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Background: Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA., Methods: The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0-10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded., Discussion: NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain., Trial Registration: ClinicalTrials.gov, NCT02693093 . Registered through the National Institutes of Health on 26 February 2016.

Objective: We aimed to evaluate the results in our case series of AP ERCP over the last three years. The prophylaxis for acute pancreatitis (AP) post-endoscopic retrograde cholangiopancreatography (ERCP) consists of rectal indomethacin, but some studies are not concordant., Patients and Methods: We compared 241 ERCP performed from January 2014 to February 2015 with intravenous gabexate mesylate (Group A), with the 387 ERCP performed from March 2015 to December 2016 with rectal indomethacin (Group B) as prophylaxis for AP post-ERCP., Results: There were 8 (3.31%) AP post-ERCP in Group A vs. 4 (1.03%) in Group B., Conclusions: Rectal indomethacin shows a better statistically significant performance than intravenous gabexate mesylate in the prophylaxis of AP post-ERCP, besides being cheaper.

The current study tested the hypothesis that cholecystokinin (CCK) A receptor (CCKAR) in areas supplied by the celiac artery (CA), stomach and upper duodenum, and the cranial mesenteric artery (CMA), small and parts of the large intestine, is necessary for reduction of meal size, prolongation of the intermeal interval (time between first and second meal) and increased satiety ratio (intermeal interval/meal size or amount of food consumed during any given unit of time) by the non-nutrient stimulator of endogenous CCK release camostat. Consistent with our previous findings camostat reduced meal size, prolonged the intermeal interval and increased the satiety ratio. Here, we report that blocking CCKAR in the area supplied by the celiac artery attenuated reduction of meal size by camostat more so than the cranial mesenteric artery route. Blocking CCKAR in the area supplied by the cranial mesenteric artery attenuated prolongation of the intermeal interval length and increased satiety ratio by camostat more so than the celiac artery route. Blocking CCKAR in the areas supplied by the femoral artery (control) failed to alter the feeding responses evoked by camostat. These results support the hypothesis that CCKAR in the area supplied by the CA is necessary for reduction of meal size by camostat whereas CCKAR in the area supplied by the CMA is necessary for prolongation of the intermeal interval and increased satiety ratio by this substance. Our results demonstrate that meal size and intermeal interval length by camostat are regulated through different gastrointestinal sites., (Published by Elsevier Inc.)

Efficacy of recombinant human soluble thrombomodulin (rhTM), which is frequently used to treat patients with disseminated intravascular coagulation (DIC), was compared with that of gabexate mesilate (GM), which was previously used routinely in the treatment of DIC patients in Japan. Although there was no significant difference in the resolution rates of the patients who were treated with rhTM and GM, the results of our analysis revealed that the mortality rate was significantly higher among infectious disease patients treated with GM than in those treated with rhTM. Levels of fibrinogen and fibrin degradation products (FDP), antithrombin (AT) activity, and thrombin AT complex (TAT) were significantly lower in the DIC patients with infectious diseases, while fibrinogen levels were high. FDP level, D-dimer, platelet count, PT ratio, and DIC score all showed significant improvement following rhTM treatment. There were no significant difference between survivors and non-survivors in terms of DIC score, FDP level, platelet count, AT activity, or in TAT, SF and PPIC levels before rhTM treatment. However, fibrinogen levels were significantly lower in non-survivors than in survivors. These results indicate that rhTM may be superior to GM for the treatment of DIC.

We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors., (Copyright © 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)

Aim: To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis., Methods: Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 μL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment., Results: Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-β-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1β were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture., Conclusion: The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.

Angiogenesis is a complex process finely regulated by the balance between angiogenesis stimulators and inhibitors. As a result of proangiogenic factors overexpression, it plays a crucial role in cancer development. Although initially mast cells (MCs) role has been defined in hypersensitivity reactions and in immunity, it has been discovered that MCs have a crucial interplay on the regulatory function between inflammatory and tumor cells through the release of classical proangiogenic factors (e.g., vascular endothelial growth factor) and nonclassical proangiogenic mediators granule-associated (mainly tryptase). In fact, in several animal and human malignancies, MCs density is highly correlated with tumor angiogenesis. In particular, tryptase, an agonist of the proteinase-activated receptor-2 (PAR-2), represents one of the most powerful angiogenic mediators released by human MCs after c-Kit receptor activation. This protease, acting on PAR-2 by its proteolytic activity, has angiogenic activity stimulating both human vascular endothelial and tumor cell proliferation in paracrine manner, helping tumor cell invasion and metastasis. Based on literature data it is shown that tryptase may represent a promising target in cancer treatment due to its proangiogenic activity. Here we focused on molecular mechanisms of three tryptase inhibitors (gabexate mesylate, nafamostat mesylate, and tranilast) in order to consider their prospective role in cancer therapy.

