Doxorubicin induced acute as well as chronic myocardial morphologic
alterations. Twenty patients with normal cardiovascular function were
randomized to 2 groups based on age and dose of doxorubicin. Group I
received placebo 1 hour before doxorubicin administration; group II received
acetylcysteine (N-acetyl-L-cysteine) (Nac) 1 hour before doxorubicin.
Endomyocardial biopsies were performed at base line at 4 and 24 hours after
doxorubicin administration. Biopsy tissue was viewed by electron microscopy,
and stereoscopic techniques were used to determine tubular and mitochondrial
area. The change of the tubular area was similar in the 2 groups, was
maximum at 4 hours, and was proportionately spread throughout the cell. The
mitochondrial swelling was also similar in the 2 groups and proportionate
throughout the cell but was maximum at 24 hours. This study demonstrated
that the acute doxorubicin-induced damage was diffuse and not prevented by
Nac.
Enantioselectivity in the metabolism of mexiletine by conjugation in
female patients with the arrhythmic form of chronic Chagas' heart disease.
Author
Lanchote VL; Cesarino EJ; Santos VJ; Mere Júnior Y; Santos SR
Address
Faculdade de CiÈencias FarmacÈeuticas de RibeirÃao Preto, Universidade
de SÃao Paulo, RibeirÃao Preto, Brazil.
Source
Chirality, 1999, 11:1, 29-32
Abstract
The phenomenon of enantioselectivity in the metabolism of mexiletine (MEX)
conjugation was investigated in eight female patients with the arrhythmic
form of chronic Chagas' heart disease treated with racemic mexiletine
hydrochloride (two 100 mg capsules every 8 hr). Blood samples were collected
up to 24 hr after the administration of the morning dose, with
discontinuation of the subsequent doses during the study period. Plasma
concentrations of N-hydroxymexiletine glucuronide were calculated as the
difference between the concentrations of unchanged and total (unchanged +
conjugated) MEX enantiomers. Total plasma MEX concentrations were analyzed
by HPLC after enzymatic hydrolysis with beta-glucuronidase, the formation of
diastereomeric derivatives with the chiral reagent N-acetyl-L-cysteine/o-phthalaldehyde,
and fluorescence detection. The differences in the pharmacokinetic
parameters of the enantiomers were evaluated by the paired t-test. The
plasma concentrations of the (+)-(S)-MEX did not differ before and after
enzymatic hydrolysis. The pharmacokinetic parameters calculated for
(-)-(R)-N-hydroxymexiletine glucuronide are presented as means (95%
confidence interval): maximum plasma concentration Cmax = 194.0 ng.ml-1
(154.3-233.7), time to maximum plasma concentration tmax = 1.4 hr (0.3-2.5),
area under the plasma concentration versus time curve AUC0-24 = 2099.2
ng.h.ml-1 (1585.6-2612.6), elimination half-life t1/2 beta = 12.8 hr
(9.9-15.6) and extent of conjugation of 31.6% (24.3-38.9%). The present data
indicate stereospecific conjugation of (-)-(R)-N-hydroxymexiletine in the
female patients with the arrhythmic form of Chagas' heart disease.
Enantioselective analysis of N-hydroxymexiletine glucuronide in human
plasma for pharmacokinetic studies.
Author
Lanchote VL; Santos VJ; Cesarino EJ; Dreossi SA; Mere Júnior Y; Santos SR
Address
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de
São Paulo, Brazil.
