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Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection. It is the primary cause of death in the intensive care unit, posing a substantial challenge to human health and medical resource allocation. The pathogenesis and pathophysiology of sepsis are complex. During its onset, pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions, possibly leading to hyperinflammation, immunosuppression, and long-term immune disease. Of all critical outcomes, hyperinflammation is the main cause of early death among patients with sepsis. Therefore, early suppression of hyperinflammation may improve the prognosis of these patients. Nafamostat mesilate is a serine protease inhibitor, which can inhibit the activation of the complement system, coagulation system, and contact system. In this review, we discuss the pathophysiological changes occurring in these systems during sepsis, and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.

We aimed to clarify the effect of nafamostat mesilate (nafamostat) on intestinal mucositis as well as the potentiation of intestinal 5-hydroxytryptamine (5-HT) dynamics induced by methotrexate, an anti-cancer drug, in rats. Rats received intraperitoneal methotrexate at 12.5 mg/kg/day for 4 days. In addition, 1, 3, or 10 mg/kg/day of nafamostat was given subcutaneously for 4 days. Ninety-six hours after the first administration of methotrexate, jejunal tissues were collected for analysis. The results showed that 1 mg/kg, but not 3 or 10 mg/kg, of nafamostat significantly ameliorated the methotrexate-induced body weight loss. Moreover, 1 mg/kg of nafamostat significantly improved methotrexate-induced mucositis, including villus atrophy. Nafamostat (1 mg/kg) significantly inhibited the methotrexate-induced mRNA expression of pro-inflammatory cytokines and cyclooxygenase-2, as well as methotrexate-induced 5-HT content and tryptophan hydroxylase (TPH) activity. In addition, it tended to inhibit the number of anti-TPH antibody-positive cells and significantly inhibited the number of anti-substance P antibody-positive cells. These findings suggest that low-dose nafamostat ameliorates tissue injury and 5-HT and substance P synthesis in methotrexate-induced mucositis. Nafamostat may be a novel therapeutic strategy for the prevention and treatment of mucositis as well as 5-HT- and/or substance P-related adverse effects in cancer chemotherapy.

Serine proteases (SPs) play physiological roles in the kidney. We previously reported that a synthetic SP inhibitor, camostat mesilate (CM), suppressed sodium reabsorption in the renal tubule and showed natriuretic effects in aldosterone-infused rats. Here, we aimed to explore novel physiological roles of SPs in the renal tubule and understand the mechanism of actions of SP inhibitors, by administering CM to healthy rats. Sprague–Dawley rats were classified into control and CM (subcutaneous sustained-release pellet) groups and sacrificed on day 7. CM significantly increased urine volumes by approximately two-fold in a urinary sodium- and osmolyte excretion-independent manner, indicating the occurrence of free water excretion. Serum vasopressin, potassium, and calcium levels and the osmolality in the renal medulla, which all affect free water reabsorption in the renal tubule, remained unchanged after CM administration. CM decreased urinary exosomal AQP2 excretion, suggesting suppression of AQP2 activity in the collecting duct. These changes were reversed by desmopressin infusion. Water diuresis caused by CM was independent of its action on prostasin or TMPRSS4. Our results revealed the association of SP inhibition with free water handling and demonstrated that CM administration exerted diuretic effects with AQP2 downregulation, suggesting SP inhibitors as a new class of aquaretic drugs.

A recent study conducted by researchers at Fudan University in Shanghai, China, explores the pathophysiology of sepsis, a life-threatening syndrome caused by a dysregulated host response to infection. The study highlights the complex nature of sepsis and the intricate interactions between pro-inflammatory and anti-inflammatory mechanisms during its onset. Hyperinflammation is identified as the main cause of early death in sepsis patients, and the researchers suggest that early suppression of hyperinflammation may improve patient prognosis. The study also discusses the potential of nafamostat mesilate, a serine protease inhibitor, as a treatment for sepsis by targeting the complement system, coagulation system, and contact system. [Extracted from the article]

