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To investigate whether the administration of nafamostat mesilate (NM) reduces the risk of posthepatectomy liver failure (PHLF) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC).We retrospectively reviewed the 1114 patients who underwent hepatectomy for HCC between 2004 and 2020. NM was selectively administered to patients undergoing major hepatectomy with an estimated blood loss of500 mL. NM group was administered via intravenous of 20 mg of NM from immediately after surgery until postoperative day 4. We performed 1:1 propensity score matching and included 56 patients in each group. PHLF was defined according to the International Study Group of Liver Surgery (ISGLS).The incidence of PHLF was lower in the NM group than control group (P = 0.018). The mean peak total bilirubin (P = 0.006), aspartate transaminase (P = 0.018), and alanine aminotransferase (P = 0.018) levels postoperatively were significantly lower in the NM group. The mean hospital stays (P = 0.012) and major complication rate (P = 0.023) were also significantly lower in the NM group.Prophylactic administration of NM reduced the risks of complication and decreased the frequency of PHLF after hepatectomy. A further prospective study is needed to verify our findings.

Background/purpose The evidence provided by syntheses of the preventative effects of gabexate mesilate against pancreatitis among patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) is limited and highly heterogeneous. To enhance the understanding of this topic, this study aimed to provide overview of gabexate mesilate on preventing post ERCP pancreatitis (PEP) by synthesizing all relevant randomized controlled trials (RCTs). Methods We searched three databases for relevant RCTs. Two authors independently extracted data of pancreatitis incidence after ERCP, abdominal pain within 48 hours, and hyperamylasemia for quality assessment and meta-analysis. Results Thirteen RCTs with 3718 patients undergoing ERCP met the eligibility criteria and were included. The results revealed that the use of gabexate mesilate led to lower PEP (Peto odds ratio: 0.66, 95% confidence interval [CI]: 0.49 to 0.89), especially in the subgroup of gabexate mesilate infusion starting more than 30 min (Risk ratio: 0.45, 95% CI: 0.29 to 0.72). Conclusion The present synthesis found that gabexate mesilate could be an option of prophylactic treatment of pancreatitis for patients undergoing ERCP, and reveals that it is favorable to administer it starting 30 min before the ERCP. This evidence may improve the clinical prevention of PEP.

Thermogravimetry and differential scanning calorimetry (DSC) are useful techniques that have been successfully applied in the pharmaceutical industry to reveal important information regarding the physicochemical properties of drug and excipient molecules such as stability, purity and formulation compatibility among others. The present work reports studies of the thermal behavior of antihypertensive drug doxazosin mesilate as raw material and in the form of tablets. The purity was determined by DSC and specialized pharmacopeial method. Analysis of the DSC data indicated that the degree of purity of doxazosin mesilate was similar to that found by the official HPLC method used in the British pharmacopoeia, BP 2011. The simplicity and sensitivity of thermal analysis justify its application in the quality control of pharmaceutical compounds.

A 65-year-old man was transferred from the Department of Vascular Surgery to Nephrology because of cardiac arrest during hemodialysis. He underwent incision and drainage for treatment of a buttock abscess. Nafamostat mesilate was used as an anticoagulant for hemodialysis to address bleeding from the incision and drainage site. Sudden cardiac arrest occurred after 15 minutes of dialysis. The patient was treated in the intensive care unit for 5 days. Continuous veno-venous hemodiafiltration was started without any anticoagulant in the intensive care unit. Conventional hemodialysis was reinitiated, and nafamostat mesilate was used again because of a small amount of continued bleeding. Ten minutes after hemodialysis, the patient complained of anaphylactic signs and symptoms such as dyspnea, hypotension, and facial swelling. Epinephrine, dexamethasone, and pheniramin were injected under the suspicion of anaphylactic shock, and the patient recovered. Total immunoglobulin E titer was high, and skin prick test revealed weak positivity for nafamostat mesilate. We first report a case of anaphylactic shock caused by nafamostat mesilate in Korea.

