Citicoline sodium

Description

Citicoline is a nucleic acid derivatives, Geiger found that citicoline can restore brain injury in the animal experiments in 1956. Kennedy study confirmed that citicoline can make brain injury recovery in 1957. Takeda pharmaceutical company in Japan developed and produced it in 1961. It was registered in China in 1988, and is currently the best-selling drug among clinical brain diseases. It plays an important role in the synthesis of lecithin, by promoting the synthesis of lecithin and improving brain function. Experiments show that citicoline can enhance the levels of norepinephrine and dopamine in the central nervous system, thereby it can treat cerebrovascular disease, traumatic brain injury and cognitive impairment caused by various reasons, and there are no obvious side effects.

Application

• Central nervous system medication.
• Coenzyme. For acute traumatic brain injury and brain surgery consciousness. Acute brain injury and brain surgery after a disturbance of consciousness, paralysis due to stroke can gradually restore the function of the limbs, it can also be used for functions and other central nervous system disorders of consciousness caused by acute injury, and also for ischemic cerebrovascular disease and vascular dementia.

Mechanism of action

Citicoline sodium can enhance the function of brain stem reticular formation, especially the ascending reticular activating system associated with human consciousness; enhance the function of the pyramidal system; inhibit the function of the external system of the cone, and promotes the recovery of the function of the system. For the treatment of sequelae of traumatic brain injury and cerebral vascular accident caused by the nervous system, it can also be used in the treatment of Parkinson's disease, senile dementia has a certain effect; for the treatment of cardiovascular and cerebrovascular diseases; it also have a certain effect for anti-aging, improving learning and memory.

Chemical Properties

White Solid

Uses

Citicoline Sodium (CDPC) is a naturally occurring nucleotide; an intermediate in the major pathway of phosphatidylcholine biosynthesis. It has neuroprotective effects. It is used to treat ischemic stroke and head trauma.Cytidine 5′-diphosphate (CDP) is used as a substrate of CDP (nucleoside diphosphate) kinase (2.7.4.6) to produce CTP in support ofDNA and RNA biosynthesis and of ribonucleotide reductase to product dCMP. Cytidine-5'-diphosphocholine sodium salt hydrate acts as a neuroprotective agent in situations of hypoxia and ischemia. It is used as biosynthetic intermediate of membrane phospholipids. It is a cerebral vasodilator and inhibits PLA2 activation.

Application

Citicoline (CDP-choline) is an essential intermediate in the synthesis of the major phospholipid of the cell membranes, phosphatidylcholine (PtdCho). It increases plasma adrenocorticotropic hormone (ACTH) levels and potentiates serum thyrotrophin (TSH) levels by activating the central cholinergic system.
Citicoline Sodium is used to treat age-related memory loss, cerebrovascular diseases such as stroke, dementia, as well as head trauma. Research has shown that it increases a chemical called phosphatidylcholine which is important for brain function. Citicoline might also decrease brain tissue damage when the brain is injured. Citicoline Sodium is also said to help with weight management when used as a dietary supplement.

brand name

CerAxon (Interneuron).

General Description

Cytidine 5′-diphosphocholine (CDP-choline) contains cytidine and choline linked via a diphosphate bridge.

Biochem/physiol Actions

Cytidine 5′-diphosphocholine (CDP-choline) plays an important role in the synthesis of phosphatidylcholine. It is also involved in the biosynthesis of acetylcholine, a neurotransmitter. CDP-choline has therapeutic effects against hypoxia, cerebral ischemia and traumatic brain injury. It also exhibits therapeutic effects against learning and memory disorders, drug addiction and Alzheimer′s and Parkinson′s diseases.

Side effects

Citicoline sodium may be safe for 12 weeks of oral use, side effects may include stomach pain, back pain, blurred vision, constipation and headache. While Citicoline 2% Eye Drops may be safe for long-term use (up to 3 years). No serious side effects have been reported by clinical investigators in the treatment of Parkinson's disease.

