Nafamostat Research Articles

Single-center experience of extracorporeal membrane oxygenation mainly anticoagulated with nafamostat mesilate.

Bleeding remains the chief concern during extracorporeal membrane oxygenation (ECMO). Recently, several studies proposed nafamostat mesilate (NM) as an alternative anticoagulant to heparin due to reduced bleeding complications and comparable thromboembolic episodes. The aim of this study was to evaluate the clinical outcomes of ECMO anticoagulated mainly with NM. This was a retrospective observational case series of patients who were placed on ECMO between January 2011 and December 2017 at Chungnam National University Hospital. The main outcomes were bleeding and thromboembolic episodes. During the study period, a total of 91 ECMO runs on 87 patients were identified. There were 54 veno-venous runs and 37 veno-arterial runs. Among the 87 patients, 47 (54.0%) patients were successfully weaned and 29 (33.3%) survived to discharge. Most of the runs were anticoagulated with NM (n=68, 74.7%), followed by heparin (n=22, 24.2%) and argatroban (n=1, 1.1%). The mean duration of ECMO support was 11.3±11.1 days. The overall incidence of bleeding was 46.2% (n=42); 26 runs were anticoagulated with NM (26/68, 38.2%) and 16 with heparin (16/22, 72.7%) (P=0.005). The overall incidence of thromboembolic episodes was 12.1% (n=11). In the NM group, the incidence of hyperkalemia requiring any type of intervention was 17.6% (n=12). In this single center study, NM appears to be associated with fewer bleeding complications during ECMO without increasing the incidence of thromboembolic episodes.

Preventative Effect of Nafamostat Mesilate Infusion into the Main Pancreatic Duct on Post-ERCP Pancreatitis in a Porcine Model: Initial Pilot Study

Background and Aim: Post endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis is not an uncommon adverse event but may not be avoidable. Various pharmacological and endoscopic techniques have been used to prevent post-ERCP pancreatitis (PEP), but most have been ineffective. The aim of this study was to evaluate the preventative effect of an intrapancreatic duct injection of nafamostat mesilate (NM) on PEP. Methods: This experimental study was conducted on 8 mini pigs. Animals were randomly allocated to a control group (n = 4) and or a NM group (n = 4). Pancreatitis was induced by infusing contrast medium into the main pancreatic duct by ERCP in all animals. After contrast medium injection, NM (50 mg/5 cc) was infused in the NM group and the same amount of 5% dextrose solution was infused in the control group. Twenty-four hours after endoscopic procedures, pancreatic inflammation, edema, vacuolization, necrosis and hemorrhage were evaluated histologically. Results: All animals survived until the end of the experiment. No peri-procedural technical difficulty or adverse event was encountered. Histologic examinations confirmed acute pancreatitis in all animals. In histologic acute pancreatitis scoring, no significant intergroup differences were observed between edema (P = 0.134), leukocyte infiltration (P = 0.356), vacuolization (P = 1.000), or hemorrhage (P = 0.071) scores. However, mean necrosis score was significantly lower in the NM group (1.0) than in controls (1.75, P = 0.024). Conclusion: NM injection into the intrapancreatic duct produced promising results with respect to the prevention of PEP development, especially regarding the prevention of necrosis.

Spontaneous iliopsoas muscle hematoma secondary to disseminated intravascular coagulation caused by nafamostat mesilate allergy: a case study

BackgroundA spontaneous iliopsoas muscle hematoma is relatively rare and often associated with abnormal coagulation. Nafamostat mesilate is an anticoagulant agent that is sometimes used to treat hemodialysis patients at high risk of bleeding. Although severe drug allergy caused by nafamostat mesilate was previously reported, spontaneous iliopsoas muscle hematoma secondary to disseminated intravascular coagulation caused by nafamostat mesilate allergy has not yet been reported.Case presentationSevere nafamostat mesilate allergy occurred in a 78-year-old male patient with a 2-year history of hemodialysis. During hospitalization, disseminated intravascular coagulation occurred followed by a progressive iliopsoas muscle hematoma a few days later. Emergent transarterial lumbar artery embolization was successfully performed.ConclusionFor dialysis patients, a detailed medical history including repeated nafamostat mesilate use and considering an allergy to nafamostat mesilate in differential diagnosis are critical. In addition to early diagnosis, when an iliopsoas hematoma occurs, early intravascular treatment is important.

