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[Pharmacodynamics of the cerebral circulation.
Results of a study on the action of 10 drugs on cerebral blood
flow and energy metabolism in cerebrovascular patients]
Marc-Vergnes JP; Bes A; Charlet JP; Delpla M; Richardot JP;
Geraud J
Pathol Biol (Paris) 1974 Nov;22(9):815-25
The authors studied the action of 10 drugs on cerebral
blood flow and metabolism in patients with cerebro vascular
insufficiency. The difficulties of this type of study are due
to the techniques of measurement of cerebral blood flow which
are traumatic, long and relatively inaccurate. Their traumatic
character, which is mainly marked in the case of xenon 133 Xe
clearance, limits their field of application and renders
difficult experimental plans. The length of the examination
restricts the possibilities offered during the same session.
Finally, owing to the relatively inaccurate measurements, only
important changes can be noted. However, during 2 successive
series of measurements, carried out by 2 different methods of
measurement of cerebral blood flow, only preparations
containing hydergine induced a statistically significant
increase in cerebral blood flow and oxygen consumption in the
brain. This finding, which proves that a drug may modify the
parameters, encourages better integration of pharmacodynamic
tests in the physiopathological investigations carried out
during the course of a disease.
Effects of ionic and nonionic contrast media on
clot structure, platelet function and thrombolysis mediated by
tissue plasminogen activator in plasma clots
Carr ME Jr, Carr SL, Merten SR
Department of Medicine, Medical College of Virginia,
Richmond, USA.
Haemostasis (Switzerland), 1995, 25/4 (172-181)
Various radiographic contrast agents have anticoagulant or
prothrombotic properties. Ionic agents are reported to have
greater antithrombotic potential while nonionic agents are
considered more thrombogenic. Some agents alter fibrin
structure and bind to platelets in purified systems. This
study compared the effects of iohexol, a nonionic agent, and
iothalamate, an ionic agent, on fibrin assembly, clot
structure, platelet function and clot dissolution in plasma.
Plasma gels containing increasing concentrations of
iothalamate were composed of thinner fibers with decreased
fiber mass/length ratios (micro) and reduced gel turbidity.
Such clots were more rigid and more resistant to fibrinolysis
induced by tissue plasminogen activator (tPA). Gel elastic
modula increased from 10,000 to 27,000 dyn/cm2 as iothalamate
concentration increased from 0 to 20 mM. 50% lysis time
increased from 800 to 1,250 s with the addition of 10 mM
iothalamate. At 20 mM, iothalamate had no effect on
ADP-induced platelet aggregation but prolonged the lag phase
seen with collagen-induced aggregation. Platelet force
development increased from 15,300 to 20,400 dyn with 20 mM
iothalamate. The effects of iohexol were similar. Gel optical
density dropped from 0.50 to 0.32, micro fell from 3.3 to 2.2
x 1013 D/cm, and elastic modulus rose from 11,000 to 24,000
dyn/cm2 as iohexol concentration was increased from 0 to 20
mM. Clots formed in the presence of 60 mM iohexol and tPA did
not dissolve in 72 h while control clot 50% lysis time was 450
s. At concentrations greater than or equal to 40 mM, iohexol
completely blocked collagen-induced platelet aggregation.
Platelet force development increased from 7,660 to 19,600 with
40 mM iohexol. Contrast media possess profound fibrin-altering
activities in plasma. Fibrin formed in the presence of some
agents may be significantly more resistant to
fibrinolysis.
Thrombolytic therapy: Recent advances. Treatment of
myocardial infarction
Appl. Cardiopulm. Pathophysiol. (Netherlands), 1991/92, 4/3
(193-204)
The objectives of thrombolytic therapy in acute myocardial
infarction are to restore coronary artery patency, salvage
myocardium, reduce infarct size, and facilitate coronary
artery repair. Urokinase and streptokinase are the two most
frequently used thrombolytic agents. Both dissolve thrombi by
converting circulating plasminogen, an inert precursor, into
plasmin. One possible advantage of urokinase and streptokinase
over new 'clot-specific' agents, recombinant tissue
plasminogen activator (rt-PA) anisolylated SK-plasminogen
activator complex (APSAC) and antibody directed UK, SK and
rt-PA, is that the former have pronounced systemic
fibrinolytic effects. This reduces blood viscosity and may
prevent other thrombi from forming. Angiography is the most
objective technique for assessing reestablished arterial
patency, but being invasive, it presents disadvantages.
Noninvasive criteria for coronary reperfusion include lowering
of elevated ST-segments, shifting creatine kinase isoenzyme MB
curves, and the appearance of reperfusion arrhythmias.
Techniques for assessing myocardial salvage include thallium
uptake, assessment of wall motion and myocardial thickening,
ejection fraction, and positron emission tomography to assess
infarct size. The role and appropriate timing of coronary
artery repair after thrombolytic therapy are being studied
intensely. There is no question that thrombolytic agents have
made a significant beneficial impact and advance in the
treatment of myocardial infarction. Considerable information
has indicated that physicians must be educated in the details
of use of thrombolytic agents and they must intensely educate
their patients on the need to make themselves available to
this treatment immediately when suggested by the symptoms and
signs of this disease process.
Selective decrease in lysis of old thrombi after
rapid administration of tissue-type plasminogen
activator
Kanamasa K, Watanabe I, Cercek B, Yano J, Fishbein MC, Ganz
W
Department of Medicine, Cedars-Sinai Medical Center, Los
Angeles, California 90048.
