Lipworth B J, Dempsey O J, Aziz I, Wilson A M
Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
Am J Med. 2000 Aug 1;109(2):114-21. doi: 10.1016/s0002-9343(00)00454-x.
In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta(2)-adrenoceptor polymorphism, which predisposes them to agonist-induced down-regulation and desensitization of the beta(2)-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta(2)-agonist (inhaled formoterol, 12 microg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype.
We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine that produced a 20% decline in forced expiratory volume in 1 second [FEV(1)]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose of each treatment.
Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9-fold) for formoterol. As compared with placebo, zafirlukast caused a significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant (P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo.
Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta(2)-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.
在英国，约40%的哮喘患者β2肾上腺素能受体甘氨酸16位点存在纯合子多态性，这使他们易于出现激动剂诱导的β2肾上腺素能受体下调和脱敏。我们评估了在吸入糖皮质激素治疗基础上，加用长效β2激动剂（吸入用福莫特罗，每日2次，每次12微克）或白三烯受体拮抗剂（口服扎鲁司特，每日2次，每次20毫克）对该基因型患者的影响。
我们纳入了24例正在接受吸入糖皮质激素治疗的轻至中度哮喘患者。患者以交叉方式随机分配接受三种治疗之一（安慰剂、扎鲁司特或福莫特罗加吸入糖皮质激素），每种治疗为期1周，中间间隔1周的安慰剂导入期和洗脱期。在每次治疗前及每次治疗最后一剂后12小时，测量支气管保护作用（以引起1秒用力呼气量[FEV(1)]下降20%的乙酰甲胆碱激发剂量衡量）、呼出一氧化氮（气道炎症的替代标志物）和症状。
与安慰剂相比，福莫特罗和扎鲁司特在维持哮喘控制方面同样有效：扎鲁司特的乙酰甲胆碱激发剂量几何平均倍数差异为1.5倍（95%置信区间[CI]：1.1至2.2倍），福莫特罗为1.9倍（95%CI：1.2至2.9倍）。与安慰剂相比，扎鲁司特使呼出一氧化氮显著降低（几何平均值差异为1.7倍，95%CI：1.1至2.6倍），而福莫特罗未使其降低（差异为1.2倍，95%CI：0.8至1.9倍）。日记卡显示，与安慰剂相比，福莫特罗（早晨和晚上）和扎鲁司特（晚上）使峰值流速有显著（P<0.05）改善。
福莫特罗和扎鲁司特可维持可能因基因因素对长效β2激动剂反应较差的患者的哮喘控制。扎鲁司特使呼出一氧化氮降低，提示其除了具有吸入糖皮质激素的作用外，可能还具有抗炎作用。
