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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.
Safety and effectiveness of
ticarcillin plus clavulanate potassium in treatment of lower
respiratory tract infections.
Am J Med (UNITED STATES) Nov 29 1985, 79 (5B) p78-80
The safety and effectiveness of ticarcillin plus
clavulanate potassium was evaluated in an open study of 43
patients with community-acquired lower respiratory tract
infections. The mean age of the 28 patients in whom
bacteriologic evaluations were possible was 55 years; at least
two thirds of the patients had a history of alcoholism or
chronic obstructive pulmonary disease. A pathogen was isolated
from sputum samples in 23 patients; five of these 23 also had
documented bacteremia. There were five additional cases of
bacteremia associated with clinical signs and symptoms of
pneumonia but with no organisms isolated from sputum cultures.
Thirty-five pathogens were isolated from the 33 evaluable
infection sites, primarily Streptococcus pneumoniae and
Hemophilus influenzae. S. pneumoniae was the causative
organism in all 10 cases of bacteremia. Ticarcillin plus
clavulanate potassium (3 g of ticarcillin and 100 mg of
clavulanic acid) was administered intravenously for a mean of
six days. All 35 organisms isolated before treatment were
eradicated. In one patient a superinfection with Pseudomonas
aeruginosa developed after treatment with ticarcillin plus
clavulanate potassium. A clinical evaluation was possible for
32 of the 33 infection sites; clinical cure was achieved at 31
sites and improvement was seen at the other site. All 43
patients were monitored for adverse reactions by both clinical
observation and laboratory tests. In one patient, reversible
thrombocytopenia developed that required discontinuation of
ticarcillin plus clavulanate potassium. In another patient,
there was a slight decrease in the potassium level during
therapy. No systemic adverse reactions occurred, nor was there
any instance of local effects associated with the intravenous
infusion of the drug.
Frequently nebulized
beta-agonists for asthma: effects on serum
electrolytes.
Ann Emerg Med (UNITED STATES) Nov 1992, 21 (11)
p1337-42
STUDY OBJECTIVE: To determine the magnitude of the changes
in serum potassium, magnesium, and phosphate during the
treatment of acute bronchospasm with repeated doses of
beta-adrenergic agonists. DESIGN: Prospective study of a
convenience sample of asthmatic patients. SETTING: University
teaching hospital emergency department. TYPE OF PARTICIPANTS:
Twenty-three patients met the inclusion criteria of age of
more than 16 years; a history of asthma or chronic obstructive
pulmonary disease; and an acute exacerbation. INTERVENTIONS:
Baseline peak expiratory flow rate and serum potassium,
magnesium, and phosphate levels were measured. Nebulized
albuterol (2.5 mg) was administered every 30 minutes until the
patient was discharged from the ED. Before each albuterol
treatment, repeat serum levels of potassium, magnesium, and
phosphate were determined. MEASUREMENTS AND MAIN RESULTS:
Baseline peak expiratory flow rate averaged 188 +/- 119 L/min.
Serum potassium levels decreased significantly (P = .0001 by
repeated-measures analysis of variance) from 4.10 +/- 0.468
(baseline) to 3.55 +/- 0.580 mmol/L (90 minutes) and 3.45 +/-
0.683 mmol/L (180 minutes). Potassium decreased to less than
3.0 mmol/L in 22% of patients at some point during the study.
Magnesium decreased from 1.64 +/- 0.133 mmol/L (baseline) to
1.48 +/- 0.184 mmol/L (90 minutes) and 1.40 +/- 0.219 mmol/L
(180 minutes) (P = .0001). Phosphate levels also decreased,
from 3.74 +/- 1.029 (baseline) to 2.84 +/- 0.957 mmol/L (90
minutes) and 2.55 +/- 0.715 mmol/L (180 minutes) (P = .0001).
CONCLUSION: Aggressive administration of nebulized albuterol
during the emergency treatment of acute bronchospasm is
associated with statistically significant decreases in serum
potassium, magnesium, and phosphate. The mechanism and
clinical significance of these findings are unknown and
warrant further study.
Effect of nebulized albuterol
on serum potassium and cardiac rhythm in patients with asthma
or chronic obstructive pulmonary disease.
