Phase 2 study of digitoxin for cystic fibrosis - IND 70279

洋地黄毒苷治疗囊性纤维化的 2 期研究 - IND 70279

• 批准号: 8238123
• 负责人: Pamela L. Zeitlin
• 金额: $ 22.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238123
• 关键词: Phase; study; digitoxin; cystic; fibrosis

DESCRIPTION (provided by the applicant): Cystic fibrosis (CF) is the most common, life limiting autosomal recessive genetic disease in the US. CF airways contain abundant IL-8, the most active known pro-inflammatory cytokine. The IL-8 in the CF airway is derived from epithelial cells, and the resulting high levels of IL-8 attract neutrophils and other inflammatory cells. IL-8 hypersecretion in the CF lung results from a dysfunctional tumor necrosis factor alpha/nuclear factor-kappa B (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. Recently, low concentrations of the drug digitoxin have been discovered to suppress IL-8 hypersecretion by CF lung epithelial cells (Srivastava et al PNAS, 2004). 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 (Yang et al, PNAS 2005). 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 the applicants have hypothesized that digitoxin will safely suppress IL-8 dependent lung inflammation when administered orally to cystic fibrosis patients. The purpose of this proposal is to test this hypothesis and find a safe and tolerable dose.

描述(由申请人提供)： 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。Cf呼吸道含有丰富的IL-8，是已知的最活跃的促炎细胞因子。CF气道中的IL-8来源于上皮细胞，由此产生的高水平的IL-8会吸引中性粒细胞和其他炎症细胞。肺组织中IL-8的高分泌是肿瘤坏死因子α/核因子-kappaB(TNFa/核因子-kappaB)信号通路功能失调的结果。出于这个原因，一个有吸引力的药物策略是找到一种药物，可以抑制参与IL-8表达的那部分途径，但不抑制对感染的生理反应所需的其他部分。最近，人们发现低浓度的洋地黄毒素可以抑制肺上皮细胞分泌IL-8(Sriastava et al PNAS，2004)。洋地黄毒素的作用机制是通过抑制TNFa/NF？B信号通路发挥作用。洋地黄毒素特别阻断了肿瘤坏死因子受体和接头蛋白之间的相互作用(Yang等人，PNAS 2005)。这个相互作用的部位被认为是组装一组其他三种接头蛋白的启动者，这三种接头蛋白是导致IL-8表达的“炎症体”。洋地黄毒素的口服生物利用度约为100%，因此申请人假设，在囊性纤维化患者口服洋地黄毒素时，将安全地抑制依赖IL-8的肺部炎症。这项建议的目的是检验这一假设，并找到安全和可耐受的剂量。