Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial
Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial
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DOI：
10.1016/s0140-6736(04)17273-5
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发表时间：
2004-10-23
期刊：
影响因子：
168.9
通讯作者：
Drazen, JM
中科院分区：
文献类型：
--
作者：
Israel, E;Chinchilli, VM;Drazen, JM
定期使用吸入性β(2)-肾上腺素能激动剂是否会恶化哮喘患者的气流和临床结果，这一问题一直存在争议。回顾性研究表明，在β(2)-肾上腺素能受体的氨基酸残基16上，基因多态性导致精氨酸（Arg/Arg）而不是甘氨酸（Gly/Gly）纯合的患者会发生不良反应。然而，任何基因型依赖性差异的存在尚未在前瞻性临床试验中进行测试。方法将未使用对照药物的轻度哮喘患者按Arg/Arg基因型（n=37； 41例配对中有4例在随机化前退出）或Gly/Gly基因型（n=41）分为1 s强迫呼气量（FEV1）配对组。定期使用沙丁胺醇或安慰剂进行16周的蒙面交叉治疗。在研究期间，按需停止使用沙丁胺醇，按需使用异丙托溴铵。晨峰呼气流量（PEFR）是主要结局变量。主要比较的是不同基因型的治疗时间；次要结果为基因型效应治疗。分析的目的是治疗。结果在磨磨期，当沙丁胺醇的使用保持在最低限度时，Arg/Arg基因型患者的晨间PEFR增加了23 L/min (p=0.0162)；Gly/Gly基因型患者的变化无统计学意义（2 L/min; p=0.8399）。在随机治疗期间，与安慰剂相比，Gly/Gly基因型患者在定期沙丁胺醇治疗期间早晨PEFR增加（14 L/min [95% CI 3 ~ 251; p=0.0175]）。相比之下，Arg/Arg基因型患者在沙丁胺醇治疗期间的晨间PEFR低于沙丁胺醇使用受限的安慰剂期（-10 L/min[49至-2]；p=0.0209）。因此，基因型归因处理差异为-24 L/min（-37至-12；p=0.0003）。在FEV1、症状和补充缓解药物的使用方面存在类似的基因型特异性效应。β(2)-肾上腺素能受体第16个氨基酸残基的基因型影响对沙丁胺醇使用的长期反应。对于Arg/Arg基因型患者，避免沙丁胺醇的支气管扩张剂治疗可能是合适的。
Background The issue of whether regular use of an inhaled beta(2)-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the beta(2)-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial.Methods Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the, study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat.Findings During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0.0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0.8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 251; p=0.0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [49 to -2]; p=0.0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0.0003). There were similar genotype-specific effects in FEV1, symptoms, and use of supplementary reliever medication.Interpretation Genotype at the 16th aminoacid residue of the beta(2)-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.