Objectives: Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells., Methods: The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated., Results: Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog., Conclusions: Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.

Introduction: To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals., Methods: We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3., Results: Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3., Conclusions: Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis., Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882.

The Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes host proteases for virus entry into lung cells. In the current study, Vero cells constitutively expressing type II transmembrane serine protease (Vero-TMPRSS2 cells) showed larger syncytia at 18 h after infection with MERS-CoV than after infection with other coronaviruses. Furthermore, the susceptibility of Vero-TMPRSS2 cells to MERS-CoV was 100-fold higher than that of non-TMPRSS2-expressing parental Vero cells. The serine protease inhibitor camostat, which inhibits TMPRSS2 activity, completely blocked syncytium formation but only partially blocked virus entry into Vero-TMPRSS2 cells. Importantly, the coronavirus is thought to enter cells via two distinct pathways, one mediated by TMPRSS2 at the cell surface and the other mediated by cathepsin L in the endosome. Simultaneous treatment with inhibitors of cathepsin L and TMPRSS2 completely blocked virus entry into Vero-TMPRSS2 cells, indicating that MERS-CoV employs both the cell surface and the endosomal pathway to infect Vero-TMPRSS2 cells. In contrast, a single camostat treatment suppressed MERS-CoV entry into human bronchial submucosal gland-derived Calu-3 cells by 10-fold and virus growth by 270-fold, although treatment with both camostat and (23,25)-trans-epoxysuccinyl-L-leucylamindo-3-methylbutane ethyl ester, a cathepsin inhibitor, or treatment with leupeptin, an inhibitor of cysteine, serine, and threonine peptidases, was no more efficacious than treatment with camostat alone. Further, these inhibitors were not efficacious against MERS-CoV infection of MRC-5 and WI-38 cells, which were derived from lung, but these characters differed from those of mature pneumocytes. These results suggest that a single treatment with camostat is sufficient to block MERS-CoV entry into a well-differentiated lung-derived cell line.

Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF)., Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach., Results: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with -8.6 mV following placebo (P<.005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters., Conclusions: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease., Trial Registration: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov.

Objective: Although endoscopic papillary large balloon dilation (EPLBD) with limited endoscopic sphincterotomy (ES) showed excellent outcomes for treatment of large bile duct stones, hemorrhage and recurrence of stones are problematic complications. Recent studies suggest that EPLBD alone is safe and effective for removal of large bile duct stones. This study aimed to determine the therapeutic outcomes and safety of EPLBD, compared with ES, for removal of large bile duct stones., Material and Methods: Eighty-three patients above 45 years of age with bile duct stones >1 cm in diameter were randomized to EPLBD and ES groups for removal of common bile duct stones from September 2010 to August 2011. Prophylactic gabexate mesilate was given to all patients., Results: Baseline characteristics were not significantly different, except diabetes and gallbladder stones between the EPLBD group (n = 40) and ES group (n = 43). The overall complete stone removal rate in each group was 97.5% (39/40) and 95.3% (41/43), respectively (p = 0.600). Requirement of mechanical lithotripsy was not significantly different between the EPLBD and ES group (10% vs. 21%, p = 0.171). Complete ductal clearance in one session was achieved in 82.4% and 81.4% of cases in each group, respectively (p = 0.577). There were no differences in complication rates between the EPLBD and ES group; pancreatitis, 5.0% vs. 7.0%; hemorrhage, 10.0% vs. 16.3%; acute cholangitis, 5.0% vs. 2.3%, and perforation, 2.5% vs. 0%., Conclusions: The therapeutic outcomes and complications of EPLBD for removal of large bile duct stones are comparable to those of ES.

It is well known that the intestinal stability and absorption of protein drugs are improved when enzyme inhibitors/permeation enhancers are coadministered. Recently, it was hypothesized that an increased effectiveness of these adjuvants might be achieved by timing their release prior to that of the protein, so that a more favorable environment would be established in advance. Therefore, an oral system was proposed for two-pulse colonic release of insulin and the protease inhibitor camostat mesilate/absorption enhancer sodium glycocholate. The device consisted of a drug-containing core, an inner swellable/erodible low-viscosity hydroxypropyl methylcellulose (HPMC) coating, an intermediate adjuvant layer, and an additional outer HPMC coating. HPMC coats and camostat mesilate/sodium glycocholate films with differing thicknesses were applied to immediate-release tablet cores by aqueous spray coating. The obtained units were characterized for weight, thickness, breaking force, and release performance. All systems showed satisfactory technological properties and the pursued pulsatile delivery behavior, with programmable delay phases preceding inhibitor/enhancer release and elapsing between inhibitor/enhancer and protein release, respectively. Indeed, both lag times linearly correlated with the relevant HPMC coating level. The system was thus proven suitable for yielding two-pulse release profiles, in which lag phases could be modulated to provide convenient concentration patterns for proteins and adjuvants., (Copyright © 2011 Wiley-Liss, Inc.)

