Newnham D M, McDevitt D G, Lipworth B J
Department of Clinical Pharmacology, Ninewells Hospital, Dundee, Scotland, United Kingdom.
Am J Med. 1994 Jul;97(1):29-37. doi: 10.1016/0002-9343(94)90045-0.
The aim of the present study was to evaluate in vivo and in vitro beta 2-adrenoceptor responsiveness after chronic inhaled therapy with the long-acting beta 2-agonist eformoterol or placebo, given twice daily, in patients with mild to moderate asthma.
Seven asthmatic patients, age 34 +/- 5 years were evaluated. Mean forced expiratory volume in 1 second (FEV1) (% predicted) at entry was 58 +/- 5%. After at least 2 weeks run-in without beta 2-agonist therapy, patients were randomized to receive regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily given by metered-dose inhaler for 4 weeks, in a double-blind, crossover design. Dose-response curves (DRC) to eformoterol (cumulative dose 6 micrograms to 126 micrograms) for airways and systemic beta 2-responses were constructed at the end of each treatment period. Responses were measured at baseline, 30 minutes after each dose, and for 6 hours after the last dose. In addition, in vitro parameters of lymphocyte beta 2-receptor function were evaluated prior to the DRC after each treatment period.
There was a nonsignificant trend towards higher baseline values after eformoterol compared with placebo for FEV1: 0.16 L (95% CI -0.04 to 0.36) and forced expiratory flow (FEF25-75): 0.27 L/sec (95% CI -0.08 to 0.62). The peak bronchodilator response from the DRC and response 6 hours after the last dose were both significantly (P < 0.05) attenuated after chronic therapy with eformoterol compared with placebo. The mean differences between eformoterol and placebo for delta FEV1 were as follows: peak: 0.26 L (95% CI 0.09 to 0.43), and at 6 hours: 0.39 L (95% CI 0.20 to 0.58). Corresponding values for delta FEF25-75 were as follows: peak: 0.41 L/sec (95% CI 0.10 to 0.71), 6 hours 0.52 L/sec (95% CI 0.22 to 0.82). Systemic responses were likewise significantly blunted after eformoterol treatment compared with placebo. There was also subsensitivity of lymphocyte beta 2-adrenoceptor function after treatment with eformoterol compared with placebo.
Our results suggest that chronic therapy with eformoterol produces (1) tachyphylaxis to its bronchodilator response, which was greatest at 6 hours after the last dose, (2) tachyphylaxis of extrapulmonary beta 2-mediated responses, and (3) subsensitivity of in vitro beta 2-adrenoceptor function.
本研究旨在评估长效β2激动剂埃福特罗或安慰剂每日两次慢性吸入治疗对轻至中度哮喘患者体内和体外β2肾上腺素能受体反应性的影响。
评估了7例年龄为34±5岁的哮喘患者。入组时第1秒用力呼气量（FEV1）（预计值%）平均为58±5%。在至少2周未使用β2激动剂治疗的导入期后，患者被随机分为两组，采用双盲交叉设计，通过定量吸入器接受为期4周的常规治疗，一组每日两次吸入24微克埃福特罗，另一组每日两次吸入安慰剂。在每个治疗期结束时，构建气道和全身β2反应对埃福特罗（累积剂量6微克至126微克）的剂量反应曲线（DRC）。在基线、每次给药后30分钟以及最后一次给药后6小时测量反应。此外，在每个治疗期的DRC之前评估淋巴细胞β2受体功能的体外参数。
与安慰剂相比，埃福特罗治疗后FEV1的基线值有升高趋势但无统计学意义：升高0.16L（95%可信区间-0.04至0.36），用力呼气流量（FEF25-75）升高0.27L/秒（95%可信区间-0.08至0.62）。与安慰剂相比，埃福特罗慢性治疗后DRC的最大支气管扩张反应和最后一次给药后6小时的反应均显著减弱（P<0.05）。埃福特罗与安慰剂之间δFEV1的平均差异如下：峰值：0.26L（95%可信区间0.09至0.43），6小时时：0.39L（95%可信区间0.20至0.58）。δFEF25-75的相应值如下：峰值：0.41L/秒（95%可信区间0.10至0.71），6小时时0.52L/秒（95%可信区间0.22至0.82）。与安慰剂相比，埃福特罗治疗后全身反应同样显著减弱。与安慰剂相比，埃福特罗治疗后淋巴细胞β2肾上腺素能受体功能也出现亚敏感性。
我们的结果表明，埃福特罗慢性治疗会产生（1）对其支气管扩张反应的快速减敏，在最后一次给药后6小时最为明显，（2）肺外β2介导反应的快速减敏，以及（3）体外β2肾上腺素能受体功能的亚敏感性。
