Eur J Pharm Sci. 2005 Jan;24(1):1-13.
Multicomponent complex formation between vinpocetine, cyclodextrins,
tartaric acid and water-soluble polymers monitored by NMR and
solubility studies.
Ribeiro L, Carvalho RA, Ferreira DC, Veiga FJ.
Laboratory of Pharmaceutical Technology, Faculty of Pharmacy,
University of Coimbra, 3000-295 Coimbra, Portugal.
This work deals with multicomponent complex formation of vinpocetine
(VP) with beta-cyclodextrin (betaCD), sulfobutyl ether beta-cyclodextrin
(SBEbetaCD) and tartaric acid (TA), in the presence or absence
of water-soluble polymers, in aqueous solution. Complexation was
monitored by phase-solubility and proton nuclear magnetic resonance
((1)H NMR) studies. TA demonstrated a synergistic effect on VP
solubility, and in the complexation efficiency of betaCD and SBEbetaCD.
Additionally, water-soluble polymers increased even more the complexation
efficiency of the CDs that was reflected by a 2.1-2.5 increase
on K(C) values for VP-CD-TA-polymer multicomponent complexes.
SBEbetaCD was more effective in VP solubilization, as K(C) values
of VP-SBEbetaCD-TA multicomponent complexes were notably higher
than in corresponding betaCD complexes. The large chemical shift
displacements from protons located in the interior of the hydrophobic
CD cavities (i.e., H-3 and H-5) coupled with significant chemical
shift displacements of VP aromatic protons suggested that this
moiety was included in the cavity of both betaCD and SBEbetaCD.
Two-dimensional rotating frame nuclear Overhauser effect spectroscopy
(ROESY) experiments were carried out in order to obtain information
about the multicomponent complex geometry in solution. Inspection
of ROESY spectra allowed the establishment of spatial proximities
between all aromatic protons of VP and the internal protons of
the CDs, confirming that the aromatic moiety of VP is included
in CD cavities being deeply inserted in SBEbetaCD multicomponent
complexes, since additional interactions with the sulfobutyl side
chains were evidenced.
Nutrition. 2003 Nov-Dec;19(11-12):957-75.
"Brain-specific" nutrients: a memory cure?
McDaniel MA, Maier SF, Einstein GO.
Department of Psychology, University of New Mexico, Albuquerque,
New Mexico 87131, USA.
OBJECTIVE: We review the experimental evaluations of several widely
marketed nonprescription compounds claimed to be memory enhancers
and treatments for age-related memory decline. We generally limit
our review to double-blind placebo-controlled studies. The compounds
examined are phosphatidylserine (PS), phosphatidylcholine (PC),
citicoline, piracetam, vinpocetine, acetyl-L-carnitine (ALC),
and antioxidants (particularly vitamin E). RESULTS: In animals,
PS has been shown to attenuate many neuronal effects of aging,
and to restore normal memory on a variety of tasks. Preliminary
findings with humans, though, are limited. For older adults with
probable Alzheimer's disease, a single study failed to demonstrate
positive effects of PS on memory performance. For older adults
with moderate cognitive impairment, PS has produced consistently
modest increases in recall of word lists. Positive effects have
not been as consistently reported for other memory tests. There
is one report of consistent benefits across a number of memory
tests for a subset of normal adults who performed more poorly
than their peers at baseline. The choline compounds PC and citicoline
are thought to promote synthesis and transmission of neurotransmitters
important to memory. PC has not proven effective for improving
memory in patients with probable Alzheimer's disease. The issue
remains open for older adults without serious degenerative neural
disease. Research on citicoline is practically nonexistent, but
one study reported a robust improvement in story recall for a
small sample of normally aging older adults who scored lower than
their peers in baseline testing. Animal studies suggest that piracetam
may improve neuronal efficiency, facilitate activity in neurotransmitter
systems, and combat the age-related decrease in receptors on the
neuronal membrane. However, for patients with probable Alzheimer's
disease, as well as for adults with age-associated memory impairment,
there is no clear-cut support for a mnemonic benefit of piracetam.
