia-reperfusion-induced testicular injury in rats.

The aim of this study was to determine the effects of a synthetic serine protease inhibitor, gabexate mesilate (GM), in rats with ischemia-reperfusion (I-R) damage due to unilateral testicular torsion. Thirty male Sprague-Dawley rats were separated into three groups, each containing ten rats. A sham operation was performed in group 1 (control). In group 2 (I-R/untreated), 1 h detorsion of the testis was performed after 6 h of unilateral testicular torsion. In group 3 (I-R/GM), after performing the same surgical procedures as in group II, gabexate mesilate was given intravenously. In all experimental rats, ipsilateral orchiectomies were performed for histological examination and measuring the tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). MDA values and the testicular injury score decreased and SOD, CAT and GSH-Px values increased in the GM-treated group compared to the I-R/untreated group. The Tc-99m pertechnetate uptake ratio and the perfusion index were significantly decreased in the group 2 compared to the group 1 and 3 rats. In group 3, these values were significantly increased compared to group 2. Most of the specimens in the GM-treated group showed grade-I testicular injury. However, the injuries in the I-R/untreated rats varied between grade-III and grade-IV. The results of this study show that GM may play a role in reducing the injury caused by I-R.

Animals↗
PubMed2005

Gabexate mesilate and acute pancreatitis: an experience of evidence based drug information for improving rational drug use.

INTRODUCTION: Gabexate mesylate is a drug marketed only in Italy and Japan and it is considered an essential drug in the treatment of acute pancreatitis. A periodic revision and evaluation of drug utilization in our hospital demonstrated that the dosages and indications of Gabexate mesilate (GM) did not follow those settled by the National Health System and by our Hospital Formulary. We therefore promoted and conducted a program of drug information and meetings with the physicians in order to improve the correct utilisation of GM and identify potential problems. METHODS: GM prescriptions in 1999 were analysed for indications and dosages. Scheduled meetings with the medical staff were successively started in order to debate current therapies and treatments of acute pancreatitis using the criteria of evidence-based medicine (EBM). Follow-up was done in 2000, 2001 and 2002 to evaluate the efficacy of our intervention. RESULTS: The hospital board and 20 physicians were involved in this program of evidence-based drug information. The follow-up and the monitoring of GM prescriptions showed a reduction in the utilisation of GM in the subsequent period. CONCLUSIONS: GM is one of the most expensive drugs in our hospital, but its benefits are not very evident. Moreover, the international guidelines and literature ascribe to GM only a marginal role in the treatment of acute pancreatitis. Evidence-based medicine strengthens clinical experience with the evidence from the literature and underlines that essential drugs are used worldwide.

Acute Disease↗
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↗
PubMed1983

Inhibition of phospholipase A2 by gabexate mesilate, camostate and aprotinine.

Gabexate mesilate (FOY, ethyl-p-[6-guanidino-hexanoyloxy]-benzoate-methanesulfonate), camostate (N,N-dimethyl-carbamoylmethyl-4-[4-guanidinobenzoyloxy]-phenylacetate), methanesulfonate (FOYPAN) 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 no inhibition by aprotinine at clinical doses; 40 million KIU/l were necessary to reduce phospholipase A2 activity by 20%.

Animals↗
PubMedDate not supplied

Beneficial effect of gabexate mesilate on microscopic polyangiitis with renal dysfunction and pulmonary hemorrhage: A case report.

Corticosteroids and cyclophosphamide are the mainstay of the treatment of microscopic polyangiitis involving pulmonary hemorrhage or rapidly progressive glomerulonephritis. However, patients with advanced age are unable to tolerate this combined therapy, because of a relatively high incidence of side effects including infection, hemorrhagic cystitis, and bone marrow suppression. The authors encountered an 80-year-old patient with pulmonary hemorrhage and renal dysfunction ascribed to microscopic polyangiitis and achieved successful treatment by employing gabexate mesilate in addition to corticosteroids. The present case suggests that gabexate mesilate may be a therapeutic option for microscopic polyangiitis with progressive renal failure and pulmonary hemorrhage.

