| Eksp Klin Farmakol. 2006 May-Jun;69(3):58-62.
[Clastogenic, aneugenic, pro- and antioxidant properties of some
neurotropic preparations]
[Article in Russian]
Gaitetdinova DD, Semenov VV, Ismagilov MF, Kharitonov VS.
National Stroke Center, Department of Vascular Neurology, Semmelweis
University, H-1085 Budapest, Hungary.
In experimental and clinical investigations, assessment was made of mutagenous,
antimutagenous, pro- and antiradical activity of some neurotropic preparations--cerebrolysin,
encephabol (pyritinol), nootropil (piracetam), actovegin and cavinton
(vinpocetine). In chemical, fermentative and cellular model systems, cerebrolysin
inhibited generation of superoxide anion-radical, nitrogen monoxide and
final products of degradation of fatty acids. Other preparations showed
both anti- and prooxidant effect. The most pronounced anticlastogenic
activity during expriments on C. capillaries had a cerebrolysin. Encephabol
had the most prooxidant effect and low anticlastogenic activity. The ability
of such preparations as ceredrolysin and encephabol to decrease erythrocyte
high level with micronuclei in peripheric blood of patients with infantile
cerebral palsy (spastic diplegia) was clinically investigated. The modifying
effect of preparations was not univalent: it was cerebrolysin that decreased
intensivity of aneu- and clastogenesis in patients in a greater degree
than encephabol. A protective effect of these preparations was pronounced
on the 10th day in group of the boys, and on the 20th day in the group
of the girls.
Pharmacol Rep. 2006 Sep-Oct;58(5):680-91.
Vinpocetine and piracetam exert antinociceptive effect in visceral
pain model in mice.
Abdel Salam OM.
Department of Pharmacology, National Research Centre, Tahrir St.,
Dokki, Cairo, Egypt.
The effect of vinpocetine or piracetam on thermal and visceral pain was
studied in mice. In the hot plate test, vinpocetine (0.9 and 1.8 mg/kg),
but not piracetam, produced a reduction in nociceptive response. Vinpocetine
(0.45-1.8 mg/kg, ip) or piracetam (75-300 mg/kg, ip) caused dose-dependent
inhibition of the abdominal constrictions evoked by ip injection of acetic
acid. The effect of vinpocetine or piracetam was markedly potentiated
by co-administration of propranolol, guanethidine, atropine, naloxone,
yohimbine or prazosin. The marked potentiation of antinociception occurred
upon a co-administration of vinpocetine and baclofen (5 or 10 mg/kg).
In contrast, piracetam antagonized antinociception caused by the low (5
mg/kg), but not the high (10 mg/kg) dose of baclofen. The antinociception
caused by vinpocetine was reduced by sulpiride; while that of piracetam
was enhanced by haloperidol or sulpiride. Either vinpocetine or piracetam
enhanced antinociception caused by imipramine. The antinociceptive effects
of vinpocetine or piracetam were blocked by prior administration of theophylline.
Low doses of either vinpocetine or piracetam reduced immobility time in
the Porsolt's forced-swimming test. This study indicates that vinpocetine
and piracetam possess visceral antinociceptive properties. This effect
depends on activation of adenosine receptors. Piracetam in addition inhibits
GABA-mediated antinociception.
J Neurol Sci. 2005 Mar 15;229-230:275-84. Epub 2005 Jan 8.
Effects of vinpocetine on the redistribution of cerebral blood
flow and glucose metabolism in chronic ischemic stroke patients: a PET
study.
Szilagyi G, Nagy Z, Balkay L, Boros I, Emri M, Lehel S, Marian
T, Molnar T, Szakall S, Tron L, Bereczki D, Csiba L, Fekete I, Kerenyi
L, Galuska L, Varga J, Bonoczk P, Vas A, Gulyas B.
National Stroke Center, Department of Vascular Neurology, Semmelweis
University, H-1085 Budapest, Hungary.
