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Inhibition of the activity of human leukocyte
elastase by lipids particularly oleic acid and retinoic
acid.
Sklan D, Rappaport R, Vered M
Faculty of Agriculture, Hebrew University, Rehovot,
Israel.
Lung 1990;168(6):323-32
The effect of various natural hydrophobic lipids on the in
vitro and in vivo activity of human leukocyte elastase has
been examined. In vitro studies using 2 different substrates
indicated that fatty acids inhibit human leukocyte elastase
activity, with maximum inhibition observed with oleic acid.
Triolein, cholesterol, and beta-carotene caused little
inhibition. The presence of a carboxyl group appears important
since retinoic acid but not retinol also inhibited activity.
In vivo studies of an emphysema model in mice indicated that
intrapulmonary instillation of oleic or retinoic acid reduced
lung injury caused by human leukocyte elastase. The
possibility of using these compounds to diminish elastolytic
damage in emphysema is raised.
Retinoic acid as a therapy for emphysema?
DeLuca LM, Ross SA
Laboratory of Cellular Carcinogenesis and Tumor Promotion,
National Cancer Institute, Bethesda, MD 20892-4255, USA.
Nutr Rev 1997 Aug;55(8):307-8
In concert with its action as a morphogen during embryonal
development, retinoic acid appears to be able to regenerate
lung alveoli in an experimental model of elastase-induced
emphysema in rats, thereby inhibiting manifestation of the
disease. The application to humans is now an interesting
possibility.
Postnatal treatment with retinoic acid increases
the number of pulmonary alveoli in rats.
Massaro GD, Massaro D
Lung Biology Laboratory, Georgetown University School of
Medicine, Washington, District of Columbia 20007, USA.
Am J Physiol 1996 Feb;270(2 Pt 1):L305-10
Dexamethasone, a glucocorticosteroid hormone, inhibits the
formation of alveoli; retinoids and glucocorticosteroid
hormones can be mutually antagonistic. These observations led
us to test the hypothesis that the administration of retinoic
acid to postnatal rats would prevent the low alveolar number
and the low body mass-specific gas-exchange surface area (Sa)
produced by treatment with dexamethasone. We used serial lung
sections to distinguish alveoli from alveolar ducts and
stereological procedures that allow quantitation of alveoli
uninfluenced by their size, shape, or distribution. Treatment
with retinoic acid prevented the low number of alveoli and the
low body mass-specific Sa caused by treatment with
dexamethasone. In otherwise untreated rats, retinoic acid
caused a 50% increase in the number of alveoli, but without an
increase in Sa, suggesting the action of a regulatory
mechanism to prevent unneeded Sa. These findings provide the
first experimental support for the possibility that, in
individuals with too few alveoli for adequate gas exchange,
treatment with a pharmacological agent may provide
preventative or remedial therapy.
Retinoic acid increases elastin in neonatal rat
lung fibroblast cultures.
Liu B, Harvey CS, McGowan SE
Department of Veterans Affairs Research Service, Iowa City,
Iowa.
Am J Physiol 1993 Nov;265(5 Pt 1):L430-7
The factors that regulate elastin synthesis during
pulmonary alveolar septal formation have not been identified.
Because maximal alveolar elastin synthesis occurs over a
relatively brief period (postnatal days 4-14 in the rat), we
hypothesized that changes in the local concentrations of
factors that regulate elastin synthesis may precede or
accompany this period. Because pulmonary retinoid stores
decline just before the fourth postnatal day, we also
hypothesized that this decline could be accompanied by the
utilization of retinoic acid, one of the most biologically
active retinoids, in a regulatory process that increases
elastin synthesis. If these hypotheses are correct, then
retinoic acid should increase elastin synthesis by pulmonary
cells. Therefore, cultures of neonatal rat lung fibroblasts
were exposed to retinoic acid, and elastin production was
quantitated. Retinoic acid produced a two- to threefold
increase in the steady-state level of elastin mRNA, in soluble
elastin, and in insoluble elastin. The transcriptional
initiation rate of the elastin gene was 1.8-fold higher in
nuclei that were isolated from retinoic acid-treated cells
than in nuclei that were isolated from control cells. This
indicates that the increase in steady-state elastin mRNA
results, at least partially, from an increase in elastin
transcription. Lung fibroblasts that were isolated from
8-day-old rats, but not cultured, contained retinoic acid.
These findings suggest that retinoic acid is a potential
regulator of elastin synthesis in developing pulmonary
alveoli.
