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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↗

PubMedDate not supplied

Acceleration of phagocytosis in human neutrophils incubated with gabexate mesilate.

It has recently been shown that gabexate mesilate inhibited human neutrophil functions including chemotaxis and reactive oxygen species production. In the present study, the effects of gabexate mesilate on phagocytosis by human neutrophils in vitro were investigated. Gabexate mesilate significantly enhanced neutrophil phagocytosis in a dose-dependent manner. This characteristic of gabexate mesilate may facilitate protection against infecting micro-organisms, although the inhibition of reactive oxygen species production by neutrophils may be a disadvantage for host-defense against infection.

Analysis of Variance↗

PubMed2002

Fatal cases of gabexate mesilate-induced anaphylaxis.

Gabexate mesilate, ethyl-4-(6-guanidinohexanoyloxy) benzoate monomethanesulfonate (C16H23N3 O4CH4O3S: M.W. 417.48), is a synthetic protease inhibitor and was introduced for clinical use in 1978. It rarely induces anaphylaxis, and patients with gabexate mesilate-induced shock had been reported to survive with appropriate treatments including respiratory support. However, there were increasing reports on fatal cases in recent years: 6 cases have been reported to develop fatal anaphylaxis following dripping infusions of gabexate mesilate. All the fatal cases rapidly developed anaphylaxis (within 5 minutes), whereas 7 out of 11 in recovered cases developed it 5 or more minutes after the injection. Venous access should be kept for at least 30 minutes to prepare for and to treat this fatal reaction in patients receiving gabexate mesilate repeatedly.

Anaphylaxis↗

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↗

PubMed1993

[Gabexate mesilate (FOY), a new synthetic protease inhibitor, in the treatment of shock. An Italian multicenter study].

BACKGROUND: Circulatory shock has been accepted as a consequence of a chain of biochemical events beginning with production of proteases and ending with an uncontrolled generation of oxygen radicals. OBJECTIVE: To evaluate the efficacy of gabexate-mesilate (FOY) in circulatory shock in man. Gabexate-mesilate is a new wide-range synthetic protease inhibitor that also has antioxidant properties. DESIGN: Clinical multicenter study with open design that has been compared with some Japanese controlled studies performed using identical parameters and very similar protocols. EXPERIMENTS: 59 shocked patients were treated with FOY in 9 italian intensive therapy units. Circulatory shock was traumatic (n = 14), traumatic-hemorrhagic (n = 25), septic (n = 11) or of mixed type (n = 9). Evaluation of seriousness of shock on beginning of therapy and during the follow-up period was performed on the basis of the same "shock score" (Ogawa and Fujita, Jap J Surg 12:122, 1982) that was used in Japanese clinical studies on FOY in shock. 1.45 mg/kg/hour of FOY were injected i.v. during 48 hours. Conventional therapy was permitted but steroids and aprotinin were excluded. The follow-up period was 9 days. RESULTS: 8 patients died. The mean initial score of the survivors was 8.2; after 8 hours it was 5.0 and after 12 it was 4.0. No adverse reactions were reported. The above quoted survival was greater than that of Japanese studies although the initial score was quite the same. However these studies were controlled and demonstrated gabexate-mesilate to be significantly more active in shock therapy than placebo. They also demonstrated an activity of FOY greater than that of aprotinin when shock was associated to acute respiratory insufficiency and to coagulopathies. CONCLUSIONS: Gabexate mesilate might be useful in therapy of circulatory shock due to its wide-range inhibition of proteases and to its antioxidant properties.

Adolescent↗

PubMed1997

Gabexate mesilate improves pancreatic microcirculation and reduces lung edema in a rat model of acute pancreatitis.

We evaluated the effects of a protease inhibitor on the progression of acute pancreatitis in rats. The model was selected and modified to mimic an intermediate stage of the disease. The degree of microcirculatory derangement in the pancrease and of lung edema was determined to assess the effects of gabexate mesilate (ethyl-4-(6-guanidinohexanoyloxy) benzoate methane sulfonate), a synthetic antiprotease, in acute pancreatitis. Male Sprague-Dawley rats (225-275 g) were used. Experimental pancreatitis was established by four intramuscular injections of cerulein (50 micrograms/kg) at 1 hour intervals. Lipopolysaccharide (10 mg/kg) was injected intraperitoneally as an acute septic challenge. Gabexate mesilate was infused intravenously 6 hours after the initiation of induction of acute pancreatitis at doses of 0.01, 0.1, 1, or 10 mg/kg/h. Microcirculatory changes in the pancreas were studied using in vivo microscopy. All animals survived until the end of the experiments. Gabexate mesilate significantly improved pathologic criteria and decreased serum lipase levels at doses of 1 and 10 mg/kg/h. It significantly lessened the severity of lung edema and improved the microcirculatory environment in the pancreas by increasing flow velocity and reducing leukocyte sticking. These results indicate the beneficial effects of gabexate mesilate on pancreatic microcirculation and lung edema in the progression of acute pancreatitis with septic challenge in rats.

Acute Disease↗

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↗

PubMed2002

Gabexate mesilate and/or octreotide in human immunodeficiency virus-associated pancreatic abnormalities.

