Brand Name: Citixa
Composition: Citicholine 500mg Tablets
Dosage Form : Tablets
Packing: 10×10 Tablets
CITIXA 500 Tablets
Each film-coated tablet contains:
Citicoline Sodium equivalent to
Citicoline …………………. 500 mg
Excipients ……………………… q.s.
Colour: Titanium Dioxide, IP
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 cystidinediphosphate choline (cytidine5’-diphosphocholine).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:
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 inthe synthesis of sphingomyelin, another neuronal membrane phospholipid component. Citicoline has shown the potential to restore post-ischaemic 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 ischaemia 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 oedema. Thus, considerable evidenceaccumulated supports the use of citicoline for increasing, maintainingand repairing the membranes and the neuronal function in situationssuch as ischaemia and traumatic injuries.
Reduction of Free Fatty Acid Build-Up
Citicoline may benefit patients experiencing ischaemia by decreasingthe accumulation of free fatty acids at the site of the lesion, which occursas a result of neuronal cell damage and death. Soon after the initiationof ischaemia, there is a significant increase in pro-inflammatoryarachidonic acid, glycerols and free fatty acids caused by thebreakdown of neuronal membranes. Toxic metabolites as well asprostaglandins, thromboxanes and free radicals can accumulate,leading to further damage. Animal studies have demonstrated evidencein suppressing free fatty acid build-up. Human data is limited.
Effect on Beta-Amyloid
Evidence has surfaced that citicoline counteracts the deposition ofbeta-amyloid, a neurotoxic protein believed to play a central role in thepathophysiology of Alzheimer’s disease (AD). The characteristic lesionin AD is the formation of plaques and neurofibrillary tangles in thehippocampus. The degree of cognitive dysfunction and neurodegenerationin AD is proportional to the build-up of beta-amyloid.
Effect on Norepinephrine
Evidence of the ability of citicoline to enhance norepinephrine release inhumans was found in a study showing that citicoline raises urinary levelsof 3-methoxy-4-hydroxyphenylglycol (MHPG), a norepinephrinemetabolite.
Citicoline increased brain levels of neurotransmitters in rats at a dose of100 mg/kg, administered daily for 7 days. Norepinephrine increased inthe cerebral cortex and hypothalamus, dopamine increased in thecorpus striatum, and serotonin increased in the cerebral cortex, striatumand hypothalamus.
Activation of the Dopaminergic System
With respect to dopaminergic activation, citicoline has been reported toexert dopaminergic agonist effects in the corpus striatum, enhancedopamine synthesis in the striate body (by activation of tyrosinehydroxylase), inhibit dopamine uptake by synaptosomes, and increasethe sensitivity of dopaminergic receptors that have been down-regulatedduring prolonged levodopa therapy. The addition of citicoline to therapy with levodopa (with or without otheranti-Parkinsonian agents) has been reported to improve symptoms inpatients with Parkinson’s disease in small open and controlled studies.
Citicoline is a water-soluble compound with an absolute bioavailabilityof 99%. Pharmacokinetic studies on healthy adults show that oral dosesof citicoline are rapidly absorbed, with less than 1% excreted in thefaeces. Plasma levels peak in a biphasic manner, at 1 hour afteringestion followed by a second larger peak at 24 hours post-dosing. Two peaks of plasma citicoline equivalents have been reported afteroral doses of radiolabelled citicoline (300 mg). An initial peak isobserved in approximately 1 hour (1.5 mcg/mL), presumably related toa mixture of unchangedciticoline and its metabolites (choline andcystidinediphosphate). A second peak of approximately 3 mcg/mL isseen 24 hours post-dose, and may be due to delayed absorption of thedrug or continued metabolite accumulation over this period.
Brain uptake of citicoline metabolites was demonstrated as early as 30minutes after administration. When labelled citicoline is administeredorally, only about 0.5% of the total radioactivity is incorporated into thebrain. Brain uptake increased to about 2% of the total radioactivity whenciticoline was administered intravenously. The cerebral levels ofciticoline after its administration are unknown. It is not known to whatextent brain tissue levels are altered at any given dose.
Following absorption, choline and cytidine are dispersed throughout thebody; they enter the systemic circulation for utilization in various biosynthetic pathways and cross the blood–brain barrier for re-synthesisinto citicoline in the brain. Choline crosses the blood–brain barrier,presumably serving as a source for acetylcholine and phosphatidylcholine. The major portion of a dose of citicoline appears to be incorporated intotissues and/or used in biosynthetic/biodegradation pathways, includinglecithin/lipid membrane synthesis.