Possible stimulatory effect of retinoic acid on
pulmonary macrophages.
Cantor JO, Shapiro SS, di Sant'Agnese PA, Cerreta JM, Trown
PW
Experientia 1979 Jul 15;35(7):895-6
Retinoic acid was administered to hamsters suffering from
N-nitroso-N-methylurethane-induced fibrosing alveolitis. A
significant increase in macrophage numbers was seen in the
lungs of retinoid-treated animals as compared to the
unsupplemented group.
Dexamethasone and retinoic acid regulate the
expression of epidermal growth factor receptor mRNA by
distinct mechanisms.
Oberg KC, Carpenter G
Department of Biochemistry, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232-0146.
J Cell Physiol 1991 Nov;149(2):244-51
Retinoic acid and dexamethasone have antagonistic effects
on epidermal growth factor (EGF) receptor expression in fetal
rat lung (FRL) cells: Receptor synthesis is enhanced by
retinoic acid and reduced by dexamethasone. In the presence of
actinomycin D, neither agent has the capacity to modify
receptor synthesis or 125I-EGF binding capacity. Northern blot
analysis demonstrates a tenfold increase in EGF mRNA following
retinoic acid treatment and a 60% decrease in receptor message
levels after dexamethasone treatment. To dissect the
mechanisms of these effects, the expression of mRNA was
separated from effects requiring protein synthesis by the use
of cycloheximide and actinomycin D. Ligand binding, EGF
receptor protein synthesis, and mRNA levels were measured in
cultures of FRL cells that were incubated with retinoic acid
or dexamethasone in the presence of cycloheximide, then washed
and reincubated with fresh media containing actinomycin D, but
not retinoic acid, dexamethasone, or cycloheximide. The
results demonstrate that dexamethasone reduces the expression
of EGF receptor mRNA in the absence of protein synthesis. In
contrast, the mechanism by which retinoic acid increases the
expression of EGF receptor mRNA requires protein synthesis.
These data indicate that, in FRL cells, dexamethasone
negatively regulates EGF receptor mRNA in a direct manner,
while retinoic acid controls transcription of an intermediate
protein, possibly a transcription factor, that subsequently
increases transcription of receptor message.
Plasma retinol-binding protein response to vitamin
A administration in infants susceptible to bronchopulmonary
dysplasia.
Shenai JP, Rush MG, Stahlman MT, Chytil F
Department of Pediatrics, Vanderbilt University School of
Medicine, Nashville, Tennessee.
J Pediatr 1990 Apr;116(4):607-14
We hypothesized that changes in plasma retinol-binding
protein (RBP) concentration in response to vitamin A
administration might be useful for evaluating vitamin A status
of very low birth weight infants susceptible to
bronchopulmonary dysplasia. We prospectively studied 24
consecutively admitted neonates (birth weight less than 1350
gm, gestational age less than 31 weeks, ventilator dependent
for greater than 24 hours after birth), who were eligible to
receive 2000 IU supplemental vitamin A by intramuscular
injection on postnatal day 1 and on alternate days thereafter
for 28 days. In addition to serial assessment of vitamin A
status, we measured plasma RBP just before and 1, 3, and 6
hours after an intramuscular injection of vitamin A (2000
IU/kg retinyl palmitate) on days 1 and 28. The percent
increase in plasma RBP (delta-RBP) was high (mean +/- SD: 61
+/- 37%) and plasma vitamin A and RBP values were low on day
1, indicative of vitamin A deficiency. Supplemental vitamin A
improved vitamin A status of all infants as shown by low
delta-RBP (mean +/- SD: 8 +/- 9%) and normal plasma vitamin A
and RBP values on day 28. Bronchopulmonary dysplasia was
diagnosed in 12 of 24 infants. Infants with bronchopulmonary
dysplasia had a higher mean (+/- SD) delta-RBP on day 28 than
those without bronchopulmonary dysplasia (13 +/- 10% vs 3 +/-
3%, p less than 0.01), indicative of persistence of low
vitamin A status in infants with lung disease despite
supplementation. We conclude that the plasma RBP response to
vitamin A is a useful indicator of vitamin A status in very
low birth weight infants. Although vitamin A supplementation
at the dosage used in this study normalizes conventional
plasma indexes of vitamin A in very low birth weight infants,
the plasma RBP response to vitamin A may continue to reflect
persistence of low vitamin A status in the more immature
infants with significant lung disease. We suggest that the
plasma RBP response to vitamin A may be a useful functional
test in such infants.
