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The most serious hepatic complication after surgical procedure is postoperative hepatic failure. There is no therapy for this condition except plasma exchange. Precise clinical definition of postoperative hepatic failure was discussed based on a questionnaire distributed by the association in 1989, and in 1991 by the working group. Giving special consideration to the use of therapeutic plasmapheresis, the clinical definition of postoperative hepatic failure was established as hepatic injury after surgery, without obstructive causative factors, laboratory values for total bilirubin over 5mg/dl with continuous elevation, and hepaplastin activity under 40%. Key factors in determining initiation, efficacy, and cessation of plasmapheresis were coma grade (II-III), total bilirubin levels, and the activities of coagulation tests. The majority of underlying diseases were hepato-biliary in nature. The causative factors of hepatic injuries were massive bleeding and infection. The morbidity was estimated at 600 to 3000 cases/year. The frequency of plasma exchange was one session every/1.4-1.6 days. The volume of exchanged fresh frozen plasma was about 3292 ml/a session. Nafamostat mesilate was used as an anticoagulant. The survival rate was 14% to 40%. Earlier initiation of plasma exchange is indicated.

An assessment was made of the serum protein binding of representative oral cephems (cefdinir, cefixime and ceftibuten) for sera from healthy subjects (HS) and patients with chronic renal failure (CRF) using an application of equilibrium dialysis under a same set of conditions in vitro. The protein binding capacity of oral cephems in CRF patients being treated with continuous ambulatory peritoneal dialysis (CAPD) or hemodialysis (HD) was significantly less than that in HS, and a marked increase in free drug concentration was observed. While examining the protein binding of oral cephems with heparin in patients on HD, binding capacity decreased significantly immediately following the completion of dialysis compared to that prior to dialysis. On the other hand, the protein binding of oral cephems did not change when used nafamostat mesilate as an anticoagulant. The addition of palmitic acid (PA), a common non-esterified fatty acid (NEFA), to pooled sera from HS caused the binding capacity of oral cephems to decrease, accompanied by increase in PA concentration. It appears from these findings that changes in the binding capacity of oral cephems with HD have possibly been caused by increase in NEFA due to activation of lipase when heparin was used as an anticoagulant. In conclusion, changes in the protein binding capacity of oral cephems in CRF patients should be taken into consideration in attempts to avoid possible side effects.

The current status and new trends of therapy for disseminated intravascular coagulation (DIC) are reviewed. The therapeutic strategies consist of elimination of the underlying diseases, anticoagulant therapy, replacement therapy and general supportive care. The approach to eliminate the underlying disease process represents the most important therapeutic modality. Most patients need anticoagulant therapy in conjunction with specific factor replacement. Unfractionated heparin, antithrombin III concentrate, gabaxate mesilate and nafamostat mesilate are currently used as anticoagulants. Low-molecular-weight heparin, heparinoid, activated protein C, argatroban, hirudin and thrombomodulin are under clinical or animal studies to evaluate their effectiveness in DIC. Clinical and laboratory manifestations are extremely variable among patients, depending in part on the underlying diseases. Management should be individualized for each patient.

Despite of many investigations addressing the problem on the diagnosis of DIC associated with liver diseases, however, an adequate clinical and laboratory criteria has not yet been established. We attempted to clarify this problem by evaluating the changes of plasma levels of PIC, D dimer, TAT and several endothelial factors in 20 patients with severe liver disease who had the evidence of hemorrhage, and were treated with AT III concentrate and gabexate mesilate (FOY). In patients who show a good response to treatment, plasma levels of PIC and D dimer before treatment were both significantly higher (p < 0.01) than those in patients who did not respond, while there was no significant difference in other coagulation fibrinolysis parameters except for platelet count which showed rather lower in the response group (p < 0.05). We believe that combination assay for both PIC and D dimer will be adequate to differentiate whether the hemostatic abnormalities are induced mainly by DIC or hepatic insufficiency.

Anticoagulant therapy, correction of the hypercoagulable state underlying DIC (disseminated intravascular coagulation), can help the treatment of DIC. Synthetic protease inhibitors, which can block serine proteases, such as thrombin and plasmin, in the coagulative-fibrinolytic system, could prevent activation of coagulation factors and development of DIC, if administered properly. Clinically applicated protease inhibitors at present, such as gabexate mesilate (FOY), nafamostat mesilate (FUTHAN), urinastatin (MIRACLID), do not have the same spectrum of action, but the common characteristics are as follows. These inhibitors may be superior to heparin and do not require antithrombin III for their activities because of the competitive inhibitors to coagulative enzymes. The half time of these agents in human circulating blood is within several minutes and shorter than that of heparin.

We had a sixty-five year old male patient who suddenly complained of dyspnea and fever with pulmonary tuberculosis, severe respiratory failure, disseminated intravascular coagulation (DIC) and intractable bilateral pneumothoraces. From the first hospital day severe hypoxemia which did not respond to conventional oxygen therapy developed with a diffuse ill-defined reticulo-nodular shadow in the plain chest x-ray film. On the 2nd hospital day mechanical ventilation with 2cmH2O PEEP was introduced. Antituberculous agents as well as corticosteroids were started suspecting acute interstitial pneumonia with pulmonary tuberculosis and adult respiratory distress syndrome (ARDS). Medication was followed by the treatment of Gabexate mesilate and heparin against DIC on laboratory data. Though clinical findings and pulmonary infiltrate on chest x-ray film transiently improved, right pneumothorax occurred suddenly on the 6th day followed with left pneumothorax on the 36th day. Tube drainage of both pleural spaces and repeated instillation of thrombin-rich oxycel cotton via bronchofiberscope failed to stop air leakage. He ultimately expired on 49th hospital day. At postmortem lung had multiple bilateral bulla several of which ruptured to the pleural site and caseating necrotic area containing bacilli positively stained with Ziehl-Nielsen stain in the bilateral upper lobe. No typical caseating necrotic lesion, however, was found in the other lung tissue. Therefore, it seemed to show a chronic phase of diffuse alveolar damage (DAD).

