Search

Aim: To compare the efficacy of two different schedules of gabexate mesilate (900 mg/day, or 1,500 mg/day) in the treatment of severe acute pancreatitis., Setting: Forty-two Italian medical and surgical centres took part in the study., Study Design: A multicentre, prospective, open label, comparative, parallel-group, randomized study., Methods: The patients enrolled in the study had acute pancreatitis as demonstrated by typical abdominal pain and baseline serum amylase concentrations more than twice the upper normal limit, findings compatible with acute pancreatitis at imaging techniques, and a Glasgow criteria score of > or =3. Patients were randomly assigned to one of the two schedules of treatment with gabexate mesilate being administered intravenously for at least 7 days. The minimum clinically relevant difference (delta), between groups, in incidence of complications due to acute pancreatitis, during the first month of the study treatment, was predefined as equal to 10%., Results: A total of 199 patients were assigned to gabexate mesilate 900 treatment and 189 to gabexate mesilate 1,500. Complications developed in 88 patients within one month of beginning treatment 44/199: patients (22.1%) in the gabexate mesilate 900 group and 44/189 patients (23.3%) in the gabexate mesilate 1,500 group (difference 1.2%; 95% confidence interval: -7.2; 9.5%)., Conclusions: Gabexate mesilate 900 mg per day is as effective as gabexate mesilate 1,500 mg per day in reducing the complications due to acute pancreatitis.

To date, gabexate mesilate, a synthetic protease inhibitor, has been used in the prophylaxis and treatment of acute pancreatitis, but has yet to be tested in preventing the postoperative complications of pancreatic surgery. For this purpose we planned a pilot study based on two treatment groups, each numbering 25 patients, submitted to high-risk pancreatic resection. In the first group, all patients received a continuous infusion of gabexate mesilate 1 g/day up to postoperative day 4; the second group of patients received the same treatment plus octreotide 0.1 mg every 8 hours for 5 days after surgery. All patients were followed until discharge with clinical and instrumental investigations to detect the onset of postoperative complications. The overall incidences of an uneventful course were 40% (10/25) and 32% (8/25), respectively. We found 12 complications closely related to pancreatic surgery in the former and 8 in the latter group. In the combined treatment group therefore we observe a 33% reduction in the incidence of related abdominal complications (12 vs 8). This favourable trend, however, needs to be confirmed in a larger multicentre trial.

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.

Liver failure due to ischemia-reperfusion injury, believed to be closely related to the generation of oxygen-free radicals, is a serious problem during liver surgery. Gabexate mesilate, a synthetic protease inhibitor, suppresses the extracellular release of oxygen-free radicals in the microvascular endothelium. To determine its effects on ischemia-reperfusion injury to the liver, we performed experiments with rats. We divided the animals into two ischemia-reperfusion groups: an experimental group, which underwent ischemic injury for 30 minutes, along with the infusion of gabexate mesilate, and a control group, which underwent injury only. Each group was then divided into four subgroups: ischemic injury only and 60-, 120-, and 180-minute reperfusion injury. The test parameters were tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) in serum and superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) in liver and lung tissues. The experimental group had a significantly higher liver SOD and catalase levels and a significantly lower level of liver and lung MDA than the control groups. TNFalpha levels in the experimental groups were significantly lower during the early phase, but a comparison of IL-6 levels between the two groups yielded no differences. Levels of lung catalase and SOD were not significantly different between the two groups. We concluded that protease inhibitor suppressed liver ischemia-reperfusion injury, and that it was due to an increase of antioxidant or suppression of oxygen-free radicals. The roles of TNFalpha and IL-6 in liver reperfusion injury were not clear, though TNFalpha might have had an effect during the early phase. With liver ischemia-reperfusion injury, the mechanism of lung involvement might be different from that of liver involvement.

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.

Objective: To evaluate the efficacy of gabexate mesilate (GM) in reducing surgical stress after esophagectomy., Methods: In a prospective, randomized, clinical study, 11 patients with squamous cell carcinoma of the esophagus were randomly assigned to two groups: 5 patients were continuously administered gabexate mesilate 1.5 mg/kg per hour from the beginning of anesthesia until the third postoperative day (preop GM group); and 6 patients were administered gabexate mesilate 1.5 mg/kg per hour continuously from the end of surgery and for the same postoperative period (postop GM group). Blood samples were taken from all patients before surgery, immediately after it, and 3 days after surgery. Serum interleukin-6 (IL-6) level, tumor necrosis factor-alpha (TNF-alpha) production, and Mac-1 antigen expression of peripheral blood monocytes were measured. Clinical courses of patients in the two groups were compared., Results: Time courses of serum IL-6 levels in the preop GM group were significantly lower than those in the postop GM group. Ex vivo TNF-alpha production by lipopolysaccharide (LPS) stimulated monocyte was much higher than that by monocyte without LPS stimulation. Gabexate mesilate showed a little inhibition of TNF-alpha production by monocyte without LPS stimulation. On the other hand, gabexate mesilate significantly inhibited TNF-alpha production by LPS stimulated monocyte. Mac-1 antigen expression by monocyte immediately after operation in the preop GM group was significantly lower than that in the postop GM group. Duration of systemic inflammatory response syndrome was significantly shorter in the preop GM group than in the postop GM group., Conclusions: Reduction of systemic inflammatory response syndrome duration after esophagectomy by the continuous administration of gabexate mesilate started before operation may be through the suppression of TNF-alpha production capacity and Mac-1 expression on monocytes immediately after operation, and to suppression of increase in serum IL-6 level.

