What is Vinpocetine?

Vinpocetine is a white crystalline powder, which is odorless and tasteless. Soluble in chloroform or 96% ethanol, almost insoluble in water. Melting point 147-153 ° C (decomposed). [] D20 + 114 ° (C = 1, pyridine). UV maximum absorption (96% ethanol): 229, 275, 315 nm ( 28200, 12000, 7100). Acutely toxic LD50 mice, rats (mg / kg): 534,503 orally; 240, 133.8 intraperitoneally; 58.7, 42.6 intravenously. Clinically improve various symptoms induced by the sequelae of cerebral infarction, sequelae of cerebral hemorrhage, and cerebral arteriosclerosis.

Chinese name: Vinpocetine
Foreign name: Vinpocetine

CAS number: 42971-09-5
Molecular weight: 350.45400

Vinpocetine compound profile

Changchun Xiting Basic Information

Chinese name

Chinese alias: Vinpocetine; (3, 16) -ivoryene-14-carboxylic acid ethyl ester;

English name: Vinpocetine

English alias: Eburnamenine-14-carboxylic acid ethyl ester; (3, 16) -Eburnamenine-14-carboxylic acid ethyl ester;

CAS number: 42971-09-5

MDL number: MFCD00211233

EINECS number: 256-028-0

RTECS number: JW4792000

PubChem number: 24278182

Molecular formula: C ₂₂ H ₂₆ N ₂ O ₂

Structural formula:

Molecular weight: 350.45400

Exact mass: 350.19900

PSA: 34.47000

LogP: 4.08620 ^[1]

Physical and Chemical Properties of Vinpocetine

Appearance and properties: white crystalline solid

Density: 1.28 g / cm ³

Melting point: 147-153ºC dec

Boiling point: 419.5ºC at 760 mmHg

Flash point: 207.5ºC

Stability: Stable at normal temperatures and pressures.

Storage conditions: Keep tightly closed.

Vinpocetine Safety Information

Customs code: 2933990090

WGK Germany: 3

Danger category code: R22

Safety instructions: S36

RTECS number: JW4792000

Dangerous goods mark: Xn ^[1]

Vinpocetine calculated chemical data

1. Hydrophobic parameter calculation reference value (XlogP): 4.1

2.Number of hydrogen bond donors: 0

3.Number of hydrogen bond acceptors: 3

4.Number of rotatable chemical bonds: 4

5.Number of tautomers: none

6. Topological molecular polar surface area 34.5

7.Number of heavy atoms: 26

8.Surface charge: 0

9.Complexity: 617

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 2

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Vinpocetine synthesis method

Vinpocetine can be obtained from (+)-vincamine, which is extracted from the vinca minor of the oleander family, and dehydrated to apovincamine, and then hydrolyzed to obtain its acid. (Apovincaminic acid). The acid (1.0 g, 0.003 mol) and 0.17 g of potassium hydroxide were dissolved in 80 ml of dry ethanol. Ethyl bromide (0.4 g, 0.0036 mol) was added and refluxed for 3 h. After the reaction was completed, it was cooled and evaporated to dryness. The residue was dissolved in 500 ml of 2% sulfuric acid and the pH was adjusted to 8. Extracted with dichloromethane, dried with potassium carbonate, evaporated most of the dichloromethane, and added ethanol. It was left at 0 ° C overnight, and the precipitated crystals were collected by filtration, washed with cold ethanol, and dried to obtain 0.66 g of vinpocetine.

(-)-Glycyrrhizin can also be extracted from the leaves of the oleander plant Glycyrrhiza uralensis or vinca seeds as a raw material and synthesized through multiple steps. The total synthesis method uses tryptamine as a raw material and is obtained by the following reaction. ^[2]

Vinpocetine uses

An alkaloid extracted from oleander plants is a derivative of Vincamine. Selectively inhibiting calcium ion-dependent phosphodiesterase of cerebral vascular smooth muscle, which increases , cerebral vasodilation, and subsequently increases cerebral blood flow and improves cerebral circulation, but has little effect on cardiac blood vessels and blood pressure. Quick onset, good tolerance, and small adverse reactions. It is used for dizziness, headache, memory impairment, movement disorder, aphasia, hypertensive encephalopathy, etc., and also for mental or neurological symptoms caused by cerebral blood circulation disorders. ^[2]

Vinpocetine Pharmacopoeia Standard

Vinpocetine main active ingredients

Ethyl apovinblastamine-22-acetate, based on the dry product, contains C22H26N2O2, which should not be less than 98.5%.