Recombinant human soluble thrombomodulin (rTM) is a new drug for the treatment of disseminated intravascular coagulation (DIC), although the effects on obstetric DIC have not yet been fully elucidated. We report herein three patients with obstetric DIC caused by placental abruption, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and atonic bleeding, respectively. In all three cases, treatment with rTM proved successful, suggesting that rTM is an efficient method for treating obstetric DIC.

The present study was designed to examine the combined effects of a synthetic protease inhibitor, gabexate mesilate, with a specific neutrophil elastase inhibitor, sivelestat sodium, on acid-induced lung injury. Adult male Sprague-Dawley rats weighing 300-350 g were anaesthetised intraperitoneally with pentobarbitone sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1N 1.5 ml/kg) or normal saline. Gabexate mesilate (10mg/kg, i.p.) and/or sivelestat sodium (10mg/kg/h, i.v.) were administered 30 min before HCl instillation. Bronchoalveolar lavage fluid samples were obtained 5h after HCl instillation. In bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm as an index of pulmonary haemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not show additive effects on HCl-induced lung injury, compared with single treatments. These findings suggested that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, but that synergistic effects of both agents are limited in this acid-induced lung injury model., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Unlabelled: BACKGOUND/AIMS: The aim of this study is to present the new method of continuously irrigated around the pancreaticojejunostomy to reduce postoperative complications after pancreaticoduodenectomy., Methodology: Twenty-seven patients underwent pancreaticoduodenectomy in our institution between 2002 and 2007. Pancreaticojejunostomy was performed with the external pancreatic duct stent tube, and continuous irrigation around the pancreaticojejunostomy was started on the operative day with physiological saline solution containing gabexate mesilate., Results: Mean duration of irrigation was 7.1 +/- 4.4 days, mean duration of drainage tube placement was 14.2 +/- 9 days, and mean duration of pancreatic duct drainage tube placement was 24.9 +/- 4.7 days. Pancreatic fistula was diagnosed in 8 patients. Three cases were classified as grade A and 5 cases were grade B. These pancreatic fistulae were closed by non-invasive treatment and the in-hospital death rate was 0%., Conclusions: External total drainage of the main pancreatic duct and continuous irrigation around pancreaticojejunostomy appears to avoid severe postoperative complications.

Background & Aims: Growth of exocrine pancreas is regulated by gastrointestinal hormones, notably cholecystokinin (CCK). CCK-driven pancreatic growth requires calcineurin (CN), which activates Nuclear Factor of Activated T cells (NFATs), but the genetic underpinnings and feedback mechanisms that regulate this response are not known., Methods: Pancreatic growth was stimulated by protease inhibitor (PI)-containing chow, which induces secretion of endogenous CCK. Expression profiling of PI stimulation was performed on Affymetrix 430A chips, and CN was inhibited via FK506. Exocrine pancreas-specific overexpression of CN inhibitor Regulator of Calcineurin 1 (Rcan1) was achieved by breeding elastase-Cre(estrogen receptor [ER]) transgenics with "flox-on" Rcan1 mice., Results: CN inhibitor FK506 blocked expression of 38 genes, as confirmed by quantitative polymerase chain reaction. The CN-dependent genes were linked to growth-related processes, whereas their promoters were enriched in NFAT and NFAT/AP1 sites. Multiple NFAT targets, including Rcan1, Rgs2, HB-EGF, Lif, and Gem, were validated by chromatin immunoprecipitation. One of these, a CN feedback inhibitor Rcan1, was induced >50 fold during 1-8 hours course of pancreatic growth and strongly inhibited (>99%) by FK506. To examine its role in pancreatic growth, we overexpressed Rcan1 in an inducible, acinar-specific fashion. Rcan1 overexpression inhibited CN-NFAT signaling, as shown using an NFAT-luciferase reporter and quantitative polymerase chain reaction. Most importantly, the increase in exocrine pancreas size, protein/DNA content, and acinar proliferation were all blocked in Rcan1 overexpressing mice., Conclusions: We profile adaptive pancreatic growth, identify Rcan1 as an important new feedback regulator, and firmly establish that CN-NFAT signaling is required for this response., (Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A case of acute necrotizing pancreatitis due to Mycoplasma pneumoniae infection was treated in an 8-year-old girl. She experienced acute pancreatitis during treatment for M. pneumoniae. Contrast-enhanced computed tomographic scan revealed necrotizing pancreatitis. The computed tomographic severity index was 8 points (grade E). A protease inhibitor, ulinastatin, was provided via intravenous infusion but was ineffective. Continuous regional arterial infusion therapy was provided with gabexate mesilate (FOY-007, a protease inhibitor) and meropenem trihydrate, and the pancreatitis improved. This case suggests that infusion therapy is safe and useful in treating necrotizing pancreatitis in children.

