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VINPOCETINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vinpocetine is a synthetic derivative of vincamine or a synthetic ethyl ester of apovincamine and in the therapeutic class of cerebral vasodilators. It is a selective phophodiesterase-l isoenzyme inhibitor. Vinpocetine is a vasoactive vinca alkaloid of the eburnamine type and derived from the lesser periwinkle plant (Vinca minor). Although this agent has been used for up to 20 years for cerebrovascular disorders and to improve thinking and concentration, it has never been approved for use by the USFDA or other regulatory agencies. It can be purchased over-the-counter or via the internet as a supplement.

Specific Substances

    1) 3-alpha,16-alpha-Apovincaminic acid ethyl ester
    2) AY-27255
    3) Ethyl apovincamin-22-oate
    4) Ethyl Apovincaminate
    5) Ethyl Apovincaminoate
    6) Ethyl (3alpha,16alpha)-eburnamenine-14-carboxylate
    7) RGH-4405
    8) TCV-3B
    9) Vincamine
    10) Molecular Formula: C22-H26-N2-O2
    11) CAS 42971-09-5
    12) AY-27,255

Available Forms Sources

    A) FORMS
    1) Vinpocetine is available over-the-counter as a 5 mg tablet (Memory Secret S.L., 2013; Prod Info Intelectol(r) tablets, vinpocetine, 2002).
    B) SOURCES
    1) Vinpocetine, a synthetic ethyl ester of apovincamine, is structurally related to the lesser periwinkle plant (ie, Vinca minor) alkaloid (ie, vincamine) (Kidd, 1999; Vas et al, 2002).
    C) USES
    1) SUMMARY
    a) Vinpocetine, an indole alkaloid of the eburnamine type, is a potent vasodilator that acts by direct relaxation of the vascular smooth muscle. It is reportedly increases cerebral blood flow in patients with cerebrovascular disorders and stimulates cerebral metabolism. Vinpocetine has shown some degree of efficacy in cerebrovascular disorders including the sequelae related to stroke events (Kidd, 1999).
    b) It was originally produced in the late 1960s from the alkaloid vincamine that was extracted from the leaf of the lesser periwinkle plant (ie, vinca minor). It has been used widely in Japan, Hungary, Germany, Poland and Russia (Patyar et al, 2011).
    c) Although this agent has been used for up to 20 years to treat cerebrovascular disorders and to improve thinking and concentration it has never been approved for use by the USFDA or other regulatory agencies. It can be purchased over-the-counter as a supplement. The recommended uses for vinpocetine by the manufacturer includes treatment of cerebrovascular disorders, cognitive decline and dementia (Szatmari & Whitehouse, 2003).
    2) CLINICAL STUDIES
    a) Although there has been some suggestion of vinpocetine use in Alzheimer's disease, a double-blind study showed no significant benefit (Kidd, 1999). Similar findings were reported in a dose escalation study in 15 Alzheimer's patients treated with vinpocetine (Thal et al, 1989a).
    b) It is also known to decrease platelet and red cell aggregation and to increase red cell membrane flexibility. Vinpocetine has the clinical ability to produce anti-ischemic activity (Kidd, 1999).
    c) CEREBROVASCULAR DISEASE: In 2008, a Cochrane review found insufficient evidence to support the use of vinpocetine for the acute phase of cerebrovascular disease (Bereczki & Fekete, 2008).
    d) ALZHEIMER'S DISEASE: In another Cochrane review to assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimer's disease, and other dementia, the evidence was inconclusive and did not support clinical use. Further large scale studies were recommended (Szatmari & Whitehouse, 2003).
    e) CEREBRAL INFARCTS: Vinpocetine has been studied in patients with multiple cerebral infarcts (Kemeny et al, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Vinpocetine is a synthetic derivative of vincamine and part of the therapeutic class of cerebral vasodilators. It has been used for cerebrovascular disorders and to improve thinking and concentration. It was originally produced in the late 1960s from the alkaloid vincamine that was extracted from the leaf of the lesser periwinkle plant (ie, vinca minor). It has been used widely in Japan, Hungary, Germany, Poland and Russia. It does not have regulatory approval in the US. It can be purchased over-the-counter or via the internet as a supplement.
    B) PHARMACOLOGY: Vinpocetine is a selective phosphodiesterase-I isoenzyme inhibitor. It purportedly can increase cerebral vasodilation and enhance cerebral metabolic activity. The increase in cerebral metabolism is attained through enhanced cerebral blood flow, an increase in consumption of glucose and oxygen in the brain, and an increased production of ATP in brain cells. Vinpocetine also inhibits platelet aggregation and enhances erythrocyte deformability, lowering the viscosity of blood.
    C) EPIDEMIOLOGY: It has been widely used outside the US; however, acute exposure has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Adverse effects are minimal. Mild effects can include nausea, dizziness, anxiety, facial flushing, insomnia, headache, drowsiness, indigestion and dry mouth. Other events that have been reported infrequently or may develop with therapeutic use include hypotension, tachycardia and rash.
    2) RISK OF BLEEDING: Vinpocetine can decrease platelet aggregation and should be used carefully with blood thinners.
    E) WITH POISONING/EXPOSURE
    1) Overdose has not been reported. Vinpocetine is a vasoactive vinca alkaloid; overdose effects are anticipated to be similar to adverse effects and may include hypotension, sinus tachycardia, headaches and flushing due to its central vasodilating mechanism of action.
    0.2.20) REPRODUCTIVE
    A) Clinical studies to determine the safety of vinpocetine in pregnant women have not been conducted. In rat studies, fetotoxicity has been reported.