The purpose of the study is to investigate the effects of protease inhibitor (Nafamostat mesilate: NM) upon myocardial protection. Hearts were subjected to 20 min working control perfusion followed by 3 min cardioplegic infusion with the St. Thomas Cardioplegic Solution (ST) contained various concentrations of NM, and global ischemia for 33 min at 37 degrees C (Exp. 1) or 150 min at 20 degrees C (Exp. 2). Hearts were then converted to Langendorff reperfusion (the leakage of Creatine Kinase (CK) and Cathepsin B (Cat-B) ware measured) and 20 min working reperfusion. Various concentrations of NM added during Langendorff reperfusion (Exp. 3). During working perfusion cardiac functions (aortic flow (AoF), coronary flow (CoF), heart rate (HR), aortic pressure (AoP)) were measured, and expressed as the percent recovery of pre-ischemic control value. Post-ischemic recovery of AoF (%AoF) showed the bell-shaped dose-response curve, and the optimal dose was 3 microM (Exp. 1) and 10 microM (Exp. 2) respectively. There was a significant (p < 0.05) increase of %AoF in optimal dose compared with that in controls (64.2 +/- 1.2% vs 52.3 +/- 2.5% in Exp. 1, 68.9 +/- 3.1% vs 54.1 +/- 1.4% in Exp. 2). These increase of functional recovery reflected in the values for CK and Cat-B leakage. The addition of NM in ST reduced CK and Cat-B leakage significantly in the concentration of 5 microM (in Exp. 1) and 10 microM (in Exp. 2) respectively. But the addition of NM in reperfusate did not reduced CK leakage significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

We performed 7 cases of pancreas transplantation (PTX), simultaneous pancreas and kidney transplantation in 4 cases, and PTX after kidney transplantation in 3 cases. The pancreas and kidney were extirpated after in situ perfusion using UW solution and stored in UW solution. The pancreas was transplanted in the left iliac fossa with bladder drainage, and the kidney was placed in the contralateral iliac fossa. The immunosuppressive regimen consisted of cyclosporine, methylprednisolone, azathioprine and antilymphocyte globulin. Gabexate mesilate (30-40 mg/kg/day) and PGE1 (5 ng/kg/min) was administered intravenously to prevent the vascular thrombosis. The original diseases of 7 patients were insulin-dependent diabetes mellitus (IDDM) with chronic renal failure, retinopathy and neuropathy. Six out of 7 patients became insulin-free after PTX, while one patient developed the vascular thrombosis in the pancreatic graft which was removed after 12 hours after the transplantation. All patients became dialysis-free and serum creatinine was ranging from 1.5 to 2.0 mg/dl. HbAlc remained within normal range in 6 out of 7 patients, who showed normal to borderline glucose tolerance in 75g oral glucose tolerance test. Although further investigation will be required, PTX from cardiac-arrest donor will be promising as one of the therapeutic modalities for IDDM patients.

Disseminated intravascular coagulation (DIC) is a severe syndrome associated with generalized, intractable bleeding and multiple organ failure. Synthesized protease inhibitors such as gabexate mesilate and nafamostat mesilate show an improving effect on DIC, which develops by a chain reaction involving the coagulation, fibrinolysis, complement and kallikrein systems. Experimental DIC was developed in Beagle dogs by infusion of 150 U/kg tissue thromboplastin (Group I), and the improving effect of a new synthetic protease inhibitor, E-3123, was examined. The following groups of animals were treated with drugs: Group II (n = 4) was given with 5 mg/kg/hr of E-3123; group III (n = 4) was given 10 mg/kg/hr of E-3123; and group IV was given 6 mg/kg/hr of gabexate mesilate (GM). Although improvement of the hemodynamics or peripheral circulation was not apparent, a slight, but insignificant, improvement of lactate/pyruvate was noted in the treated groups. On the other hand, the hemostatic abnormalities such as prolongation of prothrombin time and activated thromboplastin time; decreases of platelet count, fibrinogen and alpha 2-antiplasmin; and increases of fibrin degradation products were significantly improved in the treated groups. These results indicate that E-3123 is effective for improving experimental DIC, and it is suggested that E-3123 is applicable for the treatment of clinical DIC.

The occurrence of disseminated intravascular coagulation (DIC) is not rare in neurosurgical patients. We investigated the therapeutic effects of gabexate mesilate (FOY) for DIC or DIC preparatory state in 70 cases. Underlying diseases were head injuries in 31 cases, intracranial hemorrhages in 19, subarachnoid hemorrhages in 10, cerebral infarctions or embolisms in 5, brain tumors in 3 and other diseases in 2. DIC or DIC preparatory states were induced by severe brain damage (26 cases), infection (26 cases), failure of other organs (6 cases), shock (5 cases), and others. On the basis of the clinical coagulation studies of these patients, we retrospectively established a new scoring system for DIC (neurosurgical DIC score) associated with neurosurgical diseases and evaluated whether it was useful. Because the original DIC score proposed by the Research Committee on Blood Coagulation Disorders supported by the Japanese Ministry of Health and Welfare was not correlated with the level of consciousness representing the primary brain damage, it was likely to be underestimated in neurosurgical patients. Therefore, we included the level of consciousness with a new DIC scoring system. The neurosurgical DIC score was calculated from platelet count (score 0-3), FDP (score 0-3) and the level of consciousness (score 0-2), and was diagnosed as DIC preparatory state if it was 3, calculated from 2 of the 3 parameters, and as DIC if it was over 4. The score should be checked twice if it was 3, especially after operation. The neurosurgical DIC score was significantly correlated with the original DIC score.(ABSTRACT TRUNCATED AT 250 WORDS)

A 64-year-old man underwent CABG. 18000 unit of bovine lung heparin was used during operation for extracorporeal circulation and small amount of heparin was injected until the 5th postoperative day to keep intravenous line patent. His postoperative course was uneventful until the 10th postoperative day when marked ecchymosis developed on his eyelid. Laboratory data showed marked thrombocytopenia (1.3 x 10(4)/microliters) and disseminated intravascular coagulation. The diagnosis of heparin-induced thrombocytopenia (HIT) was confirmed by platelet aggregation test with heparin. Gabexate mesilate and platelet-concentrates were administered and platelet count returned to normal within a week. HIT usually occurs during administration of heparin. In this case, it occurred 5 days after we stopped heparin. Delayed onset of HIT might be related to delayed metabolism of heparin due to postoperative fluid shift.

