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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

Jean-Pierre LavoieDepartment of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St Hyacinthe, QC, Canada J2S 7C6.

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Renaud LéguilletteDepartment of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St Hyacinthe, QC, Canada J2S 7C6.

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Kirby PasloskeMerck & Co Inc, 126 E Lincoln Ave, Rahway, NJ 07065.

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Luc CharetteMerck Frosst, 16711 TransCanada Hwy, Kirkland, QC, Canada H9H 3L1.

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Nicole SawyerMerck Frosst, 16711 TransCanada Hwy, Kirkland, QC, Canada H9H 3L1.

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Daniel GuayMerck Frosst, 16711 TransCanada Hwy, Kirkland, QC, Canada H9H 3L1.

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Terry MurphyMerck & Co Inc, 126 E Lincoln Ave, Rahway, NJ 07065.

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Gerry J. HickeyMerck & Co Inc, 126 E Lincoln Ave, Rahway, NJ 07065.

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Abstract

Objective—To evaluate whether the leukotriene (LT) D4 receptor antagonist L-708,738 is therapeutically beneficial in treating horses with recurrent airway obstruction (heaves).

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)

Abstract

Objective—To evaluate whether the leukotriene (LT) D4 receptor antagonist L-708,738 is therapeutically beneficial in treating horses with recurrent airway obstruction (heaves).

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)