Aim: To evaluate the efficacy of continuous regional arterial infusion therapy (CRAI) with gabexate mesilate and antibiotics for severe acute pancreatitis (SAP)., Methods: We conducted a prospective study on patients who developed SAP with or without CRAI. Out of 18 patients fulfilled clinical diagnostic criteria for SAP in Japan, 9 patients underwent CRAI, while 9 patients underwent conventional systemic protease inhibitor and antibiotics therapy (non-CRAI). CRAI was initiated within 72 h of the onset of pancreatitis. Gabexate mesilate (2400 mg/d) was continuously administered for 3 to 5 d. The clinical outcome including serum inflammation-related parameters were examined., Results: The duration of abdominal pain in the CRAI group was 1.9+/-0.26 d, whereas that in the non-CRAI group was 4.3+/-0.50. The duration of SIRS in the CRAI group was 2.2+/-0.22 d, whereas that in the non-CRAI group was 3.2+/-0.28. Abdominal pain and SIRS disappeared significantly in a short period of time after the initiation of CRAI using gabexate mesilate. The average length of hospitalization significantly differed between the CRAI and non-CRAI groups, 53.3+/-7.9 d and 87.4+/-13.9 d, respectively. During the first two weeks, levels of serum CRP and the IL6/IL10 ratio in the CRAI group tended to have a rapid decrease compared to those in the non-CRAI group., Conclusion: The present results suggest that CRAI using gabexate mesilate was effective against SAP.

In mice fed trypsin inhibitor (camostat) to elevate endogenous CCK, pancreatic growth plateaus by 7 days. It is unknown whether this represents the maximum growth capacity of the pancreas. To test the ability of CCK to drive further growth, mice were fed chow containing camostat (0.1%) for 1 wk, then fed standard chow for 1 wk, and finally returned to the camostat diet for a week. Pancreatic mass increased to 245% of initial value (iv) following 1 wk of camostat feeding, decreased to 147% iv following a 1 wk return to normal chow, and increased to 257% iv with subsequent camostat feeding. Camostat feeding was associated with significant increases in circulating CCK and changes in pancreatic mass were paralleled by changes in protein and DNA content. Moreover, regression of the pancreas following camostat feeding was associated with changes in the expression of the autophagosome marker LC3. Pancreatic protein synthetic rates were 130% of control after 2 days on camostat but were equivalent to control after 7 days. Changes in the phosphorylation of 4E-BP1 and S6, downstream effectors of mammalian target of rapamycin (mTOR), paralleled changes in protein synthetic rates. Cellular content of Akt, an upstream activating kinase of mTOR, decreased after 7 days of camostat feeding whereas expression of the E3 ubiquitin-ligases and the cell cycle inhibitor p21 increased after 2 days. These results indicate that CCK-stimulated growth of the pancreas is not limited by acinar cell mitogenic capacity but is due, at least in part, to inhibition of promitogenic Akt signaling.

Gabexate mesilate is a synthetic protease inhibitor that is effective for acute pancreatitis. The effect of gabexate mesilate in influenza pneumonia in mice was investigated by examining the changes in pulmonary inflammatory cytokines and chemokines. Pathological changes in the lungs of treated mice were extremely mild, compared with changes in infected, untreated mice. Intrapulmonary levels of interleukin-6 and macrophage inflammatory protein-2 decreased in treated mice compared with untreated mice, despite similar viral titres in the lungs. Survival terms for treated and untreated groups were similar. These data indicate that gabexate mesilate has beneficial effects on influenza pneumonia, which may be due to the modulation of inflammatory cytokine/chemokine responses.

