Suppression of the Arthus reaction by Y-24180, a potent and specific antagonist of platelet-activating factor

A novel and potent antagonist of platelet-activating factor (PAF), Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobubylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine) was investigated for the effects on the skin reactions induced by chemical mediators and the Arthus reactions. In the rat dorsal skin, Y-24180 (0.1–10 mg/kg, p.o.) inhibited increase in vascular permeability by the intradermal PAF injection in a dose dependent manner and the inhibitory activity was 60 times more potent than that of WEB 2086. While even at doses as large as 10 mg/kg, p.o., it had no effect on vascular permeability in the rat skin induced by histamine, serotonin, bradykinin and leukotriene D₄. On a reversed passive Arthus reaction in rat dorsal skin, Y-24180 (0.1–1 mg/kg, p.o.) markedly inhibited vascular permeability in a dose dependent manner and the inhibitory activity was 15 times more potent than that of WEB 2086. Y-24180 also inhibited the Arthus dermal reaction in rabbits (0.03–0.3 mg/kg, p.o.) and guinea pigs (0.1–1mg/kg, p.o.). In addition Y-24180 (0.1–10 mg/kg, p.o.) significantly reduced the exudate volume and the number of infiltrated inflammatory cells in the reversed passive Arthus pleural reaction in rats. Furthermore, in rat passive Arthus pancreatitis, Y-24180 (0.3–10 mg/kg, p.o.) significantly inhibited the dye extravasation from the pancreas. These results provide strong evidence that endogenous PAF plays an important role as a mediator in the type III allergic inflammation.