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Revista de NeurologíaApril 2011. Volume 52, Supplement 2

Citicoline: pharmacological and clinical review, 2010 update

Julio J. Secades

Introduction S1

Pharmacological actions S2

Traumatic lesions and experimental cerebral oedema S2

Cerebral hypoxia and ischaemia S5

Synaptic transmission and neurotransmitter levels S13

Learning performance,

memory and brain ageing S17

Experimental withdrawal syndrome

and intoxications S19

Toxicity S20

Acute toxicity S20

Subacute toxicity S20

Chronic toxicity S20

Teratogenicity S20

Pharmacokinetics S21

Plasma level curves. Bioavailability S21

Tissue difussion and distribution. Transport and metabolism S21

Elimination route and kinetics S23

Clinical experience S23

Head injury and sequelae S23

Acute cerebrovascular disease and sequelae S28

Cognitive disorders S37

Other clinical experiences S43

Safety S45

Conclusions S47

References S48



S1www.neurologia.com Rev Neurol 2011; 52 (Suppl 2): S1-S62

rEVIEw

Introduction

Phospholipids are essential constituents o cells,specically cell membranes, and have a high turn-

over rate, which necessitates the continuous syn-thesis o these compounds to ensure the adequateunction o cell membranes and, thereore, cells[1-3].

Te chemical structure o a phospholipid showsesterication o a polyalcohol (glycerol or sphingo-sine) with two long-chain atty acids and a mole-cule o phosphoric acid that is esteried with ni-trogenated bases (choline, ethanolamine), aminoacids (serine) or inositol [3,4]. Te main phospholi-pids in humans are phosphatidylcholine, phos-phatidylethanolamine, phosphatidylinositol, andsphingomyelin [4]. Te main unction o phosphol-

ipids is to serve as components o cell membranestructures; these compounds are indispensable inullling membrane unctions, particularly themaintenance o homeostasis and cell compartmen-talisation, enzymatic activities associated with mem-brane systems and coupling between receptors andintracellular signals [1]. Additional specic unc-tions o neuronal membranes include nerve im-pulse conduction and neurotransmission [1,5].

Tere are various conditions in which the lossor decreased synthesis o a phospholipid occurs,leading to impairments in cell unctions that may

have pathophysiological impacts [1,6]. In the cen-tral nervous system, structural phospholipids o the neuronal membrane are essential or adequatebrain maturation [7-9], including the maturation

o astroglial cells [10]. Impaired cell membranesand phospholipid metabolism have been implicat-ed in the pathophysiology o cerebral oedemaand traumatic brain injury (BI) [11-20], cerebralhypoxia [21,22] and cerebral ischaemia [23-26].Moreover, there are specic changes in neuronalmembranes and the metabolism o structuralphospholipids associated with brain ageing [37-39]that contribute to neuroplasticity mechanisms[53] in certain neurodegenerative diseases, such ascognitive impairment, vascular dementia, and se-nile dementia o the Alzheimer type [32,40-52],and in other conditions where changes in neuro-

transmission [54,55,57] and excitotoxic aggression[58,59] are involved. Changes in phospholipid me-tabolism, particularly changes in phosphatidyl-choline metabolism, have been implicated asmechanisms that trigger the apoptotic cascade ina number o conditions [56-64]. Because o thesepathophysiological conditions, there is a need todevelop drugs that accelerate and/or increase thesynthesis o membrane structural phospholipidsin such situations, which would have protective,restorative and reparative eects on the nervoussystem [65-70].

Citicoline: pharmacological and clinical review,

2010 update

Julio J. Secades

Summary. This review is based on the previous one published in 2006 –Secades JJ, Lorenzo JL. Citicoline: pharmacological

and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56–, incorporating the new

reerences until now, having all the inormation available to acilitate the access to the inormación in one document. This

review is ocused on the main indications o the drug, as acute stroke and its sequelae, including the cognitive impairment,

and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both

indications.

Key words. Alcoholism. Alzheimer disease. Amblyopia. Apoptosis. CDP-choline. Cerebral edema. Cerebral ischemia. Citicoline.

Cognitive disorder. Drug addiction. Glaucoma. Head injury. Memory. Neuronal membrane. Neuroplasticity. Neuro protection.

Neurorepair. Neurotransmission. Parkinson disease. Phosphatidylcholine. Phospholipase. Senile dementia. Stroke. Structural

phospholipids. Traumatic brain injury.

Medical Department. GrupoFerrer S.A. Barcelona, Spain

Coesponding autho:Dr. Julio J. Secades. MedicalDepartament. Grupo Ferrer, S.A.Avda. Diagonal, 549. E-08029

Barcelona.

E-mail:[email protected]

Accepted: 21.12.10.

Ho to cite this aticle:Secades JJ. Citicoline:pharmacological and clinicalreview, 2010 update. Rev Neurol2011; 52 (Suppl 2): S1-62.

© 2011 revista de Neuología

Versión española disponible

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J.J. Secades

Cytidine diphosphocholine (CDP-choline orciticoline) is a mononucleotide consisting o ribose,cytosine, pyrophosphate, and choline whose chem-

ical structure (Figure 1) corresponds to 2-oxy-4-aminopyrimidine [71]. CDP-choline is an essentialintermediate in the synthesis o structural phos-pholipids o cell membranes [4,72-85], and the or-mation o this compound rom phosphorylcholineis the rate-limiting step o this biosynthetic path-way [75,86-95]. As shown in Figure 2, CDP-cholineis also related to acetylcholine metabolism. Tus,citicoline administration serves as an exogenouscholine source or acetylcholine synthesis, as willbe discussed later.

Pharmacological actions

Traumatic lesions andexperimental cerebral oedema

Horrocks et al [96] have shown that citicoline andCDP-ethanolamine prevent the degradation o choline and ethanolamine phospholipids duringdecapitation ischaemia in rats and induce a partialreversion o ree atty acid release during reperu-sion ater experimental global ischaemia in gerbils.Citicoline and CDP-ethanolamine, when adminis-tered together, have a synergistic eect and stimu-

late the resynthesis o choline, ethanolamine, andinositol phospholipids, markedly decreasing reearachidonic acid levels.

In an experimental rat model o acute inducedischaemia, LePoncin-Latte et al [97] assessed theintegrity o the blood-brain barrier (BBB) with la-beled iodinated albumin and assessed brain me-tabolism with histoenzymological studies . In thisexperimental model, citicoline administration re-sulted in a reduction in vasogenic cerebral oedemaand a restoration o BBB integrity. LePoncin-Latteet al [97] ound that the size o induced inarctswas smaller ater citicoline treatment, and this

compound decreased the activity o lactate dehy-drogenase, succinyl dehydrogenase, monoamineoxidase, and acid phosphatase, emphasising itsprotective role through direct activity at the levelo the cell membrane.

Mykita et al [98] ound that the addition o citi-coline ollowing a hypocapnic lesion in neuronalcultures resulted in neuron protection. Hypocap-nia increases the incorporation o labelled cholineinto phospholipids, whereas this process is slowedin the presence o citicoline. Tese authors con-cluded that citicoline is able to protect neurons un-

Figure 1. Chemical structure o CDP-choline (citicoline).

NH2

N

O

OH

OHO

OO O

O

PP

OCH

3

N+

CH3

CH3

OH

O

N

–

Figure 2. Relationship between citicoline and choline metabolism, cerebral phospholipids and acetylcho-line.

Phosphatidyl ethanolamine CITICOLINE

Diglyceride

Fatty acids

CTP

Phosphorylcholine

Choline

ACh

Acetate

AcetilCoA

Base exchange

reaction with serine

or ethanolamine

GlucoseCitrate

Choline

Choline in circulation

(lipid-bound and free)

Serine

Betaine

Glycerophosphocholine

Phosphatidylcholine

Glycerol phosphate

S-adenosyl methionine





der conditions o alkalosis and may promote cellprolieration.

In an electrophysiological study in rabbits, Yas-

uhara et al [99,100] showed that citicoline de-creased the threshold or the arousal reaction andthe threshold or muscle discharge, and they con-cluded that citicoline is a valuable drug or thetreatment o brain lesions because o its eects onconsciousness and on the motor activity o the py-ramidal system and its aerent pathways.

Martí-Viaño et al [101] compared the eects o pyriglutine, piracetam, centrophenoxine, and citi-coline in a study on the antagonism o barbituratecoma in mice. No dierences were seen in animalstreated with pyriglutine, piracetam or centrophe-noxine compared to the control group, whereas

with citicoline, coma duration and depth, as well asrespiratory depression, were decreased comparedto all other groups. Te arousal eects o citicolinewere ound to be due to increased cerebral bloodow (CBF), improved O2 cerebral uptake and utili-sation o energy metabolism, and enhanced mito-chondrial breathing.

In an experimental model o head injury inmonkeys, Ogashiwa et al [102] established a signi-cant dose-eect relationship between citicolinedose and coma duration, which started to be sig-nicant at doses o 60 mg/kg ( p < 0.05). Whilestudying the eects o several activators o brain

metabolism, Watanabe et al [103] ound that citi-coline increased glucose incorporation and metab-olism and decreased lactate accumulation in thebrain and induced a slight increase in CBF.