Background and Objective: Gabexate mesylate reduces the incidence of post-ERCP pancreatitis. Patient-related risk factors associated with pancreatitis can be identified before ERCP, but the procedure-related factors are recognized only at the end of the procedure. This study's aim was to evaluate whether gabexate mesylate administered after ERCP reduces the incidence of pancreatitis., Design: Randomized, prospective, double-blind, multicenter trial., Setting: Tertiary care centers., Patients and Intervention: A total of 608 patients undergoing ERCP were treated with gabexate mesylate 500 mg within 1 hour before ERCP (group A, 203 patients) or within 1 hour after ERCP (group B, 203), or with saline solution (group C, 202)., Main Outcome Measurements: The incidence and severity of pancreatitis and hyperamylasemia, as well as factors associated with the development of pancreatitis., Results: The groups were similar for demographic characteristics, indications to ERCP, risk factors for pancreatitis, and therapeutic procedures. The incidence of pancreatitis was 3.9% in group A, 3.4% in group B, and 9.4% in group C (P<.01). Two patients (in groups A and C) developed necrotizing pancreatitis, and 1 died. Hyperamylasemia occurred in 23.6% in groups A and B, and in 24.7% in group C. Levels of amylase, the incidence of abdominal pain, and other complications occurred similarly. Female sex (odds ratios [OR] 2.7, 95% CI 1.2-5.9) and difficult cannulation (OR 5.6, 95% CI 2.6-12.3) were independently associated with pancreatitis., Conclusions: The administration of gabexate mesylate after ERCP protects against the development of pancreatitis similarly to the preprocedure administration. Factors associated with pancreatitis were mainly recognized after ERCP. We suggest administering gabexate mesylate after ERCP only in those patients recognized to be at risk of developing pancreatitis.

Background: The problem of ABO-incompatible liver transplantation still remains unsolved in older children. In this article, we report on our experience of 6 successful ABO-incompatible liver transplantations in patients with biliary atresia., Material and Methods: Six patients (ABO incompatibility type A-->O:1 case, B-->O:2 cases, A-->B:3 cases) were enrolled in this study; 3 patients were aged approximately 1 year and the other 3 ranged in age from 9 to 24 years at the time of transplantation. Each patient received perioperative plasma exchange, until the anti-donor blood-type antibody titers became less than 1:16, and also systemic multidrug immunosuppressive therapy (cyclophosphamide, prednisolone, and tacrolimus). We applied the protocol of intraportal infusion therapy (local administration of prostaglandin E(1), steroid, and gabexate mesilate via a portal vein catheter), splenectomy, and rituximab administration for the older group., Results: Both the patient and graft survival rates remain at 100%, with the follow-up period of the patients ranging from 12 and 123 months. Acute cellular rejection occurred in 2 cases, and both were steroid sensitive. There was no incidence of humoral rejection. Although all cases developed viral infection, all recovered uneventfully with the administration of antiviral agents., Conclusion: ABO-incompatible liver transplantation can be performed with a low risk of humoral rejection or late biliary complications using this combined antirejection strategy, even in older children.

We report on a 41-year-old man with hematemesis and severe epigastric pain. Three hours after the onset of symptoms, we carefully performed upper gastrointestinal endoscopy for suspected upper gastrointestinal perforation. Endoscopy revealed a 2.5-cm-long longitudinal laceration of the lower esophagus without active gastric or duodenal ulcers. The laceration could be partially closed with endoscopic clipping. Computed tomography of the chest revealed a small amount of extraluminal air in the mediastinum. Neither pleural effusion nor pneumothorax was detected. We treated the patient conservatively on the basis of the following factors: a stable general condition without sepsis, limitation of the esophageal disruption to the mediastinum, and early diagnosis. The treatment course was uneventful, and the patient was discharged from the hospital after we had confirmed with endoscopy that the esophageal ulcer was completely healed. Although Boerhaave syndrome is generally considered to have poor prognosis, conservative therapy may be effective in select cases with early detection of the perforation.

Cholecystokinin (CCK)-induced pancreatic growth in mice involves parallel increases in DNA and protein. The mammalian target of rapamycin (mTOR) signalling pathway regulates mRNA translation and its activation is implicated in growth of various tissues. The aim of this study was to elucidate whether mTOR activation is required for pancreatic growth in a mouse model of increased endogenous CCK release. In mice fed chow containing the synthetic protease inhibitor camostat, protein synthetic rates and phosphorylation of two downstream targets of mTOR, eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and the ribosomal protein S6 (S6), increased in comparison with fasted controls. The camostat-induced increases in protein synthesis and 4E-BP1 and S6 phosphorylation were almost totally abolished by administration of the mTOR inhibitor rapamycin 1 h prior to camostat feeding. In contrast, the phosphorylation of ERK1/2 and JNK and the expression of the early response genes c-jun, c-fos, ATF3 and egr-1 induced by camostat feeding were not affected by rapamycin. In mice fed camostat for 7 days, the ratio of pancreatic to body weight increased by 143%, but when rapamycin was administered daily this was reduced to a 22% increase. Changes in pancreatic mass were paralleled by protein and DNA content following camostat feeding and rapamycin administration. Moreover, while BrdU incorporation, an indicator of DNA synthesis, was increased to 448% of control values after 2 days of camostat feeding, rapamycin administration completely inhibited this increase. We conclude that the mTOR signalling pathway is required for CCK-induced cell division and pancreatic growth.

