What Is Dipyridamole?

Dipyridamole (Dipyridamole, Chinese Pharmacopoeia: Dipyridamole, Persantine), is a drug that expands the coronary arteries and prevents thrombosis. It is mainly used for ischemic heart disease and stroke, and a small amount is used for the treatment of other diseases. Side effects can include headache, dizziness, nausea, vomiting, diarrhea and other adverse reactions; combined with heparin can cause bleeding tendency; occasional rash, coronary artery stealing ^[1] . There are three main medicines: dipyridamole injection, dipyridamole sustained-release capsules, and dipyridamole tablets. In the early years, it was a commonly used drug for treating coronary heart disease, and it is now rarely used as an anti-myocardial ischemia. Its anti-platelet aggregation effect can be used in cardiac surgery or valve replacement, which can reduce the formation of thromboembolism.

Dipyridamole (Dipyridamole, Chinese Pharmacopoeia: Dipyridamole, Persantine), is a drug that expands the coronary arteries and prevents thrombosis. It is mainly used for ischemic heart disease and stroke, and a small amount is used for the treatment of other diseases. Side effects can include headache, dizziness, nausea, vomiting, diarrhea and other adverse reactions; combined with heparin can cause bleeding tendency; occasional rash, coronary artery stealing ^[1] . There are three main medicines: dipyridamole injection, dipyridamole sustained-release capsules, and dipyridamole tablets. In the early years, it was a commonly used drug for treating coronary heart disease, and it is now rarely used as an anti-myocardial ischemia. Its anti-platelet aggregation effect can be used in cardiac surgery or valve replacement, which can reduce the formation of thromboembolism.

Chinese name

Dipyridamole

CAS No.

58-32-2

Molecular formula

C24H40N8O4

Molecular weight

504.63

Dipyridamole compounds

Dipyridamole Basic Information

Chinese name

Chinese alias: bipyrimidinol; dipyridamole; dipyridamole; dipyrimidinol; piperidine; pansentin

English name: dipyridamole

English alias: Corosan; RA 8; Coroxin; Piroan; Coridil; Agacore; Anginal; Apricor; Cardioflux; Cleridium; Coribon; Coronarine; DiPRAmol; Dipyrida; Fuctiocardon; Novodil; Peridamol; Prandiol; Persantin; Stenocardil; Steokolcardi;

CAS number: 58-32-2

Molecular formula: C ₂₄ H ₄₀ N ₈ O ₄

Structural formula:

Molecular weight: 504.62600

Exact mass: 504.331700

PSA: 145.44000

LogP: 0.11240

Dipyridamole physical and chemical properties

Appearance and properties: yellow powder

Density: 1.352 g / cm ³

Melting point: 165-166ºC

Boiling point: 806.5ºC at 760 mmHg

Flash point: 441.5ºC

Refractive index: 1.666

Stability: stable under normal temperature and pressure, photosensitive

Storage conditions: -20ºC

Dipyridamole Safety Information

Symbol: GHS07

Signal Word: Warning

Hazard statement: H315; H319; H335

Cautionary statement: P261; P305 + P351 + P338

Customs code: 2933990090

WGK Germany: 2

Danger category code: R36 / 37/38

Safety instructions: S26-S36

Dangerous goods mark: Xi ^[1]

Dipyridamole Safety Terms

S26In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.

After accidental contact with eyes, rinse immediately with plenty of water and seek medical advice.

S36Wear suitable protective clothing.

Wear appropriate protective clothing.

Dipyridamole risk term

R36 / 37 / 38Irritating to eyes, respiratory system and skin.

Irritation of eyes, respiratory system and skin.

Dipyridamole production method

Amino orotic acid (see 02470) is obtained by cyclization, chlorination and condensation ^[1] .

Dipyridamole uses

Antiplatelet aggregation drugs, coronary artery dilatation drugs ^[1] .

Dipyridamole Pharmacopoeia Standard

Dipyridamole source (name), content (potency)

This product is 2,2 ', 2' ', 2' ''-[(4,8-dipiperidinylpyrimido [5,4-d] pyrimidine-2,6-diyl) diazonium] -Tetraethanol. Calculated on dry basis, C ₂₄ H ₄₀ N ₈ O ₄ should be 98.0% 102.0%.

Dipyridamole traits

This product is yellow crystalline powder; odorless; slightly bitter.

This product is soluble in chloroform, soluble in ethanol, slightly soluble in acetone, almost insoluble in water; soluble in dilute acid.

