Neuroprotection
1. 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. dimiter_hadjiev@hotmail.com
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.
2. Vinpocetin protects against excitotoxic cell death in primary cultures
of rat cerebral cortex
Erdo S.L.; Nin sheng C.; Wolff J.R.; Kiss B.
Laboratory of Neurochemistry, Department of Anatomy, Georg August University,
36 Kreuzbergring, D 3400 Gottingen Germany, Federal Republic of
EUR. J. PHARMACOL. (Netherlands), 1990, 187/3 (551 553)
The protective effect of vinpocetin, a drug clinically useful in brain
hypoxia/ischemia, was examined in vitro on cerebrocortical cultures treated
with glutamate and related excitotoxins. The extent of cell death was
quantified by measuring lactic dehydrogenase activity released from damaged
cells into the culture medium. Vinpocetin partially protected the cortical
cells against cell death induced by N methyl D aspartate, quisqualate
and kainate, indicating that the drug exerts a direct protective action
on cerebrocortical cells bearing excitatory amino acid receptors.
Cerebrovascular insufficiency/disease
3. Orv Hetil. 2001 Feb 25;142(8):383-9.
[The use of vinpocetine in chronic disorders caused by cerebral hypoperfusion]
[Article in Hungarian]
Horvath S.
Pest Megyei Onkormanyzat Flor Ferenc Korhaza, Kistarcsa, Neurologiai Osztaly.
The clinical signs and symptoms of so-called "cerebrovascular insufficiency"
or
"cerebral vascular dysfunction" have the characteristics of
those of chronic
cerebral hypoperfusion. The clinical features of chronic cerebral hypoperfusion
often show the symptoms of cognitive impairment and organic psychosyndromes.
Cerebral hypoperfusion could be found in dementias of different origin
(subcortical arteriosclerotic leucoencephalopathy [Binswanger], vascular
dementia, Alzheimer's disease, etc.). Pathological changes caused by chronic
cerebral hypoperfusion often confined only to the white matter (demyelisation,
glial activation, damage of oligodendroglial cells, as well as scattered
cell death). Each therapy has an influence on the biochemical and pathophysiological
alterations caused by chronic cerebral hypoperfusion can be used with
reason in these disorders. The mechanism of action of vinpocetine is interfering
on many aspects with the biochemical and pathophysiological processes
attributable to chronic cerebral hypoperfusion, independently of the original
alteration responsible for hypoperfusion. This fact might give an explanation
on the beneficial effect of vinpocetine on clinical signs and symptoms
of chronic cerebrovascular insufficiency.
4. Ten years of experience gained with the use of cavinton in cerebrovascular
diseases
Burtsev E.M.; Savkov V.S.; Shprakh V.V.; Burtsev M.E.
USSR
ZH. NEVROPATOL. PSIKHIATR. IM. S. S. KORSAKOVA (USSR), 1992, 92/1 (56
60)
Cavinton was used for 10 years in 967 patients with different cerebrovascular
diseases. The highest effect was seen in patients with early forms and
primarily chronic forms: vegetovascular (neurocirculatory) dystonia, initial
manifestations of brain blood supply insufficiency, dyscirculatory encephalopathy
in the first and second stages. Improvement of the subjective status and
a decrease of the intensity of vestibulocerebellar disorders were recorded
by the end of the treatment in 75 85% of such patients. In ischemic brain
stroke, regress of general cerebral and focal symptoms was more rapid
and significant in the adequate reaction type of cerebral hemodynamics
to cavinton administration (a rise of pulse blood content of the brain
and a reduction of the vascular tone according to the REG data) and was
less noticeable in the hypertonic and, in particular, in the hypotonic
type. Cavinton should not be used in severe general cerebral hypertensive
crises, as well as in elderly or senile patients with acute cardiocerebral
or cerebrocardial syndrome, postinfarction cardioisclerosis, marked disorders
of heart rhythm.
5. Cavinton in the prevention of the convulsive syndrome in children
with a history of birth trauma
Dutov A.A.; Goltvanitsa G.A.; Volkova V.A.; Sukhanova O.N.; Lavrishcheva
T.G.; Petrov A.P.
Tsentral'naja NI Laboratorija Chitinskogo Meditsinskogo Instituta, Chita
USSR
ZH. NEVROPATOL. PSIKHIATR. IM. S. S. KORSAKOVA (USSR), 1991, 91/8 (21
22)
The authors studied the efficacy of cavinton as an agent helpful in preventing
neurologic disorders in the newborn with hypoxic ischemic encephalopathy
due to intracranial birth trauma. The short term results of the treatment
were elucidated in 61 children. In group I including 20 persons given
conventional therapy, the disappearance of seizures was recorded in 6
patients; out of 41 children (group II) given additionally cavinton, in
27. Twenty nine children were followed up for a year. In group I, convulsive
paroxysms recurred in 4 patients, whereas in the group II children, no
convulsive syndrome was recorded on the follow up. The group II children
also showed a decrease of the phenomena of intracranial hypertension and
normalization of the psychomotor development. The preventive effect of
cavinton seen in children with a history of birth trauma may be accounted
for by its capacity of normalizing cerebrovascular disorders and by its
own anticonvulsive properties.
6. 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.
