The effect of FUT-175 (Nafamstat Mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo

Int J Immunopharmacol. 1990;12(1):1-9. doi: 10.1016/0192-0561(90)90062-r.

Abstract

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 C3a, C4a and C5a generation induced by heat aggregated IgG, zymosan and Cobra venom factor with IC50 values in the range of 3-43 microM 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 microgram) 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 C3a, C4a and C5a 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamidines
  • Complement C3a / biosynthesis*
  • Complement C4a / biosynthesis*
  • Complement C5a / biosynthesis*
  • Complement Inactivator Proteins / pharmacology*
  • Exudates and Transudates / immunology
  • Exudates and Transudates / metabolism
  • Guanidines / administration & dosage
  • Guanidines / pharmacology*
  • Humans
  • In Vitro Techniques
  • Indomethacin / administration & dosage
  • Indomethacin / pharmacology
  • Inflammation / immunology*
  • Iodine Radioisotopes
  • Leukocytes / drug effects
  • Male
  • Rabbits
  • Skin / immunology
  • Skin / metabolism

Substances

  • Benzamidines
  • Complement Inactivator Proteins
  • Guanidines
  • Iodine Radioisotopes
  • Complement C3a
  • Complement C4a
  • Complement C5a
  • Indomethacin
  • nafamostat