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We describe a case of thoracic aortic aneurysm complicated by chronic disseminated intravascular coagulation (DIC). Initially the DIC was controlled successfully by administration of gabexate mesilate and dalteparin. However, because these drugs were given intravenously, the patient could not be discharged. Subsequently, the DIC was treated successfully by changing to orally administered camostat mesilate, warfarin and aspirin, which allowed the patient to leave hospital.

A 73-year-old man who had been receiving treatment for hypertension and angina pectoris was admitted to hospital following a transient ischemic attack. He was diagnosed as having chronic disseminated intravascular coagulation (DIC) complicated by a thoracoabdominal aortic aneurysm, and was treated with heparin sodium and a protease inhibitor. Although the DIC was controlled, the patient had to remain hospitalized in order to receive the medication by continuous infusion. Therefore, the heparin sodium and protease inhibitor were replaced by camostat mesilate, a drug suitable for oral administration and widely used for treatment of chronic pancreatitis. The drug proved effective for the chronic DIC, thus allowing the patient to receive regular treatment on an outpatient basis, and improving his quality of life.

The potential for hepatic metastasis in nude mice was studied by the intrasplenic implantation method with five human pancreatic cancer cell lines, Capan-1, BxPC-3, AsPC-1, Panc-1, and MIAPaCa-2, especially in relation to serine protease expression, including urokinase-type plasminogen activator and pancreatic trypsinogen 1 (cationic form). The inhibitory effect of a serine protease inhibitor agent, FOY-305, on hepatic metastasis was also a assessed. As a result, the potential for hepatic metastasis was well correlated with expression of pancreatic trypsinogen 1 in these cell lines, and the incidence of metastasis was significantly decreased by FOY-305. These findings suggest that pharmacologic inhibition of serine protease activity may be a new strategy for the therapy of pancreatic cancer metastasis.

Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 microM for trypsin, 0.029 microM for pancreatic kallikrein, 0.61 microM for plasma kallikrein, 0.57 microM for plasmin, 2.5 microM for thrombin, 20.4 microM for factor Xa and 6.4 microM for C1r. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for C1s, and Ki values for these proteases were 0.021 and 0.18 microM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 microM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 microM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 microM, while camostat revealed no inhibition by concentrations up to 1 microM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 microM, respectively, the corresponding values for camostat being 350 and 150 microM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and C1s in complement pathway.

A synthetic protease inhibitor FOY-305 (Foypan) not only inhibited the skin tumorigenesis in mice but also suppressed the growth of autochthonous solid tumor in mice. Furthermore, administration of FOY-305 inhibited the metastasis of Lewis lung carcinoma and colon adenocarcinoma to the lung in mice, experimentally and spontaneously. Clinically, FOY-305 prevented both recurrence and metastasis in the patients who had received many anticancer drugs. In 2 terminal secondary cases, tumor remission and elongation of survival time were observed. Above results suggest a possibility for applying a new type chemotherapy using protease inhibitors.

In order to study the effect of synthetic trypsin inhibitor on the oncogenesis of pancreatic cancer, the histology, the kinetics of the B, A and D cells in the islets of Langerhans and activities of free radical scavengers, superoxide dismutase (SOD), glutathion peroxide (GSH-Px) and malon dialdehyde (MDA) in the tumor bearing tissues were measured in hamsters with pancreatic cancer induced by di-iso-propanol nitrosamine (DIPN) with or without camostat (FOY-305). In DIPN group (DIPN alone), the tubular adenocarcinoma was found in 80%, however, in FOY group (DIPN+FOY-305), papillary adenocarcinoma was found in 91%. In both DIPN and FOY groups, the number of B cells was decreased at 8 weeks and the number of A and D cells was decreased at 16 weeks. Activities of SOD in the tumor and borderzone in DIPN group were significantly lower than those in non-tumor region and normal tissue. However, activities of SOD in the tumor and borderzone in FOY group were higher than those in DIPN group. GSH-Px and MDH levels were significantly higher in FOY group suggesting the involvement in the reaction of free radicals. These results suggest that trypsin inhibitors have a prophylactic effect on the development of pancreatic cancer.