Pharmacotherapy (UNITED STATES) Nov-Dec 1994, 14 (6)
p729-33
STUDY OBJECTIVE. To evaluate the metabolic and
cardiopulmonary effects of nebulized albuterol in patients
suffering moderate to severe exacerbations of asthma or
chronic obstructive pulmonary disease. DESIGN. Open-label,
prospective study. SETTING. The emergency department of a
university medical center. PATIENTS. Ten patients with
moderate to severe exacerbation of asthma. INTERVENTIONS. Each
patient received nebulized albuterol 2.5 mg for approximately
10 minutes. MEASUREMENTS AND MAIN RESULTS. Serum potassium,
heart rate and rhythm, blood pressure, and pulmonary function
were measured before treatment and every 15 minutes for 2
hours after treatment. Serum potassium concentrations
decreased significantly (p < 0.05) within 75 minutes after
initiation of treatment, from a baseline value of 4.5 +/- 0.6
mEq/L (range 3.5-5.5 mEq/L) to 3.7 +/- 0.5 mEq/L (range
2.8-4.4 mEq/L) at the end of the collection period (120
minutes). Forced expiratory volume in 1 second significantly
increased over time in patients with asthma (p < 0.05). No
statistically significant changes in blood pressure, heart
rate, or corrected QT intervals occurred. Pre-emergency
department use of a beta 2-agonist by metered-dose inhaler was
not associated with a decreased serum potassium on admission.
CONCLUSIONS. Nebulized beta 2-agonists are generally
efficacious and safe in patients with acute bronchospasms.
However, close monitoring of serum electrolytes, heart rate,
and rhythm in patients at risk (elderly, those with
pre-existing cardiac disease) is advised before these
individuals receive repeat doses by continuous aerosol
administration.
The intrabronchial microbial
flora in chronic bronchitis patients: a target for
N-acetylcysteine therapy?
Eur Respir J (DENMARK) Jan 1994, 7 (1) p94-101
Chronic bronchitis is common among smokers, often together
with recurrent infectious exacerbations. Streptococcus
pneumoniae and Haemophilus influenzae are the pathogens
traditionally considered most important. N-acetylcysteine
(NAC) treatment has been shown to reduce the number of
infectious exacerbations in patients with chronic bronchitis.
The mechanism behind this is unknown. We attempted to
characterize the intrabronchial bacterial flora in patients
with chronic bronchitis in an infection-free interval, and to
determine whether pharmacological and immunological factors
effected the bacterial occurrence. Twenty two smokers with
non-obstructive chronic bronchitis, 19 smokers with chronic
bronchitis and chronic obstructive pulmonary disease (COPD)
and 14 healthy nonsmokers underwent bronchoscopy. To obtain
uncontaminated intrabronchial samples, a protected specimen
brush was used. Quantitative bacterial cultures and virus
isolations were performed. Significantly positive bacterial
cultures (> 1,000 colony-forming units (cfu).ml-1) were
found only in the patients. S. pneumoniae and H. influenzae
were found in five patients, and only in the patients without
NAC treatment. The most common bacterium was alpha-haemolytic
streptococcus. Negative cultures were more common in the
healthy controls. Of the various factors examined, only NAC
medication had an influence on bacterial numbers.
Significantly fewer patients with NAC medication had positive
cultures (3 out of 16) than in the group of patients without
NAC therapy (15 out of 21). Our results confirm that chronic
bronchitis in smokers leads to increased intrabronchial
bacterial colonization. We could also confirm that 1,000
cfu.ml-1 is an adequate cut-off level for significant
bacterial growth when using the protected specimen brush. NAC
medication was associated with low bacterial numbers.
[The influence of
n-acetylcysteine on chemiluminescence of granulocytes in
peripheral blood of patients with chronic
bronchitis]
Pneumonol Alergol Pol (POLAND) 1993, 61 (11-12)
The effect of NAC on exacerbation of chronic obstructive
pulmonary disease (COPD) may be due to its mucolytic
properties due to the thiol group of NAC and to its reducing
and antioxidant properties. It has been postulated that NAC
may protect lung cells from inhaled oxidants or oxidants
produced by inflammatory leukocytes by increasing intra and
extra cellular GSH. The FMLP induced granulocyte
chemiluminescence (CL) in 6 healthy and 12 patients with COPD
was determined. Peripheral blood polymorphonuclear leukocytes
were incubated with NAC. The results obtained show a
significant decrease of CL after incubation with NAC in both
groups. We also found higher CL in healthy subjects than
patients with COPD. This study showed a significant increase
of FVC, FEV1 and a significant decrease of granulocyte CL
after treatment with oral NAC 200 mg three times daily.
