The arginine-16 β2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol
The arginine-16 β2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol
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DOI：
10.1046/j.1365-2125.2003.01955.x
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发表时间：
2004-01-01
影响因子：
3.4
通讯作者：
Lipworth, BJ
中科院分区：
文献类型：
--
作者：
Lee, DKC;Currie, GP;Lipworth, BJ
目的 β(2)-肾上腺素受体多态性与长效 β(2)-肾上腺素受体激动剂的支气管保护反应之间的关系尚不清楚。方法我们回顾性分析了六项安慰剂对照随机研究的数据，这些研究涉及皮质类固醇治疗的哮喘患者，其中福莫特罗或沙美特罗在 1-2 周内给药，事先 1-2 周冲洗，评估乙酰甲胆碱的主要终点第一次和最后一次剂量后的 PD20 和单磷酸腺苷 PC20 表示为与安慰剂相比剂量差异的两倍。结果 不同研究之间没有显着的异质性。与纯合甘氨酸 16 基因型 (Gly16-Gly16) 相比，含有精氨酸 16 多态性（Arg16-Arg16 或 Arg16-Gly16）纯合或杂合基因型的患者具有更高的支气管保护亚敏感性，相当于平均双倍剂量差异 1.49（95% Cl 0.50， 2.48），最后一次给药后。在所有基因型中，最后一次给药后，福莫特罗的反应敏感性高于沙美特罗，尤其是精氨酸 16 多态性，相当于福莫特罗和沙美特罗之间剂量差异加倍，达 3.00 (95% Cl 1.01, 4.99)。 结论 我们的回顾性分析表明，精氨酸 16 多态性与治疗反应的敏感性相关。福莫特罗的支气管保护作用强于沙美特罗。为了进一步评估这些发现，特别是评估这些差异是否会因病情恶化而反映出来，需要进行前瞻性研究。
Aims The relationship between beta(2)-adrenoceptor polymorphisms and bronchoprotective response with long-acting beta(2)-adrenoceptor agonists is unknown.Methods We retrospectively analysed data from six placebo-controlled randomized studies in corticosteroid treated asthmatics where formoterol or salmeterol were administered over a 1-2-week period, with prior 1-2 week washout, assessing the primary end point of methacholine PD20, and adenosine monophosphate PC20, following first and last dose, expressed as doubling dose difference from placebo.Results There was no significant heterogeneity between the different studies. Patients who had homozygous or heterozygous genotypes containing the arginine-16 polymorphism (Arg16-Arg16 or Arg16-Gly16) had greater bronchoprotective subsensitivity compared with the homozygous glycine-16 genotype (Gly16-Gly16), amounting to a mean doubling dose difference of 1.49 (95% Cl 0.50, 2.48), after the last dose. Subsensitivity of response was greater with formoterol than salmeterol after the last dose in all genotypes, especially with the arginine-16 polymorphism, amounting to a doubling dose difference of 3.00 (95% Cl 1.01, 4.99) between formoterol and salmeterol.Conclusions Our retrospective analysis showed that the arginine-16 polymorphism was associated with subsensitivity of response for bronchoprotection, which was greater for formoterol than salmeterol. A prospective study will be required in order to further evaluate these findings, particularly to assess whether these differences are mirrored by exacerbations.