title: The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis.
abstract: Leukotrienes are biologically active lipid mediators capable of producing airway inflammation, hyperresponsiveness and bronchoconstriction. The first enzyme in the metabolic pathway of arachidonic acid leading to the leukotrienes is 5-lipoxygenase (5-LO). A selective and potent 5-LO inhibitor, zileuton (N-1(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea, A-64077) was evaluated in models of airway anaphylaxis, where leukotrienes are a major component. In vitro, zileuton inhibited antigen-induced contractions of guinea-pig tracheal strips (GPTS) from actively sensitized animals with an IC50 of 6 microM. Similar results were obtained in human bronchial strips passively sensitized to IgE. Zileuton had little or no effect on contractions elicited by acetylcholine, prostaglandin D2 (PGD2), or the thromboxane agonist, U-44069. In anesthetized sensitized guinea-pigs pretreated with meclofenamic acid and mepyramine, a single aerosol exposure of antigen produced a substantial decrease in dynamic lung compliance (Cdyn). These profound changes in lung function were dose-dependently inhibited by orally administered zileuton (ED50 = 12 mg/kg). These results demonstrate that zileuton is a potent, selective inhibitor of in vitro contraction of GPTS and antigen-induced bronchoconstriction in vivo. These data also confirm the participation of 5-LO products in these models of airway anaphylaxis and suggest the usefulness of the guinea-pig for identifying and characterizing the pulmonary effects of 5-LO inhibitors.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064-3500.
authors.forename: P E
authors.initials: PE
authors.lastname: Malo
authors.forename: R L
authors.initials: RL
authors.lastname: Bell
authors.forename: T K
authors.initials: TK
authors.lastname: Shaughnessy
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
authors.forename: D W
authors.initials: DW
authors.lastname: Brooks
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000707:Anaphylaxis / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016084:Bronchoconstriction / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008469:Meclofenamic Acid / Q000037:antagonists & inhibitors; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011738:Pyrilamine / Q000037:antagonists & inhibitors; D013189:SRS-A / Q000037:antagonists & inhibitors; D014132:Trachea / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007191:Indazoles; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; C054217:ICI 198615; D008469:Meclofenamic Acid; D011738:Pyrilamine; C063449:zileuton; D006918:Hydroxyurea