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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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