Nafamostat mesilate

Chemical structure of nafamostat mesylate

CAS # 82956-11-4

Chemical Formula C21H25N5O8S2

Alternative Name FUT-175, Futhan, Nafamostat mesylate

Molecular Weight 539.6 Da

Description: Nafamostat mesylate, futhan or FUT-175 is a potent, synthetic, broad-spectrum, serine protease inhibitor. Nafamostat mesylate inhibits coagulation, complement proteinases, and Granzyme A. Nafamostat aids in proteomic preservation & stabilization. Nafamostat mesylate inhibits fibrinolysis. Nafamostat is caused by inactivating action on thrombin, plasmin, trypsin, kallikrein, coagulation factors XIIa and Xa, complements C1r and C1s1,2.

Coagulation Pathway (source: What are the anticoagulation options for intermittent hemodialysis?, Andrew Davenport, Nat.Rev.Nephrol. 7, 499-508 (2011))

 

THE ACTION OF NAFAMOSTAT ON CARDIOPULMONARY BYPASS

Initial sequestration of activated neutrophils and plateletmicroaggregates in capillaries are responsible for the inflammatory response associated with cardiopulmonary bypass. We assessed the inhibitory effects of nafamostat mesylate on neutrophil and platelet activation, and on the neutrophil deformability change and microaggregate formation during simulated extracorporeal circulation.

Nafamostat preserved platelet counts and inhibited platelet aggregation. Nafamostat, FUT-175 significantly reduced neutrophil elastase release and F-actin expression. The drug did not modulate the changes of CD11b, L-selectin, or C4d. Whole blood filterability was significantly preserved by nafamostat. Nafamostat preserves blood filterability during recirculation,possibly by suppression of F-actin expression and platelet activation.Nafamostat may reduce neutrophil sequestration and microaggregate formation in the microcirculation during cardiopulmonary bypass3.

The pharmacological inhibition of blood-foreign surface interactionsis an attractive strategy for reducing the morbidity associated with cardiopulmonary bypass. We compared the inhibitory effects of nafamostat mesilate and minimal-dose aprotinin on blood-surface interactionsin clinical cardiopulmonary bypass.

Platelet aggregationwas better preserved at 12 hours after surgery in the nafamostat and aprotinin groups than in the control group. Prothrombin fragment F1.2, thrombin-antithrombin complex and neutrophil elastase levels were significantly reduced by aprotinin, but not by nafamostat as compared with the control group. The 2-plasmin inhibitor-plasmin complex and D-dimer were significantly lowerwith either of the drugs. Aprotinin showed better control of D-dimer than did nafamostat. Nafamostat reduces fibrinolysis during cardiopulmonary bypass,although its effect is not as potent as aprotinin5.

Nafamostat preserved platelet counts and inhibited platelet aggregation. Nafamostat significantly reduced neutrophil elastaserelease and F-actin expression. The drug did not modulate the changesof CD11b, L-selectin, or C4d. Whole blood filterability was significantly preserved by nafamostat. Nafamostat preserves blood filterability during recirculation,p ossibly by suppression of F-actin expression and platelet activation. Nafamostat may reduce neutrophil sequestration and microaggregate formation in the microcirculation during cardiopulmonary bypass6.

Before aortic graft replacement, nafamostat mesilate was administered and the disseminated intravascular coagulation improved. Nafamostat mesilate may be useful for managing disseminated intravascular coagulation associated with chronic aortic dissection7.

Patients undergoing open cardiac surgical procedures with a history of acute stroke pose a difficult management problem. There is always the risk that cardiopulmonary bypass (CPB) and heparinization may induce intracranial hemorrhage. A multicenter study suggests that open cardiac surgical procedures can be performed safely 4 weeks after stroke; however, some patients with acute cardiogenic stroke occasionally require emergency surgery because of uncontrollable heart failure or ongoing thromboembolism.

Heparinized CPB with low systemic heparinization is among the therapeutic options when operating on patients with the risk of intracranial hemorrhage; however, low systemic heparinization could allow clot formation. Nafamostat mesilate has such activities as anticoagulant effect (by inhibiting coagulation factors, XIIa, Xa, and VIIa, along with thrombin), antifibrinolytic activities (by inhibiting tissue-type and urokinase plasminogen activators), and antiplatelet actions. Because of a short half-life of 8 minutes, it has recently been used mainly as an anticoagulant for hemodialysis and extracorporeal membrane oxygenation in patients with bleeding tendencies. Nafamostat mesilate has been widely used in Japan as an alternative anticoagulant agent during hemodialysis, and its in vivo effect as an anticoagulant has been established8.