Melting point

The melting point of this product (Appendix VIC of Part Two of the 2010 Pharmacopoeia) is 162 to 168 ° C.

Dipyridamole identification

(1) Take about 10mg of this product, add ethanol to dissolve, that is, green fluorescence, and fluorescence disappears after adding acid.

(2) Take about 10mg of this product, add 2ml of dilute hydrochloric acid to dissolve, add 1% potassium chromate solution dropwise, that is reddish purple; after shaking, red purple disappears, add excess 1% potassium chromate solution, red purple recurrent.

(3) Take this product, add 0.01mol / L hydrochloric acid solution to make a solution containing 10g per 1ml, and measure it by ultraviolet-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of 2010 Edition). It has a maximum absorption at a wavelength of 283nm. .

(4) The infrared light absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs" 557).

Dipyridamole check

Chlorinated compounds

Take about 20mg of this product, and carry out organic destruction according to the oxygen bottle combustion method (Appendix C of Part Two of the Pharmacopoeia, 2010 Edition). Take 20ml of 0.4% sodium hydroxide solution as the absorption solution. After the dysprosium is burned, shake vigorously for 15 minutes, add dilute nitric acid 10ml, transfer to 50ml Nass colorimetric tube, check according to the chloride test method (Appendix A of Pharmacopoeia Part II of the 2010 edition), and control solution (same operation as the test product, but the test paper is not included in the filter paper when burning) , And add standard sodium chloride solution 4.0ml), it must not be more concentrated (0.20%).

relative substance

Take this product, use methanol to make a solution containing 1.0mg per 1ml as the test solution; take a precise amount, use methanol to make a solution containing 10g per 1ml, and use it as a control solution. Tested according to high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 edition), using octadecylsilane bonded silica gel as filler; disodium hydrogen phosphate solution [take disodium hydrogen phosphate 250mg, add 250ml water, dissolve, drop Add the phosphoric acid solution (1 3) to adjust the pH to 4.6] methanol (25:75) is the mobile phase; the detection wavelength is 288nm, and the theoretical plate number is not less than 600 calculated from the dipyridamole peak; take 10l of the control solution, Inject into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 10% of the full range; and then accurately measure 10 l each of the test solution and the control solution, and inject them into the liquid chromatograph respectively to record the chromatogram 2 times the peak retention time of the main component. If there are impurity peaks in the chromatogram of the test solution, the sum of the area of each impurity peak must not be greater than the main peak area (1.0%) of the control solution.

remaining solvent

Take about 0.1g of methanol, acetone and ethyl acetate, weigh it accurately, place it in the headspace bottle, add 5ml of dimethylformamide precisely to dissolve, seal, and use it as the test solution; take methanol, acetone and acetic acid separately. An appropriate amount of ethyl ester was accurately weighed, and a solution containing about 50 g per 1 ml was quantitatively diluted with dimethylformamide. 5 ml was precisely measured, placed in a headspace bottle, sealed, and used as a reference solution. Tested according to the residual solvent determination method (Appendix P, Part II of the Pharmacopoeia of the 2010 edition). 6% cyanopropylphenyl-94% dimethyl polysiloxane (or similar polarity) as the fixing solution; the initial temperature is 50 ° C, maintained for 3 minutes, and heated to 160 ° C at a rate of 40 ° C per minute Maintain for 3 minutes; inlet temperature is 200 ° C; detector temperature is 250 ° C; headspace bottle equilibrium temperature is 80 ° C and equilibration time is 30 minutes. Take the reference solution headspace sample, and the resolution of each component peak should meet the requirements. Then take the test solution and the reference solution for headspace injection and record the chromatogram. The peak area calculated according to the external standard method should all meet the requirements.

Loss on drying

Take this product and dry it to constant weight at 105 ° C, and the weight loss shall not exceed 0.5% (Appendix L of Pharmacopoeia Part II of 2010 Edition).

Residue on ignition

Take 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.

Heavy metal

Take the residue left under the burning residue and inspect it according to law (Appendix H of the 2010 edition of the Pharmacopoeia, the second method). The heavy metal must not exceed 10 parts per million.

Determination of dipyridamole

Take about 0.3g of this product, accurately weigh, add 50ml of dilute hydrochloric acid to dissolve, and then titrate slowly with potassium bromate titration solution (0.016 67mol / L). When the end point is reached, shake and add dropwise until the red-purple color no longer appears. That is the end point. Each 1ml of potassium bromate titration solution (0.01667mol / L) is equivalent to 25.23mg of C ₂₄ H ₄₀ N ₈ O ₄ .

