A Pilot Study of N-acetylcysteine in Sickle Cell Disease Vaso-Occlusive Crisis

N-乙酰半胱氨酸在镰状细胞病血管闭塞危象中的初步研究

• 批准号: 9126589
• 负责人: Barbara A Konkle
• 金额: $ 39.75万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126589
• 关键词: Accident and Emergency department; Acetylcysteine; Adhesions; Adhesiveness; Adult; Antioxidants; Biological Markers; Blood Vessels; Cell Survival; Cell physiology; Cells; Chronic Disease; Cleaved cell; Clinical; Clinical Treatment; Complex; Controlled Clinical Trials; Country; Data; Enrollment; Erythrocytes; Functional disorder; Health; Hemolysis; Inborn Genetic Diseases; Infusion procedures; Inpatients; Laboratories; Laboratory Research; Measures; Medical; Medical center; Morbidity - disease rate; Multicenter Trials; Outpatients; Oxidation-Reduction; Pain; Patients; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Plasma; Play; Proteins; Provider; Randomized; Research Personnel; Safety; Sickle Cell; Sickle Cell Anemia; Universities; Washington; Whole Blood; base; clinical efficacy; cost; effective therapy; group support; improved; mortality; pilot trial; randomized placebo controlled trial; randomized trial; response; von Willebrand Factor

 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a chronic disease characterized by painful episodes, increased morbidity and mortality and has many unmet needs in effective treatment. While the pathophysiology of SCD is complex, hemolysis, red blood cell (RBC) vascular adhesion and an altered redox state all play key roles. Prior studies from our group support the hypothesis that the drug N-acetylcysteine (NAC) can modulate SCD by cleaving hyperactive von Willebrand factor, a vascular adhesion protein. In an ongoing study of NAC infusions in stable outpatients with SCD, we have found an effect on VWF, as well as an increase in the antioxidant activity in whole blood, plasma and red blood cells (RBC) and a decrease in RBC fragments and dense cells, among other findings. The drug has been well tolerated by subjects enrolled to date. We further hypothesize that NAC will be an effective treatment for SCD vaso-occlusive crisis (VOC) by decreasing VWF adhesiveness and improving red blood cell function and viability. To obtain the data needed to develop a successful multicenter randomized placebo controlled trial of NAC in VOC, we propose the following Specific Aims: 1) To conduct a pilot study of NAC in patients presenting to the University of Washington Medical Center emergency room or inpatient unit in VOC, with NAC infusions continuing for 5 days or until discharge. Endpoints for this pilot study will be feasibility, safet, and measures of clinical efficacy. 2) To assess research laboratory correlates of NAC activity in this setting, including measures of VWF activity, VWF multimer composition, RBC fragments and dense cells, cellular aggregates, and measures reflective of antioxidant activity. This will increase our understanding of the mechanism(s) of NAC in treatment of SCD and inform the selection of laboratory biomarkers for the multicenter trial. And, 3) To develop a multicenter randomized placebo-controlled clinical trial of NAC in SCD vaso-occlusive crisis, with clinical response and laboratory endpoints chosen based on findings from this pilot trial and with engagement of sickle cell medical providers/investigators across the country. NAC is a promising, low cost therapy for VOC which could provide benefit for many patients with sickle cell disease.

 描述(申请人提供)：镰状细胞病(SCD)是一种慢性疾病，以疼痛发作、发病率和死亡率增加为特征，在有效治疗方面有许多未得到满足的需求。虽然SCD的病理生理机制复杂，但溶血、红细胞(RBC)血管黏附和氧化还原状态的改变都起着关键作用。我们小组以前的研究支持这样的假设，即药物N-乙酰半胱氨酸(NAC)可以通过切割高度活跃的von Willebrand因子(一种血管黏附蛋白)来调节SCD。在一项正在进行的对稳定的SCD门诊患者输注NAC的研究中，我们发现了对VWF的影响，以及全血、血浆和红细胞(RBC)中抗氧化活性的增加，以及RBC碎片和致密细胞的减少等发现。到目前为止，登记的受试者对这种药物的耐受性很好。我们进一步假设，NAC将通过降低VWF的粘附性，改善红细胞功能和活性，成为治疗SCD血管闭塞危象(VOC)的有效药物。为了获得成功的NAC在VOC中的多中心随机安慰剂对照试验所需的数据，我们提出了以下具体目标：1)在到VOC的华盛顿大学医学中心急诊室或住院病房的患者中进行NAC的试点研究，NAC的输注持续5天或直到出院。这项初步研究的终点将是可行性、安全性和临床疗效的衡量标准。2)评估研究实验室在这种情况下NAC活性的相关性，包括VWF活性、VWF多聚体组成、RBC碎片和致密细胞、细胞聚集的测量，以及反映抗氧化活性的测量。这将增加我们对NAC治疗SCD的机制(S)的理解，并为多中心试验的实验室生物标志物的选择提供信息。以及，3)开发一项NAC治疗SCD血管闭塞危象的多中心随机安慰剂对照临床试验，临床反应和实验室终点的选择基于这一试点试验的结果，并与全国各地的镰状细胞医疗提供者/研究人员参与。NAC是治疗VOC的一种有前景的、低成本的治疗方法，可为许多镰状细胞病患者提供益处。

项目成果

Phenotypic analysis of erythrocytes in sickle cell disease using imaging flow cytometry.

• DOI: 10.1002/cyto.a.24536
• 发表时间: 2022-05
• 期刊: Cytometry. Part A : the journal of the International Society for Analytical Cytology

Epicardium-Derived Heart Repair.

• DOI: 10.3390/jdb2020084
• 发表时间: 2014-04-10
• 期刊: Journal of developmental biology
• 影响因子: 2.7
• 作者: Smits AM;Riley PR
• 通讯作者: Riley PR

The role of thymosin-β4 in kidney disease.

胸腺肽-β4 在肾脏疾病中的作用。

• DOI: 10.1517/14712598.2015.1009891
• 发表时间: 2015
• 期刊: Expert opinion on biological therapy
• 影响因子: 4.6
• 作者: Vasilopoulou,Elisavet;Winyard,PaulJD;Riley,PaulR;Long,DavidA
• 通讯作者: Long,DavidA