Nacystelyn, a novel lysine salt
of N-acetylcysteine, to augment cellular
antioxidant defence in vitro.
Respir Med (ENGLAND) Mar 1997, 91 (3)
p159-68
Nacystelyn (NAL), a recently-developed
lysine salt of N-acetylcysteine (NAC), and
NAG, both known to have excellent mucolytic
capabilities, were tested for their ability to
enhance cellular antioxidant defence
mechanisms. To accomplish this, both drugs
were tested in vitro for their capacity: (1)
to inhibit O2- and H2O2 in cell-free assay
systems; (2) to reduce O2- and H2O2 released
by polymorphonuclear leukocytes (PMN); and (3)
for their cellular glutathione (GSH) precursor
effect. In comparison with GSH, NAL and NAC
inhibited H2O2, but not O2-, in cell-free, in
vitro test systems in a similar manner. The
anti-H2O2 effect of these drugs was as potent
as that of GSH, an important antioxidant in
mammalian cells. To enhance cellular GSH
levels, increasing concentrations (0-2 x
10(-4) mol l-1) of both substances were added
to a transformed alveolar cell line (A549
cells). After NAC administration (2 x 10(-4)
mol l-1), total intracellular GSH (GSH +
2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol
per 10(6) cells, whereas NAL increased GSH to
8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC
and NAL administration also induced
extracellular GSH secretion; about two-fold
(NAC), and 1.5-fold (NAL), respectively. The
GSH precursor potency of cystine was about
two-fold higher than that of NAL and NAC,
indicating that the deacetylation process of
NAL and NAC slows the ability of both drugs to
induce cellular glut production and secretion.
Buthionine-sulphoximine, which is an inhibitor
of GSH synthetase, blocked the cellular GSH
precursor effect of all substances. In
addition, these data demonstrate that NAC and
NAL reduce H2O2 released by freshly-isolated
cultured blood PMN from smokers with chronic
obstructive pulmonary disease (COPD) (n = 10)
in a similar manner (about 45% reduction of
H2O2 activity by NAC or NAL at 4 x 10(-6) mol
l-1). In accordance with the results obtained
from cell-free, in vitro assays, O2- released
by PMN was not affected. Ambroxol
(concentrations: 10(-9)-10(-3) mol l-1) did
not reduce activity levels of H2O2 and O2- in
vitro. Due to the basic effect of dissolved
lysine, which separates easily in solution
from NAL, the acidic function of the remaining
NAC molecule is almost completely neutralized
[at concentration 2 x 10(-4) M: pH 3.6 (NAC),
pH 6.4 (NAL)]. Due to their function as H2O2
scavengers, and due to their ability to
enhance cellular glutathione levels, NAL and
NAC both have potent antioxidant capabilities
in vitro. The advantage of NAL over NAC is
two-fold; it enhances intracellular GSH levels
twice as effectively, and it forms neutral pH
solutions whereas NAC is acidic. Concluding
from these in vitro results, NAL could be an
interesting alternative to enhance the
antioxidant capacity at the epithelial surface
of the lung by aerosol administration.
Retinoic acid treatment abrogates
elastase-induced pulmonary emphysema in
rats
Nat Med (UNITED STATES) Jun 1997, 3 (6)
p675-7
Pulmonary emphysema is a common disease in
which destruction of the lung's gas-exchange
structures (alveoli) leads to inadequate
oxygenation, disability and frequently death;
lung transplantation provides its only
remediation. Because treatment of normal rats
with all-trans-retinoic acid increases the
number of alveoli, we tested whether a similar
effect would occur in rats with emphysema.
Elastase was instilled into rat lungs,
producing changes characteristic of human and
experimental emphysema: increased lung volume
reflecting a loss of lung elastic recoil,
larger but fewer alveoli and diminished
volume-corrected alveolar surface area due to
destruction of alveolar walls. Treatment with
all-trans-retinoic acid reversed these changes
providing nonsurgical remediation of emphysema
and suggesting the possibility of a similar
effect in humans.
The
level of antioxidant enzymes in red blood
cells of patients with chronic obstructive
pulmonary disease
Tuberculosis and Respiratory Diseases
(South Korea), 1997, 44/1
Background: Toxic oxygen free radicals have
been implicated as important pathological
mediators in many clinical disorders.
Enhancing the intracellular content of
antioxidant enzymes(superoxide dismutase,
glutathione peroxidase, and catalase) can
provide means of limiting biological damage
caused by oxygen free radicals. The oxygen
free radicals and changes of antioxidant
enzymes are though to play a role in
pathogenesis of chronic obstructive pulmonary
disease. Method: To investigate the pulmonary
oxygen radical injury and the protective role
of antioxidant enzymes in Chronic obstructive
pulmonary disease (COPD), author measured the
amount of thiobarbituric acid reactants, the
activities of antioxidant enzymes and the
sulfhydryl groups of glutathione in serum and
red blood cells from the patients with
COPD(COPD patients) and the normal controls.
