Calyxin Mechanism of Action

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.