Introduction The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic breast cancer (MBC). Methods This phase III open-label, randomised, parallel-group, multicentre clinical trial enrolled patients with locally recurrent or MBC who had had 2–5 prior chemotherapy regimens, including an anthracycline and taxane) from September 26, 2013, to May 19, 2015. Women were randomised 1:1 to receive eribulin (1.4 mg/m2, intravenously, on day 1 and day 8) or vinorelbine (25 mg/m2, intravenously, on day 1, day 8 and day 15) every 21 days. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response and overall survival (OS). Results Five hundred thirty women were randomised to receive eribulin (n = 264) or vinorelbine (n = 266). Improvement in PFS was observed with eribulin compared with vinorelbine (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.65–0.98, P = 0.036); median PFS was 2.8 months in both treatment arms. The median OS was 13.4 months with eribulin and 12.5 months with vinorelbine (HR: 1.03, 95% CI: 0.80–1.31, P = 0.838). The ORR was 30.7% (95% CI: 25.2%–36.6%) with eribulin and 16.9% (95% CI: 12.6%–22.0%) with vinorelbine (P Conclusions Eribulin achieved statistically significantly superior PFS (and response rate) compared with vinorelbine in previously treated women with locally recurrent or MBC. Eribulin appeared to be better tolerated than vinorelbine, with no new safety signals observed. Trial registration National Institutes of Health ClinicalTrials.gov registry, NCT02225470. Registered 05 August 2014- Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02225470?term=NCT02225470&rank=1 .

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load.Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group ( P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log 10 copies/mL ( p Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

This work presents a molecular dynamics simulation study of the vapor-liquid equilibrium curve for the 1-butyl-3-methylimidazolium mesilate ionic liquid [C4mim][OMs] along with other thermodynamic properties in condensed phase, such as: densities, surface tension, heats of vaporization, constant pressure heat capacities, and the dielectric constant. The latter were obtained using molecular simulation calculations employing a new non-polarizable classical force field developed in this work, for this ionic liquid experimental thermodynamic properties as well as calculated properties by molecular simulations are very scarce in the literature. The development of the force field for the [C4mim][OMs] ionic liquid involved first the parameterization of all-atom non-polarizable force fields for two well-studied imidazolium ionic liquids [C4mim][BF4], in order to validate first against existing experimental and calculated thermodynamic properties using molecular simulations. Even though many transferable force fields for ionic liquids have been developed in the past years, some of these force fields predict extremely well structural properties such as densities and radial distribution functions etc., while other force fields fail to predict accurately heats of vaporization, condensed phases properties such as dielectric constant and transport properties such as viscosity, diffusivity, and vice versa. The force fields developed in this work are centered on the OPLS functional, and were parameterized using a simple and robust methodology focused mainly in electrostatic charges determination and in the refinement of the most representative dihedral angles. The calculation of the electrostatic charges follows the methodology proposed by Salas et al. (J. Chem. Theory Compute. 2015, 11, 683–693) involving the inclusion of polarization effects in quantum mechanical calculations in order to represent implicitly the solvent by employing the experimental or calculated dielectric constant in conjunction with a restrain electrostatic potential fitted to an ionic liquid dimer, to account for the inclusion of solvation coordination effects. The dihedral angles were parameterized simultaneously from the energetic differences in molecular conformations between ab-initio calculations and the energies obtained with the classic force field. The force field validation for the ionic liquids 1-butyl-3-methylimidazolium tetrafluoroborate, [C4mim][BF4], and 1-butyl-3-metilimidazolium hexafluorophosphate [C4mim][PF6], gave good agreement for the properties calculated compared with experimental and literature results. Our motivation for this work focused mostly in force field development for specific individual ionic liquids capable of reproducing thermodynamic properties in condensed phase, such as density, heats of vaporization, surface tension, and static dielectric constants for applications oriented as absorption and reaction media for QM/MM and free energy calculations.