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.

Case 1. The patient was a 69-year-old man with essential thrombocythemia (ET), who underwent urgent laparotomy. On admission he was dehydrated and the platelet count was more than 160 x 10(4).microliter-1, with hematocrit of 50%. Anesthesia was induced with ketamine i.v. and maintained with nitrous oxide and sevoflurane in oxygen. Postoperative care included the administration of gabexate mesilate (GM) which is an antiplatelet agent. Case 2. An 84-year-old woman with ET was diagnosed as gastric cancer and elective gastrectomy was scheduled. The platelet count was more than 100 x 10(4).microliter-1. The patient was anesthetized with nitrous oxide and oxygen supplemented with fentanyl and mepivacaine via epidural catheter. Intravenous infusion of GM was performed at a rate of 1 mg.kg-1.hr-1 during surgery. PF-4 and beta-TG were measured. These are platelet releasing factors. The level of PF-4 decreased to normal level during this procedure. In conclusions, it will be important to use GM during anesthesia in order to avoid the complications such as myocardial or pulmonary infarction caused by thrombocythemia.

A 79-year-old woman with skin ulcers caused by disseminated intravascular coagulation (DIC) therapy is reported. The patient had been treated by injection of drugs, including gabexate mesilate, into the right great saphenous vein. The maximum concentration of gabexate mesilate was calculated as 0.893%. Although the drugs did not extravasate, purpura initially appeared around the affected vein, followed by brown pigmentation with infiltration and ulcers with widely necrotic tissue from the middle portion of her thigh to the malleolus along her right great saphenous vein. As the ulcer showed no tendency to heal for more than 3 months, surgical debridement and skin grafts were performed.

A 59-year-old Japanese man developed septal panniculitis with eosinophilic infiltration in both forearms and the dorsum of the left hand after a gabexate mesilate intravenous drip infusion for acute pancreatitis through catheters implanted in these sites. Gabexate mesilate at a dose of 1000 mg per day had been given continuously for 8 days, and antibiotics were added by the same infusion route twice a day. All the infusion routes, however, became occluded one after the other. Reddish swelling first occurred at the left wrist 6 hours after occlusion of the infusion route, and, on both forearms, reddish swelling occurred about one week after the occlusion of each route. Patch testing revealed a +2 reaction to gabexate mesilate (10% pet) at days 3 and 7, and skin testing revealed indurated erythema to gabexate mesilate (0.1% aq) at days 2 and 3. The specimens biopsied from the positive skin testing reaction sites showed perivascular infiltrate and slight septal panniculitis. The inflammatory infiltrate consisted predominantly of lymphocytes with small numbers of eosinophils. Staining of the specimen biopsied from the right forearm lesion with anti-eosinophil cationic protein (ECP) antibodies (EG1 and EG2) showed deposition of eosinophil-derived granule proteins at the damaged septal connective tissues of the panniculitis. The panniculitis improved with topical steroid treatment. This case suggested that the concentration of infused gabexate mesilate may have been high enough to damage blood vessels and that gabexate mesilate may have leaked into the surrounding connective tissues, inducing allergic reactions and resulting in lesions.

We report a case of giant hepatic angiomyolipoma in a 68-year-old woman who had an increase in the fibrinolytic activity concomitant with disseminated intravascular coagulation (DIC). The presence of the tumor was confirmed by ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen and the selective arteriography of the liver via the superior mesenteric artery. Following treatment with heparin and gabexate mesilate, abnormal hemostatic values were corrected. Furthermore, the surgical removal of the huge hepatic angiomyolipoma completely normalized the alternations of the clotting system. These findings suggest that giant hepatic angiomyolipoma was profoundly associated with DIC.