Insulin (INS) has been known to be absorbed through the intestine in small amounts and to decrease blood sugar (BS) levels. However, stable control of BS has not been attained by intestinal intake of INS. To elucidate the possibility of a surgical approach to control hyperglycemic states, Thiry-Vella loops or upper jejunal loop fistulae were constructed in mongrel dogs in hyperglycemic states. Hyperglycemic states (around 400mg/dl) were induced by injecting streptozotocin. Lente insulin was administered every day to control hyperglycemia, except for the days for studies. As we confirmed that co-administration of aprotinin (TR) or nafamostat mesilate (FT) was necessary, to decrease BS by infusing INS into the intestinal loops, safe and effective dose levels were determined by series of preliminary infusion studies in the intestinal loops of diabetic dogs. By continuous infusion of these doses into the jejunal loop fistulae, a long term stable blood sugar control was attained in the diabetic dogs as long as 7 days. These results suggest that continuous infusion of INS with antiproteolytic adjuvants like TR or FT into the isolated small intestinal loop can control BS in hyperglycemic states.

A 60-year-old man was admitted to our hospital because of fever, hemorrhagic tendency, anemia and neurological abnormality. A blood count revealed that the hemoglobin was 6.8 g/dl, the reticulocyte was 17.3 percent with 2 erythroblasts per 100 white cells, the white cell count was 7,100/microliters and the platelet count was 0.8 x 10(4)/microliters. Peripheral blood smear demonstrated marked fragmentation of red cells. Bone marrow examination disclosed the marked erythroid hyperplasia. Although the bleeding time was prolonged (14 minutes 30 seconds), the other hemostatic data were within normal limits. The serum bilirubin level was 1.57 mg/dl; LDH level, 1,437 U/l; creatinine level, 0.92 mg/dl; BUN level 14.7 mg/dl. Haptoglobin was below 10 mg/dl. Results of immunological tests were all negative except the result of PAIgG (576.6 ng/10(7) cells). The urinalysis showed proteinuria, microhematuria and trace granular and hyaline casts. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient was initially treated with prednisolone (60 mg), aspirin (1,000 mg), dipyridamole (150 mg), gabexate mesilate (1.5 g), sodium oxagrel (80 mg) daily with little response. The thirty days after admission, infusion of gamma globulin (20 g, daily) was given for 3 days. The clinical state and laboratory findings became dramatically improved shortly after the administration of gamma globulin and the laboratory data came to be normalized after 1 month. After ten months of this treatment, the patient is remained asymptomatic and the hematological data are within normal range without using any drug. A trial seems justified to confirm the value of this mode of therapy.

Fundamental study in dogs have shown that the synthetic protease inhibitor has pharmaceutical properties characterized by effect on motility of the sphincter of Oddi. Synthetic protease inhibitors, gabexate mesilate and nafamostat mesilate have effects on motility of the sphincter of Oddi in dogs. The motor effect of synthetic protease inhibitor on the sphincter of Oddi has been investigated by manometric evaluation. Immediately after intravenous administration of gabexate mesilate (5, 10, 50, and 100 mg/kg/h) the motility of the sphincter of Oddi was inhibited dose-dependently, on the other hand after intravenous administration of nafamostat mesilate (0.5, 1, and 5 mg/kg/h) motility of the sphincter of Oddi was accelerated. Therefore it was suggested that these results shown some considerable problems in clinical use.

Many reports concerning the involvement of active oxygen free radicals in the pathogenesis and progression of acute pancreatitis have been published. In this study, the direct toxic effect of active oxygen free radicals on the rat pancreas was evaluated in vivo. Superoxide anions, generated via the xanthine/xanthine oxidase (X/XO) system, and hydrogen peroxide (H2O2) were used. After continuous arterial injection of X/XO into the celiac artery hemorrhage and extensive edema developed. However, additional continuous injection of superoxide dismutase (SOD) into the external jugular vein completely suppressed the hemorrhage and relieved the edema. When hydrogen peroxide (100 microM/Kg/hour) was injected continuously through the celiac artery made hemorrhage and edema were recognized in the pancreas, both of which were suppressed by continuous injection of catalase (10 mg/Kg/hour) or gabexate mesilate (10 mg/Kg/hour) into the external jugular vein. The amylase and lipase levels in the intraperitoneal fluid rose to more than 10 times the preoperative values 5 hours after drug administration. These levels were lowered to 2 times the preoperative values by the continuous venous injection of SOD or catalase (which are specific scavengers of superoxide anions or hydrogen peroxide, respectively) or by gabexate mesilate. On the other hand, serum amylase and lipase levels remained almost constant throughout the entire experiment. Thus, the administration of active oxygen free radicals caused acute pancreatitis, which was suppressed by the systemic administration of specific scavengers for each free radical. Active oxygen free radicals were shown to have a direct, toxic effect on the pancreas.

