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PubMed1994

Protective effects of gabexate mesilate on acute pancreatitis induced by tacrolimus (FK-506) in rats in which the pancreas was stimulated by caerulein.

We investigated the acute effects of the immunosuppressive agent, tacrolimus (FK-506), on the exocrine pancreas, in rats with or without stimulation of the pancreas, and evaluated the protective effects exerted by gabexate mesilate (FOY). While an intravenous injection of FK-506 did not change serum amylase levels during the 5-h observation period, this agent increased pancreatic amylase and protein content, and decreased the content of pancreatic DNA. Histologically, we observed intra-acinar vacuolization and individual cell necrosis. When the pancreas was stimulated by two intraperitoneal injections of caerulein (5 micrograms/kg) at 1-h intervals, however, which treatment did not induce any evident pancreatic change, FK-506 significantly increased serum amylase, pancreatic wet weight, and pancreatic amylase and protein, and decreased pancreatic DNA. Histologically, there were significant dose-related differences in the severity of intra-acinar vacuolization, interstitial edema, neutrophil infiltration, individual cell necrosis, and hemorrhage. Levels of intrapancreatic elastase were elevated and local pancreatic blood flow was reduced. Treatment with FOY improved the FK-506-induced acute pancreatitis, but did not increase the pancreatic blood flow. These findings indicate that FK-506 enhances abnormal pancreatic enzyme secretion and suggest that therapeutic doses of this agent can induce acute pancreatitis when the pancreas is stimulated. A protease inhibitor may protect the exocrine pancreas in patients who receive FK-506 after organ transplantation.

Amylases↗
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↗
PubMed2005

Effects of gabexate mesilate (FOY) on amylase and phospholipase A2 in human serum and pancreatic juice.

The precise inhibitory action of gabexate mesilate (GM) on the various pancreatic enzymes remains unclear. We designed this study to investigate the enzyme inhibitory action of GM in the serum and directly in the pancreatic juice. We observed 16 cases with postoperative pancreatic drainage. Patients were randomly assigned to one of two groups, to receive GM at a dose of 600 mg/24 hr (treated group: 8 patients) or a physiological solution (control group: 8 patients) by continuous intravenous infusion. In both groups pancreatic juice and serum were sampled three times: before infusion began (T0) and at 12 hr (T1) and 24 hr after infusion ended (T2). At the end of the study, seven patients received octreotide and the volume of pancreatic secretion was determined. No statistical difference was observed in serum amylase and phospholipase A2 activity in the treated and control groups. On the contrary, amylase and phospholipase A2 activity in the pancreatic juice diminished significantly only in the treated group, and in these patients a GM metabolite was also detectable in the pancreatic secretion. The volume of pancreatic secretion decreased only after infusion of octreotide. The enzyme inhibition in the pancreatic gland itself and the central role of inhibition of phospholipase A2 in the enzyme cascade responsible for activating other proteases, confirm the therapeutic use of GM in acute pancreatitis. An association of GM and octreotide during acute pancreatitis should be useful because of their different mechanisms.

Amylases↗
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↗
PubMed1983

Application of HPLC measurement of plasma concentration of gabexate mesilate.

The plasma concentration of gabexate mesilate (ethyl-p-(6-guanidinohexanoyloxy) benzoate) methanesulfonate (GM), FOY, was measured on a high performance liquid chromatography. GM concentrations ranging from 1 to 50 micrograms/ml of whole blood were able to be determined with this method. The half-life of GM in plasma was 55 seconds and the minimum concentration of GM which affected the activated coagulation time of whole blood (ACT) was 10 micrograms/ml. This method is sensitive and accurate to provide us with the pharmacodynamic basis for the determination of the effective plasma concentration of GM with respect to its anticoagulant activity.

Anticoagulants↗
PubMed2006

Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma.

