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Department of Geriatrics, Nagoya
University School of Medicine, Japan.
Reduction in red blood cell deformability
is a contributory factor in stroke disease, and it has
been postulated that red blood cell rigidification may
be improved by drug treatment. In this paper the effect
of vinpocetine (CAS 42971-09-5) on the deformability
of red blood cells from patients with chronic ischemic
cerebrovascular disease has been examined. During the
administration of vinpocetine for 3 months a significant
improvement in red blood cell deformability was observed
without adverse effect.
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Department of Epidemiology and
Preventive Medicine, Institute of Internal Medicine,
Siberian Branch of the Russian Academy of Medical Science,
Novosibirsk, Russia.
The aim of the study was to assess
the safety and feasibility of a clinical trial on the
effect of vinpocetine, a synthetic ethyl ester of apovincamine,
in acute ischaemic stroke. Thirty consecutive patients
with computed tomography verified diagnosis of acute
ischaemic stroke, who could receive drug treatment within
72 h of stroke onset, were enrolled. The patients were
randomly allocated to receive either low-molecular weight
dextran alone or in combination with vinpocetine. Poor
outcome was defined as being dead or having a Barthel
index of < 70 or a Rankin score of 3--5. Intention-to-treat
analysis was applied. One-tenth of all hospitalized
patients with acute ischaemic stroke were eligible for
the trial. Thirty eligible patients were treated with
either low-molecular weight dextran alone (mean age
57.9 +/- 11.6 years, n = 15) or in combination with
vinpocetine (mean age 60.8 +/- 6.6 years, n = 15). The
two treatment groups were comparable with respect to
major prognostic variables. A relative risk (RR) reduction
of poor outcome at 3 months follow-up was 30% (RR =
0.7; 95% confidence interval [CI] 0.1--3.4), as defined
by the modified Barthel Index, and 60% as defined by
the modified Ranking score (RR = 0.4, 95% CI: 0.1--1.7).
The National Institute of Health (NIH--NINDS) Stroke
Scale score was marginally significantly better in the
vinpocetine treated group at 3 months of follow-up (P
= 0.05, ANOVA). No significant adverse effects were
seen. This pilot study shows that a full-scale randomized
double-blind, placebo-controlled trial of vinpocetine
treatment in acute ischaemic stroke is feasible and
warranted.
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Human Psychopharmacology Research
Unit, Department of Psychology, University of Leeds,
Leeds, England.
Critical flicker fusion threshold,
choice reaction time, total reaction time, and Sternberg-type
mernory tasks of digits/words were measured in twelve
volunteers after having received vinpocetine or placebo
for two days. A significant improvement was recorded
in the short-terrn memory test following 40 mg of the
drug when cornpared to placebo.
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Twelve healthy female volunteers
received pre-treatments with vinpocetine 10, 20, 40
mg and placebo (t.d.s.) for two days according to a
randomised, double-blind crossover design. On the third
day of treatment and 1 h following morning dosage, subjects
completed a battery of psychological tests including
Critical Flicker Fusion (CFF), Choice Reaction Time
(CRT), Subjective Ratings of Drug Effects (LARS) and
a Sternberg Memory Scanning Test. No statistically significant
changes from placebo were observed on CFF, CRT or subjective
ratings of drug effects. However, memory as assessed
using the Sternberg technique was found to be significantly
improved following treatment with vinpocetine 40 mg
when compared to placebo and results suggested a localised
effect of the drug on the serial comparison stage of
the reaction process.
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University of Rochester Medical
Center, Rochester, NY 14620, USA.
Deprenyl (selegiline) delays the
need for levodopa therapy in patients with early Parkinson's
disease, but the long-term benefits of this treatment
remain unclear. During 1987 to 1988, 800 patients with
early Parkinson's disease were randomized in the Deprenyl
and Tocopherol Antioxidative Therapy of Parkinsonism
trial to receive Deprenyl, tocopherol, combined treatments,
or a placebo and were then placed on active Deprenyl
(10mg/day). A second, independent randomization was
carried out in early 1993 for 368 subjects who by that
time had required levodopa and who had consented to
continuing the Deprenyl treatment (D subjects) or changing
to a matching placebo (P subjects) under double-blind
conditions. The first development of wearing off, dyskinesias,
or on-off motor fluctuations was the prespecified primary
outcome measure. During the average 2-year follow-up,
there were no differences between the treatment groups
with respect to the primary outcome measure (hazard
ratio, 0.87; 95% confidence interval, 0.63, 1.19; p
= 0.38), withdrawal from the study, death, or adverse
events. Although 34% of D subjects developed dyskinesias
and only 19% of P subjects did (p = 0.006), only 16%
of D subjects developed freezing of gait but 29% of
P subjects did (p = 0.0003). Decline in motor performance
was less in D subjects than P subjects. Levodopa-treated
Parkinson's disease patients who had been treated with
Deprenyl for up to 7 years, compared with patients who
were changed to a placebo after about 5 years, experienced
slower motor decline and were more likely to develop
dyskinesias but less likely to develop freezing of gait.