Effect of serine protease inhibitor Camostat Mesilate (Foipan) on primary glomerulonephritis and it's mechanism were evaluated. Forty-two patients having primary glomerulonephritis (13 cases of IgA nephropathy, 11 cases of membranous nephropathy and others), aged 18 to 81 years were selected for this study. At the start of our study, twenty-one patients had received other drugs (13 cases of dipyridamole and 13 cases of prednisolone). A control period of four weeks was established to confirm that the levels of proteinuria and renal functions were stable. Patients were orally administered with 600 mg of Camostat Mesilate per day for four weeks. Effect of Camostat Mesilate was judged by urinary protein excretion, hematuria, serum total protein, albumin, Ccr, creatinine and BUN. In order to reveal the mechanism of the effect laboratory data such as granulocyte elastase, CH50, C3, C4, fibrinogen, platelate factor 4, beta-thromboglobulin, thromboxane B2 and prostaglandin F1 alpha were evaluated before and after the treatment. Parameters were analyzed by using paired t-test. Mean (+/- SEM) urinary protein excretion reduced from 4.31 +/- 0.91 to 2.80 +/- 0.43 g/day (p less than 0.05), and score of hematuria decreased from 1.8 +/- 0.16 to 1.5 +/- 0.15. A significant decrease in urinary protein excretion was seen in membranous nephropathy and a significant decrease in hematuria was seen in IgA nephropathy. In combination therapy (dipyridamole, prednisolone) urinary protein excretion markedly decreased (p less than 0.05) and in Camostat Mesilate therapy score of hematuria markedly decreased (p less than 0.05). Camostat Mesilate had no effects on renal function assessed by Ccr, creatinine and BUN.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance hemodialysis for chronic renal failure has spread all over the country, and the number of patients in whom surgical indications are considered to concomitant diseases has been increasing. A 76-year-old male was admitted due to lung cancer on maintenance hemodialysis. The chest roentgenogram showed a 2.5 cm sized coin lesion in the right middle lung field. Preoperative examinations, chest tomography, chest CT-scanning, bone scintigraphy, bronchofiberscopic biopsy, etc. led to a diagnosis of primary lung cancer (squamous cell carcinoma). Hemodialysis with prescribing nafamostat mesilate (40 mg/hour) was performed the day before the operation and on the first, fourth and sixth postoperative days. There was no postoperative bleeding. The patient has been well for 27 months postoperatively.

Effects of low molecular weight heparin (FR-860) on experimental disseminated intravascular coagulation (DIC) models in rats were compared with those of conventional unfractionated heparin (UF-heparin) and other anticoagulants. In the endotoxin-induced DIC model, FR-860 (12.5-200 U/kg/hr) and UF-heparin (25-200 U/kg/hr) inhibited dose-dependently the decreases in platelet counts, fibrinogen, antithrombin III activity and alpha 2-plasmin inhibitor activity, and they also inhibited the increases in fibrin de-products and thrombus formation in the glomerular capillary bed. Neither gabexate mesilate (FOY, 10 mg/kg/hr) nor nafamostat mesilate (FUT, 0.1 mg/kg/hr) improved endotoxin-induced DIC. FR-860 showed comparable potency to UF-heparin in plasma anti-factor Xa (F.Xa) activity. However, FR-860 was weaker than UF-heparin in prolongation of activated partial thromboplastin time. In the thrombin-induced DIC model, both FR-860 and UF-heparin significantly improved, as seen in the endotoxin-induced DIC model, the changes in coagulation and fibrinolytic parameters and suppressed the production of pulmonary thrombus. On the other hand, both FOY and FUT showed significant but weak improvement in this model. In addition, FR-860 inhibited the enhancement of fibrinolysis and the production of pulmonary thrombus in the lactic acid-induced DIC model. These results suggest that the efficacy of FR-860 on DIC in rats is comparable to that of UF-heparin and that the efficacy can be attributed to its anti-F.Xa activity. FR-860 can be expected to be a useful therapeutic drug for DIC.

The expression of complement receptor type 1 (CR1) and type 3 (CR3) on polymorphonuclear leukocytes (PMNs) and generation of complement fragments, C3a, C5a, C4d, iC3b and Bb, were studied in patients during hemodialysis using cuprammonium rayon (Cu) membranes. Furthermore, the relation between the expression of CR1 and CR3 on PMNs from healthy donors and complement fragments was investigated. The expression of CR1 and CR3 on PMNs increased during hemodialysis. Plasma C3a, C5a and iC3b levels increased in the first 15 minutes and then decreased at 120 minutes of dialysis. But plasma Bb level remained high until the end of hemodialysis. Purified Bb had no effect on the expression of CR1 and CR3 on PMNs, but C5a augmented those expression in vitro. Nafamostat mesilate, an artificial proteinase inhibitor, inhibited augmentation of complement receptors on PMNs in concentration dependent fashion. C5a generated through the activation of complement was thought to take an important role in the increased expression of CR1 and CR3 on PMNs.

We investigated the effect of camostat mesilate (FOY-305), an oral protease inhibitor, on reflux esophagitis after total gastrectomy followed by an end-to-side esophago-jejunostomy (Billroth-II) in rats. Effects of FOY-305 were compared with those of sodium alginate (AL-Na) and cimetidine. On the basis that esophageal ulceration occurred from post-operative day 5 in this model, rodents were fed with special chows containing test drugs from day 2 for 5 or 12 days in order to examine the prophylactic effects (Exp. I) and from day 7 for two weeks in healing experiments (Exp. II). In Exp. I, FOY-305 significantly prevented esophageal ulceration on post-operative days 7 and 14. However, AL-Na significantly prevented esophageal ulceration on post-operative day 7 but not on day 14. In Exp. II, FOY-305 had a remarkable therapeutic effect on esophageal ulceration on day 21. Food intake and body weight of rodents in the FOY-305-treated group were higher than those in the control group. In pathohistological studies, FOY-305 elicited an inhibitory effect on ulceration and induced esophageal mucosal regeneration at the ulceration sites. In contrast, AL-Na and cimetidine did not have any significant therapeutic effect. These results suggest that FOY-305 is an effective agent for the treatment of reflux esophagitis after total gastrectomy.

