The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis

• Published in: Pulmonary pharmacology (Edinburgh) Vol. 7; no. 2; p. 73
• Main Authors: Malo, P E, Bell, R L, Shaughnessy, T K, Summers, J B, Brooks, D W, Carter, G W
• Format: Journal Article
• Language: English
• Published: England 01-04-1994
• Subjects: Anaphylaxis - etiology; Anaphylaxis - prevention & control; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Bronchoconstriction - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Humans; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Hydroxyurea - therapeutic use; Indazoles - pharmacology; Lipoxygenase Inhibitors - pharmacology; Lipoxygenase Inhibitors - therapeutic use; Male; Meclofenamic Acid - antagonists & inhibitors; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Pyrilamine - antagonists & inhibitors; SRS-A - antagonists & inhibitors; Trachea - drug effects
• ISSN: 0952-0600
• DOI: 10.1006/pulp.1994.1008

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.