Effect of a novel leukotoriene synthesis inhibitor, BAY x1005, on the antigen-and LPS-induced airway hyperresponsiveness in guinea pigs.
Due to the inhibition of 5-lipoxygenase-activating protein (FLAP), BAY x1005 is a new selective inhibitor of leukotriene synthesis. The effects of BAY x1005 on the antigen- and bacterial lipopolysaccharide (LPS)-induced airway hyperresponsiveness in guinea pigs were investigated. Six times provocation of aeroantigen caused biphasic increases in airway resistance which peaked at 1 hr (immediate phase reaction) and 4 hrs (late phase reaction). It also caused airway hyperreactivity to acetylcholine. BAY x1005 at doses of 10 mg/kg and 30 mg/kg significantly inhibited antigen-induced increase in respiratory resistance (Rrs) at 1 and 4 hrs after the last antigen challenge. Simultaneously, BAY x1005 inhibited the antigen-induced airway hyperresponsiveness at doses of 10 and 30 mg/kg and airway eosinophilia (bronchoalveolar lavage study) at a dose of 30 mg/kg. In addition, BAY x1005 at a dose of 30 mg/kg inhibited bacterial LPS-induced airway hyperreactivity to acetylcholine. In this model, BAY x1005 did not affect the increase of the number of leukocytes in bronchoalveolar lavage fluid. These results suggest that BAY x1005 is a potent anti-asthmatic agent with an inhibitory action to airway hyperreactivity.
Nagai
H
H
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Takeda
H
H
Uno
T
T
Tanaka
H
H
Matsuo
A
A
D000109:Acetylcholine; D000818:Animals; D000941:Antigens / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D006168:Guinea Pigs; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000276:immunology
D000941:Antigens; D015289:Leukotrienes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D000109:Acetylcholine