Aziz I, Tan K S, Hall I P, Devlin M M, Lipworth B J
Dept of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, UK.
Eur Respir J. 1998 Sep;12(3):580-4. doi: 10.1183/09031936.98.12030580.
Regular treatment with inhaled long-acting beta2-agonists leads to subsensitivity to their bronchoprotective effects, although the effect of dosing frequency on this subsensitivity is not known. The aim of this study was to assess whether a once-daily dosing regimen with formoterol might be associated with a lesser degree of subsensitivity. In a randomized placebo-controlled double-blind, double-dummy crossover study 10 asthmatics treated with inhaled steroids (mean age 31 yrs, forced expiratory volume in one second (FEV1) 82% predicted) received 1 week of treatment with: formoterol dry powder 24 microg twice daily (08:00 and 20:00 h); formoterol 24 microg once daily (20:00 h); or identical placebo. Adenosine monophosphate (AMP) bronchial challenge was performed 12 h after the first and the last dose of each treatment. There was significant loss of protection with formoterol twice daily between the first and last dose (geometric mean provocative concentration causing a 20% fall in FEV1 (PC20)): 475 versus 129 mg x mL(-1) (a 3.7-fold loss, p=0.006) and with formoterol once daily: 367 versus 127 mg x mL(-1) (a 2.9-fold loss, p=0.005), compared with placebo: 71 versus 75 mg x ml(-1) (nonsignificant). There was no significant difference in the degree of loss of protection between formoterol once and twice daily. For first-dose protection there was a significant difference between active treatments and placebo, but after the last dose the residual protection between active treatments and placebo was not significant. Thus, in patients taking inhaled corticosteroids, regular formoterol 24 micreog once daily induces a similar degree of subsensitivity to adenosine monophosphate bronchial challenge as with formoterol 24 microg twice daily. This in turn suggests that even with a 24-h dosing interval there is the development of tolerance to formoterol by prolonged occupancy of airway beta2-adrenoceptors.
长期吸入长效β2受体激动剂进行治疗会导致对其支气管保护作用产生敏感性降低，尽管给药频率对这种敏感性降低的影响尚不清楚。本研究的目的是评估福莫特罗每日一次给药方案是否与较低程度的敏感性降低有关。在一项随机、安慰剂对照、双盲、双模拟交叉研究中，10名接受吸入性糖皮质激素治疗的哮喘患者（平均年龄31岁，一秒用力呼气量（FEV1）为预测值的82%）接受了为期1周的治疗：福莫特罗干粉24微克，每日两次（08:00和20:00）；福莫特罗24微克，每日一次（20:00）；或相同的安慰剂。在每种治疗的第一剂和最后一剂后12小时进行单磷酸腺苷（AMP）支气管激发试验。福莫特罗每日两次给药时，第一剂和最后一剂之间保护作用显著丧失（导致FEV1下降20%的几何平均激发浓度（PC20））：475对129毫克·毫升-1（丧失3.7倍，p=0.006），福莫特罗每日一次给药时：367对127毫克·毫升-1（丧失2.9倍，p=0.005），而安慰剂组为：71对75毫克·毫升-1（无显著性差异）。福莫特罗每日一次和每日两次给药之间保护作用丧失程度无显著差异。对于第一剂保护作用，活性治疗组与安慰剂组之间存在显著差异，但最后一剂后活性治疗组与安慰剂组之间的残余保护作用无显著差异。因此，在吸入糖皮质激素的患者中，每日一次规律使用24微克福莫特罗与每日两次使用24微克福莫特罗相比，对单磷酸腺苷支气管激发试验产生的敏感性降低程度相似。这进而表明，即使给药间隔为24小时，气道β2肾上腺素能受体的长期占据也会导致对福莫特罗产生耐受性。