Dipyridamole Categories

Antiplatelet aggregation drugs, coronary artery dilatation drugs.

Dipyridamole storage

Shaded and sealed.

Dipyridamole

(1) Dipyridamole tablets (2) Dipyridamole injection (3) Dipyridamole sustained-release capsules ^[2]

Dipyridamole Drug Analysis

This product is an antiplatelet drug.

Method name: Dipyridamole API-Determination of Dipyridamole-Redox Titration

Scope of application: This method uses a titration method to determine the content of dipyridamole in dipyridamole drug substances.

This method is applicable to dipyridamole drug substance.

Principle of the method: After the test product is dissolved in dilute hydrochloric acid, it is titrated slowly with potassium bromate titration solution. When it is near the end point, it is shaken and added dropwise until the red-purple color no longer appears as the end point. Pyridamole content.

Reagent: 1. Dilute hydrochloric acid

2. Potassium bromate titration solution (0.101667mol / L)

Potassium iodide

4. Titrate of sodium thiosulfate (0.1mol / L)

5. Starch indicator liquid

6. Dilute sulfuric acid

7. Benchmark potassium dichromate

equipment:

Sample preparation: 1. Dilute hydrochloric acid

Take 234mL of hydrochloric acid and dilute to 1000mL with water.

2. Potassium bromate titration solution (0.101667mol / L)

Preparation: Take 2.8 g of potassium bromate, add an appropriate amount of water to dissolve into 1000 mL, and shake well.

Calibration: Precisely measure 25mL of this solution, put it in an iodine bottle, add 2.0g of potassium iodide and 5mL of dilute sulfuric acid, tightly block, shake well, and leave it in the dark for 5 minutes. mol / L) When the titration is near the end point, add 2 mL of starch indicator solution, and continue the titration until the blue color disappears. Calculate the concentration of this solution based on the consumption of the sodium thiosulfate titration solution (0.1 mol / L). When the room temperature is above 25 ° C, the reaction solution and dilution water should be cooled to about 20 ° C.

3. Sodium thiosulfate titration solution (0.1mol / L)

Preparation: Take 26 g of sodium thiosulfate and 0.20 g of anhydrous sodium carbonate, add an appropriate amount of freshly boiled cold water to dissolve into 1000 mL, shake well, and filter after leaving for 1 month.

Calibration: Take 0.15g of potassium dichromate, which is dried to constant weight at 120 , and weigh it accurately. Place it in an iodine bottle, add 50mL of water to dissolve, add 2.0g of potassium iodide, gently shake to dissolve, add 40mL of dilute sulfuric acid. Shake well, stopper, and place in a dark place for 10 minutes. Dilute with 250 mL of water. When titrating with this solution to the near end, add 3 mL of starch indicator solution. Continue to titrate until the blue disappears and become bright green. Use the blank test for the titration result. Correction. Each 1mL of sodium thiosulfate titration solution (0.1mol / L) is equivalent to 4.903mg of potassium dichromate. Calculate the concentration of this solution based on the consumption of this solution and the amount of potassium dichromate taken.

When the room temperature is above 25 ° C, the reaction solution and dilution water should be cooled to about 20 ° C.

4. Starch indicator liquid

Take 0.5g of soluble starch, add 5mL of water and stir well, then slowly pour into 100mL of boiling water. Stir with the addition, continue to boil for 2 minutes, let cool, and pour the supernatant liquid.

5. Dilute sulfuric acid

Take 57mL of sulfuric acid and dilute to 1000mL with water.

Operation steps: Weigh accurately about 0.3g of the test sample, add 50mL of dilute hydrochloric acid to dissolve, and then slowly titrate with potassium bromate titration solution (0.01667mol / L). When the end point is reached, shake and add dropwise until it no longer appears. Red purple is the end. Each 1mL of potassium bromate titration solution (0.01667mol / L) is equivalent to 25.23mg of C ₂₄ H ₄₀ N ₈ O ₄ .

Note: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weighed weight. "Precision measurement" means that the accuracy of measuring the volume should meet the accuracy requirements of the volume pipette in national standards ^[3] .

Dipyridamole Drug Description

Dipyridamole Pharmacology and Toxicology

With antithrombotic effect. Dipyridamole inhibits platelet aggregation, and high concentrations (50 g / ml) inhibit platelet release.

The mechanism may be:

inhibits platelet uptake of adenosine, which is a platelet response inhibitor;

Inhibition of phosphodiesterase and increase of cyclic adenosine monophosphate (cAMP) in platelets;

(3) Inhibition of TXA2 (TXA2) formation, a powerful agonist of TXA2 platelet activity;

Enhance endogenous PGI2.