Thrombomodulin (TM) is a constituent glycoprotein of endothelial cell membrane, and soluble TM is present also in plasma and urine. It was revealed by experiments using cultured HUVEC in vitro that TM is released from endothelial cell membrane not with monensin, thrombin, fibroblast growth factor, interleukin-1 or endotoxin, but with H2O2 or endotoxin-treated granulocytes. And the release was suppressed by the coexistence of gabexate mesilate or superoxide dismutase. It was suggested that soluble TM was released from endothelial cell membrane by its injury and digested to multiple molecular forms by endogenous and granulocytic protease(s). TM level in circulation is increased in cases of SLE, MCLS, diabetic angiopathy. It was increased in cases of overt DIC and decreased to the normal level when the patient was recovered from DIC. TM level in circulation was also increased in cases of decompensated liver cirrhosis and markedly in cases of renal insufficiency. It was concluded that plasma TM is a parameter reflecting endothelial injury due to inflammation or metabolic disorders of vascular system. But the interpretation of increased plasma TM was difficult when renal insufficiency was complicated.

We studied a role of plasminogen activator and plasmin in keratinocyte migration. First we examined the effects of various proteinase inhibitors on keratinocyte migration using wound healing model in cultured keratinocyte. Among the proteinase inhibitors tested, only an inhibitor of serine proteinases, camostat mesilate showed a concentration-dependent inhibition on the migration. Anti urokinase IgG was also able to suppress the migration. On the other hand exogenous plasminogen enhanced it. These results strongly suggest that PA/plasmin system is involved in keratinocyte migration.

Hypercoagulability develops after surgery for esophageal carcinoma, and it related closely to postoperative complications. This study evaluated the effects of the synthetic proteinase inhibitor, Cabexate Mesilate (FOY), on this hypercoagulability. The subjects used were 25 patients with a mean age of 63 who had undergone surgery for esophageal carcinoma. Of these, eight patients (test group) received FOY (2,000 mg/day) for three to 23 days after surgery, but 17 (control group) did not. In the test group, FOY controlled aggregation and release of the platelets and minimized their exhaustion. FOY almost completely checked the abnormal increase in thrombin activity which might trigger the hypercoagulability. Also, FOY suppressed the fibrinolytic activity slightly. These results indicate that FOY is effective in controlling hypercoagulability after surgery for esophageal carcinoma and in suppressing activity of the proteinases that cause both blood coagulation and fibrinolysis.

Clinical characteristics of protease inhibitor, nafamostat mesilate (FUT-175:FUT), as an anticoagulant for extracorporeal circulation (ECC) were evaluated in hemodialysis and membrane plasmapheresis. FUT inhibited broad enzymatic systems including coagulation, platelet, complement, fibrinolysis and kinin cascades, which were commonly activated in the course of ECC. FUT showed regional anticoagulability, in which anticoagulating effects were firmly limited in extracorporeal circuit, and hemostatic time after ECC was significantly shortened by the use of FUT. FUT had no effects on lipid and bone metabolisms and FUT could not be adsorbed to anion exchange resin. These results indicate that FUT possesses superior characteristics as an anticoagulant for ECC to heparin, and FUT is very useful especially for ECC of patients with high bleeding risk.

The effectiveness of continuous arterial infusion of protease inhibitor on acute experimental pancreatitis was investigated. Acute hemorrhagic pancreatitis was induced by closed duodenal loop obstruction using mongrel dogs. The obstruction was released at 16 hr, and dogs were divided into three groups; Group I: non-treated control, Group II: nafamostat mesilate (FUT-175) was admitted intravenously (5 micrograms/kg/min), Group III: FUT-175 was admitted via celiac artery. At 24 hr, the concentration of FUT-175 in the pancreatic tissues in group II and III were 905 and 4453 ng/g, respectively. The trypsin like activities in the pancreatic tissues in group I, II and III were 2.1, 1.4 and 0.7 nmol/min/mg protein, and the extent of necrosis of pancreatic parenchyma in each group were 49.5, 25.6 and 12.4%, respectively. Serum calcium, amylase and lipase levels were significantly improved in group III. These results suggest that continuous arterial infusion of protease inhibitor markedly decreases the extent of pancreatic necrosis in severe acute pancreatitis.

Early diagnosis and immediate treatment of the disease responsible for DIC are most important for successful therapy of DIC. Furthermore, it is also necessary to use anticoagulant agents in most cases of DIC. The agents may be classified on the basis of their mode of anticoagulant action into three groups: ones with antithrombin effect, ones with anti-Xa effect or ones with both effect, and each agent is hoped to be chosen appropriately for development of DIC in near future. At present, such anticoagulant agents as standard heparin, antithrombin-III concentrate, gabexate mesilate, nafamostat mesilate, MD-805, low molecular weight heparin, heparan sulfate, activated protein C, are known as drugs for DIC, and each of them was effective for improvement from DIC in our experience. Antifibrinolytic agents, which have been considered to be contraindicated for therapy of DIC, may be good indication for selected cases of DIC with enhanced fibrinolysis such cases as acute promyelocytic leukemia. Antiplatelet agents may be available for some cases of chronic DIC.

Three kinds of anticoagulant therapy for obstetrical DIC were studied. 1. Antithrombin-III (AT) or gabexate mesilate for acute DIC, mainly for abruptio placentae. 2. Heparin or heparin-AT combination therapy for toxemia pregnancy. 3. Low molecular weight heparin (LMWH) for fetus of intrauterine growth retardation (IUGR). The results obtained were as follows, 1. a) Platelet count, and fibrinogen were significantly increased in AT therapy group compared with gabexate mesilate group. b) In clinical manifestation, renal failure and hemorrhagic diathesis were improved especially in AT group. 2. In heparin-AT group, high systolic blood pressure was improved during administration of AT, the high level of thrombin antithrombin complex was also found in these period. 3. a) The improvement of the gain of estimated fetal body weight was found after administration of LMWH. b) Redistribution of blood flow in one case of severe IUGR was observed during administration of LMWH.

To investigate disseminated intravascular coagulation (DIC) after valve replacement, we studied DIC score in 80 patients with combined cardiac valvular disease. Thirty-three patients with (TR group) and 47 patients without (control group) tricuspid regurgitation were compared. 1) TR group, that included patients with severe cases, showed a significantly longer operative time and greater bleeding volume (p less than 0.01). 2) The DIC score was significantly higher in TR group. Administration of gabexate mesilate to patients with DIC improved their platelet counts. These results indicate that patients with combined cardiac valvular disease with tricuspid regurgitation have a hemorrhagic tendency and are subject to DIC. Administration of gabexate mesilate is useful for DIC.