Laboratory Monitoring

    A) Monitor blood pressure following a significant overdose. There is insufficient data to determine the duration of monitoring required.
    B) Obtain an ECG in symptomatic patients.
    C) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    D) Vinpocetine blood levels are not clinically useful or widely available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) No overdose data are available. Treatment is symptomatic and supportive. Monitor vital signs. Mild hypotension has been reported infrequently with therapeutic use.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat moderate hypotension with IV fluids as tolerated; if no improvement add dopamine, norepinephrine as needed.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is unlikely to be necessary.
    2) HOSPITAL: Gastrointestinal decontamination is unlikely to be necessary.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following exposure.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Enhanced elimination is unlikely to useful as vinpocetine has a large volume of distribution and is highly protein bound.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor (1 to 2 tablets) inadvertent exposure in an asymptomatic patient currently taking vinpocetine can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions or who develop more than mild symptoms should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with persistent hypotension should be admitted with ongoing monitoring and therapy as indicated.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.

Range Of Toxicity

    A) TOXIC DOSE: There are no published reports of acute ingestions resulting in toxicity. Adverse effects appear to be minimal, consisting of gastric effects, lowered blood pressure, increased pulse, and weakness.
    B) THERAPEUTIC DOSE: The typical dose range for vinpocetine is 15 to 45 mg per day. Patients have tolerated doses up to 60 mg/day with no significant adverse effects.