Department of Internal Medicine, University of Genoa, Genoa ITALY
J. AM. GERIATR. SOC. (USA), 1987, 35/5 (425 430)
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 evaluation 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.
7. A double blind clinical trial of vinpocetine in the treatment of cerebral
insufficiency of vascular and degenerative origin
Manconi E.; Binaghi F.; Pitzus F.
Department of Internal Medicine, University of Cagliari, Cagliari ITALY
CURR. THER. RES., CLIN. EXP. (USA), 1986, 40/4 (702 709)
We used vinpocetine, a synthetic ethyl ester of apovincamine, to treat
22 elderly patients with central nervous system degenerative disorders,
in a double blind clinical trial. Patients received 10 mg vinpocetine
TID for 30 days, then 5 mg TID for 60 days. Another 18 elderly patients
were given matching placebo tablets for the 90 day trial. Vinpocetine
treated patients scored consistently better in all evaluations of the
effectiveness of treatment, including measurements on the Clinical Global
Impressions (CGI) and Sandoz Clinical Assessment Geriatric (SCAG) scales,
and the Mini Mental Status Questionnaire. According to CGI assessments,
severity of illness decreased in 73% of the patients in the vinpocetine
group at day 30 and 77% at day 90, and improvement was seen in 77% and
87% of the patients at days 30 and 90, respectively. Patients also showed
statistically significant improvement for all SCAG items but one, at days
30 and 90. The physician rated the improvement in 59% of the vinpocetine
treated patients as 'good' to 'excellent'. No serious side effects were
related to the treatment drug.
8. Cerebral regulation and cerebral regulators
ZEREBRALE REGULATION ZEREBRALE REGULATOREN
Braun P.
Med. Abt., Krankenh. Robert Karoly Korut, Budapest HUNGARY
THER. HUNG. (HUNGARY), 1980, 28/3 (103 110)
The epidemiology and pathogenic mechanisms of disorders due to cerebral
ischemia are described and the therapeutic use of Vinca minor alkaloids
is reviewed with reference to their indications in neuropsychiatry, otology
and ophthalmology. The literature on Devincan and Cavinton is reviewed.
Devincan exerts a mild hypotensive action, while Cavinton improves the
circulation and the oxygen consumption of the brain cells, a valuable
effect in the treatment of cerebrovascular disease of ischemic etiology
(one of its main indications).
9. Comparative study of the effect of ethyl apovincaminate and xantinol
nicotinate in cerebrovascular diseases; immediate drug effects on the
concentrations of carbohydrate metabolites and electrolytes in blood and
CSF
Vamosi B.; Molnar L.; Demeter J.; Tury F.
Dept. Neurol. Psychiat., Univ. Debrecen Med. Sch., Debrecen HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1980 1984)
Randomly selected 34 cerebrovascular patients were treated with ethyl
apovincaminate (RGH 4405, Cavinton) and 109 with xantinol nicotinate.
The effects of drugs given in slow i.v. infusions on the concentration
of carbohydrate metabolites and electrolytes in serum and CSF were observed.
Cavinton improved the paresis in 60.6% of patients while xantinol nicotinate
did so only in 47.1%. On the basis of the biochemical changes, it can
be concluded that Cavinton enhances both the glycolytic and the oxidative
glucose breakdown in CNS.
10. Rheoencephalographic and psychological studies with ethyl apovincaminate
in cerebral vascular insufficiency
Hadjiev D.; Yancheva S.
Inst. Neurol., Psychiat. Neurosurg., Sofia BULGARIA
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1947 1950)
The effect of ethyl apovincaminate (RGH 4405, Cavinton) on the rheoencephalogram
and memory functions was studied in 50 patients with ischaemic disturbances
of cerebral circulation. The drug was administered in a single i.v. dose
of 10 mg and orally three times daily 5 mg for a month. Improvement of
cerebral circulation was observed after i.v. and oral medication. Blood
flow was most markedly increased in the gray matter. The effect on arterial
pressure was negligible. Improvement of memorizing capacity evaluated
by psychological tests was recorded after one month of Cavinton treatment,
associated with alleviation or complete disappearance of symptoms. No
side effects attributable to the drug were observed. It is pointed out
that Cavinton is indicated in the treatment of ischaemic disorders of
the cerebral circulation, particularly in chronic insufficiency.
11. Effect of ethyl apovincaminate on the cerebral circulation; studies
in patients with obliterative cerebral arterial disease
Solti F.; Iskum M.; Czako E.
Dept. Vasc. Heart Surg., Semmelweis Med. Univ., Budapest HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1945 1947)
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.
12. 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. dimiter_hadjiev@hotmail.com
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.
Cognitive dysfunction
13. Altern Med Rev. 1999 Jun;4(3):144-61.
A review of nutrients and botanicals in the integrative management of
cognitive dysfunction.
Kidd PM.
Dementias and other severe cognitive dysfunction states pose a daunting
challenge to existing medical management strategies. An integrative, early
intervention approach seems warranted. Whereas, allopathic treatment options
are highly limited, nutritional and botanical therapies are available
which have
proven degrees of efficacy and generally favorable benefit-to-risk profiles.