Source
Chirality, 1999, 11:2, 85-90
Abstract
Enzymatic hydrolysis with beta-glucuronidase/sulfatase was used for the
enantioselective determination of N-hydroxymexiletine glucuronide in plasma
for pharmacokinetic studies. N-Hydroxymexiletine glucuronide was determined
as the quantity of mexiletine released by hydrolysis (difference between the
enantiomeric concentrations of mexiletine obtained with and without
hydrolysis). Plasma samples (100 microliters) were treated at pH 5.0 with 10
mg of the enzyme (Limpet Acetone Powder type I) for 16 hr at 37 degrees C
and extracted at pH 10.4 with diisopropyl ether. Chiral mexiletine
discrimination was obtained by reaction with o-phthalaldehyde/N-acetyl-L-cysteine,
separation of the resulting diastereomers on a C-18 reversed-phase column
with a mobile phase of methanol-0.05 N acetate buffer, pH 5.5 (6.5:3.5,
v/v), and fluorescence detection (lambda ex 350 nm, lambda em 455 nm). The
performance characteristics for the enantioselective analysis of mexiletine
preceded by enzymatic hydrolysis were recovery approximately 90%,
quantification limit 1 ng/ml, and linearity up to 1000 ng/ml plasma for both
enantiomers. The coefficients of variation obtained in the study of intra-
and inter-day precision were respectively 5% and 7% for both enantiomers.
The assay was shown to be suitable for a pharmacokinetic study performed in
a patient with the arrhythmic form of chronic Chagas' heart disease treated
with 200 mg t.i.d. of racemic mexiletine hydrochloride. The high sensitivity
of the method allows analysis of only 100 microliters plasma.
The diagnosis of COPD can easily be made on the basis of history, physical
findings, and simple laboratory procedures. Treatment is aimed at symptoms
and is individualized to the patient's needs. Therapy must be given on a
long-term basis. The patient should be educated in the basic nature of his
disease and encouraged to return to as normal a life as possible. Patients
with COPD often are severely restricted in their earning ability, and
treatment can cause a severe financial drain. Thus the physician should
carefully consider costs--especially the cost of medications. Finally, the
correct choice and use of the many therapeutic measures available can yield
marked symptomatic relief and improvement in lifestyle--often allowing the
patient to return to productive employment.
Early changes in human myocardial nuclei after doxorubicin.
Author
Unverferth BJ; Magorien RD; Balcerzak SP; Leier CV; Unverferth DV
Address
Source
Cancer, 1983 Jul, 52:2, 215-21
Abstract
Ten nuclei from the endomyocardial biopsies for each of the following 32
patients were examined by electron microscopy: seven patients before and
then four and 24 hours after treatment with first-dose doxorubicin; seven
patients before and four and 24 hours after treatment with first-dose
doxorubicin plus N-acetyl cysteine; nine patients with doxorubicin induced
cardiomyopathy; and nine patients with idiopathic congestive cardiomyopathy.
Five criteria were used to semiquantitatively compare nuclei and nucleoli
from each group. The most dramatic changes in nuclear and nucleolar
morphology were seen four hours after doxorubicin administration. Nucleoli
were smaller, contracted or segregated and contained fewer fibrillar centers
and a collapsed or fragmented nucleolonema. The addition of N-acetylcysteine
to treatment did not alter these results. By 24 hours, nuclei had returned
to the pre-treatment status. Long-term doxorubicin therapy produced
increased chromatin clumping and slightly contracted nucleoli. The
idiopathic congestive cardiomyopathic nuclei differed significantly from
these doxorubicin cardiomyopathic nuclei in the decreased amount of
chromatin clumping and the increase in fibrillar centers and nucleonema
pattern. It is concluded from this study that: (1) doxorubicin markedly
alters the morphology of the human myocardial nucleus and nucleolus four
hours after treatment, but these changes diminish by 24 hours; (2) N-acetylcysteine
treatment fails to prevent these changes; and (3) the nuclei and nucleoli of
chronic doxorubicin-induced cardiomyopathy differ significantly from other
congestive cardiomyopathies, but do resemble changes seen four hours after
the first dose of doxorubicin.
