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PubMed1987

Gabexate mesilate (FOY) protects against ceruletide-induced acute pancreatitis in the rat.

Acute pancreatitis (AP) is believed to result from intraparenchymal activation of trypsin and other digestive enzymes within the pancreas followed by autodigestion of the gland. Gabexate mesilate (FOY), a synthetic guanidino acid ester exhibiting potent and versatile inhibitory actions on a number of proteinases (e.g., trypsin, kallikrein, C1-r, C1 esterase, plasmin, thrombin, phospholipase A2), was examined for its ability to protect the rat pancreas against development of AP induced by pharmacological doses of ceruletide (CRT). Rats were i.v. infused for 6 h with either CRT (5 micrograms/kg/h) or CRT + FOY (50 mg/kg/h). In FOY-treated rats the serum amylase and trypsinogen concentrations were reduced by 60 and 80%, respectively, compared to rats infused with CRT alone. Histologically, the extent of acinar cell vacuolization in the pancreas was significantly reduced and interstitial edema, although not assessed by quantitative morphometric techniques, appeared to be qualitatively lessened in the FOY-treated rats. The ability of FOY to inhibit significantly AP produced by supramaximal doses of CRT, coupled with its inhibitory properties on components of the coagulation and complement cascades, stress the importance of continued research on this compound as a potential therapeutic agent for treatment of AP and its systemic sequelae.

Acute Disease↗
PubMed2000

The effects of inhaled nitric oxide, gabexate mesilate, and retrograde flush in the lung graft from non-heart beating minipig donors.

BACKGROUND: The use of lung grafts from non-heart-beating donors (NHBD) is one way of solving the donor organ shortage problem. In this experiment, we studied the effect of retrograde flush (RF) from the left atrium before harvest, inhaled nitric oxide (NO), and gabexate mesilate (FOY), a protease inhibitor, in the lung grafts from NHBD. METHODS: Forty-eight Lee-Sung, small-ear, miniature pigs (15-20 kg) were divided into 24 pairs (donor and recipient) and four groups. The donor lungs were flushed and harvested 90 min after cardiac arrest. No i.v. heparin was administered until the time before flush and harvest. Left single lung transplantation was undertaken, and the recipients were observed for 18 hr. The grafts warm and cold ischemia times were 90 (controlled) and 183+/-23.4 min. Group 1 (untreated control, UC, n=6) had core perfusion through a Swan-Ganz catheter followed by a single, antegrade flush with modified Euro-Collin's solution containing heparin, urokinase, and PGE1. Group 2 (RF group, n=6) had the same as group 1, except that one additive retrograde flush through the left atrium was administered. Group 3 (NO group, n=6) had the same as group 1, except that 20 parts per million (ppm) inhaled NO was administered for the cadaver donors before the graft harvest, and for the recipients after the grafts reperfusion. Group 4 (FOY group, n=6) had the same as group 1, except that the recipients received FOY i.v. infusion from the beginning of the recipient's operation and continuously throughout the experiments. RESULTS: Compared with the group 1 (control), group 2 (RF) had significantly (P<0.05) lower mean pulmonary artery pressure, pulmonary vascular resistance (PVR), lung wet/dry ratio, histological lung injury score, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 3 (NO) had significantly lower mean pulmonary arterial pressure, PVR, lung injury score, degree of tissue neutrophils infiltration (histological and myeloperoxidase assay), bronchoalveolar lavage fluid protein content and neutrophils (PMNs) percentage, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 4 (FOY) had significantly lower PMNs infiltration, lung injury score, wet/dry ratio, bronchoalveolar lavage fluid protein and PMNs percentage, and higher PaO2/FiO2. Group 2 (RF) revealed better gas exchange (PaO2/FiO2) than the control (group 1) at earlier reperfusion periods (1st and 5th hr). On the contrary, group 4 (FOY) had higher PaO2/FiO2 than group 1 only at later period (18th hr). Pathologically, retrograde flush (group 2, RF) inhibited the intravascular thrombi formation more effectively than the NO or FOY treatment. However, the NO or FOY treatment inhibited the neutrophil infiltration more effectively than did the retrograde flush. CONCLUSION: The retrograde flush, inhaled NO and FOY infusion are beneficial to the protection of the NHBD lung grafts at an early reperfusion period, through different mechanisms. The use of these treatments in combination might help us to find a better way to protect the NHBD grafts against the preservation and reperfusion injury.