Vitamin A status of neonates with bronchopulmonary
dysplasia.
Shenai JP, Chytil F, Stahlman MT
Pediatr Res 1985 Feb;19(2):185-8
We prospectively assessed and compared the vitamin A status
of two groups of preterm neonates (less than 1500 g birth
weight, less than 32 wk gestation), one who developed clinical
and radiographic evidence of bronchopulmonary dysplasia (BPD)
(n = 10), and the other (control) who developed no significant
lung disease (n = 8). The infants with BPD in this study
required prolonged mechanical ventilation and supplemental O2
therapy, and had a higher incidence of cardiorespiratory
complications when compared to controls. Their mean plasma
vitamin A concentrations were significantly lower than those
of controls at four sampling times in the 1st postnatal month.
In contrast to the controls, infants with BPD showed a
substantial decline in their plasma vitamin A concentrations
from the initial values, and a high percentage of individual
values of plasma vitamin A concentration in these infants were
less than 10 micrograms/dl during the 8-wk postnatal period of
observation. Delayed establishment of gastrointestinal feeding
and a lower vitamin A intake in these infants relative to
controls may have accounted for this decline. Our data show
that preterm neonates who develop BPD have suboptimal plasma
vitamin A concentrations for extended periods of time
postnatally. We speculate that the necrotizing bronchiolitis
and squamous metaplasia of conducting airways associated with
vitamin A deficiency could influence the orderly repair of
lung injury in susceptible neonates who are mechanically
ventilated and could contribute to the pathophysiology of BPD
in these infants.
Clinical trial of vitamin A supplementation in
infants susceptible to bronchopulmonary dysplasia.
Shenai JP, Kennedy KA, Chytil F, Stahlman MT
J Pediatr 1987 Aug;111(2):269-77
We conducted a randomized, double-blind, controlled trial
to determine whether vitamin A supplementation from early
postnatal life could reduce the morbidity associated with
bronchopulmonary dysplasia in very low birth weight (VLBW)
neonates. Forty VLBW neonates (700 to 1300 g birth weight, 26
to 30 weeks gestational age), who were oxygen dependent and
required mechanical ventilation for at least 72 hours after
birth, were given by the intramuscular route either
supplemental vitamin A (retinyl palmitate 2000 IU) or 0.9%
saline solution on postnatal day 4 and every other day
thereafter for a total of 14 injections over 28 days. The
study groups were comparable in gestational maturity, clinical
characteristics, initial lung disease, and vitamin A status at
entry into the trial. Vitamin A administration resulted in
significantly higher mean plasma concentrations of vitamin A
and retinol-binding protein in treated infants compared with
controls. Bronchopulmonary dysplasia was diagnosed in nine of
20 infants given vitamin A supplement and in 17 of 20 control
infants (P less than 0.008). Four of 19 infants in the vitamin
A group and 11 of 20 in the control group required mechanical
ventilation on study day 28 (P less than 0.029). The need for
supplemental oxygen, mechanical ventilation, and intensive
care was reduced in infants given vitamin A supplement
compared with controls. Airway infection and retinopathy of
prematurity were less frequent in the vitamin A group. We
conclude that vitamin A supplementation at the dosage used in
this trial in VLBW neonates not only improves their vitamin A
status but also appears to promote regenerative healing from
lung injury, as evidenced by a decrease in the morbidity
associated with bronchopulmonary dysplasia.
Relationship of vitamin A (retinol) status to lung
disease in the preterm infant.
Hustead VA, Gutcher GR, Anderson SA, Zachman RD
J Pediatr 1984 Oct;105(4):610-5
Plasma concentrations of retinol and retinol-binding
protein were measured at birth in 91 preterm infants. In 64%
of these babies retinol values were less than 20
micrograms/dl, suggestive of vitamin A deficiency. Forty-seven
of these infants were observed with sequential measurements of
retinol and retinol binding protein through 21 days of age. In
babies with respiratory distress syndrome retinol values were
similar to those in babies without respiratory distress
syndrome. The retinol binding protein levels were lower on the
third day of life in babies with respiratory distress
syndrome. Babies who developed bronchopulmonary dysplasia had
lower concentrations of retinol at birth (P less than 0.05)
and on day 21 (P less than 0.05) than did babies who did not
develop bronchopulmonary dysplasia, despite receiving
recommended intakes of vitamin A. Many preterm infants are
deficient in vitamin A at birth, and failure to correct this
deficiency may contribute to the development of chronic lung
disease.