In a study on nerve tissue responses to a contu-sion lesion, Alberghina et al [11] showed that amoderate increase in the activity o cholinephos-photranserase occurred and that the increase wasassociated with a greater increase in the activity o phospholipases A2 and several lysosomal hydrolas-es. Tey also ound an increased number and sizeo lysosomes during neuronal regeneration. Arrig-oni et al [104] showed that citicoline completely in-

hibits the activation o phospholipase A2 withoutaltering cholinephosphotranserase activity. How-ever, Freysz et al [105] showed that, in addition todecreasing the activity o phospholipases A1 andA2, citicoline decreases ree atty acid release un-der hypoxic conditions, adding a protective eectto its activating capacity o phospholipid recon-struction. Massarell i et al [106] showed modulationo the activity o the phospholipases A1, and agreedwith Alberghina and Giurida [11], Arrigoni et al[104], Freysz et al [105] in their conclusions. Kita-zaki et al [107] also showed an inhibitory eect o

citicoline on membrane-associated phospholipaseA2 in the rat brain cortex. Based on these charac-teristics, citicoline is considered to be a non-speci-

ic inhibitor o phospholipase A2 at the intracellularlevel [108].Algate et al [109] tested the eects o citicoline

in an experimental model o epidural compressionin anaesthetised cats. Tey noted that animalstreated with citicoline had a greater resistance tothe eects o mechanical brain compression com-pared to animals in the control group. Tey alsoound that respiratory and cardiovascular changeswere less intense in treated animals and concludedthat citicoline provides signicant protectionagainst the lethality o epidural compression. Teseresults agreed with those obtained by Hayaishi

[110] and Kondo [111], who showed an improve-ment in EEG tracing and survival quality ollowingthe administration o citicoline to cats undergoingexperimental brain compression.

suchida et al [112] administered 3H-citicolineby intraperitoneal injection to rats subjected tocerebral cryogenic lesions by dry ice application onthe scalp and conrmed the presence o labelleddrug in the brain parenchyma, particularly in thewhite matter and most commonly in damaged ar-eas o the parenchyma in general.

Boismare [12,113] conducted research on an ex-perimental model o craniocervical trauma with-

out a direct blow (‘whiplash’) to assess its eectson central catecholamine levels. Tese experimentsresulted in increased dopamine levels and de-creased norepinephrine levels in the brain ollow-ing trauma. Tis type o lesion causes posturaldysregulation o the brain supply (CBF and nutri-ents) and behavioural and learning disorders thatare related to the accelerated degradation o cere-bral norepinephrine. In animals treated with citi-coline, trauma did not change the levels o theseamines. Te author stressed the protective role o citicoline due to its stabilising eect on brain cate-cholamine levels.

Clendenon et al [114] showed that the decreasein Mg++-dependent APase activity in mitochon-drial and synaptosomal membranes that occurs intraumatic lesions is prevented by citicoline admin-istration.

In a series o studies on a model o cryogeniccerebral oedema in rabbits, Cohadon et al [14,15,115] showed that treatment with 20 mg/kg/d citi-coline slowed the drop in enzymatic activity o mi-tochondrial APase, restored Na+/K+ APase ac-tivity, restored oligomycin-sensitive APase activ-ity and accelerated cerebral oedema reabsorption,




J.J. Secades

which reached normal values on day 4, whereassuch levels were not reached until day 10 withspontaneous reabsorption.

Tese authors stated that the benecial activity o citicoline in cerebral oedema occurred throughtwo mechanisms: by restoring the insertion o membrane enzymes and enhancing their activity and by acting on oedema by reducing water imbi-bition o the brain parenchyma.

Lauente and Cervós-Navarro [116,117] con-ducted microgravimetric studies on experimentalcerebral oedema induced by ultraviolet radiationin cats to assess the eects o citicoline in this situ-ation. Te results suggested that citicoline de-creased the amount o oedema, enhanced uid rea-bsorption and accelerated uid drainage to the

ventricles, i.e., increased cerebral compliance. Teauthors concluded that CDPamines are helpul incontrolling tissue lesions related to increased reeatty acids and to restore cell energy metabolismby restarting the Na+/K+ pump.

Majem et al [118] assessed the EEG changes thatoccur in rats when cryogenic oedema is inducedand how such EEG changes were modied by citi-coline administration. Tese authors noted a sig-nicant increase in the theta requency band dur-ing the awake state, with decreased delta and slow alpha bands and less interindividual scatter o theoverall requency bands, which resulted in in-

creased electrogenic cerebral stability. Tey con-cluded that citicoline protected brain activity romthe eects o cryogenic cerebral oedema.

In an experimental model o cryogenic cerebraloedema, Roda [119] measured extravasation o Evans blue through the BBB and uorescein uptakeby astrocytes and neurons and ound that citico-line administration signicantly reduced bothprocesses compared to control animals, support-ing the theory that citicoline has a direct eect ontransmembrane transport o sodium, potassium,water and proteins at both the BBB endothelial celllevel and the astrocyte and neuron level. Although

the exact mechanism o this action is not com-pletely understood, its eect appears to occur attwo levels: on the interace separating capillariesrom the neuroglia and on cell membranes.

Dixon et al [120] analysed the eects o exoge-nous administration o citicoline on motor de-cits, spatial memory capacity and acetylcholinelevels in the dorsal hippocampus and neocortex ina rat model o traumatic brain lesions induced by acontrolled lateral impact. Citicoline was adminis-tered intraperitoneally at a dose o 100 mg/kg or18 days rom the rst day ollowing traumatic le-

sion induction. Another group o animals wastreated with saline solution. Motor assessmentswere perormed using a balance test or which the

animals had previously been trained and cognitiveassessments were made with a variant o the Mor-ris maze test, which is sensitive to cholinergicunction. Microdialysis methods were also used toanalyse the eects upon acetylcholine release. Inthe motor unction study, citicoline-treated ani-mals showed a signicantly longer balance periodthe rst day ater lesion induction compared toanimals receiving saline (39.66 ± 3.2 seconds vs.30.26 ± 2.9 seconds; p < 0.01). In addition, animalstreated with citicoline had signicantly ewer cog-nitive decits. In microdialysis studies, ater a sin-gle intraperitoneal administration o citicoline, a

rapid increase in acetylcholine production in boththe dorsal hippocampus ( p < 0.014) and neocortex( p < 0.036), which was maintained or up to 3hours, was seen compared to baseline, whereas nochanges were noted in the animals receiving sa-line. Te authors concluded that post-traumaticdecits in spatial memory unction are at leastpartly due to deciency changes in cholinergictransmission that are attenuated with citicolineadministration.

Plataras et al [121] analysed the eects o dier-ent citicoline concentrations (0.1-1 mM) on the ac-tivities o acetylcholinesterase, Na+/K+-APase and

Mg++

-APase in total brain homogenates rom ratsand extracts o non-membrane-bound pure en-zymes. Following 1-3 h o preincubation with citi-coline, peak stimulations o 20-25% ( p < 0.001) and50-55% ( p < 0.001) were seen or acetylcholineste-rase and Na+/K+-APase, respectively, whereas nosignicant eect was seen or Mg++-APase. Teauthors concluded that citicoline may stimulatecerebral acetylcholinesterase and Na+/K+-APaseindependently rom acetylcholine and norepine-phrine, which could partly account or the clinicaleects o the drug.

Baskaya et al [122] examined the eects o citi-

coline on cerebral oedema and BBB rupture in a ratmodel o traumatic brain injury. Animals receivedciticoline (50, 100 or 400 mg/kg) or saline twice in-traperitoneally ollowing traumatic brain lesion in-duction. Induction o a traumatic lesion caused anincrease in the water content percentage and Evansblue extravasation (a marker o BBB rupture) in thedamaged cortex and ipsilateral hippocampus. At50 mg/kg, citicoline was not eective, whereas at100 mg/kg, a reduction was seen in Evans blue ex-travasation in both regions, although this doseonly decreased cerebral oedema in the damaged





cortex. A citicoline dose o 400 mg/kg signicantly reduced cerebral oedema and BBB rupture in bothregions. Te authors concluded that these results

suggest that citicoline is an eective neuroprotec-tive agent on secondary lesions occurring in asso-ciation with traumatic cerebral injury.

Using an experimental model o controlled lat-eral impact in rats, Dempsey and Rao [123] showedthat intraperitoneal administration o 200-400mg/kg citicoline ollowing BI induction preventsneuronal damage in the hippocampus associatedwith a traumatic lesion, decreases cortical contu-sion volume and improves neurological recovery.

A synergistic eect has been demonstrated be-tween propool and citicoline in an experimentalmodel o BI in rats [124]. Administration o the

two drugs together resulted in a greater reductionin lipidic peroxidation.In a study on the eects o citicoline on trau-

matic spinal cord lesions, it was shown that intra-peritoneal (i.p.) administration o 300 mg/kg citi-coline 5 minutes ater lesion induction signicantly reduced lipid peroxidation and improved motorunction in treated animals [125]. Citicoline ad-ministration had the same efcacy as methylpred-nisolone in behavioural and neuroanatomical re-covery [126]. Te administration o repeated doseso citicoline prevents tissue damage associatedwith spinal cord shock in the acute phase [127], and

the combination o ischaemic postconditioningwith citicoline coners protection in a model o is-chaemic spinal cord lesion [128] through inhibitiono the caspase pathway and an increase in the lev-els o antiapoptotic proteins.

Benecial eects o citicoline have also been ob-served in experimental models o partial opticnerve crush in rats [129], and some data suggestthat citicoline promotes nerve regeneration and re-duces postoperative scarring ater peripheral nervesurgery [130].

Because o its biochemical, pharmacologicaland pharmacokinetic characteristics, citicoline is a

potentially useul drug or the treatment o trau-matic cerebral injuries [131].

Cerebral hypoxia and ischaemia

In vitro studies using nerve tissues have shown thathypoxia induces a time-dependent decrease in thesynthesis o structural phospholipids (i.e., the lon-ger the hypoxia, the stronger the impact on neu-ronal phospholipid metabolism) [132]. Moreover,decreased incorporation o marked precursors intophospholipids o neuronal subcellular ractions in

animals subjected to experimental hypoxia hasbeen shown [21]. When cerebral ischaemia is in-duced experimentally, glycerophospholipids in cell

membranes are broken down by the actions o di-erent phospholipases, producing ree atty acidsand arachidonic acid derivatives. With prolongedischaemia, induced aggression upon membranesbecomes more intense, and membranes lose theirunctions. Na+ and Ca2+ accumulate inside the cell,triggering the ischaemic cascade and invariably leading to cell death [6,28,32,36,108,133].