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In a double-blind clinical trial,
vinpocetine, a synthetic ethyl ester of apovincamine,
was shown to effect significant improvement in elderly
patients with chronic cerebral dysfunction. Forty-two
patients received 10 mg vinpocetine three times a day
(tid) for 30 days, then 5 mg tid for 60 days. Matching
placebo tablets were given to another 42 patients for
the 90 day trial period. Patients on vinpocetine scored
consistently better in all evaluations of the effectiveness
of treatment including measurements on the Clinical
Global Impression (CGI) scale, the Sandoz Clinical Assessment-Geriatric
(SCAG) scale, and the Mini-Mental Status Questionnaire
(MMSQ). There were no serious side effects related to
the treatment drug.
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First Department of Medicine Division
of Cardiology, Department of Neurology, and the Department
of Ophthalmology, University of Pecs' School of Medicine,
Pecs, Hungary.
Oxygen-free radicals play an important
role in several physiologic and pathophysiologic processes.
In pathologic circumstances, they can modify and damage
biologic systems. Because oxygen-free radicals are involved
in a wide range of diseases (cerebrovascular, cardiovascular,
etc.), scavenging these radicals should be considered
as an important therapeutic approach. In our in vitro
study, we investigated the antioxidant capacity of three
drugs: pentoxiphylline (Sigma Aldrich, St. Louis, MO,
USA) piracetam (Sigma Aldrich), and vinpocetine (Richter
Gedeon RT, Budapest, Hungary). Phenazine methosulphate
was applied to generate free radicals, increasing red
blood cell rigidity. Filtration technique and potassium
leaking were used to detect the cellular damage and
the scavenging effect of the examined drugs. According
to our results, at human therapeutic serum concentration,
only vinpocetine (Richter Gedeon RT) had significant
(p < 0.01) scavenging activity with a protective
effect that increased further at higher concentrations.
Pentoxiphylline (Sigma Aldrich) and piracetam (Sigma
Aldrich) did not have significant antioxidant capacity
at therapeutic concentrations, but increasing their
concentrations (pentoxiphylline at 100-times, and piracetam
at 10-times higher concentrations) led to a significant
(p < 0.01) scavenger effect. Our findings suggest
that this pronounced antioxidant effect of vinpocetine
and even the milder scavenging capacity of pentoxiphylline
and piracetam may be of value in the treatment of patients
with cerebrovascular disorders, but merits further investigations.
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Department of Zoology and Faculty
of Medicine, Center for Neurosciences of Coimbra, University
of Coimbra, Portugal.
It has been suggested that reactive
oxygen species (ROS) play a role in the neuronal damage
occurring in ischemic injury and neurodegenerative disorders
and that their neutralization by antioxidant drugs may
delay or minimize neurodegeneration. In the present
study we examine whether vinpocetine can act as an antioxidant
and prevent the formation of ROS and lipid peroxidation
in rat brain synaptosomes. After ascorbate/Fe2+ treatment
a significant increase in oxygen consumption (about
5-fold) and thiobarbituric acid reactive substances
(TBARS) formation (about 7-fold) occurred as compared
to control conditions. Vinpocetine inhibited the ascorbate/Fe2+
stimulated consumption of oxygen and TBARS accumulation,
an indicator of lipid peroxidation, in a concentration-dependent
manner. The ROS formation was also prevented by vinpocetine.
