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

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。急性时，炎症由血管闭塞引起的缺氧-再灌注损伤触发;慢性时，炎症由慢性缺氧和胎盘生长因子（一种从镰状细胞病中刺激的胎盘素释放的强促炎分子）释放的异常细胞因子环境维持。我们发现，胎盘生长因子通过上调5-脂氧合酶（催化白三烯的产生）来增加白三烯的合成。白三烯是多形核细胞最有效的促炎分子之一，并增加气道高反应性、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阻断白三烯的合成。我们推测，通过齐留通抑制LT产生将是安全、可行的，并显著降低炎症、气道高反应性、改善HbF并继发地减少急性镰状事件。提出了一个两步的方法：（1）一项有限的I期初步研究将解决儿童（12-18岁）和成人（18岁及以上）镰状细胞病齐留通的安全性。虽然zileuton被FDA批准用于12岁或12岁以上的哮喘患者，但尚未在镰状人群中进行研究，也没有主要研究其在这种疾病中的抗炎作用。因此，I期部分将确定齐留通在镰状细胞病中的安全剂量，该剂量对炎症终点具有生物学效应，并将齐留通和白三烯的药代动力学与正常个体和哮喘患者的已发表数据进行比较。(2)A随机化;双盲、安慰剂对照的交叉II期试验将确定长期给予齐留通的可行性及其对炎症标志物的影响作为主要终点。 次要终点为急性镰状事件、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子。齐留通可能影响这两个方面，并对疾病发病率产生总体积极影响。 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）减少镰状细胞病炎症和改善肺功能的能力。

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.