Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Respir Res. 2011 Oct 26;12(1):140. doi: 10.1186/1465-9921-12-140.
Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.
25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.
Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.
This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.
ClinicalTrials.gov: NCT01365533.
磷酸二酯酶 4（PDE4）抑制剂可增加细胞内环腺苷酸（cAMP），从而调节炎症细胞功能。罗氟司特是一种强效且靶向的 PDE4 抑制剂。本研究旨在评估罗氟司特对轻度哮喘患者变应原吸入挑战后支气管收缩、气道高反应性（AHR）和气道炎症的影响。
25 例轻度过敏性哮喘患者随机分为口服罗氟司特 500 mcg 或安慰剂组，双盲、安慰剂对照、交叉研究，每日 1 次，共 14 天。在第 14 天进行变应原挑战，测量用力呼气量（FEV1）直至挑战后 7 小时。在第 1 天（预给药前）、第 13 天（变应原前 24 小时）和第 15 天（变应原后 24 小时）进行乙酰甲胆碱挑战，并在第 1 天、第 13 天、第 14 天（变应原后 7 小时）和第 15 天进行痰诱导。
与安慰剂相比，罗氟司特抑制了变应原引起的晚反应；最大 FEV1 下降百分比（p = 0.02）和曲线下面积（p = 0.01）。罗氟司特在变应原后 7 小时更显著地抑制了变应原引起的痰中嗜酸性粒细胞、中性粒细胞和嗜酸性粒细胞阳离子蛋白（ECP）（均 p = 0.02），并在变应原后 24 小时抑制了痰中中性粒细胞（p = 0.04）、ECP（p = 0.02）、中性粒细胞弹性蛋白酶（p = 0.0001）和 AHR（p = 0.004）。
本研究表明罗氟司特对变应原诱导的气道炎症具有保护作用。观察到痰中嗜酸性粒细胞和中性粒细胞的减少表明 PDE4 抑制具有抗炎作用，并支持这两种细胞类型在迟发性支气管收缩和 AHR 发展中的作用。
ClinicalTrials.gov：NCT01365533。
