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| Sponsored by: |
University Hospital Tuebingen |
|---|---|
| Information provided by: | University Hospital Tuebingen |
| ClinicalTrials.gov Identifier: | NCT00515229 |
Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Cystic Fibrosis Infection Pseudomonas Aeruginosa |
Drug: amitriptyline |
Phase II |
| Study Type: | Interventional |
| Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study |
| 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 - |
| Enrollment: | 18 |
| Study Start Date: | October 2006 |
| Study Completion Date: | July 2007 |
| Arms | Assigned Interventions |
|---|---|
|
1: Active Comparator
Verum 1: Each individual capsule has a filling volume of 25 mg amitriptyline, given once an day in the evening over 28 days
|
Drug: amitriptyline
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch |
|
2: Active Comparator
Verum 1: Each individual capsule has a filling volume of 50 mg amitriptyline, given once an day in the evening over 28 days
|
Drug: amitriptyline
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch |
|
3: Active Comparator
Verum 3: Each individual capsule has a filling volume of 75 mg amitriptyline, given once an day in the evening over 28 days
|
Drug: amitriptyline
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch |
|
0: Placebo Comparator
Placebo: Each individual capsule has a filling volume of 25 mg placebo (corn starch), given once an day in the evening over 28 days
|
Drug: amitriptyline
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch |
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.
Eligibility| Ages Eligible for Study: | 18 Years to 50 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations| Germany, Baden-Wuerttemberg | |
| University of Tuebingen | |
| Tuebingen, Baden-Wuerttemberg, Germany, 72076 | |
| Principal Investigator: | Joachim Reithmueller, Dr. | University of Tuebingen, Paediatric Department |
More Information
| Study ID Numbers: | APA-II |
| Study First Received: | August 9, 2007 |
| Last Updated: | August 10, 2007 |
| ClinicalTrials.gov Identifier: | NCT00515229 |
| Health Authority: | Germany: Federal Institute for Drugs and Medical Devices |
|
cystic fibrosis ceramide amitriptyline Pseudomonas aeruginosa lung function |
|
Digestive System Diseases Genetic Diseases, Inborn Respiratory Tract Diseases Cystic Fibrosis Fibrosis |
Lung Diseases Amitriptyline Infant, Newborn, Diseases Pancreatic Diseases Cystic fibrosis |
|
Neurotransmitter Uptake Inhibitors Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Adrenergic Agents Adrenergic Uptake Inhibitors Physiological Effects of Drugs Psychotropic Drugs Infection Pharmacologic Actions |
Antidepressive Agents, Tricyclic Pathologic Processes Analgesics, Non-Narcotic Sensory System Agents Therapeutic Uses Analgesics Peripheral Nervous System Agents Central Nervous System Agents Antidepressive Agents |
