The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis.
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.
Malo
P E
PE
Abbott Laboratories, Abbott Park, Illinois 60064-3500.
Bell
R L
RL
Shaughnessy
T K
TK
Summers
J B
JB
Brooks
D W
DW
Carter
G W
GW
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
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