Vinpocetine

Scientific Name(s):Ethyl-apovincaminate 1 , 2

Common Name(s): Vinpocetine , Cavinton , apovincaminic acid kavinton 1 , 3 , 4

Uses

The scientific literature contains numerous studies and investigations on the pharmacological and biochemical actions of vinpocetine, including antioxidant effects, menopause, antiulcer activity, and phosphodiesterase-1 inhibition. Vinpocetine is best known for its neuroprotective effects. However, there are limited clinical studies to support the use of vinpocetine for many of these potential uses.

Dosing

Follow suggested manufacturers' product guidelines. Most clinical studies used vinpocetine 10 mg 3 times daily, orally or parenterally.

Contraindications

The drug should not be used in patients with severe, general, cerebral hypertensive crises, or in elderly or senile patients with acute cardio-cerebral or cerebro-cardiac syndrome, postinfarction cardiosclerosis, or marked disorders of heart rhythm. 5

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of lack of clinical studies.

Interactions

Caution is warranted in patients on blood-thinning medications because vinpocetine decreases platelet aggregation. In 1 study, bioavailability increased 60% to 100% when vinpocetine was taken with food.

Adverse Reactions

One review article documents patients reporting flushing, rashes, and minor GI problems.

Toxicology

None well documented in the scientific literature.

Botany

Vinpocetine is synthesized from the alkaloid vincamine, which is extracted from the leaves of the periwinkle plant Vinca minor . 1 , 6

History

Vinpocetine was synthesized in the late 1960s and has been sold under the commercial name Cavinton since 1978. Cavinton has been used for nearly 27 years and is available in 47 countries, including Japan, Hungary, Germany, Poland, and Russia. 1 , 6 Vinpocetine is primarily used in treating cerebral disorders of vascular origin. 1 , 5 , 7

Chemistry

Review of the scientific literature reveals few chemical studies of vinpocetine, except for those analyzing its synthesis from the alkaloid vincamine. High-performance liquid chromatography determined apovincaminic acid as the primary metabolite of vinpocetine. 1 , 3

Uses and Pharmacology

The scientific literature contains numerous studies and investigations on the pharmacological and biochemical actions of vinpocetine. The various mechanism of actions include: 1) effects on brain circulation and oxygen utilization without changes in systemic circulation; 2) increased tolerance of the brain to vascular hypoxia and ischemia; 3) anticonvulsant activity; 4) phosphodiesterase-1 inhibition; and 5) lowering of blood viscosity and inhibition of aggregation of thrombocytes. 7

Antioxidant effects
In vitro and animal data

Vinpocetine has a scavenger effect similar to that of vitamin E. Its antioxidant activity also was tested in vitro against pentoxifylline and piracetam; vinpocetine had significant ( P  < 0.01) scavenging activity compared with these drugs. It demonstrated glioprotective activity during and after in vitro stimulated hypoxia in an astrocyte cell culture model. In animal models, vinpocetine inhibited the formation of reactive oxygen species and lipid peroxidation in rat brain synaptosomes. 8 , 9 , 10 , 11 , 12

Menopause
Clinical data

The therapeutic effect of Cavinton (vinpocetine) on menopausal complaints was assessed in 3 groups of women (control or group 1 [n = 30], group 2 with normolipidemia [n = 32], and group 3 with hyperlipidemia [n = 29]) in early menopause. Primary outcome measurements included: relief of climacteric symptoms assessed by the Kupperman menopausal index and the Hamilton Anxiety Scale (HAMA); and any changes in lipid metabolism (total cholesterol, HDL- and LDL-cholesterol, triglycerides, and 2 indexes of lipid atherogenic risk-total/HDL-cholesterol ratio and atherogenic index [AI] = total-HDL/LDL-cholesterol). Groups 2 and 3 received an oral dose of Cavinton 5 mg 3 times daily for 3 months. Kupperman index and HAMA scores decreased significantly on day 45 and in the third month in groups 2 and 3. A statistically significant decrease in total cholesterol and LDL-cholesterol levels was observed in group 3. 13

A comparative investigation involving 40 climacteric postmenopausal women studied the effects of hormone substitution therapy and combined hormone substitution and Cavinton adjuvant therapy. Relief or improvement of climacteric symptoms was measured by the Kupperman index. The results were statistically analyzed, and Cavinton appeared to improve symptoms experienced with estrogen substitution. 14

Antiulcer activity
Animal and in vitro data

The efficacy of vinpocetine against several agents that cause gastric mucosal damage was studied in rats. Oral and intraperitoneal administration of vinpocetine inhibited development of dose-dependent gastric lesions caused by 96% ethanol. Vinpocetine provided the most protection when given intraperitoneally 30 minutes before ethanol. It demonstrated activity against gastric injury induced by phenylbutazone, chronic gastric ulcer induced by acetic acid, and histamine-stimulated gastric acid secretion in pylorus-ligated rats. The antiulcer activity and protective effect of vinpocetine was compared with that of prostaglandin E2, sucralfate, and tripotassium dicitrate bismuthate. 15