Poly(lactic-co-glycolic acid) (PLGA) nanospheres containing protease inhibitors, camostat mesilate (CM) and nafamostat mesilate (NM), were prepared by the emulsion solvent diffusion methods in water or in oil, and the w/o/w emulsion solvent evaporation method. The average diameter of PLGA nanospheres prepared in the water system were about 150-300 nm, whereas those prepared in the oil system were 500-600 nm. Among the three methods, these drugs were the most efficiently encapsulated up to 60-70% in PLGA nanospheres in the oil system. Other factors that may influence drug encapsulation efficiency and in vitro release such as drug load, molecular weight of polymer were also investigated. Both the CM- and NM-loaded nanospheres prepared in the water system immediately released about 85% of the drug upon dispersed in the release medium while the drug initial burst of nanospheres prepared by the emulsion solvent diffusion in oil method reduced to 30% and 60% for CM and NM, respectively. Poly(aspartic acid) (PAA), a complexing agent for cationic water soluble drugs, showed little effect on the encapsulation efficiency and release behavior for CM and NM. The DSC study and AFM pictures of nanospheres demonstrated that temperature-dependent drug release behavior was ascribable to the glass transition temperature of the polymer, which also affected the morphology of nanospheres upon dispersed in the release medium and influenced the drug release consequently.

Here, we describe a case of severe pancreatitis in overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in an adult female patient. Treatment with plasmapheresis and high-dose prednisone successfully saved her life and led to remission of the pancreatitis. This is the first case report of severe acute pancreatitis in the setting of overlap syndrome of SLE and SSc. The advantages and disadvantages of the use of corticosteroids are discussed.

The objective of the present study was to determine the efficacy of prophylactic administration of gabexate for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, hyperamylasemia and pancreatic pain. Patients scheduled for ERCP were randomized into two groups in a double-blind manner: the patients in the gabexate group were treated with continuous intravenous infusion of 300 mg gabexate dissolved in 500 mL Ringer's solution at 111 mL/h, starting 30 min before the endoscopic maneuvers and continuing up to 4 h after them; placebo group patients were treated only with Ringer's solution also starting 30 min before the endoscopic maneuvers and continuing up to 4 h. Data for 193 patients were analyzed. The incidence of post-ERCP pancreatitis was 3 patients (3.1%) in the gabexate group and 10 (10.5%) in the placebo group (P = 0.040). The incidence of hyperamylasemia was 33 patients (33.7%) in the gabexate group and 42 (43.7%) in the placebo group (P = 0.133). The incidence of pancreatic pain was 15 patients (15.3%) in the gabexate group and 28 (29.5%) in the placebo group (P = 0.018). The results suggest that a 4.5-h infusion of gabexate (for a total of 300 mg) could prevent post-ERCP pancreatitis and pancreatic pain.

Background and Aim: An oral trypsin inhibitor, camostat (CM), has a beneficial effect on chronic pancreatitis, but its mechanism is not yet fully understood. Recently, pancreatic stellate cells (PSC) have been reported to play an essential role in pancreatic fibrosis. An experimental model of pancreatic fibrosis induced by a superoxide dismutase (SOD) inhibitor (diethyldithiocarbamate [DDC]) was developed in rats. Thus, the effect of an oral trypsin inhibitor on pancreatic fibrosis and PSC was investigated., Methods: Pancreatic fibrosis was induced in rats using DDC (DDC rats). DDC + CM rats were administered DDC, and subsequently were fed a diet containing CM. Immunohistochemistry of the pancreas was performed with monoclonal anti-alpha-smooth muscle actin (alpha-SMA) antibody and anti-desmin antibody., Results: The DDC rats showed a significant increase in alpha-SMA-positive cells or desmin-positive cells compared with control rats. These significant increases in the fibrotic area improved after treatment with CM. The level of prolyl hydroxylase in the pancreas, which significantly increased as a result of DDC, decreased after treatment with CM., Conclusion: Camostat has a beneficial effect on pancreatic fibrosis induced by the administration of a SOD inhibitor, which inhibits the proliferation and activation of PSC., ((c) 2005 Blackwell Publishing Asia Pty Ltd.)

Acute pancreatitis sometimes develops to severe condition with a variety of clinical manifestations and high mortality. Autodigestion of the pancreas, secondary to the activation of digestive enzymes, plays a major role in the pathogenetic mechanism of acute pancreatitis. To improve the mortality and complication rates, appropriate treatments based on the precise prediction of disease severity are required. To this end, the early administration of protease inhibitors has commonly been employed for the therapy of acute pancreatitis in Japan. However, a number of clinical trials have failed to show the clinical effects of protease inhibitors, H2 receptor antagonist and somatostatin analogue on the treatment of acute pancreatitis. To evidence the therapeutic value of these agents for acute pancreatitis, well-organized clinical studies will be required.