Results: The thiobarbituric acid reactant in
serum and red blood cells of COPD patients was
increased than those of the normal controls,
and the superoxide dismutase activity in red
blood cells was no statistical difference in
both groups. But the glutathione peroxidase
and catalase activities in red blood cells of
COPD patients were significantly lowered than
those of the normal controls. The sulfhydryl
groups in serum and in red blood cells were no
statistically difference in both groups.
Conclusion: These results suggest that the
increased thiobarbituric acid reactants in
serum and RBCs of chronic obstructive
pulmonary disease mean oxygen radical
toxicity, and the decreased glutathione
peroxidase and catalase activities in RBC
could take part in pathogenesis of chronic
obstructive pulmonary disease.
Systemic oxidative stress in
asthma, COPD, and smokers
American Journal of Respiratory and
Critical Care Medicine (USA), 1996, 154/4 I
(1055-1060)
An imbalance between oxidants and
antioxidants is proposed in smokers and in
patients with airways diseases. We tested this
hypothesis by measuring the Trolox equivalent
antioxidant capacity (TEAC) of plasma and the
levels of products of lipid peroxidation as
indices of overall oxidative stress. The
plasma TEAC was markedly reduced (0.66 plus or
minus 0.07 mmol/L; mean plus or minus SEM; n =
11), with increased levels of lipid
peroxidation products, in healthy chronic
smokers as compared with healthy nonsmokers
(1.31 plus or minus 0.10 mmol/L, n = 14, p
< 0.001), an effect that was exaggerated in
those who had smoked 1 h before the study.
Plasma TEAC was also low in patients
presenting with acute exacerbations of chronic
obstructive pulmonary disease (COPD) (0.46
plus or minus 0.10 mmol/L, n = 20, p <
0.001) or asthma (0.61 plus or minus 0.05
mmol/L, n = 9, p < 0.01) with increases in
plasma lipid peroxidation products. There was
a negative correlation between superoxide
anion release by stimulated neutrophils and
plasma antioxidant capacity (r = -0.73, p <
0.001) in patients with acute exacerbations of
COPD. The profound decrease in TEAC was
associated with a decreased plasma protein
sulfhydryl concentrations in acute
exacerbations of COPD but not in smokers or in
asthmatic subjects. Therefore smoking, acute
exacerbations of COPD, and asthma are
associated with a marked oxidant/antioxidant
imbalance in the blood, associated with
evidence of increased oxidative stress. The
decreased antioxidant capacity in plasma may
result from different mechanisms in these
conditions.
Role
of oxidants/antioxidants in smoking-induced
lung diseases
Free Radical Biology and Medicine (USA),
1996, 21/5 (669-681)
An imbalance between oxidants and
antioxidants has been considered in the
pathogenesis of smoking-induced lung diseases,
such as chronic obstructive pulmonary disease
(COPD), particularly emphysema. Recent
evidence indicates that increased neutrophil
sequestration and activation occurs in the
pulmonary microvasculature in smokers and in
patients with COPD, with the potential to
release reactive oxygen species (ROS). ROS
generated by airspace phagocytes or inhaled
directly from the environment also increase
the oxidant burden and may contribute to the
epithelial damage. Although much research has
focused on the protease/antiprotease theory of
the pathogenesis of emphysema, less attention
has been paid to the role of ROS in this
condition. The injurious effects of the
increased oxidant burden in smokers and in
patients with COPD are opposed by the lung
antioxidant defences. Hence, determining the
mechanisms regulating the antioxidant
responses is critical to our understanding of
the role of oxidants in the pathogenesis of
smoking- induced lung diseases and to devising
future strategies for antioxidant therapy. In
this article we have reviewed the evidence for
the presence of an oxidant/antioxidant
imbalance in smoking-induced lung disease and
its relevance to therapy in these
conditions.
Effect of beta2-adrenoceptor
agonists on plasma potassium and
cardiopulmonary responses on exercise in
patients with chronic obstructive pulmonary
disease
European Journal of Clinical Pharmacology
(Germany), 1996, 49/5 (341-345)
Objective: The effect of beta2-adrenoceptor
agonist-induced hypokalaemia on cardiac
arrhythmias might be exacerbated during
exercise, especially in patients with more
compromised airway function. Methods: To
evaluate the effect of beta2-adrenoceptor
agonists on plasma potassium and
cardiopulmonary function during exercise, two
identical submaximal treadmill exercise tests
were performed, at least 48 h apart, by 13
patients with moderate to severe COPD (11 men
and 2 women, mean age 66 y, mean FEV1/FVC
ratio 48.9 (2.8)%) 30 min after they had
received nebulised fenoterol or salbutamol (2
mg). The experiment was done as a randomised,
double-blind, crossover trial after an initial
baseline study with vehicle (0.45% saline).