Metabolic syndrome (MetS) is associated with chronic kidney disease and proteinuria. Previously, we reported that a synthetic serine protease inhibitor, camostat mesilate (CM), mitigated hypertension and proteinuria in rodent disease models. The present study evaluated the anti-hypertensive and anti-proteinuric effects of CM in MetS model rats (SHR/ND mcr-cp). Rats were divided into normal salt-fed (NS), high salt-fed (HS), HS and CM-treated (CM), and HS and hydralazine-treated (Hyd) groups. Rats were sacrificed after four weeks of treatment. Severe hypertension and proteinuria were observed in the HS group. Although CM and Hyd equally alleviated hypertension, CM suppressed proteinuria and glomerular sclerosis more efficiently than Hyd. The HS group revealed a decrease in podocyte number and podocyte-specific molecules, together with an increase in glomerular apoptotic cells and apoptosis-related proteins in the kidney. These changes were significantly attenuated by CM, but not by Hyd. Furthermore, CM ameliorated the apoptotic signals in murine cultured podocytes stimulated with the high glucose and aldosterone medium. In conclusion, CM could exert renoprotective effects in MetS model rats, together with the inhibition of podocyte apoptosis. Our study suggests that serine protease inhibition may become a new therapeutic strategy against MetS-related hypertension and renal injuries.

ABSTRACTObjectives: Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder that can cause acute short attacks of vertigo. This study aimed to compare the efficacy and acceptability of carbamazepine (CBZ), CBZ plus betahistine mesilate tablets (BMT) and oxcarbazepine (OXC) plus BMT in treating VP within 12 weeks.Methods: A retrospective analysis of data from 196 VP patients treated in our hospital was conducted. There were 73 patients receiving CBZ, 65 patients receiving CBZ+BMT and 58 patients receiving OXC+BMT. The frequency of vertigo, vertigo duration, vertigo score, response rate (RR) and side effects were compared between groups to assess efficacy and acceptability at the end of 12thweek.Results: After 12 weeks’ treatment, the CBZ+BMT group had a greater reduction in the frequency of vertigo, vertigo duration and vertigo score than the other two groups. The RR was highest in the CBZ+BMT group, second in the OXC+BMT group and lowest in the CBZ group. The incidence of side-effects was highest in the CBZ group, second in the CBZ+BMT group and lowest in the OXC+BMT group. Two patients in the CBZ group were withdrawn.Conclusion: These results indicated that using BMT as an augmentation for CBZ or OXC might be a good choice in treating VP.

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.

Purpose Anticoagulation is mandatory for extracorporeal membrane oxygenation (ECMO), but systemic heparinization, which has been most widely used as an anticoagulant, has been associated with bleeding complications. The present study reviewed the usefulness and safety of nafamostat mesilate as a regional anticoagulant in patients with bleeding complication during ECMO.Methods We retrospectively reviewed the record of 13 cases. The nafamostat mesilate dose was regulated to maintain the activated clotting time (ACT) or activated partial thromboplastin time (aPTT) values within an adequate range at the ECMO reinfusion route. ACT or aPTT values in blood samples from the ECMO circuit and from the patients were measured simultaneously and consecutively.Results We measured the ACT value in 6 cases and aPTT in 7 cases. The bleeding complications were treated in 11 cases. When we compared the difference in 2 anticoagulation values (ACT and aPTT) between the 2 blood samples, one taken from ECMO and the other from patients, mean anticoagulation values of blood from patients were lower than those from ECMO circuit in 11 cases. With respect to the type of ECMO reinfusion mode, the difference was significant only in veno-arterial mode ECMO group (p<0.001).Conclusions Nafamostat mesilate, with which we can reduce anticoagulation values of patient to a safe level without losing the ECMO anticoagulation values is expected to be useful as a regional anticoagulant in patients with bleeding complications or a high risk of bleeding during ECMO.