Dipyridamole has a vasodilator effect. Dogs administered dipyridamole 0.5 to 4.0 mg / kg through the duodenum produced dose-related decreases in systemic circulation and coronary vascular resistance, decreased systemic blood pressure, and increased coronary blood flow. Effective 24 minutes after administration, the effect lasts about 3 hours. The same hemodynamic effects were observed in humans. However, acute intravenous administration can reduce local myocardial perfusion in the distal coronary artery. In oral experiments at 111 weeks in mice and 128 to 142 weeks in rats, dipyridamole at 8, 25, and 75 mg / kg (1, 3.1, and 9.4 times the maximum recommended daily human dose) did not cause significant carcinogenic effects. The results of the mutagenicity test were negative. The rat reproduction test used 60 times the maximum daily human recommended dose of dipyridamole and showed no evidence of impaired reproduction. However, at 115 times the maximum recommended daily dose, the number of corpus luteum was significantly reduced, and live births were reduced. Mouse, rat, and rabbit trials did not show evidence of dipyridamole harming the fetus. The oral LD50 of mice was 2150 mg / kg; the single oral lethal dose was 6000 mg / kg in rats and 350 mg / kg in dogs.

Dipyridamole Pharmacokinetics

Dipyridamole injection: The plasma half-life is 2 to 3 hours. High binding rate to plasma proteins. Metabolized in the liver, combined with glucuronic acid, excreted from the bile.

Dipyridamole sustained-release capsules: After oral administration, the peak plasma concentration time is about 2 hours. The peak steady-state plasma concentration is 1.98 g / ml (1.01 ~ 3.99 g / ml), and the steady-state trough concentration is 0.53 g / ml (0.18 ~ 1.01 g / ml) and the plasma protein binding rate is 99%, and the half-life is about 12 hours. Metabolized in the liver, excreted from bile after binding to glucuronide.

Dipyridamole dosage

Dipyridamole injection: 0.142 mg / (kg · min), intravenous drip for a total of 4 minutes.

Dipyridamole sustained-release capsule: 200 mg orally once, twice a day.

Dipyridamole: Orally. 25 to 50 mg once, 3 times a day, before meals. Or as directed by your doctor.

Dipyridamole precautions

can cause peripheral vasodilation, so patients with hypotension should be used with caution.

It should not be mixed with drugs other than glucose.

combined with heparin can cause bleeding tendency.

Use with caution in patients with bleeding tendency.

Medications for pregnant and lactating women: Proper controlled studies have not been conducted in pregnant women and should only be used if necessary. Dipyridamole is excreted from human milk, so lactating women should be used with caution.

Medication for children: The safety and effectiveness of medication for children under 12 years of age have not been determined.

Dipyridamole drug interactions

Synergy with aspirin.

This product does not increase or increase bleeding when used together with dicoumarin anticoagulant.

Dipyridamole overdose

If hypotension occurs, booster medication may be used if necessary. Symptoms of acute poisoning include ataxia, reduced exercise, and diarrhea in rodents, and vomiting, ataxia, and depression in dogs. Dipyridamole is highly bound to plasma proteins and dialysis may not be beneficial.

Dipyridamole adverse reactions

Have gastrointestinal reactions, headache, dizziness, fatigue, rash, flushing; slow intravenous injection, otherwise it can cause hypotension, especially in patients with hypertension; long-term large-scale application can cause bleeding tendency. Hypotension patients should be used with caution. Hypotension patients with myocardial infarction should be disabled. The use of this product for the treatment of ischemic cardiomyopathy may lead to "coronary blood stealing", leading to worsening symptoms ^[4] .

Dipyridamole drug interactions

Dipyridamole, in combination with heparin, coumarins, cefmendo, cefotetan, pukamycin, or valproic acid, can aggravate hypothrombinemia or further inhibit platelet aggregation, which may cause bleeding Need to strengthen observation ^[5] .

Dipyridamole expert review

Dipyridamole is a strong coronary vasodilator, which can significantly increase coronary flow and increase myocardial oxygen supply. However, due to the main expansion of the coronary arterioles, the resistance vessels, the blood flow in the ischemic area does not increase or even decrease, so the effect on angina pectoris is uncertain. And long-term application can promote the formation of collateral circulation and have an anti-platelet aggregation effect, which is beneficial to the prevention and treatment of coronary heart disease ^[5] .