Phase 2 Study of Digitoxin for the Treatment of Cystic Fibrosis

囊性纤维化（CF）是美国最常见的限制生命的常染色体隐性遗传病之一， 患病率约为30.000例患者。囊性纤维化没有治愈和招致巨大的一生 经济负担。每天至少有一名CF患者死亡。每人CF护理的平均年成本 2006年，拥有私人医疗保险的个人为48，098美元，是个人医疗保险费用的22倍多。 没有CF。CF患者的死亡率主要是由于不可逆阻塞性呼吸衰竭引起的进行性呼吸衰竭。 肺病。肺部被感染破坏，并因内在的促炎性NF κ B而复杂化。 介导气道中的嗜中性粒细胞占主导地位的状态。航空公司被越来越多的 中性粒细胞被IL-8吸引。CF气道中IL-8的主要来源是气道上皮， 所产生的高水平IL-8吸引大量嗜中性粒细胞和其它炎性细胞流入。的cf 上皮细胞也分泌高水平的其它促炎细胞因子，但它们的丰度较低。IL-8 CF肺中的分泌过多是由于功能失调的TNF α/NF B信号通路。出于这个原因， 有吸引力的制药策略是找到一种药物来抑制这部分途径 参与IL-8表达，但不参与对感染的生理反应所需的其他部分。这个项目 当低浓度的洋地黄毒苷药物被发现抑制IL-8分泌过多时， CF肺上皮细胞。洋地黄毒苷的作用机制是抑制TNF α/NF B信号通路。 洋地黄毒苷特异性阻断TNF受体和接头蛋白TRADD之间的相互作用。这 相互作用的位点被认为是一组三种其他衔接蛋白组装的起始点， "炎性体"，其导致下游IL-8表达。洋地黄毒苷的口服生物利用度为 因此，我们假设洋地黄毒苷将安全地抑制IL-8依赖性肺 囊性纤维化患者的炎症。本提案的目的是完成第三批也是最后一批的 CF患者来检验这一假设，并选择最小安全有效剂量。主要目标： 测量洋地黄毒苷对稳定CF患者诱导痰中IL-8和中性粒细胞计数的影响。 该研究是一项随机、双盲、安慰剂对照、重复给药试验，评价28种 洋地黄毒苷对轻度至中度CF受试者诱导痰中IL-8和中性粒细胞浓度的影响 囊性纤维化肺病三组，每组8名受试者将被给予0.05 mg或0.10 mg洋地黄毒苷 或安慰剂。本研究计划共入组24例患者。 次要目的1：测定稳定型CF患者血清中洋地黄毒苷的药代动力学。 每例受试者参与研究的时长为70天，定义为筛选日（周）;-4至10天。 第-2天）治疗日（第1 - 28天）;和恢复日（第28 - 42天）。血清（药代动力学）采集时间为 间隔进行分析。 次要目的2：测量安全性指标，包括ECG变化和痰液微生物， 稳定的CF患者。 次要目的3：测定洋地黄毒苷对鼻上皮细胞基因表达的影响 稳定的CF患者在第0天研究药物给药前和第28天收集鼻上皮细胞 末次研究给药后。 次要目的4：使用CFQ-R测量生活质量评分。

Cystic Fibrosis (CF) is one of the most common, life limiting autosomal recessive genetic disease in the U.S., with a prevalence of about 30.000 total patients. Cystic Fibrosis has no cure and incurs a huge lifetime financial burden. At least one person with CF dies each day. The average annual cost of CF care per individual with private healthcare insurance in 2006 was $48,098, more than 22 times the cost of an individual without CF. Mortality in CF patients is mostly due to progressive respiratory failure from irreversible obstructive lung disease. The lung is destroyed by infection and complicated by an intrinsically pro-inflammatory NFKB- mediated neutrophil-dominated state in the airway. Airways are infiltrated with increased numbers of neutrophils that are attracted by Il-8. The major source of IL-8 in the CF airway is the airway epithelium, and the resulting high levels of IL-8 attract a large influx of neutrophils and other inflammatory cells. The CF epithelial cells also secrete high levels of other proinflammatory cytokines, but they are in less abundance. IL-8 hypersecretion in the CF lung is due to a dysfunctional TNFa/NF¿B signaling pathway. For that reason an attractive pharmaceutical strategy has been to find a drug that would suppress that part of the pathway involved in IL-8 expression, but not other parts required for physiological responses to infection. This project was devised when low concentrations of the drug digitoxin were discovered to suppress IL-8 hypersecretion by CF lung epithelial cells. The mechanism of digitoxin action is to suppress the TNFa/NF¿B signaling pathway. Digitoxin specifically blocks the interaction between the TNF Receptor and the adaptor protein TRADD. This site of interaction is known as the initiator for assembly of a set of three other adaptor proteins, the "inflammasome" which leads downstream to IL-8 expression. The oral bioavailability of digitoxin is approximately 100%, and therefore we hypothesize that digitoxin will safely suppress IL-8 dependent lung inflammation in cystic fibrosis patients. The purpose of this proposal is to complete the third and final cohort of CF patients to test this hypothesis and select the minimum safe and effective dose. Primary Objective: To measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum in stable CF patients. The study is a randomized, double blind, placebo-controlled, repeat dosing trial evaluating the effects of 28 days of digitoxin on IL-8 and neutrophil concentrations in induced sputum in CF subjects with mild to moderate cystic fibrosis lung disease. Three groups of 8 subjects each will be given either 0.05 mg or 0.10 mg digitoxin or a placebo. Twenty-four total patients are planned for the study. Secondary Objective 1: To measure the pharmacokinetics of digitoxin in serum in stable CF patients. The length of study participation for each subject is 70 days, and is defined as Screening Days (week ); -4 to day -2) Treatment Days (Day 1-28); and Recovery Days (Day 28-42). Serum (pharmacokinetics) is collected at intervals for analysis. Secondary Objective 2: To measure safety indices, including ECG changes and sputum microbiology, in stable CF patients. Secondary Objective 3: To measure the effect of digitoxin on gene expression in nasal epithelial cells of stable CF patients. Nasal epithelial cells are collected on Day 0 prior to study drug dosing and on day 28 after last study dose. Secondary Objective 4: To measure quality of life scores using the CFQ-R.