Cheung D, Timmers M C, Zwinderman A H, Bel E H, Dijkman J H, Sterk P J
Department of Pulmonology, University Hospital Leiden, The Netherlands.
N Engl J Med. 1992 Oct 22;327(17):1198-203. doi: 10.1056/NEJM199210223271703.
Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma.
In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 micrograms, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC20) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV1).
There was a significant increase in FEV1 one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV1, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC20 was significantly attenuated (P less than 0.001) to only a twofold increase. Two and four days after treatment ended, the PC20 was not significantly different from the value before treatment (P = 0.15).
Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma.
哮喘的特征是气道对支气管收缩刺激的高反应性。长效β2肾上腺素能受体激动剂已作为一种新的治疗方法被引入，但人们越来越担心长期使用这些药物是否会导致哮喘控制情况恶化。我们研究了β2激动剂沙美特罗对轻度哮喘患者支气管扩张及气道对支气管收缩剂乙酰甲胆碱高反应性的长期影响。
在一项平行双盲研究中，24例轻度哮喘患者在为期8周的试验中被随机分为两组，分别接受吸入沙美特罗（50微克，每日两次）（n = 12）或安慰剂（n = 12）治疗。在治疗期之前、期间和之后进行乙酰甲胆碱激发试验。乙酰甲胆碱反应性以引起一秒用力呼气量（FEV1）下降20%的激发浓度（PC₂₀）来衡量。
吸入沙美特罗1小时后FEV1显著增加（P = 0.006），在治疗期的第0、28和56天，FEV1增加量无显著差异（分别为预测FEV1的9.8%、9.4%和8.8%；P = 0.91）。在治疗的第一天，沙美特罗对乙酰甲胆碱诱导的支气管收缩有显著保护作用，与治疗前相比，PC₂₀增加了10倍（P < 0.001）。然而，在治疗4周和8周后，沙美特罗诱导的PC₂₀变化显著减弱（P < 0.001），仅增加两倍。治疗结束后两天和四天，PC₂₀与治疗前的值无显著差异（P = 0.15）。
对轻度哮喘患者长期使用沙美特罗治疗会导致其对支气管收缩刺激（如吸入乙酰甲胆碱）的保护作用产生耐受性，尽管支气管扩张得以维持。这一发现引发了对长效β2肾上腺素能受体激动剂在哮喘长期治疗中有效性的担忧。