Correction: Hiroshi Sugano et al. Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells. Cancers 2018, 10, 386.

The authors would like to make a correction to their published paper [...].

The Effects of Nafamostat Mesilate on a Bleeding Risk as an Anticoagulant During Use as a Continuous Renal Replacement Therapy: Systematic Review

The Effects of Nafamostat Mesilate on a Bleeding Risk as an Anticoagulant During Use as a Continuous Renal Replacement Therapy: Systematic Review

Identification of nafamostat mesilate as an inhibitor of the fat mass and obesity-associated protein (FTO) demethylase activity

Nafamostat mesilate is a serine protease inhibitor and used for the treatment of pancreatitis and cancers. The fat mass and obesity-associated protein (FTO) was identified to be a demethylase and played an important role in physiological processes. The aim of this study was to examine the inhibition of Nafamostat mesilate on FTO demethylase activity. A combination of thermodynamic and enzymatic activity studies provides an insight into the recognition of Nafamostat mesilate by FTO. The binding of Nafamostat mesilate to FTO was driven by higher positive entropy changes and smaller negative enthalpy changes. The structural and thermodynamic information provides the basis for the design of more effective inhibitors for FTO. Our results might provide a novel target protein for Nafamostat mesilate.

Oral and maxillofacial surgery in patients undergoing dialysis for advanced renal disease: report of five cases

BackgroundPerioperativemanagement of hemodialysis patients involves many difficulties. High mortality rate and circulatory or respiratory complications in these patients were reported. However, in such reports, there is no concrete information of perioperative management in hemodialysis patients to prevent surgical complications and successful outcomes.Case presentationWe retrospectively reviewed the cases of 5 hemodialysis patients who underwent oral surgery under general anesthesia between January 2005 and December 2017.Primary disease was oral squamous cell carcinoma (SCC) in 4 patients and mandibular ameloblastoma in 1 patient. Partial resection was performed in 2 cases, neck dissection in 1 case. Two cases underwent surgery including vascularized reconstruction. The patients were dialyzed the day before and after surgery for the control of fluid and electrolyte status. Patients received intraoperative and postoperative intravenous infusion of potassium-free solution at 20–40 mL/h. Erythropoiesis-stimulating agents (ESAs) were used on the day of hemodialysis during hospitalization. Nafamostat mesilate as an anticoagulant during hemodialysis were used from postoperative day (POD)1 to 7. From POD 1 to 10, cephalosporin as prophylactic antibiotics is adjusted to quarter from half the initial dose. The resuming time of oral intake was similar to that of other oral surgery patients without kidney disease. The daily intake limits of protein, salt and liquid were managed during hospitalization and no cases suffered from malnutrition. No cardiorespiratory complications occurred during the perioperative period. In a case of vascularized osteocutaneous scapular flap reconstruction, grafted scapular bone survived and scapular cutaneous flap necrotized. Necrotic tissue was debrided and split thickness skin was successfully used to cover the grafted scapular bone.ConclusionsPostoperative better result could be achieved if adequate perioperative management specific to hemodialysis patients is carried out. Vascularized flap reconstruction at oral and maxillofacial region in hemodialysis patients is beneficial treatment. Even if the first flap has wound complication secondary flap reconstruction is success and aesthetically better results could be achieved by the strict wound management and debridement.

Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells.

Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.

The effect of Nafamostat Mesilate infusion into main pancreatic duct on the prevention of post-ERCP pancreatitis in porcine model

The effect of Nafamostat Mesilate infusion into main pancreatic duct on the prevention of post-ERCP pancreatitis in porcine model

Continuous hemofiltration model using porcine blood for comparing filter life.

