title: Digitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Pamela L
authors.identifier: http://orcid.org/0000-0002-2719-1834
authors.initials: PL
authors.lastname: Zeitlin
authors.affiliation: 2 Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Marie
authors.initials: M
authors.lastname: Diener-West
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Callahan
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Seakwoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: 3 Department of Medicine, School of Medicine, and.
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: 4 Silver Pharmaceuticals, Baltimore, Maryland.
authors.forename: Bette
authors.initials: B
authors.lastname: Pollard
authors.affiliation: 3 Department of Medicine, School of Medicine, and.
authors.forename: Michael P
authors.identifier: http://orcid.org/0000-0002-9740-1630
authors.initials: MP
authors.lastname: Boyle
authors.affiliation: 3 Department of Medicine, School of Medicine, and.
authors.forename: Noah
authors.identifier: http://orcid.org/0000-0002-9088-8749
authors.initials: N
authors.lastname: Lechtzin
mesh_terms: D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000737:chemistry; D003550:Cystic Fibrosis / Q000188:drug therapy*; D004074:Digitoxin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000382:microbiology; D016209:Interleukin-8 / Q000737:chemistry; D007958:Leukocyte Count; D008168:Lung / Q000503:physiopathology; D008297:Male; D008396:Maryland; D009504:Neutrophils / Q000187:drug effects; D013183:Sputum / Q000737:chemistry / Q000382:microbiology; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; C508606:CXCL8 protein, human; D016209:Interleukin-8; D004074:Digitoxin
keywords: cardiac glycoside; inflammation; interleukins; pharmacokinetics; sputum