Aged, 80 and over↗
PubMed1999

Gabexate mesilate and antithrombin III for intraoperative anticoagulation in heparin pretreated patients.

Thirty patients scheduled for elective myocardial revascularization and having undergone preoperative heparin treatment have been admitted to this prospective, randomized study. The aim of the study was to test two different strategies for preserving circulating antithrombin III (AT-III) during cardiopulmonary bypass. Patients in the control group (group C, n = 10) were treated with a standard heparinization (300 IU/kg). Patients in group A (n = 10) received the same management plus two doses of purified antithrombin III (1000 IU each). Patients in group GA received 200 IU/kg heparin and a continuous infusion of heparin (100 IU/kg/h) and gabexate mesilate (2 mg/kg/h) plus the same dose of antithrombin III as group A. Both group A and group GA demonstrated a preservation of circulating AT-III when compared to group C; this effect was more pronounced in group GA. The total heparin dosage was less in group GA than in groups A and C. Purified AT-III administration is recommended in heparin pretreated patients; the addition of gabexate mesilate to this protocol decreases the heparin requirement and increases the AT-III preservation.

Aged↗
PubMedDate not supplied

Differential cytokine response in host defence mechanisms triggered by gram-negative and gram-positive bacteria, and the roles of gabexate mesilate, a synthetic protease inhibitor.

Bacterial infection results in the production of inflammatory mediators and may be involved in the pathogenesis of sepsis and/or systemic inflammatory response syndrome. The effect of lipopolysaccharide (LPS), a major component of the outer surface of Gram-negative bacteria, and Staphylococcal enterotoxin B (SEB), a superantigen of Gram-positive bacteria, on cytokine production in peripheral blood mononuclear cells (PBMCs) was examined. LPS significantly increased the production of proinflammatory and anti-inflammatory cytokines, and SEB enhanced the production of helper T lymphocyte type cytokines. These results illustrated the different responses to Gram-negative and Gram-positive bacterial infections. The effect of gabexate mesilate, a synthetic protease inhibitor, on cytokine production and expression of the toll-like receptor (TLR) was also examined. The results suggest that gabexate mesilate-induced inhibition of tumour necrosis factor-alpha (TNF-alpha) and interleukin-18 (IL-18) production in LPS-stimulated PBMCs is due to the inhibition of the nuclear factor-kappa B activation pathway and/or inhibition of the processing pathway of pro-TNF-alpha and pro-IL-18, not to down-regulation of TLR-2 or TLR-4.

Antigens, CD↗
PubMed1982

[Effect of secretin and gabexate-mesilate (synthetic protease inhibitor) on serum amylase level after ERCP].

Complication rate of ERCP is about 2%, mortality rate 0,2%. In about 1% acute pancreatitis or recurrency of chronic pancreatitis occurs. In 20 to 73% a rise of serum amylase is noted without clinical symptoms. In a randomized trial the influence of secretin and gabexate-mesilate (synthetic protease inhibitor) on ERCP-correlated complications was analyzed. Gabexate-mesilate caused a significant decrease of ERCP-induced hyperamylasemias, whereas secretin showed no effect.

Alkaline Phosphatase↗
PubMed1994

Protective effect of gabexate mesilate (FOY) against pancreatic injuries induced by ethanol in rats.