Phosphodiesterase-1 inhibition

Vinpocetine inhibits calcium calmodulin-dependent phosphodiesterase (PDE) type 1. This inhibition may lead to increases in cyclic adenosine 3′,5′-monophosphate and may be responsible for benefits in cerebral circulation and decreased platelet aggregation. 1

Animal and in vitro data

Vinpocetine potentiated the effect of sodium nitroprusside and nitroglycerin on the smooth muscle cells in a rat aorta model. Vinpocetine produced a dose-dependent inhibition on Ca2+ conductivity and decreased the smooth muscle contractility of the membrane at a concentration of 2 to 20 microM. PDE activity was inhibited at a concentration of 1 microM. 16

In an in situ-perfused, rat lung preparation, vinpocetine attenuated acute hypoxic vasoconstriction. 17

Clinical data

Vinpocetine was investigated in nonresponders to standard pharmacological therapy for urge incontinence and low compliance bladder. In 11 of 19 patients, clinical symptoms were improved. Vinpocetine may also have a potential role in the treatment of urgency and interstitial cystitis. 18 , 19

Neuroprotective effects
Tinnitus
Animal data

Vinpocetine 2 mg/kg prevented hearing loss induced by the aminoglycoside antibiotic amikacin 450 mg/kg in guinea pigs. 20

Clinical data

Details of the study are limited, but Cavinton prevented neurosensory hypoacusis in 118 tuberculosis patients (17 to 63 years of age) who had normal hearing or hearing problems. 21

Antiepileptic activity

Mechanism of action may involve blockade of presynaptic sodium and calcium channels. Brain gamma-aminobutyric acid and serotonergic mechanisms may be involved. 22 , 23

Animal data – Vinpocetine protected mice against convulsions induced by corazol, strychnine, and thiosemicarbazide. It also antagonized the convulsive reactions produced by systemic administration of penicillin or combined administration of penicillin with a tryptophan metabolite (quinolinic acid) in cats. 23 In guinea pigs, vinpocetine 2 to 10 mg/kg inhibited tonic-clonic convulsions and auditory alterations induced by pentylenetetrazole 100 mg/kg. Vinpocetine 2 mg/kg completely prevented electroencephalogram (EEG) changes induced by pentylenetetrazol for the ictal and postictal periods when administered prior to pentylenetetrazol. 24

Vinpocetine inhibited the EEG changes caused by 4-aminopyridine for the ictal and postictal periods and increases in auditory brainstem responses in guinea pigs. The dose used for 4-aminopyridine and vinpocetine was 2 mg/kg. 20

Clinical data – The effect of Cavinton 15 to 45 mg/day on epilepsy was studied with different anticonvulsants. In 20 of the 31 patients treated with Cavinton , frequency of attacks significantly decreased or complete disappeared; 7 patients showed no improvement and 4 experienced deterioration. Cavinton was most effective in generalized tonic-clonic convulsions. 25

The effect of Cavinton in preventing neurologic disorders was studied in 61 newborns with hypoxic ischemic encephalopathy caused by intracranial birth trauma. Group 1 included 20 patients receiving conventional therapy; seizures disappeared in 6 patients. Group 2 included 41 patients given Cavinton ; seizures disappeared in 27 patients. Twenty-nine children were subsequently followed for 1 year. Convulsive paroxysms recurred in 4 patients in group 1. No convulsive syndrome was recorded for patients in group 2; these same patients also had a decrease in intracranial hypertension and normalization of psychomotor development. 26

Psychopharmacological effects
Clinical data

Vinpocetine, at increasing doses (30, 45, and 60 mg/day), was ineffective in improving cognitive deficits in 15 Alzheimer patients participating in a 1-year, double-blind, placebo-controlled, open-labeled pilot trial. 27

In a randomized, double-blind, crossover study, 12 women receiving either vinpocetine (10, 20, 40 mg) or placebo for 2 days completed a battery of psychological tests (critical flicker fusion, choice reaction time, subjective ratings of drug effects, and a Sternberg Memory Scanning Test) on day 3 of treatment, 1 hour after the morning dose of vinpocetine. Statistically significant changes in memory as assessed by the Sternberg Memory Scanning Test were observed with vinpocetine 40 mg compared with placebo. 28

Cavinton , when combined with protiadenum, improved psychopharmacotherapy of depressive disorders in patients with organic psychosyndromes. In a 16-week, placebo-controlled, randomized, double-blind, multicenter trial, 203 patients received vinpocetine 10 or 20 mg (3 times daily) or placebo (3 times daily). Primary outcomes were assessed from the Clinical Global Impression scale, using measurements from cognitive performance and quality of life. Side effects were comparable in treatment and placebo groups. Patients treated with vinpocetine reported statistically significant improvements in all tests. 29 , 30 , 31

Acute Ischemic Stroke
Animal data

Vinpocetine significantly decreased infarct volume (42%; P < 0.05) on permanent middle cerebral artery occlusion in rats compared with control; the neuroprotective potency of vinpocetine is compared with that of flunarizine or nimodipine. Vinpocetine also may reduce the development of atherosclerosis. In a 3-month study in rabbits given cholesterol-rich diets, 3 of 4 groups (4 rabbits in each group) fed vinpocetine supplements displayed decreased calcium content in various organ systems. 32 , 33