The pharmacological effects of the neuroprotective drug vinpocetine,
administered intravenously in a 14-day long treatment regime, on the cerebral
blood flow and cerebral glucose metabolism in chronic ischemic stroke
patients (n=13) were studied with positron emission tomography in a double-blind
design. The regional and global cerebral metabolic rates of glucose (CMRglc)
and cerebral blood flow (CBF) as well as vital physiological parameters,
clinical performance scales, and transcranial Doppler parameters were
measured before and after the treatment period in patient groups treated
with daily intravenous infusion with or without vinpocetine. While the
global CMRglc values did not change markedly as a result of the infusion
treatment with (n=6) or without (n=7) vinpocetine, the global CBF increased
and regional CMRglc and CBF values showed marked changes in several brain
structures in both cases, with more accentuated changes when the infusion
contained vinpocetine. In the latter case the highest rCBF changes were
observed in those structures in which the highest regional uptake of labelled
vinpocetine was measured in other PET studies (thalamus and caudate nucleus:
increases amounting to 36% and 37%, respectively). The findings indicate
that a 2-week long intravenous vinpocetine treatment can contribute effectively
to the redistribution of rCBF in chronic ischemic stroke patients. The
effects are most pronounced in those brain regions with the highest uptake
of the drug.
Neurochem Int. 2005 Jun;46(7):533-40.
Vinpocetine blockade of sodium channels inhibits the rise in sodium
and calcium induced by 4-aminopyridine in synaptosomes.
Sitges M, Galvan E, Nekrassov V.
Departmento de Biologia Celular y Fisiologia, Instituto de Investigaciones
Biomedicas, UNAM, Apartado Postal 70228, Ciudad Universitaria 04510, Mexico,
D.F., Mexico.
The objective of this study was to get a more understandable picture
of the mechanism underlying the anticonvulsant action of vinpocetine.
The question of how the cerebral excitability is affected was investigated
by determining the effect of vinpocetine on the changes on the internal
concentrations of Na(+) (Na(i)) and Ca(2+) (Ca(i)) induced by different
concentrations of the convulsing agent 4-aminopyridine (4-AP) in striatal
isolated nerve endings. The cytosolic concentrations of Na(i) and Ca(i)
were detected fluorimetrically with sodium-binding benzofuran isophthalate
(SBFI) and fura-2, respectively. Vinpocetine, like the Na(+) channel blocker,
tetrodotoxin, abolished the increase in Na(i) induced by 0.1 mM 4-AP and
only inhibited in 30% the rise in Na(i) induced by 1mM 4-AP. In contrast
with the different sensitivity of the rise in Na(i) induced by 0.1 and
1mM 4-AP to vinpocetine and tetrodotoxin, the rise in Ca(i) induced by
the two concentrations of 4-AP was markedly inhibited by vinpocetine (and
tetrodotoxin), indicating that only the voltage-sensitive sodium channels
(VSSC)-mediated fraction of the rise in Na(i) induced by 4-AP is linked
with the activation of pre-synaptic Ca(2+) channels. The elevation of
Ca(2+) induced by high K(+) (30 mM) does not require a Na(+) gradient
and is vinpocetine and tetrodotoxin insensitive. In contrast, the elevation
of Ca(i) induced by 4-AP, requires a physiological (out/in) Na(+) gradient
and is vinpocetine and tetrodotoxin-sensitive. It is concluded that by
blocking the tetrodotoxin-sensitive fraction of the rise in Na(i) induced
by 4-AP, vinpocetine inhibits the concomitant rise in Ca(i) induced by
4-AP. The inhibitory effect of vinpocetine on pre-synaptic voltage-sensitive
sodium channels may underlie the in vivo anticonvulsant action of vinpocetine.
Eur J Clin Pharmacol. 2005 Apr;61(2):87-96. Epub 2005 Mar 11.
Enalapril dosage in progressive chronic nephropathy: a randomised,
controlled trial.
Elung-Jensen T, Heisterberg J, Sonne J, Strandgaard S, Kamper
AL.
Departments of Nephrology and Clinical Physiology and Nuclear Medicine,
Herlev Hospital, University of Copenhagen, Denmark.
OBJECTIVE: In chronic renal failure, clearance of enalapril is reduced.
Hence, a renoprotective effect may be achieved with lower doses than conventionally
used. Since marked inter-patient variation in concentrations of enalaprilat
has been shown in patients with renal failure despite equivalent dosage
of enalapril, a direct comparison of the effect of high versus low plasma
concentrations of enalaprilat on the progression of renal failure was
undertaken.METHODS: Forty patients with a median glomerular filtration
rate (GFR) of 17 (6-35) ml/min/1.73 m(2) were studied in an open-label,
randomised trial comparing patients with a high (>50 ng/ml) with patients
with a low (<10 ng/ml) target trough plasma concentration of enalaprilat.