Four-hour intravenous ethanol infusion at two doses of 0.5 and 1.0 g/kg.hr caused mild, but significant, rises in serum amylase and pancreatic water content as well as pancreatic histological changes such as interstitial edema in rats. These doses of ethanol also caused an impaired pancreatic adenylate energy charge levels and increased pancreatic mitochondrial fragility. The dose of 0.2 g/kg.hr caused only marginal changes in these parameters. Moreover, gabexate mesilate (FOY) at the dose of 20 mg/kg.hr inhibited almost completely all these pancreatic injuries induced by ethanol, exerting significant protective effects. These results suggest that impaired pancreatic energy metabolism and increased mitochondrial fragility seem to play an important role in the pathogenesis of ethanol-induced pancreatic injuries, and that some unknown protease activity, which can be inhibited by FOY, also seems to play an important role. Finally, FOY seems to be useful in protecting the exocrine pancreas in the alcoholic patients. Excessive intake of ethanol often precedes the development of both acute and chronic pancreatitis, and pancreatitis occurs more commonly in alcoholics than in the general population. Thus, alcohol has been reported to be one etiological factor in the pathogenesis of human pancreatitis. However, little is known about the mechanism whereby alcohol induces pancreatic acinar cell injuries. Moreover, there have been few reports regarding the effect of ethanol on pancreatic adenylate energy metabolism. Recently, we have reported the important role of subcellular organellar fragility in the triggering of pancreatic injuries in other models of pancreatitis such as secretagogue-induced and pancreatic duct obstruction. In this study, we evaluated the effect of ethanol administration at various doses on the exocrine pancreas from several parameters including pancreatic adenylate energy charge levels and subcellular organellar fragility as well as the protective effect of a synthetic protease inhibitor, gabexate mesilate (FOY) [ethyl-4-(6-guanidino hexanyloxy benzoate) methanesulfonate; M.W. 417 daltons].

Animals↗
PubMed1996

[Gabexate mesilate induced recovery from thrombocytopenia in a patient with acute ITP].

A 47-year-old woman was admitted to our hospital complaining of subcutaneous hemorrhages. She had taken medicine because of a common cold one month before admission, and two weeks after that, she noticed the hemorrhagic diathesis. Laboratory data on admission were as follows; 1,000/microliters of platelet count (PLT), normal myelogram, normal coagulation tests, positive PAIgG and anti-platelet antibody. She was diagnosed as idiopathic thrombocytopenic purpura and a standard dose of prednisolone was started immediately. However, on the 3rd hospital day (HD), frequent hematemesis from submucosal hematomas developed. Pulse therapy of methylprednisolone and immunoglobulin therapy were ineffective. From the 15th HD slow drip infusion of vincristine and continuous drip infusion of 1, 500 mg/day of gabexate mesilate (GM) were started. Because PLT increased to 85,000/microliters and hematemesis disappeared on the 22nd HD, GM was discontinued. However on the 25th HD, PLT decreased to 1,000/microliters again. After re-starting GM, PLT was maintained at over 100,000/microliters. Subsequent examinations ruled out collagen diseases but revealed that she had Hashimoto's thyroiditis. We concluded that the complement inhibitory action of gabexate mesilate might have contributed to PLT increase in this case, as has been previously reported in three other cases.

Acute Disease↗
PubMed1996

The effect of gabexate mesilate on pancreatic and hepatic microcirculation in acute experimental pancreatitis in rats.

Microcirculatory derangements are important early features in many organs during the process of acute pancreatitis. However, dynamic evaluation of these factors has been difficult. Antiprotease has long been used for the treatment of acute pancreatitis, although its effects and mechanism have not been fully elucidated. The involvement of proteases and microcirculatory derangement early in the course of acute pancreatitis are the main concern of this study. A severe acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by adding caerulein (15 microg/kg/ hr) in intravenous infusion fluid and intraductal injection of 0.1 ml glycodeoxycholic acid (5 mM). Gabexate mesilate [GM; ethyl-4-(6-guanidinohexanoyloxy)benzoate methanesulfonate], a synthetic antiprotease, was infused intravenously in doses of 0.01, 0.1, 1, and 10 mg as a therapeutic intervention in this model. Pathology hematocrit, serum amylase level, and glutamic-oxaloacetic transaminase (GOT) levels were used to confirm the severity of disease and effect of therapy. In vivo microscopic technique was used as a investigating tool in this study of microcirculatory derangement in pancreas and liver, 8 hr after induction of acute pancreatitis. GM can significantly improve pathologic criteria and changes of serum amylase levels in the range of 1-10 mg/kg/hr. The severity of changes of hematocrit and GOT was significantly lessened with GM in the range of 0.1-10 mg/kg/hr. This agent also could improve the microcirculatory environment in pancreas and liver after induction of acute pancreatitis according to the parameters, such as flow velocity and rolling leukocyte phenomenon, in the range of 1-10 mg/kg/hr. According to our observation, severity of hyperpermeability had not changed with the treatment of GM. These results indicated the beneficial effects of GM on pancreatic and hepatic microcirculation early in the course of acute pancreatitis. The beneficial effects were noted in serum parameters and hematocrit. The importance of protease activation and remote organ dysfunction is emphasized in the course of acute pancreatitis from this study.

