Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo
Condition: Cystic Fibrosis; Infection; Pseudomonas Aeruginosa
MeSH terms: Pseudomonas Infections; Cystic Fibrosis; Fibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Our data indicate that the CFTR-molecule functions as a transporter for
      sphingosine-1-phosphate and sphingosine or regulates the uptake of these sphingolipids by
      epithelial cells. The disturbed uptake of sphingosine and sphingosine-1-phosphate over the
      cell membrane results in an accumulation of ceramide in the cell membrane, which finally
      triggers a pro-inflammatory and pro-apoptotic status in the respiratory tract of cystic
      fibrosis patients. Amitriptyline reduces the cera-mide levels in the lung tissue, normalises
      the activity of cytokines and prevents constitutive cell death of epithelial cells observed
      in CFTR-deficient mice. Most important, amitriptyline prevents pulmonary infections of
      CFTR-deficient mice with P. aeruginosa. These effects of amitriptyline may result in an
      improved lung function of cystic fibrosis patients.
    

Detailed description: 
      Cystic fibrosis (CF), the most common autosomal recessive disorder at least in western
      countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator
      molecule (CFTR) and affects approximately 40 000 patients in Europe. Most, if not all,
      CF-patients develop a chronic pulmonary infection with Pseudomonas aeruginosa (P.
      aeruginosa). At present it is un-known why CF-patients are highly sensitive to P. aeruginosa
      infections and, most important, no curative treatment for cystic fibrosis is available.

      Our data on CFTR-deficient mice demonstrate that the CFTR-molecule does not only function as
      a chloride-channel, but also as a transporter for sphingolipids, in particular sphingosine
      and sphingosine-1-phosphate. Deficiency of functional CFTR in CFTR-knock-out mice results in
      an alteration of the sphingolipid metabolism in pulmonary epithelial cells and an
      accumulation of cellular ceramide in these cells.

      Inhibition of ceramide release in the lung was achieved by pharmacological and genetic
      inhibition of the acid sphingomyelinase (ASM) that generates ceramide from sphingomyelin.
      Amitriptyline was employed to pharmacologically block the ASM genetic inhibition of the ASM
      was achieved by crossing CFTR- and ASM-deficient mice. Although the ASM is not affected in
      cystic fibrosis, an inhibition of the enzyme should block the formation of ceramide and,
      thus, normalize the increase of pulmonary ceramide caused by CFTR-deficiency.
    

Intervention name(s): amitriptyline
Intervention type(s): Drug
Intervention description(s): Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline.
Placebo: 25 mg corn starch
Intervention MeSH terms: Amitriptyline
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: cystic fibrosis; ceramide; amitriptyline; Pseudomonas aeruginosa; lung function