BACKGROUND: Serine proteases such as mast cell tryptase and certain allergens are important in the pathogenesis of allergic inflammation of asthma. OBJECTIVE: We sought to investigate the effects of serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on airway inflammation in a mouse model of allergic asthma. METHODS: BALB/c mice were sensitized to Dermatophagoides pteronyssinus (Der p) and intratracheally challenged with Der p (0.5 mg/mL). Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), and UTI (10,000 U/kg) were intra-peritoneally injected into 3 corresponding sensitized mice during the sensitization phase (protocol 1) or 24 hours after allergen challenge (protocol 2). RESULTS: Both FUT-treated and FOY-treated sensitized mice had reduced mast cells activation, airway hyperresponsiveness, attenuated eosinophils infiltrations, and decreased Der p-induced IL-4 and TNF-alpha, but increased IL-12 cytokine production in bronchoalveolar lavage fluid compared with nontreated mice. Furthermore, FUT treatment downregulated the expression of IL-1beta, TNF-alpha, IL-6, eotaxin, inducible NO synthase, CD86, and nuclear factor-kappaB activation, but enhanced the expression of IL-12 and IL-10 in Der p-stimulated alveolar macrophages. UTI-treated mice have no significant change of the aforementioned measurements compared with nontreated sensitized mice. CONCLUSION: Nafamostat mesilate and FOY exerting the therapeutic effect in allergen-induced airway inflammation was a result not only of their inhibitory action in the early phase of mast cells activation but also of immunoregulatory function in the late phase of allergic inflammation. Such properties of FUT and FOY might be a potential therapeutic approach for asthma. CLINICAL IMPLICATIONS: The clinical used of serine protease inhibitors FUT and FOY may also have implications for treating airway inflammation of asthma.

Animals↗
PubMed2005

Effect of synthetic protease inhibitor gabexate mesilate on the attenuation of ischemia/reperfusion injury in canine kidney autotransplantation.

BACKGROUND: Kidneys from non-heart-beating donors are associated with delayed graft function and a high rejection rate due to the long period of warm ischemia. Gabexate mesilate (GM), a synthetic serine protease inhibitor, has been shown to improve organ function by suppressing cytokine activity and neutrophil function after ischemia/reperfusion. In this study, we evaluated the effect of GM on renal function after warm ischemia in a canine kidney autotransplantation model. METHODS: After 60 minutes of warm ischemia, the left kidney was transplanted into the iliac fossa, and the right kidney was removed. The control group (n = 7) and GM group (n = 7) were evaluated for serum creatinine and blood urea nitrogen (BUN) concentrations, renal tissue blood flow, resistive index, pulsatility index, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha mRNA expression levels in peripheral blood mononuclear cells, apoptotic index, CD10 immunolabeling as an indicator of brush border injury, and standard histopathology. RESULTS: Compared with controls, administration of GM resulted in lower serum creatinine concentrations (11.3 +/- 2.4 vs 5.2 +/- 3.3 mg/dL at 72 hours; P = .04) and BUN concentrations (188 +/- 26 mg/dL vs 98 +/- 41 mg/dL at 72 hours; P = .04), as well as better tissue blood flow, improvement of brush border injury and apoptotic index (each P < .05). The expression of IL-1beta and TNF-alpha mRNA did not change after administration of GM. CONCLUSIONS: The present study shows that GM protected renal function after warm ischemia/reperfusion by inhibition of serine proteases, maintenance of tissue blood flow, and amelioration of tubular apoptosis.

Animals↗
PubMed2004

Preparation and characterization of starch/cyclodextrin bioadhesive microspheres as platform for nasal administration of Gabexate Mesylate (Foy) in allergic rhinitis treatment.

Bioadhesive and biodegradable microspheres were obtained by chemical cross-linking with epichlorohydrin of an alkaline solution of a mixture of starch and alpha-, beta-, or gamma-cyclodextrin (CyD). Microspheres were characterized by scanning electron microscopy, swelling degree, and water retention. The percentage of the effective CyD in microspheres was estimated by measuring the amount of iodine and typical organic compounds (TOCs) retained in the hydrophobic cavity of CyD. Gabexate Mesylate (trade name Foy); GM), an antiallergic drug, was included in microspheres by soaking in an aqueous solution containing the drug, followed by solvent evaporation or lyophilization. UV, IR, and DSC data indicated that despite the fact that GM is a hydrophilic drug, its hydrophobic moiety close to the benzene ring is able to penetrate the CyD cavity and to form stable inclusion complexes. Values of the association equilibrium constant for GM binding to CyD, obtained by UV differential spectroscopy, indicated that the affinity of the drug for alpha- and gamma-CyD is higher than that for beta-CyD. In vitro, GM was gradually released during 1h. Even if the release rate of the drug is relatively fast, the microspheres might actually provide the best platform since the material adheres to the nasal mucosa which was proved by adhesion tests. The GM integrity was checked by comparing its anti-trypsin activity before and after release.

Adhesives↗
PubMed1996

Gabexate mesilate, a new synthetic serine protease inhibitor: a pilot clinical trial in valvular heart surgery.