The major surgery for gastroduodenal ulcer, gastric cancer, esophageal cancer, and mediastinal tumor, were performed on 5 patients during anticoagulant therapy after prosthetic valve replacement. In the postoperative management, Dipyridamole (30 mg/day) was given in case 1, Heparin sodium (24,000 mu/day) in case 2, 3, and Gabexate Mesilate in case 4, 5. Postoperative course was uneventful in case 1, 3, 4, 5, intratracheal bleeding was recognized on the 3rd postoperative day and treated by reducing of heparin dose in case 2. Gabexate Mesilate was thought to be effective and free from complication in case 4, 5.

Previous studies have demonstrated that plasma tissue plasminogen activator (t-PA) level was elevated in patients with liver disease. In this study, t-PA antigen levels were investigated in patients with acute hepatitis (AH; N = 12), chronic hepatitis (CH; N = 8), compensated liver cirrhosis (CLC; N = 40), decompensated liver cirrhosis (DLC; N = 23) and hepatocellular carcinoma (HCC; N = 35). The increased t-PA levels (higher than 14 ng/ml) were found in 33% (4/12) of AH on the early hospital days, 25% (2/8) of CH, 45% (18/40) of CLC and 91% (21/23) of DLC, and 60% (21/35) of Hcc cases. In patient with LC, the correlations between t-PA levels and serum total bilirubin (T.Bill) and hepatic synthetic functions were investigated. The results were that the t-PA levels correlated positively with T. Bil and negatively with liver synthetic functions such as albumin, protein C and choline-esterase, indicating that t-PA increased almost in proportion to the deterioration of hepatic function. Serial determination of t-PA in patients with HCC treated by transcatheter arterial embolization (TAE) revealed that TAE failed to normalize the t-PA levels. In one case of HCC complicated with disseminated intravascular coagulation (DIC), t-PA showed a marked increase at acute phase of DIC and subsequent decrease after the successful treatment for DIC by gabexate mesilate (FOY) infusion. These results suggest that increased t-PA in liver disease is due mainly to deterioration of hepatic function, and that secondary fibrinolytic state, such as DIC, is also a contributing factor.

Change in external appearance, pH values and residual antimicrobial potency of cefotiam dihydrochloride (CTM) upon combination with infusion solutions and other injections was investigated. The combinations of CTM with bromhexine hydrochloride 2 mg/ml, 2 ml, dipyridamole 5 mg/ml, 2 ml and gabexate mesilate 100 mg/vial respectively were found to be incompatible on account of turbidity produced. As for 34 other combinations, no change in their appearance, pH and potency was observed.

Oxygen free radicals have been implicated in the pathogenesis of tissue injury consequent to ischemia/reperfusion in several different organs, including heart, bowel, and kidney. In this study, the protective effect of FOY, SOD, and PEG-SOD against kidney damage resulting from warm ischemia and reperfusion was investigated in the rat. FOY (Gabexate mesilate), one of protease inhibitor, has been suggested to inhibit the activity of superoxide in polymorphonuclear leucocyte in recent reports. PEG-SOD (polyethyleneglycol-modified SOD), recently synthesized on the basis of SOD, has an additional value in comparison with SOD. WKA rats underwent right nephrectomy, and occlusion of the left renal artery, vein, and ureter for 60 minutes. FOY (50mg/kg, DIV.) was administrated from 5 minutes before reperfusion to 5 minutes after reperfusion to the rat. SOD (2mg/kg, 5mg/kg, 10mg/kg, IV.) and PEG-SOD (2mg/kg, 5mg/kg, IV.) were administrated at 10 minutes before reperfusion. 48 hours after operation, the measurement of urine output (60 minutes) was made, and BUN, Cr, K, UUN, UCr were measured at this point. Creatinine clearance was calculated from these results. The left kidney was removed and histological examination was performed. Serum BUN, Cr level were greatly elevated, and creatinine was diminished in the group of ischemic untreated rats (n = 8). In the groups of rats treated with FOY (n = 9), SOD (5mg/kg, 10mg/kg; n = 5, respectively), and PEG-SOD (2mg/kg, 5mg/kg; n = 5, respectively), serum Cr was significantly lower and creatinine clearance was significantly higher than control untreated group. Furthermore, tubular injury was less in histological examination in these groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic effects of human urinary trypsin inhibitor (MTI) on acute pancreatitis were examined. MTI potently inhibited not only proteases such as trypsin or alpha-chymotrypsin, but also inhibited lipase or creatine phosphokinase which are considered to be related to pancreatitis. Although gabexate mesilate (gabexate) and aprotinin also strongly inhibited trypsin, their inhibition spectra against pancreatic enzymes were narrower and aprotinin also strongly inhibited trypsin, their inhibition against pancreatic enzymes were narrower than MTI. MTI inhibited proteases released from pancreatic slice by trypsin more potently than gabexate or aprotinin. The therapeutic effects of MTI on experimental acute trypsin-induced pancreatitis in dogs or rats were stronger than those of gabexate or aprotinin. These results suggest that MTI may suppress pathogenesis and development of pancreatitis in several ways, for example, by directly inhibiting trypsin and by inhibiting tissue-damaging enzymes released from the pancreas by stimulation with trypsin.

