Bhagat R, Swystun V A, Cockcroft D W
Department of Medicine, Royal University Hospital, Saskatoon, Saskatchewan, Canada.
J Allergy Clin Immunol. 1996 Jan;97(1 Pt 1):47-52. doi: 10.1016/s0091-6749(96)70282-8.
Two adverse effects of inhaled beta 2-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of beta 2-agonists versus bronchoconstrictors (e.g., methacholine).
We studied three doses of inhaled salbutamol, 200, 400, and 800 micrograms/day, to determine dose-response curves for these two adverse effects.
Ten atopic patients with mild, stable asthma free of all asthma medications, allergen exposure, and respiratory tract infection for at least 4 weeks participated in a double-blind, random-order, crossover study. There were four 1-week treatment periods with a 1-week washout period: placebo, salbutamol 200 micrograms, 400 micrograms and 800 micrograms per day. After each treatment, we assessed FEV1, bronchodilation 10 minutes after administration of 200 micrograms of salbutamol, methacholine PC20, methacholine dose-shift after administration of 200 micrograms of salbutamol, and allergen PC20.
There was no significant difference in baseline FEV1, bronchodilation, or methacholine PC20. The methacholine dose shift was maximum after the placebo (3.4 +/- 0.22 doubling doses) and was significantly greater (p < 0.01) than all salbutamol regimens (2.2 to 2.6), which were not significantly different from each other (p > 0.05). Allergen PC20 was significantly lower (p < 0.02) after salbutamol 800 micrograms/day (geometric mean = 288 protein nitrogen units [PNU]/ml) than each of the other treatments (447 to 550 PNU/ml), which were not significantly different from each other (p > 0.05).
Significant increase in airway responsiveness to allergen occurred only with the largest dose of inhaled salbutamol (800 micrograms/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 micrograms/day. This suggests different mechanisms may be operative in producing these two effects.
吸入性β2受体激动剂的两个不良反应是气道对过敏原的反应性增加以及与支气管收缩剂（如乙酰甲胆碱）相比，对β2受体激动剂支气管保护作用的耐受性增加。
我们研究了三种吸入沙丁胺醇的剂量，即每天200、400和800微克，以确定这两种不良反应的剂量反应曲线。
10名患有轻度、稳定哮喘的特应性患者，至少4周未使用所有哮喘药物、未接触过敏原且无呼吸道感染，参与了一项双盲、随机顺序、交叉研究。有四个为期1周的治疗期，中间有1周的洗脱期：安慰剂、每天200微克、400微克和800微克的沙丁胺醇。每次治疗后，我们评估了第一秒用力呼气容积（FEV1）、给予200微克沙丁胺醇后10分钟的支气管扩张、乙酰甲胆碱激发试验的PC20（使FEV1下降20%时的乙酰甲胆碱浓度）、给予200微克沙丁胺醇后的乙酰甲胆碱剂量变化以及过敏原激发试验的PC20。
基线FEV1、支气管扩张或乙酰甲胆碱PC_{20}无显著差异。安慰剂后乙酰甲胆碱剂量变化最大（3.4±0.22倍剂量），且显著大于所有沙丁胺醇治疗方案（2.2至2.6）（p<0.01），而各沙丁胺醇治疗方案之间无显著差异（p>0.05）。每天800微克沙丁胺醇治疗后过敏原PC_{20}显著低于其他各治疗方案（几何平均数=288蛋白氮单位[PNU]/毫升）（p<0.02），其他各治疗方案之间无显著差异（447至550 PNU/毫升）（p>0.05）。
仅在吸入最大剂量沙丁胺醇（800微克/天）时气道对过敏原的反应性才显著增加；然而，所有三种沙丁胺醇治疗方案，甚至是每天200微克，均观察到对沙丁胺醇急性支气管保护作用的耐受性。这表明产生这两种效应可能涉及不同的机制。
