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: 8698387
• 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/8698387
• 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/工作完成：越来越多的数据表明，哮喘和慢性阻塞性肺疾病（COPD）等阻塞性肺疾病（旧）患者对阻塞性睡眠呼吸暂停的易感性增加，但该机制仍然未知。这些患者共享的一个特征是使用吸入的皮质类固醇（ICS）。我们最近发现ICS使用与高OSA风险的剂量依赖性关系。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上空气道（UAW）的可折叠性增加，这是通过临界关闭压力（PCRIT）衡量的，平行于下气道阻塞的改善，而在大多数睡眠状态下，最大的PCRIT降低了pcrit diseptial（SDB），该pcrit降低了。这些发现表明，IC对类固醇反应式患者的“统一气道”以及基线上更可折叠的上呼吸道的影响。我们还发现IC与肥胖的剂量依赖性关系。根据它们已知的效果，ICS可以通过诱导扩张剂的肌病和脂肪沉积来影响UAW的可折叠性。 FP是最有效，常用的IC。 假设/目的：中心假设是，FP会增加UAW可折叠性（负PCRIT），并使类固醇反应型老年患者的SDB恶化，而UAW的患者则通过舌头肌肉功能和脂肪在UAW周围结构中的累积而易于崩溃。为了解决这一假设，我们建议测试吸入FP对：1）在睡眠和SDB严重程度期间的UAW可折叠性的影响，通过PCRIT和多聚疗法（PSG）测量评估。探索目的将测试类固醇反应性和基线可折叠性作为FP对PCRIT和SDB效应的决定因素。 2）周围UAW结构中的舌强度和疲劳性以及脂肪的积累（分数和体积，在MRI上测量）。探索目的将测试这些影响是否构成了UAW可折叠性的增加以及类固醇反应性状态作为这些FP效应的中介的作用。 设计：我们提出了一项概念验证和机理，随机控制的，平行组的高（220 mcg，每天两次4次泡芙），而低（每天两次MCG两次）吸入FP（随后是每天两次MCG），然后进行8周的洗涤周期，在58个类固醇含量的情况下。在基线PCRIT，PSG，MRI和舌函数（使用爱荷华州口服仪器）测量之后，受试者将进入2周的低剂量FP跑步，随后随后的随后随机分组为高剂量FP，持续16周。在期间，将确定PCRIT，舌功能和类固醇反应性状态（定义为FEV1％的E5％提高）。在治疗结束时，将进行PCRIT，PSG，MRI和舌头测量。然后，受试者将进入一个为期8周的洗涤，以重复的PCRIT和舌功能评估结束。 意义：数以百万计的人，包括许多退伍军人，接受了旧的IC，其中包括COPD的人，这些数字可能会升级。但是，这些药物是否会像我们的初步观察结果那样改变某些个体的UAW可折叠性并易于OSA？这项研究具有创新性，因为它将直接评估IC对睡眠和清醒过程中UAW结构和功能的影响。在研究完成期间，我们期望我们将阐明ICS对UAW通畅性和SDB严重程度的影响和管理机制。生成的数据将构成未来研究的基础，旨在扩大我们对ICS对UAW影响的理解，并意味着减轻/防止它们。我们发现的临床意义将是基于实验性的ICS对UAW和OSA风险有害影响的验证，这最终将对VA和旧管理计划具有巨大的经济利益。