J. Am. Coll. Cardiol. (USA), 1989, 14/5
(1359-1364)
The safety of thrombolytic therapy of acute myocardial
infarction could be improved if a method were developed to
dissolve fresh occlusive coronary thrombus without
simultaneously dissolving hemostatic thrombi outside the
coronary arteries. This study is based on the assumption that,
in a patient with evolving acute myocardial infarction,
hemostatic thrombi are likely to be older than the thrombus
responsible for occlusion of the coronary artery. It explored
whether the relative rates of lysis of fresh and old thrombi
could be influenced by the rapidity of recombinant tissue-type
plasminogen activator (rt-PA) administration. In each of 17
dogs, two 1 h and two 24 h old thrombi were produced by
inserting copper coils into both jugular and both femoral
veins. After 24 h and 1 h, respectively, the coils with the
thrombi were removed, weighed and inserted into the adjacent
carotid and femoral arteries. A 1 mg/kg body weight dose of
rt-PA was given either over 180 or over 30 min. The coils were
removed and weights of the residual thrombi determined at the
end of the 180 min infusion (Group I), at the end of the 30
min infusion (Group IIA) and 45 min after the 30 min infusion
(Group IIB). The 24 h old thrombi were lysed significantly
less than the 1 h old thrombi in all three experimental group:
53.9 plus or minus 4.8% (mean plus or minus SE) versus 86.1
plus or minus 2.5% in Group I (p < 0.001), 16.6 plus or
minus 3.5% versus 65.2 plus or minus 6.0% in Group IIA (p <
0.001) and 21.6 plus or minus 5.4% versus 91.7 plus or minus
1.7% in Group IIB (p < 0.001). The 24 h old thrombi were
also lysed significantly less by the 30 min infusion than by
the 180 min infusion (p <0.001 for both). The ratio of
lysis of 1 and 24 h old thrombi was markedly higher in Groups
IIA (7.95 plus or minus 2.16) and IIB (6.52 plus or minus
1.50) than in Group I (1.71 plus or minus 0.17)(p < 0.01
for both). These findings suggest that rt-PA administered
rapidly over a shorter period is less likely to lyse older
thrombus, whereas the effect on fresh thrombus is preserved
and probably enhanced. Clinical studies are needed to confirm
the conclusions of this experimental study.
Antioxidant Curcuma extracts decrease the blood
lipid peroxide levels of human subjects
Ramirez-Bosa A, Solfer A, Gutierrez M, Alvarez J, Almagro
E
Age (USA), 1995, 18/4 (167-169)
Extracts of the rhyzome of Curcuma longa are widely used as
food additives in India and other Asiatic and Central American
countries. Moreover, it has been recently shown that these
extracts ('turmeric'), as well as 'curcumin' and related
phenolic compounds isolated from Curcuma, have a powerful
lipid antioxidant action, when tested in in vitro systems.
This justifies the present attempt to find out whether
hydroalcoholic extracts of Curcum longa also exert an
antioxidant effect in human subjects. Our data show that a 45-
day intake (by healthy individuals ranging in age from 27 to
67 years) of Curcuma hydroalcoholic extract (at a daily dose
equivalent to 20 mg of curcumine) results in a significant
decrease in the levels of serum lipid peroxides. These
peroxides probably play an important pathogenic role in normal
senescence and age-related diseases such as atherosclerosis.
Therefore, hydroalcoholic extracts of Curcuma longa (that have
very low toxicity and have been cleared as food additives in
the above countries) may find use in future preventive
geriatrics after further clinical studies.
Inhibition of tumor necrosis factor by curcumin, a
phytochemical
Chan MM
Department of Biological Sciences, Rutgers, State University
of New Jersey, Piscataway 08855-1059, USA.
Biochem Pharmacol 1995 May 26;49(11):1551-6
Curcumin, contained in the rhizome of the plant Curcuma
longa Linn, is a naturally occurring phytochemical that has
been used widely in India and Indonesia for the treatment of
inflammation. The pleiotropic cytokine tumor necrosis
factor-alpha (TNF) induces the production of interleukin-1beta
(IL-1), and, together, they play significant roles in many
acute and chronic inflammatory diseases. They have been
implicated in the pathogenesis of intracellular parasitic
infections, atherosclerosis, AIDS and autoimmune disorders.
This report shows that, in vitro, curcumin, at 5 microM,
inhibited lipopolysaccharide (LPS)-induced production of TNF
and IL-1 by a human monocytic macrophage cell line, Mono Mac
6. In addition, it demonstrates that curcumin, at the
corresponding concentration, inhibited LPS-induced activation
of nuclear factor kappa B and reduced the biological activity
of TNF in L929 fibroblast lytic assay.
Inhibitory effect of curcumin, an anti-inflammatory
agent, on vascular smooth muscle cell proliferation
Huang HC; Jan TR; Yeh SF
Department of Pharmacology, College of Medicine, National
Taiwan University, Taipei.
Eur J Pharmacol 1992 Oct 20;221(2-3):381-4
The effects of curcumin, an anti-inflammatory agent from
Curcuma longa, on the proliferation of blood mononuclear cells
and vascular smooth muscle cells were studied. Proliferative
responses were determined from the uptake of tritiated
thymidine. In human peripheral blood mononuclear cells,
curcumin dose dependently inhibited the responses to
phytohemagglutinin and mixed lymphocyte reaction at the dose
ranges of 10-6 to 3 x 10-5 and 3 x 10-6 to 3 x 10-5 M,
respectively. Curcumin (10-6 to 10-4 M) dose dependently
inhibited the proliferation of rabbit vascular smooth muscle
cells stimulated by fetal calf serum. Curcumin had a greater
inhibitory effect on platelet-derived growth factor-stimulated
proliferation than on serum-stimulated proliferation. Cinnamic
acid, coumaric acid and ferulic acid were much less effective
than curcumin as inhibitors of serum-induced smooth muscle
cell proliferation, suggesting that the cinnamic acid and
ferulic acid moieties alone are not sufficient for activity,
and that the characteristics of the diferuloylmethane molecule
itself are necessary for activity. Curcumin may be useful as a
new template for the development of better remedies for the
prevention of the pathological changes of atherosclerosis and
restenosis.
