A PHASE I/II TRIAL OF ZILEUTON IN SICKLE CELL DISEASE

Zileuton 治疗镰状细胞病的 I/II 期试验

基本信息

批准号：
8150160
负责人：
Punam Malik
金额：
$ 20.93万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150160
关键词：
12 year old 18 year old Acute Address Adhesions Adult Affect Age Anti-Inflammatory Agents Anti-inflammatory Arachidonate 5-Lipoxygenase Asthma Basic Science Biological Blood Blood Platelets Blood Vessels CCL2 gene Child Chronic Clinical Clinical Chemistry Clinical Trials Cross-Over Studies Data Disease Dose Double-Blind Method Drug Kinetics Edema Endothelial Cells Erythroid Erythroid Cells Event FDA approved Fetal Hemoglobin Fibrosis Functional disorder Goals Growth Factor Hospitalization Hypoxia IL8 gene In Vitro Incidence Individual Infant Inflammation Inflammatory Inflammatory Response Intake Knockout Mice Laboratories Leukocytes Leukotriene Production Leukotrienes Licensing Link Lipoxygenase Inhibitors Lung Lung Inflammation Lung diseases Measures Mediating Methodology Monitor Morbidity - disease rate Oral Oral Administration Organ Pain Pathology Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Pilot Projects Placebo Control Placental Growth Factor Plasma Population Process Production Publishing Pulmonary Emphysema Pulmonary Hypertension Pulmonary function tests Quality of life Questionnaires Randomized Rattus Reactive Oxygen Species Reperfusion Injury Respiratory physiology Running Safety Secondary to Serum Severity of illness Sickle Cell Sickle Cell Anemia Signal Transduction Smooth Muscle Stimulus Symptoms Testing Time Transgenic Mice Translating United States National Institutes of Health Up-Regulation Urine Work Zileuton acute chest syndrome airway hyperresponsiveness constriction cysteinyl-leukotriene cytokine diaries hydroxyurea improved inflammatory marker instrument macrophage monocyte mortality neutrophil novel pulmonary function sickling trend

项目摘要

Inflammation is increasingly recognized as a key feature of sickle cell disease, potentially linking vaso-occlusion, endothelial cell dysfunction, reactive airway disease and pulmonary hypertension. Acutely, inflammation is triggered by hypoxia-reperfusion injury resulting from vaso-occlusion; chronically, it is sustained by the abnormal cytokine milieu perpetuated by chronic hypoxia and by release of placenta growth factor, a strong proinflammatory molecule released from the stimulated erythron in sickle cell disease. We show that placenta growth factor increases leukotriene synthesis via upregulation of 5-lipoxygenase, which catalyzes production of leukotrienes. Leukotrienes are among the most potent proinflammatory molecules for polymorphonuclear cells, and increase airway hyperreactivity, vascular leak, and edema. Chronic leukotriene elevation has been also shown to be associated with pulmonary hypertension and fibrosis. We propose to block leukotriene synthesis with a 5-lipoxygenase inhibitor, zileuton. We postulate that inhibition of LT production by zileuton will be safe, feasible and significantly reduce inflammation, airway hyperreactivity, improve HbF and secondarily reduce acute sickle events. A two-step approach is proposed: (1) A limited Phase I pilot study will address the safety of zileuton in children (12-18 yrs of age) and adults (18 years and older) with sickle cell disease. While zileuton is FDA approved for asthma in individuals 12 years or older, it has not been studied in the sickle population, nor has it been studied primarily for its anti-inflammatory effects in this disease. The Phase I component will therefore determine a safe dose of zileuton in sickle cell disease that has a biological effect on inflammatory endpoints and compare zileuton and leukotriene pharmacokinetics to published data on normal individuals and patients with asthma. (2) A randomized; double-blind, placebo-controlled crossover Phase II trial will determine the feasibility of chronic zileuton administration and its effect on inflammatory markers as primary endpoints. Secondary endpoints will be acute sickle events, Hb F levels, pulmonary function, and markers of pulmonary hypertension. Inflammation and pulmonary disease are two strong predictors of sickle cell disease severity and mortality. Zileuton may affect both these aspects and have an overall positive impact on disease morbidity. Lay Summary: Inflammation and lung disease are important features of sickle cell disease. This study will test the ability of Zileuton, an anti-inflammatory drug licensed for treatment of asthma, to reduce inflammation in sickle cell disease and improve lung function.

炎症越来越被认为是镰状细胞病的一个关键特征，可能与血管闭塞、内皮细胞功能障碍、反应性气道疾病和肺动脉高压有关。急性炎症是由血管闭塞引起的缺氧再灌注损伤引发的；长期而言，它是通过慢性缺氧和胎盘生长因子的释放而持续存在的异常细胞因子环境来维持的，胎盘生长因子是镰状细胞病中受刺激的红细胞释放的强促炎分子。我们发现胎盘生长因子通过上调 5-脂氧合酶来增加白三烯的合成，5-脂氧合酶催化白三烯的产生。白三烯是多形核细胞最有效的促炎分子之一，会增加气道高反应性、血管渗漏和水肿。慢性白三烯升高也被证明与肺动脉高压和纤维化有关。我们建议用 5-脂氧合酶抑制剂齐留通来阻断白三烯的合成。我们假设齐留通抑制 LT 产生将是安全、可行的，并且可显着减少炎症、气道高反应性、改善 HbF，进而减少急性镰状细胞事件。提出了分两步走的方法：(1) 一项有限的 I 期试点研究将解决齐留通对患有镰状细胞病的儿童（12-18 岁）和成人（18 岁及以上）的安全性。虽然齐留通已被 FDA 批准用于 12 岁或以上个体的哮喘治疗，但尚未在镰刀型人群中进行研究，也未主要研究其在这种疾病中的抗炎作用。因此，第一阶段将确定齐留通治疗镰状细胞病的安全剂量，该剂量对炎症终点具有生物效应，并将齐留通和白三烯的药代动力学与已发表的正常个体和哮喘患者的数据进行比较。 (2) 随机化；双盲、安慰剂对照交叉 II 期试验将确定长期齐留通给药的可行性及其对炎症标志物的影响作为主要终点。次要终点是急性镰状事件、Hb F 水平、肺功能和肺动脉高压标志物。炎症和肺部疾病是镰状细胞病严重程度和死亡率的两个强有力的预测因素。齐留通可能会影响这两个方面，并对疾病发病率产生总体积极影响。简单总结：炎症和肺部疾病是镰状细胞病的重要特征。这项研究将测试 Zileuton（一种被许可用于治疗哮喘的抗炎药物）减少镰状细胞病炎症和改善肺功能的能力。