Background and overview[1][2][3]
In the 1950s, K ennedy et al. discovered citicoline, then chemically synthesized it and determined its molecular structure. Kennedy’s research in 1957 confirmed that it is crucial in the synthesis of cerebrolipids. In 1961, Japan’s Takeda Pharmaceutical Company developed and produced Citicoline Sodium and registered it in my country in 1988. Citicoline sodium raw material drug has been included in the second part of the 2005 edition of the Chinese Pharmacopoeia. Currently, it has been produced and marketed by many domestic pharmaceutical factories, and three imported companies: Japan’s Kyowa, Takeda, and Italy’s Pro.Bio.Sint.
Currently, citicoline sodium injection is mainly used clinically, and oral preparations include citicoline sodium oral liquid and citicoline sodium capsules. Citicoline is an intermediate in the endogenous synthesis of phosphatidylcholine and an important component in building biological membranes. After central nervous system injury, citicoline sodium participates in repair and regeneration and plays a neuroprotective role; it also plays an important role in the transfer of nerve media and the conduction of bioelectricity.
Citicoline sodium is mainly used clinically for head trauma and brain surgery accompanied by disturbance of consciousness, acute disturbance of consciousness due to cerebral infarction, promoting the recovery of upper limb function in patients with hemiplegia after stroke, and acute pancreatitis. It is also used for acute stroke, Nerve damage and disturbance of consciousness caused after surgery have obvious therapeutic effects on Parkinson’s syndrome, dementia, glaucoma, etc. Citicoline sodium is currently the most clinically used neuroactivator. Stearic acid has the following characteristics: (1) Reduces cerebral vascular resistance, increases cerebral blood flow, promotes brain substance metabolism, and improves cerebral circulation; (2) Strengthens the brainstem The function of the reticular structure can enhance the function of the pyramidal system, improve motor paralysis, promote lecithin synthesis, and improve brain metabolism. It can be combined with brain peptides to have a synergistic effect on improving brain function.
Indications[4]
The main indications are acute craniocerebral surgery and post-brain surgery disorder of consciousness; it is also clinically used for other functional and consciousness disorders caused by acute injury to the central nervous system, paralysis shaking, tinnitus and neurological deafness, sleeping pill poisoning, etc.; in recent years It is widely used clinically for ischemic stroke, cerebral arteriosclerosis, multi-infarct dementia, Alzheimer’s disease, viral encephalitis in children, etc.
Specifications[4]
Tablet: 100 mg. Injection: 200 mg/2 ml, 250 mg/2 ml.
Usage and dosage[4]
Orally, take 2 tablets (0.2g) each time, 3 times a day, with warm water.
Intravenous drip: 0.25~0.5g per day, diluted with 5% or 10% glucose injection and then infused slowly, every 5~10 days is a course of treatment; simple intravenous injection: 100~200mg each time. Intramuscular injection: 0.1 to 0.3 g per day, divided into 1 to 2 injections.
Pharmacological effects[5]
Citicoline is an intermediate product of phospholipid biosynthesis. It exists in all cells and is the main coenzyme for phospholipid synthesis. It improves brain function by promoting the synthesis of lecithin, which is manifested by improved consciousness and increased cerebral blood flow. And the uptake of oxygen is significantly improved. By increasing cerebral blood flow, it improves brain metabolism and wakes up.
Pharmacokinetics[4]
There are no human pharmacokinetic data on oral administration of citicoline sodium. Literature data shows that after injection of citicoline sodium, the blood concentration drops rapidly, to 1/3 of the level at the time of injection in 30 minutes, and is basically stable in 1-2 hours. The largest distribution is in the liver, accounting for 10%, and most of it is in the liver. It is excreted into the urine within 2 hours. It is difficult for this product to pass through the blood-brain barrier. Only a small amount of the drug enters the brain, accounting for only 0.1%. However, the drug stays in the brain for a long time. The drug concentration reaches the peak within 3 hours after injection. And remained unchanged within 24 hours, and the content of citicoline in the injured brain was significantly higher than that in the normal brain and in the injured hemisphere compared with the undamaged hemisphere.