Background The primary end points of this study were to determine the dose-limiting toxic effects (DLTs), maximum tolerated dose, and a recommended phase II dose of a synthetic serine protease inhibitor, nafamostat mesilate, in combination with full-dose gemcitabine in patients with unresectable locally advanced or metastatic pancreatic cancer. The secondary end point was to assess therapeutic response. Patients and methods Patients with previously untreated pancreatic cancer received gemcitabine (1 000 mg/m2 i.v. for 30 min) on days 1, 8, and 15, with nafamostat mesilate (continuous regional arterial infusion for 24 h through a port-catheter system) on days 1, 8, and 15; this regimen was repeated at 28-day intervals. The initial dose of nafamostat mesilate was 2.4 mg/kg and was escalated in increments of 1.2 mg/kg until a dose of 4.8 mg/kg was achieved. A standard ‘3+3’ phase I dose-escalation design was used. Therapeutic response and clinical benefit response were assessed. Results Twelve patients were enrolled in this study. None of the patients experienced DLTs, and nafamostat mesilate was well tolerated at doses up to 4.8 mg/kg in combination with full-dose gemcitabine. This combination chemotherapy yielded a reduction of a high serum level of the tumor marker CA19-9. Pain was reduced in three of seven patients without oral morphine sulfate. Overall survival was 7.1 months for all patients. Conclusion This phase I study was carried out safely. This combination chemotherapy showed beneficial improvement in health-related quality of life. The recommended phase II dose of nafamostat mesilate in combination with full-dose gemcitabine is 4.8 mg/kg.

Postreperfusion syndrome (PRS), an acute decrease in blood pressure after reperfusion of the liver graft, occurs frequently during liver transplantation surgery. We supposed that the activation of the kallikrein-kinin system leading to extensive systemic vasodilatation was a possible cause. The effect of pretreatment with nafamostat mesilate (NM), a broad spectrum serine protease inhibitor, on the occurrence of PRS was evaluated. Sixty-two adult liver recipients were randomized to receive an intravenous bolus of either 0.02 mg/kg of NM (NM group, n = 31) or an equal volume of normal saline (control group, n = 31) just before reperfusion of the liver graft. Occurrence of PRS and intraoperative use of vasoactive drugs were compared between the two groups. Postoperative recovery was also compared. PRS was significantly less frequent (48% vs. 81%, p = 0.016) requiring less vasopressors in the NM group compared to the control group. The NM group also showed faster recovery of the mean arterial pressure. Perioperative laboratory values were similar between the two groups. Pretreatment with 0.02 mg/kg of NM immediately before reperfusion decreases the frequency of PRS and vasopressor requirements during the reperfusion period in liver transplantation.

Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen alpha1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-alpha production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen alpha1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.

To elucidate the mechanism of propofol-induced pain on injection, we performed several studies using nafamostat mesilate, a kallikrein inhibitor, or lidocaine. As both pretreatment and low-dose mixing with nafamostat produced the same effects on pain reduction, we used the latter method in the following experiments. Low-dose mixing had the same effect on injection pain as mixing with lidocaine. The extent of pain was assessed by measuring bradykinin concentrations by mixing with blood. Propofol and its lipid solvent mixed with blood produced approximately two-fold generation of bradykinin compared with the saline control, and this was inhibited completely by nafamostat and lidocaine. Injection of the lipid solvent before propofol significantly aggravated pain compared with prior injection of saline, although the lipid solvent injected twice caused no change in pain. These results suggest that the lipid solvent for propofol activates the plasma kallikrein-kinin system and produces bradykinin which modifies the injected local vein. This modification of the peripheral vein may increase the contact between the aqueous phase propofol and the free nerve endings of the vessel, resulting in aggravation of propofol-induced pain.

Background. Nafamostat mesilate (FUT-175) is a synthetic serine protease inhibitor that inactivates coagulation, fibrinolysis, and platelet aggregation. Nafamostat mesilate may suppress the blood-foreign surface reaction similar to biocompatible materials by blocking factor XIIa. Methods. We performed an in vitro study of cardiopulmonary bypass (CPB) with fresh human blood among the following three groups: standard CPB sets (C), biocompatible CPB sets (B), and standard CPB sets with FUT-175 (10 mg/L) (F). A clinical study using these same CPB groups also was performed in 45 patients undergoing aortocoronary bypass operations (15 patients each). We injected FUT-175 at 40 mg/h during CPB. Results. In the in vitro study, both groups B and F showed significantly lower levels of coagulation factors, thrombin-antithrombin III complex, fibrinopeptide A, β -thromboglobulin, complement C3a, granulocyte elastase, and free hemoglobin than group C at the conclusion of the study. Thrombin-antithrombin III complex and free hemoglobin in group F also were lower than in group B. The platelet count remained at a higher level in group F than in the other groups. Separation of bradykinin was suppressed most significantly in group F. In the clinical study, group F also showed significantly lower levels of α 2-plasmin inhibitor plasmin complex and C3a than both groups C and B. There were minimal levels of free hemoglobin in group F. Conclusions. Nafamostat mesilate may contribute major beneficial effects toward conservation of blood during CPB and prevention of coagulopathy after CPB.