Acute Disease↗
PubMed1999

Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung injury in dogs.

BACKGROUND: To assess the effects of gabexate mesilate (FOY), a protease inhibitor, on a canine model of pulmonary ischemia-reperfusion injury. FOY has been applied clinically to treat acute pancreatitis and disseminated intravascular coagulation (DIC) and has been found to suppress some leukocyte-mediated tissue injuries in both in vitro and in vivo studies. MATERIALS AND METHODS DESIGN: Comparison of four experimental groups: group 1 (untreated control, n = 8), unilateral (left) pulmonary ischemia due to perfusion and ventilation obstruction followed by reperfusion, without receiving any specific treatment; group 2 (negative control, sham operation, n = 8), left pulmonary hilar dissection without ischemia; group 3 (FOY posttreatment, n = 8), FOY treatment during the reperfusion stage only; and group 4 (FOY pretreatment, n = 8), FOY treatment before ischemia and then continued during reperfusion. SETTING: University animal laboratory. SUBJECTS: Heart-worm-free mongrel dogs (12 to 15 kg body wt) were anesthetized with pentobarbital and mechanically ventilated. INVESTIGATIONS: Lung ischemia was made by snaring the left pulmonary artery and veins and clamping the bronchus with peribronchial tissue for 90 min followed by reperfusion for 18 h. Animals of the two treatment groups received a 1 mg/kg bolus of FOY at the beginning of reperfusion, with infusion of 2 mg/kg/h of FOY continuously starting 30 min before ischemia (group 4) or after reperfusion (group 3). During this study the following were measured: hemodynamics and aerodynamics, blood gas, bronchoalveolar lavage (BAL) fluid neutrophil percentage and protein concentration, lung wet to dry weight ratio (W/D ratio), myeloperoxidase (MPO) activity of the lung tissue, alveolar neutrophil infiltration, and degree of injury. RESULTS: This model of lung ischemia-reperfusion induced significant pulmonary hypertension, increased pulmonary vascular resistance, decreased pulmonary dynamic compliance and arterial hypoxemia, increased BAL fluid total protein amount and neutrophil percentage, and increased alveolar neutrophil infiltration, histological injury score, and lung tissue MPO assay (group 1). Animals of the sham operation (negative control, group 2) showed only minimal changes in the above parameters. Treatment with FOY significantly attenuated the injury by decreasing the lung W/D ratio, alveolar neutrophil infiltration, histological injury score, lung tissue MPO assay, BAL fluid neutrophil percentage, and protein amount. Pretreatment with FOY (group 4) attenuated the injury to a significantly greater degree than it did when administered at the reperfusion stage only (group 3), which was reflected by the above-mentioned parameters, and as well significantly improved gas exchange function. FOY treatment was found to have little effect in altering hemodynamics and aerodynamics at most time points in this model of lung injury. CONCLUSIONS: FOY can attenuate the ischemia-reperfusion-induced acute lung injury in dogs by ameliorating the degree of alveolar membrane permeability change, neutrophil aggregation, and activation. FOY treatment starting before ischemia attenuated this injury to a significantly higher degree than its use after ischemia. However, the effect of FOY may be partial because it cannot alter the hemodynamics or aerodynamics as prominently as other parameters in this type of lung injury. Concomitant use of FOY with other agents will have additive or synergic effects in preventing lung ischemia-reperfusion injury.

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↗