We conducted a randomized prospective trial in 19 disease-free soft tissue
sarcoma patients with doxorubicin-induced cardiomyopathy identified by ECG
radionuclide angiography at rest and during exercise to determine the
efficacy of the free radical scavenger, N-Acetyl Cysteine (NAC), in
reversing the drug's cardiotoxic effect. Of the 19 patients, 11 received
oral NAC (5.5 gm/m2 daily for 30 days) and eight patients served as
controls. Patients were stratified for age less than greater than 45 years,
time from final dose of doxorubicin to randomization less than greater than
8 months, and history of treatment with mediastinal irradiation. The two
groups were well-matched for all parameters. Cumulative mean doxorubicin
dose (523 mg/m2 and 532 mg/m2) and range 500-600 mg/m2 was comparable. Left
ventricular (LV) ejection fraction before randomization was not
significantly different between the two groups either at rest (39 +/- 10%
control, 38 +/- 13% NAC) or during exercise (38 +/- 12% control, 35 +/- 11%
NAC). Neither rest nor exercise ejection fraction values changed
significantly in either group between prerandomization and 1-month
postrandomization studies. Late studies performed in seven NAC patients 3-5
months after randomization revealed no difference in LV ejection fraction
compared to 1-month postrandomization values. Clinical course in patients
with overt congestive heart failure was similar in both groups. LV function
did not return to normal in any patient in either group. We conclude that
N-Acetyl Cysteine has no effect in reversing long standing doxorubicin-induced
cardiomyopathy.
Potentiation of isosorbide dinitrate effects with N-acetylcysteine in
patients with chronic heart failure.
Author
Mehra A; Shotan A; Ostrzega E; Hsueh W; Vasquez Johnson J; Elkayam U
Address
Department of Medicine, University of Southern California School of
Medicine, Los Angeles 90033.
Source
Circulation, 1994 Jun, 89:6, 2595-600
Abstract
BACKGROUND: Supply of sulfhydryl groups with the administration of N-acetylcysteine
(NAC) has been reported to reverse tolerance to nitroglycerin but not to
isosorbide dinitrate (ISDN). Lack of interaction between NAC and ISDN was
suggested as an explanation for these findings. The present study was
therefore designed to further evaluate this hypothesis. For this purpose, we
compared the hemodynamic and hormonal effects of ISDN when given alone and
in combination with NAC. METHODS AND RESULTS: We performed a randomized,
cross-over design evaluation of the hemodynamic and hormonal effects of ISDN
and ISDN + NAC in 14 patients with chronic congestive heart failure due to
left ventricular systolic dysfunction. The findings of this study
demonstrated a substantial NAC-mediated potentiation of ISDN effect on mean
right atrial pressure (-11 +/- 21% versus -38 +/- 27%, -17 +/- 20% versus
-34 +/- 27%, and -7 +/- 20% versus -25 +/- 26% at 2, 3, and 4 hours,
respectively; all P < .05), mean pulmonary artery wedge pressure (-18 +/-
16% versus -33 +/- 14%, -15 +/- 25% versus -33 +/- 19%, -14 +/- 22% versus
-25 +/- 22%, and -16 +/- 16% versus -26 +/- 16% at 2, 3, 4, and 5 hours,
respectively; all P < .05), mean pulmonary artery pressure (-8 +/- 11%
versus -20 +/- 15% at 3 hours, P < .05), and cardiac output (an increase
of 2 +/- 16% versus 25 +/- 20% at 4 hours, P < .05). Although there were
no significant changes in serum catecholamine levels and plasma renin
concentration with both regimens, ISDN + NAC resulted in a greater fall in
plasma levels of atrial natriuretic peptide (296 +/- 251 pg/mL after ISDN
versus 202 +/- 118 pg/mL after ISDN + NAC, P < .05). CONCLUSIONS: The
results of this study provide strong evidence for the existence of an
interaction between thiols and ISDN and further support the role of
sulfhydryl groups in the activation and therapeutic action of organic
nitrates. The discrepancy between the results of this study demonstrating
NAC-induced potentiation of ISDN effects and a previous study showing
failure to reverse ISDN tolerance with NAC may suggest that ISDN-NAC
interaction requires normal intracellular levels of sulfhydryl groups and
does not occur after intracellular sulfhydryl group depletion.