Citicoline is metabolized in the gut wall and liver. Exogenous citicoline ishydrolysed and absorbed as cytidine and choline. Following absorption,choline and cytidine are re-phosphorylated, and citicoline is synthesizedfrom cytidine triphosphate and choline monophosphate by cytidinetriphosphate phosphocholinecytidyl transferase (PCCT). As therate-limiting intermediate in phosphatidylcholine biosynthesis, it wasbelieved that citicoline administration would provide benefit in pathologicalconditions such as central nervous system (CNS) injury wheremembrane damage contributes to neuronal death. During phosphatidylcholinesynthesis, choline monophosphate is incorporated intophosphatidylcholine and cytidine 5′-monophosphate (CMP) is released.CMP can be utilized for the synthesis of RNA, or of DNA as thedeoxyribonucleotide. The choline moiety from citicoline is also acetylated to the neurotransmitter, acetylcholine, or metabolized to betaine, which serves as a sourceof methyl groups in the synthesis of methionine and S-adenosyl-Lmethionine.AdoMet is the methyl donor in the methylation of proteinsand nucleotides, and the conversion of phosphatidyl-ethanolamine(PtdEtn) to phosphatidylcholine. The product, S-adenosyl-Lhomocysteine,can be metabolized further to glutathione (GSH).
Pharmacokinetic studies using 14C-citicoline show that citicolineelimination occurs in two phases mirroring the biphasic plasma peaks,mainly via respiratory carbon dioxide (CO2) and urinary excretion. The initial peak inplasma concentration is followed by a sharp decline, which then slowsover the next 4–10 hours. In the second phase, an initial rapid declineafter the 24-hour plasma peak is similarly followed by a slowerelimination rate.Small amounts of a dose are recovered in the urine (2–3%) and in thefaeces (less than 1%). Approximately 12% of a dose is eliminated asrespiratoryCO2. The elimination half-life of citicoline is 3.5 hours(first peak concentration), and 125 hours (second peak concentration).
CITIXA Tablets are indicated in the treatment of patients withserious cerebral injuries of a vascular or traumatic nature, with orwithout loss of consciousness. They are also indicated for the treatmentof degenerative damages and chronic cerebral vascular injuries insenile dementia.
Dosage and Administration
Dosage should be individualized. The usually recommended dose of CITIXA Tablet is 500–1,000 mg daily. No dosage adjustment is required forthe elderly population and the usual recommended adult dose can beadministered.
Hypersensitivity to CITIXA Tablets or any other component of the formulation.
Warnings and Precautions
In case of persistent intracranial haemorrhage, it is recommended not toexceed the dose of 1,000mg of Citicoline daily.
Carbidopa, Levodopa and Entacapone
Citicoline may enhance the effects of levodopa, carbidopa andentacapone. The exact mechanism is unknown, but animal modelssuggest that citicoline may increase dopamine levels in the brain and/orimprove dopaminergic cell survival. In patients with Parkinson’s disease,a few studies have demonstrated levodopa-saving effects, whereby theaddition of citicoline (500–1,200 mg/day) allowed for lower dosages oflevodopa to be used with stable or improved therapeutic efficacy andreduced the side effects in some patients. However, data are limited.
Co-administration with Centrophenoxine
Must not be administered in conjunction with medications containingcentrophenoxine.
There are no adequate and well-controlled studies of citicoline duringpregnancy and lactation. Citicolineshould be used duringpregnancy only if the potential benefitjustifies the potential risk to thefoetus.
Caution should be exercised during breastfeeding because it is notknown whether citicoline is excreted in breast milk.
No dosage adjustment is required in this patient population and theusually recommended adult dose can be administered.
Citicoline is a safe and effective nutraceutical, and toxicological testshave shown no serious side effects even after prolonged treatment. Themost commonly seen undesirable effects on the administration ofciticoline are anxiety, leg oedema, agitation, coughing, diarrhoea,dizziness, ECG abnormality, fever, auricular fibrillation, headache,haematuria, hypertension, hypokalaemia, hypotension, urinary tractinfection, insomnia, joint pain, nausea, vomiting, pain(back/chest/shoulders), rash and restlessness.Citicoline may cause hypotension and,if necessary, the hypotensiveeffect can be treated with corticosteroids or sympathomimetics.In a short-term, placebo-controlled, crossover study, 12 healthy adultstook citicoline at daily doses of 600 and 1,000 mg or placebo forconsecutive 5-day periods. Transient headaches occurred in 4 subjectson the 600mg dose, 5 on the 1,000mg dose, and 1 on placebo. No changes or abnormalities were observed in haematology, clinicalbiochemistry or neurological tests.A large drug surveillance study analysed the results of citicolinetreatment in 2,817 patients aged 60 to 80 years, suffering from senilityand cerebral vascular insufficiency. A total of 151 incidents of sideeffects were recorded, representing 5% of the patient sample. The mostcommon adverse effects were transient in nature and included stomachpain and diarrhoea in 102 cases. Vascular symptoms of hypotension,tachycardia or bradycardia occurred in 16 cases.
There are no known cases of overdose in humans available forciticoline.
Storage and Handling Instructions
Store in a cool and dry place. Protect from light and moisture.
CITIXA 500: Strip of 10 tablets