Clinical Effects

Summary Of Exposure

    A) USES: Vinpocetine is a synthetic derivative of vincamine and part of the therapeutic class of cerebral vasodilators. It has been used for cerebrovascular disorders and to improve thinking and concentration. It was originally produced in the late 1960s from the alkaloid vincamine that was extracted from the leaf of the lesser periwinkle plant (ie, vinca minor). It has been used widely in Japan, Hungary, Germany, Poland and Russia. It does not have regulatory approval in the US. It can be purchased over-the-counter or via the internet as a supplement.
    B) PHARMACOLOGY: Vinpocetine is a selective phosphodiesterase-I isoenzyme inhibitor. It purportedly can increase cerebral vasodilation and enhance cerebral metabolic activity. The increase in cerebral metabolism is attained through enhanced cerebral blood flow, an increase in consumption of glucose and oxygen in the brain, and an increased production of ATP in brain cells. Vinpocetine also inhibits platelet aggregation and enhances erythrocyte deformability, lowering the viscosity of blood.
    C) EPIDEMIOLOGY: It has been widely used outside the US; however, acute exposure has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Adverse effects are minimal. Mild effects can include nausea, dizziness, anxiety, facial flushing, insomnia, headache, drowsiness, indigestion and dry mouth. Other events that have been reported infrequently or may develop with therapeutic use include hypotension, tachycardia and rash.
    2) RISK OF BLEEDING: Vinpocetine can decrease platelet aggregation and should be used carefully with blood thinners.
    E) WITH POISONING/EXPOSURE
    1) Overdose has not been reported. Vinpocetine is a vasoactive vinca alkaloid; overdose effects are anticipated to be similar to adverse effects and may include hypotension, sinus tachycardia, headaches and flushing due to its central vasodilating mechanism of action.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) Overdoses may result in lowered blood pressure due to its vasodilating properties.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Although not reported, it is possible that tachycardia may accompany hypotension in severe overdoses due to one of its mechanisms of action as a phosphodiesterase inhibitor (Hall, 1993; Nicholson, 1990). An increase in heart rate, stroke volume and cardiac output may be expected to occur following overdose due to a direct relaxation of vascular smooth muscle. This effect is seen more on arterioles than veins. Diastolic blood pressure may be more frequently lowered more than systolic (Nicholson, 1990).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Slight reductions in systolic and diastolic blood pressure have been observed during prolonged oral vinpocetine administration (Manconi et al, 1986).
    b) LACK OF EFFECT: In a pilot, single-blind, randomized clinical trial (n=30) to evaluate the safety and efficacy of the early administration of vinpocetine in patients with acute ischemic stroke, treatment included IV vinpocetine 10 mg once daily for 5 to 7 days followed by oral vinpocetine 10 mg 3 times daily for 30 days. The treatment protocol was well tolerated with no adverse effects reported. There were also no significant changes in blood pressure between the groups with no reports of hypotension (Feigin et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) Although not reported clinically, vasodilatation and hypotension may develop following a significant overdose due to its vasodilating effect (Nicholson, 1990). A massive overdose could result in hypotension, tachycardia, palpitations and cardiac dysrhythmias. Severe hypotension could result in myocardial and cerebral ischemia.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Sleep disturbances and internal restlessness were more frequent with vinpocetine treatment in a double-blind, placebo-controlled study (Blaha et al, 1989). The side-effects were transient; most reports occurred after ten weeks of treatment. A greater number of patients (9 of 124) experienced pressure headache than those on placebo (Hindmarch, 1992).
    2) WITH POISONING/EXPOSURE
    a) Headache, dizziness and sweating may be expected in overdose due to vasodilating properties of vinpocetine (Nicholson, 1990).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) RAT/MOUSE: Seizures or effect on seizure threshold were noted in LD50 studies with rats and mice (RTECS , 2002).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) Stomach disorders were reported more frequently with vinpocetine treatment than with placebo (Blaha et al, 1989; Hindmarch et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) PDE5 and PDE1 are expressed in gastrointestinal smooth muscle, thus overdoses are expected to result in gastric irritation and dyspepsia (Hall, 1993; Nicholson, 1990).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) COAG./BLEEDING TESTS ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Although not yet reported in humans, toxicity may result in increased bleeding times due to its inhibition of platelet aggregation (Patyar et al, 2011; Prod Info Intelectol(r) tablets, vinpocetine, 2002; Akopov & Gabrielian, 1992; Bayer et al, 1988).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Facial flushing and rash have occurred infrequently during vinpocetine therapy (Manconi et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) Facial flushing may be seen at toxic doses due to its mechanism of action (ie, an indirect adenosine-like effect) (Storm et al, 1994; Hall, 1993; Nicholson, 1990).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Slight reductions in plasma glucose have been reported during oral therapy with vinpocetine (Manconi et al, 1986), although clinical relevance is questionable.