Cardioprotection in patients undergoing chemo- and/or radiotherapy for
neoplastic disease. A pilot study.
Author
Wagdi P; Fluri M; Aeschbacher B; Fikrle A; Meier B
Address
Department of Cardiology, University Hospital, Bern, Switzerland.
Source
Jpn Heart J, 1996 May, 37:3, 353-9
Abstract
OBJECTIVES: To assess the cardioprotective efficiency of an antioxidant
regimen (vitamins E, C and N-acetylcysteine) in patients receiving high dose
chemo- and/or radiotherapy for malignant disease. METHODS: Prospective,
placebo controlled, randomized and double blinded pilot study involving 13
patients receiving chemotherapy and 12 patients receiving radiotherapy.
RESULTS: In patients receiving antioxidants, left ventricular ejection
fraction did not change (63 +/- 4% to 63 +/- 4%). In the placebo group,
ejection fraction changed from 67 +/- 6% to 61 +/- 4% (p = 0.03). No patient
in the antioxidant group and 6/13 (46%) patients in the placebo group showed
a fall of > 10% in the left ventricular ejection fraction. In the
chemotherapy group, the left ventricular ejection fraction changed from 62%
(+/- 2) to 63% (+/- 2) in the patients treated with antioxidants (ns) and
from 63% (+/- 5) to 61% (+/- 5) in patients treated with placebo (ns). No
patient showed a significant fall in ejection fraction in the antioxidant
group, whereas 2/7 (29%) in the placebo group showed a reduction > or =
10%. In the radiotherapy group, left ventricular ejection fraction did not
change 64% (+/- 6) to 64% (+/- 5) in patients treated with antioxidants (ns)
and changed from 70% (+/- 8) to 60% (+/- 4) in patients treated with placebo
(p = 0.008). No patient in the antioxidant group, but 4/6 (66%) patients in
the placebo group showed a fall of > or = 10% in ejection fraction.
CONCLUSION: The small number of patients in the study precludes a definitive
statement. The preliminary results however suggest
efficient cardioprotection by this nontoxic and inexpensive antioxidant
combination, so larger studies are warranted for confirmation.
The author reviews obscure or unusual antidote recommendations,
emphasizing antidotes or antidote uses that are not generally acknowledged
or that have little experimental or clinical confirmation of their efficacy.
Also included are unusual uses of well known antidotes. Among the antidotes
considered are naloxone, physostigmine, folate, Prussian blue, n-acetylcysteine,
cimetidine, subcutaneous magnesium salts, nicotinamide, and thioctic acid.
Homocysteine redox receptor and regulation of extracellular matrix
components in vascular cells.
Author
Tyagi SC
Address
Department of Physiology and Biophysics, University of Mississippi Medical
Center, Jackson 39216, USA.
Source
Am J Physiol, 1998 Feb, 274:2 Pt 1, C396-405
Abstract
Dynamic changes in the reduction-oxidation (redox) state of the tissue
lead to the pathophysiological condition. Reduced homocysteine causes
dysfunctions in endothelium. The proliferation of smooth muscle cells may
lead to occlusive vascular disease, ischemia, and heart failure, but whether
fibrosis and hypertension are a consequence of smooth muscle proliferation
is unclear. Redox changes during hyper-homocyst(e)inemia may be one of the
causes of premature atherosclerotic heart disease. To examine the effect of
homocystine on human vascular smooth muscle cells (HVSMC), we isolated HVSMC
from idiopathic dilated cardiomyopathic hearts. Coronaries in these hearts
were apparently normal. HVSMC numbers in culture were measured by
hemocytometer in the presence and absence of homocystine. Results show that
homocystine induced cellular proliferation. This proliferation was reversed
by the addition of the antioxidant N-acetylcysteine (NAC). Homocystine
induces collagen expression in a dose- and time-dependent manner, as
measured by Northern blot (mRNA) analysis. The 50% inhibitory concentration
of 5 microM for collagen was estimated. The induction of collagen was
reversed by the addition of NAC and reduced glutathione. To localize the
receptor for homocystine on HVSMC, we synthesized fluorescamine-labeled
homocystine conjugate. Incubation of labeled homocystine with HVSMC
demonstrated membrane and cytosol localization of homocystine binding. The
receptor-ligand binding was disrupted by NAC. Based on sodium dodecyl
sulfate-polyacrylamide gel electrophoresis fluorography, we observed a 40-
to 25-kDa homocystine redox receptor in HVSMC. Our results suggested that
the redox homocysteine induces HVSMC proliferation by binding to the redox
receptor and may exacerbate atherosclerotic lesion formation by inducing
collagen expression.
