Calyxin

Each film-coated contains: Citicoline (as sodium) 500 mg.
Each mL contains: Citicoline (as sodium) 250 mg.

Pharmacologic Category: Psychostimulant/Nootropic.
Pharmacology: Pharmacodynamics: Citicoline is a complex organic molecule that functions as an intermediate in the biosynthesis of cell membrane phospholipids. Citicoline is also known as CDP-choline and cytidine diphosphate choline (cytidine 5'-diphosphocholine).
Film-coated tablet: CDP-choline belongs to the group of biomolecules in living systems known as nucleotides that play important roles in cellular metabolism.
The pharmacologic action of citicoline appears to involve mechanisms that extend beyond phospholipid metabolism. Citicoline metabolites - choline, methionine, betaine, and cytidine-derived nucleotides - enter a number of metabolic pathways.
Biochemical markers of cholinergic nerve transmission are known to be deficient in conditions characterized by degeneration of cholinergic neurons, such as Alzheimer's disease. Citicoline modestly improves cognitive function in Alzheimer's disease by serving as an acetylcholine precursor. The brain uses choline preferentially for acetylcholine synthesis, which can limit the amount of choline available for phosphatidylcholine production.
Citicoline has been investigated as a therapy for stroke patients. Three mechanisms are postulated: (1) repair of the neural membrane via increased synthesis of phosphatidylcholine; (2) repair of damaged cholinergic neurons via potentiation of acetylcholine production; and (3) reduction of free fatty acid build-up at the site of stroke-induced nerve damage.
Citicoline protects cholinergic neurons from auto cannibalism, a process in which membrane phospholipids are catabolized to provide choline for the synthesis of acetylcholine. This occurs when choline supplies are depleted, necessitating sacrifice of membrane phospholipids to maintain neurotransmission. As an exogenous source of choline for acetylcholine production, citicoline thus spares membrane phospholipids (in particular, phosphatidylcholine) and prevents neuronal cell death.
Solution for injection: Citicoline is composed of two essential moieties, cystidine and choline, linked by a diphosphate bridge, and serves as the phosphocholine donor to 1, 2-diacylglycerol (DAG) to form phosphatidylcholine. It is a pyrimidine 5'-nucleotide, which serves as an essential precursor in the synthesis of lecithin (phosphatidylcholine) and other phospholipids, the extensive damage caused by stroke requires repair and regeneration of the axons and synapses of neurons, so new membrane production is necessary.
Results of various studies have suggested the following actions of Citicoline: Phospholipid Precursor: Evidence of citicoline's role as a phosphatidylcholine precursor has been found in animal studies. The brain uses choline preferentially for acetylcholine synthesis, which can limit the amount of choline available for phosphatidylcholine production. When the demand for acetylcholine increases or choline stores in the brain are low, phospholipids in the neuronal membrane can be catabolized to supply the needed choline, Exogenous citicoline, thus, helps preserve the structural and functional integrity of the neuronal membrane. In an in vitro study, citicoline at high concentrations stimulated brain acetylcholinesterase (AChE) along with Na+/K+-ATPase. The postulated mechanism involves the bioconversion of citicoline to phosphatidylcholine.
Neuronal Membrane Repair: Citicoline has been investigated as a therapy for stroke patients. Three mechanisms are postulated: (1) ability to repair neuronal membranes via increased synthesis of phosphatidylcholine; (2) repair of damaged cholinergic neurons via potentiation of acetylcholine production; and, (3) reduction of free fatty acid build-up at the site of stroke-induced nerve damage. In addition to phosphatidylcholine, citicoline serves as an intermediate in the synthesis of sphingomyelin, another neuronal membrane phospholipid component. Citicoline has shown the potential to restore post-ischemic sphingomyelin levels. Citicoline also restores the levels of cardiolipin, a phospholipid component of the inner mitochondrial membrane. The mechanism for this is unknown, but data suggest that citicoline inhibits enzymatic hydrolysis of cardiolipin by phospholipase A2. Citicoline avoids, reduces or reverses the effects of ischemia and/or hypoxia in the major part of animals and cellular models studied; it also acts in the cranial traumatic forms, reduces and limits the injuries to the membranes of the nerve cells re-establishes the sensitivity and the function of the regulatory intracellular enzymes and accelerates the re-absorption of cerebral edema. Thus, considerable evidence accumulated supports the use of citicoline for increasing, maintaining and repairing the membranes and the neuronal function in situations such as ischemia and traumatic injuries.