Under ischaemic conditions with the attendantneuronal distress, endogenous CDP-choline syn-thesis is compromised because under such condi-tions, the cell lacks the high-energy phosphatecompounds necessary or this biosynthetic route

[32,134].Because o the importance o restoring neuronalactivity ollowing cerebral ischaemia [4] and basedon previous experimental data, many studies haveinvestigated the eects o citicoline in various ex-perimental models o cerebral ischaemia and/orhypoxia.

Boismare et al [135] reported that treatmentwith 20 mg/kg citicoline i.p. in acutely hypoxicrats induced a decrease in vegetative responses,protection rom conditioned avoidance responsesand stabilisation o brain dopamine and norepine-phrine levels. Tis same group [136] ound in-

creases in blood pressure, heart rate, cardiac out-put and regional blood ows in dogs subjected tonormobaric hypoxia, whereas no changes were ob-served in total peripheral resistance. Administra-tion o citicoline abolished the haemodynamic e-ects induced by acute hypoxia, suggesting thatthis action was correlated with a dopaminergicagonistic eect o the drug. In cats subjected toshort periods o cerebral ischaemia, researchers[137] noted that a depression occurred in corticalevoked potentials. Tis depression was attenuatedby prior intracarotid administration o citicoline.Tese authors believed that the protective eects

o citicoline are metabolic/biochemical ratherthan haemodynamic in origin and do not rule outa direct action o the drug on central dopaminer-gic structures.

Alberghina et al [138] investigated the eects o citicoline on the incorporation o labelled precur-sors into cerebral phospholipids o guinea pigs sub-

jected to hypoxia. A group o animals were given100 mg/kg citicoline i.p. en minutes later, the la-belled precursors [2-3H]glycerol and [1-14C]palmi-tate were administered intraventricularly. Anothergroup o animals received precursors only and act-




J.J. Secades

ed as the control group. Compared to the controlgroup, the citicoline-treated animals showed an in-crease in specic radioactivity o total lipids and

phospholipids in puried mitochondria obtainedrom the brain hemispheres, cerebellums and brainstems. In a subsequent study, this same group [139]showed that citicoline was able to counteract theeects o hypoxia upon incorporation o labelledprecursors into RNA and proteins, particularly atthe nuclear and mitochondrial levels.

Various experimental studies have shown thatciticoline prevents atty acid release during cere-bral ischaemia and hypoxia and increases the syn-thesis o structural phospholipids [140-159]. Usingan experimental model o global cerebral ischae-mia by decapitation, Horrocks et al [140,143,145]

showed that the administration o a mixture o citicoline and CDP-ethanolamine decreased reeatty acid release and increased synthesis o thecorresponding glycerophospholipids, suggesting aninvolvement o choline and ethanolamine phos-photranserases.

Using an experimental global ischaemia modelconsisting o bilateral carotid ligation in gerbils,rovarelli et al [141,142] ound that intraperitonealciticoline administration partially prevents thechanges in lipid metabolism that are induced by cerebral ischaemia by correcting the increase inree atty acid levels, the changes in the levels o

neutral lipids such as diacylglycerol and the de-crease in phosphatidylcholine levels. Suno and Na-gaoka [144] studied the eects o citicoline admin-istration in rats on ree atty acid release caused by total cerebral ischaemia lasting 5 minutes. Tetested drug reduced the increase in ree atty acidlevels and that the intensity o this eect dependedon the dose used. Te arachidonic acid levels inbrains rom control group animals subjected to is-chaemia were 174 ± 22 mmol/g, compared to 119 ±8 mmol/g and 61 ± 8 mmol/g in animals receiving200 and 1,000 mg/kg i.p. o citicoline, respectively.Te authors concluded that citicoline administra-

tion prevents ischaemic cerebral damage. Agut etal [146] treated male rats weighing 190-200 g with4 mg/kg o 14C-methyl-Citicoline (50 μmCi) orally.At 24 hours, brain radioactivity levels and the pres-ence o labelled phospholipids were assessed underconditions o normoxia, hypoxia and hypoxia ol-lowing an additional administration o 100 mg/kgo unlabeled citicoline. Tey ound marked incor-poration o radioactivity into the brains o nor-moxic and hypoxic animals that was mostly asso-ciated with phosphatidylcholine. In addition, theadministration o unlabeled citicoline reduced

the elevation in cerebral lysophosphatidylcholinelevels caused by hypoxia. Rao et al [150] showedthat citicoline signicantly decreased BBB dys-

unction ater ischaemia with a 6-hour reperusionin gerbils and, in the same model o transient cere-bral ischaemia, considerably reduced the increasein arachidonic acid and leukotriene C4 synthesis 24hours ater ischaemia induction. Tey also showedthat the cerebral oedema volume was substantially lower at 3 days in animals treated with citicoline.Following 6 days o reperusion, ischaemia caused80 ± 8% neuronal death in the hippocampal CA1 layer level, and citicoline provided neuroprotectiono 65 ± 6%. In a subsequent study, these authors[151] showed that citicoline is able to signicantly restore phosphatidylcholine, sphingomyelin and

cardiolipin levels ater the induction o transientcerebral ischaemia in gerbils. For these authors,the main action mechanism o citicoline would bethe inhibition o stimulation o phospholipase A2 activity in ischaemic conditions, though they alsostress its eects on glutathione synthesis and glu-tathione reductase activity. Tus, the drug may prevent membrane destruction, decrease ree radi-cal generation and preserve the natural deences o the nervous system against oxidative damage [152-156]. More recently, this group showed that citi-coline enhances phosphatidylcholine synthesis,which is impaired under ischaemic conditions, at-

tenuating the loss o CP-phosphocholine cytidyl-transerase activity [157-158]. Tus, the drug prevents phospholipid degradation and its down-stream eects and promotes the regeneration o cerebral phosphatidylcholine, eects that result ina decreased volume o the cerebral ischaemic le-sion [159].

ornos et al [160] conducted a pharmacologicalstudy on the protective eects o citicoline againsttoxicity in an experimental model o hypoxia in-duced by potassium cyanide. Tey ound that treat-ment with oral citicoline or 4 days beore hypoxiainduction had a protective eect, as demonstrated

by a longer survival time in treated animals. Tesebenets o citicoline may also be ascribed to theactivation o cerebral energy metabolism [161] andthe increased activity o mitochondrial cytochromeoxidase [162] induced by this drug.

Narumi and Nagaoka [163] investigated the e-ects o citicoline administration on the metabo-lism o cerebral monoamines in two rat models o global cerebral ischaemia. In the rst model, they perormed cerebral ischaemia using bilateral ca-rotid occlusion or 30 minutes in spontaneously hypertensive rats and noted that a signicant de





crease in norepinephrine levels occurred in thebrain cortex. In this model, the administration o 1,000 mg/kg o citicoline decreased the dopaminelevels in the striatum and diencephalon, normalis-ing the decrease in the dopamine metabolites/dopamine ratio induced by ischaemia. In the sec-ond model, bilateral carotid occlusion was per-ormed 24 hours ater electrocauterisation o both

vertebral arteries in Wistar rats. In this model,norepinephrine, dopamine and serotonin levelsdecreased 70-80% in the brain cortex. Similar de-creases were seen or norepinephrine and seroton-

in levels in the hippocampus, dopamine levels inthe nucleus accumbens, dopamine and serotoninlevels in the striatum and norepinephrine levelsin the diencephalon and brain stem. Te adminis-tration o 500 mg/kg citicoline signicantly en-hanced the ischaemia-induced decrease in striataldopamine levels. Tereore, these authors suggest-ed that citicoline restores dopamine turnover inthe striatum o rats subjected to experimental cer-ebral ischaemia.

Nagai and Nagaoka [164] reported the results o a study investigating the eects o citicoline on

glucose uptake in dierent brain areas rom ratswith global cerebral ischaemia induced by the oc-clusion o both carotid arteries or 30 minutes aterelectrocauterisation o both vertebral arteries. Glu-cose uptake by the brain was measured our daysater recirculation. Without citicoline administra-tion, global cerebral uptake was reduced to 81% o the normal value. Ater the administration o 250mg/kg i.p. citicoline twice daily or 3 days ater thestart o recirculation, the postischaemic reductionin glucose uptake was signicantly lower in thebrain cortex. Tis nding suggests that citicoline

improves energy metabolism in the brain under is-chaemic conditions.Hurtado et al [165] showed that the administra-

tion o citicoline signicantly increased brain APlevels in both healthy and ischaemic animals. Tisincrease in AP was correlated with a positive e-ect on glutamate transporters by restoring theirnormal activity and thereby decreasing both brainparenchymal and circulating glutamate levels. Tisincrease in AP was correlated with a decreasedcerebral inarct volume. Tese authors demon-strated that citicoline redistributes the glutamate

Figure 3. Eect o citicoline on arachidonic acid release in ischaemic rat brains. Citicoline (200 and 1,000 mg i.p.) was administered 10 min beoredecapitation. Five minutes later, ree atty acids were extracted. Arachidonic acid levels were determined by gas chromatography.a p <0.05; b p <0.001 vs. untreated ischaemia.