Change of fatty acid composition, platelet
aggregability and RBC function in elderly subjects with
administration of low dose fish oil concentrate and comparison
with those in younger subjects
Terano T, Kobayashi S, Tamura Y, Yoshida S, Hirayama T
Second Department of Internal Medicine, Chiba University,
School of Medicine.
Nippon Ronen Igakkai Zasshi 1994
Aug;31(8):596-603
Anti-thrombotic and anti-atherogenic effects of
eicosapentaenoic acid (EPA) through the modulation of various
cell functions related to thrombogenesis have been reported
recently. We previously reported that the administration of
EPA at low doses could more effectively elevate the plasma EPA
concentration in elderly subjects than in younger ones.
Magnetic resonance imaging examination of the brain often
reveals lacunar lesions in elderly subjects without any signs
or symptoms of cerebrovascular diseases. In this study we
clarified the effect of administration of low doses of fish
oil concentrate on platelet and RBC function in elderly
subjects, compared with younger subjects. Thirty-six elderly
subjects (mean age 78) without any signs or symptoms of
cerebrovascular diseases, all receiving the same diet in the
same lodging house for the aged, were divided into 3 groups.
Different amounts of fish oil concentrate (0.25-0.5 g/day of
EPA) were administered to the 3 groups, daily for more than 1
month. Changes of plasma fatty acid composition, platelet
aggregability, whole blood viscosity and RBC deformability was
examined before and after EPA administration. One month after
EPA treatment, the plasma EPA content had increased dose
dependently, with suppression of platelet aggregation and
improvement of RBC function. In younger subjects receiving the
same amount of EPA, the elevation of plasma EPA was less than
that observed in the elderly. In summary, low dose EPA
administration can improve the function of platelet and RBC to
an anti-thrombotic state and would be useful to prevent the
occurrence of cerebrovascular diseases in elderly subjects
without any side effects.
Premature Carotid Atherosclerosis: Does It Occur in
Both Familial Hypercholesterolemia and Homocystinuria?
Ultrasound Assessment of Arterial Intima-Media Thickness and
Blood Flow Velocity"
Rubba P, Mercuri M, Faccenda F, Iannuzzi A, Irace C,
Strisciuglio P, Gnasso A, Tang R, Andria G, Bond MG, et
al
Institute of Internal Medicine and Diseases of Metabolism,
Medical School, University Federico II, Naples, Italy.
Stroke, May 1994;25(5):943-950
This study evaluated 12 patients with homocystinuria due to
cystathionine B-synthase deficiency, 10 patients with
homozygous familial hypercholesterolemia and 11 healthy
controls for the possibility that different patterns of
carotid wall damage and cerebral blood flow hemodynamics were
present. B-mode ultrasound mean maximum intima-media thickness
was 1.4 mm in patients with familial hypercholesteremia, 0.6
mm in patients with homocystinuria and 6 mm in control
subjects. The difference between hypercholesterolemic and
homocystinuric patients or control subjects was statistically
significant. Diastolic blood flow velocities were
significantly reduced in the middle cerebral arteries of
hypercholesterolemic patients compared with homocystinuric
patients or control subjects, whereas systolic or mean
velocities did not differ. The pulsatility index, a possible
indicator of vascular resistance in cerebral circulation, was
significantly higher in hypercholesterolemic patients compared
with the homocystinuric patients or healthy control subjects.
There was a direct relationship demonstrated between the
pulsatility index of the middle cerebral artery and the mean
maximum intima-media thickness of the carotid arteries on the
same side. The authors conclude familial hypercholesterolemia
is responsible for diffuse and focal thickening of the
coronary arteries and possibly for the hyperlipidemic
endothelial dysfunction seen in the small resistance arteries
leading to a disturbed cerebral blood flow. Patients with
homocystinuria seldom have plaques in their carotid arteries.
In fact, their arteries are similar to healthy controls with
regards to intima-media thickness and blood flow velocity in
the middle cerebral artery. It is not likely that typical
atherosclerotic lesions precede thrombotic events in
homocystinuria. It may be that arterial dilations caused by
medial damage lead to thrombosis in homocystinuric patients.
The mechanism underlying the thrombotic events seen in
early-treated vitamin B6 responsive homocystinuric patients is
not known.
Fibrinogen, Arterial Risk Factor in Clinical
Practice
Potron G, Nguyen P, Pignon B
Clinical Hemorrheology, 1994;14(6):739-767
Ten large studies have confirmed that fibrinogen is a risk
factor of equal or higher value than total cholesterol.
Fibrinogen is an independent risk factor and is an independent
and prognostic risk factor for coronary artery disease. After
a stroke an elevated fibrinogen is an index of the severity of
the condition. In peripheral arterial disease it is an
indicator of the risk to reocclusion after surgery.
Fibrinogen's role in arterial occlusion include the
composition of the atheroma plaque, thrombi formation,
endothelial injury and hyperviscosity. Fibrinogen can be
increased by inflammation, aging and smoking. Drugs that may
reduce fibrinogen include fibrates and the platelet inhibitor
ticlopidin. Physical exercise if sustained can reduce
fibrinogen.
Fibrinogen and Cardiovascular Disorders
Lip GY
Department of Cardiology, Stobhill Hospital, Glasgow.