A 66-year-old male was admitted to our hospital because of persistent fever. Laboratory data revealed leukopenia, thrombocytopenia, marked elevation of serum lactic acid dehydrogenase and ferritin levels, as well as disseminated intravascular coagulophathy (DIC). Bone marrow aspiration showed increased numbers of mature histiocytes with hemophagocytosis and a diagnosis of reactive hemophagocytic syndrome was made. In the broad spectrum of this syndrome, we suspected virus-associated hemophagocytic syndrome (VAHS) but no causative viral infection was detected. Since DIC is known to be a poor prognostic factor, he was given combination chemotherapy containing VP-16 in addition to pulse therapy of methylprednisolone. He completely recovered after the treatment. Chemotherapy is one option in the treatment of adult onset reactive hemophagocytic syndrome.

The administration of a high-dose of a serine protease inhibitor is recommended in patients complicated by multiple organ failure (MOF), including adult respiratory distress syndrome (ARDS), induced by acute pancreatitis. The accumulation of polymorphonuclear leukocytes (PMN) in affected organs is considered to be one of the causative factors of MOF. Adhesion to endothelial cells (EC), via adhesion molecules, and the transendothelial migration of PMN is closely associated with the accumulation of PMN. We examined the effects of two serine protease inhibitors, ulinastatin (UT) and gabexate mesilate (GM), on EC-PMN adhesion and transendothelial migration in human umbilical vein EC and 51Cr-labeled PMN in vitro. EC-PMN adhesion, and the expression of intercellular adhesion molecule-1 (ICAM-1) and endothelial cell adhesion molecule-1 (ELAM-1) on EC induced by IL-1 beta and TNF alpha, were reduced by the pretreatment of EC with these inhibitors. The transendothelial migration of PMN stimulated by IL-8 was also inhibited by pretreating PMN with UT or GM. We also examined whether these inhibitors reduced PMN accumulation in the lung in rats with acute pancreatitis induced by a closed duodenal loop. The myeloperoxidase activity in and histological findings of the lung suggested that UT and GM reduced PMN accumulation. In conclusion, serine protease inhibitors may inhibit PMN accumulation in ARDS due to acute pancreatitis.

Despite controversial experimental and clinical findings, the use of Aprotinin (A) in the treatment of acute pancreatitis (AP) is still widespread in our country. Compared to A, Gabexate Mesilate (FOY) should have the following advantages: lack of antigenicity, low molecular weight with better cellular penetrance, wide inhibitory spectrum (against phospholipase A2 too) and good tolerability. In order to verify the efficacy of FOY versus, we decided to carry out a prospective multicenter (34 centers) randomized double blind trial in moderate-severe AP with FOY 3g/day versus A 1,500,000 U.I.K./day infused for 7 days with central venous line. Based on standard clinical, biochemical and radiological data, 199 patients suffering from AP were enrolled to the study from January 1989 to December 1990. The main admission criteria were: onset of the disease from no more than 72 hours, at least 2 Ranson positive criteria and C.T. evidence of acute pancreatic damage. Seventeen no protocol patients were excluded. The Etiology in the 182 analyzed patients (106 male, 76 female; mean age 57.6 years, range 21-91) were: biliary 102 (56%), alcohol 47 (25.8%), post-operative 13 (7.1%), unknown causes 13 (7.1%) and others 7 (3.8%). Median Ranson's Score was 3. CT examination showed 66 AP with edema, while 116 cases (63.7%) were recognized as severe forms with pancreatic necrotic involvement of 30% of the gland in 71 (61.2%), 50% in 31 (26.7%), and more than 50% in 14 (12.1%). Out of 182 patients, 91 were treated with A and 91 with FOY. The two groups were comparable regarding the main prognostic factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Modulation of serum levels of circulating cytokines and inflammatory responses with a serine protease inhibitor was studied in 34 patients with hepatocellular carcinoma (HCC) after transcatheter arterial embolization (TAE)., Methods: The 34 patients were randomly divided into two groups: 17 patients received 500 mg gabexate mesilate, a serine protease inhibitor, intravenously twice a day for 5 days after TAE, and the remaining 17 patients did not receive the drug., Results: In the patients not given the drug, circulating interleukin-6 (IL-6) markedly increased 1 day after TAE, reached a peak (approximately 8 times the pretreatment value) after 4 days, and remained elevated 7 days after TAE. In comparison, in the patients given the drug, circulating IL-6 was at a significantly lower level at 4 and 7 days after TAE (P < 0.05, respectively). Both groups did not show significant change in circulating interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) during the week after TAE. The drug also showed a tendency to keep patient temperature below 38 degrees C, and the elevation of serum C-reactive protein (CRP) concentration to less than 1 mg/dl after TAE (P < 0.05, respectively)., Conclusions: The serum level of circulating IL-6 can be modulated by serine protease inhibitor, and this may contribute to suppressing inflammatory responses, such as fever and acute-phase protein synthesis, in the liver after TAE.

