Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease

吸入氟替卡松对阻塞性肺疾病上呼吸道通畅的影响

• 批准号: 8447351
• 负责人: Mihaela Teodorescu
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447351
• 关键词: Address; Adrenal Cortex Hormones; Affect; Asthma; Breathing; Caliber; Chairperson; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical assessments; Data; Department of Defense; Deposition; Deterioration; Development; Diagnosis; Dilator; Disease Management; Dose; Fatty acid glycerol esters; Fluticasone propionate; Foundations; Functional disorder; Future; Goals; Guidelines; Hearing; High Prevalence; Hypoxia; Individual; Inflammatory; International; Investigation; Iowa; Isometric Exercise; Magnetic Resonance Imaging; Measurement; Measures; Mediator of activation protein; Muscle; Muscle function; Myopathy; Obesity; Obstructive Lung Diseases; Obstructive Sleep Apnea; Oral; Participant; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Polysomnography; Positioning Attribute; Predisposition; Prevalence; Process; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Randomized Controlled Trials; Reporting; Research; Research Methodology; Risk; Risk Factors; Role; Running; Severities; Sleep; Sleep Apnea Syndromes; Steroids; Structure; Study Subject; Surveys; Symptoms; System; Testing; Tongue; Veterans; Wakefulness; Work; airway obstruction; base; design; disability; disorder control; evidence base; expectation; fluticasone; innovation; instrument; obesity risk; pharyngeal critical pressure; pressure; prevent; programs; response; risk benefit ratio

DESCRIPTION (provided by applicant): BACKGROUND/WORK ACCOMPLISHED: Growing data suggest that patients with obstructive lung disease (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) have an increased predisposition for obstructive sleep apnea, but the mechanism(s) remain unknown. One characteristic these patients share is use of inhaled corticosteroid (ICS). We recently found a dose-dependent relationship of ICS use with high OSA risk. Furthermore, in a 16-week observational inhaled fluticasone (FP) treatment study, we observed increased upper airway (UAW) collapsibility during sleep, as measured by the critical closing pressure (Pcrit), parallelin the improvement in lower airways obstruction, with the largest Pcrit deterioration in the subject with most sleep-disordered breathing (SDB) at baseline. These findings suggest an effect of ICS on the "unified airway" of steroid responsive patients and of those with more collapsible upper airways at baseline. We also found a dose-dependent relationship of ICS with obesity. Based on their known effects, ICSs could deleteriously affect UAW collapsibility through inducing dilators' myopathy and fat deposition around the UAW. FP is the most potent and commonly used ICS. HYPOTHESIS/AIMS: The central hypothesis is that FP will increase UAW collapsibility (less negative Pcrit) and worsen SDB in steroid responsive patients with OLD and those with UAWs more susceptible to collapse at baseline, through alterations in tongue muscle function and fat accumulation in the UAW surrounding structures. To address this hypothesis, we propose to test the effects of inhaled FP on: 1) UAW collapsibility during sleep and SDB severity, assessed by Pcrit and polysomnographic (PSG) measures. Exploratory aims will test the role of steroid responsiveness and baseline collapsibility as determinants of FP effects on Pcrit and SDB; 2) tongue strength and fatigability, and fat accumulation (fraction and volume, measured on MRI) in the surrounding UAW structures. Exploratory aims will test whether these effects underlie the increase in UAW collapsibility and the role of steroid responsiveness status as a mediator of these FP effects. DESIGN: We propose a proof-of-concept and mechanistic, randomized-controlled, parallel groups study of high (220 mcg, 4 puffs twice a day) vs. low (44 mcg twice a day) dose inhaled FP, followed by an 8- week wash-out period, in 58 steroid-naive subjects with OLD. Following baseline Pcrit, PSG, MRI and tongue function (using the Iowa Oral Performance Instrument) measurements, subjects will enter a 2-week low-dose FP run-in, with subsequent randomization to either high- vs. low-dose FP, for 16 weeks. At mid-period, Pcrit, tongue function and steroid responsiveness status (defined as e5% improvement from baseline in FEV1%) will be determined. At the end of treatment, Pcrit, PSG, MRI and tongue measurements will be taken. Then, subjects will enter an 8-week wash-out that ends with repeat Pcrit and tongue function assessments. SIGNIFICANCE: Millions of people, including many Veterans, are treated with ICS for OLD, and among those with COPD, these numbers are likely to escalate. However, do these medications alter UAW collapsibility and predispose to OSA in some individuals, as our preliminary observations suggest? This research is innovative because it will directly evaluate the effects of ICS on the UAW structure and function during sleep and wakefulness. At the study completion, it is our expectation that we will have elucidated the effects and governing mechanisms of ICS on UAW patency and SDB severity. Data generated will form the foundation for future research aimed at expanding our understanding of ICS's effects on UAW and means to mitigate/prevent them. The clinical implication of our findings will be experimental-based verification of deleterious effects of ICS on UAW and risk for OSA, which will ultimately be of enormous financial benefit to the VA and OLD management programs.

