The University of Manchester, Manchester Academic Health Science Centre, University Hospital Of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK.
Respir Res. 2010 Mar 1;11(1):26. doi: 10.1186/1465-9921-11-26.
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.
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 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR.
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.
GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma.
GSK256066 是一种选择性磷酸二酯酶 4 抑制剂，可通过吸入给药，最大限度地减少潜在的副作用。我们评估了 GSK256066 对轻度哮喘患者气道对变应原挑战反应的影响。
在一项随机、双盲、交叉研究中，24 例初次（EAR）和晚期（LAR）对吸入变应原均有反应的、未经激素治疗的特应性哮喘患者，每天吸入 GSK25606687.5mcg 一次或安慰剂 7 天，然后进行变应原挑战。在变应原后 24 小时测量乙酰甲胆碱反应性。测量血浆药代动力学。主要终点是 LAR 的影响。
与安慰剂相比，GSK256066 显著降低了 LAR，使最小和加权平均 FEV1 的下降分别减少了 26.2%（p = 0.007）和 34.3%（p = 0.005）。GSK256066 显著降低了 EAR，使最小和加权平均 FEV1 的下降分别减少了 40.9%（p = 0.014）和 57.2%（p = 0.014）。对变应原前 FEV1 或变应原后乙酰甲胆碱反应性无影响。GSK256066 耐受性良好，全身暴露量低；大多数受试者在 4 小时后血浆水平无法检测。
GSK256066 对 EAR 和 LAR 具有保护作用。这是第一种在哮喘中显示出治疗潜力的吸入型 PDE4 抑制剂。