Sepsis and its associated multiple organ failure are related to high mortality in critical patients. Several studies have reported that gabexate mesilate, a synthetic inhibitor of trypsin-like serine protease, protects tissues/organs against injury in the models of endotoxemia. The aim of this study was to examine whether gabexate mesilate could attenuate coagulopathy and organ dysfunction in lipopolysaccharide (LPS)-induced sepsis model by using thrombelastography (TEG). LPS (7.5 mg/kg/h, intravenouly for 4 h) was administered to male adult Wistar rats. Some of the LPS rats received a continuous infusion of gabexate mesilate (10 mg/kg/h, intravenously for 8.5 h) for 30 min before the LPS administration. Variable parameters of hemodynamics, biochemistry, hemostasis and inflammatory response were measured for 6 h after the LPS infusion. TEG variables (R-time, K-time, α-angle, and maximal amplitude) were also measured. The pretreatment of LPS rats with gabexate mesilate significantly attenuated the lung, liver and kidney dysfunction, consumptive coagulopathy, the increases in serum tumor necrosis factor-α, interleukin-6, plasma thrombin–antithrombin complex and plasminogen activator inhibitor-1, and neutrophils infiltration score in lung, liver and kidney, compared with the LPS alone group. In addition, TEG parameters correlated with tissue and liver injury in the late phase of endotoxemia. In particular, a strong negative correlation between maximal amplitude at 4 h and Ln (lactate dehydrogenase) at 6 h after LPS infusion was noted (r = −0.752, P < 0.001, R2 = 0.566). These results indicate that beneficial effects of anticoagulants (e.g. gabexate mesilate) in endotoxemia could be monitored by TEG per se.

Purpose Nafamostat mesilate (NM) can be used as a regional anticoagulant for continuous renal replacement therapy (CRRT). The primary aim of this study was to assess the association of the use of NM with risk of bleeding complications and compare it with the use of unfractionated heparin (UFH).Methods We conducted a single-center retrospective observational study. We included adult patients who required CRRT in our intensive care unit from 2011 to 2013. The primary outcome was the risk of bleeding complications during CRRT and the secondary outcome was filter life for the first filter of CRRT.Results We included 101 patients (76 with NM, 25 with UFH). Among the 101 patients, use of NM tended to be associated with lower risk of bleeding complications (6.6% vs. 16%; odds ratio, 0.37; p = 0.16). Propensity score matching generated 30 patients with NM and 15 patients with UFH with well-balanced baseline characteristics. Among the propensity score-matched cohorts, use of NM was significantly associated with decreased risk of bleeding complications (3.3% vs. 27%; odds ratio, 0.09; p = 0.04). In multivariate logistic analysis using the inverse probability of treatment weighting for sensitive analysis, the use of NM was independently associated with reduced risk of bleeding complications (p = 0.02). The median filter life was not significantly different for patients with NM and patients with UFH (25.5 hours vs. 30.5 hours, p = 0.16).Conclusions In our retrospective analysis, the use of NM as an anticoagulant during CRRT was associated with decreased incidence of bleeding complications compared with the use of UFH.

The objective of this study was to investigate whether prophylactic administration of nafamostat mesilate reduces the incidence of post–endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), its efficacy, and risk factors for PEP.

AbstractBackground/Aims:We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. Methods:In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75 adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. Results:CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. Conclusion:Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD. © 2015 S. Karger AG, Basel

For islet transplantation, maintaining organ viability after pancreas procurement is critically important for optimal graft function and survival. We recently reported that islet yield was significantly higher in the modified ET-Kyoto (MK) solution, which includes a trypsin inhibitor (ulinastatin), compared with the UW solution, and that the advantages of MK solution are trypsin inhibition and less collagenase inhibition. In this study, we compared ulinastatin with other trypsin inhibitors, gabexate mesilate, and nafamostat mesilate, in preservation solution for islet isolation. Ulinastatin was easily dissolved in ET-Kyoto solution, while ET-Kyoto with gabexate mesilate and nafamostat mesilate became cloudy immediately after addition. Although there were no significant differences in islet yield among the three groups, viability was significantly higher for the MK group than for the GK group or the NK group. The stimulation index was significantly higher for the MK group than for the GK group. In summary, there are no other trypsin inhibitors that are more effective than ulinastatin. Based on these data, we now use ET-Kyoto solution with ulinastatin for clinical islet transplantation.