Adverse reactions[4]
Gastrointestinal reactions are occasionally seen, mild and short-lasting
Drug interactions[4]
Do not take this product in combination with drugs containing chloromethane.
Notes[4]
Before using this product, please read the drug instructions carefully; use it according to your doctor’s advice.
Taboo[4]
Do not take this product in combination with drugs containing chloromethane
Preparation [3][6]
Method 1: Biosynthesis of citicoline sodium using 5’-cytidylic acid and phosphocholine as reactants and yeast as biocatalyst. The reaction flow is:
Method 2: A method for producing citicoline sodium catalyzed by an immobilized enzyme, including the following steps:
1) Engineering bacterial fermentation:
Inoculate the seed liquid of Escherichia coli engineering strain with molecular cloning of cytidine phosphotransferase gene into the culture medium system and culture it for 26 to 32 hours. The added volume is 5% to 10% of the volume of the culture medium system; during this period, appropriate amounts of glucose, peptone and yeast extract are added. After the fermentation is completed, the fermentation liquid is centrifuged to collect the cells.
2) Prepare cytidine phosphotransferase serum:
Suspend the above bacteria in phosphate buffer and crush it with ultrasonic wave or homogenizer to obtain a crushing liquid. Add ammonium sulfate to the above crushing liquid for salting out to obtain a salting out liquid with a saturation of 25% to 45%. Then use a ceramic membrane filter with a pore size of 100 to 500nm to separate the above-mentioned salting-out liquid from solid to liquid to obtain a cytidine phosphotransferase serum, wherein the suspension of the bacterial cells and the phosphate buffer is obtained.The ratio is 1:4~1:10.
3) Immobilization of cytidine phosphotransferase serum:
Add an immobilized carrier to the above cytidine phosphotransferase clear liquid, stir and solidify, and obtain immobilized cytidine phosphotransferase. The ratio of the added amount of the immobilized carrier to the cytidine phosphotransferase clear liquid is 100~ 200g/L.
4) Synthesis of citicoline sodium:
Mix an aqueous solution containing cytidine triphosphate disodium 30~80mmol/L, phosphocholine 60~mmol/L and magnesium acetate 10~50mmol/L to prepare a synthesis reaction solution, and adjust the pH value of the synthesis reaction solution to 6.0-9.0, add immobilized cytidine phosphotransferase, and stir and react at a water bath temperature of 10-50°C for 4-10 hours. The clear liquid obtained after filtration is citicoline sodium solution. The immobilized cytidine phosphotransferase is added. The ratio of the added amount of glycoside phosphotransferase to the synthesis reaction solution is 10-50g/L.
5) Extraction and purification
The above citicoline sodium solution is separated and crystallized by chromatography and dried to obtain a dry product of citicoline sodium.
Main reference materials
[1] Zhou Changkui; Wu Xiaohua. Research progress on neuroprotective agent-citicoline. Chinese Journal of Biochemical Drugs, 2004, 25.4: 255-256.
[2] Chen Qian. Application of Citicoline in Clinical Treatment[J]. Tianjin Pharmacy, 2012, 24(5): 60-63.
[3] Hu Jianrong. A citicoline sodium compound and its new method. CN201010578120.1, application date 20101202
[4] Citicoline instructions
[5] Tang Zhongping, Li Weilin, Tang Jimin, et al. Clinical application of citicoline in neurology [J]. Chinese Modern Drug Application, 2014, 8(17): 225-227.
[6] Liu Guizhen; Huang Jiongwei; Zhou Huarun; Mo Shiyi; Lao Ruixiong. A method for the production of citicoline sodium catalyzed by immobilized enzyme. CN201310167034.5, application date 20130508
