title: Pharmacological effects of oral E6123, a novel PAF antagonist, on biological changes induced by PAF inhalation in guinea pigs.
abstract: The effects of a newly synthesized PAF antagonist E6123, (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2, 3,4,5- tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine, on in vivo inhaled PAF-induced pulmonary changes were investigated. E6123 inhibited PAF inhalation-induced bronchoconstriction in guinea pigs with an ED50 value (p.o.) of 1.3 micrograms/kg which was lower than those of other PAF-antagonists such as WEB2347 (ED50 = 26 micrograms/kg) and Y-24180 (ED50 = 12 micrograms/kg). E6123 significantly inhibited PAF inhalation-induced eosinophil infiltration into the bronchiole and trachea, and bronchial hyperreactivity in guinea pigs after oral administration at 1 and 10 micrograms/kg, respectively. E6123 inhibited the PAF-induced increase in intracellular free calcium ion concentration ([Ca2+]i) in guinea pig eosinophils with an IC50 value of 14 nM. The present results suggest that E6123 may be beneficial for the treatment of asthma, in which PAF is assumed to be involved.
authors.affiliation: Tsukuba Research Lab., Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma
authors.forename: H
authors.initials: H
authors.lastname: Tsunoda
authors.forename: M
authors.initials: M
authors.lastname: Shirato
authors.forename: S
authors.initials: S
authors.lastname: Katayama
authors.forename: I
authors.initials: I
authors.lastname: Yamatsu
authors.forename: K
authors.initials: K
authors.lastname: Katayama
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006168:Guinea Pigs; D008168:Lung / Q000473:pathology; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C068034:WEB 2347; 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; C068033:E 6123; D002118:Calcium