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

The effects of camostat mesilate (CM), a derivative of gabexate mesilate developed for oral use, on primary glomerulonephritis (GN) and chance hematuria and/or proteinuria were evaluated. Fourteen patients (6 males, 8 females) with a mean age of 11 years and 3 months (range 4-16 years) were enrolled. Histological and clinical diagnoses of the 14 patients were as follows: IgA nephropathy 3, non-IgA GN 2, and asymptomatic significant microscopic hematuria [more than 100 red blood cells per high-power field (x400)] with or without proteinuria 9. They were consecutively treated with oral CM (100 mg twice a day) when they were confirmed to have continuous significant microscopic hematuria and/or proteinuria after a few months of observational follow-up. Urinary findings were normalized in 10 of the 14 patients (85.7%) between 1 month 1 week and 10 months (mean 4 months) after administration of CM. Hematuria cleared in 11 of 13 patients, and proteinuria disappeared in 4 of 5 patients. The mean duration of CM administration was 21.7 +/- 9.1 months (range 4-37 months). At present, 3-12 years after discontinuation of CM therapy, their urinary findings remain normal at 9 years 10 months to 26 years 6 months of age. In conclusion, there appears to be an association between the oral use of CM and reduction in significant microscopic hematuria and/or proteinuria. Oral CM therapy could represent a practical primary care approach to chance hematuria and/or proteinuria in children.

Bioadhesive and biodegradable microspheres were obtained by chemical cross-linking with epichlorohydrin of an alkaline solution of a mixture of starch and alpha-, beta-, or gamma-cyclodextrin (CyD). Microspheres were characterized by scanning electron microscopy, swelling degree, and water retention. The percentage of the effective CyD in microspheres was estimated by measuring the amount of iodine and typical organic compounds (TOCs) retained in the hydrophobic cavity of CyD. Gabexate Mesylate (trade name Foy); GM), an antiallergic drug, was included in microspheres by soaking in an aqueous solution containing the drug, followed by solvent evaporation or lyophilization. UV, IR, and DSC data indicated that despite the fact that GM is a hydrophilic drug, its hydrophobic moiety close to the benzene ring is able to penetrate the CyD cavity and to form stable inclusion complexes. Values of the association equilibrium constant for GM binding to CyD, obtained by UV differential spectroscopy, indicated that the affinity of the drug for alpha- and gamma-CyD is higher than that for beta-CyD. In vitro, GM was gradually released during 1h. Even if the release rate of the drug is relatively fast, the microspheres might actually provide the best platform since the material adheres to the nasal mucosa which was proved by adhesion tests. The GM integrity was checked by comparing its anti-trypsin activity before and after release.

The purpose of this study was to test the hypothesis that circulating ethanol at concentrations of approximately 0.1 mg% stimulates pancreatic secretion. Awake rats recovered from surgery were used in these experiments. Intravenous infusion protocols were established that produced blood ethanol concentrations 0.1 mg% for over an hour. Maintenance of 0.1 mg% blood ethanol concentration or transient concentrations as high as 0.17 mg% did not cause significant increases in pancreatic protein or fluid secretion. To test whether elevated blood ethanol would augment stimulated pancreatic secretion, the trypsin inhibitor camostat was infused intraduodenally at doses of 0.05, 0.2, and 0.5 mg/hr, each dose level infused for 2 hours. Elevated blood ethanol concentrations (0.1 mg%) did not significantly affect camostat-stimulated pancreatic protein or fluid secretion. In contrast to intravenous infusion, intraduodenal infusion of ethanol significantly stimulated pancreatic protein and fluid secretion, which was associated with blood ethanol concentrations of > or =0.19 mg%. The increases in pancreatic secretion were completely blocked by intravenous infusion of the cholecystokinin (CCK) receptor antagonist CR1409. We conclude that circulating ethanol does not stimulate pancreatic secretion in awake, recovered rats and that intraduodenal ethanol-stimulated pancreatic secretion is mediated by CCK.

We reported two cases of massive bleeding due to critical hyperfibrinolysis during living-related liver transplantation (LRLT) for end stage liver cirrhosis. The total volume of bleeding amounted to 57930 ml with the case 1, and amounted to 55980 ml with the case 2. TEG was useful for diagnosis of the hyperfibrinolysis. We administrated large amounts of FFPs, MAPs, PLTs, and gabexate mesilate. By rapid transfusion, we could manage to finish the procedures without hypotension, and complications were not observed at the early postoperative stage. We thought that the cause of the hyperfibrinolysis is the increasing blood tissue plasminogen activator (t-PA) due to long-anhepatic stage and small graft size. During anesthesia, since the functional start of a transplant liver is indispensable to it, in order to support a transplant liver for an improvement of hyperfibrinolysis, it is important to keep the homeostasis, such as body temperature, blood pressure.