Vinpocetine traits

White or light yellow crystalline powder; odorless and tasteless.

This product is easily soluble in chloroform and glacial acetic acid, slightly soluble in acetone, ethyl acetate, dimethylformamide, slightly soluble in methanol, ethanol, and ether, and insoluble in water.

Vinpocetine melting point

The melting point of this product (Appendix 15 of Part Two of the 1990 Chinese Pharmacopoeia) is 149-153 ° C.

Vinpocetine specific rotation

Take this product, weigh it accurately, add dimethylformamide to make a solution containing 10mg per 1ml, and determine it according to law (Chinese Pharmacopoeia 1990 Edition, Appendix II, page 17). The specific rotation should be +127. To + 134 °.

Vinpocetine identification

(1) Take about 0.5mg of this product, add 2-3 drops of 1% ceric ammonium sulfate phosphoric acid solution, that is, the color is dark green.

(2) Take this product, add methanol to make a solution containing 10 g per 1 ml, and determine it by spectrophotometry (Chinese Pharmacopoeia 1990 Version Two Appendix Appendix 24 page). It has the maximum absorption at the wavelengths of 229nm, 274nm and 314nm, at 274nm The absorption at the wavelength is about 0.34.

(3) The infrared absorption spectrum of this product should be consistent with the reference spectrum.

Vinpocetine test

Clarity of the solution Take 1g, add 10ml of chloroform, the solution should be clear.

Take 1g of sulphate , boil with 50ml of water, cool to room temperature, and filter; separate 25ml of the filtrate and check according to law (Chinese Pharmacopoeia 1990 Edition, Appendix II, page 48), and compare with the control solution made from 1.0ml of standard potassium sulfate solution Must not be thicker (0.02%).

Relevant substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 1990 edition, Appendix II, page 34).

System suitability test Use 5 octadecylsilane bonded silica gel as filler; amine acetate (0.2mol / L) -acetonitrile (30:70) as mobile phase; detection wavelength is 280nm. The number of theoretical plates should be no less than 3500 according to the calculation of Changchun Xiting Peak. The resolution of the vinpocetine peak and the impurity peak should meet the requirements.

Preparation of test product solution Take this product and add mobile phase to make a solution containing 0.125mg per 1ml.

Preparation of reference solution Precisely take 1ml of the test solution, dilute to 100ml with mobile phase and shake to obtain.

Assay method Precisely measure 20l of the reference and test solution into the liquid chromatograph, and quantify by the external standard method. Among them, apovinamine must not be greater than 1.1%, vinblastine ethyl ester must not be greater than 0.5%, and the total amount of its related substances must not exceed 1.7% (tR1 is vinblastamine ethyl ester and tR2 is apovinblastamine).

Loss on drying Take this product and dry it at 105 for 4 hours. The weight loss should not exceed 0.5%. (Appendix 55, Part Two, Chinese Pharmacopoeia 1990)

Ignition Residue Take 1.0g of this product and inspect it according to law (Chinese Pharmacopoeia 1990 Version Two Appendix Appendix 56). The residual residue shall not exceed 0.1%.

Heavy metals Residues left under the item of burning residues shall be inspected according to law (the second method on page 51 of Appendix 2 of the 1990 edition of the Chinese Pharmacopoeia). The content of heavy metals shall not exceed 10 parts per million.

Arsenic salt Take 1g of anhydrous sodium carbonate, spread it on the bottom and around the crucible, take another 1g, place it on anhydrous sodium carbonate, moisten with a small amount of water, dry it, burn it with a low fire to carbonize it, and then burn it at 600 Completely ash, let cool, add 5ml of hydrochloric acid and 23ml of water to dissolve, check according to law (Chinese Pharmacopoeia 1990 Edition, Appendix II, Page 53, the first method) The arsenic content must not exceed 2 parts per million.

Determination of Vinpocetine

Take about 0.3g of this product, accurately weigh, add 25ml of glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, titrate with perchloric acid solution (0.1mol / L) until the solution is blue-green, and test the titration result with blank Correction. Each 1ml of perchloric acid solution (0.1mol / L) is equivalent to 35.05mg of C22H26N2O2. ^[3]

Vinpocetine pharmacological effects

Vinpocetine is a semi-synthetic vinblastine derivative. The effect is similar to that of vincamine, and it has a higher selective expansion effect on cerebrovascular. The pharmacological effects are as follows:

Inhibition of calcium-dependent phosphodiesterase activity increases the cAMP content of relaxed vascular smooth muscle, thereby relaxing vascular smooth muscle and increasing cerebral blood flow.