Ischemia +

1 g citicoline a

0 50 100 150 200

Arachidonic acid (mmol/g tissue)

Ischemia +

0.2 g citicoline a

Ischemia

Control




J.J. Secades

transporter EAA2 to lipid rat microdomainsand improves glutamate uptake, an eect that isalso ound ater experimental stroke when citico-

line is administered 4 h ater the ischaemic occlu-sion [166]. Another study [167] ound that chronictreatment with citicoline, initiated 24 h ater in-sult, increases neuronal plasticity within non-in-

jured and unctionally connected brain regionsand promotes unctional recovery. o assess unc-tional recovery, they perormed the staircasereaching test and elevated body swing test (EBS)to study sensorimotor integration and asymmet-rical motor unction, respectively. reatment withciticoline, initiated 24 h ater middle cerebral ar-tery occlusion (MCAO) and maintained or 28days, improved the unctional outcomes o the

staircase test (MCAO + CDP = 87.0 ± 6.6% pel letseaten vs. MCAO + SAL = 40.0 ± 4.5%; p < 0.05)and the EBS (MCAO + CDP = 70.0 ± 6.8% vs.MCAO + SAL = 88.0 ± 5.4%; contralateral swing

p < 0.05). In addition, to study potential neuronalsubstrates o this improved unction, we examinedthe dendritic morphology o layer V pyramidalcells in the undamaged motor cortex using a Gol-gi-Cox procedure. Te animals treated with citico-line showed increased dendritic complexity andspine density compared with the saline group.Zhao et al [168] also showed a positive eect o citi-coline on the spatial learning and memory o rats

ater ocal cerebral ischaemia.Kakihana et al [169] investigated the distribu-tion o labelled citicoline and its eects on acetyl-choline synthesis rom glucose in the brain cortexo rats subjected to 30 minutes o ischaemia ol-lowed by reperusion. reatment with citicolineimproved glucose metabolism and signicantly re-stored acetylcholine synthesis rom glucose. Teseauthors concluded that citicoline improves brainenergy metabolism in ischaemic conditions. Tey [170] subsequently evaluated the eects o citico-line on neurological sequelae and glucose metabo-lism in the brain in an experimental rat model o

transient cerebral ischaemia, showing that highdoses o citicoline improved the neurological stateo animals subjected to ischaemia, which was cor-related to improved brain energy metabolism anddrug incorporation in the raction o membranephospholipids. Tese results agree with those ob-tained in a preliminary study by Fukuda et al [171].

Nagaoka [172] studied the eects o citicolineon stroke onset and mortality in spontaneously hy-pertensive rats subjected to cerebral ischaemia.Occluding both common carotid arteries inducedischaemia. Citicoline (200-1,000 mg/kg i.p.) admin-

Figure 4. Eect o chronic treatment with CDP-choline on unctional recovery, as determined as senso-rimotor integration (a) and asymmetrical motor behaviour (b). CDP-choline (MCAO+CDP) or saline(MCAO+SAL) were administered 24 h ater pMCAO and or 28 days ollowing pMCAO. Sensorimotor inte-

gration and asymmetrical motor behaviour were studied by the staircase skilled reaching test and the el-evated body swing test (EBST), respectively. Data are means ± SEM, n = 16. a p < 0.05 vs. MCAO+SAL.

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istered beore ischaemia induction caused a dose-dependent delay in the onset o stroke and respira-tory arrest. Tese eects were also seen in animals

treated ater ischaemia induction. In addition, 500mg/kg i.p. citicoline improved the neurological sta-tus o rats undergoing brain ischaemia or 40 min-utes ollowed by reperusion. Tese results suggestthat citicoline plays a neuroprotective role againstcerebral ischaemia and reperusion.

Saligaut and Boismare [173] studied the eectso citicoline administered at a dose o 1,000 mg/kgper os (p.o.) in Wistar rats undergoing acute hypo-baric hypoxia (15 minutes at a simulated altitude o 7,180 meters) by assessing a behaviour-condition-ing test, striatal dopamine uptake and levels o dopamine and its metabolites in the striatum. In

the behaviour-conditioning test, citicoline protect-ed against hypobaric hypoxia in a dierent way and to a greater extent than apomorphine. Bio-chemical studies have shown a presynaptic eectthat induced changes in dopamine uptake and im-proved dopamine release, which are likely due tothe activation o tyrosine hydroxylase. Other teamsound that citicoline exerted similar eects on ty-rosine hydroxylase activity [174].

LePoncin-Latte et al [97] studied the eects o citicoline on various histological brain changes inan experimental model o multiocal cerebral is-chaemia in cats, in which introducing calibrated

microspheres into the internal carotid artery caused an ischaemic lesion. Calibrated micro-spheres produce cerebral microinarctions that arecharacterised by a central necrosis area surround-ed by a penumbra area and also cause oedema dueto rupture o the blood-brain barrier. Citicolineadministration decreased the number o lesionsand the amount o extravasated albumin consider-ably, which conrms these authors’ hypothesis thatciticoline exerts its neuroprotective eects againstischaemia by acting on cell membranes. Araki et al [175] also ound some neuroprotective eects o citicoline in complete cerebral ischaemia induced

by decapitation and potassium cyanide poisoningin mice.Aronowski et al [176] evaluated the eects o

chronic citicoline administration (500 mg/kg) onrecovery in spontaneously hypertensive rats un-dergoing occlusion o the middle cerebral artery or 30-120 minutes. Either drug or saline was ad-ministered intraperitoneally, starting 15 minutesater ischaemia induction and continuing or 14days. Morphological lesions and neurological dis-orders (motor and sensorimotor capacities) wereanalysed by measuring the maximum morphologi-

cal lesion volume, maximum neurological changeand ischaemia duration causing hal o the maxi-mum morphological lesion or maximum neuro-

logical change. Te maximum morphological le-sion volume was not aected by citicoline (101.6 ±11.4 mm3 or citicoline, 103.3 ± 13.6 mm3 or sa-line); however, citicoline signicantly increased theischaemia duration required to cause hal o themorphological lesion, which changed rom 38.3 ±5.9 to 60.5 ± 4.3 min ( p < 0.05). Similarly, citicolinedid not change the value o the maximum neuro-logical change (8.5 ± 0.7 or citicoline, 10.1 ± 4.0 orcontrol), but it did signicantly increase the ischae-mia duration required to cause hal o the maxi-mum neurological change rom 41.9 ± 4.6 to 72.9 ±24.5 min ( p < 0.05). According to these authors,

citicoline has greater efcacy in animals that expe-rience a submaximal lesion, which occurred with30-75 minutes o ischaemia in this model.

Schäbitz et al [177] evaluated the eects o long-term treatment with citicoline in a model o tran-sient ocal ischaemia (2 hours) in rats. en animalswere randomly assigned to each group: placebo(saline 0.3 ml/d/7 d), low dose (citicoline 100 mg/kg/d/7 d i.p.) and high dose (500 mg/Kg/d/7 d i.p.).reatment was started at the time o reperusion,ater the 2-hour ischaemia period had ended. Daily neurological assessments were made (modied ZeaLonga scale), and surviving animals were sacriced

on day 7, ater which cerebral oedema and inarct volume were calculated. No dierences were seenin the neurological assessments o animals at theend o the study, but a more avourable trend inthem was noted in the citicoline high-dose group.Te mean inarct volume (Figure 5) was 243.5 ±88.6 mm3 in the placebo group, 200.2 ± 19.9 mm3 in the low-dose group and 125.5 ± 45.2 mm3 in thehigh-dose group. Tese dierences were statisti-cally signicant ( p < 0.01). A dose-dependent de-crease in cerebral oedema volume was also ob-served, but the decrease did not reach statisticalsignicance.

In a series o studies, citicoline was shown tohave a synergistic eect with other drugs, includ-ing thrombolytic [178-181] and neuroprotectivedrugs [182-185], in the treatment o cerebral is-chaemia. Andersen et al [178] conducted an exper-imental study in a rat model o carotid embolismto evaluate the eects o dierent doses o citico-line, administered alone or combined with recom-binant tissue plasminogen activator (rPA), on in-arct size. Ninety Sprague-Dawley rats that weresubjected to embolism in the carotid territory wererandomised into 6 groups: (1) saline-treated ani-




J.J. Secades

mals, (2) citicoline 250 mg/kg, (3) citicoline 500mg/kg, (4) rPA 5 mg/kg, (5) rPA 5 mg/kg + citi-coline 250 mg/kg and (6) rPA5 mg/kg + citicoline500 mg/kg. reatment with rPA was given at asuboptimal dosage (5 mg/kg inused over 45 min-utes, starting treatment 45 minutes ater embolisa-tion). Citicoline was administered i.p. daily or 4days. Brains rom surviving animals were xed atour days, and the inarct volume, calculated as apercentage o the total volume o the aected hem-isphere, was measured using a microscope. Temean inarct volume values suggested that high-

dose citicoline and the combination o citicolinewith rPA decreased the sizes o ischaemic lesions(Figure 6). In the control group, the mean inarct

volume was 41.2% (5.9-87.0%). In groups treatedwith citicoline alone, the values were 30.4% (1.0-70.0%, n.s.) or group 2 and 22.2% (0.7-76.6%, p <0.05) or group 3. With rPA alone (group 4), themean volume was 24.5% (1.4-71.1%, n.s.), whereaswith combined treatment, the mean volumes were13.5% (0.2-47.8%, p = 0.002) or group 5 and 29.2%(0.11-72.1%, n.s.) or group 6. Tis study showedthat high-dose citicoline and a combination o citi-

coline at lower doses with rPA signicantly re-duced the sizes o brain inarcts. Díez-ejedor et al [179-180] reported similar results, stating that the

results o this association are improved when citi-coline is administered immediately ater rPA ad-ministration. Shuaib et al [181] investigated theneuroprotective eects o citicoline alone or com-bined with urokinase in a rat model o ocal cere-bral ischaemia induced by embolisation at the ori-gin o the middle cerebral artery. Both drugs wereadministered 2 hours ater ischaemia induction.Animals were killed at 72 hours. In saline-treatedanimals, the inarct volume was 33.1 ± 9.7%. Teciticoline-treated animals were divided into twogroups: one group was given a single dose o citico-line 300 mg/kg i.p., and the other group received a