Extracorporeal membrane oxygenation (ECMO) was successfully used to treat a patient with acute respiratory failure from pulmonary hemorrhage after living-donor lobar lung transplantation with nafamostat mesilate as an anticoagulant. Nafamostat mesilate may be the first choice as an ECMO for patients with a high risk of bleeding ECMO is administered to patients with respiratory and circulatoryfailure in a state of shock accompanied by risk of bleeding.Thus the use of heparin is restrained. Nafamostat mesilate was used as an anticoagulant during ECMO, because acuterespiratory failure caused by pulmonary hemorrhage, accompaniedby high risk of bleeding9.

Nafamostat vs Heparin; Clinical Usage for ECMO

The study investigated the ideal dosage and efficacy of nafamostat mesilate for use with ECMO(extracorporeal membrane oxygenator) in patients with acute cardiac or respiratory failure. 73 consecutive patients received ECMO due to acute cardiacr or respiratory failure between January 2006 and December 2009. To evaluate the efficacy of nafamostat mesilate, we divided the patients into 2 groups according to the anticoagulants used during ECMO suport. All patients of nafamostat mesilate group were male with a mean age of 49.2 yr. Six, 3, 5, and 3 patients were diagnosed with acute myocardial infarction, cardiac arrest, septic chock, and acute respiratory distress syndrome, respectively.

 

Table 1. Patients' clinical characteristics 

jkms-26-945-i001-l

SD, standard deviation; BMI, body mass index; AMI, acute myocardial infarction; ARDS, adult respiratory stress syndrome; ECMO, extracorporeal membrane oxygenation; CPR, cardiopulmonary resustitation; VA, venoarterial; VV, venovenous; SOFA, Sepsis-related Organ Failure Assessment; SAPS, Simplified Acute Physiologic Score; i, initial; p,peak;BUN, blood urea nitrogen; Cr, creatinine; TB, total bilirubin; DB, direct bilirubin; CRRT, continuous renal replacement therapy.

 

Table 2. Comparison of the overall use of exygenators, transfusions, thrombotic and hemorrhagic complications 

jkms-26-945-i002-l

RBC, red blood cell; FFP, fresh frozen plasma; ICH, intracerebral hemorrhage.

 

Table 3. Long-term survival and cause of death according to anticoagulants

jkms-26-945-i003-l

MOF, multiorgan failure; ICH, intracerebral hemorrhage.

 

PROMOSING OINTMENT SOURCE; NAFOMOSTAT IMPROVES THE ABSORPTION EFFICACY.

Nafomostats low molecular weight enables it to easily permeate skin & produce an efficacy of ointment form. It has the advantages of convenient preparation and application and of exerting beneficial effects continuously. It is likely that application of nafamostat ointment to the skin is a very promising method to improve the absorption efficacy of subcutaneously injected insulin in patients with subcutaneous insulin resistance4.

 

 

REFERENCES:

  • Hitomi Y, Ikari N, Fujii S. Inhibitory effect of a new synthetic protease inhibitor (FUT-175) on the coagulation system. Haemostasis 1985;15: 164-168.
  • Fujii S, Hitomi Y. New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin. Biochim Biophys Acta 1981 13; 661:342-345.
  • Yuji Hiramatsu, MD, PhD et al. Nafamostat Preserves Neutrophil Deformability and Reduces Microaggregate Formation During Simulated Extracorporeal Circulation. Ann Thorac Surg 2005; 79:1326-1332
  • Satoshi Kawashima MD et al. Dramatic Improvement of Subcutaneous Insulin Resistance with Nafamostat Ointment Treatment Diabetes care Vol 31, NO. 3, MARCH 2008.
  • Yuichiro Kaminishi, et al Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypassAnn Thorac Surg 2004;77:644-650.
  • Yuji Hiramatsu, MD, PhD et al. Nafamostat Preserves Neutrophil Deformability and Reduces Microaggregate Formation During Simulated Extracorporeal Circulation. Ann Thorac Surg 2005; 79:1326-1332.
  • Kiyohito Yamamoto, MD et al. Effects of Nafamostat Mesilate on Coagulopathy With Chronic Aortic Dissection. Ann Thorac Surg 2009;88:1331-1333.
  • Naoto Morimoto, MD, PhD et al. Cardiopulmonary bypass strategy with low-dose heparin and nafamostat mesilate in cardiac surgery: A safe option for patients with acute stroke. J Thorac Cardiovasc Surg 2012;144:726-728.
  • Kazutoshi Kotani, MD et al. Extracorporeal membrane oxygenation with nafamostat mesilate as an anticoagulant for massive pulmonary hemorrhage after living-donor lobar lung transplantation. J Thorac Cardiovasc Surg 2002;124:626-627.Sang Jin Han, et al. Use of Nafamostat Mesilate as an Anticoagulant during Extracorporeal Membrane Oxygenation, J Korean Med Sci 2011; 26(7):945-950

 

 

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  1. Nafamostat Mesylate
    Nafamostat Mesylate
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