The dose of enalapril was titrated accordingly. The patients were followed
for 12 months or until they needed renal replacement therapy. GFR was
measured at 3-month intervals by the plasma clearance of (51) Cr-EDTA,
and the individual rates of progression of renal failure were calculated
as the slope of GFR versus time plot.RESULTS: In the high-concentration
group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0
ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml)
at 3 months follow-up (P<0.001). The median daily doses of enalapril
were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups,
respectively (P<0.001). In the high-concentration group, the mean+/-SE
decline in renal function was 6.1+/-1.5 ml/min/1.73 m(2) per year and
in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m(2) per
year (P=0.48). Five patients in the high-concentration group reached end-stage
renal failure whereas none in the low-concentration group did (P=0.04).
There were no statistically significant differences in blood pressure
level, concomitant antihypertensive therapy or urinary albumin excretion.
However, the high-enalaprilat concentration group had an overall higher
plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001).CONCLUSION:
In patients with moderate to severe renal insufficiency, a low concentration
of enalaprilat afforded the same degree of renoprotection, blood pressure
control and minimisation of proteinuria as a high concentration, during
12 months of follow-up. The high-dosage treatment was associated with
a more pronounced tendency to hyperkalaemia. Thus, there seems to be no
indication for increasing the daily dose of enalapril beyond what achieves
adequate blood pressure control in this group of patients.
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.
J Neurol Sci. 2005 Mar 15;229-230(1):275-84. Epub 2005 Jan 8.
Effects of vinpocetine on the redistribution of cerebral blood
flow and glucose metabolism in chronic ischemic stroke patients: a PET
study.
Szilagyi G, Nagy Z, Balkay L, Boros I, Emri M, Lehel S, Marian
T, Molnar T, Szakall S, Tron L, Bereczki D, Csiba L, Fekete I, Kerenyi
L, Galuska L, Varga J, Bonoczk P, Vas A, Gulyas B.
National Stroke Center, Department of Vascular Neurology, Semmelweis University,
H-1085 Budapest, Hungary.
The pharmacological effects of the neuroprotective drug vinpocetine,
administered intravenously in a 14-day long treatment regime, on the cerebral
blood flow and cerebral glucose metabolism in chronic ischemic stroke
patients (n=13) were studied with positron emission tomography in a double-blind
design. The regional and global cerebral metabolic rates of glucose (CMR(glc))
and cerebral blood flow (CBF) as well as vital physiological parameters,
clinical performance scales, and transcranial Doppler parameters were
measured before and after the treatment period in patient groups treated
with daily intravenous infusion with or without vinpocetine. While the
global CMR(glc) values did not change markedly as a result of the infusion
treatment with (n=6) or without (n=7) vinpocetine, the global CBF increased
and regional CMR(glc) and CBF values showed marked changes in several
brain structures in both cases, with more accentuated changes when the
infusion contained vinpocetine. In the latter case the highest rCBF changes
were observed in those structures in which the highest regional uptake
of labelled vinpocetine was measured in other PET studies (thalamus and
caudate nucleus: increases amounting to 36% and 37%, respectively). The
findings indicate that a 2-week long intravenous vinpocetine treatment
can contribute effectively to the redistribution of rCBF in chronic ischemic
stroke patients. The effects are most pronounced in those brain regions
with the highest uptake of the drug
Biochem Pharmacol. 2004 Nov 15;68(10):2087-2094.
Inhibitory effects of flavonoids on phosphodiesterase isozymes from
guinea pig and their structure-activity relationships.
Ko WC, Shih CM, Lai YH, Chen JH, Huang HL.
Graduate Institute of Pharmacology, College of Medicine, Taipei Medical
University, Taipei, Taiwan.
The structure-activity relationships of flavonoids with regard to their
inhibitory effects on phosphodiesterase (PDE) isozymes are little known.
