title: Suppression of the Arthus reaction by Y-24180, a potent and specific antagonist of platelet-activating factor.
abstract: A novel and potent antagonist of platelet-activating factor (PAF), Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)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 (0.1-1 mg/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.
authors.affiliation: Research Laboratory, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Okamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Iwahisa
authors.forename: M
authors.initials: M
authors.lastname: Terasawa
mesh_terms: D000818:Animals; D001183:Arthus Reaction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D001381:Azepines / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D008297:Male; D015394:Molecular Structure; D010047:Ovalbumin / Q000276:immunology; D010195:Pancreatitis / Q000188:drug therapy / Q000209:etiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012867:Skin / Q000098:blood supply*; D012871:Skin Diseases / Q000139:chemically induced / Q000209:etiology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C068035:4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine; D010047:Ovalbumin