The purpose of the present study was to establish a continuous hemofiltration model using porcine blood to compare filter life. Continuous hemofiltration (CHF) experiments were performed using an in vitro hemofilter evaluation system utilizing porcine blood containing trisodium citrate in addition to nafamostat mesilate as anticoagulants. The lifetime of the hemofilter was evaluated using the transmembrane pressure and the pressure drop across the hemofilter at varying trisodium citrate concentrations. The porcine blood used in this experiment was considered to be in a slightly hypercoagulable state because of the continuous contact with non-biological materials and calcium inflow from substitution fluid. Blood containing 7 or 8mM of trisodium citrate and nafamostat mesilate could be effectively used to compare the lifetimes of hemofilters utilized under the same conditions. In this CHF model using porcine blood, the plugging of the hollow fibers occurred shortly after the plugging of the membrane pores. In conclusion, a CHF model using porcine blood can be established by adjusting the concentration of trisodium citrate added to the blood.

Tu1373 - The Effect of Nafamostat Mesilate Infusion Into Main Pancreatic Duct on the Prevention of Post-ERCP Pancreatitis

Tu1373 - The Effect of Nafamostat Mesilate Infusion Into Main Pancreatic Duct on the Prevention of Post-ERCP Pancreatitis

Validation of Nafamostat Mesilate as an Anticoagulant in Extracorporeal Membrane Oxygenation: A Large-Animal Experiment.

BackgroundUnfractionated heparin is commonly used for anticoagulation in extracorporeal membrane oxygenation (ECMO). Several studies have shown that nafamostat mesilate (NM) has comparable clinical outcomes to unfractionated heparin. This study compared anticoagulation with NM and heparin in a large-animal model.MethodsBeagle dogs (n=8; weight, 6.5–9 kg) were placed on venovenous ECMO. Blood samples were taken every hour and the following parameters were compared: hemoglobin level, activated partial thromboplastin time (aPTT), thromboelastography (TEG) data, platelet function, and inflammatory cytokine levels.ResultsIn both groups, the aPTT was longer than the baseline value. Although the aPTT in the NM group was shorter than in the heparin group, the TEG parameters were similar between the 2 groups. Hemoglobin levels decreased in both groups, but the decrease was less with NM than with heparin (p=0.049). Interleukin (IL)-1β levels significantly decreased in the NM group (p=0.01), but there was no difference in the levels of tumor necrosis factor alpha or IL-10 between the 2 groups.ConclusionNM showed a similar anticoagulant effect to that of unfractionated heparin, with fewer bleeding complications. NM also had anti-inflammatory properties during ECMO. Based on this preclinical study, NM may be a good alternative candidate for anticoagulation in ECMO.

Nafamostat mesilate attenuates inflammation and apoptosis and promotes locomotor recovery after spinal cord injury.

Spinal cord injury (SCI) leads to severe neural damage for which there is currently no effective treatment. Exploration of the neuroprotective effect among clinically approved drugs will speed up clinical translation of SCI. Nafamostat mesilate (NM) as a synthetic serine protease inhibitor has been used clinically in pancreatitis treatments. However, its effectiveness in SCI is unknown. The aim of this study was to confirm the efficacy of NM in ameliorating SCI. Intraperitoneal administration of NM was performed on a contusion SCI model in Wistar rat. Hematoxylin and eosin staining (H&E staining) and Luxol fast blue (LFB) staining were used to observe the histological lesions. Apoptosis was examined by TUNEL staining, Annexin V-FITC/PI, caspase-3, and Bcl-2. Cytokines and neurotrophins were tested by Western blot. Locomotion recovery assessed by hindlimb BBB score and the inclined plane test. Nafamostat mesilate treatment significantly improved locomotion recovery as assessed by hindlimb BBB scores and the inclined plane test. H&E staining and LFB staining showed a significant increase in spared tissue in both gray matter and white matter. NM decreased the expression of the proinflammatory cytokines TNF-α and IL-6. In addition, apoptosis was also significantly decreased, as shown by TUNEL staining and Annexin V-FITC/PI and by Western blotting for caspase-3 and Bcl-2 expression. Due to the mechanism of action of NM as a serine protease inhibitor, the drug decreased thrombin expression in the damaged spinal cord. Furthermore, NM increased the expression of neurotrophins (NT-3, BDNF, and NGF). Upon NM treatment, the functional and histological outcomes were improved, and microenvironment upon SCI was modulated. As a clinically approved drug, NM holds promise for clinical use after spinal cord injury.

