The effect of FUT-175 (nafamstat mesilate) on C3_a, C4_a and C5_a generation in vitro and inflammatory reactions in vivo

FUT-175 is a synthetic protease inhibitor and an inhibitor of the classical and alternate pathways of complement activation. In human serum, FUT-175 inhibited C3_a, C4_a and C5_a generation induced by heat aggregated IgG, zymosan and Cobra venom factor with IC₅₀ values in the range of 3-43 μM depending on the stimulus and the fragments. To assess in vivo anti-inflammatory activity, inflammatory reactions induced in the skin of rabbits were quantitated by using ¹²⁵I-albumin extravasation, ⁵¹Cr-labelled leukocyte accumulation and ⁸⁶RbCl accumulation as a measure of hyperemia. Infusion of FUT-175 at 2 mg/kg/h inhibited all three parameters by 50-80% in dermal reactions induced by killed E. coli, zymosan, immune complexes, the reversed Arthus reaction, zymosan activated plasma (ZAP), f-norleu-leu-phe (FNLP) and LTB₄. In contrast, the response to endotoxin (0.1 μg) was not effected by FUT-175 treatment. The effect of FUT-175 was comparable to that of local or systemic therapy with indomethacin, but unlike indomethacin, the effect of FUT-175 was not reversed by local PGE₂ administration. Furthermore, indomethacin and FUT-175 had additive anti-inflammatory effects. These results suggest that although FUT-175 is a potent inhibitor of C3_a, C4_a and C5_a generation, it has novel and broad anti-inflammatory effects, possibly through actions in addition to complement inhibition as indicated by inhibition of FNLP-, LTB₄- and ZAP-induced reactions.