Six cases of pulmonary alveolar proteinosis: presentation of unusual
associations.
Author
García Río F; Alvarez Sala R; Caballero P; Prados C; Pino JM; Villamor J
Address
Dept of Pulmonology, La Paz Hospital, School of Medicine, Autonoma
University, Madrid, Spain.
Source
Monaldi Arch Chest Dis, 1995 Jan, 50:1, 12-5
Abstract
We report the cases of six patients with pulmonary alveolar proteinosis
(PAP). Four of the patients were adults, two males and two females (mean age
39 +/- 19 yrs). The other two patients were children, both females, one aged
6 years and one 3 days old. The diagnosis was made by thoracotomy-lung
biopsy in two subjects, autopsy in two, transbronchoscopic biopsy in one and
bronchoalveolar lavage (BAL) in one. Some of our cases presented unusual
associations that have not been described previously in the medical
literature: renal tubular acidosis, Fanconi's disease, glioblastoma
multiforme and atrioventricular septal defect. In two patients, treatment
with acetylcysteine and ambroxol was unsuccessful. Therapeutic BAL improved
the clinical, analytical, functional and radiological aspects of two cases.
In one subject, three months after the diagnosis of PAP, pulmonary
tuberculosis appeared. Both diseases disappeared with antituberculous
treatment.
Different susceptibility to the development of nitroglycerin tolerance in
the arterial and venous circulation in humans. Effects of N-acetylcysteine
administration.
Author
Ghio S; de Servi S; Perotti R; Eleuteri E; Montemartini C; Specchia G
Address
Division of Cardiology, IRCCS S. Matteo Hospital, Pavia, Italy.
Source
Circulation, 1992 Sep, 86:3, 798-802
Abstract
BACKGROUND. Tolerance to the effects of organic nitrates develops rapidly
during continuous exposure to these drugs; its main mechanism seems to be an
intracellular sulfhydryl group depletion. However, the relative
susceptibility to the development of nitroglycerin tolerance of the arterial
or venous circulation in humans is still a matter of dispute. METHODS AND
RESULTS. Twenty patients with coronary artery disease underwent a continuous
24-hour nitroglycerin infusion followed by a bolus administration of N-acetylcysteine.
Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were
measured by strain gauge plethysmography under control conditions, at the
end of nitroglycerin titration, after 24-hour infusion, and after N-acetylcysteine;
vascular resistance was calculated as mean cuff blood pressure divided by
flow. After 24 hours of nitroglycerin infusion, the initial increase in
venous volume was reduced 48% (p less than 0.01), whereas the acute effects
on vascular resistance were not attenuated in the whole group.
N-Acetylcysteine completely restored nitroglycerin venodilator effects in
all 10 patients in whom attenuation of the venous effects was observed
during the infusion period. CONCLUSIONS. The data
indicate that the susceptibility to the development of nitrate tolerance in
humans is higher in the venous than in the arterial circulation, and that
the sulfhydryl group donor N-acetylcysteine is extremely effective in
reversing nitroglycerin tolerance in the venous circulation in humans.