描述（由申请人提供）： 背景/完成的工作：越来越多的数据表明，患有阻塞性肺病（OLD）（如哮喘和慢性阻塞性肺病（COPD））的患者患阻塞性睡眠呼吸暂停的倾向增加，但其机制仍不清楚。这些患者的一个共同特征是使用吸入性皮质类固醇（ICS）。我们最近发现ICS使用与OSA高风险存在剂量依赖关系。此外，在一项为期16周的观察性吸入氟替卡松（FP）治疗研究中，我们观察到睡眠期间的上气道（UAW）通畅性增加（通过临界闭合压（Pcrit）测量），与下气道阻塞的改善平行，在基线时大多数睡眠呼吸障碍（SDB）受试者中Pcrit恶化最大。这些发现表明ICS对类固醇反应患者和基线时上气道塌陷较多的患者的“统一气道”有影响。我们还发现了ICS与肥胖的剂量依赖关系。基于其已知的作用，ICSs可能通过诱导UAW周围的扩张肌病变和脂肪沉积而对UAW的可接受性产生不利影响。FP是最有效和最常用的ICS。 假设/目标：中心假设是，FP将通过舌肌功能和UAW周围结构中脂肪积聚的改变，增加UAW可吸收性（阴性Pcrit较少），并使类固醇应答的OLD患者和基线时更易塌陷的UAW患者的SDB恶化。为了解决这一假设，我们建议测试吸入FP对以下方面的影响：1）通过Pcrit和多导睡眠图（PSG）测量评估的睡眠期间UAW可接受性和SDB严重程度。探索性目的将测试类固醇反应性和基线耐受性作为FP对Pcrit和SDB影响的决定因素的作用; 2）舌强度和疲劳性，以及周围UAW结构中的脂肪积累（分数和体积，在MRI上测量）。探索性目的将测试这些效应是否是UAW可接受性增加的基础，以及类固醇反应性状态作为这些FP效应的介导者的作用。 产品设计：我们提出了一个概念验证和机制，随机对照，平行组研究高（220微克，4喷，每天两次）与低（44微克，每天两次）剂量吸入FP，随后8周的洗脱期，在58例激素初治的受试者与OLD。在基线Pcrit、PSG、MRI和舌功能（使用爱荷华州口腔性能仪器）测量后，受试者将进入为期2周的低剂量FP导入期，随后随机分配至高剂量与低剂量FP，持续16周。在中期，将测定Pcrit、舌功能和类固醇反应性状态（定义为FEV1%较基线的e5%改善）。治疗结束时，将进行Pcrit、PSG、MRI和舌测量。然后，受试者将进入为期8周的洗脱期，以重复Pcrit和舌功能评估结束。 重要性：数百万人，包括许多退伍军人，接受ICS治疗老年人，在COPD患者中，这些数字可能会上升。然而，正如我们的初步观察所示，这些药物是否会改变UAW的可接受性并使某些个体易患OSA？这项研究是创新的，因为它将直接评估ICS对睡眠和觉醒期间UAW结构和功能的影响。在研究完成时，我们预期将阐明ICS对UAW通畅性和SDB严重度的影响和控制机制。所产生的数据将形成未来研究的基础，旨在扩大我们对ICS对UAW的影响以及减轻/预防这些影响的方法的理解。我们的研究结果的临床意义将是基于实验的验证ICS对UAW的有害影响和OSA的风险，这最终将对VA和OLD管理计划产生巨大的经济效益。