Citicoline for

traumatic
brain injury
a systematic review and meta-
analysis

Journal review
Citicolin: farmakodinamik,
farmakokinetik

– Citicoline (cytidine-5′-diphosphocholine,CDP-choline) merupakan senyawa yang

identik dengan precursor phospholipid phosphatidylcholine. Yang berperan
dalam aktivitas ATPase mitokondria dan Na+K+ ATPase membran, menghambat
aktivasi fosfolipase A dan mempercepat reabsorpsi edema serebral.
Mekanisme kerja citicoline
– citicoline mencegah kerja enzim fosfolipase ( berperan dalam pemecahan fosfolipid dan
pembentukan asam archidonat serta pembentukan radikal bebas) sehingga menjaga keutuhan
fosfolipid dan meningkatkan pembentukan fosfotidilkolin sebagai komponen dari sel membrane.
Citicoline berfungsi menignktakan sintesis fosfotidilkolin pada sel iskemik serta menekan aktivitas
fosfolipase A2 yang meningkat saat terjadinya iskemik. Penigkatan aktivitas fosfolipase A2 dipicu
oleh lepasnya glutamate yang menstimulasi reseptor NMDA di post sinaptik. Mengakibatkan
peningkatan intraseluler Ca++.
– selanjutnya citicoline dalam proses metabolism nya akan membentuk kolin. Kolin in akan diubah
menjadi glutation. Glutation adalah salah satu antioksiden endogen primer dalam tubuh yang
berperan sebagai system pertahanan sel terhadap radikal bebas (pada kondisi iskemik terjadi
metabolism asam arakidonat yang menstimulasi pembentukan radikal bebas dan menekan aktivitas
antioksidan endogen.
– Citicoline mengahsilkan kardiolipin dan sfingomielin yang merupakan sumber dasar fosfotidilkolin
dan menstimulasi sintesis glutation.dan menjamin keseimbangan aktivitas NaK-ATPase sel.
– Pemberian sitikolin meminimalkan pemecahan fosfolipid sehingga menekan pemecahan asam
arachidonat.yang juga berarti mecegah proses inflamasi.
– Citicoline memiliki potensi mengurangi kerusakan otak akut dan meningkatkan pemulihan
fungsional. Fosfatidilkolin dalam citicoline dapat meregenerasi fosfolipid mebran yang terdegradasi
selama iskemia otak oleh asam lemak dan radikal bebas.
Waktu paruh dan efek samping

– Pharmacokinetics

– Absorption

– 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.

– Distribution

– 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.

– Metabolism

– 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).

– Elimination

– 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).

–
Undesirable Effects

– 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
Traumatic brain injury

– Clasifikasi traumatic brain injury pada jurnal ini berdasarkan GCS

– Cedera kepala ringan (13-15)
– Cedera kepala sedang( 9-12)
– Cedera kepala Berat (3-8)
Glasgow outcome scale
Judul jurnal
Introduction

– Traumatic brain injury is the leading cause of mortality and morbidity.

– Mostly affects young people. It has an incidence ratio of 558 new cases per 100,000 people
each year. More than 50.000 mortalities, cause 33 new disabilities per 100.000 people in a
year. Cost more than $48 billion a year.
– Survivors of TBI are often left with significant cognitive, behavioural and communicative
disabilities.
– Adenosine tri-phosphate (ATP) is responsible for cell membrane Sodium-Potassium (NA-K)
ATPase pump’s function
– TBI related to cell membrane un integrity and accumulation of extracellular water lead to the
brain edema and formation of lipid peroxidase.
– Cholinergic agents (citicoline) have effects on cell-Oxygenation cycles and formation of ATP,
(indirectly rebuild cell wall integrity) reducing further secondary injuries.
Methods

– Study design: systematic review and – Patients of any age,any severity

meta-analysis of RCTs (mild,moderate, severe) of focal or
– Search strategy and inclusion:
– Search strategy was not restricted by
date, race, gender and publication
status; date limitation to reference
data base was implemented after
2000
– Cochrane Central, Pubmed, Scopus,
Thomson reuters web of science,
SID.ir, IRAN Medex and
clinicaltrials.gov
diffuse, acute or chronic TBI
– Exclude: animals study or in-vivo trials
– Intervention: any form and dosage of
citicoline use
– Outcomes:
– Favorably outcome of intervention (good
recovery and mild disability based on GOS )
– Mortality and vegetative state (based on
GOS)
– Probable side-effects of citicoline
Search strategies
Cont.. 1756 of records
identified through data
3 of additional records
identified through other
base searching sources

1291 of records after

duplicates removed by zotero

101 of records
1190 of records excluded
screened

5 full text
93 of full-text articles assessed for articles
eligibility excluded
with reason:
1 review
article in
10 of 93 French
articles language, 2
were for review
citicoline article on
topic pre-clinical
studies, 2
protocols for
studies
5 of studies included in
qualitative synthesis

4 of studies included in quantitative synthesis

(meta-analysis)
Assessment of potential biases in
studies
– Two authors assessed RCTs using the chochrane risk of bias tool.

Data extraction and data

Sources
– One author extracted data from the included studies into extraction table including sample size, patients condition (acute/chronic TBI), outcome
measures (favourable, mortality and side effect), citicolinre dosage and route of use.
– Other authors checked accuracy and completeness of the extracted data
analysis

– The outcome were analysed in two main group for acute TBI management
– Mortality and vegetative state (assessed in a single group) and good recovery
and mild disability (assessed in single group as favourable outcome) with GOS
after 3-6 months follow up as primary outcomes
– Citicoline adverse effects was analysed as secondary outcome.
– Chronic TBI management ,outcomes were analysed for improvement in
neuropsychological state.
– P <0.05 statistically significant in this review, effect size pooled in this meta-
analysis included risk ratio (RR) and standardized means difference (SMD) along
with their confidence interval (CI)= 95%.
Result