daily dose o 300 mg/kg i.p. or 3 days. A signicantreduction in inarct volume was seen in bothgroups (20.9 ± 9.7% with a single dose, p = 0.01;18.9 ± 11.4% with multiple doses, p = 0.008). Teanimals treated with urokinase alone, at doses o 5,000 IU/kg, had a smaller inarct volume (19.5 ±12.5%, p = 0.01); however, the greatest volume re-duction was achieved in the group o animalstreated with the combination o citicoline andurokinase (13.6 ± 9.1%, p = 0.0002). Tese authorsconcluded that citicoline provides a signicantneuroprotective eect that may be enhanced by as-sociation with a thrombolytic. Synergistic eects

have also been shown between citicoline and MK-801 (dizocilpine) [182], basic broblast growth ac-tor (bFGF) [183], lamotrigine [184] and nimodipine[185,186] in models o cerebral ischaemia. It hasbeen demonstrated that citicoline with hypother-mia is more eective than either condition alone inameliorating cerebral damage ater transient ocalischaemia [187]. In addition, citicoline and the ad-ministration o mesenchymal stem cells show equal efcacy in neurological recovery, decreasingneuronal death and increasing neuronal repair in amodel o cerebral inarction in rats, but the com-bined treatment does not increase the benet [188].

Fresta et al conducted a series o experiments inmodels o transient cerebral ischaemia in rats us-ing liposomal citicoline. Tis study showed signi-cantly increased survival o animals treated withthis citicoline ormulation [189-191]; more recently,they showed that this same drug ormulation sig-nicantly reduces the maturation phenomenon(i.e., a delayed cerebral neurodegenerative lesionthat occurs ater an ischaemic event and results ina signicant improvement in brain unction) [192].Tese results agree with previously discussed re-sults [159] showing that the administration o li-

Figure 5. Eect o citicoline at a low dose (100 mg/kg) or high dose (500 mg/kg) on inarct volume. Thevalues represent the mean ± SD. The inarct volume was signicantly smaller ( p < 0.01) in the high-doseciticoline group than in the control group.

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posomal citicoline is more eective than non-lipo-somal citicoline.Citicoline also has a neuroprotective eect against

neurotoxic damage induced by kainic acid in reti-nal cells [193-196].

Hamdor et al [197] exposed 48 rats to a decreas-ing amount o oxygen or 103 days, i.e., they wereexposed to chronic hypoxia. Citicoline showed aprotective eect by increasing vigilance undermoderate hypoxic conditions (15% O2). In a subse-quent study, these authors [198] analysed the e-ects o citicoline in Wistar rats subjected to hy-poxia or 5 months. Behavioural changes induced

by hypoxia were attenuated in the group o animalstreated with citicoline. Interestingly, the therapeu-tic administration o citicoline was more eectivethan prophylactic administration. In addition, un-der extreme hypoxia conditions, citicoline showeda protective eect by lengthening survival times.Lee et al [199] demonstrated that citicoline pro-tects against cognitive impairment in a rat modelo chronic cerebral hypoperusion.

However, Masi et al [200] showed that citicolinehas certain antiplatelet aggregant eects, whichmay provide an additional benet or the treatment

o cerebral vascular disease. Pinardi et al [201] investigated the eects o citicoline inusion inSprague-Dawley rats on relaxation induced by ex-ogenous acetylcholine in the isolated external ca-rotid vascular bed, which has no cholinergic nervesupply, and the isolated internal carotid vascularbed, which has an abundant cholinergic nerve sup-ply. Changes in perusion pressure were measuredduring a dose-response curve to acetylcholine andollowing an inusion o 1 mg/min/30 min o citi-coline. Te authors noted that citicoline caused re-laxation in both vascular beds, which suggests thepresence o muscarinic receptors. In the internal

carotid vascular bed, citicoline inusion or 30minutes signicantly shited the dose-responsecurve to acetylcholine to the let, increasing relax-ation. However, this eect did not occur in the ex-ternal carotid bed. Te eect o citicoline wasmasked when it was jointly inused with hemicol-inium. According to these authors, these resultssuggest that citicoline acts by increasing cholinelevels at cholinergic endings, increasing acetylcho-line synthesis and/or release.

Clark et al [202] examined whether citicolinewas able to reduce ischaemic damage and improve

Figure 6. Eect o the association o citicoline (CIT) and rtPA on inarct size in a model o embolic stroke in rats. C250: citicoline 250 mg/kg; C500:citicoline 500 mg/kg; rtPA: rtPA, 5 mg/kg.

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J.J. Secades

unctional neurological results in an intracerebral

haemorrhage model in mice. Tey caused haemor-rhage in 68 Swiss albino mice by injecting colla-genase at the caudate nucleus. Animals randomly received saline or 500 mg/kg i.p. citicoline beorethe administration o collagenase and at 24 and 48hours. Mice were assessed using a 28-item neuro-logical scale and were sacriced at 54 weeks to as-sess haematoma volume, total damage and sur-rounding ischaemic damage. With regard to theneurological course, citicoline-treated animalshad a better score than placebo-treated animals(10.4 ± 2.0 vs. 12.1 ± 2.4; p < 0.01). No dierenceswere observed in haematoma volumes, but a sig-

nicant reduction in the volume o the surround-ing ischaemic damage was noted in animals treat-ed with citicoline (13.8 ± 5.8 mm3; 10.8 ± 4.3% o the hemisphere) compared to the placebo (17.0 ±7.1 mm3; 13.3 ± 5.1%) ( p < 0.05). According to theauthors, these results support a potential role o citicoline or the treatment o intracerebral haem-orrhage.

Apoptotic mechanisms have been shown to play a primary role in the pathophysiology o cerebralischaemic damage, both at the experimental level[203-207] and in humans [208,209]. We thereore

investigated [210] whether citicoline could inu-

ence apoptotic mechanisms ollowing ocal cere-bral ischaemia. A model o permanent distal oc-clusion o the middle cerebral artery was used inSprague-Dawley rats. Animals were randomisedinto 4 groups: B + A, citicoline 500 mg/kg i.p. 24and 1 hour beore occlusion and 23 hours ater oc-clusion; A, citicoline 500 mg/kg i.p. within 30 min-utes and 23 hours ollowing occlusion; C, salinesolution i.p.; D, sham-operated. Animals werekilled at 12 (7 animals per group) and 24 hours (7animals per group) ollowing occlusion. Immuno-histochemistry or procaspases 1, 2, 3, 6 and 8 wasperormed using goat polyclonal antibodies. Using

gel electrophoresis and western blotting, specicsubstrates or caspase action were tested using po-ly-ADP-ribose polymerase (PARP) antibodies. Is-chaemia induced the expression o all procaspasesand PARP in both the inarct and penumbra areas12 and 24 hours ollowing ischaemia. Citicoline re-duced the expression levels o all procaspases at 12and 24 hours ollowing ischaemia, except or pro-caspase 3 at 24 hours in group A and PARP expres-sion (Figure 7), and the results were more evidentin group B + A, suggesting a prophylactic role o citicoline. Citicoline has recently been shown to

Figure 7. Band densitometry analysis or PARP by western blotting in dierent groups o rats in the inarct zone and penumbra zone 12 and 24 hater ischaemia. a p < 0.05; b p < 0.025; c p < 0.0001.

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inhibit certain intracellular signals involved in ap-optotic processes [211] and to maintain these in-hibitory eects in dierent experimental models to

study apoptotic mechanisms [128,187,212-216].Fiedorowicz et al [217] ound that citicoline canattenuate brain damage in a rat model o birth as-phyxia.

Giralt et al demonstrated that meta-analysis provides an eective technique or aggregating datarom experimental stroke studies. With this tech-nique, they conrmed that citicoline reduces theinarct volume and improves outcomes [218],pointing to doses o 300-500 mg/kg as the optimaldoses to be translated into a candidate neuropro-tective drug or human stroke [219].

According to Drago et al [220], citicoline is a

drug o choice or the treatment o cerebrovasculardiseases, particularly in its chronic orm, becauseits clinical use is justied by the pharmacologicalactions that it exerts on the central nervous sys-tem. o summarise, citicoline (Figure 8) intererespositively with brain energy metabolism, stimu-lates central neurotransmission, activates cell re-pair mechanisms, decreases ischaemic lesion size,inhibits apoptosis associated with ischaemia andhas synergistic eects with thrombolytic and neu-roprotective drugs.

Tese characteristics provide citicoline with asuitable pharmacological prole or the treatment

o cerebral ischaemia [34,25,221,222]. In addition,a role has been proposed or citicoline in the treat-ment o complications o inectious diseases suchas cerebral malaria [223].

Synaptic transmission and neurotransmitter levels

As discussed previously, citicoline exerts some o its eects through its action on certain neurotrans-mitters. Tis section discusses these specic e-ects on neurotransmission. Most studies have o-cused on analysing the eects o citicoline on cen-tral dopaminergic transmission.

