Impact of quercetin on inflammatory and oxidative stress markers in COPD

槲皮素对慢性阻塞性肺病炎症和氧化应激标志物的影响

• 批准号: 10701080
• 负责人: Nathaniel Marchetti
• 金额: $ 37.54万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701080
• 关键词: Adrenal Cortex Hormones; Agonist; Allium cepa; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Apple; Asthma; Biological; Biological Availability; Biological Process; Blood; Blood Glucose; Bronchial Hyperreactivity; Bronchoalveolar Lavage; Cause of Death; Chemicals; Chronic; Chronic Disease; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Clinical Trials; Data; Development; Diet; Disease; Dose; Environmental Risk Factor; Epithelium; Flavonoids; Food; Future; Goals; Human; Immune response; Incidence; Individual; Inflammation; Inflammatory; Inhalation; Lung; Lung diseases; Measures; MicroRNAs; Morbidity - disease rate; Multi-Institutional Clinical Trial; Mus; Natural Products; Oral; Outcome; Oxidants; Oxidative Stress; Participant; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physical Examination; Placebos; Plants; Plasma; Platelet Count measurement; Play; Pre-Clinical Model; Prevalence; Property; Protease Inhibitor; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Pulmonary Sarcoidosis; Quercetin; Questionnaires; Randomized; Research; Rhinovirus; Risk; Role; Running; Safety; Smoking History; Structure of parenchyma of lung; Supplementation; Symptoms; Therapeutic Effect; Tissue-Specific Gene Expression; Tissues; United States; anti-cancer; clinically relevant; comorbidity; design; dietary; disease natural history; disease phenotype; dosage; efficacy evaluation; epidemiology study; inflammatory marker; influenza pneumonia; metabolic profile; meter; mortality; novel; novel therapeutics; patient population; prevent; pulmonary function; safety assessment; side effect; volunteer

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity in the United States and growing cause of chronic disease globally. At present the treatment options for COPD are limited and new therapies are needed to treat/prevent progression of COPD. Environmental factors and host response leading to imbalance in the ratio of oxidants to antioxidants, and proteases to antiproteases leading to chronic inflammation and tissue destruction is thought to play crucial role in development and progression of COPD. Quercetin is a plant flavonoid and has potent antioxidant and anti-inflammatory properties. Quercetin supplementation decreased markers of oxidative stress and inflammation in the plasma of patients with another chronic lung disease, pulmonary sarcoidosis. Quercetin also decreased both oxidative stress and lung inflammation in a preclinical model of chronic obstructive pulmonary disease (COPD). However the impact of quercetin in altering biological signatures in COPD subjects is yet to be determined. The proposed study is conducted in two phases, R61/R33 to define and confirm the biological effects of quercetin in COPD, bioavailability, safety, identification of the appropriate biological signatures which reflect clinical outcomes in COPD. This study will also define the optimal dose of quercetin required for altering biological signatures favorably. This information is necessary to conduct the future clinical trials with quercetin in COPD patients. In R61 Phase, there will be 15 study participants with moderate COPD with FEV1 ranging between 45 and 70 % of predicted and they will be randomized to receive either placebo or quercetin 2000 mg/day for 6 months. In R33 phase there will be 35 COPD subjects, who will be randomized to receive placebo, or one of the 3 quercetin doses, 500, 1000 or 2000 mg/day. Outcome of R61 phase will determine the feasibility of R33 Phase. In both R61 and R33 phases, all subjects will be characterized using a validated symptom questionnaire, medication and smoking histories, analysis of co-morbidities, and physical examination. All subjects will be asked to go on a low quercetin diet 7 days prior to start of quercetin or placebo supplementation to until the end of trial. Blood and bronchoalveolar lavage (BAL) will be collected after 7 days washout period (run-in) and after study drug treatment. Blood will also be collected at 3 months of study drug treatment. Plasma and BAL quercetin levels, markers of inflammation and oxidative stress in blood and BAL will be measured. Pulmonary function, and blood profiles (CBC and CMP) will be performed at run-in and at 3 and 6 months of study drug treatment to assess the safety. Results from these studies will provide information on biological endpoints, safety, bioavailability, and quercetin dosage required to carry out large clinical trials examining the efficacy of quercetin in COPD patients.

慢性阻塞性肺病 (COPD) 是美国死亡率和发病率的主要原因，也是全球慢性病发病率日益增长的原因。目前，慢性阻塞性肺病的治疗选择有限，需要新的疗法来治疗/预防慢性阻塞性肺病的进展。环境因素和宿主反应导致氧化剂与抗氧化剂、蛋白酶与抗蛋白酶比例失衡，导致慢性炎症和组织破坏，被认为在 COPD 的发生和进展中发挥着至关重要的作用。 槲皮素是一种植物类黄酮，具有有效的抗氧化和抗炎特性。补充槲皮素可降低另一种慢性肺病肺结节病患者血浆中氧化应激和炎症的标志物。槲皮素还可以减少慢性阻塞性肺病 (COPD) 临床前模型中的氧化应激和肺部炎症。然而，槲皮素在改变慢性阻塞性肺病受试者的生物特征方面的影响尚未确定。 拟议的研究分两个阶段进行，R61/R33，以定义和确认槲皮素在 COPD 中的生物效应、生物利用度、安全性、反映 COPD 临床结果的适当生物特征的识别。这项研究还将确定有利地改变生物特征所需的槲皮素的最佳剂量。这些信息对于未来在慢性阻塞性肺病患者中进行槲皮素临床试验是必要的。 在 R61 阶段，将有 15 名患有中度 COPD 的研究参与者，其 FEV1 范围在预测的 45% 至 70% 之间，他们将随机接受安慰剂或槲皮素 2000 毫克/天，为期 6 个月。在 R33 阶段，将有 35 名 COPD 受试者，他们将被随机接受安慰剂，或 3 种槲皮素剂量之一，即 500、1000 或 2000 毫克/天。 R61阶段的结果将决定R33阶段的可行性。 在 R61 和 R33 阶段，所有受试者都将使用经过验证的症状问卷、药物和吸烟史、合并症分析和体检来表征。所有受试者将被要求在开始补充槲皮素或安慰剂前 7 天进行低槲皮素饮食，直至试验结束。将在 7 天冲洗期（磨合期）和研究药物治疗后收集血液和支气管肺泡灌洗液 (BAL)。还将在研究药物治疗 3 个月时采集血液。将测量血浆和 BAL 槲皮素水平、血液和 BAL 中的炎症和氧化应激标志物。将在磨合期以及研究药物治疗的 3 个月和 6 个月时进行肺功能和血液分析（CBC 和 CMP），以评估安全性。这些研究的结果将提供有关开展大型临床试验所需的生物学终点、安全性、生物利用度和槲皮素剂量的信息，以检查槲皮素对慢性阻塞性肺病患者的疗效。