In the present study, biomolecule-stabilized Au nanoclusters were demonstrated as a novel fluorescence probe for sensitive and selective detection of pazufloxacin mesilate (PZFX) for the first time. The linear decrease in the fluorescence intensity of Au nanoclusters induced by PZFX allowed for the quantitative detection of PZFX in the range of 0.15 μg/mL to 1 mg/mL, and the detection limit for PZFX was 0.2 μg/mL. Circular dichroism spectroscopy and fluorescence decay studies were then performed to discuss the quenching mechanism. In addition, practical application of the present approach was also demonstrated for real samples, which suggested its great potential for accurate analysis of similar drugs.

Gabexate mesilate (GM) is a synthetic inhibitor of plasmatic and pancreatic serine proteases licensed for the treatment of pancreatitis. Here we show that in suspensions of isolated hepatocytes, profound changes in extracellular, cytoplasmic, and vesicular pH occur after addition of GM. Isolated hepatocytes obtained by collagenase perfusion of rat liver were pre-incubated with 1, 2, and 4 mM GM. Extracellular pH (pH in the incubation medium) was measured by a conventional pH electrode, cytosolic and vesicular pH were measured by fluorescence changes of 2',7'-biscarboxyethyl-5,6-carboxyfluorescein acetoxymethyl ester (BCECF-AM) and fluorescein dextran, respectively. Incubation of hepatocytes with GM resulted in a dose-dependent decrease of extracellular pH. Cytosolic pH decreased rapidly and markedly in a dose-dependent manner during the first minutes and gradually returned towards baseline. Simultaneously, GM induced a rapid alkalinization of acidic vesicles. The presence of bis-(p-nitrophelyl) phosphate (BNPP), an esterase inhibitor, reduced the extent of extracellular acidification. Incubation of hepatocytes in the presence of dimethylamiloride, an Na+/H+exchanger inhibitor, or in a sodium-free medium, did not modify the rate and extent of extracellular acidification. GM, a commercially available pharmacological agent, could be useful to manipulate extra- and intracellular pH.

Purpose During continuous renal replacement therapy (CRRT), anticoagulation of the extracorporeal circuit is required. The aim of this study was to assess the efficacy and safety of nafamostat mesilate, a serine protease inhibitor, compared with heparin.Methods We retrospectively studied 222 patients treated with CRRT in the intensive care unit (ICU). Clinical and filter-related data were extracted.Results We reviewed the medical records of the patients treated with CRRT. Initial anticoagulation methods were 56 heparin and 25 nafamostat mesilate; 10 patients received infused heparin systemically, and 131 patients were treated without anticoagulation. Total number of filters used was 1,236. Median filter lifespan with nafamostat mesilate was significantly greater than heparin (24.3 vs. 17.5 hours, p<0.001) and Kaplan-Meier survival plots revealed the longer survival of the circuits using nafamostat mesilate than heparin or without anticoagulation. In Cox proportional hazard models, nafamostat mesilate predicted longer filter survival. Although nafamostat mesilate induced activated partial thromboplastin time prolongation in 11 circuits (5.4%), bleeding episodes were not increased.Conclusions Nafamostat mesilate anticoagulation was associated with prolonged filter survival compared with heparin. These data suggest that nafamostat mesilate is a good choice for anticoagulant with prolonged filter survival during CRRT in critically ill patients.

Objective:The aim of this study was to investigate the pharmacokinetics and dose proportionality of a single, intravenous dose of pazufloxacin mesilate, an injectable fluoroquinolone antibiotic, in healthy Korean male volunteers.Methods:In this open-label, four-dose, parallel study, subjects were randomized to receive a single dose of pazufloxacin mesilate 300, 500, 600, and 1,000 mg (n 6, 20, 6, and 8, respectively) administered as a 1-h intravenous infusion. Blood and urine samples were collected serially from 0 to 24 h after drug administration and analyzed using a validated HPLC method. Tolerability was assessed by monitoring clinical laboratory parameters and adverse events.Results:After single-dose intravenous administration of pazufloxacin mesilate, the mean Cmaxfor groups treated with 300, 500, 600, and 1,000 mg doses ranged from 5.11 to 18.06 μg/mL; the mean AUC0-tranged from 13.70 to 58.60 μg × h/mL. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 – 1,000 mg, based on linear regression model and power model. At all four dosages studied, pazufloxacin mesilate was well tolerated.Conclusions:Our data suggest that all regimens of pazufloxacin administration were well tolerated. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 – 1,000 mg.