Enhance the ability of red blood cells to deform, reduce blood viscosity, and inhibit platelet aggregation, thereby improving blood fluidity and microcirculation.

Promote the uptake of glucose by brain tissue, and promote the metabolism of monoamine in the brain.

During cerebral ischemia, it can inhibit the increase of lactic acid in the brain, increase the ATP content, inhibit the production of peroxidized lipids in the brain, and delay the occurrence of cerebral ischemic spasm, so it has the effect of improving brain metabolism and protecting brain function. ^[4]

Vinpocetine Toxicology Study

Repeated administration of Vinpocetine

Rats were orally administered vinpocetine at 5, 25, 125, and 625 mg / kg for 5 consecutive weeks. The weight gain of the animals in the two high-dose groups was suppressed, the water intake of the animals increased, the weight of the liver and kidneys increased, and the adrenal cortical sac band The medium and small lipid droplets increased; in the 625 mg / kg group, urine and feces darkened due to vinpocetine metabolites, thyroid and adrenal weight increased, and thyroid follicular epithelium hypertrophy. The above changes resumed after discontinuation. The non-toxic dose of this test is 25 mg / kg. Rats were orally administered with 5, 20, and 80 mg / kg of this product daily for 26 consecutive weeks. The animals in the high-dose group showed transient inhibition of weight gain and increased liver weight. Mild enlargement and degeneration of renal tubular epithelium also occurred in male rats, but no abnormal changes in blood biochemical parameters were observed. Dogs were orally administered with this product at 5, 25 mg / kg daily for 6 consecutive months. No animal death was observed, and no abnormal changes were found in blood biochemical and histological examinations.

Vinpocetine Reproductive Toxicity

Oral administration of vinpocetine 25 to 125 mg / kg / day before and after pregnancy in rats. No abnormalities in fertility and fetal development were observed in female rats, but the animals in the high-dose group showed inhibition of weight gain, liver, kidney And an increase in adrenal weight. Oral administration of vinpocetine at 5, 25, 125 mg / kg / day in the teratogenic period of rats, increased fetal death and developmental inhibition in the high-dose group; oral administration of vinpocetine 1, 5, 25 in the teratogenic period of rabbits , 125mg / kg / day, animals with doses above 5mg / kg / day had abortion. Live animals were normal in both animals. No teratogenic effect was seen. Rat test results suggest that vinpocetine can be secreted through milk. ^[5]

Vinpocetine pharmacokinetics

Vinpocetine is highly fat-soluble, easily absorbed by tissues, and widely distributed. It can pass through the blood-brain barrier and is mainly metabolized to apovincristine in the liver and excreted by the kidneys. ^[4]

Vinpocetine drug properties and application

Vinpocetine, also known as Vincristine, Covibrain, Caran, Apovinyl Vincristine, is a natural drug extracted from Vinca minor and belongs to the class of indole alkaloids. Now artificially synthesized. Its pharmacological effects: increase cerebral blood flow, inhibit Ca2 + -dependent phosphodiesterase activity, increase the effect of cyclophosphine guanosine, selectively relax smooth muscle, increase cerebral blood flow; improve blood flow and microcirculation, that is, by enhancing Deformation of red blood cells, reducing blood viscosity, inhibiting platelet aggregation to play this role; improving brain metabolism: increasing cerebral oxygen supply, promoting glucose uptake by brain tissue, promoting monoamine metabolism in the brain, inhibiting increased lactic acid metabolism in ischemic brain And increase ATP content, increase the degree of oxygen dissociation of hemoglobin; increase the ability of the brain to resist hypoxia, inhibit the occurrence of ischemic cerebral vasospasm and the production of lipid peroxides. Oral absorption is good, peaking in 1h, and metabolized into apovinblastic acid in the body. Plasma elimination half-life is about 1 hour. After 4 weeks of continuous administration, there was no accumulation in the body. Clinically used for clinical manifestations such as sequelae of cerebral infarction, sequelae of cerebral hemorrhage, cerebral arteriosclerosis, cerebral vasospasm, dizziness caused by cerebral arterial endometritis, tinnitus, headache, dizziness, numbness of limbs, incontinence, and depression, anxiety, Sleep disorders and other mental symptoms. Clinical experience shows that it is effective regardless of the duration of the disease and whether the symptoms are fixed. ^[4]