Martinet et al [224] assessed the eects o citico-line administration on norepinephrine, dopamineand serotonin levels in dierent regions o the ratbrain. For this study, conversion o 3H-tyrosine and3H-tryptophan, administered intravenously, into3H-norepinephrine, 3H-dopamine and 3H-seroton-in was measured. Te results obtained with salineadministration and those obtained ater citicolineadministration at dierent doses were compared.Te metabolism o each neurotransmitter wasstudied in the brain regions in which it has unc-tional activity. Tus, or catecholamines, citicoline

action was studied in the striate body, brain cortexand midbrain, whereas or serotonin, the same ar-eas were studies plus hypothalamus. Te synthesis

rates o dopamine, norepinephrine and serotoninwere expressed as conversion indices equal to theratio between the amount o labelled neurotrans-mitter per gram o brain (cpm/g) and the tyrosine-or tryptophan-specic radioactivity (cpm/mmol)in the brain. As shown in Figure 9, citicoline sig-nicantly increased the levels and the synthesisrate o dopamine in the striate body. Te eect ex-erted on tyrosine levels was very similar. Norepine-phrine levels were increased in the cortex butshowed no changes compared to the control in thebrain stem. With regard to the eects on seroton-in, the drug caused decreases in the levels and syn-

thesis rate o this neurotransmitter in the brainstem and hypothalamus, but no changes were seenin the cortex or striatum. According to these au-thors, increased dopamine synthesis could be at-tributed to a citicoline-related increase in tyrosinehydroxylase activity, the rate-limiting step indopamine synthesis. Tis activation o tyrosine hy-droxylase leads to an inhibition o dopamine re-uptake at the synapse, an activity that has beenshown in ex vivo studies [225,226]. In contrast, theincrease in dopamine synthesis does not appear tobe related to increased levels o tyrosine because in-creased levels completely saturate tyrosine hydrox-

ylase under physiological conditions. Te eects o citicoline on striatal dopamine synthesis are par-ticularly interesting because changes in dopaminesynthesis by extrapyramidal dopaminergic neuronsare the origins o Parkinson’s disease.

Saligaut et al [227] obtained results in agree-ment with previous results when studying dopaminereuptake in synaptosomes taken rom the striatebody o rats previously treated with citicoline. Fol-lowing long-term treatment with this drug, de-creased dopamine reuptake by synaptosomes wasseen, and the authors related this act to the in-crease in tyrosine hydroxylase activity, which in-

volves increased dopamine synthesis. Tey believethat a structural change in neuronal membranes,mainly at the phospholipid level, could be one o the actors responsible or the change in synapto-somal reuptake o dopamine induced by citicoline.Hypobaric hypoxia was also seen to antagonise theinhibitory eect o citicoline on dopamine re-uptake by synaptosomes. Tis antagonism may beexplained by the act that hypoxia decreases theactivity o tyrosine hydroxylase, an enzyme thatrequires oxygen, counteracting the enzyme activa-tion exerted by citicoline. Tis leads to decreased




J.J. Secades

dopamine synthesis and a subsequent increase indopamine reuptake. Tese authors studied citico-line action in experimental oxotremorine-inducedcholinergic syndrome in mice [228] and showedthat citicoline pretreatment does not potentiatethis syndrome but inhibits salivation induced by oxotremorine. Levodopa antagonises brain symp-toms such as the tremor-akinesia induced by ox-otremorine. However, this antagonism disappeared

in animals under long-term oral treatment withciticoline, conrming the action o citicoline ondopaminergic pathways. Te eects o citicolineappear to be mediated by the hypersensitivity o some dopaminergic receptors rather than by a di-rect stimulating eect on striatal dopaminergic re-ceptors. In another series o experiments, theseauthors examined the eects o citicoline on cate-cholamine metabolism in the striatum and hy-pothalamus rom rats subjected to acute hypobarichypoxia [229]. Teir results show that citicolinepartially counteracts the eects o hypoxia on the

release and metabolism o certain neurotransmit-ters. In another study, Saligaut et al analysed theeects o citicoline in rats with a unilateral nigros-triatal lesion induced by 6-hydroxydopamine [230].In damaged animals, amphetamine administrationinduced ipsiversive circling behaviour, whereassuch circling behaviour was contraversive ater ad-ministration o levodopa and apomorphine. Tiseect appears to be mediated by the development

o a supersensitivity o postsynaptic dopaminergicreceptors in the damaged side. Subchronic treat-ment with citicoline did not induce behavioural e-ects. Citicoline did not change the stimulatingeect o apomorphine but potentiated the eectso levodopa and amphetamine. Tese data show that the eects o citicoline are mediated by a pres-

ynaptic mechanism. Although the potentiation o levodopa may not be explained by the activation o tyrosine hydroxylase, this eect appears to be re-lated to the improved release o dopamine synthe-sised rom exogenous levodopa.

Figure 8. Ischaemic cascade. Darkest boxes show the processes where citicoline has demonstrated pharmacological eects.

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Cansev et al [231] ound that peripheral admin-istration o citicoline increases plasma adrenalineand noradrenaline concentrations.

Agut et al [232] indirectly studied the eects o citicoline on dopamine synthesis in the striatebody by measuring the local levels o dopaminemetabolites in animals in which a blockade o dopaminergic receptors was induced by haloperi-dol administration. Pretreatment with 100 mg/kg/d/5 d citicoline signicantly increased the levels o homovanillic acid (HVA) and 3,4-dihydroxypheny-lacetic acid (DOPAC) in the striatum o treatedanimals compared to a control group. Te increasein the levels o these metabolites was even strongerin a group o animals that also received apomor-phine. Te results obtained in this study suggest

that citicoline increases dopamine synthesis in thestriatum o rats in which the activation o suchsynthesis has been experimentally induced by ha-loperidol administration. Tis same investigatingteam subsequently studied whether citicolinealone, without provoking an increased dopaminedemand by dopaminergic receptors, caused in-creased synthesis o this neurotransmitter, whichresulted in increased striatal levels o its main me-tabolites, HVA and DOPAC [233].

Te action o citicoline on the dopaminergicsystem was also studied by investigating its phar-macological actions in experimental models used

or that purpose, hypothermia induced by apomor-phine, tardive dyskinesia induced by haloperidoland acrylamide-induced lesions. Agut et al [234]studied the eects o citicoline administration onhypothermia induced by apomorphine, which isconsidered to be the result o the agonist action o apomorphine on D2 receptors. In addition to apo-morphine, experimental animals received halo-peridol at a sufcient dose to partially block apo-morphine-induced hypothermia to obtain a phar-macological system that is sensitive to citicolineaction on the dopaminergic system. A group o animals received a dose o 100 mg/kg p.o. citico-

line, and haloperidol 0.15 mg/kg i.p. was adminis-tered at 30 minutes. Tirty minutes later, the rectaltemperature was measured, and 1 mg/kg s.c. apo-morphine was administered. Te rectal tempera-ture was again measured at 30, 60 and 90 minutes.Another group o animals received water insteado citicoline using the same scheme. Te eects o the chronic administration o citicoline at a dose o 100 mg/kg/d p.o. or 5 days were also analysed. Tesame protocol used or acute administration wasollowed on the last day. able I shows the meantemperature decrease seen in each animal group

and at the dierent evaluation time points. Teacute administration o citicoline causes hypother-

mia, which is signicant or all control time points.Chronic administration only achieves a signicantresult at 90 minutes. Te authors concluded that a100 mg/kg dose o citicoline, administered acutely by the oral route, has a hypothermising eect thatis similar to the eect reported or various dopa-minergic agonists. However, they believed that theact that chronic citicoline administration only caused signicant hypothermia at the last timepoint analysed reected that, with this orm o ad-ministration, the tested product predominately acts upon phospholipids rather than upon acetyl-

Figure 9. Infuence o citicoline (30 mg/kg i.v.) on catecholamine synthesis at dierent time points ateradministration. The graphs show variations in catecholamine concentrations and rates o synthesis, inpercentages with respect to the control, at dierent locations. Corpus striatum; Cortex; Brainstem-

mesencephalon;a

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J.J. Secades

choline synthesis. Tis second pathway o citico-line action would predominate with acute admin-istration, as this would involve relatively rapid uti-lisation o the choline provided, which would beused or acetylcholine synthesis, increasing tyro-

sine hydroxylase activity through cholinergic in-terneurons. In contrast, the chronic administra-tion o citicoline would result in progressively greater availability o cytidine and would thereoredivert cerebral choline toward the synthetic path-way o citicoline and phospholipids, which wouldindirectly result in a dopaminergic agonistic eect.Tese authors developed an experimental model o tardive dyskinesia induced by haloperidol (2 mg/kg/d/7 d) in rats in a study including the chronicadministration o haloperidol or water to a total o 120 animals [235]. Teir study ound that the ad-ministration o citicoline plus apomorphine in rats

treated with haloperidol induced a motor activity similar to that seen in the group receiving citico-line alone. Te data provided in this study show that, in a model o haloperidol-induced dopamin-ergic hypersensitivity, oral administration o citi-coline induces hypermotility; this administrationmay induce a phenomenon o competition againstother agonists, leading to a partial reduction o theeect o apomorphine in animals pretreated withciticoline. In the model o acrylamide-induced le-sion, these authors [236] showed that the adminis-tration o low oral doses o citicoline, on the order

o 50 mg/kg, is eective to correct the neurologicalsyndrome induced by acrylamide. Te simultane-ous administration o both substances, which in-duces obvious weight loss in mice, has also beenshown to cause activation o the dopaminergic sys-

tem, as seen in results obtained with the apomor-phine stereotype test.Shibuya et al [237] measured the striatal dopa-

mine level using uorometry ater the administra-tion o a single dose o 500 mg/kg i.p. citicoline andound that a signicant increase occurred in thestriatal dopamine level one hour ater injection( p < 0.05). However, Stanzani [238] showed thatciticoline has a neuroprotective eect in the sub-stantia nigra, noting how citicoline protects thisarea against lesions induced by (horseradish) per-oxidases and achieves an increased number o sur-

viving cells. Porceddu and Concas [239] also re-

ported a trophic and/or stimulating eect o citico-line on nigrostriatal dopaminergic neurons in amodel o lesions induced by kainic acid. Tere havealso been experimental studies showing protectiveeects o citicoline in cultures o dopaminergicneurons exposed to 6-hydroxydopamine [240], MPP+ [241,242] and glutamate [241]. Miwa et al [243]suggested that citicoline may act as a dopamine re-uptake inhibitor ater administration o a singledose and that this drug may change the activity o dopaminergic neurons through changes in thecomposition o the neuronal membrane ollowing

Table I. Decrease in temperature or each batch studied relative to time zero, expressed as the mean orn = 20.

