Exhaled Nitric Oxide and Oxidative Stress in Pulmonary Arterial Hypertention Asso

肺动脉高压症中的呼出一氧化氮和氧化应激

• 批准号: 7755378
• 负责人: REDA E GIRGIS
• 金额: $ 28.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-10 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755378
• 关键词: Alveolar; Ancillary Study; Antioxidants; Behavior Therapy; Biological Markers; Blood Vessels; Carbon Monoxide; Cause of Death; Clinical; Clinical Management; Clinical Treatment; Clinical Trials; Cohort Studies; Complement; Data; Deterioration; Development; Diffuse; Disease; Early Diagnosis; Early treatment; Endothelin Receptor Antagonist; Enrollment; Event; Exercise; Exhalation; F2-Isoprostanes; Foundations; Funding; Generations; Impairment; Individual; Institution; Isoprostanes; Lung; Lung Capacity; Lung diseases; Measurement; Measures; Medical; Monitor; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Outcome; Oxidative Stress; Parents; Pathogenesis; Pathway interactions; Patient Selection; Patients; Pharmacotherapy; Pulmonary Hypertension; Randomized; Reactive Oxygen Species; Recruitment Activity; Research; Resources; Right Ventricular Function; Risk; Severity of illness; Specialized Center; Surrogate Endpoint; Systemic Scleroderma; Testing; Therapeutic; Urine; Validation; Vascular Diseases; abstracting; base; bosentan; clinically relevant; cohort; hemodynamics; high risk; improved; indexing; inhibitor/antagonist; insight; mortality; novel; novel therapeutics; phosphoric diester hydrolase; programs; public health relevance; pulmonary arterial hypertension; response; sildenafil; urinary

DESCRIPTION (provided by applicant): This research application proposes to conduct an ancillary study to a clinical trial planned soon as a component of the recently funded, multi-disciplinary Specialized Center of Clinically Oriented Research (SCCOR) in Pulmonary Hypertension at our institution, which has as its focus, Pulmonary Arterial Hypertension Associated with Systemic Sclerosis (PAH-SSc). This study seeks to develop and validate exhaled nitric oxide (NO) and urine isoprostanes as clinically relevant biomarkers in PAH-SSc. Excessive oxidative stress with consequent impairment in NO, may be critical events in the development of PAH- SSc that can be targeted by current PAH therapies. We hypothesize that these markers will: 1) predict the subsequent response to PAH therapy and 2) serve as surrogate therapeutic end-points to clinically relevant outcomes. In the parent clinical trial, treatment naove PAH-SSc patients (N=75) will be enrolled in a randomized study of bosentan, sildenafil or the combination of both for 16-weeks. These agents are currently the most widely employed therapies for this condition. Detailed clinical, functional and hemodynamic assessments will be conducted as part of the parent trial. This ancillary study will obtain exhaled NO and urine F2-isoprostane (a marker of oxidative stress) measurements at baseline and after therapy. In our first aim, baseline measures will be compared with those obtained from SSc patients without lung disease and healthy control subjects. The latter groups will be recruited from two other parent studies that are components of our SCCOR program. In aim 2, baseline biomarker measurements will be correlated with response to therapy. In addition, changes in these indices after 4, 8 and 16 weeks of therapy will be correlated with changes in clinical measures of disease severity after 16 weeks. The long-term objectives of this research are to identify reliable biomarkers in PAH-SSc and advance our understanding of the mechanism(s) of action of medical therapy for this devastating disease. Validation of these measurements may ultimately allow tailoring of therapy to individual patients or identify those who are unlikely to benefit from a certain therapy early, so that a change can be made before clinical deterioration occurs. Subsequent studies could determine if these simple, readily obtained, non-invasive tests prove to be useful in identifying asymptomatic patients with SSc at high-risk for subsequent development of clinically manifest PAH, allowing the potential application of preventative therapies. By providing mechanistic insights, this research may also serve as a basis for the testing of novel therapeutic classes, such as anti-oxidants and/or NO donors. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension currently represents the leading cause of death in patients with systemic sclerosis, despite the availability of approved therapies. Conventional assessments of disease severity are crude and unable to predict or adequately monitor the response to therapy. This study aims to develop and validate novel, easily-obtained biomarkers in exhaled breath and urine that may ultimately improve clinical management of these patients and allow early detection of disease. (End of Abstract)

描述(由申请人提供)： 这项研究申请建议对一项计划不久的临床试验进行辅助研究，该临床试验是我们研究所最近资助的多学科临床导向研究(SCCOR)专门中心的一部分，该中心的重点是肺动脉高压伴系统性硬化症(PAH-SSC)。本研究旨在开发和验证呼出的一氧化氮(NO)和尿异前列腺素作为PAH-SSC的临床相关生物标志物。过量的氧化应激导致NO的损伤，可能是PAH-SSC发展过程中的关键事件，目前的PAH治疗可以针对这一事件。我们假设这些标记物将：1)预测PAH治疗的后续反应，2)作为临床相关结果的替代治疗终点。在母体临床试验中，治疗PAH-SSC患者(N=75)将参加波生坦、西地那非或两者的组合的随机研究，为期16周。这些药物目前是治疗这种疾病最广泛使用的疗法。作为母公司试验的一部分，将进行详细的临床、功能和血流动力学评估。这项辅助研究将在基线和治疗后测量呼出的NO和尿F2-异前列腺素(氧化应激的标志)。在我们的第一个目标中，基线测量将与无肺部疾病的SSC患者和健康对照组的测量结果进行比较。后一组将从另外两项家长研究中招募，这两项研究是SCCOR计划的组成部分。在目标2中，基线生物标记物测量将与治疗反应相关。此外，这些指标在治疗4周、8周和16周后的变化将与16周后疾病严重程度的临床测量的变化相关。本研究的长期目标是在PAH-SSc中寻找可靠的生物标志物，促进我们对药物治疗这种毁灭性疾病的作用机制(S)的理解。这些测量的有效性最终可能允许为个别患者量身定做治疗，或者及早识别那些不太可能从某种治疗中受益的人，以便在临床恶化之前做出改变。随后的研究可以确定这些简单、容易获得的非侵入性测试是否有助于识别无症状的SSc患者，这些患者具有随后发展为临床表现的PAH的高风险，从而允许潜在的预防性治疗。通过提供机械性的见解，这项研究也可以作为测试新的治疗类别的基础，例如抗氧化剂和/或没有供体。公共卫生相关性：尽管已有批准的治疗方法，但肺动脉高压目前仍是系统性硬化症患者死亡的主要原因。传统的疾病严重程度评估是粗略的，无法预测或充分监测治疗反应。这项研究旨在开发和验证呼气和尿液中新的、容易获得的生物标记物，这些标记物可能最终改善这些患者的临床管理，并允许早期发现疾病。(摘要结束)