Vinpocetine indications

1. Neurology: various cerebrovascular diseases and their sequelae.

2. Cardiology: Coronary heart disease, arteriosclerosis, and abnormal blood viscosity.

3. Ophthalmology: visual impairment caused by poor blood circulation in the fundus.

4. Otorhinolaryngology: hearing impairment, tinnitus, vestibular dysfunction, etc.

5. Neurosurgery: rehabilitation of brain function after various craniocerebral surgery. ^[4]

Vinpocetine Usage and Dosage

1. Oral: 5mg each time, 3 times a day.

2.Intravenous injection or intravenous drip, 10mg each time, 1-3 times a day, diluted 5 times with 0.9% physiological saline when used, suitable for acute cases. ^[6]

Vinpocetine adverse reactions

1. Allergies: Sometimes allergic symptoms such as rash, occasional urticaria, and pruritus may occur. If this symptom occurs, the drug should be discontinued.

2. Psycho-nervous system: Sometimes headache, heavy head, dizziness, occasionally drowsiness, numbness of the side limbs.

3 Digestive tract: Sometimes nausea, vomiting, and occasionally symptoms such as loss of appetite, abdominal pain, and diarrhea.

4 Circulatory organs: Sometimes symptoms such as facial flushing, dizziness, and occasionally low blood pressure and tachycardia can be seen.

5. Blood: Leukopenia can sometimes occur.

6. Liver: Sometimes transaminase elevations can occur, occasionally elevated alkaline phosphatase and jaundice.

7. Kidney: Occasionally elevated blood urea nitrogen. ^[5]

Vinpocetine Taboo

1. Those who are allergic to this product are prohibited.

2. Those who have not completely stopped bleeding after intracranial hemorrhage are disabled.

3 Severe ischemic heart disease and severe arrhythmia are disabled. ^[5]

Precautions for Vinpocetine

This product cannot be injected intramuscularly and cannot be used intravenously without dilution.
Do not dilute with infusions containing amino acids.
The concentration of vinpocetine intravenous infusion should not exceed 0.06mg / ml, otherwise there may be hemolysis.
This injection is not compatible with heparin, so it is recommended not to mix the two in the same syringe, but anticoagulation can be performed at the same time.
If it is used in combination with antiarrhythmic drugs, or if there is elevated intracranial pressure, arrhythmia and QT interval prolongation syndrome, the benefits and risks of applying this product should be fully weighed. ECG monitoring is recommended for patients with prolonged QT interval syndrome or QT interval prolonged by medication.
Because this injection contains sorbitol (160mg / 2ml), patients with diabetes should control blood glucose levels during treatment. Patients with intolerance to fructose or lack of fructase 1,6-bisphosphate should avoid using it. ^[5]

Vinpocetine medication for pregnant, elderly and lactating women

Banned for pregnant and lactating women.

Vinpocetine pregnant women

Vinpocetine can pass through the placenta, but its concentration in the placenta and fetus is lower than that in the blood of pregnant women. No teratogenic or fetal toxic effects were observed. In animal experiments, large doses can cause placental bleeding and miscarriage in some animals, which may be the result of increased placental blood flow.

Vinpocetine lactating women

Vinpocetine can be secreted into milk. Radiolabeled experiments show that the radioactivity in milk is 10 times that in maternal blood. The amount of drug contained in the milk secreted within 1 hour is 0.25% of the administered dose. Because the drug appears in secreted milk and there is no reliable data on its effects on infants, it should be avoided for breastfeeding women.

Vinpocetine medication for the elderly

The indication group of this product is mainly the elderly, so the main content of the manual is for the elderly, please refer to the relevant content. ^[5]

Vinpocetine drug interactions

In clinical trials when vinpocetine is combined with beta-blockers (such as cloralolol, indololol) cloparamide, glibenclamide, digoxin, acenocoumarol or hydrochlorothiazide, No interaction with these drugs was observed.

The combination of vinpocetine and methyldopa has occasionally increased its hypotensive effect, so blood pressure should be monitored when combined.

Although clinical studies have not found that Vinpocetine interacts with drugs that act on the nervous system, antiarrhythmic drugs, and anticoagulants, it is still recommended to pay attention to observation when combining drugs. ^[5]