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
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
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DOI：
10.2460/ajvr.2002.63.579
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发表时间：
2002-04-01
影响因子：
1
通讯作者：
Hickey, GJ
中科院分区：
文献类型：
--
作者：
Lavoie, JP;Léguillette, R;Hickey, GJ
目的探讨白三烯（LT）D4受体拮抗剂L-708，738对马反复气道阻塞（heaves）的治疗作用。对出现呕吐的马给予安慰剂14天，并从第14天至第28天给予L-708，738（n = 6; 2.5 mg/kg PO，q12 h）或地塞米松（6; 0.04 mg/kg，IV，q24 h）。每周测量肺功能36天，并收集支气管肺泡细胞在第0，14和29天的细胞学检查。结果纳摩尔浓度的L-708，738是有效的拮抗LTD 4诱导的支气管收缩和LTD 4受体结合在肺叶。在治疗期间，L-708，738血浆浓度的平均峰值和谷值分别为1.54和0.28 μ M。在第21天和第29天，地塞米松给药组马的肺力学显著改善，但L-708，738给药组马无此改善。地塞米松和L-708，738对细胞学结果均无显著影响。结论和临床相关性-L-708，738在口服给药后具有生物利用度，并且在给药期间血浆中的持续浓度超过体外疗效值，但是，气道功能没有改善，提示肺中的药物浓度低于治疗浓度，或者半胱氨酰LT可能不是气喘患者气道炎症的重要介质。结果提供了第一个证据的半胱氨酰LT 1受体在气道的马。
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 muM, 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.