Disease relevance of Nafamostat

• A synthetic serine protease inhibitor, nafamostat mesilate (NM), which is commonly used for the treatment of pancreatitis and disseminated intravascular coagulation in Japan, also inhibited the secretion of prostasin in M-1 cells [1].
• Potassium secretion in the CCD is tightly linked to sodium reabsorption through EnaC; therefore, NM-induced decrease in prostasin secretion and subsequent inhibition of ENaC activity could account for the side effects of hyponatremia and/or hyperkalemia that are found sometimes in patients treated with NM [1].
• FUT-175 dose-dependently inhibited the classical pathway of complement in a hemolysis protection assay of sensitized sheep erythrocytes with guinea pig serum or by cell-lysis assay of mouse fibroblasts with human serum [2].
• Thus, the co-administration of FUT-175 with retroviruses may make retrovirus-mediated in vivo gene transfer feasible for the treatment of patients [2].
• Protective effects of FUT-175 on acute massive hepatic necrosis induced in mice following endotoxin injection and immunization with liver proteins [3].

High impact information on Nafamostat

• FUT-175 inhibits fibrinolysis and preserves platelet counts and function during CPB and reduces blood loss during open heart surgery [4].
• FUT-175 was infused at a rate of 40 mg/h during cardiopulmonary bypass (CPB) along with 300 IU/kg of heparin in 20 patients undergoing aortocoronary bypass surgery (FUT group) [4].
• These effects were not elicited when an inhibitor of complement activation (FUT-175) was present or when heat-inactivated plasma was used [5].
• In the histological study, it was demonstrated that FUT-175 suppresses the production of platelet-derived growth factor (PDGF)-BB in the neointima and the medial smooth muscle cell layer [6].
• However, increasing the FUT-175 concentration by 10-fold (10 microM) did not produce further protection against retroviral inactivation in most human sera [2].

Chemical compound and disease context of Nafamostat

• FUT-175 did not modify heparin + protamine-induced leukopenia, suggesting that FUT-175 incompletely blocked C5a production [7].
• Preventive effect of synthetic serine protease inhibitor, FUT-175, on cerebral vasospasm in rabbits [8].
• Platelet involvement in the nephritis of acute serum sickness in rabbits: protection by dipyridamole and FUT-175 [9].
• Blood platelet function in canine acute pancreatitis with reference to treatment with Nafamostat mesilate (FUT-175) [10].
• In in vivo experiments, at doses of 0.5-50 micrograms/kg/min, FUT-175 suppressed the elevated protease activities in the experimental acute pancreatitis more potently than gabexate [11].

Biological context of Nafamostat

• RESULTS: Significantly higher platelet membrane GPIb expression and lower plasma beta-thromboglobulin levels were observed in the circuits holding FUT-175, suggesting a lower degree of platelet activation [12].
• BACKGROUND: Nafamostat mesilate (FUT-175) is a synthetic serine protease inhibitor that inactivates coagulation, fibrinolysis, and platelet aggregation [13].
• In the FUT-175 group, prolongation of APTT, no decline in the platelet count and AT-III levels, and normal levels of FDP were observed [14].
• These results indicated that FUT-175 prevents intravascular hemolysis of mouse erythrocytes through the inhibitory effect of both alternative and classical complement pathway [15].
• FUT-175 inhibited the alternative complement pathway-mediated hemolysis with IC50 values of 1.3 X 10(-7) to 4.0 X 10(-7) M [15].

Anatomical context of Nafamostat

• We examined the effect of the synthetic serine protease inhibitor FUT-175 (developed as a potent inhibitor of thrombin and the complement system) on vascular lesions using balloon dilatation-induced neointimal formation in the carotid artery of rats [6].
• The enzymatic activity of human cytotoxic T-lymphocyte granzyme A and cytolysis mediated by cytotoxic T-lymphocytes are potently inhibited by a synthetic antiprotease, FUT-175 [16].
• METHODS AND RESULTS: In the clinical study, 20 patients who underwent coronary artery bypass grafting were divided into 2 groups: group F, in which patients were treated with a serine protease inhibitor (FUT-175, 2 mg/kg per hour) during cardiopulmonary bypass, and group C (untreated patients) [17].
• Both heating of the serum and adding NM to the medium decreased damage of porcine hepatocytes [18].
• Intravenous administration of FUT-175 at a dose of 3 or 10 mg/kg inhibited intravascular hemolysis of mouse erythrocytes regardless of whether it was administered before or after injection of human serum [15].

Associations of Nafamostat with other chemical compounds

• Nafamostat mesilate (FUT-175) is a protease inhibitor inactivating coagulation, fibrinolysis, and platelet aggregation [4].
• In addition, this protease cleaved arginyl or lysyl residue containing substrates selectively and was only inhibited by aprotinin, FUT-175, and soy bean trypsin inhibitor and not by chymostatin, E-64 and iodoacetic acid [19].
• Protease inhibitors including FUT-175, Pefabloc, and E-64d prevented CCK stimulation of intracellular trypsinogen and NF-kappaB activation [20].
• This activation was accompanied by complement activation as detected by C3 cleavage, and was abolished by heat inactivation or by adding the complement inhibitor FUT-175 [21].
• In in vitro experiments, FUT-175 inhibited the pancreatic protease activities 10 to 100 times more potently than gabexate [11].

Gene context of Nafamostat

• FUT-175 inhibits the production of IL-6 and IL-8 in human monocytes [22].
• These data suggest that FUT-175 may reduce the pathological inflammatory conditions associated with enhanced production of proinflammatory cytokines including IL-6 and IL-8 [22].
• FUT-175 was found to inhibit, in an intense, specific and reversible way, the enzyme activities of trypsin, C1r, C1s, thrombin, kallikrein and plasmin with IC50 values of the order of 10(-6)-10(-8) M [23].
• FUT-175 also inhibited complement-mediated hemolysis, including both classical and alternative pathways, sites of inhibition being on C1r and C1s as evidenced by the intermediate-cell technique [23].
• Serum HGF levels on day 0 and day 7 were significantly higher in Group NM than those in Group C [24].

Analytical, diagnostic and therapeutic context of Nafamostat

• Blood concentrations of FUT-175 and activated clotting time increased after cooling, peaking at 2050 +/- 1190 ng/mL and 2136 +/- 983 seconds at the lowest temperature and recovered after rewarming to values of 166 +/- 118 ng/mL and 510 +/- 148 seconds, respectively, at the end of CPB [4].
• Three groups of these rats (n=8, each) were treated with daily intraperitoneal injections of 1 of the following doses of FUT-175: 0.5, 1.0, or 2.0 mg/d in 1 mL of saline for 7 consecutive days [6].
• The incidence of a delayed ischemic neurological deficit significantly decreased from 55% in the control group to 13% in all patients treated with FUT-175 and to 7% in the patients treated with higher doses (P less than 0.05) [25].
• NM thus appears to be a useful and safe anti-coagulant not only for hemodialysis but also for MP in high bleeding risk patients [26].
• Nafamostat mesilate (FUT-175) is a strong protease inhibitor and is used as an anticoagulant in extracorporeal circulation [27].

References