Clinical data

A reduction in red blood cell deformability is a contributory or risk factor for stroke. Vinpocetine, administered in a single oral dose of 10 mg, increased red blood cell deformability in 5 healthy men. When compared with single oral doses of pentoxifylline 300 mg and nicergoline 20 mg, vinpocetine was more effective in increasing red blood cell deformability. 34 , 35 , 36

The effect of a single-dose intravenous infusion of vinpocetine on cerebral blood flow and glucose metabolism was studied in poststroke patients. Results indicated that glucose transport (intracellular uptake and release) was affected in the whole brain, in the contralateral hemisphere, and in the peri-infarction area of the symptomatic hemisphere. Numerous studies document the effect of vinpocetine-modifying utilization of glucose in the brain (in acute ischemic and chronic stroke patients), particularly in the affected hemisphere. 37 , 38 , 39

A pilot, single-blind, randomized trial examined the effect of vinpocetine on 30 patients diagnosed with acute ischemic stroke who could be treated within 72 hours of stroke onset. Patients were randomly assigned to receive either low-molecular weight dextran alone (mean age, 57.9 +/- 11.6 years; n = 15) or in combination with vinpocetine (mean age, 60.8 +/- 6.6 years; n = 15). The vinpocetine-treated group scored only marginally better at 3 months follow-up ( P = 0.05, ANOVA). Patients did not report any adverse reactions. 40

The effect of vinpocetine on compromised cerebral blood perfusion and oxygenation in 43 patients with ischemic stroke was examined in a double-blind, randomized, placebo-controlled study. Patients received either a single dose of intravenous vinpocetine 20 mg in saline 500 mL or saline 500 mL alone as placebo. Results from transcranial Doppler and near infrared spectroscopy methods indicated increased cerebral perfusion and parenchymal oxygen extraction frontolaterally on the side of the lesion. 41

Chronic Cerebral Vascular Ischemia

Results from animal and human data postulate that the neuroprotective action of vinpocetine is associated with its effect on calcium- and calmodulin-dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated calcium channels, glutamate receptors, and voltage-dependent sodium channels. 42 , 43 , 44

Clinical data

Eighty-one patients with chronic forms of cerebral ischemia were treated orally or parenterally with Cavinton . Patients reported reduction in subjective manifestations of the disease such as asthenic disturbances. The therapeutic effect ranged from 40 minutes to 6 hours with intravenous infusion. The authors concluded that Cavinton increased cardiac output and cerebral blood supply, and decreased peripheral resistance of the cerebral vessels. A similar study was completed in 38 patients with cerebral ischemia and atherosclerosis alone (n = 22) or hypertension (n = 16). Results for patients receiving Cavinton demonstrated decreased peripheral vascular resistance and tone of small and median vessels of the brain, increased cardiac output, and improved rheological properties of the blood (lower globular volume, viscosity, and hematocrit). A study involving 171 patients found the drug to be more effective in young to middle-aged patients versus elderly patients, perhaps because of the organic changes in cerebral vessels in the elderly. Vinpocetine effects on the rheological properties of blood have been documented in other studies, particularly with parenteral administration. 45 , 46 , 47 , 48

In a double-blind clinical trial, 42 patients with chronic vascular senile cerebral dysfunction received vinpocetine 10 mg 3 times daily for 30 days followed by 5 mg 3 times daily for 60 days. Placebo tablets were given to another 42 patients over 90 days. Evaluations of the effectiveness of treatment from the Clinical Global Impression scale, the Sandoz Clinical Assessment-Geriatric scale, and the Mini-Mental Status Questionnaire were consistently higher in patients receiving vinpocetine. No serious side effects were reported. 49

Dosage

Follow the suggested manufacturers' guidelines. Most clinical studies used vinpocetine 10 mg 3 times daily orally or parenterally.

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of lack of clinical studies.

Interactions

Because vinpocetine decreases platelet aggregation, caution is warranted in patients receiving blood thinning agents. The effect of pretreatment with vinpocetine on prothrombin prolongation was studied in 18 men receiving warfarin 25 mg. A clinically important interaction was not demonstrated. 50 , 51

Drug/Food Interactions

In an open-label, crossover study, the bioavailability of vinpocetine was increased 60% to 100% when taken with food compared with fasting conditions. 52 , 53 , 54 , 55

Adverse Reactions

One review article reported flushing, rashes, and minor GI problems. 1

Toxicology

None well documented in the scientific literature. The drug is metabolized exclusively in the liver in dogs and humans. In rats, vinpocetine was widely distributed in lung, spleen, liver, and kidney tissues, and also was found in brain, heart, muscle, and blood. Both vinpocetine and apovincaminic acid are absorbed from the GI tract. Vinpocetine appears to follow linear pharmacokinetics. 56 , 57 , 58 , 59

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