Has this been looked at by anyone, could be interesting.
http://www.spp-sphingolipide.de/Publications/Riethmueller et al - Therapeutic Efficacy.pdf
In summary, the present findings demonstrate the
safety and the efficacy of treatment of CF patients with
low doses of amitriptyline and justify to continue the
development of amitriptyline as a new strategy to fight
lung infections in patients with CF. It should be pointed
out that an increase of 4-5% of lung function (FEV1) is
comparable to the beneficial effects of other drugs commonly
used to treat cystic fibrosis. Furthermore, the potential
of drugs that target the acid sphingomyelinase in
cystic fibrosis might be increased by more efficient inhibition
of the acid sphingomyelinase and/or local pulmonary
application of higher doses without systemic effects.
Key Words
Cystic Fibrosis • Amitriptyline • P. aeruginosa •
Ceramide • CFTR
Abstract
Amitriptyline, a blocker of acid sphingomyelinase and
acid ceramidase, significantly reduces Pseudomonas
aeruginosa lung infection in cystic fibrosis (CF) mice
with concurrent increase of survival. Our aim was to
establish whether amitriptyline is safe and effective
in the treatment of CF patients. In a randomised,
double-blinded, placebo-controlled, cross-over pilot
study, 4 adult CF patients received 37.5 mg of
amitriptyline or placebo twice daily for 14 days.
Subsequently in a phase II study 19 adult CF patients
were randomly allocated to three treatment groups
receiving amitriptyline once daily for 28 days at doses
of 25 mg (n=7), 50 mg (n=8), or 75 mg (n=8) or
placebo (n=13). The primary outcome was the
difference of forced expiratory volume in 1 sec (FEV1)
at day 14 between amitriptyline and placebo. Primary
endpoint measures improved significantly in three of
four patients in the pilot study after amitriptyline
treatment vs placebo (relative FEV1: 14.7±5%;
p = 0.006) and in the 25 mg treatment group of the
phase II study (relative FEV1: 4.0±7%; p = 0.048).
Amitriptyline was well tolerated in both studies and
96% of the patients completed the studies.
Amitriptyline as a novel therapeutic option in patients
with CF is safe and seems to be efficacious.
Introduction
The hereditary disease cystic fibrosis (CF), caused
by mutations in the gene encoding the CF Transmembrane
conductance Regulator (CFTR) [1-3], affect epithelial
ion and water transport in cells in the respiratory,
gastrointestinal, hepatobiliary and reproductive tracts.
Reduced chloride secretion causes a viscous mucus, overlaying
the respiratory epithelium, leading to impaired
mucociliary clearance [4]. This supports chronic bacterial
respiratory infections, which have the greatest impact
on morbidity and mortality of the patients [5]. Mostly
due to the endobronchial location of mucoid Pseudomonas
aeruginosa [6], the major opportunistic pathogen in CF,
66
which is surrounded by masses of dead neutrophils [6],
high doses of antibiotics are required for treatment of CF
lung disease [7]. Nevertheless, once P. aeruginosa infections
become chronic, eradication by antibiotics cannot
be any more accomplished [7]. Thus, other strategies
have to be established.
http://www.spp-sphingolipide.de/Publications/Riethmueller et al - Therapeutic Efficacy.pdf
In summary, the present findings demonstrate the
safety and the efficacy of treatment of CF patients with
low doses of amitriptyline and justify to continue the
development of amitriptyline as a new strategy to fight
lung infections in patients with CF. It should be pointed
out that an increase of 4-5% of lung function (FEV1) is
comparable to the beneficial effects of other drugs commonly
used to treat cystic fibrosis. Furthermore, the potential
of drugs that target the acid sphingomyelinase in
cystic fibrosis might be increased by more efficient inhibition
of the acid sphingomyelinase and/or local pulmonary
application of higher doses without systemic effects.
Key Words
Cystic Fibrosis • Amitriptyline • P. aeruginosa •
Ceramide • CFTR
Abstract
Amitriptyline, a blocker of acid sphingomyelinase and
acid ceramidase, significantly reduces Pseudomonas
aeruginosa lung infection in cystic fibrosis (CF) mice
with concurrent increase of survival. Our aim was to
establish whether amitriptyline is safe and effective
in the treatment of CF patients. In a randomised,
double-blinded, placebo-controlled, cross-over pilot
study, 4 adult CF patients received 37.5 mg of
amitriptyline or placebo twice daily for 14 days.
Subsequently in a phase II study 19 adult CF patients
were randomly allocated to three treatment groups
receiving amitriptyline once daily for 28 days at doses
of 25 mg (n=7), 50 mg (n=8), or 75 mg (n=8) or
placebo (n=13). The primary outcome was the
difference of forced expiratory volume in 1 sec (FEV1)
at day 14 between amitriptyline and placebo. Primary
endpoint measures improved significantly in three of
four patients in the pilot study after amitriptyline
treatment vs placebo (relative FEV1: 14.7±5%;
p = 0.006) and in the 25 mg treatment group of the
phase II study (relative FEV1: 4.0±7%; p = 0.048).
Amitriptyline was well tolerated in both studies and
96% of the patients completed the studies.
Amitriptyline as a novel therapeutic option in patients
with CF is safe and seems to be efficacious.
Introduction
The hereditary disease cystic fibrosis (CF), caused
by mutations in the gene encoding the CF Transmembrane
conductance Regulator (CFTR) [1-3], affect epithelial
ion and water transport in cells in the respiratory,
gastrointestinal, hepatobiliary and reproductive tracts.
Reduced chloride secretion causes a viscous mucus, overlaying
the respiratory epithelium, leading to impaired
mucociliary clearance [4]. This supports chronic bacterial
respiratory infections, which have the greatest impact
on morbidity and mortality of the patients [5]. Mostly
due to the endobronchial location of mucoid Pseudomonas
aeruginosa [6], the major opportunistic pathogen in CF,
66
which is surrounded by masses of dead neutrophils [6],
high doses of antibiotics are required for treatment of CF
lung disease [7]. Nevertheless, once P. aeruginosa infections
become chronic, eradication by antibiotics cannot
be any more accomplished [7]. Thus, other strategies
have to be established.