Quarterly Journal of Medicine, 1995;88:155-165
This is an extensive review article on the role of
fibrinogen and cardiovascular disease. Fibrinogen is involved
in blood coagulation and is an important determinant of blood
viscosity and blood flow. Elevated plasma fibrinogen levels
have been epidemiologically shown to increase the risk for
cardiovascular disorders. These include ischemic heart
disease, stroke and other thromboembolic events. Increased
plasma fibrinogen may promote a prothrombotic or
hypercoagulable state, and may, in part, explain the risk of
stroke and thromboembolism in conditions such as atrial
fibrillation and cardiac dysfunction. Human fibrinogen is a
large glycoprotein (340,000 Da) composed of 3 pairs of
nonidentical polypeptide chains (A alpha, B beta and gamma)
joined together by disulphide bonds. Fibrinogen is an
important determinant of both rheological characteristics of
blood flow and of platelet aggregability. Fibrinogen is an
essential component of the blood coagulation system, being the
precursor of fibrin. Usual plasma levels are between 1.5 and
4.5 g/l, a concentration far greater than the minimum
concentration needed of 0.5 to 1 g/l for haemostasis. In 9 out
of 10 studies, plasma fibrinogen levels correlated
significantly with the degree of coronary artery disease. A
positive correlation between plasma fibrinogen and fibrin
D-dimer has been seen in patients with atrial fibrillation.
Intermediate levels of plasma fibrinogen have also been found
in patients with paroxysmal atrial fibrillation. Psychological
and mental stress can increase plasma fibrinogen levels.
Fibrinogen levels are significantly associated with
cerebrovascular disease. Plasma fibrinogen concentrations have
been shown to be an important independent predictor of
coronary death in patients with intermittent claudication. In
patients with systemic hypertension, fibrinogen concentrations
and plasma viscosity are independent predictors of blood
pressure. In diabetic patients, a significant positive
correlation has been found between plasma fibrinogen and
fasting glucose levels, serum cholesterol levels, glycosylated
hemoglobin and urinary albumin excretion rates. In individuals
who use oral contraceptives, an increased risk of thrombotic
events measured by elevated platelet aggregation and plasma
fibrinogen levels has been discovered. There appears to be a
hormonal influence on fibrinogen levels. Smoking has a dose-
effect relationship on plasma fibrinogen levels. In obese
patients with a body mass index of more than 30, plasma
viscosity and fibrinogen levels are significantly increased.
Strenuous exercise is associated with lower fibrinogen and
cholesterol concentrations. Increased alcohol consumption may
have a small but significant effect on decreasing plasma
fibrinogen levels. The role of social class and psychosocial
factors in determining plasma fibrinogen levels is
controversial. Plasma fibrinogen levels are increased in
patients with hyperlipidaemia. Dental disease is associated
with myocardial infarction, and increased fibrinogen and white
blood cell counts may partly explain this. The genetic
influence on plasma fibrinogen formation, and genetic
heritability, may account for 51% of the variance of plasma
fibrinogen levels. There is a wide range of reference values
for plasma fibrinogen with a mean "normal" value between 2.3
and 3.1 g/l in different population studies. Elevated plasma
fibrinogen levels are consistently associated with various
cardiovascular disorders. Because the process of atherogenesis
has similarities to inflammatory diseases, the elevation of
plasma fibrinogen levels may reflect the severity of the
vascular disorder as a secondary phenomenon rather than act as
a true prognostic factor. The strong hereditary determination
of fibrinogen makes it less likely that raised fibrinogen
levels are simply a secondary response to cardiovascular
disorders. Raised plasma fibrinogen levels are known to
precede in cardiovascular disorders. Raised plasma fibrinogen
levels are likely to reflect a pre-existing prothrombotic, or
hypercoagulable, state. Acts to lower fibrinogen levels
include ceasing smoking and increasing exercise. Drugs that
may lower fibrinogen include ticlopidine, stanzolol,
oxypentifylline, calcium dobesilate, propanolol, nislodipine
and the fibrates. These drugs have other pharmacologic effects
other than lowering fibrinogen concentrations and are not
practical therapeutic options. There is controversy with
regards to diet lowering plasma fibrinogen levels. Fish oil
supplementation may result in the reduction in plasma
fibrinogen levels. Moderate alcohol consumption, increased
garlic, regular exercise, weight loss and better diabetic
control are also favorable to lowering fibrinogen levels.
Can Lowering Homocysteine Levels Reduce
Cardiovascular Risk?
Stampfer MJ, Malinow MR
The New England Journal of Medicine, February 2,
1995;332(5):328-329.
Consistent findings have emerged from more than 20
case-control and cross-sectional studies of over 2,000
subjects indicating that patients with stroke and other
cardiovascular diseases tend to have higher levels of
homocysteine than those without the disease even though most
have values within the normal range. In the Physician's Health
Study, the 271 men who later had myocardial infarctions had
significantly higher mean base-line levels of homocysteine
than matched controls who were free of infarction. Men whose
homocysteine levels were in the highest 5 percent had three
times the risk of myocardial infarction than those with lower
levels, even after adjustment for coronary risk factors. The
prevalence of carotid-artery stenosis has been shown to be
related to increasing plasma levels of homocysteine. One
hypothesis regarding homocysteine's effects on cardiovascular
disease is that damage stems from a toxic effect by
homocysteine on vascular endothelium, which impairs the
production of endothelium-derived relaxing factor.
Homocysteine may stimulate the proliferation of smooth muscle
cells, which is part of atherogenesis. Homocysteine can also
act as a thrombogenic agent. The most dramatic elevations of
homocysteine, which lead to life threatening vascular
abnormalities at a young age, are due to an enzyme defect.
Inadequate folic acid intake is the main determinant of
homocysteine-related increase in carotid-artery thickening.