This review covers five such therapies: phosphatidylserine (PS),
acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and
Bacopa
monniera (Bacopa). PS is a phospholipid enriched in the brain, validated
through
double-blind trials for improving memory, learning, concentration, word
recall,
and mood in middle-aged and elderly subjects with dementia or age-related
cognitive decline. PS has an excellent benefit-to-risk profile. ALC is
an
energizer and metabolic cofactor which also benefits various cognitive
functions
in the middle-aged and elderly, but with a slightly less favorable
benefit-to-risk profile. Vinpocetine, found in the lesser periwinkle Vinca
minor, is an excellent vasodilator and cerebral metabolic enhancer with
proven
benefits for vascular-based cognitive dysfunction. Two meta-analyses of
GbE
demonstrate the best preparations offer limited benefits for vascular
insufficiencies and even more limited benefits for Alzheimer's, while
"commodity" GbE products offer little benefit, if any at all.
GbE (and probably
also vinpocetine) is incompatible with blood-thinning drugs. Bacopa is
an
Ayurvedic botanical with apparent anti-anxiety, anti-fatigue, and
memory-strengthening effects. These five substances offer interesting
contributions to a personalized approach for restoring cognitive function,
perhaps eventually in conjunction with the judicious application of growth
factors.
Vasodilator
14. Circulation. 2001 Nov 6;104(19):2338-43.
Upregulation of phosphodiesterase 1A1 expression is associated with the
development of nitrate tolerance.
Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC,
Yan C.
Department of Medicine, University of Rochester, Rochester, NY, USA.
BACKGROUND: The efficacy of nitroglycerin (NTG) as a vasodilator is limited
by
tolerance, which develops shortly after treatment begins. In vascular
smooth
muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which
activates guanylyl cyclase and generates cGMP. cGMP plays a key role in
nitrate-induced vasodilation by reducing intracellular Ca(2+) concentration.
Therefore, one possible mechanism for development of nitrate tolerance
would be increased activity of the cGMP phosphodiesterase (PDE), which
decreases cGMP levels. METHODS AND RESULTS: To test this hypothesis, rats
were made tolerant by continuous infusion of NTG for 3 days (10 microgram
kg(-1). min(-1) SC) with an osmotic pump. Analysis of PDE activities showed
an increased function of Ca(2+)/calmodulin (CaM)-stimulated PDE (PDE1A1),
which preferentially hydrolyzes cGMP after NTG treatment. Western blot
analysis for the Ca(2+)/CaM-stimulated PDE revealed that PDE1A1 was increased
2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA
upregulation as measured by relative quantitative reverse transcription-polymerase
chain reaction. The PDE1-specific inhibitor vinpocetine partially restored
the sensitivity of the tolerant vasculature to subsequent NTG exposure.
In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1
activity, and vinpocetine blocked the effect of Ang II on decrease in
cGMP accumulation. CONCLUSIONS: Induction of PDE1A1 in nitrate-tolerant
vessels may be one mechanism by which NO/cGMP-mediated vasodilation is
desensitized and Ca(2+)-mediated vasoconstriction is supersensitized.
Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic
approach to limit nitrate tolerance.
15. Mechanism of vasodilative action of cavinton on brain vessels
Plotnikov M.B.; Kotov A.N.
Kafedra Farmakologii, Tomskogo Meditsinskogo Instituta, Tomsk USSR
FARMAKOL. TOKSIKOL. (USSR), 1983, 46/6 (36 39)
Experiments on human middle cerebral and cat internal maxillary arteries
have shown high vasodilative activity of cavinton. The mechanism of the
vasodilative action of the drug involves inhibition of the ingress of
exocellular calcium via electrogenic and chemosensitive channels, suppression
of calcium mobilization from the intracellular depot with depolarization
of the membranes of vascular smooth cells and a decrease in phosphodiesterase
activity.
16. Cavinton, a new cerebral vasodilator
Solti F.
Inst. Gefasschir., Semmelweis Med. Univ., Budapest HUNGARY
THER. HUNG. (HUNGARY), 1979, 27/1 (15 16)
Vincamine, an alkaloid isolated from Vinca minor, exerts not only a moderate
antihypertensive effect but also increases the cerebral blood flow c.q.
significantly decreases resistance of cerebral vessels. The substance
is a potent cerebral vasodilator which gives particularly good results
in disorders of the cerebral circulation in which hypertension is present.
It proved possible by chemical alteration of the vincamine molecule to
synthetize a number of derivatives. Among these, cavinton proved to be
the apovincamine acid ethylester with the most intensive action. Experiments
in animals showed that cavinton increases the cerebral blood flow without
significantly altering the blood pressure or cardiac effort.
17. Study on the vasodilator effects of ethyl apovincaminate in neurosurgical
patients
Fenyes Gy.; Tarjanyi J.; Ladvanszky Cs.
II Dept. Surg., Med. Univ. Szeged HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1956 1962)
Studies have been performed in a series of 44 neurosurgical cases. The
patients were subjected to detailed neurological examination and EEG after
admission and before being discharged. The effect of ethyl apovincaminate
(RGH 4405, Cavinton) on cortical electric activity was investigated after
the administration of 10 mg i.v. Cavinton. In cases on long term courses
of three times daily 5 mg Cavinton in tablets, control EEG was performed
one and two mth, resp., after the start of medication. The state of vessels
of the eye ground was also checked. In cerebral angiography attention
was concentrated on width of the vascular lumen and visualization of Cavinton
effect on vessels which on account of narrowing or spasm had not filled
up with contrast medium prior to Cavinton. During angiography the patients
were given i.v. 10 mg Cavinton diluted to 10 ml with physiological saline.
