Objective: To determine the effect of Vinpocetine on objective measures of cognitive function and memory based on a critical review of the current literature.
Methods: An attempt was made to identify all English and non-English-language articles in which Vinpocetine was used for the treatment of dementia, memory deficits, or cognitive impairment. The methodological quality of clinical trials utilizing Vinpocetine for the purpose of cognition and memory enhancement was assessed. Trial outcomes were interpreted in relation to their quality and predefined criteria of good study methodology was used.
Results: Of 39 articles reviewed only three met all inclusion criteria. In total 327 patients in the Vinpocetine or placebo group participated in the selected clinical trials.
Overall there was a statistically significant improvement in the Clinical Global Impression (CGI) scale, Sandoz Clinical Assessment Geriatric (SCAG) scale, and Mini Mental Status Questionnaire (MMSQ) in the Vinpocetine treatment arm. No adverse events were reported and side effects were mostly related to gastrointestinal discomfort.
Conclusion: Based on the selected clinical trials there is a significant effect of Vinpocetine in the management of cognitive impairment and memory loss in patients with early dementia or other related symptoms of cerebrovascular diseases. Vinpocetine is not indicated in the treatment of Alzheimer disease due to limited and inconsistent data. Additional research is needed to define the clinical application of Vinpocetine in the management of cognitive impairment.
Vinpocetine, a vincamine derivative, is a synthetic ethyl ester of apovincamine (3,16-eburnamenine-14-carboxylic acid ethyl ester). Vincamine is an extract of the periwinkle plant (Vinca Minor) and chemically is an indole alkaloid (eburnarnine-type, 25-65%). Other alkaloids include vincin, apovincamine and vincadifformin. The plant is indigenous to northern Spain, and grows throughout western France, eastwards via central and southern Europe as far as the Caucasus. The dried leaves, the fresh aerial parts of the flowering plant, and the whole fresh flowering plant are used for medicinal purposes. Vinpocetine has been widely used and studied in Europe for over 25 years, but is not well known in the United States and has only recently been introduced in the United States for use as a nutraceutical supplement.
The therapeutic utilization of Vinpocetine is based on pharmacological research of cognitive deficits caused by hypoxia and ischemia as well as in the cellular and biochemical investigations related to cyclic nucleotides.
In animal experiments Vinpocetine and its derivatives have been shown to increase cerebral blood flow, 1,2,3 increase blood flow in the vertebral and coronary arteries of dogs, 4-9 and increase brain glucose uptake in mice. 10 The reduction in cerebral vascular resistance is due to an increase in the cGMP content in smooth vasculature by selective inhibition of Ca 2+/Calmodulin-dependent cGMP-phosphodiesterase. 11-15
Phosphodiesterase inhibitors (PDEis) suppress the production of tumor necrosis factor (TNF-alpha) in various cells and are also reported to reduce experimental demyelination of brain cells. 16 Vinpocetine is a PDE-1 selective inhibitor and is a potentially useful anti-inflammatory agent via down-regulating inflammatory cytokines and up-regulating inhibitory cytokines in the central nervous system (CNS). 17-18 One study cites prevention of contrast medium induced renal vasospasmt. 19 Vinpocetine was also reported to protect against excitotoxic cell death in cell cultures of rat cerebral cortex 20 and in striatal slices of rat brain. 21 In vitro models of cerebral ischemia indicated calcium antagonist activity 22 and neuroprotective and anticonvulsant effects by blocking voltage-gated NA-channels in cortical neurons of rats 23 and gerbils. 24 Vinpocetine prevented postischermic increase in glucose utilization and decrease in local blood flow in the hippocampus of rats, 25 decreased neuronal cell loss in a rat model of forebrain ischemia, 26 and increased the neuroprotective effect of adenosine in hypoxemic cultures. 27 Vinpocetine's indirect adenosine-like activity 28,29 might explain the protective cerebral action.