Reproductive

    3.20.1) SUMMARY
    A) Clinical studies to determine the safety of vinpocetine in pregnant women have not been conducted. In rat studies, fetotoxicity has been reported.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) SUMMARY
    a) Clinical studies to determine the safety of vinpocetine in pregnant women have not been conducted (Patyar et al, 2011).
    B) ANIMAL STUDIES
    1) FETOTOXICITY
    a) RATS: Fetotoxicity was reported in rat studies when the dam was administered vinpocetine, 450 mg/kg, on days 7 to 15 of pregnancy (RTECS , 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure following a significant overdose. There is insufficient data to determine the duration of monitoring required.
    B) Obtain an ECG in symptomatic patients.
    C) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    D) Vinpocetine blood levels are not clinically useful or widely available.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels of vinpocetine may not be useful, since therapeutic and toxic levels have not been established.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Due to the potential for hypotension, monitor blood pressure in all significant overdose cases. There is insufficient data to determine the duration of monitoring required.

Methods

    A) CHROMATOGRAPHY
    1) A gas chromatography-mass spectrometry assay method, without transesterification due to solvents, for the determination of vinpocetine in human plasma is described. The limit of determination for this method is 0.1 ng/mL (Hammes & Weyhenmeyer, 1991; Lohmann & Dingler, 1990; Hammes & Weyhenmeyer, 1987).
    2) A high-performance liquid chromatography method, using ion pair extraction, has been described for the quantitative analysis of apovincaminic acid, the main metabolite of vinpocetine, in human plasma and urine. A sensitivity of 20 ng/mL in plasma and urine samples was reported in one study (Kozma et al, 1982) and 5 ng/mL was reported in other studies (Maya et al, 1996; Kraus et al, 1992).
    3) A validated method for the quantitation of vinpocetine in human plasma using a combination of solid-phase extraction as a cleaning step followed by gas chromatography-mass spectrometry is described. A limit of detection of 0.01 ng/mL, with a limit of quantitation of 0.10 ng/mL, is reported (Vatsova et al, 1997).
    B) IMMUNOASSAY
    1) A sensitive enzyme immunoassay (ELISA) was developed for the quantitative determination of vinpocetine in human plasma. A lower limit of detection is 0.1 ng/mL. No cross reactivity with apovincaminic acid, the major metabolite, is reported. An inter- and intra-assay reproducibility (coefficient of variation) of the test is reported in the range of 1.1% and 18.3% (Reck et al, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent hypotension should be admitted with ongoing monitoring and therapy as indicated.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor (1 to 2 tablets) inadvertent exposure in an asymptomatic patient currently taking vinpocetine can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions or who develop more than mild symptoms should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor blood pressure following a significant overdose. There is insufficient data to determine the duration of monitoring required.
    B) Obtain an ECG in symptomatic patients.
    C) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    D) Vinpocetine blood levels are not clinically useful or widely available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) At the time of this review, there have been no reports of significant adverse events following vinpocetine use and there are no reports of overdose. Gastrointestinal decontamination is unlikely to be necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) At the time of this review, studies have reported NO or mild adverse events following vinpocetine exposure. Gastrointestinal decontamination is unlikely to be necessary. It is not known if activated charcoal will be useful in treating ingestions. Activated charcoal is recommended in symptomatic patients and those with significant coingestants.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific treatment for vinpocetine overdose other than supportive care. No overdose data are available.
    2) Monitor vital signs. Mild hypotension has been reported with therapeutic use.
    B) MONITORING OF PATIENT
    1) Monitor vital signs in all symptomatic exposures. There is insufficient data to determine the duration of monitoring required.
    2) Obtain an ECG in symptomatic patients.
    3) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated. Vinpocetine blood levels are not clinically useful or widely available.
    C) HYPOTENSIVE EPISODE
    1) Mild hypotension has been reported with therapeutic use. Vinpocetine is a highly potent vasodilator, that acts by direct relaxation of the vascular smooth muscle.
    2) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with vinpocetine. Because vinpocetine is highly protein bound and has a large volume of distribution (32 L/kg), hemodialysis or other forms of extracorporeal elimination are not expected to be of benefit in overdose.

