Cystic Fibrosis Clinical Trial
Official title:
Protocol for a Phase II-Study Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo - Randomised, Double-Blinded, Placebo-Controlled, Cross Over - Study -
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.
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.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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