The Use of Nafamostat Mesilate as an Anticoagulant during Continuous Renal Replacement Therapy for Children with a High Risk of Bleeding

이상택,조희연,Lee, Sang Taek,Cho, Heeyeon Korean Society of Pediatric Nephrology 2014 Childhood kidney diseases Vol.18 No.2

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. 목적: Nafamostat mesilate는 출혈성 경향이 있는 성인 환자에서 지속적 신대체 요법시 항응고제로 사용되고 있지만 소아에서의 경험은 잘 알려지지 않았다. 본 연구는 출혈 성향이 높은 소아에서 지속적 신대체 요법을 시행하는 경우에 항응고제로서 Nafamostat mesilate의 용량, 효과, 및 안전성에 대하여 알아보기 위해 수행하였다. 방법: 2011년 1월부터 2013년 10월까지 최소 24시간이상 지속적신대체요법을 받은 40명의 소아환자들을 대상으로 하여 의무기록을 후향적으로 분석하였다. 환자들은 출혈 위험군(그룹 1: 항응고제 사용 안함, 그룹 2: 항응고제로 Nafamostat mesilate 사용)과 출혈 위험이 없는 군(그룹 3: 항응고제로 헤파린 사용)으로 분류하였다. 결과: 40명의 환자 중에서 남아는 25명 여아는 15명 이었으며 평균 나이는 $8.2{\pm}6.6$세 이었다. 지속적신대체요법의 평균 시간은 13일 이었다. 평균 혈액 필터 수명은 그룹 1에서는 39.3시간 이었고, 그룹 3에서는 11.3시간이었다. 그룹 2에서는 Nafamostat mesilate 사용 전에는 7.5시간 이었으나 Nafamostat mesilate 사용 후에는 27.4시간으로 연장되었으며 통계학적으로 유의하였다(P=0.001). 평균 혈액 필터 수명은 Nafamostat mesilate을 사용한 그룹에서는 헤파린을 사용한 그룹보다 통계적으로 의미 있게 연장되었다(P=0.018). Nafamostat mesilate 사용한 군에서 의미있는 출혈이 동반되지는 않았다. 결론: Nafamostat mesilate은 출혈 성향이 높은 소아에서 지속적 신대체 요법을 시행하는 경우에 헤파린을 대체해서 사용될 수 있는 항응고제로 생각된다.

Nafamostat Mesilate 전처치를 시행한 환자에서의 내시경역행담췌관조영술 후 급성췌장염의 위험인자

김일두,강대환,박진현,배정호,김표준,김용욱,최철웅,엄재섭,이선미,김태오,김광하,송근암 대한소화기내시경학회 2008 Clinical Endoscopy Vol.37 No.4

목적: 내시경역행담췌관조영술(ERCP)은 췌장 및 담도 질환의 진단과 치료에 중요한 역할을 하고 있으나 시술에 따른 췌장 손상을 비롯한 다양한 합병증을 유발할 수 있다. 이 중 특히 ERCP 후 급성 췌장염은 때때로 사망까지 초래할 수 있어 임상에서 예방을 위한 전처치와 예측할 수 있는 위험인자를 인지하는 것이 중요하다. 이에 nafamostat mesilate를 예방으로 사용하여 ERCP를 시행한 환자에서 ERCP 후 고아밀라제혈증과 급성 췌장염의 발생률을 알아보고 발생에 관련된 요인들을 전향 분석하여 위험인자들을 알아보고자 하였다. 대상 및 방법: 2005년 4월부터 2006년 4월까지 부산대학교병원에서 ERCP를 시행 받은 247명의 환자를 대상으로 하여 이들에게 예방 목적으로 투여한 nafamostat mesilate의 ERCP 후 고아밀라제혈증과 급성 췌장염의 발생률을 조사하였다. 또한 환자와 시술에 관련된 인자들에 대하여 단변량 및 다변량 분석을 시행하여 ERCP 후 급성 췌장염의 발생에 영향을 미치는 위험 인자들을 분석하였다. 결과: Nafamostat를 투여 받은 총 247명의 환자 중 고아밀라제혈증이 24명(9.7%), ERCP 후 급성 췌장염이 9명(3.6%)에서 발생하였다. ERCP 후 고아밀라제혈증에서는 20분이 넘는 시술 시간, 4회 이상의 췌관 삽관 횟수, 이전 ERCP 후 급성 췌장염의 병력, 총담관 담석이 없는 경우 등이 의미 있는 위험인자로 나타났으며 ERCP 후 급성 췌장염에서는 60세 미만의 나이, 20분이 넘는 시술시간, 4회 이상의 췌관 삽관 횟수, 총담관 담석이 없는 경우 등이 의미 있는 위험인자로 나타났다(p<0.05). 의미 있게 나타났던 변수들에 대하여 다변량 분석을 시행하였을 때, 4회 이상의 췌관 삽관 횟수가 고아밀라제혈증(p=0.038, OR 5.165, 95% CI 1.093∼24.412)과 ERCP 후 급성췌장염(p=0.002, OR 33.122, 95% CI 3.526∼311.138)에서 모두 통계에서 유의한 차이를 보이는 위험인자로 나타났다. 결론: ERCP의 전처치로 nafamostat를 사용한 경우 ERCP 후 고아밀라제혈증은 9.7%, 급성 췌장염은 3.6%에서 발생하였다. ERCP 후 고아밀라제혈증과 급성 췌장염의 발생은 4회 이상의 췌관 삽관 횟수가 독립적인 위험인자로 나타났다.

