title: Activity of a novel thienodiazepine derivative as a platelet-activating factor antagonist in guinea pig lungs. Effects on platelet-activating factor and allergen induced eosinophil accumulation.
abstract: Platelet-activating factor (PAF) inhalation in guinea pigs caused a significant increase in the number of eosinophils recovered from bronchoalveolar lavage fluid (BALF). Oral administration of (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 (E-6123), a novel PAF antagonist, at the dose of 100 micrograms/kg completely inhibited the PAF-induced eosinophil accumulation. Antigen inhalation in passively sensitized guinea pigs caused a significant increase in lung contents of PAF at 5 min, and accumulation of eosinophils in the bronchi 1 and 2 days thereafter, E-6123 inhibited the antigen-induced eosinophil accumulation and the maximum inhibition was approximately 65%. On the other hand, methylprednisolone completely inhibited the antigen-induced eosinophil accumulation. The results suggest that PAF is a potent attractant of eosinophils and is involved in antigen-induced eosinophil infiltration into bronchi. The results also suggest that E-6123 may be of therapeutic value in the treatment of asthma exhibiting eosinophil recruitment in airways.
authors.affiliation: Allergy and Asthma Research Unit, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tsunoda
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma
authors.forename: M
authors.initials: M
authors.lastname: Shirato
authors.forename: H
authors.initials: H
authors.lastname: Obaishi
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: N
authors.initials: N
authors.lastname: Shimomura
authors.forename: Y
authors.initials: Y
authors.lastname: Machida
authors.forename: I
authors.initials: I
authors.lastname: Yamatsu
authors.forename: K
authors.initials: K
authors.lastname: Katayama
mesh_terms: D000336:Aerosols; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004804:Eosinophils / Q000187:drug effects*; D006168:Guinea Pigs; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000336:Aerosols; D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C068033:E 6123; D008775:Methylprednisolone