Introduction:In the last decade, the introduction of imatinib mesilate into the clinical practice has resulted in a dramatic improvement in the treatment of gastrointestinal stromal tumor (GIST). Nowadays, the median overall survival in patients with advanced disease has increased to 5 years, while recent Phase III trials demonstrated that imatinib mesilate can be successfully employed as adjuvant therapy in patients at significant risk of recurrence. Despite these good results, the emergence of secondary resistance represents the main cause of treatment failure. In recent years, many efforts have been made in search of drugs to overcome imatinib mesilate resistance; some of these have been employed as second-line treatment or salvage therapy.Areas covered:Summarized and investigated in this paper are the results obtained by imatinib mesilate in advanced and adjuvant setting, the role of sunitinib malate as second-line therapy in imatinib mesilate-resistant patients and the clinical results concerning new drugs, mainly tyrosine-kinase inhibitors.Expert opinion:Current research on novel therapeutic agents, as third-line treatments in GIST, is ongoing. However, despite the promising results obtained with the new molecules, imatinib mesilate remains the cornerstone in the medical treatment of GIST and to date no other drugs can replace it.

Infusion of the protease inhibitor nafamostat mesilate (20 mg) effectively prevents post-ERCP pancreatitis, but only in low-risk groups. This study was performed to evaluate the use of high-dose nafamostat mesilate (50 mg) for prevention of post-ERCP pancreatitis (PEP), especially in high-risk groups.

Introduction Although nafamostat mesilate, a synthetic serine protease inhibitor, has been commonly used in Japan as an anticoagulant during continuous renal replacement therapy (CRRT), its clinical utility has not been well determined. The aim of this study was to evaluate the efficacy (filter survival) and safety (bleeding complications) of nafamostat mesilate in CRRT for acute kidney injury (AKI) among critically ill patients.Methods We retrospectively studied consecutive patients with AKI treated with continuous veno-venous hemodialysis and nafamostat mesilate from April 2005 to March 2008. Demographic, clinical and laboratory data were extracted from the clinical chart.Results Fifty-eight patients were enrolled in this study (45 males with an average age of 66±15 years). The median filter survival was 21.8 h (range: 2.8–55.5 h), and the mean was 20.8±8.4 h. Only 38 out of 181 filters (21%) were interrupted because of filter failure within 24 hours and 89 filters (49%) were electively renewed within 24 hours. Activated partial thromboplastin time was elevated especially during the first 24 hours (46.7±13.1 s at baseline versus 73.9±24.3 s at day 1; ANOVA p<0.01). Hematocrit level was kept around 30% and did not change significantly (ANOVA p=0.69). No patients experienced major bleeding while treated with CRRT.Conclusions Nafamostat mesilate provided sufficient filter survival without causing major bleeding complications despite the prolongation of APTT.

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.

