Systemic effects in patients with COPD; training or treatment

Systemic effects of COPD (Chronic Obstructive Pulmonary Disease) are now
recognized as important features of the disease. The most extensively studied
features are cachexia and muscle wasting. Several aspects may contribute to
these features including inactivity, systemic inflammation and oxidative
stress. For example, in stable COPD patients increased levels of circulating
neutrophils are present in an activated status. Furthermore, increased levels
of tumour necrosis factor (TNF-α) and its receptors (TNFR-55 and TNFR75),
interleukin(IL)-6, IL-8, Fas and Fas Ligand, and elevated levels of acute phase
proteins C-reactive protein and lipopolysaccharide-binding protein are found.
Systemic inflammation and enhanced production of reactive oxygen species (ROS)
are closely related. This increase in ROS production may lead to an imbalance
in oxidant and antioxidant production, resulting in local as well as systemic
oxidative stress.
In response to physical activity, all the above mentioned is further increased,
especially in muscle wasted COPD patients. The actual mechanism between
oxidative stress, systemic inflammation and muscle wasting is unknown. Because
fat-free mass is an independent predictor of mortality in COPD patients, it is
important to investigate the relationship between muscle wasting, oxidative
stress and systemic inflammation in order to explore new possible
pharmacological interventions. We hypothesize that muscle damage in patients
with COPD is related to systemic inflammation and oxidative stress and can be
decreased by reduction of these systemic effects with anti-inflammatory and
anti-oxidative therapy.

To study the possible relation between systemic inflammation and oxidative
stress and muscle breakdown using pharmacological interventions.

First, a pilot study will be conducted. Two muscle wasted COPD patients will
subsequently visit the clinic 9 times. One patient will receive
n-acetylcysteine 600 mg and placebo 3-times daily and the other will receive
rosuvastatin 20 mg and placebo 1 time daily. This pilot study will consist of
three pairs of treatment periods. Each period consists of treatment with
placebo and active substance, both for 7 days. After each pair of treatment,
there is a washout period of one week. During each visit, blood samples will be
taken to be analyzed for markers of muscle damage (skeletal muscle troponin I)
and muscle breakdown (activity of the ubiquitin-proteasome system).


This study is a double-blind randomized placebo-controlled cross-over trail.
Before the start of the protocol, subjects will be subjected to complete
lungfunctiontesting and a maximal incremental exercisetest to characterize
their condition. At the start of the protocol subjects will be subjected to
complete lungfunction testing after which an exercise test on a bicyle
ergometer is preformed. After the exercise test, subjects are instructed to
take 1 tablet (600 mg) fluimucil or placebo three times daily for 7 days. After
7 days subjects will return to the hospital and the complete lungfunction
testing and the exercise test are repeated. The next 7 days will serve as a
wash-out period and no additional treatment is prescribed. After the wash-out
period of 7 days subjects again will visit the hospital and complete
lungfunction testing and the exercise test are repeated. After the exercise
test subjects are instructed to take 1 tablet (600 mg) placebo or fluimucil
three times daily for 7 days. After 7 days subjects will return to the hospital
for the last time and again complete pulmonary function testing and the
exercise test are repeated.
Before, during and after each bicylce ergometry test arterial blood samples
will be taken. Bloodsamples will be analysed for markers of oxidative stress;
Thiobarbituric acid reactive substance (TBARs), Malondialdehyde (MDA), oxidized
versus reduced glutathione (GSSG/GSH) and antioxidant capacity (ferric reducing
ability of plasma (FRAP)). Furthermore ROS-production by neutrophils will be
determined. Also, leukocyt concentration, high sensitivity C-reactive protein
(HS CRP), interleukin (IL)-6, IL-8, IL-1ra and TNFα will be determined.
Finally, blood will be analysed for markers of muscle damage (troponin I) and
muscle breakdown (activity of the ubiquitin-proteasome system).

The same protocol will be applied for rosuvastatin. Subjects will take 1 tablet
(20 mg) per day for 7 days. During the protocol the investigator and
laboratories will be blinded for treatment groups.

We study the influence of n-acetylcysteine and rosuvastatin on the parameters
of systemic inflammation, oxidative stress and muscle breakdown in bloodsamples
of muscle depleted COPD patients, before and after bicycle ergometry.
Rosuvastatin has antiinflammatory properties by reducing the number of adhesion
molecules on endothelial cells, through a proces which involves endothelial
nitric oxide synthase and nitric oxide. Eventually it prevents the adhesion of
the leukocytes to the endothelial cells. Furthermore, in vitro crestor induced
hemeoxygenase, an enzyme that catalyzes the degradation of heme to form
biliverdin and its metabolic product bilirubin. Both products are strong
antioxidants.
N-acetylcysteine acts as a precursor of cysteine. The availibility of cysteine
is the rate limiting step in the synthesis of glutathione, which plays an
important role in the prevention of oxidative damage.

Pilot study
One patient will receive n-acetylcysteine 600 mg and placebo 3-times daily and
the other will receive rosuvastatin 20 mg and placebo 1 time daily according to
the design shown in figure 1. This pilot study will consist of three pairs of
treatment periods. Each period consists of treatment with placebo and active
substance, both for 7 days. After each pair of treatment, there is a washout
period of one week.

Main experiment
After inclusion, one group of patients and one group of healthy subjects
receives 3 times daily 600 mg n-acetylcysteine or placebo (randomized, dubbel
blind) for one week. After this week a wash-out period of one week is included
in the protocol. After the wash-out the groups receive the other treatment
(placebo or n-acetylcysteine) for one week.
The same protocol will be applied for rosuvastatin. Subjects will take 1 tablet
(20 mg) per day for 7 days.

Measurements involving bicycle ergometry including the obtainment of blood
samples are part of the regular controle, treatment and rehabilitation program
of COPD patients and are generally beared well. During exercise testing vital
functions are constantly monitored. The test is immediatly aborted when
abnormalities occur. Blood is obtained by placing an arterial cannula in the
arteria radialis. Placement of the cannula will be done under locale anesthesia
and can cause a little discomfort. This rarely leads to hematoma, flebitis,
thrombosis, sepsis or local stimulation of the nerve. These complications have
not occured last decade at our department.