In the cases where investigations failed to reveal any change requiring
neurosurgical intervention and insufficient cerebral circulation had to
be held responsible for the patient's condition, 3 times 10 mg Cavinton
i.v. was administered daily as long as the patient was at our Department.
After having been discharged these patients took 3 times daily 5 mg Cavinton
in tablets. Duration of the course of oral Cavinton depended on the degree
of improvement in the patient's condition. Cavinton was used with success
in cases where cerebral circulation was damaged for functional or organic
reasons. Allergic hypersensitivity did not occur in any of the cases,
either on single doses or long term use of parenteral or oral Cavinton.
18. General and cerebral haemodynamic activity of ethyl apovincaminate
Karpati E.; Szporny L.
Dept. Pharmacol., Chem. Works Gedeon Richter Ltd, Budapest HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1908 1912)
Systemic and cerebral haemodynamic effects of ethyl apovincaminate (RGH
4405, Cavinton), a new compound, have been investigated in anaesthetized
dogs. The compound was administered i.v. and produced an increase in the
cerebral blood flow accompanied by a decrease in cerebral vascular resistance
which persisted for 15 min. The effective dose was 0.2 0.5 mg/kg. Mean
arterial blood pressure, total peripheral resistance and cardiac work
were decreased, heart rate and cardiac output were increased. Cerebral
metabolic rate of oxygen was enhanced. It is assumed that the compound
has a direct effect on cerebral metabolism. RGH 4405 has a weak antiarrhythmic
and coronary dilating activity. Its effect on smooth muscle is more marked
than that of papaverine. RGH 4405 appears to be a potent cerebral vasodilator
enhancing cerebral metabolism.
Cerebral ischemia
19. Calcium antagonist activity of vinpocetine and vincamine in several
models of cerebral ischaemia
Lamar J.-C.; Poignet H.; Beaughard M.; Dureng G.
Department of Pharmacology, Riom Laboratories-Cerm, F-63203 Riom Cedex
France
DRUG DEV. RES. (USA), 1988, 14/3 4 (297 304)
The potency and selectivity (i.e., the central vs. peripheral vascular
smooth muscle activity) of the calcium antagonist (CA) effects of vinpocetine
and vincamine have been compared with those of the standard CAs: flunarizine,
verapamil, dilitazem, and nimodipine in rabbit basilar and splenic artery
preparations. The cerebral antiischemic activity of these substances also
was evaluated in five well documented in vivo models, i.e., hypobaric
and normobaric hypoxia, global cerebral ischemia to MgCl2, cytotoxic anoxia
with KCN, and cerebral edema induced by triethyl tin. Both vinpocetine
and vincamine possess only weak CA activity, the potency order being:
nimodipine > dilitazem > flunazine = verapamil > vinpocetine
> vincamine, with vinpocetine and flunarizine, in contrast to other
compounds, showing a clear, 6 to 13 fold selectivity for cerebral vascular
smooth muscle. In the in vivo models, vinpocetine and flunarizine, together
with vincamine, proved most active and had a larger spectrum of activity
than the other CAs. These results suggest that the cerebrally selective
CA effects of vinpocetine are at most only partly responsible for the
effects of this compound in the in vivo models of cerebral ischemia.
20. Study on the anti-hypoxic effect of some drugs used in the pharmacotherapy
of cerebrovascular disease.
Milanova D, Nikolov R, Nikolova M.
Methods Find Exp Clin Pharmacol. 1983 Nov;5(9):607-12.
The anti-hypoxic effect of some agents used in the pharmacotherapy of
cerebrovascular disease was studied using the following methods: incomplete
ischemia by bilateral carotid ligation in rats, anoxic hypoxia by inhalation
of
argon in mice, and hemic hypoxia induced by injection of sodium nitrite
(120
mg/kg s.c.) in rats. The following drugs were studied: piracetam, orotic
acid,
centrophenoxine, pentobarbital, vincamine, vinpocetine, cinnarizine, aligeron,
xanthinol nicotinate and papaverine. The most pronounced anti-hypoxic
effect was shown primarily with the metabolic acting drugs, such as orotic
acid,
centrophenoxine, piracetam and pentobarbital, followed by the preparations
with
combined metabolic and vasoactive properties (vincamine and vinpocetine).
The
predominantly vasoactive drugs were less effective in anoxic hypoxia,
but showed more pronounced effect in incomplete ischemia.
Mechanism of action
21. On the mechanism of action of vinpocetine
Kiss B.; Karpati E.
Farmakologiai Kutato Kozpont, Richter Gedeon Vegyeszeti Gyar Rt., Pf.
27, H 1475 Budapest Hungary
Acta Pharmaceutica Hungarica (Hungary), 1996, 66/5 (213 224)
Cavinton was introduced into the clinical practice some twenty years
ago in Hungary for the treatment of cerebrovascular disorders and related
symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical
utilization, has become a reference compound in the pharmacological research
of cognitive deficits caused by hypoxia and ischaemia as well as in the
cellular and biochemical investigations related to cyclic nucleotides.