BACKGROUND: Human immunodeficiency virus (HIV)-associated pancreatic alterations are frequent, but poorly investigated, notwithstanding their potential consequences on the course and management of HIV infection. No epidemiological or clinical data on pancreatic alterations have been published since the introduction of highly active antiretroviral therapy, and no indications of the pharmacological management of symptomatic or prolonged laboratory pancreatic abnormalities have been reported. AIM: To investigate the therapeutic role of gabexate mesilate and octreotide in HIV-infected patients with elevated, symptomatic or instrumentally confirmed pancreatic anomalies persisting for more than 3 months. METHODS AND RESULTS: An open-label, prospective, 5-year case-control study was conducted involving 185 consecutive patients with pancreatic alterations. Treatment of patients with severe laboratory and/or clinical involvement with low-dose gabexate mesilate and/or somatostatin was effective and safe and led to a lower recurrence rate and a better tolerability of concomitant drug regimens compared with supportive therapy taken by control patients. Combined gabexate-octreotide proved to be more active than single drug administration. CONCLUSIONS: Epidemiological and therapeutic data on the frequency, risk factors and clinical significance of pancreatic abnormalities during HIV infection are required, as are studies investigating the need for and choice of antisecretory and/or antiprotease compounds.

Adult↗

PubMed2005

Use of low dose dopamine, gabexate mesilate and ulinastatin reduces the water balance and pulmonary complication in thoracic esophagectomy patients.

SUMMARY: In spite of improvements in surgical technique and perioperative care, severe lung complication remains as the leading cause of morbidity in thoracic esophageal cancer patients who undergo esophagectomy. The purpose of this study was to evaluate the safety and effectiveness of postoperative drug therapy using low dose dopamine, gabexate mesilate, and ulinastatin on postoperative lung complication in esophageal cancer patients. Sixty-one patients operated for esophageal cancer from 1996 to 2000 were treated postoperatively with low dose dopamine (300 microg/kg/h), gabexate mesilate (80 mg/h), and ulinastatin (300 000 unit/day) as a study group. Seventy-four patients operated from 1987 to 1994 served as an historical control group. Various preoperative and perioperative medical parameters and water balance were analyzed. Postoperative pulmonary complications were observed in 26 patients (35.1%) in the control group and three patients (4.9%) in the study group, respectively (P < 0.0001). Preoperative and perioperative variables were not significantly different between the groups. Water balance from operation to postoperative day 3 in the study group was significantly lower than the control group. Postoperative use of low dose dopamine, gabexate mesilate, and ulinastatin significantly reduced pulmonary complications after esophagectomy. This may be partly attributable to negative water balance during the early postoperative days.

Carcinoma, Squamous Cell↗

PubMed1998

Competitive inhibition of Lens culinaris L. copper amine oxidase by amiloride, p-aminobenzamidine, clonidine, 4',6-diamidino-2-phenylindole and gabexate mesylate: a comparative study.

The competitive inhibition of Lens culinaris L. copper amine oxidase by amiloride (Ki = 4.1 x 10(-4) M), p-aminobenzamidine (Ki = 6.0 x 10(-4) M), clonidine (Ki = 5.0 x 10(-4) M), 4',6-diamidino-2-phenylindole (DAPI; Ki = 1.9 x 10(-5) M) and gabexate mesylate (Ki = 2.5 x 10(-4) M) has been investigated, at pH 7.0 and 25 degrees C. The affinity of p-aminobenzamidine, clonidine and DAPI for plant and mammalian copper amine oxidase is closely similar. However, values of Ki for amiloride and gabexate mesylate binding to swine kidney copper amine oxidase are lower than those observed for inhibitor binding to Lens culinaris L. cooper amine oxidase. Thus, amiloride and gabexate mesylate may represent useful model compounds for the development of selective inhibitors of mammalian copper amine oxidase, which may be important in view of the potential use of plant copper amine oxidase as drugs.

Amiloride↗

PubMedDate not supplied

Results of treating severe acute pancreatitis with gabexate is associated with neutrophil apoptosis activity.

BACKGROUND/AIMS: A delay in polymorphonuclear neutrophil apoptosis has been implicated in the pathogenesis of systemic inflammatory reactions in certain conditions. Gabexate mesilate has been proven effective in the treatment of severe acute pancreatitis with organ dysfunction. In this study, we attempted to answer the questions of whether neutrophil apoptosis is associated with the conditions of various major organs in patients with severe acute pancreatitis and receiving gabexate. METHODOLOGY: A total of 45 patients were included in this study. We divide the patients into two groups. Group A included patients with > or = 2 complications after one-week treatment (n = 31), and Group B included patients with < 2 complications after one-week treatment (n = 14). Serum interleukin-6 and interleukin-8 was detected at day 1, 3, and 7 of treatment using enzyme-linked immunosorbent assay kits. The neutrophil CD18 expression and apoptosis activity were evaluated flowcytometrically at day 1, 3, and 7 of treatment. RESULTS: At day 7 of treatment, interleukin-6 levels were significantly higher in Group B while interleukin-8 levels were not different. The neutrophil CD18 expression was significantly higher and delayed ex vivo apoptosis was significantly lower in the group B than that of group A at day 7 of treatment. CONCLUSIONS: In patients of severe acute pancreatitis with organ dysfunction and receiving gabexate treatment, neutrophil apoptosis is associated with the severity of organ dysfunction.

Apoptosis↗

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↗