Plasma potassium concentration, spirometry and
the degree of breathlessness (Borg scale) were
measured before treatment and immediately
after exercise; oxygen saturation, QTc
interval and cardiac rhythm were monitored
continuously before, during and for 30 min
after exercise. Results: After the saline
control, exercise caused an increase in Borg
rating (of 4.9), a premature ventricular
contractions (VPC) (2.8 beats/min), and a fall
in oxygen saturation (-6.7%), but no
significant change in plasma potassium (+0.04
mEq . dl-1), FEV1 or QTc interval. Inhalation
of fenoterol and salbutamol did not affect QTc
interval, Borg scale or VPC frequency at rest,
but significantly increased the duration of
exercise undertaken to reach the submaximal
levels (786 s, versus 783 s) compared to the
vehicle control. Following exercise, plasma
potassium fell after fenoterol by 0.2 mEq .
dl-1 and it increased after salbutamol by 0.1
mEq . dl-1 compared to baseline levels. Plasma
potassium after exercise was significantly
lower after fenoterol (3.2 mEq . dl-1)
compared to the saline control (3.7 mEq .
dl-1) and salbutamol (3.6 mEq . dl-1). Neither
fenoterol nor salbutamol had any significant
effect on the change in FEV1, oxygen
saturation, Borg scale, frequency of VPCs or
QTc interval during or after exercise compared
to the saline control. Conclusion: When
compared to salbutamol 2 mg, fenoterol 2 mg
caused more marked hypokalaemia but no
significant difference in cardiopulmonary
response in patients with COPD during
exercise.
Muscle and serum magnesium in
pulmonary intensive care unit
patients.
Crit Care Med (UNITED STATES) Aug 1988, 16
(8) p751-60
Muscle specimens by means of quadriceps
femoris needle biopsy and blood samples were
obtained in 32 patients consecutively admitted
to a pulmonary ICU for chronic obstructive
pulmonary disease and acute respiratory
failure, and in 30 age and sex-matched healthy
control subjects. Muscle magnesium (Mg) and
potassium (K) content was assessed by atomic
absorption spectrophotometry; serum
electrolytes were also measured. The presence
of clinical and biochemical correlates of low
serum and muscle Mg was investigated. Three
(9.4%) out of 32 patients had hypomagnesemia
(Mgs less than or equal to 0.7 mmol/L) with
normal muscle Mg values, whereas low muscle Mg
values were found in 15 (47%) of 32 patients,
with no alterations of serum Mg levels. Muscle
Mg was decreased significantly in pulmonary
ICU patients as compared to control subjects.
No significant correlation was present between
serum and muscle Mg, or between serum and
muscle K. Significant relationships between
muscle Mg and both muscle and intracellular K
concentrations were also found. Lower values
for muscle and intracellular K and a higher
incidence of both more prolonged ICU stays and
ventricular extrasystolic beats characterized
the ICU patients with altered muscle Mg
levels. We conclude that, given the serious
complications of Mg metabolism derangements,
the presence of altered cell Mg content should
be taken into account in pulmonary ICU
patients. Moreover, in these patients, serum
Mg levels are of little value in the diagnosis
of intracellular Mg deficits.
Fluid
and electrolyte considerations in diuretic
therapy for hypertensive patients with chronic
obstructive pulmonary disease.
Arch Intern Med (UNITED STATES) Jan 1986,
146 (1) p129-33
When a patient with chronic obstructive
pulmonary disease (COPD) requires medical
therapy for systemic hypertension, a number of
special considerations may affect the choice
of antihypertensive drug and subsequent
management. Thiazide diuretics have no adverse
effect on airway function and are the agents
of choice for initial therapy.
beta-Antagonists are usually considered
first-line agents in antihypertensive therapy,
but even relatively cardioselective ones may
increase airway resistance in patients with
obstructive lung diseases, and they should be
used with caution, if at all, in such
patients. Although potassium-wasting diuretics
are the preferred agents for treating
hypertension in patients with COPD, they may
worsen carbon dioxide retention in
hypoventilating patients and potentiate
hypokalemia in those receiving
corticosteroids. In addition, beta-agonists
may substantially lower serum potassium levels
in patients already rendered hypokalemic by
diuretics. Patients with COPD receiving
potassium-wasting diuretics who have chronic
respiratory acidosis or are receiving
corticosteroids or beta-agonists should
undergo close monitoring of electrolyte levels
and be considered for therapy with potassium
supplements or, preferably, potassium-sparing
agents.
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