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: 8009484
• 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/8009484
• 关键词: Alveolar; Ancillary Study; Antioxidants; 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; Health; Impairment; Individual; Institution; Isoprostanes; Lung; Lung Capacity; Lung diseases; Measurement; Measures; Medical; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; 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; 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）： 本研究申请拟对一项临床试验进行辅助研究，该临床试验计划很快成为我院最近资助的多学科肺动脉高压临床导向研究专业中心（SCCOR）的一个组成部分，该中心的重点是系统性硬化症相关的肺动脉高压（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。过度氧化应激导致NO受损可能是PAH-SSc发展中的关键事件，可通过当前PAH治疗靶向。我们假设这些标志物将：1）预测PAH治疗的后续反应，2）作为临床相关结局的替代治疗终点。在母临床试验中，未接受治疗的PAH-SSc患者（N=75）将入组波生坦、西地那非或两者联合治疗的随机研究，持续16周。这些药物是目前最广泛使用的治疗这种情况。详细的临床、功能和血流动力学评估将作为母试验的一部分进行。这项辅助研究将在基线和治疗后获得呼出NO和尿F2-异前列烷（氧化应激的标志物）测量值。在我们的第一个目标中，将基线测量与从没有肺部疾病的SSc患者和健康对照受试者中获得的测量进行比较。后一组将从另外两项母研究中招募，这两项母研究是我们SCCOR计划的组成部分。在目标2中，基线生物标志物测量值将与治疗应答相关。此外，治疗4周、8周和16周后这些指数的变化将与16周后疾病严重程度的临床指标变化相关。这项研究的长期目标是确定PAH-SSc中可靠的生物标志物，并促进我们对这种毁灭性疾病的药物治疗作用机制的理解。这些测量的验证可能最终允许为个体患者定制治疗或识别那些不太可能从早期某种治疗中受益的患者，以便在临床恶化发生之前进行改变。随后的研究可以确定这些简单、容易获得的非侵入性检测是否证明可用于识别随后发生临床表现PAH的高风险无症状SSc患者，从而允许预防性治疗的潜在应用。通过提供机制的见解，这项研究也可以作为测试新的治疗类别，如抗氧化剂和/或NO供体的基础。公共卫生关系：肺动脉高压目前是系统性硬化症患者死亡的主要原因，尽管有批准的治疗方法。疾病严重程度的常规评估是粗略的，不能预测或充分监测对治疗的反应。这项研究旨在开发和验证呼出气和尿液中新的、容易获得的生物标志物，最终可能改善这些患者的临床管理，并允许早期发现疾病。(End摘要）