OBJECTIVE: To assess the effects of gabexate mesilate ([GM], Foy, ONO Pharmaceutical Co, Osaka, Japan) on blood loss in cardiac valve replacement surgery and to establish whether GM reduces blood loss or transfusion requirements after this surgery. DESIGN: Randomized single-blind trial in 30 patients receiving either GM (2 mg/kg/h in a central venous catheter), or no GM, after heparin. SETTING: Department of Anesthesia and Intensive Care, Cardiac Surgery, in a hospital in Italy. PARTICIPANTS: Consent patients. INTERVENTIONS: Cardiac valve replacement surgery. MEASUREMENT AND MAIN RESULTS: Intraoperative and postoperative bleeding, blood transfusion, hemoglobin, and hematocrit were compared. In the GM group bleeding was reduced and no transfusions were required. CONCLUSION: GM appears to play a useful role in reducing blood loss during extracorporeal circulation in cardiac surgery.

Adult↗
PubMed2002

Protective effects of inhaled nitric oxide and gabexate mesilate in lung reperfusion injury after transplantation from non-heart-beat donors.

BACKGROUND: The use of lung grafts from non-heart-beat donors (NHBDs) is one way of solving the critical donor organ shortage. Inhaled nitric oxide (NO) and gabexate mesilate (FOY), a protease inhibitor, can attenuate some types of neutrophil-mediated tissue injury. Using an isolated lung ventilation and perfusion model, we studied the effects of these agents on reperfusion injury following lung transplantation from NHBDs. METHODS: Five groups of minipigs were studied. In group 1(n = 6), the lungs were flushed and harvested after cardiac arrest, and were reperfused for 2 hours after 2 hours of cold ischemia. In group 2 (n = 6), the lungs were harvested after 2 hours of in situ warm ischemia, followed by 2 hours of cold ischemia and 2 hours of reperfusion. In groups 3 (n = 7), 4 (n = 7), and 5 (n = 6), the procedure was the same as in group 2, except in group 3, NO was inhaled before and after ischemia, in group 4, FOY was given intravenously, and in group 5, a combination of inhaled NO and intravenous FOY were administered. RESULTS: Compared with group 1, group 2 had higher mean pulmonary arterial pressure, vascular resistance, and lower arterial blood oxygen tension. Furthermore, these negative effects of warm ischemia were also reflected in the contents of bronchoalveolar lavage fluid, tissue myeloperoxidase (MPO) activity, histology, and permeability change. Either FOY or NO administration (groups 3 or 4) ameliorated the associated injury. A combination of FOY and NO use (group5) decreased the parameters of lung reperfusion injury measurement to a larger degree than either agent individually. CONCLUSIONS: The inhaled NO and FOY can protect NHBD lung grafts at an early reperfusion period. Their use in combination has an additive protective effect that might be applied to the protection of NHBD grafts from preservation and reperfusion injury.

Administration, Inhalation↗
PubMed1998

Cross-enzyme inhibition by gabexate mesylate: formulation and reactivity study.

Gabexate mesylate (GM; commercialized under the brand name FOY) is a nonantigenic synthetic inhibitor of plasmatic and pancreatic serine proteinases that is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for hemodialysis. The inhibitory effect of GM on nitric oxide synthase as well as serine proteinases and swine kidney copper amine oxidase, all acting on cationic substrates, has been investigated. On the basis of the available X-ray crystal structures of the enzymes considered, the possible binding mode(s) of GM has(have) been analyzed. The enzyme cross-inhibition by GM suggests that the use of this drug should be under careful control. With the aim to improve the scarce plasma stability of GM, the positively charged drug has been complexed to the surface of preformed anionic liposomes. The liposome-complexed GM half-life increases about five-fold, indicating the protective effect of liposomes on GM degradation. Moreover, the GM complexation with liposomes does not alter its inhibitory activity on NOS-I and porcine pancreatic trypsin.

Drug Carriers↗
PubMed1998

Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis.

BACKGROUND: Autodigestion of the pancreas, secondary to the activation of digestive enzymes, is the pathogenetic mechanism of acute pancreatitis (AP). AIM: Clinical trials in which somatostatin (SS), octreotide (OCT) and gabexate mesilate (FOY) were used to treat patients with AP, were submitted to a meta-analytical evaluation. Five end-points were evaluated: early and overall mortality, patients with complications, complication rate, and patients who needed surgery. RESULTS: In mild AP, no agent proved of value. In severe AP, both SS and OCT were beneficial in improving the overall mortality: the odds ratios (OR) were, respectively, 0.36 (95% CI: 0.20-0.64, P = 0.001) and 0.57 (95% CI: 0.35-0.88, P = 0.006). FOY had no effect on either early or overall mortality, but was effective in improving complication rate (OR = 0.70, 95% CI: 0.56-0.88, P = 0.02), number of patients with complications (OR = 0.61, 95% CI: 0.41-0.91, P = 0.01), and number of cases submitted to surgery (OR = 0.60, 95% CI: 0.39-0.92, P = 0.01). SS and OCT had no effect on these latter outcomes. CONCLUSIONS: Antisecretory agents, such as SS and OCT, are able to reduce mortality without affecting complications, whereas antiproteases, such as FOY, have no effect on mortality but do reduce complications. A trial exploring the efficacy of combining antisecretory agents with antiproteases would be of great benefit in patients with severe AP.

