Aziz I, Lipworth B J
Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
Chest. 1999 Mar;115(3):623-8. doi: 10.1378/chest.115.3.623.
Subsensitivity of airway beta2-adrenoceptors develops readily in asthmatics receiving regular long-acting beta2-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid.
Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (+/- SD) FEV1 of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV1 (PC20) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 microg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 microg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte beta2-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol.
There was no significant difference in the geometric mean PC20 after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC20 after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte 02-adrenoceptor density (geometric mean Bmax: fmol/10(6) cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80).
We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated beta2-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with beta2-agonists during an acute episode of bronchoconstriction.
接受常规长效β2激动剂治疗的哮喘患者气道β2肾上腺素能受体容易出现敏感性下降。使用全身性皮质类固醇可迅速逆转这种敏感性下降。本研究的目的是调查使用大剂量吸入性皮质类固醇时是否会产生相同的急性促进作用。
招募了10名稳定的轻至中度哮喘患者，平均年龄27岁，平均（±标准差）第一秒用力呼气容积（FEV1）为2.95升（0.94升），为预测值的81%（15%），均接受吸入性皮质类固醇治疗，对单磷酸腺苷（AMP）有反应，激发浓度使FEV1下降20%（PC20）<200毫克/毫升，纳入一项随机双盲交叉研究。受试者接受两个为期1周的福莫特罗干粉治疗期，每日两次，每次24微克，初始有1周导入期，治疗期间有1周洗脱期。在两个治疗期的最后一剂药物时，分别服用单剂量安慰剂或1600微克布地奈德都保。在首次和最后一次服用福莫特罗后2小时进行AMP激发试验。还在福莫特罗治疗前后测量淋巴细胞β2肾上腺素能受体密度（Bmax）。
比较两个治疗期，首次服用福莫特罗后的几何平均PC20无显著差异：362毫克/毫升对391毫克/毫升。与安慰剂相比，最后一次服用福莫特罗时联合布地奈德的PC20显著更高（p<0.05）：427毫克/毫升对99毫克/毫升，相差4.3倍（95%置信区间[CI]，1.1至16.6）。为了在每个治疗期内进行比较，当福莫特罗与安慰剂联用时，首次和最后一次服用福莫特罗之间存在显著的敏感性下降（p<0.05）：391毫克/毫升对99毫克/毫升，下降3.9倍（95%CI，1.0至15.2），但当福莫特罗与布地奈德联用时则不然：362毫克/毫升对427毫克/毫升，上升1.2倍（95%CI，0.5至2.8）。淋巴细胞β2肾上腺素能受体密度（几何平均Bmax：飞摩尔/10⁶细胞）也显示，福莫特罗与安慰剂联用时显著下调（p<0.05）：服用福莫特罗前为2.53，服用后为1.91，但福莫特罗与布地奈德联用时则不然：服用福莫特罗前为2.43，服用后为2.67。与福莫特罗+安慰剂相比，福莫特罗+布地奈德的Bmax显著更高（p<0.05），相差1.40倍（95%CI，1.09至1.80）。
我们已表明，大剂量吸入布地奈德可迅速逆转服用常规福莫特罗的哮喘患者对AMP支气管保护作用的敏感性下降及相关的β2肾上腺素能受体下调。有必要进一步研究以评估在支气管收缩急性发作期间，高剂量吸入性皮质类固醇是否应与β2激动剂一起尽快给药。
