Wilson A M, Lipworth B J
Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, United Kingdom.
Am J Med. 2000 Mar;108(4):269-75. doi: 10.1016/s0002-9343(99)00435-0.
Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function, surrogate markers of airway inflammation, and tests of adrenal function.
After a 10-day placebo run-in, we evaluated the effects of 200 microg, 400 microg, and 800 microg of inhaled budesonide, each dose given twice daily sequentially for 3 weeks in 26 patients, aged 35 +/- 12 years (mean +/- SD), with mild-to-moderate asthma. Measurements were made of bronchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor.
For measurements of pulmonary function and exhaled nitric oxide, there was a plateau in the mean response to budesonide between 400 microg (low dose) and 800 microg (medium dose) per day, whereas for eosinophilic cationic protein and bronchial challenge, maximal benefits occurred between 800 and 1,600 microg (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway response (fourfold decrease in bronchial hyperreactivity) and minimal systemic response (overnight urinary cortisol greater than 20 nmol), was similar at low-dose (46%) and at high-dose (52%) budesonide. The proportion of patients with a suboptimal therapeutic index, a good airway response with a marked systemic response (overnight urinary cortisol greater than 20 nmol), increased from 4% at low dose to 38% at high dose.
In patients with mild-to-moderate atopic asthma, there were dose-related effects of budesonide on surrogate markers of inflammation (bronchial hyperreactivity and serum eosinophilic cationic protein), although higher doses were associated with adrenal suppression and a decrease in the therapeutic index.
吸入性糖皮质激素对哮喘患者的肺功能和炎症有有益作用，但也会引起全身不良反应，如肾上腺抑制。我们通过比较吸入性糖皮质激素对肺功能、气道炎症替代标志物和肾上腺功能测试的剂量反应效应，评估其在哮喘患者中的治疗指数。
在进行为期10天的安慰剂导入期后，我们评估了26例年龄为35±12岁（平均±标准差）的轻至中度哮喘患者吸入200微克、400微克和800微克布地奈德的效果，每种剂量每日分两次依次给药，持续3周。测量指标包括支气管反应性、呼出一氧化氮（气道炎症标志物）、肺量计、血清嗜酸性阳离子蛋白浓度以及10小时夜间尿皮质醇排泄量。于上午8点及用人促肾上腺皮质激素释放因子刺激后测量血浆皮质醇水平。
对于肺功能和呼出一氧化氮的测量，布地奈德每日平均反应在400微克（低剂量）至800微克（中剂量）之间达到平稳状态，而对于嗜酸性阳离子蛋白和支气管激发试验，最大益处出现在每日800至1600微克（高剂量）之间。对血浆皮质醇水平的影响显示，每日1600微克布地奈德时抑制作用最大。就良好的气道反应（支气管高反应性降低四倍）和最小的全身反应（夜间尿皮质醇大于20纳摩尔）而言，低剂量（46%）和高剂量（52%）布地奈德时具有最佳治疗指数的患者比例相似。治疗指数欠佳（良好的气道反应伴有明显的全身反应，夜间尿皮质醇大于20纳摩尔）的患者比例从低剂量时的4%增至高剂量时的38%。
在轻至中度特应性哮喘患者中，布地奈德对炎症替代标志物（支气管高反应性和血清嗜酸性阳离子蛋白）存在剂量相关效应，尽管较高剂量与肾上腺抑制及治疗指数降低相关。