In this review a survey is given on the experimental data obtained with
vinpocetine and an attempt is made to outline the drug's mechanism of
action. Early experiments with vinpocetine indicated five main pharmacological
and biochemical actions: (1) selective enhancement of the brain circulation
and oxygen utilization without significant alteration in parameters of
systemic circulation, (2) increased tolerance of the brain toward hypoxia
and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase
(PDE) enzyme and (5) improvement of theological properties of the blood
and inhibition of aggregation of thrombocytes. Later studies in various
laboratories confirmed the above effects and clearly demonstrated that
vinpocetine offers significant and direct neuroprotection both under in
vitro and in vivo conditions. Evidence has been obtained that neuroprotective
action vinpocetine is related to the inhibition of operation of voltage
dependent neuronal Na+ channels, indirect inhibition of some molecular
cascades initiated by the rise of intracellular Ca2+ levels and, to a
lesser extent, inhibition of adenosine reuptake. Vinpocetine has been
shown to be selective inhibitor of Ca2+ calmodulin dependent cGMP PDE.
It is assumed that this inhibition enhances intracellular a GMP levels
in the vascular smooth muscle leading to reduced resistance of cerebral
vessels and increase of cerebral flow. This effect might also beneficially
contribute to the neuroprotective action.
22. Biochemical effects of ethyl apovincaminate
Rosdy B.; Balazs M.; Szporny L.
Dept. Pharmacol., Chem. Works Gedeon Richter Ltd, Budapest HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1923 1926)
Some cerebrobiochemical effects of a new cerebrovasodilatory agent, ethyl
apovincaminate (RGH 4405, Cavinton) were studied. Changes of biogenic
amines, 5 hydroxyindole acetic acid (5 HIAA) levels, serotonin (5 HT)
turnover rate, and the effect on 3',5' cyclic nucleotide phosphodiesterase
(PDE; E.C. 3.1.4.c) activity, isolated from different tissues, were determined.
Lasting increase of cerebral 5 HIAA level was observed after treatment
with the compound, 5 HT levels were transitorily enhanced 2 hr following
i.p. treatment. At later periods (4 6 hr) after treatment catecholamine
levels were significantly raised. 5 HT turnover was practically uninfluenced
by the compound. Activities of PDE preparations isolated from cerebral
tissues were markedly inhibited. Various hypotheses are suggested in order
to explain the biochemical mechanism of action of the compound.
Learning
23. Nootropic drugs have different effects on kindling induced learning
deficits in rats
Becker A.; Grecksch G.
Otto von Guericke University, Faculty of Medicine, Inst. Pharmacology
and Toxicology, Leipziger Str, 44, 39120 Magdeburg Germany
Pharmacological Research (United Kingdom), 1995, 32/3 (115 122)
Kindling represents an accepted model of human epileptogenesis. Furthermore,
it has been demonstrated that kindled rats show a diminished learning
performance in an active avoidance task. In our study we administered
different nootropic drugs to kindled rats to test their effects on learning
a two way active avoidance task in the shuttle box. Kindling was induced
by repeated intraperitoneal injections of 45 mg kg 1 pentylenetetrazol
(PTZ) once every 48 h. The substances vinpocetine (0.1 and 1.0 mg kg 1),
methylglucamin orotate (225 and 450 mg kg 1), piracetam (100 mg kg 1,
and meclofenoxate (100 mg kg 1) were administered during kindling development
and after kindling completion prior to each session in the learning experiment.
The nootropic drugs had little if any effect on severity of seizures.
Concerning their effect on learning the substances each acted in a specific
manner. Methylglucamin orotate enhanced the learning deficit induced by
kindling. Meclofenoxate injected prior to the kindling stimulation was
ineffective, whereas administration prior to the learning test improved
the learning performance effectively. A complementary action was shown
in experiments with vinpocetine. Only piracetam prevented the occurrence
of kindling induced learning deficits regardless the administration schedule.
24. Effect of vinpocetine on noradrenergic neurons in rat locus coeruleus
Gaal L.; Molnar P.
Department of Biochemistry, Pharmacological Research Centre, Chemical
Works of Gedeon Richter Ltd., P.O. Box 27, H 1475 Budapest Hungary
EUR. J. PHARMACOL. (Netherlands), 1990, 187/3 (537 539)
Conventional extracellular single unit recordings were used to investigate
the effect of vinpocetine on locus coeruleus noradrenergic neurons in
chloral hydrate anesthetized rats. Vinpocetine produced a significant
and dose dependent increase in the firing rate of locus coeruleus neurons
(ED30 = 0.75 mg/kg i.v.) up to 1 mg/kg i.v., followed by a complete blockade
of spiking activity at doses higher than this. The effective dose range
was in very good agreement with the dose range corresponding to the memory
enhancing effects of the compound. Our results supplied direct electrophysiological
evidence that vinpocetine increases the activity of ascending noradrenergic
pathways. This effect can be related to the cognitive enhancing characteristics
of the compound.
25. Comparison of the effects of vinpocentine, vincamine, and nicergoline
on the normal and hypoxia damaged learning process in spontaneously hypertensive
rats
Groo D.; Palosi E.; Szporny L.