The activities of PDE1-5 were measured by a two-step procedure using cAMP
with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present
results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea
pig lungs in that order, and PDE3 was from the heart. The IC(50) values
of PDE1-5 were greater than those reported previously for the reference
drugs, vinpocetin, EHNA, milrinone, Ro 20-1724, and zaprinast, by 5-,
5-, 7-, 5-, and 3-fold, respectively. As shown in Table 2, luteolin revealed
non-selective inhibition of PDE1-5 with IC(50) values in a range of 10-20μM,
as did genistein except with a low potency on PDE5. Daidzein, an inactive
analogue of genistein in tyrosine kinase inhibition, showed selective
inhibition of PDE3 with an IC(50) value of around 30μM, as did eriodictyol
with an IC(50) value of around 50μM. Hesperetin and prunetin exhibited
more-selective inhibition of PDE4 with IC(50) values of around 30 and
60μM, respectively. Luteolin-7-glucoside exhibited dual inhibition of
PDE2/PDE4 with an IC(50) value of around 40μM. Diosmetin more-selectively
inhibited PDE2 (IC(50) of 4.8μM) than PDE1, PDE4, or PDE5. However, biochanin
A more-selectively inhibited PDE4 (IC(50) of 8.5μM) than PDE1 or PDE2.
Apigenin inhibited PDE1-3 with IC(50) values of around 10-25μM. Myricetin
inhibited PDE1-4 with IC(50) values of around 10-40μM. The same was true
for quercetin, but we rather consider that it more-selectively inhibited
PDE3 and PDE4 (IC(50) of <10μM). In conclusion, it is possible to synthesize
useful drugs through elucidating the structure-activity relationships
of flavonoids with respect to inhibition of PDE isozymes at concentrations
used in this in vitro study.
Life Sci. 2004 Aug 27;75(15):1833-42.
Phosphodiesterase inhibition by a gastroprotective agent irsogladine: preferential blockade of cAMP hydrolysis.
Kyoi T, Oka M, Noda K, Ukai Y.
Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan. t.kyoi@po.nippon-shinyaku.co.jp
The effect of irsogladine [2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate], an antiulcer drug, on contents of cyclic nucleotides including cAMP and cGMP was investigated in rat stomachs. Irsogladine concentration-dependently increased cAMP content in rat glandula stomach. However, irsogladine at higher concentration (10(-5) M) was unable to further increase cAMP level in the presence of non-selective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine, although 3-isobutyl-1-methylxanthine by itself increased cAMP level. On the other hand, irsogladine had no effect on the glandula cGMP content. Subsequently, the effect of irsogladine on the cyclic nucleotide degradation by purified bovine brain and heart PDEs was investigated. The cAMP degradation by purified bovine brain PDE was partially suppressed by PDE1 inhibitor vinpocetin, PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride and PDE4 inhibitor rolipram but not by PDE3 inhibitor cilostamide, and completely inhibited by 3-isobutyl-1-methylxanthine, suggesting that is attributed almost exclusively to PDE1, PDE2 and PDE4. Meanwhile, cGMP degradation by purified bovine brain PDE was partially suppressed by erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride. Irsogladine preferentially inhibited the response to cAMP degradation compared with cGMP degradation by this brain PDE. The cAMP degradation by bovine heart PDE was almost completely inhibited by the combination with vinpocetine and cilostamide, indicating that is mediated almost exclusively by PDE1 and PDE3. Irsogladine suppressed this cAMP degradation measured in the presence of vinpocetine to almost the same extent as that determined in the presence of cilostamide. These results indicate that irsogladine produces the increase of intracellular cAMP content via non-selective inhibition of PDE isozymes, which may be a key mechanism involved in its gastroprotective actions.
Ann N Y Acad Sci. 2004 Jun;1019:64-9.
Antiaging treatments have been legally prescribed for approximately thirty years.
Ukraintseva SV, Arbeev KG, Michalsky AI, Yashin AI.
Max Planck Institute for Demographic Research, 18057 Rostock, Germany. ukraintseva@cds.duke.edu
There is an interesting divergence between the achievements of geriatrics and gerontology. On the one hand, during the last 30 years physicians in many developed countries have successfully prescribed several medicines to cure various symptoms of senescence. On the other hand, the influence of such medicines on human life span practically has not been studied. The most common of the relevant medicines are nootropic piracetam, gamma-aminobutyric acid (GABA), selegiline, Ginkgo biloba, pentoxifylline, cerebrolysin, solcoseryl, ergoloid, vinpocetin, sertraline, and estrogens, among others. Available data from human clinical practices and experimental animal studies indicate that treatments with these drugs improve learning, memory, brain metabolism, and capacity. Some of these drugs increase tolerance to various stresses such as oxygen deficit and exercise, stimulate the regeneration of neurons in the old brain, and speed up the performance of mental and physical tasks. This means that modern medicine already has "antiaging" treatments at its disposal. However, the influence of such treatments on the mean and maximal life span of humans, and on the age trajectory of a human survival curve has been poorly studied. The increase in human life expectancy at birth in the second half of the last century was mostly caused by the better survival at the old and oldest old rather than at the young ages. In parallel, the consumption of brain protective and regenerative drugs has been expanding in the elderly population. We provide evidence in support of the idea that the consumption of medicines exerting antiaging properties may contribute to the increase in human longevity.