Folic acid, vitamins B6 and B12, all play an important role in
homocysteine metabolism. Homocysteine levels reach a stable
low level only when folic acid intakes of approximately 400 ug
per day or more are sustained. Folic acid supplements in the
range of 1 to 2 mg per day are generally innocuous, and
usually are sufficient to reduce or normalize high
homocysteine levels, even if the elevation is not due to
inadequate folic acid supplementation. When folic acid
consumption is high the minor and common genetic variances
have no clinical significance. But when folic consumption is
marginal the risk may be elevated. In the Physician's Health
Study, 5 percent of the controls had plasma homocysteine
levels above 15.8 umol/L, the level which is associated with a
three-fold increased risk of myocardial infarction. In the
older and less highly selected population of the Framingham
Heart Study, 21 percent had high levels of homocysteine. The
author notes, "Because the weight of evidence is substantial
and the intervention appears to be benign, it may be possible
to make broad preliminary recommendations based on trials of
secondary prevention or disease progression rather than wait
for large, expensive and prolonged trials of primary
prevention. In the meantime, it will be prudent to ensure
adequate dietary intake of folate".
The Lipoprotein(a). Significance and Relation to
Atherosclerosis
Heller FR, Parfonry A, Hondekijn JC
Service de Medecine Interne, Hopital de Jolimont, Haine St
Paul, Belgique.
ACTA Clinica Belgica, 1991;46(6):371-383
Lipoprotein(a) is very similar to low density lipoprotein,
but possesses a unique protein moiety called apolipoprotein
(A). The plasma concentration of lipoprotein(a) is mainly
under genetic control. Nicotinic acid (vitamin B3) and
neomycin are able to reduce its concentration. Epidemiologic
studies suggest that high levels of lipoprotein(a), greater
than 30 mg per dl, are an independent risk factor for
atherosclerosis of the coronary and carotid arteries. The risk
is highest in those with hypercholesterolemia. High
lipoprotein(a) levels could also favor thrombosis. Reducing
hypercholesterolemia is important when lipoprotein(a) levels
are greater than 30 mg per dl.
Diminished production of malondialdehyde after
carotid artery surgery as a result of vitamin
administration
Rabl H.; Khoschsorur G.; Hauser H.; Petek W.; Esterbauer
H.
Austria
Medical Science Research (United Kingdom), 1996, 24/11
(777-780)
The objective of this study was to establish the
antioxidative effect of the vitamins E, C and retinyl
palmitate (vitamin A), contained in a multivitamin solution,
in carotid artery revascularisation surgery. 57 patients,
67.84 plus or minus 5.72 years of age, 39 men and 18 women,
were divided into a control group (27 subjects) and a group
with 30 subjects (mean age 68.46 plus or minus 5.09 years) who
received the vitamin treatment immediately before the start of
reperfusion of the brain. The control group (mean age 67.14
plus or minus 6.37 years) received physiological sodium
chloride as placebo. All of the patients suffered from
ischaemic cerebrovascular insufficiency manifested as TIA
(transitory ischaemic attack) due to haemodynamically
significant stenosis of the extracranial part of the ICA
(internal carotid artery). Oxidative burst was measured by
malondialdehyde (MDA) - thiobarbituric acid reactive
substances (TBARS) perioperatively before and 0.5, 1, 2 and 3
h after revascularisation. In the control group MDA-TBARS
significantly increased from 0.91 plus or minus 0.49 to 1.15
plus or minus 0.41 nmol mL-1 (p < 0.003) 1 h after
reperfusion onset and returned to baseline after 2-3 h. In the
vitamin-treated group MDA-TBARS steadily decreased during the
reperfusion period (1.11 plus or minus 0.39, 0.91 plus or
minus 0.42, 0.81 plus or minus 0.29, 0.78 plus or minus 0.39,
0.72 plus or minus 0.24 nmol mL-1). The significant difference
in MDA-TBARS between control and treatment groups, 1 h after
the start at reperfusion was 1.15 plus or minus 0.41 vs 0.81
plus or minus 0.29 nmol mL-1; (p < 0.001). As an indirect
parameter of reperfusion injury 13% (4/30 patients) of the
patients in thetreatment group suffered... The perioperative
use of antihypertensive drugs was 20% (6/30) in the treatment
group, as compared to 78% (21/27) in the control group. These
results suggests that vitamin treatment prior to reperfusion
might be of beneficial effect, alleviating lipid peroxidation
and leading to a better clinical course as regards the central
nervous system.
Spermine partially normalizes in vivo antioxidant
defense potential in certain brain regions in transiently
hypoperfused rat brain
Farbiszewski R.; Bielawska A.; Szymanska M.; Skrzydlewska
E.
Poland
Neurochemical Research (USA), 1996, 21/12
(1497-1503)
Activities of the antioxidant enzymes such as superoxide
dismutase (Cu,Zn-SOD), glutathione peroxidase (GSH-Px),
glutathione reductase (GSSG-R) as well as the level of reduced
glutathione and the concentration of thiobarbituric
acid-reactive substance (TBARS) in brain regions in
transiently hypoperfused rat brain with or without intravenous
infusion of spermine were evaluated. Cerebral hypoperfusion
was induced by temporary occlusion of common carotid arteries
for 30 min and subsequently, by reperfusion for 60 min.
Infusion of spermine reversed the decrease in SOD activity in
the cerebral cortex, striatum, hippocampus, hypothalamus and
midbrain, and amounted to 50.1 U, 61.5 U, 50.3 U, 30.0 U, 38.0
U, respectively, while GSH-Px restored to normal values only
in the cerebral cortex and striatum and amountter use of
spermine no changes in GSSG-R were seen in the hypothalamus
and midbrain. The activity of GSSG-R was in accordance with
the control for the striatum and amounted to 39.0 IU after
using spermine, GSH content returned to normal values in the
striatum and midbrain after i.v. use of spermine and amounted
to 210 and 240 nmol/g of wet tissue, respectively. In
addition, the production of TBARS dropped markedly (P <
0.05) in the hippocampus and midbrain and amounted to 100 and
105 micromol/g of wet tissue, respectively. Partially
beneficial effect of spermine could result from the inhibition
of free radical generation and capability of chelate formation
with iron ions.