Objectives: A continuous 13-h infusion of gabexate starting 30-90 min before endoscopic cholangiopancreatography (ERCP) can reduce postprocedural pancreatitis, the onset of which is generally observed within the first 6 h after ERCP. This study was designed to verify whether a 6.5-h infusion of gabexate was as effective as a 13-h infusion, at the same concentration, for reducing the incidence of post-ERCP pancreatitis (primary endpoint) and pancreatic hyperenzymemia and pain (secondary endpoints)., Methods: A total of 434 patients (201 male and 233 female; mean age 63.9 yr, range 18-96 yr) scheduled for ERCP were prospectively recruited in 25 Italian centers. Patients were randomized double-blind to two treatment groups. All subjects enrolled were first treated with a 500-mg continuous intravenous infusion of gabexate, starting 30 min before the endoscopic maneuvers and continuing up to 6.5 h after it. Over the next 6.5 h, 214 patients (group I) continued the infusion of gabexate (for a total of 1 g over 13 h) and 220 patients (group II) were given placebo (saline solution)., Results: The overall incidence of acute pancreatitis was 1.8% (eight patients), which included 1.4% in group I (three of 214 patients) and 2.2% in group II (five of 220 patients). Serum amylase and lipase values over time, peak levels of the two enzymes, pancreatic pain, and need for analgesics did not significantly differ in the two groups., Conclusions: These results suggest that a 6.5-h infusion of gabexate (for a total of 500 mg) is not less effective than a 13 h infusion, with evident savings.

Background/aims: To explore the possibility that the preventive effect of gabexate mesilate on endoscopic retrograde cholangiopancreatography-related acute pancreatitis may be mediated by its modulation of acute phase proteins., Methodology: Thirty consecutive patients who underwent endoscopic retrograde cholangiopancreatography were randomly assigned to receive 1g of gabexate mesilate (13 patients) or a placebo (17 patients) by continuous i.v. infusion starting 30 minutes before the endoscopy session and continuing for 12 hours afterward. In all patients, C-reactive protein, serum amyloid A and interleukin 6 serum concentrations were determined before endoscopy and 4, 8, 12 and 24 hours afterward., Results: Interleukin 6 basal serum concentrations were not statistically different between patients who had been treated with gabexate mesilate and those who had received the placebo (P = 0.279), whereas C-reactive protein (P = 0.033) and serum amyloid A (P = 0.022) basal values were significantly lower in the gabexate mesilate group than in the placebo group. Compared to basal values, serum interleukin 6 concentrations significantly increased at 4 (P = 0.048) and at 8 (P = 0.025) hours; the increase of serum interleukin 6 concentrations was not significant at 12 (P = 0.092), but became significant at 24 (P = 0.025) hours. C-reactive protein and serum amyloid A serum concentrations increased significantly only at 12 (P = 0.001, P = 0.012, respectively) and 24 (P < 0.001, P = 0.013, respectively) hours. The modifications of serum concentrations of interleukin 6, C-reactive protein and serum amyloid A were not significantly different between the gabexate mesilate and the placebo groups., Conclusions: Gabexate mesilate does not affect serum concentrations of acute phase proteins after endoscopic retrograde cholangiopancreatography examination and it is able to prevent acute pancreatitis related to endoscopic retrograde cholangiopancreatography via a different mechanism than that explored in this study.

We evaluated the usefulness of continuous regional arterial infusion (CRAI) of protease inhibitors and antibiotics in 156 patients with acute necrotizing pancreatitis (ANP) collected in a cooperative survey carried out in 1997 in Japan. The overall mortality rate was 18.6%, and the frequency of infected pancreatic necrosis was 12.8%. There was no significant difference in mortality rates between patients who received the protease inhibitor via CRAI and the antibiotics intravenously (group A) and patients who received both the protease inhibitor and the antibiotics via CRAI (group B), but the frequency of infected pancreatic necrosis was significantly lower in group B (7.6%) than in group A (23.5%). The mortality rate in patients in whom CRAI therapy was initiated within 48 h after the onset of ANP (11.9%) was significantly lower than that in patients in whom CRAI therapy was initiated more than 48 h after the onset (23.6%). These results suggested that CRAI of both protease inhibitors and antibiotics was effective in reducing mortality and preventing the development of pancreatic infection in ANP when initiated within 48 h after the onset of ANP.