Leukocytes are thought to have a role in tissue injury induced by stress. Synthetic protease inhibitors can suppress the leukocyte-dependent tissue injury; however, the effect of camostat mesilate on microcirculatory disturbance has not been reported. Male Wistar rats were anesthetized, and a 30% full skin-thickness dorsal scald burn was inflicted. Rolling or sticking of leukocytes and deposits of Monastral blue B (MBB) in gastric venules was observed by using intravital microscopy. Oral administration of camostat mesilate 100 mg/kg was performed twice: 40 minutes before the thermal injury and 2.5 hours after injury. Microscopy was performed 5 hours after the thermal injury, and showed that camostat mesilate suppressed the percentage of MBB deposit areas, and the rolling or sticking of leukocytes in the gastric venules. Camostat mesilate appears to protect against gastric microcirculatory disturbance induced by thermal injury in rats.

Gabexate mesilate, a potent serine proteinase inhibitor, has been reported to modulate the immune response; however, studies of gabexate therapy in human acute pancreatitis are not available. Therefore, the purpose of this study was to evaluate the immuno-modulatory effect of gabexate in patients with severe acute pancreatitis. Twenty-four patients (17 men, 7 women; mean age, 67 years; range, 32 to 97 years) were included in the study. Nine patients received gabexate 900 mg/d and 15 received placebo. In all patients, serum C-reactive protein (CRP) was determined using a commercial kit both on admission and for 5 days after the beginning of treatment. No statistically significant differences in age, sex, or etiology were found between the two groups of patients. On the first, second, third, and fourth days after treatment was begun, serum concentrations of CRP were significantly lower in gabexate-treated patients than in those who received placebo. On the fifth day, no statistically significant differences in serum levels of CRP were found between the two treatment groups. We concluded that gabexate may contribute to reducing the inflammatory response in patients with severe acute pancreatitis in the early phases of the disease

Effects of dermatan sulfate (DS) on the endotoxin-induced disseminated intravascular coagulation (DIC) rat model were compared with those of low-molecular weight heparin (LMWH), nafamostat mesilate (NM) and argathroban (AR). At doses of 5, 10 or 20 mg/kg/4 hr, DS significantly ameliorated the decrease of fibrinogen (Fbg), the increase of fibrin-fibrinogen degradation products (FDP) and except at the highest dose (20 mg/kg/4 hr), the prolongation of thrombin clotting time (TCT). It also decreased the glomerular fibrin deposits (%GFD) at doses of 10 or 20 mg/kg/4 hr. LMWH suppressed the decrease of Fbg and the increase of FDP at doses of 1.4 or 2.8 mg/kg/4 hr. Only the highest dose of LMWH suppressed the decrease of the platelet count (PL), the prolongation of prothrombin time, and improved the %GFD. AR suppressed the decrease of PL and improved the %GFD. At the dose required to improve the %GFD, DS (5, 10 mg/kg/4 hr) significantly suppressed the prolongation of TCT, which is related to the bleeding frequency, while LMWH and AR further increased the prolongation of the TCT. These results suggest that DS has potential as a therapeutic drug with a lower hemorrhagic risk as compared with LMWH and AR in the treatment of DIC.

Background: A multicenter controlled study was performed to evaluate the effect of high doses of the low molecular weight protease inhibitor gabexate mesilate on mortality and complications associated with moderate and severe acute pancreatitis. Methods: Two hundred twenty-three patients from 29 hospitals were entered in the randomized, double-blind trial. Admission to the study was based on strict criteria excluding mild acute pancreatitis. The patients received placebo or 4 g gabexate mesilate per day intravenously for 7 days. All patients were followed up for 90 days after randomization. The analysis was based on 14 complications, including death. Results: There was no statistical difference in either mortality or complications associated with acute pancreatitis between the placeboand gabexate mesilate groups. Conclusions: The results show that gabexate mesilate was not effective in preventing complications and mortality in acute pancreatitis.