Effects of coenzyme Q10
administration on pulmonary function and exercise performance
in patients with chronic lung diseases.
Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS162-6
Serum coenzyme Q10 (CoQ10) levels were measured at rest and
during incremental exercise in 21 patients with chronic
obstructive pulmonary disease (COPD) and 9 patients with
idiopathic pulmonary fibrosis (IPF). The mean serum CoQ10
levels at rest in patients with COPD and IPF were 0.56 +/-
0.20 and 0.45 +/- 0.16 microgram/ml, respectively. In both
groups these levels were decreased compared with those of
healthy subjects. In the patients with COPD, CoQ10 levels were
significantly correlated with body weight, however, there was
no correlation between CoQ10 levels and ventilatory function,
PaO2, VO2/kg at rest, or maximal VO2. In eight of nine
patients whose PaO2 at rest was lower than 75 torr, serum
CoQ10 levels were lower than 0.5 microgram/ml. We studied the
effects of the oral administration of CoQ10 at 90 mg/day for 8
weeks on pulmonary function and exercise performance in eight
patients with COPD. Serum CoQ10 levels were significantly
elevated in association with an improvement in hypoxemia at
rest, whereas pulmonary function was unaltered. Oxygen
consumption during exercise was not changed, whereas PaO2 was
significantly improved, and heart rate was significantly
decreased compared with the results obtained at an identical
workload at baseline. Furthermore, lactate production was
suppressed during the anaerobic exercise stage after CoQ10
administration, and exercise performance tended to increase.
These data suggested that CoQ10 has favorable effects on
muscular energy metabolism in patients with chronic lung
diseases who have hypoxemia at rest and/or during
exercise
Protection by N-acetylcysteine
of the histopathological and cytogenetical damage produced by
exposure of rats to cigarette smoke.
Cancer Lett (NETHERLANDS) Jun 15 1992, 64 (2) p123-31
Adult male Sprague-Dawley rats were exposed whole-body to
mainstream cigarette smoke (CS) once daily for 40 consecutive
days. Such a treatment resulted in a significant decrease of
body weight growth and in intense histopathological changes of
terminal airways, including a severe inflammation of bronchial
and bronchiolar mucosae, with multiple hyperplastic and
metaplastic lesions and foci of micropapillomatous growth as
well as emphysema, with extensive disruption of alveolar
walls. All histopathological changes were efficiently
prevented by the daily administration of the thiol
N-acetyl-L-cysteine (NAC) by gavage. Cytological and
cytogenetical changes were monitored in bronchoalveolar lavage
(BAL) fluid and bone marrow cells of groups of rats killed
after 1, 3, 8, 28, or 40 days of treatment. From the first day
of exposure, CS significantly enhanced the proportion of
polymorphonucleates among BAL cells and the frequency of
micronucleated (MN) bone marrow polychromatic erythrocytes.
After 8 days, a reduction was observed in the
polychromatic/normochromatic erythrocytes ratio and an
increase in the frequency of MN pulmonary alveolar macrophages
(PAM) was also recorded, followed, after 28 days, by an
increase of binucleated PAM. All these alterations immediately
reached a plateau and persisted unchanged until the end of the
experiment. NAC administration exhibited a significant and
considerable protective effect towards the CS-induced
alterations of BAL cellularity, the increase of MN PAM and
bone marrow cytotoxicity.
Investigation of the
protective effects of the antioxidants ascorbate, cysteine,
and dapsone on the phagocyte-mediated oxidative inactivation
of human alpha-1-protease inhibitor in vitro.
