Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction.
OBJECTIVE
To evaluate whether the leukotriene (LT) D4 receptor antagonist L-708,738 is therapeutically beneficial in treating horses with recurrent airway obstruction (heaves).


METHODS
12 adult horses with heaves and healthy lung lobes from 20 slaughtered horses.


METHODS
Lung lobes were used for smooth muscle tension and radioligand binding studies. Horses with heaves were given a placebo for 14 days and administered L-708,738 (n = 6; 2.5 mg/kg PO, q 12 h) or dexamethasone (6; 0.04 mg/kg, IV, q 24 h) from days 14 to 28. Pulmonary function was measured weekly for 36 days, and bronchoalveolar cells were collected on days 0,14, and 29 for cytologic examination.


RESULTS
Nanomolar concentrations of L-708,738 were effective at antagonizing LTD4-induced bronchoconstriction and LTD4-receptor binding in lung lobes. Mean peak and trough L708,738 plasma concentrations during the treatment period were 1.54 and 0.28 microM, respectively. On days 21 and 29, lung mechanics were significantly improved in the dexamethasone-treated horses but not in the L-708,738-treated horses. Neither dexamethasone nor L-708,738 had a significant effect on cytologic findings.


CONCLUSIONS
L-708,738 was bioavailable after oral administration and sustained concentrations in plasma during the dosing period that exceeded in vitro efficacy values. However, airway function did not improve, suggesting that either drug concentrations in the lungs were subtherapeutic or that cysteinyl LT may not be important mediators of airway inflammation in heaves. Results provide the first evidence of cysteinyl LT1 receptors in airways of horses.
Lavoie
Jean-Pierre
JP
Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St Hyacinthe, QC, Canada.
Léguillette
Renaud
R
Pasloske
Kirby
K
Charette
Luc
L
Sawyer
Nicole
N
Guay
Daniel
D
Murphy
Terry
T
Hickey
Gerry J
GJ
D000402:Airway Obstruction / Q000188:drug therapy / Q000662:veterinary*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000097:blood / Q000494:pharmacology*; D006734:Horse Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006736:Horses; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists / Q000097:blood / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D012129:Respiratory Function Tests / Q000662:veterinary
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020024:Leukotriene Antagonists; D017998:Leukotriene D4; D003907:Dexamethasone