Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo
Information source: University Hospital Tuebingen
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Cystic Fibrosis; Infection; Pseudomonas Aeruginosa
Intervention: amitriptyline (Drug)
Phase: Phase 2
Sponsored by: University Hospital Tuebingen
Official(s) and/or principal investigator(s):
Joachim Reithmueller, Dr., Principal Investigator, Affiliation: University of Tuebingen, Paediatric Department
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.
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 -
Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study
Primary outcome: Increase in lung function, especially the FEV1 increase
Increase of CO-Diffusion
Pulmonary Ceramide expression
Decrease of cytokine-concentrations
Decrease of leukocytes (sputum)
Decrease of Pseudomonas
Infection parameters in serum
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.
Minimum age: 18 Years.
Maximum age: 50 Years.
1. Cystic Fibrosis is proved
2. The patient are older than 18 years (<50 years)
3. No sec discrimination
4. The patient is pulmonal colonized with bacteria
5. Signs of pulmonary exacerbation are not present
6. A full course of therapy is possible without any restrictions
7. Lung function measurement is possible
1. Poor metabolizer for amitriptyline (CYP2D6 genotyping)
2. Glaucoma, seizures, heart insufficiency or depression is present
3. Signs of acute pulmonary illness (bronchial or tracheal stenosis, tuberculosis, thorax
trauma, acute pneumonia, pneumothorax, bronchial haemorrhage, ARDS) are present
4. intravenous antibiotic treatment was necessary in the last 4 weeks
5. Involvement of the patient in another study
Locations and Contacts
University of Tuebingen, Tuebingen, Baden-Wuerttemberg 72076, Germany
Starting date: October 2006
Ending date: July 2007
Last updated: August 10, 2007