Objective—To evaluate whether the leukotriene (LT)
D4 receptor antagonist L-708,738 is therapeutically
beneficial in treating horses with recurrent airway
Animals—12 adult horses with heaves and healthy
lung lobes from 20 slaughtered horses.
Procedure—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 L-708,738 plasma concentrations
during the treatment period were 1.54 and
0.28 μM, 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 and Clinical Relevance—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. (Am J Vet Res 2002;63:579–585)