Lipworth B J, Aziz I
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.
J Allergy Clin Immunol. 1999 Jan;103(1 Pt 1):88-92. doi: 10.1016/s0091-6749(99)70530-0.
Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for bronchoprotective effects. It is not known whether a high dose of short-acting beta2 -agonist could overcome this subsensitivity.
The objective of this study was to investigate the acute effects of a high dose of inhaled albuterol on methacholine-induced bronchoconstriction in patients receiving regular treatment with salmeterol or formoterol.
Ten stable asthmatic subjects (mean age, 34 years; FEV1, 77% of predicted value), all taking inhaled corticosteroids (methacholine PD20 < 500 microg), were recruited into a randomized, single-blind, crossover study. After an initial 1-week run-in period, subjects underwent 3 separate treatment periods each of 9 days (separated by a washout of at least 5 days) comprising inhaled placebo twice daily, inhaled salmeterol dry powder 50 microg twice daily, or inhaled formoterol dry powder 12 microg twice daily. Methacholine challenge was performed 1 hour after the first dose and after 7 days of treatment. After 9 days of treatment, a third methacholine challenge was performed 1 hour after inhalation of a single 1600 microg dose of albuterol dry powder.
There was significant (P <.001) improvement in geometric mean PD20 after the first dose of active treatment as compared with placebo (78 microg) versus salmeterol (266 microg, a 3.4-fold difference [95% CI 1.9 to 6.1]) and versus formoterol (318 microg, a 4.1-fold difference [95% CI 2.3 to 7.3]). This bronchoprotection diminished with regular treatment, although it remained significant (P <.01) compared with placebo (68 microg) versus salmeterol (144 microg, a 2.1-fold difference [95% CI 1.2 to 3.8]) and versus formoterol (230 microg, 3.4-fold difference [95% CI 1.9 to 6.2]). After 9 days, the protection afforded by a single dose of albuterol after placebo pretreatment (889 microg) was significantly (P =.005) higher in comparison with albuterol protection after salmeterol pretreatment (338 microg, a 2.7-fold difference [95% CI 1.1 to 6.8]) and after formoterol pretreatment (247 microg, a 3.6-fold difference [95% 1.4 to 9.1]).
Thus in stable asthmatic subjects receiving regular salmeterol or formoterol, bronchoprotective subsensitivity was not overcome by administering a high dose of albuterol. Further studies are required to evaluate the clinical relevance of this pharmacologic phenomenon when albuterol is used in acute asthma.
长期吸入长效β2受体激动剂治疗与支气管保护作用的敏感性降低有关。高剂量短效β2受体激动剂是否能克服这种敏感性降低尚不清楚。
本研究旨在探讨高剂量吸入沙丁胺醇对接受沙美特罗或福莫特罗常规治疗的患者乙酰甲胆碱诱导的支气管收缩的急性影响。
招募10名稳定期哮喘患者（平均年龄34岁；FEV1为预测值的77%），均吸入糖皮质激素（乙酰甲胆碱PD20<500μg），进行随机、单盲、交叉研究。在最初1周的导入期后，受试者接受3个独立的治疗期，每个治疗期9天（间隔至少5天洗脱期），包括每日2次吸入安慰剂、每日2次吸入50μg沙美特罗干粉或每日2次吸入12μg福莫特罗干粉。在首剂给药后1小时和治疗7天后进行乙酰甲胆碱激发试验。治疗9天后，在吸入单剂量1600μg沙丁胺醇干粉1小时后进行第三次乙酰甲胆碱激发试验。
与安慰剂（78μg）相比，首次给予活性治疗后几何平均PD20有显著改善（P<.001），与沙美特罗（266μg，相差3.4倍[95%CI 1.9至6.1]）和福莫特罗（318μg，相差4.1倍[95%CI 2.3至7.3]）相比也是如此。这种支气管保护作用随常规治疗而减弱，尽管与安慰剂（68μg）相比仍有显著差异（P<.01），与沙美特罗（144μg，相差2.1倍[95%CI 1.2至3.8]）和福莫特罗（230μg，相差3.4倍[95%CI 1.9至6.2]）相比也是如此。治疗9天后，安慰剂预处理后单剂量沙丁胺醇提供的保护（889μg）与沙美特罗预处理后沙丁胺醇保护（338μg，相差2.7倍[95%CI 1.1至6.8]）和福莫特罗预处理后沙丁胺醇保护（247μg，相差3.6倍[95%CI 1.4至9.1]）相比显著更高（P=.005）。
因此，在接受常规沙美特罗或福莫特罗治疗的稳定期哮喘患者中，高剂量沙丁胺醇不能克服支气管保护的敏感性降低。当沙丁胺醇用于急性哮喘时，需要进一步研究评估这种药理现象的临床相关性。