Prostasin, a glycosylphosphatidylinositol-anchored serine protease, regulates epithelial sodium channel (ENaC) activity. Sodium reabsorption through ENaC in distal nephron segments is a rate-limiting step in transepithelial sodium transport. Recently, proteolytic cleavage of ENaC subunits by prostasin has been shown to activate ENaC. Therefore, we hypothesized that serine protease inhibitors could inhibit ENaC activity in the kidney, leading to a decrease in blood pressure. We investigated the effects of camostat mesilate, a synthetic serine protease inhibitor, and FOY-251, an active metabolite of camostat mesilate, on sodium transport in the mouse cortical collecting duct cell line (M-1 cells) and on blood pressure in Dahl salt-sensitive rats. Treatment with camostat mesilate or FOY-251 decreased equivalent current (Ieq) in M-1 cells in a dose-dependent manner and inhibited the protease activity of prostasin in vitro. Silencing of the prostasin gene also reduced equivalent current in M-1 cells. The expression level of prostasin protein was not changed by application of camostat mesilate or FOY-251 to M-1 cells. Oral administration of camostat mesilate to Dahl salt-sensitive rats fed a high-salt diet resulted in a significant decrease in blood pressure with elevation of the urinary Na/K ratio, decrease in serum creatinine, reduction in urinary protein excretion, and improvement of renal injury markers such as collagen 1, collagen 3, transforming growth factor-β1, and nephrin. These findings suggest that camostat mesilate can decrease ENaC activity in M-1 cells probably through the inhibition of prostasin activity, and that camostat mesilate can have beneficial effects on both hypertension and kidney injury in Dahl salt-sensitive rats. Camostat mesilate might represent a new class of antihypertensive drugs with renoprotective effects in patients with salt-sensitive hypertension.

Background: The molecular hallmark of gastrointestinal stromal tumours (GISTs), the mutation of the KITgene, was discovered 10 years ago. GISTs have since been recognized as separate pathological entities among sarcomas, and have become a model for targeted treatment of solid tumours. Imatinib mesilate, which was approved in 2002 for the treatment of patients with advanced GIST, has dramatically changed the course of the disease. Objective: This article will focus on the development of imatinib mesilate in the treatment of patients with GIST. Methods: A Pubmed search was performed using the keywords ‘imatinib’, ‘gastrointestinal stromal’, ‘GIST’, ‘KIT’ and ‘PDGFR’. Websites of the American Society of Clinical Oncology and the European Society of Medical Oncology were searched for data reported in abstract form at recent symposiums. Personal communications from opinion leaders were sought for additional information that might be relevant. Results: Imatinib has changed the clinical course of patients with advanced GISTs and further development in the adjuvant setting as well as prospective assessment of predictive factors are the current focus of ongoing research.

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.

Gabexate mesilate (GM), a serine protease inhibitor, often causes severe vascular injury, when injected in high concentration. In the present study, we investigated the mechanisms for the cytotoxicity of GM on porcine aorta endothelial cells (PAECs). GM (0.5 –5.0 mM) decreased cell viability in a dose-dependent manner and caused cell injury, whilst nafamostat mesilate (NM), another serine protease inhibitor, or mesilate itself had no effect on cell viability. zVAD-fmk, a pancaspase inhibitor, or zDEVD-fmk, a caspase-3 inhibitor, did not affect the GM (1.5 mM)-induced decrease of cell viability. Apoptotic cells or DNA fragmentation were also not observed after GM treatment. Moreover, Ca2+chelators, a nitric oxide (NO) synthase inhibitor, antioxidants, and radical scavengers had no effect on the GM-induced cell injury. On the other hand, cellular ATP content was decreased in the GM (2.0 mM)-treated cells. Surprisingly, GM (2.0 mM) immediately increased cellular uptake of propidium iodine. These findings suggest that GM induces necrotic cell death via injury of the cell membrane.

To clarify the involvement of serine proteases in the development of allergic airway inflammation, we investigated the effect of nafamostat mesilate, a serine protease inhibitor, in a murine model of allergic asthma. Mice were sensitized to ovalbumin (OA) with alum and then exposed to 1% OA for 30 min, three times every 4th day. Nafamostat mesilate was administered orally for 10 days during the allergen challenge. In sensitized mice, repeated allergen challenge induced an increase in tryptase proteolytic activity in bronchoalveolar lavage fluid (BALF). In addition, marked increases in the numbers of inflammatory cells, levels of T helper type 2 (Th2) cytokines and eotaxin in BALF, numbers of goblet cells in the epithelium, and level of OA-specific IgE in serum were observed after repetitive allergen inhalation. Treatment with nafamostat mesilate significantly inhibited not only increased proteolytic activities, but also increases in the numbers of eosinophils and lymphocytes in the BALF. Nafamostat mesilate also dose-dependently inhibited increases in the levels of interleukin-13 and eotaxin in BALF and goblet cell hyperplasia. These findings suggest that increased serine protease activity in the airways is involved in the development of antigen-induced allergic eosinophilic inflammation and epithelial remodeling in bronchial asthma.