Acute Disease↗
PubMedDate not supplied

Gabexate mesilate (FOY) inhibition of amylase and phospholipase A(2) activity in sow pancreatic juice.

We designed this study in sows to investigate the enzyme inhibitory action of gabexate mesylate (GM) directly in the pancreatic juice. We studied 16 sows, each weighing about 130 kg. The pancreatic duct was identified and cannulated to collect the pancreatic juice. Sows in the treated group received intravenous GM infusion at a dose of 1000 mg over 24 h. Control sows underwent the same sampling schedule while receiving physiological solution. GM inhibited the two pancreatic enzymes amylase and phospholipase A(2) (PA(2)) in pancreatic juice. Thus, the enzyme inhibition in the pancreatic gland itself and the central role of (PA(2)) inhibition in enzyme cascade responsible for activating other proteases confirm the therapeutic use of GM in acute pancreatitis.

Acute Disease↗
PubMed1982

New approach to regional anticoagulation in hemodialysis using gabexate mesilate (FOY).

Gabexate mesilate (FOY), a synthetic serine proteinase inhibitor, prevented and controlled bleeding during hemodialysis of 3 patients with active bleeding sites and/or hemorrhagic tendencies. The effectiveness of regional anticoagulation was evaluated by activated coagulation time (ACT). The ACTs of blood sampled from the outlet of dialyzer were significantly prolonged; however, systemic ACTs were almost normal. ACTs immediately after dialysis were not prolonged compared with those before dialysis. In 1 patients, renal function was improved after dialysis. No harmful side effects of FOY were observed. We consider FOY to be superior to other drugs for hemodialysis in that: (1) it can provide sufficient regional anticoagulation; (2) it has a very short half-life and need not be antagonized after dialysis; and (3) it can be used in patients with sepsis and/or disseminated intravascular coagulation (DIC) because it inhibits proteinase and also prevents platelet aggregation.

Aged↗
PubMed1983

Gabexate mesilate (FOY) therapy of disseminated intravascular coagulation due to sepsis.

Gabexate mesilate (FOY), a synthetic serine proteinase inhibitor, has an anticoagulant activity in the absence of antithrombin-III. We investigated FOY therapy for the treatment of disseminated intravascular coagulation (DIC) associated with sepsis in 15 patients (group F), and compared it with heparin therapy in 8 patients (group H). Successful treatment was observed in 13 patients in group F and in 4 patients in group H. The efficacy of the therapy in both groups was not significantly different. However, in patients whose antithrombin-III values were less than 20 mg/dl at the initiation of the therapy, FOY therapy was successful in 6 of 7 patients, whereas heparin therapy was not at all successful in 4 patients (rho less than 0.05). We conclude that FOY can be used as effectively as heparin for the treatment of DIC, and that FOY therapy is superior to heparin therapy in DIC associated with decreased antithrombin-III.

Adult↗
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↗
PubMed1992

Veno-occlusive disease of the liver after combined adjuvant chemotherapy for a 1-year-old boy with rhabdomyosarcoma: potential usefulness of the gabexate mesylate (FOY).

A tumor in the left thigh of a 1-year-old boy was diagnosed as rhabdomyosarcoma (stage 1). The tumor was excised and vincristine (1.5 mg/m2 given twice), actinomycin D (15 micrograms/kg given five times), and cyclophosphamide (600 mg/m2 given once) were prescribed. On the 12th day after initiating this chemotherapy, his liver rapidly enlarged and ascites, pleural effusion, and disturbance of consciousness due to hepatic failure successively appeared. Before these clinical signs appeared, laboratory data demonstrated enhanced coagulation and fibrinolysis such as thrombocytopenia refractory to platelet transfusion and a marked increase in fibrinogen and fibrin degradation product (FDP). Hepatic veno-occlusive disease (VOD) was suspected, and based on the laboratory data indicating enhanced coagulation, anticoagulant (gabexate mesylate; FOY), diuretic, and supportive therapy for hepatic failure was begun. The clinical course was favorable and recovery was complete in 2 months, with no sequelae. We propose that platelet count, coagulation factor levels, and FDP may be useful for the early detection of VOD, and an anticoagulant drug such as FOY is worthy of consideration for the prevention and treatment of VOD.

Anemia↗