Chemical Works of Gedeon Richter Ltd., Pharmacological Research Centre,
H 1475 Budapest Hungary
DRUG DEV. RES. (USA), 1988, 15/1 (75 85)
Vinpocetine (Cavinton (R)), vincamine, and nicergoline (Sermion (R))
were evaluated for the ability to protect cognitive function of spontaneously
hypertensive rats from the damaging effect of hypoxia. Normobaric hypoxia
(6% oxygen) was applied during the acquisition of a two way active avoidance
task (3 sessions, 50 trials/session). Hypoxia decreased the percentage
of conditioned avoidance responses by 50% on day 3. Vinpocetine (1.25
10 mg/kg) administered orally 60 min prior to the daily sessions did not
significantly improve learning in normoxic conditions; however, it prevented
hypoxia induced learning deficit (1.25 mg/kg peak effect dose). The dose
response relationship for the compounds is an inverted U shaped curve.
Vincamine (2.5 20 mg/kg p.o.) did not facilitate learning under normoxic
conditions, but afforded protection against hypoxia at the 20 mg/kg dose.
Nicergoline (2.5 20 mg/kg p.o.) did not increase acquisition of the normoxic
avoidance response, and it also showed a moderate antihypoxic effect.
Vinpocetine, and to a lesser degree vincamine and nicergoline drugs useful
in the therapy of cognitive disturbances following cerebral ischemic hypoxic
states proved effective in the prevention of a hypoxia induced learning
deficit.
26. Int Clin Psychopharmacol. 1987 Oct;2(4):325-31.
Vinpocetine effects on cognitive impairments produced by flunitrazepam.
Bhatti JZ, Hindmarch I.
Human Psychopharmacology Research Unit, University of Leeds, U.K.
The effects of pre-treatment with vinpocetine 40 mg, on flunitrazepam-induced
impairment of memory, were studied in 8 normal volunteers. Tests of Critical
Flicker Fusion Threshold, a Sternberg Memory Scanning Task, along with
subjective ratings of drug action were used. Drug effects were found to
be
modest. Treatment with vinpocetine was associated with improvements in
short-term memory processes.
Retina
27. Clinical and immunological signs of retinal involvement and potentialities
of its drug correction in patients with chronic diffuse viral diseases
of the liver and in Australian antigen carriers
Slepova O.S.; Kushnir V.N.; Zaitseva N.S.; Titarenko Z.D.; Dumbrava V.A.
Mosk. NI Institut Glaznykh Boleznej, Minzdravmedproma Rossii, Moskva Russian
Federation
Vestnik Oftalmologii (Russian Federation), 1994, 110/4 (27 29)
A total of 133 subjects aged 15 to 55 were followed up, the main group
(n = 87), patients with chronic diffuse diseases of the liver caused by
hepatitis B virus, and two reference groups, 26 patients with uveitis
and 20 normal subjects, 13 and 4 subjects of each group, respectively,
were Australian antigen (HBsAg) carriers. Functional disorders of the
retina were detected in 93.2% of group 1 patients, as well as intensified
local (tears) and total system (blood) autoimmune reactions to tissue
specific retinal S antigen (mol.mass 48 kD). An increased detection rate
of antibodies to S antigen and its higher titers were found in healthy
virus carriers as compared to HBsAg seronegative donors. These data may
be regarded as evidence of an increased risk of uveoretinal pathology
in subjects infected with hepatitis B virus, this being confirmed by a
higher incidence (50%) of latent virus carriership in the group of patients
with uveoretinitis. Stabilizing effect of cavinton in functional changes
of the retina was revealed, this recommending this drug for combined therapy
of patients with chronic diffuse diseases of the liver and for prevention
of ocular diseases. The majority of the examinees in whom retinal abnormalities
were found being young, the authors draw attention to the social aspect
of the problem.
Absorption
28. Study on the absorption of vinpocetine and apovincaminic acid
Pudleiner P.; Vereczkey L.
Chemical Works of Gedeon Richter Ltd, PO Box 27, 1475 Budapest 10 Hungary
EUR. J. DRUG METAB. PHARMACOKINET. (Switzerland), 1993, 18/4 (317 321)
The absorption of vinpocetine (Cavinton) and apovincaminic acid, compounds
showing a marked difference in their physico chemical properties, was
studied in rats in in situ loop experiments by using radiolabelled compounds.
In the case of apovincaminic acid, the investigations also involved the
estimation of the portion of radioactivity excreted in urine and faeces
after i.v. and p.o. administration of the compound. According to our results,
it can be concluded that both vinpocetine and apovincaminic acid are absorbed
from the gastrointestinal tract apovincaminic acid mainly from the stomach,
while vinpocetine is absorbed from the small intestine.
Gastroprotective
29. Protective action of vinpocetine against experimentally induced gastric
damage in rats
Nosalova V.; Machova J.; Babulova A.