Continuous hemodiafiltration (CHDF) has recently been used for treatment of severe acute pancreatitis. CHDF is capable of eliminating small molecules from blood, but whether trypsin can be eliminated by CHDF is not clear. In this study, elimination of trypsin-like enzyme activity (TLE) and cationic trypsin-like immunoreactivity (TLI) using low-volume CHDF was examined at the first CHDF session in eight patients with severe acute pancreatitis. CHDF was performed with a polysulfone hemofilter (membrane area, 0.7 m2) and nafamostat mesilate, a protease inhibitor and anticoagulant, at a blood flow rate of 100 ml/min and a filtration and dialysis flow rate of 10 ml/min each. Before beginning CHDF, plasma TLE was 3.41 ± 2.86 nmol/(ml·min), and TLI was 5,900 ± 9,008 ng/ml. The average plasma clearances of TLE and TLI achieved by the circuit during the 12-hour therapy were 56.7 ± 4.9 ml/min and 8.0 ± 7.2 ml/min, respectively. The average plasma clearance of TLI into the waste fluid was 2.4 ± 1.6 ml/min whereas TLE was below the measurable sensitivity. The plasma concentration of TLE and TLI remained unchanged. These results indicate that low-volume CHDF using nafamostat mesilate as an anticoagulant can increase trypsin plasma clearance. However, low-volume CHDF is not effective to eliminate the plasma trypsin concentration.

The purpose of this study was to investigate the effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats. The blood concentration-time course and pharmacokinetic parameters of ciclosporin did not significantly change after intravenous injection of ciclosporin (10mg kg−1) in) rats treated with imatinib mesilate (50mg kg−1) as compared with a control. When ciclosporin (10mg kg−1) was orally administered, the time course, area under the curve, bioavailability and peak blood concentration of ciclosporin were significantly increased in rats that had been treated with imatinib mesilate 2 h before ciclosporin administration as compared with the control. Because both drugs are transported via P-glycoprotein and breast cancer resistance protein and metabolized by cytochrome P450 3A2, the interaction of imatinib mesilate with these proteins may be responsible for the increased intestinal absorption of ciclosporin in rats. These results indicate that imatinib mesilate enhanced the intestinal absorption of ciclosporin in rats with only the oral administration of ciclosporin, suggesting that our results support clinical data. In addition, imatinib mesilate may increase the pharmacological effects and possibly toxicity of ciclosporin.

The purpose of this study was to investigate the effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats. The blood concentration‐time course and pharmacokinetic parameters of ciclosporin did not significantly change after intravenous injection of ciclosporin (10mg kg−1) in) rats treated with imatinib mesilate (50mg kg−1) as compared with a control. When ciclosporin (10mg kg−1) was orally administered, the time course, area under the curve, bioavailability and peak blood concentration of ciclosporin were significantly increased in rats that had been treated with imatinib mesilate 2 h before ciclosporin administration as compared with the control. Because both drugs are transported via P‐glycoprotein and breast cancer resistance protein and metabolized by cytochrome P450 3A2, the interaction of imatinib mesilate with these proteins may be responsible for the increased intestinal absorption of ciclosporin in rats. These results indicate that imatinib mesilate enhanced the intestinal absorption of ciclosporin in rats with only the oral administration of ciclosporin, suggesting that our results support clinical data. In addition, imatinib mesilate may increase the pharmacological effects and possibly toxicity of ciclosporin.

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy‐induced myocardial damage might be irreversible and lethal. This in‐vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg−1intraperitoneally and 30 mg kg−1orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK‐MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination‐treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced‐GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre‐existing cardiac dysfunction.

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg−1intraperitoneally and 30 mg kg−1orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.