Treatment strategy for successful hepatic resection of icteric liver.

The treatment strategy for jaundiced patients with hilar cholangiocarcinoma (HC) is not well established. In this study, we evaluate the feasibility of our perioperative protocol for jaundiced patients with HC. Twenty patients with HC who underwent hepatic resection at our institute were enrolled, and patients were divided into icteric(n=6) and normal(n=14) group. As a perioperative protocol, Oral administration of Inchinkoto(ICKT), steroid and nafamostat mesilate were introduced. The evaluation of functional future remnant liver(FRL) by asiaroscintigraphy, and postoperative outcomes were retrospectively compared. Indocyanine green dye retention rate at 15 minutes was higher, and LHL15 values was lower in icteric group. However, in the functional evaluation of FRL, which was the sum of GSA uptake of the future FRL, there was no significant difference of LHL15 values of the remnant liver functional reserve between the two groups. As results, according to the difference of liver function, serum AST level was not different between two groups. The number of patients with postoperative morbidity in the two groups was comparable. Even in HC patients with icteric liver, accurate assessment of liver functional reserve and effective perioperative treatment may attribute to successful hepatectomy and favorable post-operative outcomes. J. Med. Invest. 65:37-42, February, 2018.

Current Practices in Acute Blood Purification Therapy in Japan and Topics for Further Study.

Continuous venovenous hemodiafiltration is the modality of choice for acute blood purification therapy at almost all medical institutions in Japan. Nafamostat mesilate, an ultrashort-acting anticoagulant, is widely used for anticoagulation. Due to restrictions imposed by national health insurance, Japanese institutions use an effluent flow rate of 15 mL/kg/h, which is lower than the standard effluent flow rate used in the West. In addition, hemofilters are believed to adsorb cytokines, and thus some institutions also proactively perform continuous renal replacement therapy with a hemofilter at an early stage for cytokine modulation in patients with sepsis. Although some aspects of these Japanese practices differ greatly from Western practices, there has not been much evidence to support current standard methods. Therefore, Japanese researchers must continue working to produce evidence for those methods, at least those that are widely used in Japan.

Study on the site and dose of nafamostat mesilate administration in cases of continuous hemodiafiltration using the AN69ST membrane hemofilter

Study on the site and dose of nafamostat mesilate administration in cases of continuous hemodiafiltration using the AN69ST membrane hemofilter

C-Kit receptor and tryptase expressing mast cells correlate with angiogenesis in breast cancer patients.

C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic-pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients. It has been found a strong correlation between MVD and MCDPT, and MCs-c-KitR, MVD and MCs density positive to tryptase (MCDPT), and MCs-c-KitR and MCDPT by Pearson correlation. These data suggest an involvement of both MCDPT and MCs-c-KitR in BC tumor angiogenesis. Furthermore, BC tissue expressing c-KitR could be a putative predictive factor to c-KitR-TK inhibitors. In this way, selected patients with higher MCs-c-KitR could be candidate to receive c-KitR-TK inhibitors (e.g. masitinib, sunitinib) or tryptase inhibitors (e.g. nafamostat mesilate, gabexate mesilate).