Administration, Inhalation↗
PubMed1986

Pancreatic secretion in the rat influenced by the low molecular weight serine proteinase inhibitor Gabexate mesilate.

The effect of intravenous or intragastric administration of the synthetic proteinase inhibitor Gabexate mesilate (GM) on the pancreas of rats was investigated. Infused intravenously at 4 mg kg-1 h-1, GM inhibited both basal or cerulein (0.2 microgram kg-1 h-1)-stimulated pancreatic protein secretion. Intracellular transport and secretion of newly synthesized pancreatic enzymes was not influenced by intravenous infusion of GM. Intragastric administration of GM (400 mg kg-1) on four consecutive days increased pancreatic wet weight, protein and enzyme content of the gland. A preferential increase of proteinases above glucosidases was observed. Pancreatic lobules from inhibitor-treated rats released 30% less amylase in response to cerulein or carbachol when the rate of discharge was expressed in percent of initial content. Expressed in ku amylase/microgram DNA secretion rate was two-fold higher than in controls. In pancreatic duct cannulated rats GM (400 mg kg-1 h-1), introduced intragastrically on five consecutive days, stimulated volume-bicarbonate and protein secretion rate, the secretory response on the fifth day being significantly higher than on the first day. Enzyme pattern in pancreatic juice changed characteristically: mainly the amount of acidic proteinases increased, whereas the amount of the basic isoforms was altered only slightly.

Animals↗
PubMedDate not supplied

Protection by gabexate mesilate (FOY) of the exocrine pancreas in rats with acute pancreatitis induced by a supramaximal dose of caerulein.

Earlier studies have reported that interstitial oedematous pancreatitis characterized by hyperamylasaemia can be seen during the early stage of stimulation of supramaximal dose of caerulein. The present study investigated the changes in both cellular and lysosomal fragility and the protective effects of a synthetic protease inhibitor gabexate mesilate (FOY) on this non-invasive model of experimental pancreatitis. The infusion of FOY (50 mg/kg/h) prevented the caerulein-induced increase in serum amylase and pancreatic oedema formation and reduced the elevated amylase content significantly. The administration of FOY with caerulein also reduced the increased lactic dehydrogenase (LDH) discharge significantly and inhibited the cathepsin B leakage from lysosomes in an in vitro incubation system. These results indicate that FOY plays its protective role at the subcellular level--that is, in lysosomes by inhibiting some proteases such as phospholipase A2. The importance of esterases in the pathogenesis of acute pancreatitis is demonstrated. This type of esterase inhibitor may be valuable clinically in the treatment of acute pancreatitis and these results also suggest the role of lysosomal fragility in the pathogenesis of progression of acute pancreatitis.

Acute Disease↗
PubMed2004

Gabexate mesilate inhibits colon cancer growth, invasion, and metastasis by reducing matrix metalloproteinases and angiogenesis.

Gabexate mesilate (GM), a synthetic protease inhibitor, has an antiproteinase activity on various types of plasma serine proteases. However, its role on matrix metalloproteinases (MMPs) has not been identified. In this study, we investigated the effect of GM on MMPs and on the invasion and metastasis of human colon cancer cell lines and neoangiogenesis. The activities of MMPs secreted from these cells were significantly reduced by GM but unaffected by the serine protease inhibitor aprotinin. GM directly inhibited purified progelatinase A derived from T98G human glioblastoma cells. In vitro, GM significantly reduced the invasive ability of colon cancer cells but not cellular motility, whereas aprotinin affected neither. Liver metastatic ability and tumorigenic potential in nude mice were remarkably reduced on treatment with GM. Immunohistochemical analysis of GM-treated tumors in mice showed a marked increase in apoptosis and a significant reduction in tumor angiogenesis. Human umbilical vein endothelial cell proliferation, tube formation, and neoangiogenesis in the rabbit cornea and Matrigel implanted in mice were significantly inhibited by GM. These results suggest that GM is a novel inhibitor of MMPs and that it may inhibit the invasion and metastasis of human colon cancer cells by blocking MMPs and neoangiogenesis.

Animals↗
PubMed1995

Effect of gabexate mesilate on thrombin and plasmin generation after hepatic resection in cirrhotic patients.

The effect of the gabexate mesilate (Gab) on thrombin and plasmin generation following liver resection in cirrhotic patients was studied. Six cirrhotic patients received an infusion of Gab after liver resection (Gab group), and another 6 patients did not receive such treatment (Con group). The parameters measured were thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex (PAP) and D-dimer. The real increases of D-dimer and PAP were significantly higher in Con group after surgery while no significant difference was observed in the increase of TAT. These results show that Gab suppresses plasmin generation and following D-dimer production more effectively than thrombin generation after hepatic resection.