Sulfated polysaccharides prevent human leukocyte
elastase-induced acute lung injury and emphysema in
hamsters.
Rao NV, Kennedy TP, Rao G, Ky N, Hoidal JR
Division of Pulmonary Medicine, University of Tennessee,
Memphis.
Am Rev Respir Dis 1990 Aug;142(2):407-12
Studies were designed to explore the possibility that
sulfated polysaccharides had the potential to prevent human
leukocyte elastase (HLE)-induced lung injury. Arteparon
(GAGPS), heparin, heparan sulfate, chondroitin sulfate, and
dextran sulfate, but not dextran, inhibited HLE-mediated
hydrolysis of succinyl-ala2-val-pNA. GAGPS, used as a
paradigmatic sulfated polysaccharide, was a potent inhibitor
of elastolysis in vitro. GAGPS given intratracheally prevented
acute injury and emphysema in hamsters when administered up to
8 h before HLE insufflation. The results suggest that sulfated
polysaccharides may be potent inhibitors of HLE-mediated lung
injury.
[The effect of retinoic acid on DNA synthesis of
fibroblast in vitro culture].
[Article in Chinese]
Song W, Guan Z, Sun G
Plastic Surgery Hospital, Chinese Academy of Medical
Sciences, Beijing.
Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih 1995
Mar;11(2):135-6
The effect of retinoic acid on DNA synthesis of fibroblast
was studied in vitro culture. The results demonstrated that
retinoic acid significantly (P < 0.01) inhibited the DNA
synthesis of fibroblast in vitro culture and a dose-dependent
relationship between DNA synthesis and retinoic acid
concentration was observed. The possible mechanism of retinoic
acid used for the treatment of scar was discussed.
Retinoic acid: biochemistry and metabolism.
Chytil F
J Am Acad Dermatol 1986 Oct;15(4 Pt 2):741-7
Retinoic acid, unlike the naturally occurring vitamin A
(retinol), is a minor component of the human diet. It is
formed in vivo from retinol and has many metabolites. The
biological activity of the metabolites is not higher than that
of retinoic acid itself, indicating that the metabolites must
be products of retinoic acid catabolism. Little is known about
the enzymatic systems responsible for forming retinoic acid or
about how it enters the cell. Discovering the molecular
mechanism(s) of retinoic acid activity in cellular metabolism
is important to understanding its physiologic role. The
pharmacologic effects of high doses of retinoic acid may be
caused by its action on cellular membranes. Conversely, low
concentrations appear to produce physiologic effects. Results
of experiments with animals and with cell cultures indicate
that the primary physiologic role of retinoic acid is in
cellular differentiation. Retinoic acid influences genomic
expression, inducing the appearance of some proteins while
suppressing the expression of others. The existence of an
intracellular retinoic acid-binding protein suggests that it
may mediate the physiologic effects of retinoic acid on
cellular differentiation.
The induction of pulmonary emphysema with human
leukocyte elastase.
Senior RM, Tegner H, Kuhn C, Ohlsson K, Starcher BC, Pierce
JA
Am Rev Respir Dis 1977 Sep;116(3):469-75
Purified human leukocyte elastase was injected into the
tracheas of 46 hamsters. Thirteen animals died spontaneously
within 1 week, with extensive lung hemorrhage. The elastin
content of the lungs was only slightly less than control
values 3 hours after injection. At 2 months, the lungs of the
remaining animals showed mild, patchy emphysema and
morphometric changes consistent with emphysema. These results
contrasted with the effects of a similar elastolytic dose of
pancreatic elastase administered to 26 other hamsters in that
only one animal died spontaneously, the lung elastin content 3
hours after injection was substantially decreased, and severe
emphysema was present 2 months later. Leukocyte elastase
appears to be capable of causing emphysema; but unlike
pancreatic elastase, leukocyte elastase produces emphysema
that is mild, even at a dose sufficient to produce intense
lung hemorrhage and a high mortality.
Regulation of alveolar formation.
Massaro D
Georgetown University, Washington, D.C.
Hosp Pract (Off Ed) 1990 Sep 15;25(9):81-4, 87-8
Postnatal formation of alveoli and their capillaries is
essential to overall development. It enables pulmonary gas
exchange to keep pace with the body's metabolism. Hormones,
nutrition, and oxygen tension appear to regulate alveolar
formation, perturbations of which may lead to normal
variations in lung function or contribute to lung disease.