Septicemia encountered at Kawasaki Municipal Hospital between 1985 and 1986 were studied clinically. Forty six patients had monomicrobial and 5 has polymicrobial infections, respectively. Out of these 46 patients with septicemia, 17 were due to Escherichia coli, 7 were due to Klebsiella pneumoniae and 4 were due to Staphylococcus aureus. Ten patients had hepatobiliary, 7 had hematological, 7 had malignant diseases as underlying diseases, respectively. Out of 10 patients complicated with septic shock, 7 died. Twenty three patients were community acquired infections. The age of most of the patients were over 50. The mortality rate of more than 65-year-old patients were higher than that of other patients. Our of 5 patients with septicemia due to polymicrobial infection, only 1 patient with erythroleukemia died. Fifty patients were treated mainly with beta-lactam antibiotics such as piperacillin or cefmetazole alone or in combination with aminoglycosides and so on. Three patients with infective endocarditis were encountered during this period. Two were due to alpha-streptococcus and 1 was due to Enterococcus. A 41-year-old patient with mitral valve insufficiency and metastatic gastric carcinoma to the bone marrow were complicated with disseminated intravascular coagulation. This patient, however, was successfully treated with a daily dose of 24 mega units of benzylpenicillin, and was given gabexate mesilate, concomitantly.

Unlabelled: Protease inhibitors, such as ulinastatin and gabexate mesilate, are widely used for the patients in shock state. The purpose of this study was to evaluate the effects of these protease inhibitors on renal protection and coagulofibrinolytic disorders. The obtained results were as follows: 1. Ulinastatin studies. 1) Beta 2-microglobulin (BMG) excretion and N-acetyl-beta-D-glucosaminidase (NAG) activity in urine were increased in cases of emergency operation (10 patients) compared with elective operation (38 patients). 2) In canine experimental model of renal ischemia, ulinastatin significantly improved urine volume and urine NAG levels. 3) Administration of ulinastatin suppressed urine NAG level in 12 patients, but BMG level did not significantly change. 2. Gabexate mesilate (FOY) studies. 1) All patients in shock state showed coagulofibrinolytic disorders. Especially remarkable hypercoagulability was observed in 21 patients. 2) FOY suppressed platelet aggregation and the release of beta-thromboglobulin and platelet factor 4. 3) In 24 patients, administration of FOY markedly increased the antithrombin III levels in early postoperative period. 4) Fibrinolytic system was not affected any significant changes with administration of FOY., Conclusion: Our results suggested that protease inhibitors are useful for management of the patients in shock state.

During a period of ten years ranging from January 1973 to February 1983, a total of 51 patients with primary cancer of the liver underwent hepatic resection at the Keio University Hospital. Thirty five of 51 patients were cirrhotic and two were jaundiced. Six cirrhotic patients died of liver failure within one month following hepatic resection. In order to minimize the postoperative death, it is mandatory to maintain the integrity of circulatory dynamics and microcirculation. Monitoring of circulatory dynamics with the use of Swan-Ganz catheter is very useful for managing the patients with massive transfusion, copious production of ascites and adult respiratory distress syndrome and is indispensable for hepatic resection using vascular exclusion technique. Disseminated intravascular coagulation occurs frequently after hepatic resection. It will cause hepatic failure due to microthrombi, unless prompt treatment is instituted. Score count was designed to facilitate diagnosis using platelet count, fibrinogen level, quantity of fibrin degradation product and protamine sulfate test as parameters. It is difficult to determine the optimal dose of heparin because of decreased antithrombin III and metabolism in the liver due to loss of hepatic parenchyma. Gabexate mesilate (FOY) is very effective and safe agent, since it works without antithrombin III.

4-(2-Succinimidoethylthio) phenyl 4-guanidinobenzoate (E-3123) potently inhibited trypsin, plasmin and thrombin with IC50 values of 3.9 x 10(-8) M, 9.5 x 10(-7) M and 1.9 x 10(-6) M, respectively. Experimental acute pancreatitis was induced by injection of a mixture of trypsin and taurocholate into the pancreas in rats and rabbits or by an application of a closed duodenal loop in dogs. Intravenous infusion of E-3123 at 0.03-0.3 mg/kg in rats or at 0.3-3.0 mg/kg in rabbits reduced mortality after the induction of pancreatitis in a dose-dependent manner. Light microscopy of the pancreas in the E-3123-treated rabbits revealed marked decrease in cell necrosis and acinar cell vacuolation. Increase in plasma lipase activities associated with the progression of pancreatitis in rabbits was also reduced by the infusion of E-3123. In dogs with pancreatitis, increases in serum trypsin and lipase activities were significantly reduced by infusion of E-3123 at 1.0 and 3.0 mg/kg. The efficacies of E-3123 in the in vivo experiments were higher than those of nafamostat mesilate. These results show that E-3123 may possess suppressing effects on pathogenesis and development of acute pancreatitis.

The usefulness of a chemical prosthesis was studied for the diagnosis and treatment of 20 patients with erectile impotence (14 due to diabetes, 2 due to pelvic surgery and 4 due to psychogenic factors) using papaverine hydrochloride and phentolamine mesilate. Absolute erection was observed in 16 patients (80%) and coital penetration was possible in all 9 patients who actually tried sexual intercourse. Penile arterial blood flow was measured in 15 patients using a real-time mechanical sector duplex scanner (Diasonics DRF/400V) just before and after the chemical prosthesis, and a marked increase in blood flow was observed in all patients after administration. From these results, it is considered that measurement of the penile blood flow using a mechanical sector duplex scanner is useful in the diagnosis and monitoring of impotence. Furthermore, a chemical prosthesis is suitable mainly for the treatment of impotence due to diabetes, by adjusting the dosage and administration.

Left ventricular assist device was attached to five patients suffered from severe low cardiac output after open heart surgery. In two patients, anticoagulation therapy with heparin started just after the operation. Repeated operations for hemostasis were required because of massive bleeding in these two patients. Anticoagulation therapy was not performed in another one, and thrombus formation in the device was recognized in this patient. In the other two patients, anticoagulation therapy was started with large dose of protease inhibitor (gabexate mesilate or nafamstat mesilate). Heparin infusion was combined with protease inhibitor during the period of weaning from the device. Thrombosis and massive bleeding were not recognized in these two patients, and they were able to wean from the device successfully.

