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.