Furthermore Vinpocetine was reported to decrease the size of cerebral infarction after middle cerebral artery occlusion in both rats 30 and mice. 31 In human studies, vinpocetine was reported to increase cerebral blood flow in previously ischemic cerebral regions, 32 had a viscosity-lowering effect on blood and plasma, 33 decreased platelet and red cell aggregation, 34,35 and increased erythrocyte deformability in patients after ischemic stroke. 36 Based on the findings of animal experiments and the result of pharmacological studies. 37 Vinpocetine was recommended as a treatment modality for patients with stroke in several European countries (Hungary, Poland, Germany, Russia) and Japan. A recently published meta-analysis 38 does not support the assumption that the use of Vinpocetine can decrease the morbidity and mortality in acute stroke.
It was also reported that Vinpocetine enhances the intracerebral metabolism of biogenic monoamins, including serotonin, dopamine, and norepinephrine, 39,40 the intracerebral concentration of ATP, 41 and facilitates neurotransmitter turnover particularly 5-HIAA and serotonin. 1
These effects combined might synergistically con- tribute to the significant neuroprotective action of Vinpocetine demonstrated in both in vitro and in vivo experiments. To help to define the efficacy of Vinpocetine in the clinical management of cognitive impairment and memory disorders, a review of the current literature was performed and studies identified that met minimally acceptable scientific standards.
The search for potentially relevant studies was per- formed through MEDLINE and EMBASE using the key- words "vinpocetine," "apovincamine", "Vincamine" and "Periwinkle." Additional search words included manufacturer brand, code and trade names for Vinpocetine (e.g., Cavinton, Kavinton). Furthermore the manufacturers of Vinpocetine products were contacted to provide information of all known randomized controlled trials. All scientific studies including animal experiments, in-vitro trials, and clinical studies were evaluated (both English and non-English language) to identify randomized placebo-controlled clinical trials in which Vinpocetine was administered to patients with and without cognitive impairment. Trials referenced by articles that were found were also screened.
The goal was to identify and evaluate only those studies that met minimally acceptable scientific standards applying the following inclusion criteria:
All studies that met those inclusion criteria are listed in Table l.
A meta-analysis of the available studies could not be performed due to variation in methodology used in the studies. Studies often did not state exclusion criteria for dementia or other neurological diseases causing cognitive impairment, did not use standardized Vinpocetine formulas, or omitted a clear definition of outcome criteria.Table l. Studies Satisfying Inclusion Criteria
|Source||Diagnosis||Subjects||Age Mean||Duration wk||Dosage mg||Outcome Measures|
|Balesteri 1978 (43)||CVD||84||78.3||12||30, 15||CGI, SCAG, MMSQ|
|Manconi 1986 (44)||Dementia||40||68.3||8.5||30, 15||CGI, SCAG, MMSQ|
|Hindmarch et al 1991 (45)||Dementia OBS||203||73.7||16||30, 60||CGI, SKT|
CVD = Cerebrovascular Disease, CGI = Clinical Global Impression Scale, MMSQ =Mini-Mental Status Questionnaire, SCAG = Sandoz Clinical Assessment Geriatric Scale, SKT = Cognitive Performance
Thirty-nine articles regarding the clinical application of Vinpocetine and its derivatives were identified and reviewed. 42-80 The clinical studies involved 1,912 subjects aged 8 to 93. Multiple articles were published in German, Hungarian, Italian, Japanese, and Russian literature, requiring the assistance of interpreters to evaluate the scientific value of their content. The majority of the articles reported positive effects of Vinpocetine administration (oral, intra-venous) in the treatment of cerebral insufficiency and cerebrovascular disease. Other applications include the use of Vinpocetine and its derivatives in the treatment of ischemic stroke, 58-60 Alzheimer disease. 65 convulsive disorders as the result of birth injuries, 66 treatment of sensorineural hearing impairment, 67 and acoustic trauma. 68 Articles using diagnostic descriptions not listed in the Diagnostic and Statistical Manual of Mental Disorders, and those using terms such as dizziness, fatigue, and tinnitus to describe symptoms of cerebral insufficiency were excluded from the analysis.