We reported a case of 64 a year-old male patient of miliary tuberculosis associated with ARDS, DIC and pneumothorax, who had a history of gastric ulcer and pulmonary tuberculosis. On admission his chief complaints were fever, fatigue, palpitation, appetite loss and weight loss, and most noticeable abnormalities were bleeding from the gastric ulcer and miliary shadow on the chest x-ray film with hypoxemia. On the day after admission to the hospital he was diagnosed as ARDS as he showed severe hypoxemia due to extensive tuberculous infiltration in bilateral lung fields, and treatment with antituberculous drugs and steroids were started. On the third hospital day DIC appeared on laboratory data, Gabexate mesilate (FOY) for DIC and respirator for ARDS were introduced. Two weeks later pulmonary infiltration, PaO2 and general condition were somewhat improved. On the 15th day after admission pneumothorax occurred on the right side, and on the 20th day on the left. Tube drainage of both pleural cavities, and instillation of OK-432 and Fibrinogen HT into the right pleural cavity were done, but it showed no effect. Two months after admission pouring Fibrinogen HT and thrombin into the left B1+2 and right B1 with cannula washing pipe through the instrument channel of bronchoscope was carried out. A few days later air leakage stopped and collapsed lungs were completely expanded. This method is effective in the case of incurable pneumothorax with pulmonary hypofunction.

Coagulation studies were performed in patients who underwent abdominal surgery. One hundred and twenty six patients with cholelithiasis, peptic ulcer and gastric cancer were examined. Although fibrinogen increased up to 560 mg/dl postoperatively, DIC did not occur among these patients, at all. For 30 patients who underwent hepatectomy, esophageal transection or pancreatoduodenectomy, HPT, PT, fibrinogen, platelet count, alpha 2-PI, AT-III, plasminogen and DIC score were investigated until 10 postoperative days. As for 13 patients without liver cirrhosis in this group, deterioration of HPT, PT and AT-III was noted on the second postoperative day, however these parameters improved on the fifth postoperative day and all patients recovered uneventfully. On the contrary, as to patients with liver cirrhosis, changes of coagulation parameters were drastic. Significant decrease of HPT, PT, AT-III, plasminogen and increase of FDP and DIC score were noted after operation and these values deteriorated with time in certain cases. Seven patients out of 17 died of DIC and multiple organ failure. More than half of these patients received Gabexate Mesilate (GM) injection in a dose of 1200 mg/day postoperatively for more than 5 days to prevent DIC. In patients who underwent hepatectomy due to hepatocellular carcinoma with liver cirrhosis, the increase of FDP and DIC score seemed to be inhibited by GM on the fifth postoperative day.

We studied the effects of heparin, dextran sulphate (MDS), gabexate mesilate (FOY), nafamostat mesilate (FUT-175) and argipidine (MD-805) on APTT, PT, thrombin time (TT) and kaolin-activated PTT (KPTT) with various concentrations of phospholipid for screening of lupus anticoagulants (LA). Heparin, MDS and FUT-175 had a greater effect on APTT than PT. On the contrary, MD-805 had a similar effect on both APTT and PT, which suggests that MD-805 inhibits thrombin generation equally on intrinsic and extrinsic coagulation pathways. Heparin and MD-805 were more effective on TT than MDS, FUT-175 and FOY at high concentrations significantly prolonged TT. But, at even higher concentrations of FUT-175, prolongation of TT was reduced contrary to our expectation. With FOY TT became less prolonged with a passage of time, suggesting time-dependent reduction of its anticoagulant activity. Heparin (0.1-0.2 U/ml) and MDS (0.1-0.3 mg/ml) did not have any effect on KPTT with high concentration of phospholipid, but did FUT-175. It suggests that phospholipid inhibits anticoagulant activity of heparin and MDS. Anti-phospholipid activity of heparin and MDS is similar to that of LA. We concluded that the differentiation of LA from heparin-like inhibitors is needed.

Acute respiratory failure after hepatic resection, especially in case of concomitant liver dysfunction, is the most troublesome postoperative complication. In order to clarify the pathophysiological mechanism of acute respiratory failure, EVLW (extravascular lung water) was measured by double indicator dilution method in canine model. Mongrel dogs underwent laparotomy and the common bile duct was ligated and divided. After 6 weeks, EVLW was significantly elevated compared with that of normal dogs (p less than 0.05). From 4 hours after 70% hepatic resection dextran-40 was loaded to increase PWP (pulmonary wedge pressure). EVLW was increased accompanying the elevation of PWP in all groups, but in the group with biliary obstruction EVLW was significantly increased for the same elevation of PWP. These results suggest that permeability of pulmonary capillary was highly increased after hepatic resection in biliary obstruction group. Pulmonary edema in this canine model seems to resemble ARDS in human and the pathophysiological mechanism was thought to be related with depression of RES phagocytic function, activation of complement system and pulmonary vascular plugging by aggregates of degenerating granulocytes and endothelial injury. Gabexate mesilate blocked the increase of the lung vascular permeability and was thought to be effective to protect the lung from postoperative acute respiratory failure.

The present study was performed to evaluate the mechanism of the protective effect of urinastatin (US) against cisplatin (CDDP) induced nephrotoxicity. We measured consecutively the change in the creatinine clearance (Ccr) level, urinary arylamidase (AA) activity, and urinary gamma-glutamyl transpeptidase (gamma-GTP) activity as the indices of nephrotoxicity. These drugs such as US (10,000 U/kg, 3h: group 1), gabexate mesilate (2mg/kg/h, 4h: group 2), and aprotinin (5,000 U/kg/h, 4h: group 3) as protease inhibitors, and dopamine HCl (0.3mg/kg/h, 4h: group 4) for the increase in renal blood flow were used with the hydration of 15 ml/kg/h during 4 hours of experiments on rabbits. The change in the Ccr value after the intravenous administration of CDDP indicated that the level in groups 3, 4 decreased significantly at one day after the administration of CDDP. On the other hand, there was little significant increase in urinary AA activity and/or urinary gamma-GTP activity in group 1, while a transitional increase was observed in groups 2, 3, and 4, among which the highest level was found in group 4. These results are attributed to the protective action of US against CDDP mainly in the inhibition of the lysosomal enzyme released by the destruction of lysosomes in the proximal tubule cells of the kidney.