Zeitlin Pamela L, Diener-West Marie, Callahan Karen A, Lee Seakwoo, Talbot C Conover, Pollard Bette, Boyle Michael P, Lechtzin Noah
1 Department of Pediatrics.
2 Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
Ann Am Thorac Soc. 2017 Feb;14(2):220-229. doi: 10.1513/AnnalsATS.201608-649OC.
Cystic fibrosis (CF) lung disease progresses by a combination of airway inflammation, bacterial colonization, and infection. Airway inflammation is predominantly neutrophilic and complicates airway clearance therapies through cellular debris; excessive DNA; excessive and viscous mucus; and high concentrations of neutrophils, IL-8, and related cytokines liberated along the nuclear factor-κB signaling pathway.
We conducted a preliminary, single-site, randomized, double-blind, placebo-controlled study to evaluate the effects over 28 days of two dose levels (0.05 mg and 0.1 mg daily) of an older cardiac glycoside, digitoxin, as compared with placebo, on safety, pharmacokinetics, and inflammatory markers in induced sputum obtained from 24 subjects with mild to moderate CF lung disease.
Patients with CF 18-45 years old with any genotype combination were eligible. The primary objective was to measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum. Secondary objectives were to measure (1) the pharmacokinetics of digitoxin in sera of patients with stable CF; (2) safety indices, including ECG changes and sputum microbiology; (3) the effect of digitoxin on gene expression in nasal epithelial cells of patients with stable CF; and (4) quality-of-life scores using the Cystic Fibrosis Questionnaire-Revised.
It took several weeks to achieve a therapeutic serum level of digitoxin in subjects with CF. No safety concerns emerged during the study. Digitoxin treatment showed a trend toward reduction in sputum free neutrophil elastase and neutrophil counts, but not a reduction in sputum IL-8. Digitoxin treatment did not reach statistical significance for the primary or secondary outcome measures over the 28-day study period. However, the nasal mRNA from the group receiving 0.1 mg of digitoxin daily had a distinct distribution of global gene expression levels as compared with either the 0.05-mg dose or placebo treatment. The mRNAs encoding chemokine/cytokine or cell surface receptors in immune cells were decreased in nasal epithelial cells at the higher dose, leading to pathway-mediated reductions in IL-8, IL-6, lung epithelial inflammation, neutrophil recruitment, and mucus hypersecretion.
At a dose of 0.1 mg daily for 28 days, digitoxin was safe for adults with CF lung disease, but it did not achieve a significant decrease in sputum inflammatory markers. Clinical trial registered with www.clinicaltrials.gov (NCT00782288).
囊性纤维化（CF）肺部疾病通过气道炎症、细菌定植和感染共同作用而进展。气道炎症主要为中性粒细胞性炎症，会因细胞碎片、过量DNA、过量且黏稠的黏液以及沿核因子κB信号通路释放的高浓度中性粒细胞、白细胞介素-8（IL-8）及相关细胞因子而使气道清除治疗变得复杂。
我们进行了一项初步的、单中心、随机、双盲、安慰剂对照研究，以评估一种较老的强心苷地高辛的两个剂量水平（每日0.05毫克和0.1毫克）与安慰剂相比，在28天内对24例轻至中度CF肺部疾病患者诱导痰中的安全性、药代动力学和炎症标志物的影响。
年龄在18至45岁、具有任何基因型组合的CF患者符合条件。主要目的是测量地高辛对诱导痰中IL-8和中性粒细胞计数的影响。次要目的是测量：（1）稳定期CF患者血清中地高辛的药代动力学；（2）安全指标，包括心电图变化和痰微生物学；（3）地高辛对稳定期CF患者鼻上皮细胞基因表达的影响；（4）使用修订后的囊性纤维化问卷的生活质量评分。
CF患者达到地高辛治疗性血清水平需要数周时间。研究期间未出现安全问题。地高辛治疗显示出痰中游离中性粒细胞弹性蛋白酶和中性粒细胞计数有降低趋势，但痰中IL-8未降低。在28天的研究期内，地高辛治疗在主要或次要结局指标上未达到统计学意义。然而，与每日接受0.05毫克剂量或安慰剂治疗相比，每日接受0.1毫克地高辛治疗组的鼻mRNA具有独特的整体基因表达水平分布。高剂量时，免疫细胞中编码趋化因子/细胞因子或细胞表面受体的mRNA在鼻上皮细胞中减少，导致通过信号通路介导的IL-8、IL-6、肺上皮炎症、中性粒细胞募集和黏液分泌过多减少。
对于患有CF肺部疾病的成年人，每日服用0.1毫克地高辛，持续28天是安全的，但痰炎症标志物未显著降低。临床试验已在www.clinicaltrials.gov注册（NCT00782288）。