Nafamostat mesilate negatively regulates the metastasis of triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) lacking of oestrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2 is a highly malignant disease which results in a poor prognosis and rare treatment options. Despite the use of conventional chemotherapy for TNBC tumours, resistance and short duration responses limit the treatment efficacy. Therefore, a need exists to develop a new chemotherapy for TNBC. The aim of this study was to examine the anti-cancer effects of nafamostat mesilate (NM), a previously known serine protease inhibitor and highly safe drug on breast cancer cells. Here, we showed that NM significantly inhibits proliferation, migration, and invasion in MDA-MB231 cells, induces G2/M phase cell-cycle arrest, and inhibits the expression of cyclin-dependent kinase 1 (CDK1). Exposure of MDA-MB231 cells to NM also resulted in decreased transcription factor activities accompanied by the regulated phosphorylation of signalling molecules and a decrease in metalloproteinases, the principal modulators of the extracellular environment during cancer progression. Especially, inhibition of TGFβ-stimulated Smad2 phosphorylation and subsequent metastasis-related gene expression, and downregulation of ERK activity may be pivotal mechanisms underlying inhibitory effects of NM on NM inhibits lung metastasis of breast cancer cells and growth of colonized tumours in mice. Taken together, our data revealed that NM inhibits cell growth and metastasis of TNBC cells and indicated that NM is a multi-targeted drug that could be an adjunct therapy for TNBC treatment.

Nafamostat mesilate, a serine protease inhibitor, suppresses interferon-gamma-induced up-regulation of programmed cell death ligand 1 in human cancer cells

Programmed cell death ligand-1 (PD-L1) plays a pivotal role in the suppression of antitumour immunity by binding to programmed cell death-1 (PD-1) on tumouricidal cytotoxic T lymphocytes (CTLs), rendering them inactive. As blockade of PD-1/PD-L1 interaction by the monoclonal antibodies induced effective T cell-mediated antitumour response, suppression of PD-L1 expression in tumour cells by the chemical agent might contribute to treatment against malignant tumours. Nafamostat mesilate (NM), a serine protease inhibitor that is frequently used in the clinic, potently suppressed interferon-gamma (IFN-gamma)-induced up-regulation of PD-L1 in cultured human lung cancer cells (HLC-1) at both the messenger RNA (mRNA) and protein levels. Interestingly, suppression of IFN-gamma-induced up-regulation of human leukocyte antigen (HLA)-ABC by NM was limited, suggesting that NM did not block CTL responses to tumour cells. NM treatment did not affect the activation status of signal transducer and activator of transcription (STAT) 1 or the induction of interferon regulatory factor (IRF)-1 expression in IFN-gamma-treated HLC-1 cells. Although NM treatment promoted the phosphorylation of extracellular signal-regulated kinases (Erk) 1/2, an Erk inhibitor, U0126, could not reverse the suppression of PD-L1 up-regulation by IFN-gamma. Suppression of IFN-gamma-induced up-regulation of PD-L1 by NM was not associated with the inhibition of nuclear factor kappa B (NF-kB) or protease-activated receptor (PAR)-1 pathway. Besides HLC-1 cells, NM suppressed IFN-gamma-induced PD-L1 up-regulation in three human pancreatic cancer cell lines. NM could potentiate the antitumour effect of cancer vaccines or immune checkpoint inhibitors by preventing IFN-gamma-induced PD-L1 up-regulation and blocking immune checkpoint suppression.

Adsorption of Nafamostat Mesilate on AN69ST Membranes: A Single-Center Retrospective and In Vitro Study.

We examined whether AN69ST (acrylonitrile and methallyl sulfonate copolymer) membranes adsorb nafamostat mesilate. This study retrospectively analyzed 87 continuous hemodiafiltration sessions in vivo. We divided the continuous hemodiafiltration sessions into AN69ST and non-AN69ST groups using the nafamostat mesilate dose and activated clotting time as indicators of nafamostat mesilate adsorption onto the membrane. Furthermore, we studied the in vitro adsorption of nafamostat mesilate from nafamostat mesilate solutions onto four different hemodialysis membranes. This in vivo study shows that nafamostat mesilate doses were significantly higher, but activated clotting times were shorter (P < 0.001) in the AN69ST group than in the non-AN69ST group. These results suggest that AN69ST adsorbs nafamostat mesilate. Further, the in vitro experiments show that nafamostat mesilate adsorbs AN69ST on membranes significantly more than the other membranes tested. These in vitro and clinical findings provide evidence that AN69ST may adsorb nafamostat mesilate.