Institute of Pharmacology, Slovak Academy of Sciences, Dubravska cesta
9, 84216 Bratislava Slovak Republic
ARZNEIM. FORSCH. DRUG RES. (Germany), 1993, 43/9 (981 985)
The efficacy of vinpocetine (CAS 42971 09 5) to prevent gastric mucosal
damage induced by several noxious agents and its antisecretory effect
were studied in rats. Vinpocetine administered orally or intraperitoneally
inhibited the development of gastric lesions induced by 96% ethanol in
a dose dependent way. The highest protective activity was observed when
vinpocetine was given intraperitoneally 30 min before ethanol, and its
effect was still significant when administered 120 min before ethanol
exposure. Oral administration of vincamine also displayed gastroprotective
action in this model. Pretreatment with indometacin counteracted the protective
action of vinpocetine against ethanol induced damage, suggesting the involvement
of a prostaglandin mediated mechanism. The protective effect of vinpocetine
was compared with that of prostaglandin E2, sucralfate, and tripotassium
dicitrate bismuthate. The antiulcer activity of vinpocetine was demonstrated
also in gastric injury induced by phenylbutazone and in chronic gastric
ulcer induced by acetic acid. Histamine stimulated gastric acid secretion
in pylorus ligated rats was partially inhibited by vinpocetine administered
intraduodenally. The activity of vinpocetine established in these experiments
is indicative of its potential clinical value as a gastroprotective agent.
Quisqualate/AMPA antagonist
30. Vinpocetine preferentially antagonizes quisqualate/AMPA receptor
responses: Evidende from release and ligand binding studies
Kiss B.; Cai N. S.; Erdo S.L.
Laboratory of Cellular and Molecular Pharmacology, Gedeon Richter Ltd.,
P.O. Box 27, H 1475 Budapest Hungary
EUR. J. PHARMACOL. (Netherlands), 1991, 209/1 (109 112)
The effect of vinpocetine on excitatory amino acid receptors was examined
in the rat brain by two different biochemical approaches. In release experiments
with striatal slices, vinpocetine reduced the efflux of dopamine and acetylcholine
evoked by glutamate, quisqualate and N methyl D aspartate (NMDA), but
not that evoked by kainate. In binding experiments with cortical membranes,
vinpocetine reduced the binding of (3H)2 amino 3 3 hydroxy s methylisoxasole
4 yl propionic acid ((3H)AMPA), a quisqualate partial agonist, in an incomplete
manner, but failed to influence the binding of (3H)kainate and (3H)3 (2
carboxypyperazine 4 yl) p ropyl 1 phosphonic acid ((3H)CPP), an NMDA agonist.
These findings suggest that vinpocetine is a quisqualate/AMPA antagonist
of some specificity and selectivity.
Microcirculation
31. Microcirculation, rheological properties of blood and their correction
in ischemic disorders of cerebral circulation
Veselsky I.Sh.; Sanik A.V.
Kafedra Nervnykh Boleznej Poltavskogo Meditsinskogo Stomatologicheskogo
Instituta, Poltava Ukrainian SSR
ZH. NEVROPATOL. PSIKHIATR. IM. S. S. KORSAKOVA (USSR), 1991, 91/11 (67
70)
A study was made of microcirculation using bulbar biomicroscopy and of
the aggregation properties of platelets in 94 patients with initial manifestations
of cerebral circulatory failure and dyscirculatory encephalopathy before
and after the treatment with vasoactive drugs and actovegin. It has been
recorded that the impairment of hemomicrocirculation progresses with the
rise of the disease stage, being more pronounced in patients with vegetovascular
crises. To correct microcirculatory disorders and the rheological properties
of blood, the authors provide evidence for administering cavinton, euphylline
and nicotinic acid combined with actovegin.
32. Effect of ethyl apovincaminate on the cerebral circulation; serial
angiography and regional cerebral circulation studies in neurosurgical
patients
Orosz E.; Deak Gy.; Benoist Gy.
Nat. Sci. Inst. Neurosurg., Budapest HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1951 1956)
The effect of ethyl apovincaminate (RGH 4405, Cavinton) on the cerebral
circulation has been studied with two methods in a series of neurosurgical
patients. Regional circulation was studied with the Hsub 2 clearance method
in five patients in whom deep electrodes were lodged in various cerebral
structures with stereotactic surgery performed for the underlying disease.
In connection with serial angiography of 25 patients 10 mg Cavinton was
injected i.v.; circulation time of the contrast medium, arterial circulation
time, changes of normal and pathological filling were appraised. Registered
15 min after administration, regional circulation showed significant increase,
but slight increase was demonstrable in every structure investigated.
The change was more marked in two elderly patients over 60 years. In eight
cases of serial angiography marked difference was seen in filling by normal
and pathological vessels on Cavinton effect; arterial circulation time
changed in three cases, contrast medium circulation time did in any of
the cases. The most marked changes occurred in three cases of cerebral
vascular disease. In two cases of glioma vascularization of the tumour
was visualized by Cavinton.
33. Effect of ethyl apovincaminate on cerebral circulation of dogs under
normal conditions and in arterial hypoxia
Bencsath P.; Debreczeni L.; Takacs L.
II Dept. Med., Semmelweis Univ. Med. Sch., Budapest HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1920 1923)
Effects of 1, 2 and 4 mg/kg i.v. doses of ethyl apovincaminate (RGH
4405, Cavinton) on cerebral blood flow, determined in the internal carotid
and vertebral artery, were studied in anaesthetized dogs under 21, 16
and 11% Osub 2 inhalation. Total cerebral blood flow was increased by
4 mg/kg Cavinton under normal Osub 2 and between 100 and 200 mmHg perfusion
pressures, while 2 mg/kg doses were effective under hypoxia. Similar phenomena
were observed in the carotid and vertebral flow, separately. Arterial
hypoxia seems to potentiate the effect of Cavinton on cerebral blood flow.
