Phase 2 Study of Digitoxin for the Treatment of Cystic Fibrosis

囊性纤维化是美国最常见的限制生命的常染色体隐性遗传病之一， 总患病率约为30.000。囊性纤维化无法治愈，并导致巨大的终生 经济负担。每天至少有一名CF患者死亡。每名患者的平均每年CF护理成本 2006年，个人拥有私人医疗保险的费用为48,098美元，是个人费用的22倍多 不带配置文件慢性阻塞性肺疾病患者的死亡主要是由于不可逆转的梗阻导致的进行性呼吸衰竭。 肺部疾病。肺部被感染破坏，并因内在的促炎NFKB而复杂化- 介导的中性粒细胞在呼吸道中的主导状态。航空公司被越来越多的 被IL-8吸引的中性粒细胞。慢性阻塞性肺疾病中IL-8的主要来源是气道上皮细胞。 由此产生的高水平的IL-8吸引了大量的中性粒细胞和其他炎症细胞的涌入。CF卡 上皮细胞也分泌高水平的其他促炎细胞因子，但它们的数量较少。IL-8 肺组织中的高分泌是由于TNFa/NFB信号通路功能失调所致。出于这个原因，一个 有吸引力的药物策略一直是找到一种可以抑制这一途径的药物 参与IL-8的表达，但不参与对感染的生理反应所需的其他部分。这个项目 是在发现低浓度的洋地黄毒素通过以下方式抑制IL-8过度分泌时设计的 Cf肺上皮细胞。洋地黄毒素的作用机制是通过抑制TNFa/NFB信号通路发挥作用。 洋地黄毒素特别阻断肿瘤坏死因子受体和连接蛋白Tradd之间的相互作用。这 相互作用的部位是已知的组装一组其他三个接头蛋白的启动子， “炎症体”导致下游IL-8的表达。洋地黄毒素的口服生物利用度为 接近100%，因此我们假设洋地黄毒素将安全地抑制IL-8依赖的肺 囊性纤维化患者的炎症反应。这项提案的目的是完成第三批也是最后一批 Cf患者验证这一假设，并选择最小安全有效剂量。主要目标： 检测洋地黄毒素对缓解期CF患者诱导痰中IL-8和中性粒细胞计数的影响。 这项研究是一项随机、双盲、安慰剂对照、重复给药的试验，评估了28 洋地黄毒素用药天数对轻中度慢性萎缩性胃炎患者诱导痰中IL-8和中性粒细胞浓度的影响 囊性纤维性肺病。三组各8名受试者将被给予0.05毫克或0.10毫克洋地黄毒素 或者是安慰剂。这项研究计划了24名患者。 第二目的1：测定缓解期CF患者血清中洋地黄毒素的药代动力学。 每个科目的学习参与时间为70天，定义为筛选日(周)；-4至 第二天)治疗天数(第1-28天)；恢复天数(第28-42天)。血清(药代动力学)在以下位置收集 分析的时间间隔。 第二个目标2：测量安全性指标，包括心电图变化和痰微生物， 在稳定的CF患者中。 第二目标3：检测洋地黄毒素对鼻黏膜上皮细胞基因表达的影响 稳定期的CF患者。在研究给药前第0天和第28天收集鼻黏膜上皮细胞。 在上一次研究剂量后。 次要目标4：使用CFQ-R测量生活质量得分。

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.