Nacystelyn, a novel lysine salt of
N-acetylcysteine, to augment cellular antioxidant defence in
vitro.
Gillissen A; Jaworska M; Orth M; Coffiner M; Maes P; App EM;
Cantin AM; Schultze-Werninghaus G
Department of Internal Medicine, University Hospital
Bergmannsheil, Bochum, Germany.
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
Massaro GD; Massaro D
Lung Biology Laboratory, Georgetown University School of
Medicine, Washington, DC 20007-2197, USA.
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
Lee S.-I.
S.-I. Lee, Department of Internal Medicine, Chosun University
Medical College, Kwangju South Korea
Tuberculosis and Respiratory Diseases (South Korea), 1997,
44/1, p104
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
Rahman I.; Morrison D.; Donaldson K.; MacNee W.
Respiratory Medicine Unit, Department of Medicine, Royal
Infirmary, Lauriston Place, Edinburgh EH3 9YW United
Kingdom
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
Rahman I.; MacNee W.
Unit of Respiratory Medicine, Department of Medicine, Royal
Infirmary, Lauriston Place, Edinburgh EH3 9YW United
Kingdom
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
Yang C.-T.; Lin H.-C.; Lin M.-C.; Wang C.-H.; Lee C.-H.; Kuo
H.-P.
Department of Thoracic Medicine, Chang Gung Memorial
Hospital, Taipei Taiwan
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.
Fiaccadori E, Del Canale S, Coffrini E, Melej R, Vitali P,
Guariglia A, Borghetti A
Istituto di Clinica Medica e Nefrologia, Universita degli
Studi di Parma, Italy.
Crit Care Med 1988 Aug;16(8):751-60
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
Hill NS
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.
Mostow SR; O'Brien RF
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.
Bodenhamer J; Bergstrom R; Brown D; Gabow P; Marx JA;
Lowenstein SR
Emergency Medical Services, Denver General Hospital.
Ann Emerg Med 1992 Nov;21(11):1337-42
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.
Dickens GR, McCoy RA, West R, Stapczynski JS, Clifton
GD
Division of Pharmacy Practice and Science, College of
Pharmacy, University of Kentucky, Lexington.
Pharmacotherapy 1994 Nov-Dec;14(6):729-33
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?
Riise GC, Larsson S, Larsson P, Jeansson S, Andersson
BA
Dept of Pulmonary Medicine, Renstrom's Hospital, Gothenburg,
Sweden.
Eur Respir J 1994 Jan;7(1):94-101
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]
Jankowska R, Passowicz-Muszynska E, Medrala W, Banas T,
Marcinkowska A
Katedry i Kliniki Chorob Wewnetrznych i Alergologii AM,
Wroclawiu.
Pneumonol Alergol Pol 1993;61(11-12):586-91
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.
Fujimoto S, Kurihara N, Hirata K, Takeda T
First Department of Internal Medicine, Osaka City University
Medical School.
Clin Investig 1993;71(8 Suppl):S162-6
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.
Balansky RB, D'Agostini F, Zanacchi P, De Flora S
Institute of Hygiene and Preventive Medicine, University of
Genoa, Italy.
Cancer Lett 1992 Jun 15;64(2):123-31
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.
Theron A, Anderson R
Am Rev Respir Dis 1985 Nov;132(5):1049-54
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 in the treatment of cystic
fibrosis.
Cramer GW, Bosso JA
Department of Pharmacy Services, Medical University of South
Carolina, Charleston 29425, USA.
Ann Pharmacother 1996 Jun;30(6):656-61
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).
Gonda I.
Aradigm Corp.,Hayward, CA 94545 United States
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) in cystic
fibrosis.
Bates RD, Nahata MC
College of Pharmacy, Ohio State University, Columbus 43210,
USA.
J Clin Pharm Ther 1995 Dec;20(6):313-5
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
Tournier G; Sardet A; Grosskopf C; Baculard A; Delaisi
B
Service de Pediatrie et de Pneumologie de l'Enfant, Hopital
d'Enfants Armand Trousseau, Paris.
Rev Pneumol Clin 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
Pathirana C, Grimble RF
Institute of Human Nutrition, University of Southampton,
U.K.
J Nutr 1992 Jul;122(7):1369-75
Published erratum appears in J Nutr 1993
Mar;123(3):600
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 half-life 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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