吸入磷酸二酯酶4抑制剂GSK256066能抑制哮喘患者的过敏原刺激反应
2010/07/05
摘要：GSK256066是一种选择性磷酸二酯酶4抑制剂，可通过吸入给药，从而可减少其副作用。本试验在轻度哮喘患者中评价GSK256066对过敏原诱导的气道反应的作用。
方法：在一项随机、双盲的横断面研究中，24名无激素使用史的特应性哮喘患者，对吸入过敏原存在早期气道反应（EAR）和晚期气道反应（LAR），这些患者采用吸入GSK256066（87.5 mcg，每日一次）或安慰剂连续治疗7天，随后给予过敏原刺激。过敏原刺激后24 h检测乙酰甲胆碱反应性、血浆药代动力学。首要终点是研究GSK256066对LAR的作用。
结果：GSK256066能显著降低LAR。与安慰剂组相比，GSK256066分别将最小平均FEV1和加权平均FEV1减少26.2%（P=0.007）和34.3%（P=0.005）。GSK256066能显著降低EAR。与安慰剂组相比，GSK256066分别将最小平均FEV1和加权平均FEV1减少40.9%（P=0.014）和57.2%（P=0.014）。但GSK256066对抗原致敏前FEV1和抗原致敏后乙酰甲胆碱反应性无显著影响。患者能耐受GSK256066吸入治疗，全身药物水平低。大部分患者在用药后4 h后检测不到血浆药物水平。
结论：GSK256066对EAR和LAR具有保护作用。本文首次采用PDE4抑制剂吸入治疗哮喘。本研究在以下网站注册：clinicaltrials.gov NCT00380354。
(刘国梁 审校)
Singh D, et al. Respir Res. 2010 Mar 1;11(1):26. [Epub ahead of print]
The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma.
Singh D, Petavy F, Macdonald AJ, Lazaar AL, O Connor BJ.
ABSTRACT: GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics.
METHODS: In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR.
RESULTS: GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p=0.007) and 34.3% (p=0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p=0.014) and 57.2% (p=0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects.
CONCLUSIONS: GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma. This study is registered on clinicaltrials.gov NCT00380354.
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小鼠早期病毒感染和过敏原暴露两者相互作用诱导哮喘表现型
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过敏性哮喘患者的气道IL-6水平独立于炎症，但与气道功能下降相关