Range Of Toxicity

Summary

    A) TOXIC DOSE: There are no published reports of acute ingestions resulting in toxicity. Adverse effects appear to be minimal, consisting of gastric effects, lowered blood pressure, increased pulse, and weakness.
    B) THERAPEUTIC DOSE: The typical dose range for vinpocetine is 15 to 45 mg per day. Patients have tolerated doses up to 60 mg/day with no significant adverse effects.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY
    1) The typical dose range for vinpocetine is 15 to 45 mg daily (Kidd, 1999).
    B) ORAL ADMINISTRATION
    1) Vinpocetine 5 to 10 mg orally 3 times daily has been administered in the treatment of vascular or degenerative cerebral insufficiency (Manconi et al, 1986).
    2) Doses of up to 20 mg 3 times daily have been given to patients with dementia of the Alzheimer type, without apparent benefit (Thal et al, 1989).
    3) Patients with mild to moderately severe organic psychosyndrome experienced greater therapeutic benefits at higher vinpocetine doses of 10 to 20 mg 3 times daily, as compared to patients receiving 5 mg 3 times daily (Blaha et al, 1989).
    C) CLINICAL TRIALS
    1) In a pilot single-blind, randomized clinical trial (n=30) to evaluate the safety and efficacy of the early administration of vinpocetine in patients with acute ischemic stroke, treatment included IV vinpocetine 10 mg once daily for 5 to 7 days followed by oral vinpocetine 10 mg 3 times daily for 30 days. The treatment protocol was well tolerated and no adverse effects were reported with no significant changes in blood pressure between the groups (Feigin et al, 2001).
    2) In a small clinical trial of 15 patients with Alzheimer's disease, increasing doses of vinpocetine of 30 mg, 45 mg and 60 mg daily were administered over one year. Vinpocetine was well tolerated with no adverse effects reported with dose escalation. However, vinpocetine did not appear to be beneficial in improving or halting the progression of the disease (Thal et al, 1989a).
    D) COCHRANE REVIEW
    1) ISCHEMIC STROKE: In 2008, a Cochrane review found insufficient evidence to support the use of vinpocetine for the acute phase of cerebrovascular disease (Bereczki & Fekete, 2008).
    2) ALZHEIMER'S DISEASE: In another Cochrane review to assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimer's disease, and other dementia, the evidence was inconclusive and did not support clinical use. Further large scale studies were recommended (Szatmari & Whitehouse, 2003).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) SUMMARY
    1) No significant adverse effects of vinpocetine were observed during one year of therapy (up to 60 mg daily) in patients with Alzheimer's disease (Thal et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 117 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 534 mg/kg (RTECS, 2002)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 119 mg/kg (RTECS, 2002)
    4) LD50- (ORAL)RAT:
    a) 503 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY
    1) Vinpocetine is a synthetic ethyl ester of apovincamine derivative (Miyazaki, 1995), that is reported to increase cerebral vasodilating/metabolic enhancing activity that has been used in the treatment of cerebral circulatory disorders (ie, dementia and acute stroke) (Patyar et al, 2011; Nicholson, 1990; Groo et al, 1987; Thal et al, 1989; Hindmarch, 1992). The increase in cerebral metabolism is attained through enhanced cerebral blood flow, an increase in consumption of glucose and oxygen in the brain, and an increased production of ATP in brain cells. In addition, there appears to be an increase in levels of neurotransmitters involved in memory in particular noradrenaline, dopamine and serotonin (Patyar et al, 2011).
    2) Vinpocetine also has properties of inhibiting platelet aggregation and as an activator of erythrocyte deformability it can lower the viscosity of blood, thus making it beneficial in the treatment of ischemic stroke (Patyar et al, 2011; Kidd, 1999).