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. szapary@neuro.pote.hu
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.
Cochrane Database Syst Rev. 2003(1):CD003119.
Vinpocetine for cognitive impairment and dementia.
Szatmari SZ, Whitehouse PJ.
4300, Targu Mures, str. Gral I., Dumitrache 22, Romania. szatmari@netsoft.ro
BACKGROUND: Vinpocetine is a synthetic ethyl ester of apovincamine, a vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca minor) and discovered in the late 1960s. Although used in human treatment for over twenty years, it has not been approved by any regulatory body for the treatment of cognitive impairment. Basic sciences studies have been used to claim a variety of potentially important effects in the brain. However, despite these many proposed mechanisms and targets, the relevance of this basic science to clinical studies is unclear. OBJECTIVES: To assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimer's disease, mixed (vascular and Alzheimer's disease) and other dementias. SEARCH STRATEGY: The Cochrane Dementia & Cognitive Improvement Group's Specialized Register was searched using the terms vinpocetin*, cavinton, kavinton, Rgh-4405, Tcv-3B, "ethyl apovincaminate", vinRx, periwinkle, "myrtle vincapervinc" and cezayirmeneksesi. The manufacturers of vinpocetine were asked for information on trials of vinpocetine for dementia. In addition we tried to collect articles not listed in MEDLINE or other sources on the Internet (e.g. articles in Hungarian and Romanian). SELECTION CRITERIA: All human, unconfounded, double-blind, randomized trials in which treatment with vinpocetine was administered for more than a day and compared to control in patients with vascular dementia, Alzheimer's dementia or mixed Alzheimer's and vascular dementia and other dementias. Non-randomized trials were excluded. DATA COLLECTION AND ANALYSIS: Data were independently extracted by the two reviewers (SzSz and PW) and cross-checked. Data from "washout" periods were not used for the analysis. For continuous or ordinal variables, such as cognitive test results, the main outcomes of interest were the change in score from baseline. The categorical outcome of global impression was transformed to binary data (improved or not improved) as was the occurrence of adverse effects; here the endpoint itself was of interest the Peto method of the "typical odds ratio" was used. A test for heterogeneity of treatment effects between the trials was made if appropriate. Data synthesis and analysis were performed using the Cochrane Review Manager software (RevMan version 4.1). MAIN RESULTS: All identified studies were performed before the 1990s and used various terms and criteria for cognitive decline and dementia. The three studies included in the review involved a total of 583 people with dementia treated with vinpocetine or placebo. The reports of these studies did not make possible any differentiation of effects for degenerative or vascular dementia. The results show benefit associated with treatment with vinpocetine 30mg/day and 60 mg/day compared with placebo, but the number of patients treated for 6 months or more was small. Only one study extended treatment to one year. Adverse effects were inconsistently reported and without regard for relationship to dose. The available data do not demonstrate many problems of adverse effects but intention-to-treat data were not available for any of the trials. REVIEWER'S CONCLUSIONS: Although the basic science is interesting, the evidence for beneficial effect of vinpocetine on patients with dementia is inconclusive and does not support clinical use. The drug seems to have few adverse effects at the doses used in the studies. Large studies evaluating the use of vinpocetine for people suffering from well defined types of cognitive impairment are needed to explore possible efficacy of this treatment.
Orv Hetil. 2002 Nov 24;143(47):2631-6.
Cerebral uptake and regional distribution of [11C]-vinpocetin after intravenous administration to healthy men: a PET study
Vas A, Sovago J, Halldin C, Sandell J, Karlsson P, Karpati E, Kiss B, Cselenyi Z, Farde L, Gulyas B.
