Tan K S, Grove A, McLean A, Gnosspelius Y, Hall I P, Lipworth B J
Department of Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom.
Am J Respir Crit Care Med. 1997 Jul;156(1):28-35. doi: 10.1164/ajrccm.156.1.9610113.
There is evidence that downregulation and desensitization of airway beta 2-adrenoceptors (beta 2-AR) develops after continuous exposure to long-acting beta 2-agonists such as formoterol and salmeterol. To investigate the facilitatory effects of acute administration of systemic corticosteroid on bronchodilator subsensitivity, as might occur in the setting of acute asthma, 12 subjects with moderately severe asthma, with a mean FEV1 of 66% predicted, of whom were all receiving inhaled corticosteriod, were randomized to receive either inhaled placebo (PL) or inhaled formoterol (FM) 24 micrograms twice daily for 4 wk in a double-blind crossover study. Subjects were also genotyped in terms of beta 2-Ar polymorphism at loci 16 and 27. A dose-response curve (DRC) and duration-time profile for FM (12 to 108 micrograms) was produced 1 h after administration of placebo tablets and after injection at 3 wk, and 1 h after administration of oral prednisolone, 50 mg, and intravenous hydrocortisone, 200 mg, at 4 wk. Comparisons between treatments were made with area-under-curve (AUC) measurements as the change from baseline. There was a significant rightward shift in the DRC after FM as opposed to placebo for delta FEV1 (as AUC, L.h): 2.51 versus 4.22 (95% CI: 0.54 to 2.89; p = 0.01) and delta FEF25-75 (as AUC, L x 10(3)): 11.30 versus 19.94 (95% CI: 2.12 to 15.12; p = 0.01). This was significantly reversed by steroid (S) for FEV1 (FM versus FM+5): 2.51 versus 3.57 (95% CI: 0.11 to 2.27; p = 0.03) and for FEF25-75: 11.30 versus 18.47 (95% CI: 2.52 to 11.70; p = 0.005). Lymphocyte beta 2-AR density (log Bmax; fmol/10(6) cells) showed significant upregulation 3 h after steroid (FM+5 versus FM): 0.34 versus 0.24 (95% CI: 0.02 to 0.18; p = 0.01). For heart-rate response (as AUC, beats), there was subsensitivity with FM versus PL: 2,700 versus 5,200 (95% CI: 40 to 5,000; p < 0.001), and this was reversed by steroid (FM+5 versus FM): 9,600 versus 2,700 (95% CI: 4,900 to 8,800; p < 0.001). This reversal by systemic corticosteroid appears to be generally independent of beta 2-AR polymorphism at loci 16 and 27. In conclusion, we have demonstrated that bronchodilator subsensitivity occurs after regular inhaled FM in asthmatic patients, and is rapidly reversed by systemic corticosteroid. Thus, in acute asthma, systemic corticosteroid should be administered a soon as possible, in order to restore normal airway beta 2-AR sensitivity, particularly in patients who are receiving regular long-acting beta 2-agonists.
有证据表明，持续接触长效β2-肾上腺素能受体激动剂（如福莫特罗和沙美特罗）后，气道β2-肾上腺素能受体（β2-AR）会发生下调和脱敏。为了研究急性全身性皮质类固醇给药对支气管扩张剂敏感性降低的促进作用（如在急性哮喘发作时可能出现的情况），12名中度重度哮喘患者（预测平均FEV1为66%，均接受吸入性皮质类固醇治疗）被随机分为两组，在一项双盲交叉研究中，一组接受吸入安慰剂（PL），另一组接受吸入福莫特罗（FM）24微克，每日两次，共4周。受试者还就β2-AR基因座16和27处的多态性进行了基因分型。在服用安慰剂片后1小时、第3周注射后1小时以及第4周口服泼尼松龙50毫克和静脉注射氢化可的松200毫克后1小时，绘制了FM（12至108微克）的剂量反应曲线（DRC）和持续时间曲线。以曲线下面积（AUC）测量值作为相对于基线的变化，对各治疗组进行比较。与安慰剂相比，FM给药后，FEV1变化量（以AUC计，L·h）的DRC出现显著右移：2.51对4.22（95%CI：0.54至2.89；p = 0.01），FEF25-75变化量（以AUC计，L×10(3)）：11.30对19.94（95%CI：2.12至15.12；p = 0.01）。对于FEV1（FM组与FM + S组相比）和FEF25-75，这种情况被类固醇显著逆转：2.51对3.57（95%CI：0.11至2.27；p = 0.03）以及11.30对18.47（95%CI：2.52至11.70；p = 0.005）。类固醇给药3小时后，淋巴细胞β2-AR密度（log Bmax；fmol/10(6)细胞）显示出显著上调（FM + S组与FM组相比）：0.34对0.24（95%CI：0.02至0.18；p = 0.01）。对于心率反应（以AUC计，次），FM组相对于PL组存在敏感性降低：2700对5200（95%CI：40至5000；p < 0.001），而这种情况被类固醇逆转（FM + S组与FM组相比）：9600对2700（95%CI：4900至8800；p < 0.001）。全身性皮质类固醇的这种逆转作用似乎总体上与基因座16和27处的β2-AR多态性无关。总之，我们已经证明，哮喘患者定期吸入FM后会出现支气管扩张剂敏感性降低，而全身性皮质类固醇可迅速逆转这种情况。因此，在急性哮喘发作时，应尽快给予全身性皮质类固醇，以恢复气道β2-AR的正常敏感性，特别是对于正在接受常规长效β2-激动剂治疗的患者。
