Inhibition of Various Immunological Reactions in vivo by a New Synthetic Complement Inhibitor

Abstract

FUT-175 (6-amidino-2-naphthyl-4-guanidino benzoate-dimethanesulfonate), a new synthetic protease inhibitor, inhibits the enzyme activities of various proteases, such as C1r, CĪ esterase, thrombin, kalli-krein, plasmin and trypsin. FUT-175 strongly inhibited complement-mediated hemolysis via the classical and alternative pathways. The effects of FUT-175 on various immunological reactions in vivo were studied. The minimal effective dose of FUT-175 in systemic Forssman shock in guinea pigs was 6.25 mg/kg i.p. and 25 mg/kg p.o. In passive Arthus reactions in rats, the effective dose was 25 mg/kg i.p. and 250 mg/kg p.o. FUT-175 also inhibited other immunological reactions, such as passive cutaneous anaphylaxis and delayed hypersensitivity. Furthermore, at a dose of 25 mg/kg i.p. it strongly protected mice from death in endotoxin shock.

Broad-Spectrum and Selective Serine Protease Inhibitors Prevent Expression of Platelet-Derived Growth Factor–BB and Cerebral Vasospasm After Subarachnoid Hemorrhage

“…The synthetic serine protease inhibitor with broad-spectrum FUT-175 (nafamostat mesylate) 18,19 (a gift from Torii Pharmaceutical Co Ltd, Tokyo, Japan) competitively and specifically blocks the active sites of multiple serine proteases, including complement components Clr, Cls, B factor, and D factor; a component of the coagulation system, thrombin; and a component of the fibrinolytic system, plasmin. 18,19 The serine protease inhibitor argatroban (a gift from Mitsubishi Chemical Co, Yokohama, Japan) competitively and selectively blocks the active site of thrombin.…”

“…18,19 The serine protease inhibitor argatroban (a gift from Mitsubishi Chemical Co, Yokohama, Japan) competitively and selectively blocks the active site of thrombin. 20,21 Fifty-four rabbits were randomly divided into 9 groups (nϭ6 each) and used for experiments 1 and 2.…”

Pharmacological Studies of FUT-175, Nafamstat Mesilate I. Inhibition of Protease Activity in in Vitro and in Vivo Experiments

“…1. It has been developed by Torii & Co., Ltd., and its basic biochemical and pharmacological properties have already been published by Fujii and Hitomi (1,2).…”

Anticomplement therapy

“…This molecule inhibits C1r, C1s, C3 convertase, C5 convertase, and FD (Fujii and Hitomi 1981;Inagi et al 1991). Nafamastat mesilate is not entirely complement-specifi c, however, and can inhibit several other plasma proteases (Hitomi and Fujii 1982 C5b,6,7,8,9 (C5b-9) Membrane attack complex C4b,2b C4b,2b C3b,Bb Figure 2 The complement system and its effectors.…”