Cardiac arrest caused by nafamostat mesilate

( Hyo Shik Kim ),( Kyung Eun Lee ),( Ji Hyun Oh ),( Chan Sung Jung ),( Dughyun Choi ),( Yunsuek Kim ),( Jin Seok Jeon ),( Dong Cheol Han ),( Hyunjin Noh ) 대한신장학회 2016 Kidney Research and Clinical Practice Vol.35 No.3

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.

혈액 투석의 항응고제로서 Nafamostat mesilate와 Enoxaparin sodium의 비교

이은경 ( Eeun Kyoung Lee ),조종태 ( Jong Tae Cho ),윤성철 ( Sung Chul Yoon ) 대한신장학회 2008 춘계학술대회 초록집 Vol.28 No.1

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

강혜영,문수지,강영주 한국보건의료기술평가학회 2018 보건의료기술평가 Vol.6 No.2

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.

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

Sunam Mander,유동주,박수미,김동휘,용효정,김동식,Curie Ahn,김윤희,성재영,황종익 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.2

Triple-negative breast cancer (TNBC) lacking ofoestrogen receptor, progesterone receptor, and epidermalgrowth factor receptor type 2 is a highly malignant diseasewhich results in a poor prognosis and rare treatmentoptions. Despite the use of conventional chemotherapy forTNBC tumours, resistance and short duration responseslimit the treatment efficacy. Therefore, a need exists todevelop a new chemotherapy for TNBC. The aim of thisstudy was to examine the anti-cancer effects of nafamostatmesilate (NM), a previously known serine protease inhibitorand highly safe drug on breast cancer cells. Here, weshowed that NM significantly inhibits proliferation,migration, and invasion in MDA-MB231 cells, induces G2/M phase cell-cycle arrest, and inhibits the expression ofcyclin-dependent kinase 1 (CDK1). Exposure of MDAMB231cells to NM also resulted in decreased transcriptionfactor activities accompanied by the regulated phosphorylationof signalling molecules and a decrease in metalloproteinases,the principal modulators of the extracellularenvironment during cancer progression. Especially, inhibitionof TGFb-stimulated Smad2 phosphorylation andsubsequent metastasis-related gene expression, and downregulationof ERK activity may be pivotal mechanismsunderlying inhibitory effects of NM on NM inhibits lungmetastasis of breast cancer cells and growth of colonizedtumours in mice. Taken together, our data revealed thatNM inhibits cell growth and metastasis of TNBC cells andindicated that NM is a multi-targeted drug that could be anadjunct therapy for TNBC treatment.

Nafamostat Mesilate Inhibits TNF-α-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production

강민웅,송희정,강신광,김용환,정샛별,지성주,문재영,서광선,이상도,전병화,김국성 대한약리학회 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.3

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-α (TNF-α ). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α 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∼100 μ g/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-α (3 ng/mL), and it dose dependently prevented the TNF-α -induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-α -induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-α -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.

Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway

Choi, Sujeong,Kwon, Hyon-Jo,Song, Hee-Jung,Choi, Si Wan,Nagar, Harsha,Piao, Shuyu,Jung, Saet-byel,Jeon, Byeong Hwa,Kim, Dong Woon,Kim, Cuk-Seong The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.5

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.

Nafamostat Mesilate Inhibits TNF-${\alpha}$-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production

Kang, Min-Woong,Song, Hee-Jung,Kang, Shin Kwang,Kim, Yonghwan,Jung, Saet-Byel,Jee, Sungju,Moon, Jae Young,Suh, Kwang-Sun,Lee, Sang Do,Jeon, Byeong Hwa,Kim, Cuk-Seong The Korean Society of Pharmacology 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.3

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.

Nafamostat Mesilate Inhibits TNF-α-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production

Min-Woong Kang,Hee-Jung Song,Shin Kwang Kang,Yonghwan Kim,Saet-byel Jung,Sungju Jee,Jae Young Moon,Kwang-sun Suh,Sang Do Lee,Byeong Hwa Jeon,Cuk-Seong Kim 대한생리학회-대한약리학회 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.3

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-α (TNF-α). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α 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∼100 μg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-α (3 ng/mL), and it dose dependently prevented the TNF-α-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-α-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-α-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.