title: Therapy of CF-patients with amitriptyline and placebo--a randomised, double-blind, placebo-controlled phase IIb multicenter, cohort-study.
abstract: OBJECTIVE
  Several recent studies revealed an accumulation of ceramide in bronchial, tracheal and intestinal epithelial cells of mice and patients with cystic fibrosis (CF). Normalization of ceramide concentrations in lungs of CF mice employing the functional acid sphingomyelinase inhibitor amitriptyline also normalized mucociliary clearance, chronic inflammation and infection susceptibility to pulmonary P. aeruginosa in these mice.
  
  
  METHODS
  To test for a beneficial effect of amitriptyline in vivo, we performed a phase IIb randomised, double-blind, placebo-controlled study. Twenty-one CF patients were treated with 25 mg/d amitriptyline twice daily for 28 days. The placebo consisted of 19 patients and was also treated twice per day. The primary endpoint was the change in lung function in the intention-to-treat (ITT) population. Secondary endpoints were ceramide levels in epithelial cells and safety.
  
  
  RESULTS
  After treatment, forced expiratory volume in 1 sec predicted (FEV1) increased 6.3 ± 11.5% (p=0.08) in the ITT population (36 of 40 CF patients) and 8.5 ± 10% (p=0.013) in the per protocol (PP) population (29 of 40 patients). Ceramide levels decreased in nasal epithelial cells after amitriptyline treatment. Amitriptyline had no severe and only mild and mostly transient adverse effects, i.e. xerostomia and tiredness.
  
  
  CONCLUSIONS
  Amitriptyline is safe in CF-patients, increases FEV1 and reduces ceramide in lung cells of CF patients.
authors.affiliation: Department of Paediatrics, University Hospital Giessen, Giessen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Nährlich
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Mainz
authors.forename: Constantin
authors.initials: C
authors.lastname: Adams
authors.forename: Corinna
authors.initials: C
authors.lastname: Engel
authors.forename: Gloria
authors.initials: G
authors.lastname: Herrmann
authors.forename: Vanya
authors.initials: V
authors.lastname: Icheva
authors.forename: Josefine
authors.initials: J
authors.lastname: Lauer
authors.forename: Caroline
authors.initials: C
authors.lastname: Deppisch
authors.forename: Andreas
authors.initials: A
authors.lastname: Wirth
authors.forename: Katy
authors.initials: K
authors.lastname: Unger
authors.forename: Ute
authors.initials: U
authors.lastname: Graepler-Mainka
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Susanne
authors.initials: S
authors.lastname: Heyder
authors.forename: Martin
authors.initials: M
authors.lastname: Stern
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Joachim
authors.initials: J
authors.lastname: Riethmüller
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000328:Adult; D000639:Amitriptyline / Q000627:therapeutic use*; D002518:Ceramides / Q000032:analysis; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D015990:Placebo Effect; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D002518:Ceramides; D000639:Amitriptyline