Richter Gedeon Vegyeszeti Gyar Rt., Budapest.
INTRODUCTION: Vinpocetine is a compound widely used in the prevention and treatment of cerebrovascular diseases. The exact mechanism of action of the drug is still not known. The objective of the present investigation was to determine the global uptake and regional distribution of radiolabelled vinpocetine in the human brain. Three healthy persons were examined with positron emission tomography (PET) and [11C]-vinpocetine. RESULTS: The uptake of [11C]-vinpocetine in brain was rapid and on average as a maximum 3.7% of the total radioactivity injected was in the brain 2 minutes after radioligand administration. The uptake was heterogeneously distributed among brain regions. When compared with the cerebellum, an a priori reference region, the highest regional uptake was in the thalamus, the upper brain stem, the striatum and the cortex. CONCLUSIONS: The brain regions showing increased uptake in the human brain correspond to those in which vinpocetine has previously been shown to induce elevated metabolism and blood flow by PET clinical studies in patients with chronic ischaemic post-stroke condition.
Orv Hetil. 2003 Nov 16;144(46):2271-6.
Vas A, Christer H, Sovago J, Johan S, Cselenyi Z, Kiss B, Karpati E, Lars
F, Gulyas B.
Department of Clinical Neuroscience, Psychiatry Section, Karolinska
Institute, Stockholm.
INTRODUCTION: Positron emission tomography (PET) is a useful tool for
the investigation of certain physiological changes and for the evaluation
of the distribution, and receptor binding of drugs labelled with positron
emitting isotopes. Vinpocetine (ethyl-apovincaminate) is a neuroprotective
drug widely used in the prevention and treatment of cerebrovascular diseases.
In the clinical practice vinpocetine is usually administered to the patients
in intravenous infusion followed by long-term oral treatment. Until presently
human data describing vinpocetine's kinetics and brain distribution came
from ex vivo (blood, plasma, liquor) and post mortem (brain autoradiography)
measurements. AIM: The authors wished to investigate the kinetics and
distribution of vinpocetine in the brain and body after oral administration
with PET in order to prove, that PET is useful in the non-invasive in
vivo determination of these parameters. METHOD: Vinpocetine was labelled
with carbon-11 and the radioactivity was measured by PET in the stomach,
liver, brain, colon and kidneys in healthy male volunteers. The radioactivity
in the blood and urine was also determined. RESULTS: After oral administration,
[11C]vinpocetine appeared immediately in the stomach and within minutes
in the liver and the blood. In the blood the level of radioactivity continuously
increased until the end of the measurement period, whereas the fraction
of the unchanged mother compound decreased. Radioactivity uptake and distribution
in the brain were demonstrable from the tenth minute after the oral administration
of the labelled drug (average maximum uptake: 0.7% of the administered
total dose). Brain distribution was heterogeneous (with preferences in
the thalamus, basal ganglia and occipital cortex), similar to the distribution
previously reported by the authors after intravenous administration. CONCLUSIONS:
Vinpocetine, administered orally to human volunteers, readily entered
the bloodstream from the stomach and the gastrointestinal tract and thereafter
passed the blood-brain barrier and entered the brain. Radioactivity from
[11C]vinpocetine was also demonstrated in the kidneys and in urine. The
study demonstrates that PET might be a useful, direct and non-invasive
tool to study the distribution and pharmacokinetics of orally administered
labelled drugs active in the central nervous system in the living human
body.
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.
Cochrane Database Syst Rev. 2003;(1):CD003119.
Vinpocetine for cognitive impairment and dementia.
Szatmari SZ, Whitehouse PJ.
4300, Targu Mures, str. Gral I., Dumitrache 22, Romania.
BACKGROUND: Vinpocetine is a synthetic ethyl ester of apovincamine, a
vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca
minor) and discovered in the late 1960s. Although used in human treatment
for over twenty years, it has not been approved by any regulatory body
for the treatment of cognitive impairment. Basic sciences studies have
been used to claim a variety of potentially important effects in the brain.