Development of nitrate tolerance in human arteries and veins: comparison
of nitroglycerin and SPM 5185.
Author
Arnet U; Yang Z; Siebenmann R; von Segesser LK; Turina M; Stulz P; Lüscher
TF
Address
Department of Research, University Hospitals, Basel, Switzerland.
Source
J Cardiovasc Pharmacol, 1995 Sep, 26:3, 401-6
Abstract
Nitrate tolerance is a clinical problem in patients with coronary artery
disease and heart failure. Human internal mammary arteries and saphenous
veins obtained intraoperatively were suspended in organ chambers, and
isometric tension was measured. In the artery, nitroglycerin elicited a
potent relaxation, which was significantly diminished after prolonged
incubation with nitroglycerin (10(-6) M, 1 h). In contrast, no tolerance
occurred in saphenous vein under the same conditions. However, incubation
with 10(-5) M nitroglycerin also developed tolerance. Compared to
nitroglycerin, the new cysteine-containing mononitrate SPM 5185 exhibited a
lower sensitivity but comparable maximal relaxation in arteries and veins.
In nitroglycerin-tolerant arteries and veins, SPM 5185 caused relaxations
similar to those under control conditions. Our results show that in isolated
blood vessels, vascular nitrate tolerance occurs more readily in the mammary
artery than in the saphenous vein. SPM 5185 seems to be less prone to the
development of tolerance, which may be advantageous during chronic nitrate
therapy.
Department of Molecular and Cellular Physiology, Louisiana State
University Medical Center, Shreveport 71130-3932, USA.
Source
Methods Enzymol, 1999, 300:, 345-63
Abstract
It is becoming increasingly apparent that NF-kappa B plays a critical role
in regulating the inflammatory response. Data obtained from studies in our
laboratories demonstrate that the proteasome plays an important role in the
inflammatory cascade by regulating the activation of NF-kappa B. Indeed, the
availability of selective and orally active proteasome inhibitors should
prove useful in delineating the roles of the proteasome and NF-kappa B in
other pathophysiological conditions such as cancer and heart disease.
N-acetylcysteine (NAC), the acetylated variant of
the amino acid L-cysteine, is an excellent source of sulfhydryl (SH) groups,
and is converted in the body into metabolites capable of stimulating
glutathione (GSH) synthesis, promoting detoxification, and acting directly
as free radical scavengers. Administration of NAC has historically been as a
mucolytic agent in a variety of respiratory illnesses; however, it appears
to also have beneficial effects in conditions characterized by decreased GSH
or oxidative stress, such as HIV infection, cancer, heart disease, and
cigarette smoking. An 18-dose oral course of NAC is currently the mainstay
of treatment for acetaminophen-induced hepatotoxicity. N-acetylcysteine
also appears to have some clinical usefulness as a chelating agent in the
treatment of acute heavy metal poisoning, both as an agent capable of
protecting the liver and kidney from damage and as an intervention to
enhance elimination of the metals.
Managing patients with acute myocardial ischemia and reperfusion injury
with N-acetylcysteine.
Author
Stewart S; Ryan C; Poropat S
Address
Department of Cardiology, Queen Elizabeth Hospital, Woodville, South
Australia.
Source
Dimens Crit Care Nurs, 1997 May, 16:3, 122-31
Abstract
Previously administered in cases of acetaminophen toxicity,
N-Acetylcysteine (NAC) is now also being used in the management of acute
myocardial ischemia and reperfusion injury. NAC potentiates the beneficial
effects of nitrates such as nitroglycerin and reduces oxidative stress on
the heart. The critical care nurse plays an important role in optimizing the
therapeutic benefits of NAC and minimizing its potential harmful effects.
Acute Disease; Aged; Case Report; Critical Care; Drug Monitoring; Human;
Male; Nursing Assessment
Publication Type
JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN
0730-4625
Country of Publication
UNITED STATES
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