Aged↗
PubMed1992

Multicenter double-blind trial of gabexate mesylate (FOY) in unselected patients with acute pancreatitis.

A multicenter, randomized, double-blind trial was carried out to evaluate the efficacy of gabexate mesylate (FOY) in acute pancreatitis. One hundred unselected patients were randomly allocated into two groups: 51 were assigned to receive FOY (12 mg/kg/day as continuous intravenous infusion for a minimum of 4 days and a maximum of 12 days), and 49 were allocated to placebo. The groups were comparable in demographic, clinical and biochemical parameters, etiology of pancreatitis, and disease severity, which was generally mild. Gallstones were the main etiological factor. All patients received fluid and electrolyte replacement, analgesia and nasogastric suction for at least 48 h after admission. Experimental therapy was initiated no later than 12 h after the beginning of symptoms. The results showed no statistically significant differences between the two groups with respect to the evolution of clinical and biochemical parameters, analgesic requirements, development of complications, hospitalization time or mortality at completion of the trial. In conclusion, early treatment with FOY does not appear to have any demonstrable beneficial effects in acute pancreatitis.

Acute Disease↗
PubMed1983

Protective effect of gabexate mesilate against experimental disseminated intravascular coagulation in rats.

Experimental disseminated intravascular coagulation (DIC) can be induced by 4 h sustained infusion of endotoxin at a dose of 100 mg/kg in rats. The experimental model of DIC in rats was used to study the preventive effect of gabexate mesilate (GM) against DIC. Before the infusion of endotoxin, 10(-6), 10(-3), 1, 10, 50 or 100 mg/kg of GM was injected intraperitoneally. The preventive effects against DIC were noted in all the parameters, such as fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count, and the number of renal glomeruli with fibrin thrombi, in rats treated with 1, 10 or 50 mg/kg of GM. From these results it was shown that GM inhibited the aggravation of endotoxin-induced experimental DIC in rats.

Animals↗
PubMed2005

Distribution of protease inhibitors in lipid emulsions: gabexate mesilate and camostat mesilate.

Gabexate mesilate (GM) and camostat mesilate (CM) are protease inhibitors used for the treatment of pancreatitis, and have been reported to show anticancer effects in vivo. Lipid emulsions (20% fractionated soybean oil) were investigated in terms of physicochemical interaction between the drugs and lipid emulsions as a possible drug carrier. The result showed that the drugs did not distribute in the oil phase but were adsorbed at the phospholipid interface of oil droplets. With increasing concentration of the drugs, the adsorption amount at the interface rose steeply to around 2.2x10(-11) mol/cm2 for GM and 1.2x10(-11) mol/cm2 for CM, respectively, followed by further adsorption deviated from the Langmuir adsorption manner after the inflection. To interpret this two-stage adsorption of the drugs, surface potential and fluorescence changes were examined in addition to thermodynamics for their interaction with the interfacial lipid layer. The primary adsorption was exothermic and was due to electrostatic interaction and van der Waals interaction between drug molecules and phospholipid molecules. Both acidic and neutral phospholipids in the lipid were involved in the adsorption of GM, while acidic phospholipids were mainly involved in the adsorption of CM. On the other hand, the secondary adsorption was endothermic and was entropy-driven most probably due to hydrophobic interaction for GM and CM in common, including peripheral penetration of drug molecules into the interfacial lipid layer.

Emulsions↗
PubMed1984

Gabexate mesilate (FOY) and aprotinin. A comparative study of the effects on trypsin-induced activation of the kinin and complement systems in vivo and in vitro.

The effect of gabexate mesilate (FOY) was studied in vitro in human and canine serum upon the addition of trypsin, and in vivo in dogs during intravenous trypsin infusion. The effect of FOY was compared with the effect of aprotinin. FOY did not show any protection against trypsin-induced activation of the complement and kinin systems in vitro or in vivo, while aprotinin did. All dogs exhibited signs of circulatory shock together with a consumption of the two main proteinase inhibitors, alpha-macroglobulin and alpha 1-proteinase inhibitor, when intravenous infusions of FOY and trypsin were performed simultaneously. However, all dogs survived without signs of shock if aprotinin was given instead of FOY. The ineffectiveness of FOY in serum is explained by the complete dissociation of FOY trypsin complexes together with a rapid degradation of FOY to inactive metabolites. Although FOY is an effective proteinase inhibitor in defined buffer systems in vitro, the results of the present study indicate that it is not an effective proteinase inhibitor in vivo. Aprotinin protects against trypsin-induced activation reactions, although much higher concentrations are needed in human than in canine serum.