However, despite these many proposed mechanisms and targets, the relevance
of this basic science to clinical studies is unclear. OBJECTIVES: To assess
the efficacy and safety of vinpocetine in the treatment of patients with
cognitive impairment due to vascular disease, Alzheimer's disease, mixed
(vascular and Alzheimer's disease) and other dementias. SEARCH STRATEGY:
The Cochrane Dementia & Cognitive Improvement Group's Specialized
Register was searched using the terms vinpocetin*, cavinton, kavinton,
Rgh-4405, Tcv-3B, "ethyl apovincaminate", vinRx, periwinkle,
"myrtle vincapervinc" and cezayirmeneksesi. The manufacturers
of vinpocetine were asked for information on trials of vinpocetine for
dementia. In addition we tried to collect articles not listed in MEDLINE
or other sources on the Internet (e.g. articles in Hungarian and Romanian).
SELECTION CRITERIA: All human, unconfounded, double-blind, randomized
trials in which treatment with vinpocetine was administered for more than
a day and compared to control in patients with vascular dementia, Alzheimer's
dementia or mixed Alzheimer's and vascular dementia and other dementias.
Non-randomized trials were excluded. DATA COLLECTION AND ANALYSIS: Data
were independently extracted by the two reviewers (SzSz and PW) and cross-checked.
Data from "washout" periods were not used for the analysis.
For continuous or ordinal variables, such as cognitive test results, the
main outcomes of interest were the change in score from baseline. The
categorical outcome of global impression was transformed to binary data
(improved or not improved) as was the occurrence of adverse effects; here
the endpoint itself was of interest the Peto method of the "typical
odds ratio" was used. A test for heterogeneity of treatment effects
between the trials was made if appropriate. Data synthesis and analysis
were performed using the Cochrane Review Manager software (RevMan version
4.1). MAIN RESULTS: All identified studies were performed before the 1990s
and used various terms and criteria for cognitive decline and dementia.
The three studies included in the review involved a total of 583 people
with dementia treated with vinpocetine or placebo. The reports of these
studies did not make possible any differentiation of effects for degenerative
or vascular dementia. The results show benefit associated with treatment
with vinpocetine 30mg/day and 60 mg/day compared with placebo, but the
number of patients treated for 6 months or more was small. Only one study
extended treatment to one year. Adverse effects were inconsistently reported
and without regard for relationship to dose. The available data do not
demonstrate many problems of adverse effects but intention-to-treat data
were not available for any of the trials. REVIEWER'S CONCLUSIONS: Although
the basic science is interesting, the evidence for beneficial effect of
vinpocetine on patients with dementia is inconclusive and does not support
clinical use. The drug seems to have few adverse effects at the doses
used in the studies. Large studies evaluating the use of vinpocetine for
people suffering from well defined types of cognitive impairment are needed
to explore possible efficacy of this treatment.
Acta Pharm Hung. 2002;72(2):84-91.
Neuroprotective effects of vinpocetine in vivo and in vitro. Apovincaminic
acid derivatives as potential therapeutic tools in ischemic stroke
Dezsi L, Kis-Varga I, Nagy J, Komlodi Z, Karpati E.
Richter Gedeon Vegyeszeti Gyar Rt., Budapest, Gyomroi ut 19-21.-1103.
The aim of the present study was to review neuroprotective therapy from
the preclinical point of view as a potential tool for the treatment of
stroke, as well as to discuss neuroprotective effects of the apovincaminic
acid derivative vinpocetine (Cavinton). Our own in vivo and in vitro experiments
were aimed at further characterizing pharmacological effects involved
in the vinpocetine-induced neuroprotection. The effect of vinpocetine
on infarct volume (obtained by 2,3,5-triphenyltetrazolium-chloride staining)
was studied in permanent middle cerebral artery occlusion (MCAO) in rats
(3 mg/kg i.p., 30 min postischemia). Vinpocetine treatment significantly
decreased infarct volume (by 42%, p < 0.05) compared to control, which
was better than the effect of nimodipine (17%) or MK-801 (18%). Neurotoxicity
measurements were made in primary cortical cell culture using LDH release
as an indicator. Vinpocetine dose-dependently inhibited prolonged (24
h) or transient (15 min) glutamate, and transient N-metil-D-aspartate
(NMDA) or veratridine (0.1-1 mM) induced excitotoxicity (IC50 = 2-7 x
10(-6) M). In these tests the neuroprotective potency of vinpocetine was
lower than that of MK-801, but it was similar to those of flunarizine
or nimodipine. These results together with former literature data indicate
that apovincaminic acid derivatives possessing strong neuroprotective
potential may play an important role in the therapy of ischemic stroke.
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