Anti-inflammatory Pulmonal Therapy of Cystic Fibrosis (CF) Patients With Amitriptyline and Placebo
Status:
Unknown status
Trial end date:
2011-05-01
Target enrollment:
Participant gender:
Summary
Cystic fibrosis patients suffer from a chronic destruction of the lung, frequent and finally
chronic pneumonia and a reduced life expectancy. Unfortunately, no curative treatment for
cystic fibrosis is available, neither are treatments established that prevent the disease.
Our data identify ceramide as a potential novel target to treat cystic fibrosis.
Two smaller trials support the notion that inhibition of the acid sphingomyelinase by
amitriptyline improves the lung function of CF-patients even at a dose that is low enough to
avoid adverse effects.
In the present proposal the investigators, therefore, aim to test in a larger cystic fibrosis
patient population whether an inhibition of ceramide release in the lung caused by the lack
of functional CFTR improves the lung function of cystic fibrosis patients. Inhibition of
ceramide-release in the lung will be achieved by treatment with amitriptyline, which is used
as an anti-depressant drug for almost 50 years. Although it is not absolutely specific, it
seems to be relatively specific for the degradation of acid sphingomyelinase (typically
60-80% of cellular acid sphingomyelinase are degraded), which releases ceramide from
sphingomyelin.
If the data confirm the beneficial effect of amitriptyline already observed in our
preliminary studies, the present clinical study may establish a novel treatment to improve
clinical symptoms of cystic fibrosis and, moreover, to prevent or at least delay the onset of
cystic fibrosis.
Hypothesis
- Amitriptyline reduces ceramide concentrations in respiratory epithelial cells (measured
in nasal epithelial cells obtained by brushing nasal mucosa).
- Amitriptyline treatment reduces cell death in bronchi and deposition of DNA on the
respiratory epithelium, which permits elimination of P. aeruginosa from the lung
(measured as P. aeruginosa counts in tracheal fluid).
- Amitriptyline treatment results in normalization of the function of leukocytes (number
determined in serum and tracheal fluid)
- Amitriptyline reduces systemic and local inflammation (measured as cytokines in plasma
and tracheal fluid).
Based on these effects amitriptyline increases the lung function of cystic fibrosis patients
(measured by FEV1).
Phase:
Phase 2
Details
Lead Sponsor:
University Children's Hospital Tuebingen University Children’s Hospital Tuebingen
Collaborators:
Universität Duisburg-Essen University of Ulm
Treatments:
Amitriptyline Amitriptyline, perphenazine drug combination Anti-Inflammatory Agents Mannitol