DESCRIPTION: Nafamostat mesylate aka futhan, is a potent, synthetic, serine protease inhibitor. Nafamostat mesylate inhibits coagulation, complement proteinases, and Granzyme A. Nafamostat aids in proteomic preservation & stabilization. Nafamostat is utilized as combination chemotherapy with Gemcitabine for treatment of pancreatic cancer targeting NF-kB Activation1,2.
Nafamostat mesylate inhibits coagulation and fibrinolysis. Nafamostat is caused by inactivating action on thrombin, plasmin, trypsin, kallikrein, coagulation factors XIIa and Xa, complements C1r and C1s3,4.
Initial sequestration of activated neutrophils and plateletmicroaggregates in capillaries are responsible for the inflammatoryresponse associated with cardiopulmonary bypass. We assessedthe inhibitory effects of nafamostat mesylate on neutrophiland platelet activation, and on the neutrophil deformabilitychange and microaggregate formation during simulated extracorporeal circulation.
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, possibly by suppression of F-actin expression and platelet activation. Nafamostat may reduce neutrophil sequestration and microaggregate formation in the microcirculation during cardiopulmonary bypass5.
Nafmostat, protease inhibitors exert beneficial effects on the absorption of subcutaneously injected insulin5. Although the effect of an ointment containing a protease inhibitor has been shown in normal volunteers, there has been no report on the ointments effect in patients with subcutaneous insulin resistance. First report showing that nafamostat ointment is markedly effective in patients with subcutaneous insulin resistance. 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 resistance6.
The brain liver intestine Na_ channel (BLINaC) is a member of the degenerin/epithelial Na_ channel gene family of unknown function. Elucidation of the physiological function of BLINaC would benefit greatly from pharmacological tools that specifically affect BLINaC activity. we discovered in this study that rat BLINaC (rBLINaC) and mouse BLINaC are inhibited by micromolar concentrations of diarylamidines and nafamostat, similar to acid-sensing ion channels. Inhibition was voltage-dependent, suggesting pore block as the mechanism of inhibition. The predominant expression of BLINaC in non-neuronal tissues (Sakai et al., 1999; Schaefer et al., 2000) suggests that it might be involved in epithelial transport, like ENaC (Wiemuth and GrÃ¼nder, 2010)7.
Tryptase, a serine protease stored and released from mast cells granules has been identified as a new non-classical angiogenetic factor. Published in vitro data suggest that tryptase induce angiogenesis in vascular endothelial cells and breast cancer cells lines. According to these data we shown that MVD, MCDPT and C-KREC paralleled to each other suggesting a role in in vivo breast cancer angiogenesis. In this context several tryptase inhibitors such as gabexate mesilate or nafamostat mesylate might be evaluated in clinical trials as a new antiangiogenetic approach8. Tryptase is a serine protease stored in mast cell granules that plays a role in tumor angiogenesis. Mast cells (MCs) can release tryptase following c-Kit receptor activation. On the other hand colo-rectal cancer (CRC) is a well-established angiogenesis dependent tumor and antiangiogenic based therapy is a standard treatment in metastatic CRC. We demonstrated higher serum tryptase levels CRC patients suggesting the release of tryptase from MCs of primary CRC tissue. After radical surgical resection, serum tryptase levels had decreased. We suggest that tryptase may play a role as a new predictive biomarker in CRC patients. In this context several tryptase inhibitors such as gabexate mesilate and nafamostat mesylate might be evaluated as adjuvant treatment in clinical trials8.
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1.) T. Uwagawa et al, Combination Chemotherapy of Nafamostat Mesilate with Gemcitabine for Pancreatic Cancer Targeting NF-kB Activation. Anticancer Research 29: 3173-3178 (2009).
2.) T. Uwagawa et al. Prognostic Factors of Unresectable Pancreatic Cancer Treated with Nafamostat Mesilate Combined with Gemcitabine Chemotherapy Anticancer Res. November 2012 32 (11). 5121-5126.
3.) 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.
4.) Fujii S, Hitomi Y. New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin. Biochim Biophys Acta 1981 13; 661:342-345.
5.) 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.
6.) Paulsen EP, Courtney JW, Duckworth WC: Insulin resistance caused by massive degradation of subcutaneous insulin. Diabetes . 28:640-645, 1979.
7.) Satoshi Kawashima MD et al. Dramatic Improvement of Subcutaneous Insulin Resistance with Nafamostat Ointment Treatment Diabetes care Vol 31, NO. 3, MARCH 2008.
8.) Girolamo Ranieri, et al. Primary breast cancer tryptase expression as novel molecular drug target. Journal of Clinical Oncology, 2012 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 30, No 15_suppl (May 20 Supplement), 2012: e21113.
9.) Dominik Wiemuth and Stefan GrÃ¼nder. The Pharmacological Profile of Brain Liver Intestine Na_Channel: Inhibition by Diarylamidines and Activationby Fenamates Mol Pharmacol . V80:No. 5. 911-919, 2011.