Oxidative stress increased significantly the fluorescence
of the probes 2',7'-dichlorodihydrofluorescein (DCFH2-DA)
(about 6-fold) and dihydrorhodamine (DHR) 123 (about
10-fold), which is indicative of intrasynaptosomal ROS
generation. Vinpocetine at 100 microM concentration
decreased the fluorescence of DCFH2-DA and DHR 123 by
about 50% and 83%, respectively. We conclude that the
antioxidant effect of vinpocetine might contribute to
the protective role exerted by the drug in reducing
neuronal damage in pathological situations.
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Institute of Experimental Medicine,
Hungarian Academy of Sciences, Budapest.
The alkaloid derivative vinpocetine
(14-ethoxycarbonyl-(3alpha,16alpha-ethyl)-14,15-eburnamine;
Cavinton) has a well known beneficial effect on brain
function in hypoxic and ischemic conditions. While it
increases CNS blood flow and improves cellular metabolism,
relatively little is known about vinpocetine's underlying
molecular mechanisms on the single cell level. Since
apoptotic and necrotic cell damage is always preceded
by an increase in [Ca2+]i, this study investigated the
effect of vinpocetine on [Ca2+]i increases in acute
brain slices. Sodium influx is an early event in the
biochemical cascade that takes place during ischemia.
The alkaloid veratridine can activate this Na+ influx,
causing depolarization and increasing [Ca2+]i in the
cells. Therefore, it can be used to simulate an ischemic
attack in brain cells. Using a cooled CCD camera-based
ratio imaging system and cell loading with fura 2/AM,
the effect of vinpocetine on [Ca2+]i changes in single
pyramidal neurons in the vulnerable CA1 region of rat
hippocampal slices was investigated. Preperfusion and
continuous administration of vinpocetine (10 microM)
significantly inhibited the elevation in [Ca2+]i induced
by veratridine (10 microM). When the drug was administered
after veratridine, it could accelerate the recovery
of cellular calcium levels. Piracetam, another nootropic
used in clinical practice, could attenuate the elevation
of [Ca2+]i only at a high, 1 mM, concentration. We have
concluded that vinpocetine, at a pharmacologically relevant
concentration, can decrease pathologically high [Ca2+]i
levels in individual rat hippocampal CA1 pyramidal neurons;
this effect might contribute to the neuroprotective
property of the drug.
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The effect of ethyl apovincaminate
(RGH-4405, Cavinton) on the cerebral and systemic circulations
has been studied in detail in ten cases of cerebrovascular
disease. 10 mg doses of Cavinton were given as infusion
within 4-6 min; circulatory tests were carried out prior
to administration of the drug and 3-6 min after. The
principal results showed the following: On Cavinton
cerebral vascular resistance was strongly reduced, while
cerebral fraction of cardiac output significantly increased.
On acute effect of the drug arterial mean pressure slightly
decreased but cerebral blood flow nevertheless increased
in general. Total vascular resistance also decreased
but this decrease was less marked than that registered
in cerebral vascular resistance.
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Department of Neurosurgery. Kobe
University School of Medicine. Kobe, Japan.
The 133xenon inhalation method
was used in an open-label clinical trial to examine
changes in cerebral blood flow (CBF) after vinpocetine
treatment in 13 patients with cerebrovascular disorders.
In all patients, measurement of regional cerebral blood
flow (RCBF) was made prior to and after treatment with
vinpocetine 5 mg t.i.d. for five to seven weeks. In
ten of the patients, treatment was continued for a total
of 8 to 16 weeks with an additional RCBF measurement
at the end of their treatment. The resulte showed a
significant increase in the Initial Slope Index (ISI)
values of mean total CBF, and RCBF for the involved
hemisphere after six weeks of treatment with vinpocetine.
The CBF for the involved lobe was significantly increased
for ISI and flow rate of gray matter at six weeks and
at the end of treatment. No adverse reactions were reported.
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Department of Biochemistry, Pharrnacological
Research Centre, Chemical Works of Gedeon Richter Lld.,
Budapest, Hungary.
The effects of vinpocetine, a
recently described cerebral blood flow enhancer having
antihypoxic, anti-ischemic, and cognitive-function-improving
actions, on rat brain monoaminergic neurotransmission
have been studied under normoxic and hypoxic conditions.