The three randomized, placebo-controlled and double-blind studies selected 43,44,45 reported analyzable data for 174 patients treated with a standardized Vinpocetine extract and 114 with placebo. A total of 327 patients participated in the clinical trials; 35 were excluded due to lack of compliance, or from deviating from the protocol. Four patients dropped out due to side effects including anxiety, vertigo, gastric discomfort, and unrelated problems such as glaucoma and biliary colic with previous history of gallbladder stones. No death occurred during the study periods and no data of fatalities were reported after conclusion of the clinical trials. Individual group sample size ranged from 18 to 56 and the mean age from 68.3 to 78.3. Outcome measures were clearly defined, documented, and utilized in the statistical analysis. Neurophysiological outcome measures, including electroencephalographic data analysis, from small animal 62 and human studies, 63 were utilized.
Balestreri, Fontana, and Astengo 43 reported a consistently significant improvement in all evaluations of treatment including measurements of the CGI scale (44%), SCAG scale (26%), and the MMSQ. Applying a similar methodology Manconi, Binaghi and Pitzus 44 demonstrated statistically significant improvements in the SCAG and MMSQ scale with impressive improvement of the CGI assessment in the Vinpocetine group, ranging from 73% (30 days) to 87% (90 days). Hindmarch, Fuchs, and Erxigkeir 45 documented a significant change of the CGI-Global improvement rating in the vinpocetine group of more than 21 %, and on the SKT, a short cognitive performance test for the assessment of memory and attention, an improvement by as much as 87%.
In all reviewed studies listed, and those included in our analysis, no significant adverse effects were reported. The three studies selected provide documentation of twenty-five side effects including seven in the placebo group. Gastrointestinal discomfort was the most common reported side effect, affecting sixteen patients in the Vinpocetine group. 45 Two patients complained about vertigo compared to one in the placebo group. 45 Vinpocetine treatment was stopped after six days in one patient who experienced an episode of biliary colic, 43 and was suspended for ten days in a second patient due to dyspepsia after 20 days of treatment.
The treatment of cognitive impairment and memory loss associated with senile dementia and Alzheimer disease often addresses the symptoms of the disease rather than the causative factors involved. Pharmacological interventions intended to improve the quality of life and to slow progress of the disease can demonstrate well-documented efficacy but not effectiveness. Nootropic agents including vitamin E, 81 folic acid, 82 and Ginkgo biloba 83 have been studied and have demonstrated some clinical benefits in the treatment of Alzheimer's disease and senile dementia.
Unfortunately, most treatment approaches are initiated during the clinical phase of the disease manifestation. It has been documented 84 that the diagnosis of Alzheimer's disease is preceded by a long preclinical phase in which cognitive impairment and deficits in memory performance are common. These symptoms, classified as mild cognitive impairment, remain often unrecognized 85 and stable until the time that a dementia or Alzheimer's disease diagnosis can be rendered. The early diagnosis of mild cognitive impairment can identify individuals with an increasing risk of developing Alzheimer's disease at the rate of 10%-12% per year. 86 Those patients have significant memory impairment, while other cognitive functions and activities of daily living are only slightly abnormal.
In this "window of opportunity" between mild cognitive impairment and the development of senile dementia or Alzheimer's disease, the utilization of nootropic agents such as Vinpocetine might slow the disease process and decrease its incidence.
All three studies suggest a significant improvement during the treatment with Vinpocetine in the cognitive function of patients suffering from dementia or other symptoms of cerebrovascular diseases. The demonstrated safety, absence of serious adverse effects, and the significant improvement of cognitive function even in healthy individuals 87 suggest a clinical application of Vinpocetine in the early phases of mild cognitive impairment.
However, it should be noted that other than the studies by Baliestreri et al., Manconi et al., and Hindmarch et al., most of the published studies that were reviewed had no functional, behavioral, or global outcome measures. The sample size and duration of the clinical studies is at this point insufficient to develop clinical treatment guidelines.
Further large-scale clinical trials should be performed with long-term follow-up (>2 years) to determine the long-term neuroprotective effect of Vinpocetine and to ascertain its beneficial effect for cognitive function and memory.
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