Animals↗
PubMed2004

The effect of continuous arterial infusion of gabexate mesilate (FOY-007) on experimental acute pancreatitis.

The effectiveness of continuous arterial infusion of Gabexate Mesilate (FOY-007) on experimental acute pancreatitis was investigated. Acute necrotizing pancreatitis was induced by an injection of 10% Na-taurocholate (1ml/kg) into the main pancreatic duct of mongrel dogs. Animals were divided into three groups; Group A: non-treated control, Group B: after the induction of pancreatitis, injected with FOY-007 intravenously (5mg/kg/hr), Group C: after the induction of pancreatitis, injected with FOY-007 via the celiac artery. The changes in the values of amylase and lipase in serum and ascites etc. were examined. A histological examination was done and the FOY-007 concentration of the pancreas was measured. In both groups B and C, the serum levels of amylase and lipase reached significantly to low levels compared with those in group A. The extents of pancreatic parenchyma necrosis in each group were 36.1, 25.3 and 19.5%, respectively, and were significantly improved in group C. In addition, the FOY-007 levels in pancreas specimens in the intraarterial infusion group exceeded those in the intravenous infusion group by 32 times. The results suggest that continuous FOY-007 arterial infusion therapy is useful as a local treatment for severe acute pancreatitis.

Amylases↗
PubMed1979

Reduction of unfavourable effects of heparin with use of gabexate mesilate in dialysis.

Gabexate mesilate (GM), a potent synthetic proteinase inhibitor has been evaluated as an alternative anticoagulant to heparin for haemodialysis. GM haemodialysis was achieved at a dose of 1,600mg/hr. GM was found to be dialysable and so rapidly degraded that dialysis with GM anticoagulation was analogous to regional heparinisation. Although heparin induced considerable lipolytic activity, GM showed no particular effect on lipids. Some patients reported mild nausea and there was evidence of slight clot formation around the top of the venous drip chamber. GM anticoagulation is easier than the conventional unreliable techniques of regional heparinisation.

Anticoagulants↗
PubMed2004

Efficacy of gabexate mesilate on disseminated intravascular coagulation as a complication of infection developing after abdominal surgery.

BACKGROUND AND PURPOSE: Gabexate mesilate (GM) is a promising anticoagulation treatment for disseminated intravascular coagulation (DIC). This study was designed to examine the effect of GM on DIC associated with the development of infection after abdominal surgery in the intensive care unit (ICU). METHODS: From January 1999 to March 2002, 50 consecutive ICU patients suffering DIC associated with the development of infection after abdominal surgery were enrolled in this study. Twenty five of the patients were randomized to receive treatment with GM by central intravenous infusion at 1 mg/kg/hour for 5 days or longer, while the remaining 25 were not treated. Blood clotting tests were performed and cytokine levels including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were examined on days 1, 3, and 7 after admission. General blood tests and D-dimer tests were conducted before and after GM administration. The gender, age, mortality, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores and severity of DIC were compared between the 2 groups. RESULTS: No significant difference was found between the 2 groups in TNF-alpha and IL-6 concentration on days 1, 3, and 7. The mortality rate was similar between the 2 groups. However, DIC and APACHE-II scores were significantly lower in the GM-treated patients than in controls. CONCLUSION: In this study, GM (1 mg/kg/hour) did not reduce the concentration of TNF-alpha and IL-6, or alter the mortality rate in patients with DIC resulting from infectious complications after surgery. Nevertheless, APACHE-II scores indicated that GM reduced the DIC severity and improved the clinical condition of patients.

APACHE↗
PubMed1991

Early graft injuries after pancreatic transplantation in syngeneic rats. Cytoprotective effects of gabexate-mesilate.

Failures in experimental and human pancreatic transplantation are mainly attributable to rejection, graft thrombosis, and technical problems. There are, however, problems related to other causes, such as preservation injuries, which we found to exhibit, at least within the first 6 h, the same histological patterns seen in experimental acute pancreatitis. We performed pancreatic transplantation in 110 syngeneic rats under different preservation techniques and administration of gabexate mesilate, a synthetic protease inhibitor. The results showed that antiprotease treatment reduces graft preservation injuries significantly.

