Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo

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.

Inclusion criteria

• Cystic Fibrosis is proved
• The patient are older than 18 years (<50 years)
• No sec discrimination
• The patient is pulmonal colonized with bacteria
• Signs of pulmonary exacerbation are not present
• A full course of therapy is possible without any restrictions
• Lung function measurement is possible

Exclusion criteria

• Poor metabolizer for amitriptyline (CYP2D6 genotyping)
• Glaucoma, seizures, heart insufficiency or depression is present
• Signs of acute pulmonary illness (bronchial or tracheal stenosis, tuberculosis, thorax trauma, acute pneumonia, pneumothorax, bronchial haemorrhage, ARDS) are present
• intravenous antibiotic treatment was necessary in the last 4 weeks
• Involvement of the patient in another study
• Pregnancy