Reduction of Free Fatty Acid Build-Up: Citicoline may benefit patients experiencing ischemia by decreasing the accumulation of free fatty acids at the site of the lesion, which occurs as a result of neuronal cell damage and death. Soon after the initiation of ischemia, there is a significant increase in proinflammatory arachidonic acid, glycerols and free fatty acids caused by the breakdown of neuronal membranes. Toxic metabolites as well as prostaglandins, thromboxanes and free radicals can accumulate, leading to further damage, Animal studies have demonstrated evidence in suppressing free fatty acid build-up. Human data is limited.
Effect on Beta-Amyloid: Evidence has surfaced that citicoline counteracts the deposition of beta-amyloid, a neurotoxic protein believed to play a central role in the pathophysiology of Alzheimer's disease (AD). The characteristic lesion in AD is the formation of plaques and neurofibrillary tangles in the hippocampus. The degree of cognitive dysfunction and neurodegeneration in AD is proportional to the build-up of beta-amyloid.
Effect on Norepinephrine: Evidence of the ability of citicoline to enhance norepinephrine release in humans was found in a study showing that citicoline raises urinary levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a norepinephrine metabolite. Citicoline increased brain levels of neurotransmitters in rats at a dose of 100 mg/kg, administered daily for 7 days. Norepinephrine increased in the cerebral cortex and hypothalamus, dopamine increased in the corpus striatum, and serotonin increased in the cerebral cortex, striatum and hypothalamus.
Activation of the Dopaminergic System: With respect to dopaminergic activation, citicoline has been reported to exert dopaminergic agonist effects in the corpus striatum, enhance dopamine synthesis in the striate body (by activation of tyrosine hydroxylase), inhibit dopamine uptake by synaptosomes, and increase sensitivity of dopaminergic receptors that have been downregulated during prolonged levodopa therapy. The addition of citicoline to therapy with levodopa (with or without other anti-Parkinsonian agents) has been reported to improve symptoms in patients with Parkinson's disease in small open and controlled studies.
Pharmacokinetics: Film-coated tablet: Citicoline is a water-soluble compound with greater than 90% bioavailability. Pharmacokinetic studies in healthy adults have shown oral doses of citicoline to be rapidly absorbed, with less than 1% excreted in the feces. Plasma levels peak in a biphasic manner, at 1 hour after ingestion followed by a second larger peak at 24 hours post dosing.
Citicoline is metabolized in the gut wall and liver. The byproducts of exogenous citicoline formed by hydrolysis in the internal wall are choline and cytidine. After absorption, choline and cytidine are dispersed throughout the body, enter systemic circulation for utilization in various biosynthetic pathways and cross the blood-brain barrier for resynthesis into citicoline in the brain.
Pharmacokinetic studies using ¹⁴C citicoline show citicoline elimination occurs mainly via respiratory CO₂ and urinary excretion, in two phases, mirroring the biphasic plasma peaks. The initial peak in plasma concentration is followed by a sharp decline, which then slows over the next 4 to 10 hours. In the second phase, an initially rapid decline after the 24-hour plasma peak is similarly followed by a slower elimination rate. The elimination half-life is 56 hours for CO₂ and 71 hours for urinary excretion.
Solution for injection: Absorption: Citicoline is well absorbed following intramuscular administration. After intramuscular doses of citicoline 1,000 mg, peak increases in plasma choline levels were seen in 0.4 hrs with levels increasing 11 micromol/L (baseline) to 25 micromol/L.
Distribution: Choline derived from citicoline crosses the blood-brain barrier presumably serving as a source of acetylcholine and phosphatidylcholine (lecithin) synthesis. The major portion of a dose of citicoline appears to be incorporated into tissues and/or used in biosynthetic/biodegradation pathways, including lecithin/lipid membrane synthesis.
Metabolism: Citicoline is metabolized in the liver to free choline. The liver is capable of synthesizing lecithin from choline. The half-life of free choline is of 2 hours after intramuscular administration.
Excretion: Only small amounts of dose are recovered in the urine and feces (less than 3% each). Approximately 12% of a dose is eliminated through the lungs as carbon dioxide.