Glucose utilization
34. Effect of ethyl apovincaminate on the utilization of 14C glucoses
by rat brain in vitro
Matkovics B.; Szabo L.; Kiss B.; Szpornyi L.
Biological Isotope Laboratory, 'Atilla Jozsef' University, Kozepfasor
52, H 6726 Szeged Hungary
ARZNEIM. FORSCH. DRUG RES. (Germany, Federal Republic of), 1991, 41/2
(107 108)
The effect of the presence of 500 microg ethyl epovincaminate (Cavinton
(R)) on the aerobic metabolism of 14C labelled glucoses was studied in
vitro. The drug tested increased the metabolism of (1 14C) D glucose first
of all, which indicated a significant activation of pentose phosphate
shunt.
35. Cerebral effects of a single dose of intravenous vinpocetine in chronic
stroke patients: a PET study.
Szakall S, Boros I, Balkay L, Emri M, Fekete I, Kerenyi L, Lehel S, Marian
T,
Molnar T, Varga J, Galuska L, Tron L, Bereczki D, Csiba L, Gulyas B.
PET Centre, Debrecen University Medical School, Hungary.
J Neuroimaging. 1998 Oct;8(4):197-204.
The effects of vinpocetine (Cavinton) on the cerebral glucose metabolism
of
chronic stroke patients are studied with positron emission tomography.
The
regional and global cerebral metabolic rates of glucose (CMRglu) and the
kinetic
constants related to them are quantified before and after single-dose
intravenous vinpocetine treatment. These measurements are completed with
transcranial Doppler sonography and single photon emission computed tomography
to explore the possible mechanisms underlying the resulting changes in
glucose uptake and metabolism in the brain. The authors' findings indicate
that a single-dose vinpocetine treatment, although it does not affect
significantly the regional or global metabolic rates of glucose, improves
significantly the transport of glucose (both uptake and release) through
the blood-brain barrier in the whole brain, the entire contralateral hemisphere,
and in the brain tissue around the infarct area of the symptomatic hemisphere.
These changes are in accord with increased blood flow in the entire contralateral
hemisphere as well as decreased blood flow velocity and increased peripheral
vessel resistance in the entire symptomatic hemisphere.
Space motion sickness
36. Experimental assessment of selected antimotion drugs
Matsnev E.I.; Bodo D.
Institute of Biomedical Problems, 123007 Moscow USSR
AVIAT. SPACE ENVIRON. MED. (USA), 1984, 55/4 (281 286)
Space motion sickness (SMS) has been a perplexing problem in both the
Soviet and U.S. manned space programs. Both the sensory conflict theory
(neuronal signal mismatch) and the cephalad fluid shift concept explain
the mechanism. This paper reviews the mechanism of action of various drugs
that primarily affect brain blood flow or brain metabolism. In particular,
Cavinton (apovincamic acid ethyl ester) has been used successfully in
offsetting SMS in experimental test subjects.
Cardiac output
37. Effect of oral pretreatment with ethyl apovincaminate on the cardiac
output and nutritive blood flow of various organs in rats
Debreczeni L.; Takacs L.
II Dept. Med., Semmelweis Univ. Med. Sch., Budapest HUNGARY
ARZNEIMITTEL FORSCH. (GERMANY, WEST), 1976, 26/10A (1912 1917)
Effects of ethyl apovincaminate (RGH 4405, Cavinton), administered repeatedly
p.o. in doses of 0.5 1.5 4.5 mg/100 g body weight for 5 days, on cardiac
output and organ fractions of cardiac output were studied in rats anesthetized
with sodium pentobarbital by Evans blue dilution and the isotope fractionation
technique of Sapirstein. Cardiac output, cerebral, coronary, renal, intestinal
and dermal blood flow was increased by 18 42% after 4.5 mg/100 g Cavinton,
while blood pressure was unaltered. Total peripheral resistance, cerebral,
coronary, dermal resistance and that of the carcas decreased significantly.
Organ fractions of the cardiac output were not significantly altered after
treatment.
Meniere's disease
38. Vestn Otorinolaringol. 1980 May-Jun;(3):18-22.
[Prospects of using cavinton for treating Meniere's disease]
[Article in Russian]
Nikolaev MP, Konstantinova ZD, Mertsalova ON, Sheremet AS.
Cavinton, a new drug made by Gedeon Richter, was used for the treatment
of 20 patients with Meniere's disease and frequent attacks of vertigo
according to the following scheme: 4 ml (20 mg) in 5-20 ml of physiological
saline was injected intravenously daily for up to 10 days, then 2 ml (10
mg) intramuscularly twice a day for 20 days, and then 1 ml (5 mg) three
times a day for 10 to 20 days. As a result the attacks were arrested in
all patients. In 15 cases vertigo disappeared, tinnitus aurium diminished,
and static imbalance was eliminated. In 10 patients who had monthly attacks
of the disease before treatment, the remission persisted for up to 6 months.
Cavinton is believed to be effective enough and thus promising for the
treatment of Meniere's disease with frequent attacks of vertigo.
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