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、反应性呼吸道疾病和肺动脉高压有关。急性炎症由血管闭塞引起的缺氧-再灌注损伤触发；慢性炎症由慢性缺氧和胎盘生长因子释放持续的异常细胞因子环境维持，胎盘生长因子是镰状细胞疾病中刺激的红细胞释放的一种强烈的促炎分子。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，而5-脂氧合酶催化白三烯的产生。白三烯是中性粒细胞最有效的促炎分子之一，可增加呼吸道高反应性、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。我们推测，齐留通抑制LT的产生是安全可行的，可以显著减轻炎症、气道高反应性，改善HBF，继而减少急性镰刀事件。提出了一种分两步进行的方法：(1)有限的第一阶段试点研究将解决齐留通在患有镰状细胞疾病的儿童(12-18岁)和成人(18岁及以上)中的安全性。虽然齐留通被FDA批准用于12岁或12岁以上的哮喘患者，但它还没有在镰刀人群中进行研究，也没有主要研究它在这种疾病中的抗炎作用。因此，第一阶段的组成部分将确定治疗镰状细胞疾病的齐留通的安全剂量，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已公布的正常人和哮喘患者的数据进行比较。(2)一项随机、双盲、安慰剂对照的交叉II期试验将确定作为主要终点的长期服用齐留通的可行性及其对炎症标记物的影响。次要终点将是急性镰刀事件、Hb F水平、肺功能和肺动脉高压的标志物。炎症和肺部疾病是镰状细胞疾病严重程度和死亡率的两个强有力的预测因子。齐留通可能会影响这两个方面，并对疾病发病率产生总体上的积极影响。 摘要：炎症和肺部疾病是镰状细胞病的重要特征。这项研究将测试齐鲁通，一种被批准用于治疗哮喘的抗炎药物，在减少镰状细胞疾病的炎症和改善肺功能方面的能力。

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.