Batch Dugs

Time

+ 30 min + 60 min + 90 min

AWater (10 mL/kg v.o.)Apomorphine (1 mg/kg s.c.)Haloperidol (0.5 mg/kg i.p.)

1.19 ± 0.23 0.61 ± 0.17 0.19 ± 0.15

BCiticoline (0.1 g/kg v.o.)Apomorphine (1 mg/kg s.c.)Haloperidol (0.5 mg/kg i.p.)

1.39 ± 0.18 b 0.74 ± 0.17 a 0.38 ± 0.14 b

CWater (10 mL/kg/5 d v.o.)Apomorphine (1 mg/kg s.c.)Haloperidol (0.5 mg/kg i.p.)

1.13 ± 0.22 0.63 ± 0.25 0.26 ± 0.12

DCiticoline (0.1 g/kg/5 d v.o.)Apomorphine (1 mg/kg s.c.)Haloperidol (0.15 mg/kg i.p.)

1.11 ± 0.25 0.70 ± 0.19 0.41 ± 0.12 b

a p < 0.05; b p < 0.01 vs. controls.





repeated doses. In addition, these authors oundthat citicoline has certain muscarinic eects. Gi-ménez et al [244] showed that chronic administra-

tion o citicoline to aged mice promotes partial re-covery o the unctions o dopaminergic and mus-carinic receptors that normally decrease with age-ing, and they believe that this action may be ex-plained based on mechanisms involving the uidi-ty o the neuronal membrane, in agreement withresults obtained by Petkov et al [245]. When com-paring the eects o citicoline to those o the noot-ropic drugs adaenoxate and mecloenoxate on thelevels o the cerebral biogenic monoamines nore-pinephrine, dopamine and serotonin in the rontalcortex, striatum, hippocampus and hypothalamuso rats [246], this latter group ound that adaenox-

ate increased norepinephrine levels in the striatumand decreased norepinephrine levels in hypothala-mus, increased dopamine levels in the cortex andhypothalamus and decreased these levels in thestriatum, and increased serotonin levels in the cor-tex but decreased these levels in the hippocampus.Mecloenoxate induced decreases in norepinephrinelevels in the cortex and hypothalamus, whereas itincreased dopamine levels in the hippocampus andhypothalamus and serotonin levels in the cortex,striatum, hippocampus and hypothalamus. Te ad-ministration o citicoline has also recently beenshown to increase dopamine levels in the retina

[247]. Citicoline increases norepinephrine levels inthe cortex and hypothalamus, dopamine levels inthe striatum and serotonin levels in the cortex, stria-tum and hippocampus, which is a slightly dierentprole than that seen or nootropic drugs. With re-gard to the action o citicoline on norepinephrine,a study by López González-Coviella et al [248]showed that citicoline administration increasedthe total urinary excretion o 3-methoxy-4-hy-droxyphenylglycol in rats and humans, reectingnoradrenergic activity and suggesting that citico-line increases norepinephrine release. Recently,citicoline has been experimentally shown to inu-

ence the relationship between excitatory (glutama-te) and inhibitory (GABA) amino acids in the braincortex o rats [249]. A series o experiments as-sessed the potential o citicoline to produce centralcholinergic activation. Intracerebroventricular ad-ministration o citicoline causes an increase in thelevels o vasopressin [250] and other pituitary hor-mones [251], mainly due to central cholinergic acti-

vation. Citicoline has been shown to have a pressoreect in hypotensive animals [252] or in cases o hypotension due to haemorrhagic shock [253,254].In addition, a contribution o the central histamin-

ergic system is involved in this eect o citicoline[255]. Te central cholinergic activating eect ex-erted by citicoline was again emphasised, and this

eect was used to explain the cardiovascular [256-258] and metabolic eects [269-261] o the drug.Ilcol et al [262] observed that citicoline treatmentalters serum lipid responses to endotoxins andprevents hepatorenal injury during endotoxemiathrough a nicotinic acetylcholine receptor-mediat-ed mechanism. Yilmaz et al. [263] showed that citi-coline administration restores abnormalities in pri-mary, secondary and tertiary haemostasis and pre-

vents the development o disseminated intravascu-lar coagulation during experimental endotoxemiain dogs, likely by increasing both neuronal and non-neuronal cholinergic activity.

Citicoline also has antinociceptive eects involving the cholinergic system [264,265], opioidand GABA receptors [266] and Na+/K+ APase ac-tivity [267].

o summarise, the eects o citicoline have beenstudied in experimental models that are used toreveal pharmacological actions on the dopaminer-gic system. Citicoline has been shown to act as adopaminergic agonist and has a particularly sig-nicant eect on the levels o dopamine and itsmetabolites in the corpus striatum. Te results ob-tained suggest that striatal dopamine synthesis isincreased ater citicoline administration, probably

through tyrosine hydroxylase activation. An in-crease in dopamine levels would partly result roman inhibition o dopamine reuptake, possibly relat-ed to citicoline action on phospholipid synthesis.In addition, citicoline has eects on other monoam-ines; serotonin and norepinephrine; muscarinicand nicotinic receptors; and glutamate, opioids andGABA.

Learning perormance, memory and brain ageing

It has been shown that hypobaric hypoxia decreas-es learning perormance in rats undergoing sound

avoidance conditioning and that this eect may beantagonised by pretreatment with apomorphineor other dopaminergic agonists. Tese eects o hypoxia appear in relation to an inhibition o themetabolism o cerebral catecholamines that wouldbe ultimately responsible or an understimulationo central postsynaptic dopaminergic receptors.Based on these assumptions, Saligaut and Bois-mare [173] conducted a study on the eects o citi-coline administration on learning perormance inrats subjected to hypobaric hypoxia. Under hy-poxic conditions, citicoline was administered at




J.J. Secades

300 mg/kg/d or 12 days to a group o rats that un-derwent learning tests o sound avoidance condi-tioning in the last 5 days o treatment. Te eects

seen in this group were compared to those seen inanother group receiving apomorphine 0.5 mg/kg30 minutes beore each daily conditioning sessionand to those recorded in animals receiving bothtreatments. A group o animals acted as the con-trol and received an ascorbic acid solution underthe same experimental conditions. Citicoline par-tially restored learning perormance. Te same e-ect (but to a lesser extent) was seen with apomor-phine administration and with the combined ad-ministration o both drugs. Tese results suggestthat citicoline administration counteracts, as withdopaminergic agonists, the eects o hypoxia. Pre-

viously, we commented on the protective eect o citicoline against the cognitive impairment in-duced by chronic cerebral hypoperusion [199].

Drago et al [268] administered 10-20 mg/kg/di.p. citicoline or 20 days to 24-month-old Sprague-Dawley male rats rom a strain showing cognitiveand motor decits. Te drug was also given to ratswith behavioural changes induced by a single in-

jection o scopolamine, a cholinergic antagonist,by prenatal exposure to methylazoxymethanol orby bilateral injections o kainic acid into the mag-nocellular basal nuclei. In all cases, citicoline im-proved learning and memory perormance, as

evaluated using active and passive avoidance tests.In the aged rat group, improved motor capacity and coordination was also observed. For these au-thors, these results suggest that citicoline aectsthe central mechanisms involved in cognitive be-haviour, probably through a cholinergic action.

Petkov et al [269] showed that citicoline prevents amnesia induced by scopolamine in a modelo scopolamine-induced memory impairment.Subsequently, Mosharro al [270] showed that 100mg/kg citicoline completely prevented amnesia in-duced by scopolamine, as did the association o 50mg/kg citicoline and 500 mg/kg piracetam, which

also caused a signicant increase in retention. Teauthors suggested that this eect is mediated by drug actions on neurotransmission. Citicoline actsas a memory-enhancing drug, and this eect isparticularly marked in animals with memory de-cits [271]. However, Álvarez et a l [272] showed thatciticoline antagonised amnesia induced by bro-mazepam in rats. Bruhwyler et al [273] ound thatchronic administration o citicoline acilitateslearning and memory processes in dogs; however,it does not aect the established capacities and, inthis model, does not show any eect on the motor,

neurovegetative, or motivational systems. Accord-ing to these authors, this nding represents an ar-gument in avour o the selectivity o drug action

in memory processes. Citicoline has even beenshown to have a protective eect against mnesicdisorders in aged animals [274], in animals in iso-lation conditions [275], and in spontaneously hy-pertensive rats when administered as a dietary supplement [276].