    3) Pharmacologic effects of vinpocetine are numerous and complex, some are not well-substantiated, and mechanisms of action are obscure. In vivo, the drug has been shown in some studies to enhance cerebral blood flow (in normal conditions and during arterial hypoxia) without significantly affecting peripheral blood flow, suggesting selective vasodilatory effects (Nicholson, 1990; Manconi et al, 1986; Subhan & Hindmarch, 1985); however, this selectivity has not been demonstrated in vitro (Nicholson, 1990), and other investigators have been unable to confirm any in vivo cerebral vasodilatory effect (Thal et al, 1989).
    B) HUMAN STUDIES
    1) Vinpocetine has improved memory in healthy subjects (Sternberg Scanning Test) in one report (Subhan & Hindmarch, 1985). Indirect or direct cholinergic activity, increased turnover of brain catecholamine levels, and enhancement of norepinephrine effects on cortical cyclic adenosine monophosphate (AMP) levels have been suggested as potential mechanisms for nootropic-like effects of vinpocetine (Nicholson, 1990; Groo et al, 1987).
    2) Other pharmacologic effects reported for vinpocetine include increased cerebral glucose utilization, anticonvulsant activity, neuronal protectant activity, adenosine-like effects, and phosphodiesterase inhibition (Hall, 1993; Nicholson, 1990). Elevated levels of cyclic GMP due to phosphodiesterase inhibition may be involved in vasodilator actions of vinpocetine (van Staveren et al, 2001; Nicholson, 1990). Vinpocetine is a highly selective PDE1 inhibitor (van Staveren et al, 2001).
    a) In chronic stroke patients, vinpocetine has been shown, via PET studies, to significantly improve the transport of glucose (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 (Szakall et al, 1998).
    C) IMPROVED CEREBRAL BLOOD FLOW
    1) Vinpocetine has been demonstrated to inhibit platelet aggregation induced by a variety of platelet aggregating agents. Other in vitro data have reported improved filterability of aged red blood cells (6 hours) with vinpocetine, suggesting potential beneficial effects on microvascular perfusion related to cell deformability (Bayer et al, 1988). In stroke patients, vinpocetine has been shown to improve red blood cell deformability, thus increasing cerebral blood flow (Hayakawa, 1992).
    D) NEUROPROTECTIVE EFFECTS
    1) Vinpocetine reduced hippocampal neuronal necrosis and increased local cerebral blood flow. Other investigators have reported that vinpocetine possesses sodium channel-blocking activity, a possible mechanism for its neuroprotective and anticonvulsant properties. In vitro studies have also demonstrated that vinpocetine is a potent blocker of voltage-gated central Na+ channels, and it antagonizes maximal electric shock-induced seizures in a dose-dependent manner (Kidd, 1999; Bonoczk et al, 2000; Erdo et al, 1996; Lakics et al, 1995; Molnar & Erdo, 1995). Wei et al (1997) demonstrated reversible and concentration-dependent inhibition of sodium currents in isolated rat ventricular cardiomyocytes. One investigator found an enhancement of the low-threshold A-current (depolarization-activated K+ channels of surface membrane of excitable cells) of the neuronal membrane by vinpocetine in isolated cell studies (Solntseva & Bukanova, 2000).
    a) Trejo et al (2001) demonstrated that in addition to inhibition of presynaptic voltage-sensitive Na+ channels permeability, vinpocetine also increases DOPAC (dopamine main metabolite) via impairing the vesicular storage of dopamine. Thus, the inhibition of neurotransmitter release is likely to contribute to the neuroprotective capability of vinpocetine in the CNS (Trejo et al, 2001).
    E) ANIMAL STUDIES
    1) A cerebral metabolic stimulant activity has been reported in animal studies, with prolonged survival after exposure to anoxia and a reduction in triethyl tin-induced cerebral edema (Nicholson, 1990); antihypoxic activity has also been reported in models of asphyxic anoxia and hypobaric or anemic hypoxia (Groo et al, 1987).
    2) Vinpocetine has enhanced learning and memory capabilities in animal studies (Nicholson, 1990; Groo et al, 1987).
    3) Vinpocetine has demonstrated neuroprotective effects against ischemia-induced brain damage in animal studies (Rischke & Krieglstein, 1991).

Physicochemical

Molecular Weight

    A) 350.5 (S Sweetman , 2002)

References

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