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 (CF) 是美国最常见的、限制生命的常染色体隐性遗传病。 CF气道含有丰富的IL-8，这是已知最活跃的促炎细胞因子。 CF气道中的IL-8源自上皮细胞，由此产生的高水平IL-8吸引中性粒细胞和其他炎症细胞。 CF 肺中 IL-8 分泌过多是由于肿瘤坏死因子 α/核因子-κ B (TNFa/NF?B) 信号通路功能失调所致。因此，一种有吸引力的药物策略是寻找一种药物，能够抑制参与 IL-8 表达的途径部分，但不抑制对感染的生理反应所需的其他部分。最近，已发现低浓度的洋地黄毒苷药物可抑制 CF 肺上皮细胞过度分泌 IL-8（Srivastava 等人 PNAS，2004）。洋地黄毒苷的作用机制是抑制 TNFa/NF?B 信号通路。洋地黄毒素特异性阻断 TNF 受体和衔接蛋白之间的相互作用（Yang 等人，PNAS 2005）。该相互作用位点被称为组装其他三种衔接蛋白的起始子，即导致下游 IL-8 表达的“炎性体”。洋地黄毒苷的口服生物利用度约为100％，因此申请人假设洋地黄毒苷当口服给予囊性纤维化患者时将安全地抑制IL-8依赖性肺部炎症。该提案的目的是检验这一假设并找到安全且可耐受的剂量。