Vinpocetine increases blood circulation and metabolism in the
brain. Animal studies have shown that vinpocetine can reduce the
loss of neurons due to decreased blood flow. In three studies
of older adults with memory problems associated with poor brain
circulation or dementia-related disease, vinpocetine produced
significantly more improvement than a placebo in performance on
global cognitive tests reflecting attention, concentration, and
memory. Effects on episodic memory per se have been tested minimally,
if at all. ALC participates in cellular energy production, a process
especially important in neurons, and in removal of toxic accumulation
of fatty acids. Animal studies show that ALC reverses the age-related
decline in the number of neuron membrane receptors. Studies of
patients with probable Alzheimer's disease have reported nominal
advantages over a range of memory tests for ALC-treated patients
relative to placebo groups. Significant differences have been
reported rarely, however. Whether ALC would have mnemonic benefits
for aging adults without brain disease is untested as far as we
know. Antioxidants help neutralize tissue-damaging free radicals,
which become more prevalent as organisms age. It is hypothesized
that increasing antioxidant levels in the organism might retard
or reverse the damaging effects of free radicals on neurons. Thus
far, however, studies have found that vitamin E does not significantly
slow down memory decline for Alzheimer's patients and does not
produce significant memory benefits among early Parkinson's patients.
Neither did a combination of vitamins E and C significantly improve
college students' performance on several cognitive tasks. CONCLUSIONS:
In sum, for most of the "brain-specific" nutrients we
review, some mildly suggestive effects have been found in preliminary
controlled studies using standard psychometric memory assessments
or more general tests designed to reveal cognitive impairment.
We suggest that future evaluations of the possible memory benefits
of these supplements might fruitfully focus on memory processes
rather than on memory tests per se.
Ideggyogy Sz. 2003 May 20;56(5-6):166-72.
Asymptomatic ischemic cerebrovascular disorders and neuroprotection
with vinpocetine.
Hadjiev D.
University Hospital of Neurology and Psychiatry, St. Naum Compl.
Javorov, B-1504 Bulgaria, Sofia, bl. 21. A.
The asymptomatic ischemic cerebrovascular disorders (AICVD) is
an early manifestation of cerebrovascular disease. It is also
known as latent insufficiency of the cerebrovascular circulation
or as asymptomatic cerebrovascular disorders. Recently, the term
subclinical disease, detected noninvasively, has been introduced
by American Heart Association. The diagnosis is based on the following
criteria: evidence of vascular risk factors; episodic nonspecific
complaints without any focal cerebral symptoms; mild cognitive
deficit, detected by neuropsychological tests; carotid ultrasonography
often shows intimal-medial thickening, atherosclerotic plaques
and carotid stenosis; CT and MRI occasionally reveal silent cerebral
infarctions, white matter hyperintensities or cerebral atrophy;
regional hypoperfusion above the ischemic threshold is also seen
by rCBF measurements. Treatment of the AICVD, modifying the vascular
risk factors and using neuroprotective agents, should be the cornerstone
of primary prevention of ischemic stroke and cognitive decline,
caused by cerebrovascular disorders. Vinpocetine has been found
to interfere with various stages of the ischemic cascade: ATP
depletion, activation of voltage-sensitive Na(+)- and Ca(++)-channels,
glutamate and free radicals release. The inhibition of the voltage-sensitive
Na(+)-channels appears to be especially relevant to the neuroprotective
effect of vinpocetine. Pronounced antioxidant activity of the
drug could also contribute to the neuroprotection. PET studies
in primates and man showed that 11C labelled vinpocetine passes
the blood-brain barrier rapidly. Heterogeneous brain distribution
of the compound was observed mainly in the thalamus, basal ganglia,
occipital, parietal and temporal cortex, regions which are closely
related to the cognitive functions. PET studies in chronic ischemic
stroke patients revealed favourable effects of vinpocetine on
rCBF and glucose metabolism in the thalamus, basal ganglia and
primary visual cortex. It seems, vinpocetine, affecting the multiple
mechanisms of the AICVD, could be of benefit for the treatment
in this early stage of cerebrovascular disease. Vinpocetine may
also become a new therapeutic approach to prophylactic neuroprotection
in patients at high risk of ischemic stroke.
Orv Hetil. 2003 May 18;144(20):973-8.
Effect of vinpocetin on the hemorheologic parameters in patients
with chronic cerebrovascular disease.