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)

Esophagitis after total gastrectomy has been associated with biliary and pancreatic reflux into the esophagus. The purpose of this study is to clarify the effect of FOY-305 on these factors in the esophagitis. We initially produced esophagitis in rats with total gastrectomy followed by an end-to-side esophago-jejunostomy (Billroth-II). After treatment of FOY-305 on post-operative day 7 in this model, esophageal washout samples were analyzed for increases in activity of trypsin and total bile acid concentration. FOY-305 completely inhibited increases of trypsin activity in 2 and 4 hr, and it significantly (P less than 0.05) reduced bile acid concentration in 4 hr after initiating treatment. In addition, we evaluated the injurious effect of trypsin and sodium taurocholate (Tc-Na) on isolated esophagus of rats by measuring released tyrosine in the medium and used it as an index of the degree of injury. Tc-Na (3-fold of enteral bile acid concentration) inflicted only a slight injurious effect with negligible tyrosine release increases, and it did not show synergistic action when concomitantly used with trypsin. However, trypsin clearly induced increased tyrosine release from the esophageal mucosa, and this effect was significantly (P less than 0.001) inhibited by FOY-305 (50 microM). These results indicate that trypsin is one of the important factors in the pathogenesis of reflux esophagitis after total gastrectomy, and FOY-305 exerts a therapeutic effect by eliciting an inhibitory action against trypsin activity.

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.

Pancreatic injury was induced to rats with intraperitoneal injection of ethionine 60 mg per 100 g BW twice or three times weekly for 6 weeks. These rats were given 100 mg/kg of Camostate mesilate (CM) via a gastric tube daily for 14 days. CM administration resulted in an increase of pancreatic wet weight, hypertrophy and hyperplasia of acinar cells, and an increase of exocrine pancreatic function. Acini prepared from CM and ethionine-treated rats exhibited increased response to caerulein, but decreased sensitivity to caerulein. The plasma CCK level in rats with CM administration 24 hours later was higher than that without CM administration. However, there were no significant changes in plasma CCK and secretin level thereafter. We concluded that CM had a trophic effect on the pancrease with ethionine-induced pancreatic injury, and CCK was considered playing the same role in injured pancreas as the normal rat pancreas. Studies using CCK receptor antagonist are needed for further clarification.

The influences of truncal vagotomy or surgical sympathectomy on the pancreatic trophic effect of oral administration of synthetic trypsin inhibitor (FOY-305) were examined upon normal rats and 85% major pancreatectomized rats. On normal rats, oral administration of trypsin inhibitor increased pancreatic weight, DNA content RNA content, protein content, pancreatic weight/DNA, RNA/DNA and protein/DNA. This pancreatic trophic effect seemed to be consisted of hyperplasia and hypertrophy of pancreatic acinar cell. Under truncal vagotomy or surgical sympathectomy, this trophic effect was not diminished. On major pancreatectomized rats, oral administration of trypsin inhibitor also caused pancreatic trophic action, consisted of hyperplasia mainly. And truncal vagotomy or surgical sympathectomy did not decrease this action. These results suggested that oral administration of trypsin inhibitor might be a beneficial method for functional recovery of remnant pancreas after major pancreatectomy even under the denervated state.

The effect of long-term oral synthetic protease inhibitor (FOY 305) administration on fasting blood sugar (FBS), body weight, glucose tolerance, plasma insulin and glucagon levels, pancreatic insulin and glucagon contents, hepatic enzyme activities, and plasma lipids in normal and streptozotocin (STZ)-induced diabetic rats was studied. Normal rats treated with oral FOY 305 for 9 weeks were found to have pancreatic hypertrophy and decreased body weight gain as compared with the untreated normal controls. FBS, glucose tolerance, plasma insulin and glucagon levels, pancreatic insulin and glucagon contents, and plasma lipids were uninfluenced in FOY 305 treated normal rats. STZ-induced diabetic rats treated with oral FOY 305 were found to have decreased FBS for 5 weeks after the beginning of FOY 305 administration as compared with the untreated diabetic controls, whereas at the 7th and 9th week after treatment there was no difference in FBS between FOY 305 treated and untreated diabetic rats. In the metabolic balance observed at the 4th week after treatment, a slight improvement of the diabetic state was found in FOY 305 treated diabetic rats. There was no apparent difference in the blood sugar curve and insulin response following oral glucose load between diabetic rats treated for 7 weeks and untreated diabetic rats. All the rats were sacrificed after 9 weeks of treatment. Diabetic rats treated with oral FOY 305 for 9 weeks showed pancreatic hypertrophy and decreased plasma glucagon level and decreased pancreatic glucagon content as compared with the untreated diabetic controls, whereas there was no difference in body weight, plasma insulin level and pancreatic insulin content between FOY 305 treated and untreated diabetic rats. Furthermore, oral FOY 305 treatment improved hyperlipidemia in STZ-induced diabetic rats and also significantly improved the hepatic pyruvate kinase and phosphoenlpyruvate carboxykinase activities of diabetic rats. These improvements might partly be due to a decreased pancreatic content and secretion of glucagon and/or a direct action of the synthetic PI, FOY 305 to tissues.