Positron-labeled antioxidant
6-deoxy-6-(18F)fluoro-L-ascorbic acid: Increased uptake in
transient global ischemic rat brain
Yamamoto F.; Shibata S.; Watanabe S.; Masuda K.; Maeda
M.
Faculty of Pharmaceutical Sciences, Kyushu University,
Fukuoka 812-82 Japan
Nuclear Medicine and Biology (USA), 1996, 23/4
(479-486)
The in vivo uptake and distribution of
6-deoxy-6-(18F)fluoro-L-ascorbic acid (18F-DFA) were
investigated in rat brains following postischemic reperfusion.
Global cerebral ischemia was induced in male Wistar rats for
20 min by occlusion of four major arteries. Two time paints
were chosen for 18F-DFA injection to rats subjected to
cerebral ischemia, at the start of recirculation and 5 days
following recirculation. The rats were then killed at 2 h
after tail-vein administration of 18F-DFA and tissue
radioactivity concentration was determined. Increased uptake
of radioactivity in particular brain regions, including the
cerebral cortex, hypothalamus, and amygdala following
injection of 18F-DFA, compared to the sham operated control,
was observed 5 days after reperfusion. Similar results were
also obtained in in vitro experiments using brain slices.
Abnormal in v45Ca, a marker of regional postischemic injury,
was observed in these brain regions in tissue dissection
experiments. Furthermore, metabolite analysis of
nonradioactive DFA using 19F-NMR showed that DFA remained
intact in the postischemic reperfusion brain. The present
results indicate that 18F-DFA increasingly accumulates in
damaged regions of postischemic reperfusion brain.
Stroke is an emergency
[No authors listed.]
Disease-a-Month (USA), 1996, 42/4 (202-264)
Stroke is an emergency. Ischemic stroke is similar to
myocardial infarction in that the pathogenesis is loss of
blood supply to the tissue, which can result in irreversible
damage if blood flow is not restored quickly. Public education
is needed to emphasize the warning signs of stroke. Patients
should seek medical help immediately, using emergency
transport systems. Therapy geared toward minimizing the damage
from an acute stroke should be started without delay in the
emergency room. This includes measures to protect brain
tissue, support perfusion pressure, and minimize cerebral
edema. Strategies for improving recovery should also begin
immediately. All major medical centers need stroke teams and
stroke units. Stroke prevention should be given high priority
as a public health strategy. Risk factor management should be
part of general health care and should begin in childhood,
with emphasis on nutrition, exercise, weight control, and
avoidance of tobacco. Health screening and early treatment of
hypertension and hypercholesterolemia has decreased the
incidence of stroke and heart disease, but these efforts need
to be expanded to reach all segments of the population. Basic
research has opened the door to new therapies aimed at
re-establishing blood flow and limiting tissue damage.
Clinical trials have already led to changes in stroke
prevention, including studies of carotid endarterectomy and
ticlopidine and warfarin therapy (for patients with atrial
fibrillation). Trials in progress are testing the usefulness
of ancrod, neuroprotective agents, antioxidant agents,
anti-inflammatory agents, low-molecular-weight heparin,
thrombolytic drugs, and angioplasty. Any delay starting
therapy after an acute stroke will reloss of brain tissue.
Clinicians should remember that for a stroke patient, time is
brain tissue.
Antithrombotic agents in cerebral ischemia
Albers G.W.
Dept. of Neurology/Neurological Sci., Stanford Stroke Center,
Stanford University Medical Center, 701 Welch Road, Palo Alto,
CA 94304-1704 USA
American Journal of Cardiology (USA), 1995, 75/6
(34B-38B)
The choice of antithrombotic agent in cerebral ischemia
depends on the pathogenesis: thrombosis, embolism, or
hemorrhage. Antiplatelet agents are considered most beneficial
in thrombotic stroke, anticoagulants are most effective in
cardioembolic stroke; antithrombotic agents are generally
contraindicated in hemorrhagic stroke. A meta-analysis of 18
trials documented a 23% reduction in stroke risk with
antiplatelet agents; aspirin is typically the antiplatelet
agent of choice for stroke prevention. There are no definitive
data regarding the optimal aspirin dose for stroke prevention
and this issue remains controversial. Ticlopidine is the most
effective antiplatelet agent, but its adverse effect profile
restricts its use. Anticoagulants are highly effective for
preventing cardioembolic stroke, but their effectiveness in
non-cardioembolic stroke is uncertain because of lack of trial
data. Results of the ongoing Warfarin/Aspirin Recurrent Stroke
Study (warfarin (INR 1.8-2.8) vs aspirin (325 mg/day)) may
clarify this issue. There is renewed interest ta indicate that
reperfusion within a few hours of stroke onset appears to be
effective in preventing neuronal damage. In addition, when
given within 6 hours of stroke onset, thrombolytic appear to
be relatively safe. Several direct thrombin inhibitors are
being evaluated. Experimentally, hirudin, hirulog,
D-Phe-L-Pro-L-Arg-CH2Cl (PPACK), and argatroban are clearly
more effective than heparin in inhibiting platelet deposition
and thrombus formation, and also show promise in preventing
reocclusion after thrombolysis for both experimental
thrombotic and embolic stroke. However, the risk of hemorrhage
in patients with cerebrovascular disease is unknown for these
agents. New antiplatelet agents, most of which inhibit the
platelet IIb/IIIa receptor, have also shown a significant
reduction in ischemic complications in experimental thrombosis
models.
