Lipworth B, Tan S, Devlin M, Aiken T, Baker R, Hendrick D
Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland.
Am J Med. 1998 May;104(5):431-8. doi: 10.1016/s0002-9343(98)00086-2.
In addition to their bronchodilatory effects, beta(2)-agonists protect against bronchoconstriction, such as that caused by methacholine challenge. However, tachyphylaxis to this beneficial effect develops after chronic use of beta(2)-agonists. We studied whether the frequency or dose of treatment with a long-acting beta(2)-agonist (formoterol) affects the degree of bronchoprotection afforded against methacholine challenge and to compare this with the effects of a short-acting beta(2)-agonist (terbutaline).
In a randomized, parallel group, double-blind study at two centers, patients with stable asthma of mild to moderate severity who were treated with inhaled corticosteroids were treated with formoterol 6 micrograms twice daily, 24 micrograms twice daily, 12 micrograms once daily; terbutaline 500 micrograms four times daily; or placebo. Treatments were given by dry powder inhaler for a period of 2 weeks. Of the 72 patients who were enrolled, 67 completed the study. Methacholine challenge was performed to calculate the provocative dose that caused a 20% fall in forced expiratory volume in 1 second at baseline (unprotected) after an initial 1-week run-in without beta(2)-agonists, 1 hour after the first dose of study treatment, and again 1 hour after 7 and 14 days of study treatment.
Each of the four active treatments exhibited significant tachyphylaxis (P < 0.05) to protection against methacholine challenge when comparing first/last dose (as geometric mean protection ratio versus baseline): formoterol 24 micrograms twice daily (9.6-fold/1.6-fold), 12 micrograms once daily (7.1-fold/2.2-fold), 6 micrograms twice daily (6.2-fold/2.3-fold), and terbutaline 500 micrograms four times daily (2.9-fold/2.0-fold). There were no significant differences among treatments after 2 weeks in bronchoprotection against methacholine challenge. For all formoterol regimens, the bronchodilator response 1 hour after inhalation was maintained over the 2-week treatment period. Diurnal control of morning and evening peak flow was significantly better with formoterol 24 micrograms twice daily than with terbutaline.
Tachyphylaxis to bronchoprotection against methacholine challenge develops after 2 weeks of therapy with formoterol, a long-acting beta(2)-agonist, at all three dosage regimens that were tested. In contrast, the bronchodilator effects of formoterol were maintained during the 2 weeks of treatment.
β₂受体激动剂除具有支气管扩张作用外，还能预防支气管收缩，如乙酰甲胆碱激发试验所诱发的收缩。然而，长期使用β₂受体激动剂后会出现对这种有益作用的快速耐受。我们研究了长效β₂受体激动剂（福莫特罗）的治疗频率或剂量是否会影响对乙酰甲胆碱激发试验的支气管保护程度，并将其与短效β₂受体激动剂（特布他林）的效果进行比较。
在两个中心进行的一项随机、平行组、双盲研究中，吸入糖皮质激素治疗的轻至中度稳定哮喘患者被分为以下几组接受治疗：福莫特罗6微克，每日两次；24微克，每日两次；12微克，每日一次；特布他林500微克，每日四次；或安慰剂。通过干粉吸入器给药，为期2周。72名入组患者中，67名完成了研究。在最初1周不使用β₂受体激动剂的导入期后、首次给药后1小时以及研究治疗7天和14天后1小时，进行乙酰甲胆碱激发试验，计算在基线（未保护）时导致第1秒用力呼气量下降20%的激发剂量。
比较首次/末次剂量（作为几何平均保护率与基线相比）时，四种活性治疗方案对乙酰甲胆碱激发试验的保护作用均出现了显著的快速耐受（P<0.05）：福莫特罗24微克，每日两次（9.6倍/1.6倍）；12微克，每日一次（7.1倍/2.2倍）；6微克，每日两次（6.2倍/2.3倍）；特布他林500微克，每日四次（2.9倍/2.0倍）。治疗2周后，各治疗方案在预防乙酰甲胆碱激发试验的支气管保护方面无显著差异。对于所有福莫特罗治疗方案，吸入后1小时的支气管扩张反应在2周治疗期内得以维持。福莫特罗24微克，每日两次在早晚峰流速的日间控制方面显著优于特布他林。
在测试的所有三种剂量方案中，长效β₂受体激动剂福莫特罗治疗2周后，对乙酰甲胆碱激发试验的支气管保护作用出现快速耐受。相比之下，福莫特罗的支气管扩张作用在2周治疗期间得以维持。