Am Rev Respir Dis (UNITED STATES) Nov 1985, 132 (5)
p1049-54
Oxidants derived from the atmosphere or from activated
pulmonary phagocytes mediate functional inactivation of
alpha-1-protease inhibitor (alpha-1-PI). Chronic exposure to
these oxidants may cause emphysema. In this study we have
investigated the effects of the antioxidants ascorbate,
cysteine (10(-4) M to 10(-1) M), and dapsone (10(-6) M to
10(-3) M) on the oxidative inactivation of human alpha-1-PI by
leukoattractant-activated polymorphonuclear leukocytes (PMNL)
in vitro. During exposure of alpha-1-PI to stimulated PMNL in
the presence of ascorbate and cysteine at concentrations of
greater than 10(-4) M and dapsone at greater than 10(-6) M,
the elastase inhibitory activity of alpha-1-PI was preserved.
However, exposure of the alpha-1-PI to the antioxidants
subsequent to PMNL-mediated oxidative inactivation was not
associated with reactivation of elastase inhibitory capacity.
Ascorbate, cysteine, and dapsone at concentrations that caused
50% protection of alpha-1-PI did not affect degranulation or
the binding of radiolabeled leukoattractant to PMNL. It is
suggested that the protective effects of the antioxidants are
related to their ability to scavenge superoxide and oxidants
generated by the PMNL-myeloperoxidase/H2O2/halide system.
Because the effects of ascorbate and especially those of
dapsone were observed at concentrations of these agents that
are attainable in vivo, our results may have clinical
significance
The role of dornase alfa
(PULMOZYME) in the treatment of cystic
fibrosis
Annals of Pharmacotherapy (USA), 1996, 30/6 (656-661)
Objective: To review the current utility and proper role of
domase alfa (recombinant human DNase or rhDNase), which has
been approved for use in cystic fibrosis. Several aspects
related to these issues are addressed including the drug's
mechanism of action, administration and dosing, and clinical
safety and efficacy. We also critically examine the agent's
role in the treatment of cystic fibrosis and consider the
controversies involved with its use. Data Source: A MEDLINE
search was conducted to identify pertinent literature,
including review articles and clinical trials. Study
Selection: Studies examining the efficacy and safety of
dornase alfa in patients with cystic fibrosis. Data
Extraction: Results from published, prospective, randomized
trials are presented and critique. Data Synthesis: Production
of viscous respiratory secretions is a hallmark phenomenon of
cystic fibrosis, leading to a variety of symptoms. Dornase
alfa targets this symptom and decreases the viscosity of these
secretions. Clinical trials have indicated a small but
statistically significant improvement in forced expiratory
volume in 1 second and forced vital capacity. Enhancement in a
patient's dyspnea and quality of life has varied between the
trials, with few of the studies noting no statistically
significant improvement. Adverse reactions are minimal and did
not result in any patients withdrawals from the trials. A
positive impact on infection rates, length of hospitalization,
and need for intravenous antibiotic therapy was noted in one
trial. However, reports of similar results have not yet been
published, and thus the clinical significance or impact of
this phenomenon is not fully understood. Moreover, results of
more long-term use and in patients whose conditions are less
stable have yet to undergo the scrutiny of peer/editorial
review. Administration of the drug, which must be maintained
continuously, is relatively expensive. Conclusions: dornase
alfa appears to produce small but sustained improvement in
lung function in patients with cystic fibrosis. It may also
slow the progression of pulmonary disease. Infection rate
appear to be reduced, which may well have important long-term
consequences. However, evidence to date has not clarified the
most appropriate use of dornase alfa in the treatment of
cystic fibrosis. Whether quality of life is affected in a
meaningful and measurable way is yet to be clarified. A trial
of the drug in patients with cystic fibrosis who have obvious
lung disease is reasonable, but continued treatment should be
based on clear clinical response. Therefore, questions about
the drug's exact role in the overall management of cystic
fibrosis remain to be answered. Although benefits received may
not prove to be cost-effective, long-term effects on disease
progression may well justify use of this agent.
Inhalation therapy with
recombinant human deoxyribonuclease I Gonda I
(PULMOZYME).
Advanced Drug Delivery Reviews (Netherlands), 1996, 19/1
(37-46)
Infections of the respiratory tract are often associated
with production of purulent sputum. One of the most important
components contributing to the abnormal rheological properties
of this sputum is neutrophil-derived extracellular DNA.
