Aziz I, McFarlane L C, Lipworth B J
Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Scotland, UK.
Eur J Clin Pharmacol. 1998 Jul;54(5):377-81. doi: 10.1007/s002280050478.
The aim of the present study was to evaluate the effects of concomitant inhaled corticosteroid therapy on the sensitivity of cardiac beta2-adrenoceptors in patients receiving regular long-acting beta2-agonists.
Twelve healthy subjects (6 female), mean age 29 years, were randomised in a double-blind cross-over study to receive either inhaled placebo or inhaled budesonide 1.2 mg twice daily, each for 7 days, with a minimum of 7 days washout period between the two treatments. Patients also received concomitant treatment with inhaled eformoterol 24 microg twice daily during each of the 2 treatment periods. The patients attended the laboratory during both treatment periods at 0730 hours, when a dose-response curve for systemic beta2-adrenoceptor responses to inhaled salbutamol (0.8-3.2 mg) was constructed before and after completing 7 days of each treatment. Early morning (0800 hours) plasma cortisol was also evaluated as a marker of systemic glucocorticoid activity.
There was a significant fall in 0800 hours plasma cortisol induced by budesonide comparing pre- and post-values (407 vs 322 nmol.1(-1), but not with placebo. There were no differences in the response to salbutamol prior to treatment when comparing eformoterol with placebo versus eformoterol with budesonide. Comparing before and after within-treatment heart rate response, there was a significant reduction in peak salbutamol response with eformoterol and placebo, which was partially reversed by eformoterol and budesonide. For between-treatment comparisons after eformoterol treatment, the heart rate was significantly higher in the presence of budesonide in comparison with placebo for peak salbutamol response (change from baseline), i.e. 24.2 vs 34.7 beats min(-l). There was, however, no significant difference in the peak delta potassium response to salbutamol after eformoterol treatment when comparing budesonide with placebo (-0.39 vs -0.48 mmol.1(-1)).
Concomitant therapy with inhaled budesonide resensitised the cardiac beta2-adrenoceptor response to salbutamol in subjects who were receiving regular twice-daily eformoterol. This may be of clinical relevance in terms of the propensity for systemic beta2-mediated adverse effects with repeated puffs of salbutamol, which might conceivably occur in the setting of acute asthma.
本研究旨在评估在接受常规长效β2受体激动剂治疗的患者中，联合吸入糖皮质激素治疗对心脏β2肾上腺素能受体敏感性的影响。
12名健康受试者（6名女性），平均年龄29岁，在一项双盲交叉研究中被随机分组，分别接受每日两次吸入安慰剂或1.2毫克布地奈德，各治疗7天，两种治疗之间至少有7天的洗脱期。在两个治疗期的每个阶段，患者还接受每日两次吸入24微克福莫特罗的联合治疗。在两个治疗期，患者均于0730时到实验室，在完成每种治疗7天后，分别构建吸入沙丁胺醇（0.8 - 3.2毫克）后全身β2肾上腺素能受体反应的剂量反应曲线。清晨（0800时）血浆皮质醇也作为全身糖皮质激素活性的标志物进行评估。
与治疗前相比，布地奈德诱导的0800时血浆皮质醇显著下降（407对322纳摩尔·升⁻¹），而安慰剂组无此现象。在比较福莫特罗与安慰剂以及福莫特罗与布地奈德治疗前对沙丁胺醇的反应时，未发现差异。比较治疗期间心率反应的前后变化，福莫特罗和安慰剂组沙丁胺醇的峰值反应显著降低，福莫特罗和布地奈德可部分逆转此现象。在福莫特罗治疗后的治疗组间比较中，对于沙丁胺醇的峰值反应（相对于基线的变化），布地奈德组的心率显著高于安慰剂组，即24.2对34.7次·分钟⁻¹。然而，在比较布地奈德与安慰剂时，福莫特罗治疗后沙丁胺醇的峰值钾离子反应差异无统计学意义（-0.39对-0.48毫摩尔·升⁻¹）。
在每日两次规律使用福莫特罗的受试者中，联合吸入布地奈德治疗可使心脏β2肾上腺素能受体对沙丁胺醇的反应重新敏感化。就反复吸入沙丁胺醇可能引发全身β2介导的不良反应倾向而言，这可能具有临床相关性，在急性哮喘发作时可能会出现这种情况。