One hundred and ninety-one patients with disseminated intravascular coagulation syndrome (DIC) or its prodromal stage (preDIC) were treated with only gabaxate mesilate (FOY) (group G) or a combination of gabaxate and unfractionated heparin (group GH), and the efficacy of gabaxate was evaluated in a multicenter study. Following the treatment, the mean DIC score, which was evaluated on the basis of clinical symptoms and hemostatic parameters, decreased significantly to 5.58 +/- 3.48 from 6.75 +/- 3.14 in group G (p < 0.001) and to 6.34 +/- 3.33 from 7.31 +/- 3.00 in group GH (p < 0.05). In patients with overt DIC, the mean score decreased to 6.71 +/- 3.54 from 8.42 +/- 2.84 (p < 0.001). In DIC, the rate of overall efficacy was 46.2% in group G and 35.1% in group GH. In preDIC, it was 41.5% in group G and 27.3% in group GH. No side effects, including severe bleeding, were found in this study. The results indicate that gabaxate mesilate is clinically effective for patients with DIC and preDIC.

A case of disseminated intravascular coagulation (DIC) in a patient with systemic lupus erythematosus (SLE) with acute liver dysfunction is described. A 37-year-old man with SLE developed acute DIC and marked liver damage after fracture of the right clavicle and pharyngitis. Treatment with high-dose steroids, heparin, antithrombin III, gabexate mesilate, and antibiotics resulted in prompt improvement. The recovery of an SLE patient after acute DIC and marked liver damage is considered very rare. We report here such a case and discuss the previous reports.

A supramaximal dose of caerulein (5 micrograms/kg.hr for 3.5 hours) caused an acute pancreatitis with marked hyperamylasemia and intense interstitial edema in rats. In this model of pancreatitis, the redistribution of lysosomal enzyme in acinar cells as well as the increased lysosomal and mitochondrial fragility were also observed. The combined therapy of a low molecular weight protease inhibitor, FOY, a synthetic platelet activating factor (PAF) antagonist, CV 6209, and a xanthine oxidase inhibitor, allopurinol produced more significant improvements in all the parameters examined than the therapy of any only one of these three agents, each only one therapy exerting a partial significant protective effect. These results indicate that several factors, such as unknown proteases activities, PAF and oxygen-derived free radicals may be involved in the pathogenesis of pancreatic injuries in this caerulein-induced pancreatitis. These results also suggest that such a combined therapy of different kinds of agents, whose therapeutic mechanisms are also different, is useful in the clinical treatment of acute pancreatitis.

The clinical profiles of 15 patients with acute pulmonary embolism (APE) were analysed. The most common symptoms of APE were tachypnea and tachycardia with sudden onset. Both PO2 and PCO2 had decreased in almost all patients (mean PO2: 50 mmHg, PCO2: 30 mmHg). Chest roentgenogram (X-P) revealed hyperlucency of the lung field, prominence of proximal pulmonary artery and cardiac enlargement. ECG showed SI QIII TIII and ST-T changes in half of the cases. These changes, however, disappeared within 4 days in most patients. Lung scan and digital subtraction pulmonary angiography were useful for the diagnosis. Sixty percent of patients recovered only by medical therapy, and embolectomy was performed in only two patients. Fifty-three percent of patients were, however, considered to be candidates for the embolectomy, and half of them died because of ineffective medical therapy. From these results we concluded that the combination of severe hypoxemia and hypocapnia with abnormal chest X-P can be used for a diagnostic or therapeutic decision. If a patient has those findings, pulmonary angiography is recommended together with thrombolytic therapy. If a large embolus is detected, embolectomy is mandatory. The need for surgical therapy for APE is greater than we had imagined.

Unlabelled: Sequential therapy consisting of methotrexate (MTX) and 5-FU was performed together with the administration of heparin and FOY in 10 cases of gastric cancer with disseminated intravascular coagulation (DIC) causing systemic bone metastasis. The ages of the subjects ranged from 29 to 65 years (median: 49 years) with systemic bone metastasis and bone marrow carcinosis observed in all cases. Histological types consisted of 6 cases of poorly differentiated adenocarcinoma, 2 cases of signet-ring cell carcinoma, and one case each of mucocellular and tubular adenocarcinoma. Therapy consisted of intravenous injection of 30 mg-100 mg/m2 (one case, 20 mg) of MTX followed three hours later by intravenous injection of 600 mg/m2 of 5-FU weekly. Determination of DIC was made in accordance with the DIC diagnostic standards of the Ministry of Health and Welfare, and determination of tumor effectiveness was based on gastric cancer handling codes., Results: PR was observed in 3 cases. Diffuse metastasis observed in the entire lung field disappeared in one case, while remarkable improvement was observed in systemic bone metastasis in scintigram findings for the other 2 cases. All 3 cases were able to be discharged. Reduction of DIC score and absence of pain were observed in 8 cases. Based on the above, aggressive implementation of this treatment method is suggested.

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.