*Asthma and Allergy Research Group, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, U.K.
Clin Sci (Lond). 2014 Dec;127(11):635-43. doi: 10.1042/CS20140249.
The murine asthma model shows that switching off airway β2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 μg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 μg/day compared with placebo plus HFA-BDP at 400 μg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 μg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.
在小鼠哮喘模型中，使用反向激动剂阻断气道β2 受体可能具有抗炎作用以及皮质类固醇节省作用。我们评估了与高剂量 ICS 相比，添加到低剂量吸入皮质类固醇（ICS）中的普萘洛尔（一种反向激动剂）是否具有皮质类固醇节省作用。在轻度至中度持续性哮喘患者中进行了一项随机、双盲、安慰剂对照交叉试验。在使用氢氟烷烃-倍氯米松二丙酸酯（HFA-BDP）100 μg/天（HFA-BDP100）进行 2 周的预试验（run-in）后，患者接受了为期 4 周的随机治疗（HFA-BDP100 加 80 mg/天的普萘洛尔）与安慰剂加 HFA-BDP400（400 μg/天）（HFA-BDP400）。普萘洛尔在最初的 2 周内逐渐增加到 80 mg/天。噻托溴铵在每次组胺挑战前 5 天共同给药（主要终点）。16 名患者完成了研究[平均年龄 38 岁；用力呼气量第一秒（FEV1），86.4%；组胺引起 FEV1 下降 20%的浓度（PC20），1.39 mg/ml；ICS 剂量 406 μg/天]。与基线（HFA-BDP100）相比，在 HFA-BDP100 中添加普萘洛尔并未改变组胺 PC20[0.17 倍稀释度（dd）差异[95%置信区间（CI）：-0.58 至 0.92]），但与基线相比，HFA-BDP400 有显著改善[1.05 dd（95% CI：0.43-1.66）；P=0.02]，与普萘洛尔+HFA-BDP100 相比也有显著改善[0.88 dd（95% CI：0.45-1.30）；P=0.006]。与普萘洛尔+HFA-BDP100 相比，HFA-BDP400 还显著改善了呼出一氧化氮、血液嗜酸性粒细胞、血清嗜酸性阳离子蛋白和哮喘生活质量问卷症状。与安慰剂+HFA-BDP100 相比，普萘洛尔部分抑制了沙丁胺醇的恢复（中位延长 5 分钟；P=0.002）。普萘洛尔+HFA-BDP100 后夜间家庭 FEV1 也下降[与基线相比平均下降 0.22 升（95% CI：0.10-0.34）；P=0.012]，而哮喘控制问卷无变化。总之，在低剂量 ICS 中使用反向激动剂普萘洛尔并没有改善，而高剂量 ICS 则进一步显著改善了气道高反应性和炎症。因此，普萘洛尔在持续性哮喘中不能提供皮质类固醇节省作用。
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