Platelet activity and stroke severity
Joseph R, Han E, Tsering C, Grunfeld S, Welch KM
Department of Neurology, Henry Ford Hospital and Health
Sciences Center, Detroit, MI 48202.
J Neurol Sci 1992 Mar;108(1):1-6
Although platelets constitute the major component of a
thrombus, its role in determining the clinical severity of
thrombotic stroke is unknown. Therefore, we investigated the
relationship between platelet ionized calcium ((Ca(i)2+ )), a
measure of platelet activity and presumably proneness to
thrombosis, and clinical stroke severity in 45 consecutively
studied acute ischemic stroke patients. Even though there was
no correlation between the clinical neurological scores and
the levels of baseline and activated platelet (Ca(i)2+),
stroke was less severe in patients who had been taking aspirin
at the time of stroke onset. These results raise several
important questions: (a) is the extent of platelet activation
a reflection of thrombus volume, (b) does the clinical
severity of neurological deficit reflect the causative
thrombus volume, and (c) whether the beneficial effect of
aspirin in stroke prophylaxis is through its inhibition of
platelets alone.
The use of antithrombotic drugs in artery
disease
Gallus A.S.
School of Medicine, Flinders University of South Australia,
Flinders Medical Centre, Bedford Park, SA 5042 Australia
Clin Haematol 1986 May;15(2):509-59
Evaluating the use of antithrombotic drugs in artery
disease has been a long and difficult process, which is far
from complete. The aims of treatment have ranged from the
primary prevention of myocardial infarction or stroke, through
the restoration of blood flow to ischaemic organs in order to
salvage threatened tissue, to the prevention of recurrent
vascular occlusion. Drugs studied in depth by clinical trial
include the oral anticoagulants, antiplatelet drugs
(especially aspirin), and thrombolytic agents. Their results
are considered under the headings of coronary artery disease,
cerebral ischaemia, and peripheral vascular disease. Aspirin,
with or without dipyridamole, prevents progression of unstable
angina to myocardial infarction or death, probably reduced
long-term mortality after myocardial infarction, and prevents
aortocoronary bypass graft occlusion. It of stroke or death in
patients with transient cerebral ischaemia, diminishes
cardiovascular morbidity after a thrombotic stroke, and may
improve the outcome after some kinds of surgery for peripheral
vascular disease. The benefits of oral anticoagulant treatment
to prevent artery occlusion remain poorly defined. Oral
anticoagulants prevent systemic embolism in many groups of
high-risk patients, and probably reduce the risk of recurrence
after embolism has occurred. Whether their long-term use to
prevent reinfarction in patients with a previous myocardial
infarct can be justified remains uncertain. They are of little
or no proven value in patients with transient cerebral
ischaemia or thrombotic stroke. On the other hand, there is
increasing support for early thrombolytic treatment after
myocardial infarction, especially since two multicentre trials
have now shown reduced mortality in patients treated with
intracoronary streptokinase within 4-6 hours of infarction and
a further large multicentre study also demonstrate reduced
mortality in patients treated with early intravenous
streptodkinase. In addition, the local infusion of
streptokinase leads to recanalization in a high proportion of
patients with a recent peripheral artery occlusion who are
poor candidates for surgery.
Medical management in the endovascular treatment of
carotid-cavernous aneurysms
Polin RS, Shaffrey ME, Jensen ME, Braden L, Ferguson RD, Dion
JE, Kassell NF
Department of Neurosurgery, University of Virginia Health
Sciences Center, Charlottesville, USA.
J Neurosurg 1996 May;84(5):755-61
Carotid-cavernous aneurysms account for between 1.9% and
9.0% ofintracranial aneurysms. Entirely intercavernous
aneurysms are believed to have a relatively benign course,
with cranial nerve findings or headache being the usual
initial symptomatology; however, subarachnoid hemorrhage or
carotid-cavernous fistula formation can result from rupture.
Over the past 15 years endovascular parent artery occlusion
has essentially replaced surgical carotid occlusion as the
treatment of choice. The authors describe a series of 39
consecutive patients at the University of Virginia Health
Sciences Cid-cavernous aneurysm. Aggressive invasive
hemodynamic monitoring and maintenance of a state of normo- to
mild hypervolemia in the asymptomatic patient was used
throughout the periprocedural period. Rapid institution of
hypervolemic-hypertensive therapy can reverse early
neurological deficits related to hypoperfusion in these
patients. Only one individual managed with this protocol
developed neurological deficits not reversible with
hypertensive-hypervolemic therapy. Heparin therapy was
administered for 48 hours after occlusion, with patients
receiving subsequent aspirin therapy for 6 months to combat
distal embolism secondary to thrombosis. Long-term
complications were not seen in patients receiving aneurysm
trapping; however, two individuals with proximal carotid
occlusion developed late optic neuropathy and one had
recurrent transient ischemic attacks that ceased with
supraclinoidal carotid clipping.
Mechanism of hydrogen peroxide and hydroxyl free
radical-induced intracellular acidification in cultured rat
cardiac myoblasts
Wu M.-L.; Tsai K.-L.; Wang S.-M.; Wu J.-C.; Wang B.-S.; Lee
Y.-T.
