Effect of Losartan on Progression of Emphysema

氯沙坦对肺气肿进展的影响

• 批准号: 10004773
• 负责人: Janet T. Holbrook
• 金额: $ 36.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004773
• 关键词: Alveolar; Angiotensin Receptor; Angiotensins; Anti-Inflammatory Agents; Antihypertensive Agents; Apoptosis; Biological; Bronchial Spasm; Bronchodilator Agents; Cause of Death; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; Communities; Consent; Controlled Clinical Trials; Data Collection; Data Quality; Databases; Development; Diagnostic radiologic examination; Disease; Disease Progression; Epithelial; Exhibits; Goals; Heterogeneity; High Resolution Computed Tomography; Hospitalization; Individual; Institutional Review Boards; Leadership; Losartan; Lung; Manuals; Measures; Mediating; Mediator of activation protein; Monitor; Morbidity - disease rate; Multi-Institutional Clinical Trial; Mus; Neptune; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Pilot Projects; Placebos; Prevention; Procedures; Protocols documentation; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Receptor Activation; Reporting; Research; Respiratory Muscles; Respiratory physiology; Safety; Scanning; Signal Transduction; Skeletal Muscle; Spirometry; Standardization; Structure; Structure of parenchyma of lung; Subgroup; Suggestion; System; Testing; Training; Transforming Growth Factor beta; United States; United States National Institutes of Health; X-Ray Computed Tomography; airway inflammation; cardiovascular risk factor; cigarette smoke; design; disability; distributed data; exposure to cigarette smoke; fibrillin; interest; irbesartan; lung volume; mortality; muscle strength; patient subsets; pragmatic trial; preclinical study; prevent; public health relevance; receptor; reduce symptoms; secondary analysis; smoking cessation; symptom treatment; treatment effect; web site

 DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a major cause of death and disability in the United States. Current treatments target bronchospasm and inflammation of airways with the goal to reduce symptoms and prevent exacerbations. However, other than smoking cessation, no treatment has been found that modifies the progression of this disease. Moreover, COPD is a heterogeneous disease involving remodeling of both lung parenchyma (emphysema) and airways (chronic bronchitis). Research in mice exposed to cigarette smoke implicates TGF-beta signaling as a mediator of apoptosis that leads to emphysema. The development of emphysema can be prevented by blockade of the angiotensin-1 (AT1) receptor with drugs such as losartan. A pilot study of losartan in patients with COPD showed no overall improvement, but patients who had the emphysema phenotype demonstrated no progression of emphysema at 1 year compared to placebo treated patients who increased the percent of lung occupied by emphysema. These results did not reach statistical significance (p = 0.06) but were strongly suggestive of a benefit in COPD patients with emphysema. The aim of this proposal is to conduct a definitive randomized, placebo-controlled, clinical trial to test whether administration of 100mg/day of losartan to patients with radiographic evidence of emphysema will slow progression of their disease compared to comparable individuals given placebo. Emphysema progression will be measured by high-resolution computed tomography using standardized procedures. The trial is designed to be a highly-focused pragmatic trial with sparse data collection that can be accomplished in community as well as academic settings.

 描述（由适用提供）：慢性阻塞性肺疾病（COPD）是美国死亡和残疾的主要原因。目前的治疗方法针对支气管痉挛和气道炎症，目的是减轻症状并防止加剧。但是，除了戒烟之外，尚未发现修饰这种疾病进展的治疗方法。此外，COPD是一种异质疾病，涉及肺实质（肺气肿）和气道（慢性支气管炎）的重塑。暴露于香烟烟雾的小鼠中的研究意味着TGF-β信号传导是导致肺气肿的凋亡的介体。肺气肿的发育可以通过用氯沙坦等药物阻断血管紧张素1（AT1）受体来预防肺气肿的发展。对COPD患者的Losartan的试点研究显示没有总体改善，但是与安慰剂治疗的患者相比，患有肺气肿表型的患者在1年中没有表现出肺气肿的进展。这些结果没有达到统计学意义（p = 0.06），但强烈暗示对COPD肺气肿患者有好处。该提案的目的是进行一项确定的随机，安慰剂对照的临床试验，以测试氯沙坦对具有肺气肿的放射学证据的患者的100mg/天的给药是否会减慢其疾病进展，而不是给予安慰剂。肺气肿的进展将通过使用标准化程序进行高分辨率计算机断层扫描来测量。该试验旨在是一项高度注重的实用试验，其稀疏数据收集可以在社区和学术环境中完成。

项目成果

Reply to Polverino and Celli.

• DOI: 10.1164/rccm.202207-1316le
• 发表时间: 2022-10-15
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7

Losartan Effects on Emphysema Progression Randomized Clinical Trial: Rationale, Design, Recruitment, and Retention.

• DOI: 10.15326/jcopdf.2021.0210
• 发表时间: 2021-08
• 期刊: Chronic obstructive pulmonary diseases
• 作者: R. Wise;J. Holbrook;Robert H. Brown;G. Criner;M. Dransfield;M. Han;J. Krishnan;E. Looney;E. Neptune;Vicky Palombizio;Alexis L Rea