title: Effect of T-440, a novel type IV phosphodiesterase inhibitor, on allergen-induced immediate and late asthmatic reaction and leukocyte infiltration into the airways of guinea pigs.
abstract: Type IV phosphodiesterase (PDE IV) is expressed in many tissues including airway smooth muscle and inflammatory cells, suggesting that this isozyme has a regulatory role in the pathogenesis of bronchial asthma. We investigated the effect of a novel selective PDE IV inhibitor, T-440, on immediate asthmatic reaction (IAR), late reaction (LAR) and leukocyte infiltration into the airways after allergen challenge in guinea pigs. Inhalation of ovalbumin by sensitized guinea pigs induced an immediate increase in specific airway resistance that peaked at 15 min. LAR was only produced in combination with chronic treatment with metyrapone, an inhibitor of the biosynthesis of adrenocortical steroids, and was suppressed by administration of dexamethasone, suggesting that the expression of LAR is dependent on an intrinsic steroid hormone. These reactions were accompanied by increases in the number of eosinophils and neutrophils recovered in bronchoalveolar lavage fluid. Oral administration of T-440 significantly inhibited IAR, LAR and the infiltration of eosinophils, whereas it suppressed neutrophil accumulation with relative low potency. These findings imply that the inhibition of PDE IV activity is a reasonable target for the management of obstructive airway diseases associated with airway inflammation such as asthma.
authors.affiliation: Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Kaminuma
authors.forename: H
authors.initials: H
authors.lastname: Kikkawa
authors.forename: S
authors.initials: S
authors.lastname: Matsubara
authors.forename: K
authors.initials: K
authors.lastname: Ikezawa
mesh_terms: D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects*; D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*
chemical_list: D000485:Allergens; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; C101791:T 440; D003907:Dexamethasone; D010047:Ovalbumin