Vinpocetine slightly affected the steady-state levels
of monoamines and their metabolites in whole brain,
but a tendency was seen to increase dopamine (DA) and
its metabolites in lower brain parts and to reduce noradrenaline
(NA) in "terminal" regions. MHPG-SO4 leveis
were enhanced in whole brain and in almost all regions
examined. There was a tendency to increase S-hydroxyindole-acetic
acid (S-HIAA) in some areas. It accelerated the whole
brain NA turnover dose-dependently, but lett that of
DA unchanged. Enhancement of NA turnover was most noted
in the lower brain areas. On the other hand, no change
was found in DA accumulation, an index of heart NA turnover
after inhibition of dopamine-beta-hydroxylase. The rate
of probenecide- induced accumulation of cerebral MHPG-SO4
and, to a lesser extent, that of 5-HIAA was also increased.
No change was seen in the pargyline-induced serotonin
(5-HT) accumulation. Although vinpocetine had slight
or no effects on regional levels of monoamines and their
metabolites, and did not alter their in vivo biosynthesis
rate under normoxic conditions, it was able partially
or totally to prevent reductions in the biosynthesis
rate of rnonoamines and antagonized the decrease of
NA, 5-HT, and 5-HIAA (but not that of DA) induced by
normobaric hypoxia. This effect was mainly confined
to lower brain areas. From the results, we conclude
that vinpocetine primarily aflects cell body regions
(e.g., brainstem) of the rat brain.
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Department of Neurology, Iwate
Medical University, Japan.
Oxygen affinity of hemoglobin,
erythrocyte 2,3-diphosphoglycerate (DPG) and adenosine
triphosphate (ATP) concentrations were compared before
and after oral administration of vinpocetine (TCV-3B)
(15 mg/d), a primarily vasodilating agent, for three
weeks in eight patients with vascular dementia of the
Biswanger type which is characterized by diffuse myelin
pallor and multiple lacunes in the cerebral white matter.
After vinpocetine administration, oxygen affinity of
hemoglobin (P50) was significantly increased (26.5 +/-
0.55 to 27.6 +/- 0.62 mmHg; mean and standard deviation,
p less than 0.05), red blood cell (RBC) ATP concentrations
were significantly increased (846 +/- 168 to 1,158 +/-
130 mumol/l RBC, p less than 0.05), while DPG concentrations
were unaltered (4.46 +/- 0.48 to 4.59 +/- 0.57 mmol/l
RBC). There was a significant positive correlation between
the increase of P50 and the increase of erythrocyte
ATP concentrations (r = 0.67, p less than 0.05). The
effect of vinpocetine of enhancing oxygen release of
hemoglobin may offer an additional benefit to its primary
vasodilating action in the treatment of vascular dementia
of the Binswanger type due to chronic ischemia.
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Department of Pharmacology, Yerevan
Medical Institute, Armenia.
The effects of vinpocetine, a
recently described cerebral blood flow enhancer having
antihypoxic, anti-ischemic, and cognitive-function-improving
actions, on rat brain monoaminergic neurotransmission
have been studied under normoxic and hypoxic conditions.
Vinpocetine slightly affected the steady-state levels
of monoamines and their metabolites in whole brain,
but a tendency was seen to increase dopamine (DA) and
its metabolites in lower brain parts and to reduce noradrenaline
(NA) in "terminal" regions. MHPG-SO4 leveis
were enhanced in whole brain and in almost all regions
examined. There was a tendency to increase S-hydroxyindole-acetic
acid (S-HIAA) in some areas. It accelerated the whole
brain NA turnover dose-dependently, but lett that of
DA unchanged. Enhancement of NA turnover was most noted
in the lower brain areas. On the other hand, no change
was found in DA accumulation, an index of heart NA turnover
after inhibition of dopamine-beta-hydroxylase. The rate
of probenecide- induced accumulation of cerebral MHPG-SO4
and, to a lesser extent, that of 5-HIAA was also increased.
No change was seen in the pargyline-induced serotonin
(5-HT) accumulation. Although vinpocetine had slight
or no effects on regional levels of monoamines and their
metabolites, and did not alter their in vivo biosynthesis
rate under normoxic conditions, it was able partially
or totally to prevent reductions in the biosynthesis
rate of rnonoamines and antagonized the decrease of
NA, 5-HT, and 5-HIAA (but not that of DA) induced by
normobaric hypoxia. This effect was mainly confined
to lower brain areas. From the results, we conclude
that vinpocetine primarily aflects cell body regions
(e.g., brainstem) of the rat brain.
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