Safety

There are two forms of citicoline: citicoline sodium and citicoline free-base. Citicoline sodium is the form that is approved as a prescription medication in some European countries and throughout Asia. Citicoline free-base is the form that is available as a dietary supplement and food/beverage ingredient in the United States. In Europe, citicoline is approved as a Novel Food ingredient and is authorized to be used in food supplements up to 500 mg per day. It is also authorized to be used for Food for Special Medical Purposes (FSMPs) in amounts of 250 mg/serving and up to 1,000 mg per day.
Citicoline free-base is produced in Japan by Kyowa Hakko Bio Co. Ltd. under the brand name of Cognizin. Cognizin is considered to be safe and received self-designated Generally Recognized As Safe (GRAS) status in 2009. In Europe, citicoline was approved as a Novel Food ingredient in 2014. Whereas most companies produce citicoline synthetically, Cognizin is produced using a patented, natural fermentation process. It is vegetarian and allergen-free. Kyowa Hakko manufactures and supplies Cognizin as a raw ingredient to many manufacturers around the world.

Synthesis

987-78-0

33818-15-4

2-(((((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)oxophosphoryl)oxy)-N,N,N-trimethylethanaminium was used as a raw material to synthesize 2-((((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)oxophosphoryl)oxy)-N,N,N-trimethylammonium ethyl. -amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)oxidizedphosphoryl)oxy)-N,N,N-trimethylethane-1-ammonium sodium salt (1:1) in the following general procedure: CMP (100 mg, 0.31 mmol) was prepared in DMF (2 mL) and tributylamine (150 μL , 0.62 mmol) in a free acid-stirred suspension was heated at 50 °C for 10 min and subsequently cooled to room temperature. Upon addition of CDI (250 mg, 1.55 mmol), the suspension changed to a clarified solution within minutes. The reaction mixture was stirred anhydrically at room temperature for 30 min, followed by treatment with anhydrous methanol (100 μL, 2.48 mmol) to hydrolyze the excess of CDI.After 30 min, anhydrous zinc chloride (59 mg, 0.43 mmol) was added, followed by choline phosphate solution (0.77 M anhydrous DMF solution, 2 mL, 1.55 mmol). The reaction mixture was stirred at room temperature for 24 hours. After evaporation of the solvent in vacuo, CDP-Cho 5 was purified by anion-exchange chromatography.The residue was dissolved in water and purified by ion-exchange column chromatography on a Sephadex DEAE A-25 resin using a linear gradient elution of 0-0.5 M ammonium bicarbonate, followed by chromatographic separation on an RP-18. Triethylammonium counterbalance ions were exchanged for sodium ions by passing the nucleotide solution through a Dowex 50WX8 column. Freeze-drying gave 1-(β-D-ribofuranosyl)cytosine-5'-diphosphorylcholine (sodium salt) as a white solid (115 mg, 74% yield). hplc: tR = 8.8 min (λmax 276 nm); 1H NMR (400 MHz, D2O) δ 7.86 (d, 1H, H6, J6-5 = 7.6 Hz), 6.04 ( d, 1H, H5, J5-6 = 7.6 Hz), 5.92 (d, 1H, H10, J10-20 = 4.0 Hz), 4.31 (sl, 2H, CH2-O), 4.28-4.08 (m, 5H, H2O H30H40H50 and H50b), 3.60 (t, 2H, CH2-N, J = 4.2 Hz), 3.14 ( s, 9H, CH3); 13C NMR (101 MHz, D2O) δ 166.2 (s, C4), 157.7 (s, C2), 141.4 (s, C6), 96.6 (s, C5), 89.3 (s, C10), 82.6 (d, C40, JC-P = 8.9 Hz), 74.1 (s, C20), 69.3 (s C30), 65.9 (s, CH2N), 64.7 (d, C50, JC-P = 5.1 Hz), 59.9 (s, CH2O), 53.9 (s, CH3); 31P NMR (162 MHz, D2O) δ 11.35 (d, 2Jab = 21.4 Hz), 12.14 (d, 2Jab = 21.4 Hz); HRMS (ESI) m/z: [M + H]+ C14H26N4O11NaP2 calculated value 511.0971, measured value 511.0973.

Metabolism

Citicoline can be administered orally, intramuscularly, or intravenously. Oral administration is most common because its bioavailability is approximately 92%. After oral ingestion, citicoline is hydrolyzed in the small intestine and liver into 2 major metabolites: cytidine and choline.
Cytidine and choline enter the systemic circulation, where cytidine is further metabolized into uridine. Both uridine and free choline cross the blood-brain barrier. In the central nervous system, uridine is converted to cytidine triphosphate, choline is converted to phosphocholine, and the 2 combine to resynthesize CDP-choline.

References

[1] Tetrahedron Letters, 2014, vol. 55, # 38, p. 5306 - 5310