Beneficial effects of quercetin in COPD - a preliminary clinical trial

描述（由申请人提供）：槲皮素是一种广泛存在于水果和蔬菜中的植物类黄酮，是一种有效的抗氧化剂和抗炎物质。我们最近发现，每天口服低水平的槲皮素可以降低慢性阻塞性肺疾病（COPD）小鼠的氧化应激、炎症和预防肺部疾病的进展。我们的初步研究还表明，槲皮素可以抑制鼻病毒的复制，鼻病毒是COPD恶化的主要原因。最后，大型流行病学研究表明，高槲皮素饮食可降低COPD的风险。总之，这些数据表明槲皮素对慢性阻塞性肺病的治疗是有益的。然而，关键的方法学问题尚未得到解决，包括补充的剂量和频率、生物利用度、安全性、剂量-反应关系，或反映该疾病临床结果的适当生物标志物。该应用程序的总体目标是获得COPD大型临床试验所需的信息。为实现这一目标，我们提出以下具体目标：确定每日一次的槲皮素剂量是否安全、可接受并达到COPD患者血浆中的治疗浓度。使用一种被FDA“普遍认为是安全的”槲皮素配方（Quercegen Pharma, Sudbury， MA），我们将测试以下假设：1)通过问卷调查可以准确监测饮食中的类黄酮摄入量；2)每日补充槲皮素可提高COPD患者血浆槲皮素水平；3)槲皮素可用于不同严重程度的COPD患者，无不良副作用。2. 测定槲皮素对COPD患者氧化应激、肺部炎症及肺功能的影响。我们假设：1)在COPD患者的血清和痰液中可以安全、准确地测量氧化和炎症生物标志物；2)每日应用槲皮素可降低血浆和痰液中氧化应激和炎症标志物；3)每日应用槲皮素可改善COPD患者肺功能。这些研究的结果将提供有关槲皮素剂量和生物学终点的数据，以开展大型临床试验，检查槲皮素在COPD中的疗效。

DESCRIPTION (provided by applicant): Quercetin, a plant flavonoid widely found in fruits and vegetables, is a potent antioxidant and anti- inflammatory. We recently showed that daily oral treatment with low levels of quercetin decreases oxidative stress, inflammation and prevents progression of lung disease in mice which display typical features of chronic obstructive lung disease (COPD) Our pilot studies also suggest that quercetin inhibits replication of rhinovirus, a major cause of COPD exacerbations. Finally, large epidemiological studies have suggested that a high- quercetin diet decreases the risk of COPD. Together, these data suggest that quercetin would be beneficial in the treatment of COPD. Nevertheless, key methodologic issues have not been resolved, including the dosage and frequency of supplementation, bioavailability, safety, dose-response relationship, or the appropriate biomarkers which reflect clinical outcomes in this disease. The overall goal of this application is to obtain the information necessary for large clinical trials in COPD. To accomplish this goal, we propose the following Specific Aims. 1. Determine if once-daily doses of quercetin are safe, acceptable and reach therapeutic concentrations in the plasma of patients with COPD. Using a quercetin formulation that has been "generally recognized as safe" by the FDA (Quercegen Pharma, Sudbury, MA), we will test the hypotheses that: 1) dietary flavonoid intake can be accurately monitored by questionnaire; and 2) daily supplementation of quercetin increases plasma quercetin levels in COPD patients; and 3) quercetin can be administered to patients with COPD of varying severity without adverse side effects. 2. Determine the effect of quercetin on oxidative stress, lung inflammation and pulmonary function in patients with COPD. We hypothesize that: 1) oxidative and inflammatory biomarkers can be safely and accurately measured in the serum and sputum of patients with COPD; 2) daily treatment with quercetin will reduce plasma and sputum markers of oxidative stress and inflammation; 3) daily treatment with quercetin will improve pulmonary function in patients with COPD. Results from these studies will provide data on the quercetin dosage and biological endpoints needed to carry out large clinical trials examining the efficacy of quercetin in COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the U.S. Current treatment regimens for COPD are only partially effective, expensive, and often not adhered to by patients. In contrast to standard medications, natural products may have fewer side effects and be easy and inexpensive to use. Quercetin, a dietary chemical found in foods such as apples and onions is a natural product with anti- oxidant and anti-inflammatory properties. Our preliminary data and published studies suggest that quercetin may be useful in the treatment of COPD. The goal of this proposal is to perform a pilot study of quercetin in patients with COPD. The information gained from this study, including the correct dosage of medication and safety profile, will enable researchers to plan a large clinical trial of quercetin in the future.