Szapary L, Horvath B, Alexy T, Marton Z, Kesmarky G, Szots M,
Nagy F, Czopf J, Toth K.
Pecsi Tudomanyegyetem, Altalanos Orvostudomanyi Kar, Neurologiai
Klinika.
INTRODUCTION: Data collected from large number of multicenter,
randomized trials in acute and chronic stroke patients provide
evidence, that incidence and high mortality of cerebrovascular
disorders can be decreased mainly by prevention and that the effectiveness
of acute stroke treatment is limited. The terminology of "chronic
cerebrovascular diseases" involves many pathologic entities
and often atypical clinical symptoms refer to the focal or global
hypoperfusion of the brain. However, hemorheological disturbances
seem to be important factors of the complex pathomechanism. Vinpocetine
has successfully been used in the treatment of cerebrovascular
diseases, the part of the mechanism of action are the favourable
rheological effects demonstrated after oral administration in
more previous studies. AIMS AND METHODS: In this study the hemorheological
changes after administration of small (30 mg/day) and high dose
(increased to 70 mg/day) intravenous vinpocetine for 7 days in
30 patients in chronic phase of ischemic cerebrovascular disease
were investigated. RESULTS: High dose parenteral vinpocetine treatment
significantly (p < 0.05-0.005) decreased the hematocrit, the
whole blood and plasma viscosity and red blood cell aggregation
compared to the values before the treatment. Only red blood cell
aggregation was improved significantly (p < 0.05) by small
dose treatment. CONCLUSION: This study and other hemorheological
studies in cerebrovascular patients demonstrated persistent rheological
abnormalities despite the preventive therapy. The beneficial rheological
effect of high dose parenteral vinpocetine indicates the use of
this drug in the treatment of chronic cerebrovascular diseases.
Ann Neurol 2002 May;51(5):604-12.
Impact of sustained deprenyl (selegiline) in levodopa-treated
Parkinson's disease: a randomized placebo-controlled extension
of the deprenyl and tocopherol antioxidative therapy of parkinsonism
trial.
Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow
CW, Penney JB, Tanner C, Kieburtz K, Rudolph A; Parkinson Study
Group.
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.
Clin Neuropharmacol 2002 Jan-Feb;25(1):37-42.
In vitro antioxidant properties of pentoxifylline, piracetam,
and vinpocetine.
Horvath B, Marton Z, Halmosi R, Alexy T, Szapary L, Vekasi J,
Biro Z, Habon T, Kesmarky G, Toth K.
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.
Neurochem Res 2001 Sep;26(8-9):1095-100.
The nootropic drug vinpocetine inhibits veratridine-induced [Ca2+]i
increase in rat hippocampal CA1 pyramidal cells.
Zelles T, Franklin L, Koncz I, Lendvai B, Zsilla G.
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.
Eur J Neurol 2001 Jan;8(1):81-5.
Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind
randomized clinical trial.
Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV.
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.
Eur J Clin Pharmacol 1992;42(3):257-9.
Effects of aspirin, dipyridamole, nifedipine and cavinton which
act on platelet aggregation induced by different aggregating agents
alone and in combination.
Akopov SE, Gabrielian ES.
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.
Arzneimittelforschung 1990 Jun;40(6):640-3.
Effect of vinpocetine on oxygen release of hemoglobin and erythrocyte
organic polyphosphate concentrations in patients with vascular
dementia of the Binswanger type.
Tohgi H, Sasaki K, Chiba K, Nozaki Y.
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.
Arzneimittelforschung 1992 Apr;42(4):425-7.
Effect of vinpocetine on red blood cell deformability in stroke
patients.
Hayakawa M.
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.
Drug Develop Res 1988; 14: 191-3.
Possible Memory-Enhancing Properties of Vinpocetine.
Donna M. Coleston and Ian Hindrnarch.
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.
J Am Geriatr Soc 1987 May;35(5):425-30.
A double-blind placebo controlled evaluation of the safety and
efficacy of vinpocetine in the treatment of patients with chronic
vascular senile cerebral dysfunction.
Balestreri R, Fontana L, Astengo F.
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.
Eur J Clin Pharmacol 1985;28(5):567-71.
Psychopharmacological effects of vinpocetine in normal healthy
volunteers.
Subhan Z, Hindmarch I.
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.