Film-coated tablet: Acute and recovery phase of cerebral infarction (e.g. ischemia due to stroke).
Cognitive dysfunction due to degenerative (i.e. Alzheimer's disease) and cerebrovascular disease.
Cerebral insufficiency (e.g. dizziness, memory loss, poor concentration, disorientation) due to head trauma or brain injury.
Parkinson's disease.
Solution for injection: Used for the treatment of patients with disturbance of consciousness resulting from a head injury brain operation, and in the acute stage of cerebral infarction.

Film-coated tablet: Dosing must be individualized and adjusted according to disease severity.
DOSE IN ADULTS (500 mg): One tablet once or twice a day or as prescribed by the physician.
Solution for injection: Disturbance of Consciousness Resulting from Head injury or Brain Operation: Usually, for adults, a dose of 100 mg to 500 mg of Citicoline injection is administered once or twice a day, by intravenous drip infusion, intravenous injection or intramuscular injection.
The dose may be adjusted according to the patient's age and condition.
Disturbance of Consciousness in the Acute Stage of Cerebral Infarction: Usually, a dose of 1,000 mg of Citicoline Injection is administered once a day by intravenous injection for 2 consecutive weeks.

Citicoline exhibits very low toxicity profile in humans.
Film-coated tablet: In clinical use it has been observed to be safe at doses up to 2g/day.
Solution for injection: In a short term, placebo-controlled, cross-over study, 12 healthy adults took citicoline at daily doses of 600 and 1000 mg or placebo for consecutive five-day periods. Transient headaches occurred in four subjects on 600 mg dose, five on the 1000 mg dose, and one in placebo. No changes or abnormalities were observed in hematology, clinical biochemistry or neurological test.
The LD50 of a single intravenous dose of citicoline was 4,600 mg/kg and 4,150 mg/kg in mice and rats, respectively.
In an unpublished acute toxicity study, free-base citicoline was administered to male and female rats at a dose of 2000 mg/kg body weight for 14 days. No changes in body weight, deaths, clinical symptoms or gross pathological changes were observed.

Film-coated tablet: Hypersensitivity to any component of the product.
Patients with hypertonia of the parasympathetic nervous system.
Solution for injection: Hypersensitivity to Citicoline or any other component of the formulation.

Film-coated tablet: Large doses of citicoline could aggravate increase in cerebral blood flow in episodes of persistent intracranial hemorrhage.
Solution for injection: General: For patients with acute, severe and progressive disturbance of consciousness resulting from a head injury or brain operation, citicoline injection should be administered in conjunction with hemostatics and an intracranial pressure relieving drug, or a treatment such as hypothermia. For patients with disturbance of consciousness in the acute stage of cerebral infarction, it is recommended to start the administration of citicoline injection within 2 weeks after an apoplectic stroke.
In administering citicoline injection intramuscularly, caution should be exercised so as not to affect the tissues, nerves, etc. Intramuscular injection should be given only when indispensable, and should be restricted to the minimum to be required. Intraparticular, repeated injection at the same site should be avoided. Care should be exercised to avoid injection at sites along the course of the nerves. In case of intense pain or backflow of blood upon insertion of the injection needle, the needle should be withdrawn immediately and injected at a different site. In intravenous administration, inject as slowly as possible. Since shock may occur, a close observation should be maintained. If any such abnormalities such as drop in blood pressure, distressed feeling of the chest or dyspnea are observed, citicoline injection should be discontinued and appropriate measures taken.
Persistent Intracranial Hemorrhage: In case of persistent intracranial hemorrhage, it is recommended not to exceed the dose of 1,000 mg of citicoline daily, given through very slow intravenous administration (30 drops/min).

Film-coated tablet: There is not enough evidence on citicoline's safety in pregnant and breastfeeding women. Citicoline should be used in pregnancy and breastfeeding only when benefits justify the potential risks.
Solution for injection: Pregnancy: There are no adequate and well-controlled studies of citicoline during pregnancy. Citicoline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: Caution should be exercised during breastfeeding because it is not known whether citicoline is excreted in breast milk.

Film-coated tablet: Cardiovascular: Bradycardia, tachycardia, hypotension.
Gastrointestinal: Diarrhea, epigastric distress, stomach pain.
Nervous: Dizziness, headache, fatigue.
Skin: Rash.
Solution for injection: The commonly observed adverse effects (0.1-5%) with intravenous use of citicoline were rash, insomnia, occurrence or intensification of numbness of paralyzed extremities (when used in patients with post-apoplectic hemiplegia), nausea, abnormal laboratory values for function of the liver and feeling of warmth.
The other adverse reactions (<0.1%) were excitation, convulsions, anorexia, transient diplopia, transient blood pressure changes, malaise, shock, distressed feeling of the chest, and dyspnoea. In a short-term, placebo-controlled, crossover study, 12 healthy adults took citicoline at daily doses of 600 mg and 1,000 mg or placebo for consecutive 5-day periods. Transient headaches occurred in 4 subjects on the 600 mg dose, 5 on the 1,000 mg dose, and 1 on placebo. No changes or abnormalities were observed in hematology, clinical biochemistry or neurological tests. A large drug surveillance study analysed the results of citicoline treatment in 2,817 patients aged 60 to 80 years, suffering from senility and cerebral vascular insufficiency. A total of 151 incidents of side effects were recorded representing 5% of the patient sample. The most common adverse effect was transient in nature and included stomach pain and diarrhea in 102 cases. Vascular symptoms of hypotension, tachycardia or bradycardia occurred in 16 cases.
Seek medical attention immediately at first sign of any adverse drug reaction.

Film-coated tablet: Citicoline must not be administered with products containing meclofenoxate.
Citicoline potentiates the effects of L-dopa.
Solution for injection: Carbidopa, Levodopa and Entacapone: Citicoline may enhance the effects of levodopa, carbidopa and entacapone. The exact mechanism is unknown, but animal models suggest that citicoline may increase dopamine levels in the brain and/or improve dopaminergic cell survival. In patients with Parkinson's disease, a few studies have demonstrated levodopa-saving effects, whereby the addition of citicoline (500-1,200 mg/day) allowed for lower dosages of levodopa to be used with stable or improved therapeutic efficacy and reduced the side effects in some patients. However, data are limited.
Co-administration with Centrophenoxine: Must not be administered in conjunction with medications containing centrophenoxine.

Store at temperatures not exceeding 30°C.
Film coated tablet: Protect from light.

Nootropics & Neurotonics/Neurotrophics / Peripheral Vasodilators & Cerebral Activators

N06BX06 - citicoline ; Belongs to the class of other psychostimulants and nootropics.

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