Analysis of Variance↗
PubMed1991

[Gabexate mesilate induced remarkable transient reversal of thrombocytopenia in a ITP patient].

A 46-year-old woman was admitted to our hospital because of hemorrhagic tendency. Normal coagulation test results conflicted with the diagnosis of disseminated intravascular coagulation (DIC). Furthermore, we saw no evidence of autoantibodies, including antinuclear antibodies and splenomegaly, and there was no past history of infection or medication. Peripheral blood test showed marked decrease of platelets only. Bone marrow aspiration revealed increased megakaryocytes. Morphology of other blood components was normal. Thus, we diagnosed this case as idiopathic thrombocytopenic purpura (ITP). Administration of prednisolone and an immunosuppressants did not improve symptoms. So patient was temporarily discharged and treated with 6-MP at the outpatient department. She was rehospitalized for liver damage caused by the drug. Patient then developed sepsis from acinetobactor. We administered gabexate mesilate (FOY, 2,000 mg/day) for four days to prevent DIC. Platelet count, which was 1.5 X 10(4)/microliter before FOT administration, began increasing on the second day, reaching 25. 5 X 10(4)/microliter on the fourth. Count rapidly decreased to 2.8 X 10(4)/microliter on the seventh day after administration had been discontinued. Two-time FOY administration after patient's recovery from sepsis led to a definite, similar transient increase in platelet count. As ITP patients with transient increase in platelet count by FOY administration had not been reported, this case is thought to be an interesting case in the pathogenesis and treatment of ITP.

Female↗
PubMed1983

[Therapy of acute pancreatitis with a synthetic protease and phospholipase A2 inhibitor gabexate mesilate].

In order to evaluate the efficacy and safety of gabexate mesilate (FOY = [ethyl-4-(6-guanidinohexanoyloxy) benzoate methane sulfonate]), a synthetic inhibitor of various proteases as well as phospholipase A 2, 17 patients with acute pancreatitis were treated with FOY in doses of 3 X 150 mg/day per i.v. perfusor. The clinical course of the disease and the laboratory findings were compared with the results of a control group of 21 patients also suffering from acute pancreatitis. 30% of the patients in the FOY-group and 40% in the control group had different complications during the first week after admission to the hospital. The laboratory findings in the two groups revealed that alpha-amylase levels in serum and urine in the FOY-group were significantly lower than in the control group. Side effects of the drug were not observed. FOY may be considered a promising drug for treatment of acute pancreatitis in view of its few side effects and especially with regard to its mode of action.

Acute Disease↗
PubMed1983

Antishock effect of gabexate mesilate (FOY).

The antishock effects of gabexate mesilate (FOY) were investigated in rats subjected to hemorrhagic hypotension, with particular attention focused on the stabilizing effects of hepatic lysosomes. The survival time of rats treated with FOY, infused for 2 hours intravenously at a rate of 50 mg/kg/hr, was significantly prolonged, accompanied by a tendency to decreased activity of plasma lysosomal enzymes. FOY, at a concentration of 10(-3) M, exerted a significant decrease in the extralysosomal release of acid phosphatase (15%, P less than 0.05), beta-glucuronidase (25%, P less than 0.05) and cathepsin D (25%, P less than 0.02) following hyposmotic labilization of lysosomes. Although the release of lysosomal enzymes might be counterbalanced by 50 mg/kg/hr of FOY, favorable cytochemical findings indicating stabilization of lysosomal membranes were consistently observed. The data suggest that FOY has antishock properties, and that these properties are caused, at least partially, by the stabilization of lysosomes.

Acid Phosphatase↗
PubMed1983

Effects of gabexate mesilate on the reactions of lipid metabolism in endotoxic shock.

Endotoxic shock was induced in rabbits of either sex by IV injection of 50 micrograms/kg endotoxin (ET) extracted from E coli O-55 by Boivin's method. A polyvinyl catheter was introduced into the superior vena cava under local anesthesia 1 day prior to the experiments. We observed a rise of plasma-free fatty acids (FFA) from an initial mean value of 190 muEq/liter to a level of 290 muEq/liter within 6 h after injection of endotoxin. The increase of FFA was followed by a rise of plasma triglycerides (TG) and an increase of very low-density lipoproteins (VLDL), beginning 1-2 h later. The rise of FFA and the following increase of TG and VLDL were significantly reduced by infusion of 14 micrograms/kg X min gabexate mesilate (GM). Our results indicate that GM--in addition to its well-known proteinase inhibitory action--effects fatty acid metabolism.

Animals↗