Department of Internal Medicine, Medical College, National
Taiwan University Hospital, 7, Chung-Shan South Rd, Taipei
Taiwan
Circulation Research (USA), 1996, 78/4 (564-572)
After a transient ischemic attack of the cardiac vascular
system, reactive oxygen-derived free radicals, including the
superoxide (O2-.) and hydroxyl (.OH) radicals can be easily
produced during reperfusion. These free radicals have been
suggested to be responsible for reperfusion-induced cardiac
stunning and reperfusion-induced arrhythmia. Hydrogen peroxide
(H2O2) is often used as an experimental source of
oxygen-derived free radicals. Using freshly dissociated single
rat cardiac myocytes and the rat cardiac myoblast cell line,
H9c2, we have shown, for the first time, that an intriguing
pH(i) acidification (similar0.24 pH unit) is induced by the
addition of 100 micromol/L H2O2 and that this dose is without
effect on the intracellular free Ca2+ levels or viability of
the cells. Using H9c2 as a model cardiac cell, we have shown
that it is the intracellular production of .OH, and not O2-.
or H2O2, that results in this acidification. We have excluded
any involvement of (1) the three known cardiac pH(i)
regulators (the Na+-H+ exchanger, the Cl--HCO3 exchanger, and
the Na+-HCO3 cotransporter), (2) a rise in intracellular Ca2+
levels, and (3) inhibition of oxidative phosphorylation.
However, we have found that H2O2-induced acidosis is due to
inhibition of the glycolytic pathway, with hydrolysis of
intracellular ATP and the resultant intracellular
acidification. In cardiac muscle and in skinned cardiac muscle
fiber, it has been shown that a small intracellular
acidification may severely inhibit contractility. Therefore,
the sustained pH(i) decrease caused by hydroxyl radicals may
contribute, in some part, to the well-documented impairment of
cardiac mechanical function (ie, reperfusion cardiac stunning)
seen during reperfusion ischemia
Thrombolysis of the cervical internal carotid
artery before balloon angioplasty and stent placement: Report
of two cases
Guterman L.R.; Budny J.L
Gibbonpartment of Neurosurgery, 3 Gates Circle, Buffalo, NY
14209-1194 USA
Neurosurgery (USA), 1996, 38/3 (620-624)
The application of endovascular techniques to the treatment
of cervical carotid artery bifurcation atherosclerosis has
been delayed because of the fear of causing embolic events
while traversing the diseased portion of the artery with an
angioplasty balloon catheter. Symptomatic carotid arteries
often contain fresh or partially digested intraluminal
thrombus. Before we cross certain carotid bifurcation lesions
with angioplasty catheters, we deliver 100,000 to 200,000
units of urokinase in an attempt to digest loose thrombus. We
have witnessed changes in the angiographic appearance of the
diseased portion of the vessel after urokinase treatment, such
as widening of the lumen, that suggest clot lysis. We present
two patients who had symptomatic internal carotid artery
stenosis. Angiography showed irregular narrowing of the
internal carotid artery origin. One patient was selected for
angioplasty instead of carotid endarterectomy because of
severe cardiac risk factors. The other patient had major
angiographic risk factors manifested by poor collateral
circulation. The angiographic findings and history of
transient ischemic attacks led us to suspect the presence of
soft, loose plaque debris or thrombus in both cases.
Therefore, we performed thrombolysis with urokinase before
angioplasty. Repeat angiography showed widening of the
arterial lumen and smoothing of theplaque profile. Subsequent
angioplasty and stent placement were uneventful. Intraarterial
thrombolysis can produce a change in the angiographic
appearance of symptomatic atherosclerotic lesions of the
cervical carotid artery bifurcation. Digestion of
intralesional thrombus may provide a safer environment for
deployment of endovascular remodeling devices by decreasing
the likelihood of embolic phenomena. We believe thrombolysis
should be done before angioplasty in select patients.
Aspirin at any dose above 30 mg offers only modest
protection after cerebral ischaemia
Algra A.; Van Gijn J.
Clinical Epidemiology Unit, University Hospital Utrecht, PO
Box 85500, 3508 GA Utrecht Netherlands
Journal of Neurology Neurosurgery and Psychiatry (United
Kingdom), 1996, 6 0/2 (197-199)
There is continuing debate about the relative efficacy of
low (< 100 mg per day), medium (300 to 325 mg per day), and
high (> 900 mg per day) doses of aspirin in patients after
a transient ischaemic attack or non-disabling stroke. The
purpose of this study was to resolve the issue. Thus a
minimeta-analysis was performed on data from 10 randomised
trials of aspirin only v control treatment in 6171 patients
after a transient ischaemic attack or non-disabling stroke.
The data on the trials were listed in an appendix of the
report on the second cycle of the Antiplatelet Trialists'
Collaboration. There was virtually no difference in relative
risk reduction for low, medium, and high doses of aspirin
(13%, 9%, and 14%respectively). This equivalence corresponds
with the results of the UK-TIA trial in a direct comparison of
300 and 1200 mg. The Dutch TIA trial showed no difference in
efficacy of 30 and 283 mg. It is concluded that aspirin at any
dose above 30 mg daily prevents 13% (95% confidence interval
4-21) of vascular events and that there is a need for more
efficacious drugs.
Mild hyperhomocysteinemia and hemostatic factors in
patients witharterial vascular diseases.
Freyburger G; Labrouche S; Sassoust G; Rouanet F; Javorschi
S; Parrot F
Laboratoire d'Hematologie, Hopital Pellegrin, Bordeaux,
France.
Thromb Haemost (Germany) Mar 1997, 77 (3)
p466-71
Mild hyperhomocysteinemia, due to genetic or to
environmental factors, is now recognized as a risk factor for
premature arterial disease, including peripheral arterial
occlusion, thrombotic stroke and myocardial infarction. It is
defined by either an increased level of fasting homocysteine
or by an increased level after loading with methionine, which
is more frequently altered than the former. We studied the
hemostatic parameters in 88 patients with premature arterial
disease (mean age 43 +/- 11 years). We confirmed previously
known hemostatic alterations described in vascular patients
when compared to controls, but found that, among patients,
some of these parameters were more altered in
hyperhomocysteinemic patients. Whenfasting homocysteine was
increased, higher alterations were found in factors VIIIc,
vonantithrombin complexes were more elevated. When
post-methionine load homocysteine was increased, alterationsin
fibrinolytic parameters were more pronounced.
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