• The Journal of Health Technology Assessment
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• v.6 no.2
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• pp.133-141
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• 2018

Objectives: In the past, the pharmaceutical drug heparin was mostly used as the anticoagulant for continuous renal replacement therapy (CRRT), but the duration time is long to have the risk of a bleeding adverse effect, and in that case the drug therapy Nafamostat mesilate was utilized instead, as it is more safe in this case, with a short half-life and is increasing in use to permit lower concerns for bleeding incidents. However, there are insufficient number of large-scale studies on the comparison of Nafamostat mesilate and heparin. Methods: In this study, a systematic review are used to compare the bleeding risk of Nafamostat mesilate and Heparin, as subjected to patients and procedures for measuring risks performed with a CRRT, and the filter life span is to be evaluated as well in this patients. Results: As a result of literature review search, a total of 6 studies were included in systematic review. The reducing risk of bleeding and filter life span was analyzed. The retrospective cohort studies confirm that Nafamostat mesilate is less at risk of bleeding than heparin. And a cohort study confirms that Nafamostat mesilate is longer filter lifespan than heparin and randomized controlled trial studies show that Nafamostat mesilate is longer filter lifespan than not using the anticoagulants. Conclusion: Nafamostat mesilate is considered to be a good therapeutic option because it has a longer filter life span as well as the advantage of reducing bleeding.

• Childhood Kidney Diseases
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• v.18 no.2
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• pp.98-105
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• 2014

Purpose: Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has been investigated as an anticoagulant for adult patients with a high risk of bleeding, who need chronic renal replacement therapy (CRRT). However, little is known about the use of NM as an anticoagulant in pediatric CRRT. The aim of this study was to evaluate the ideal dosage, efficacy, and safety of NM in pediatric CRRT. Methods: We conducted a retrospective study of 40 pediatric patients who had undergone at least 24 h of venovenous CRRTs between January 2011 and October 2013. We divided the patients according to risk of bleeding. Those at high risk received no anticoagulation (group 1) or NM as an anticoagulant (group 2), while those at low risk received heparin (group 3). Results: Forty patients (25 male and 15 female; mean age, $8.2{\pm}6.6$ years) were enrolled. The mean duration of CRRT was 13.0 days, and the survival rate was 57.5%. The mean hemofilter lifespan was 39.3 h in group 1 and 11.3 h in group 3. In group 2, hemofilter lifespan was extended from 7.5 h to 27.4 h after the use of NM (P =0.001). The mean hemofilter lifespan with NM was greater than with heparin (P =0.018). No patient experienced a major bleeding event during treatment with NM. Conclusion: NM may be a good alternative anticoagulant in pediatric patients with a high risk of bleeding requiring CRRT, and is not associated with bleeding complications.

• Journal of Chest Surgery
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• v.51 no.2
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• pp.114-121
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• 2018

Background: Unfractionated 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. Methods: Beagle 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. Results: In 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 $(IL)-1{\beta}$ 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. Conclusion: NM 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.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.5
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• pp.539-545
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• 2016

Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has anticoagulant and anti-inflammatory properties. The intracellular mediator and external anti-inflammatory external signal in the vascular wall have been reported to protect endothelial cells, in part due to nitric oxide (NO) production. This study was designed to examine whether NM exhibit endothelium dependent vascular relaxation through Akt/endothelial nitric oxide synthase (eNOS) activation and generation of NO. NM enhanced Akt/eNOS phosphorylation and NO production in a dose- and time-dependent manner in human umbilical vein endothelial cells (HUVECs) and aorta tissues obtained from rats treated with various concentrations of NM. NM concomitantly decreased arginase activity, which could increase the available arginine substrate for NO production. Moreover, we investigated whether NM increased NO bioavailability and decreased aortic relaxation response to an eNOS inhibitor in the aorta. These results suggest that NM increases NO generation via the Akt/eNOS signaling pathway, leading to endothelium-dependent vascular relaxation. Therefore, the vasorelaxing action of NM may contribute to the regulation of cardiovascular function.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.3
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• pp.229-234
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• 2015

Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$ ). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-${\alpha}$ for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogenactivated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM ($0.01{\sim}100{\mu}g/mL$) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-${\alpha}$ (3 ng/mL), and it dose dependently prevented the TNF-${\alpha}$ -induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-${\alpha}$ -induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-${\alpha}$ -induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation.

• Journal of Chest Surgery
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• v.46 no.6
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• pp.413-425
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• 2013

Background: Graft vessel preservation solution in coronary artery bypass surgery is used to maintain the graft conduit in optimal condition during the perioperative period. Nafamostat mesilate (NM) has anticoagulation and anti-inflammatory properties. Therefore, we investigated NM as a conduit preservative agent and compared it to papaverine. Methods: Sprague-Dawley (SD) rat thoracic aortas were examined for their contraction-relaxation ability using phenylephrine (PE) and acetylcholine (ACh) following preincubation with papaverine and NM in standard classical organ baths. Human umbilical vein endothelial cells (HUVECs) were cultured to check for the endothelial cell viability. Histopathological examination and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were performed on the thoracic aortas of SD rats. Results: The anti-contraction effects of papaverine were superior to those of NM at PE (p<0.05). The relaxation effect of NM on ACh-induced vasodilatation was not statistically different from that of papaverine. Viability assays using HUVECs showed endothelial cell survival rates of >90% in various concentrations of both NM and papaverine. A histopathological study showed a protective effect against necrosis and apoptosis (p<0.05) in the NM group. Conclusion: NM exhibited good vascular relaxation and a reasonable anti-vasocontraction effect with a better cell protecting effect than papaverine; therefore, we concluded that NM is a good potential conduit preserving agent.