Recombinant human deoxyribonuclease I (rhDNase, dornase alfa)
was developed as a therapeutic protein that is administered by
inhalation of a nebulized aqueous solution to break up this
DNA into small fragments, and thus to correct the viscoelastic
properties of the sputum. The stability of rhDNase during
storage and aerosol generation was investigated. The
methodology used in these studies and in the quantitation of
the therapeutic aerosol available to the patient is reviewed.
The results of the key findings in the clinical trials in
cystic fibrosis and other chronic obstructive pulmonary
diseases are presented.
Aerosolized dornase alpha
(rhDNase-PULMOZYME)) in cystic fibrosis
Journal of Clinical Pharmacy and Therapeutics (United
Kingdom), 1995, 20/6
Advances in the treatment and management of respiratory and
pancreatic disorders has increased the life expectancy of
patients with cystic fibrosis to 28 years (1). Despite the use
of potent antibiotics and chest physiotherapy, persistent
bacterial infection of the lung is the major cause of
morbidity and mortality in these patients (2). This occurs, in
part, because of the production of copious amounts of
pulmonary secretions. It has been found that these secretions
contain high amounts of human DNA (3-8). This high DNA
concentration causes two problems. First, it increases the
viscosity of sputum. This, in conjunction with reduced
mucociliary clearance, decreases the removal of sputum.
Second, the DNA binds to aminoglycosides, which decreases
their antimicrobial efficacy (9, 10). Until recently there was
no effective drug to decrease the viscosity of sputum in
patients with cystic fibrosis. Dornase alpha (Pulmozyme (R))
is the first drug to offer a safe and effective method to
treat excessive DNA in sputum. In vitro studies demonstrated
that rhDNase greatly decreased the viscosity of sputum by
decreasing the concentration of DNA in a
concentration-dependent manner.
New pharmacologic approaches:
rhDNase
Revue de Pneumologie Clinique (France), 1995, 51/3
(193-200)
rhDNase (Pulmozyme (R)) is a new agent in the therapeutic
strategy for patients with cystic fibrosis. It is one of the
first specific treatments aimed at the respiratory tract. It
affects the extracellular DNA which is present in abundant
quantities in the bronchial secretions of these patients.
rhDNase significantly reduces the incidence of infections and
improves respiratory function. It should be used as a major
treatment in combination with all other treatments in patients
over 5 years of age with a vital capacity of at least 40% the
theoretical value. It is important to schedule the respiratory
exercises as a function of rhDNase intake. The long-term
therapeutic benefit remains to be evaluated.
Taurine and serine
supplementation modulates the metabolic response to tumor
necrosis factor alpha in rats fed a low protein
diet
J. NUTR. (USA), 1992, 122/7 (1369-1375)
Plasma taurine and serine decrease following trauma and in
severe inflammatory disease. These changes may signify an
increase in requirements for sulfur amino acids. We previously
demonstrated that cysteine supplementation can restore the
impaired ability of rats fed an 8% casein diet to increase
hepatic zinc, glutathione (GSH) and protein concentrations in
response to tumor necrosis factor alpha (TNFalpha). Here we
examined whether serine or taurine produces a similar effect,
because serine provides the carbon skeleton of cysteine and
taurine is its major metabolite. After 7 d of receiving either
a 20% casein diet supplemented with cysteine or an 8% casein
diet supplemented with alanine, serine or taurine, rats
received an intraperitoneal injection of human TNFalpha. Tumor
necrosis factor caused no change in hepatic GSH but resulted
in a lower GSH concentration in lung in rats fed the
alanine-supplemented diet. Neither taurine nor serine
increased liver GSH relative to that in rats fed alanine, but
the depression in lung due to TNF injection was lessened. The
absolute increase in ceruloplasmin in response to TNF was
enhanced in rats fed the alanine-supplemented diet relative to
those fed the 20% casein diet. Serine normalized this
response. This observation-the effects of taurine and serine
on lung GSH and a significant negative correlation between
ceruloplasmin and liver and lung GSH concentration in rats fed
TNF-suggests that supplemental serine and taurine may improve
antioxidant defenses when dietary supplies of cysteine are low
but do not influence cysteine availability for a normal
response to TNF.
L-Carnitine and its role in
medicine: A current consideration of its pharmacokinetics, its
role in fatty acid metabolism and its use in ischaemic cardiac
disease and primary and secondary L-carnitine
deficiencies
Epitheorese Klinikes Farmakologias kai Farmakokinetikes
(Greece), 1996, 14/1 (11-64)
L-Carnitine (L-beta-hydroxy-4-N-trimethylaminobutyric acid)
is an essential nutrient in animals and humans, which is
synthesised endogenously, mainly in liver and kidney, or
obtained from diet, with principal sources red meat in adults
and human milk in infants. L-Carnitine is a cofactor of
several enzymes, including carnitine-acylcarnitine translocase
embedded in the inner mitochondria membrane, and two
acylcarnitine (palmitoyl) transferases I and II, located
respectively in the outer and inner mitochondrial membrane;
these biomolecules are required in mammalian tissues to
transfer long-chain acyl CoAs across the inner membrane for
beta-oxidation in the matrix. Furthermore, intramitochondrial
L-carnitine and the matrix enzyme L-carnitine
acetyltransferase can react with short- and medium-chain acyl
CoAs to produce acylcarnitines, which can be shuttled out of
mitochondria. Through this mechanism, L-carnitine is able to
modulate the intracellular concentrations of free CoA and
acetyl CoA via reversible formation of acetylcarnitine.
Therefore, besides shuttling long-chain fatty acids into
mitochondria, L-carnitine facilitates the oxidation of
pyruvate and branched-chain ketoacids and, by preventing their
accumulation, it contributes to the protection of cells from
the potentially membrane-destabilising acyl CoAs. In the
absence of L-carnitine, the accumulation of free fatty acids
in the cytoplasm produces a toxic effect on the cell, and an
energy deficit arises from the unavailability of fatty acids
within the mitochondria. L-Carnitine is present in tissues and
biological fluids in free and esterified forms. In humans,
acylcarnitine esters account for about 25% of total
L-carnitine in serum and for about 15% of total L-carnitine in
liver and skeletal muscle. Total L-carnitine concentration in
human tissues is higher in the heart and skeletal muscle
(3.5-6.0 and 2.0-4.6 micromol/g, respectively) than in the
liver and the brain (1.0-1.9 and 0.5-1.0 micromol/g,
respectively): these values reflect the higher rates of fatty
acid oxidative metabolism in the former tissues. The
pharmacokinetics of exogenously administered L-carnitine have
not been completely described. In the case of L-carnitine
preparations from Sigma Tau Pharmaceuticals, peak plasma
concentrations of free L-carnitine of 25 and 91 micromol/l
have been attained 3 and 3,5 hours following single oral 30
and 100 mg/kg doses, respectively. L-Carnitine is actively
transported into tissues via a saturable system, although
passive diffusion also occurs. The apparent volume of
distribution is about 37 l. The compound is likely metabolised
in humans by partial conversion to acyl-carnitine esters and
therefore is eliminated through the kidneys. The portion of a
dose of L-carnitine excreted in the urine within 24 hours
depends on the route of administration; thus, after an
intravenous dose 86% has been recovered, in contrast to 7% of
a dose recovered within 24 hours after an oral dose. Faecal
elimination accounts for less than 2% of a dose. In healthy
volunteers, the biological hallife of L-carnitine varies from
3 to 12 hours, depending on the dosage schedule. Over the past
decade many clinical trials have suggested that L-carnitine
may be administered to patients with ischaemic cardiac
disease. The rationale for the use of L-carnitine in such
patients initially originated from the findings that
myocardial L-carnitine concentrations are lower in patients
with fatal myocardial infarction, due to an increased lactate
production and decreased energy output of cardiac muscle, than
in those dying from non-cardiac causes. L-Carnitine has been
shown to improve pyruvate metabolism, to reduce lactate
production and acidosis and to act as a scavenger of toxic
catabolic products of free fatty acids, which accumulate in
the heart during ischaemia. Also, there is evidence for
skeletal muscle L-carnitine deficiency in some patients with
atherosclerotic vascular disease; therefore, L-carnitine
supplementation may have potential to improve skeletal muscle
metabolic and mechanical function. This double effect in
cardiac and skeletal muscle makes L-carnitine attractive for
patients with ischaemic heart disease; L-carnitine seems to
play an important role, not only by enhancing carbohydrate
utilisation, but also by reducing FFA toxicity and acting as a
metabolic modulator in the heart.
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