Tere are multiple morphological, neurochemi-cal and physiological changes that characterisebrain ageing in mammals. General agreement ex-ists on the existence o age-related changes in cer-tain neurochemical parameters, including enzymeactivity, receptor binding and neurotransmission.Biochemical evidence is available or the existence

o a component o cholinergic dysunction andimpaired cerebral phospholipid metabolism in thepathophysiology o brain ageing [1,4,5]. De Medioet al [277] investigated the eects o citicoline onchanges in lipid metabolism in the brain duringageing. Tey measured in vivo lipid synthesis indierent brain areas rom 12-month-old male rats.For this experiment, they administered (by injec-tion into the lateral cerebral ventricle) a mixtureo (2-3H)glycerol and (Me-14C)choline, as lipid pre-cursors, and measured the incorporation o theseprecursors into the ractions o total l ipids, water-soluble intermediates and choline phospholipids

at 1 hour ater isotope administration. In anotherseries o experiments, citicoline was injected in-traventricularly into aged rats 10 minutes beoresacrice, and the same radioactivity tests as de-scribed above were perormed. In the studied are-as, the distribution o the radioactivity containedin citicoline in the brain 10 minutes ollowing ad-ministration showed the enrichment o nucle-otides and related water-soluble compounds. Teincorporation o labelled glycerol, which is greatly decreased in aged rats, increased in all areas. Teincorporation o labelled choline also decreaseswith ageing, and citicoline increased such incor-

poration in the cortex. As a result, the3

H/14

C ratiowas increased in total lipids and in phosphatidyl-choline and choline plasmalogens ollowing citi-coline treatment. Following this line o study,López González-Coviella et al [278] studied the e-ects o oral citicoline on the phospholipid contentin mouse brains. Tese authors supplemented theanimal diet with 500 mg/kg/d citicoline or 27months in 3-month-old mice and or 90, 42 and3 days in 12-month-old mice, ater which phos-phatidylcholine, phosphatidylethanolamine andphosphatidylserine levels and the contents o phos-





phatidylinositol plus phosphatidic acid were meas-ured in brain cortex. Ater 27 months o treat-ment, phosphatidylcholine and phosphatidyleth-

anolamine levels increased signicantly, by 19%and 20%, respectively, whereas phosphatidylserinelevels increased by 18%, but this change was notstatistically signicant (Figure 10). Similar in-creases were noted when 12-month-old animalswere treated or 3 months but not with shortertreatment periods. Tese results suggest thatchronic administration o citicoline may havesigniicant eects on the phospholipid composi-tion o the brain that may be partly responsibleor the reported therapeutic eicacy o this drug.Wang and Lee [279] obtained similar results intheir study. Plataras et al [280] showed that citi-

coline restores the activity o hippocampal ace-tylcholinesterase and Na+/K+ pumps, indicatingthat these mechanisms are involved in the im-provement o memory perormance exerted by citicoline. Giménez et al [281] showed that citico-line, administered or 2 months to aged rats,caused signicant activation o cytidine triphos-phate:phosphocholine cytidyltranserase, which,according to the authors, would explain the repar-ative eects o the drug on damaged membraneso aged animals. Tis same investigating teammade a more extensive study o the eects o citi-coline on the activity o this enzymatic system and

showed that, in addition to its eect on phospholi-pid metabolism, citicoline has a regulatory eecton platelet-activating actor levels in the brain[282,283]. All o these eects occur with no chang-es in the plasma levels o homocysteine, a knownrisk actor [284]. However, citicoline also oersbenecial actions on the brain metabolism o nucleicacids and proteins [279,285-287], on dopaminer-gic, nicotinic and muscarinic receptors [256], andon neuroendocrine and neurosecretory changes[288-290] in experimental ageing models, as wellas a neuroprotective eect against neurotoxic ag-gressions [291-293], an immunomodulatory eect

[294] and an antiapoptotic eect [295] in variousneurodegeneration models. Because o such ac-tions, various studies have shown the positive e-ects o citicoline on learning and memory in agedanimals [273,296-298]. Based on these eectsand the eects on neuroplasticity [299] and onprolieration and dierentiation o astroglial cells[10,300], the use o citicoline in neurodegenerativediseases has been proposed, but there are someexceptions, including the lack o a protective eecto the drug in a model o Huntington’s disease[301].

Experimental withdrawalsyndrome and intoxications

I 300 mg citicoline is injected by the intracarotidroute into cats, eects similar to those seen withthe administration o 2 mg o morphine by thesame route are obtained. Te animal shows symp-toms o anger and alertness, and the tail is placedin a rigid and upright position. Tis nding led tothe thinking that both substances could have par-allel eects on neuroreceptors o endogenous opi-ates and that citicoline administration could be

valuable in opiate withdrawal syndrome by slow-ing the eects o sudden drug discontinuation[302]. ornos et al [303] studied the eects o citi-coline administration on experimental withdrawalsyndrome by analysing various methods, such asthe jumping test in mice and studies o behaviourand body temperature changes in rats. Te with-drawal syndrome caused by naloxone administra-tion to morphine-dependent mice was assessedbased on the number o jumps by the animals. Adecrease in severity was seen in the group o ani-mals treated with 2 g/kg p.o. citicoline compared

Figure 10. Eect o chronic administration o citicoline on the brain titres o phospholipids in 30-month-old mice ed a dietary supplement with citicoline (500 mg/kg/day) or placebo or 27 months. a p < 0.05;b p < 0.01.

Placebo

a

b

Phosphatidylcholine Phosphatidyl

ethanolamine

Phosphatidyl

serine

Phosphatidylinositol

+ phosphatidic acid

250

200

150

100

50

0

Citicoline




J.J. Secades

to the untreated animal group. Tis decreased severity o the withdrawal syndrome was shown by a39% decrease in the mean number o jumps by ani-

mals within 10 minutes o administration o theopiate antagonist. Similarly, the behavioural study in morphine-dependent rats showed that adminis-tration o a 2 g/kg oral dose o citicoline simultane-ously with naloxone was able to signicantly de-crease the severity o maniestations that charac-terise the withdrawal picture provoked. With re-gard to hypothermia caused by naloxone adminis-tration in morphine-dependent rats, administrationo a single oral dose o citicoline almost completely neutralises this eect.

Characteristic histological ndings o oetal al-cohol syndrome include delayed maturation and

late development o dendrites in the neocortex,hippocampus and cerebellum. Based on these data,Patt et al [304] conducted a study to investigate theeects o citicoline on Purkinje cells rom newbornrats rom alcoholic dams and showed that this sta-bilising agent o neuronal membranes decreasesthe harmul eects o alcohol on the central nerv-ous system. Petkov et al [305] showed that citico-line decreases mnesic decits in rats pre- and post-natally exposed to alcohol, which may be related tothe benecial eects on acetylcholine synthesisand release shown using cerebral microdialysis inrats that were chronically exposed to alcohol

[306,307]. Citicoline also has as protective eect innicotine intoxication [308].

Toxicity

Acute toxicity

oxicity was studied or single administration o citicoline with dierent administration routes. in

various animal species. Te intravenous LD50 inmice, rats and rabbits is 4.6, 4.15 and 1.95 g/kg, re-spectively [309,310]. Oral LD50 is 27.14 g/kg in mice

and 18.5 g/kg in rats [311]. Te intravenous LD50 o citicoline is approximately 44 times higher thanthe LD50 o choline hydrochloride at equivalentdoses and it has been shown that choline doses in-ducing cholinergic crises do not cause any signs o toxicity when equivalent doses o citicoline are ad-ministered [312,313]. Tis nding suggests that theadministration o choline has metabolic implica-tions that are clearly dierent rom those o exoge-nous choline administration. Te administrationo 2,000 mg/kg o citicoline p.o. or 14 days waswell tolerated [314].

Subacute toxicity

Intraperitoneal administration o doses up to 2 g/

kg/d o citicoline to rats or 4.5 weeks did not resultin clinical signs o toxicity or signicant changesin the haematological, biochemical, or histologicalparameters analysed. A slight decrease in intakeand weight gain was observed only ater 2 weeks o the study [311]. Similar results were seen ollowingsubcutaneous administration o up 1 g/kg or 4weeks to male rats [310]. Oral administration o 1.5 g/kg/d to rats or 30 days did not cause weight,haematological, biochemical or histological chang-es [315].

Chronic toxicity

Chronic oral (1.5 g/kg/d or 6 months in dogs) andintraperitoneal (1 g/kg/d or 12 weeks in rats) tox-icity studies did not reveal signicant abnormali-ties related to drug administration [310,316]. Intra-

venous administration o 300-500 mg/kg/d citico-line or 3 months in dogs only caused toxic signsimmediately ater injection, including vomitingand occasional diarrhoea and sialorrhoea [313]. Ina 90-day study in rats, 100, 350 and 1,000 mg/kg/day oral doses resulted in no mortality. In males,slight but signicant increases in serum creatinine(350 and 1,000 mg/kg/day) and decreases in urine

volume (all treated groups) were observed. In e-males, slight signicant increases in total whiteblood cell and absolute lymphocyte counts (1,000mg/kg/day) and blood urea nitrogen (BUN) (100and 350 but not 1,000 mg/kg/day) were noted. Adose-related increase in renal tubular minerali-sation, without degenerative or inammatory re-action, was ound in emales (all treated groups)and two males (1,000 mg/kg/day). Renal minerali-sation in rats (especially emales) is inuenced by calcium:phosphorus ratios in the diet. A high levelo citicoline consumption resulted in increasedphosphorus intake in rats and likely explains this

result [314].

Teratogenicity

Citicoline was administered to albino rabbits at adose o 800 mg/kg during the organogenesis phase,i.e., rom days 7 to 18 o pregnancy. Te animalswere sacriced on day 29, and a detailed examina-tion was made o the oetuses and their mothers.No signs o maternal or embryooetal toxicity wereobserved. Te eects on organogenesis were im-perceptible, and only a slight delay in cranial os-





teogenesis was observed in 10% o treated oetuses(unpublished data).

Pharmacokinetics

Plasma level curves. Bioavailability

Labelled citicoline (methyl 14C) was administeredto rats at a dose o 4 mg/kg by jugular vein injec-tion and orally using a nasogastric tube [317]. Teresults obtained, expressed as the percent radio-activity in 10 mL o blood or each administrationroute, are shown in able III. From these data, theratio between the bioavailability o the oral andthe intravenous administration route was esti-

mated and ound to be virtual ly one, which agreeswith the act, demonstrated in the same study,that no residual radioactivity is ound in aecesexcreted in the 72 hours ollowing oral adminis-tration.

López González-Coviella et al [318] studied theeects o citicoline on the plasma levels o cytidine,choline and citicoline in healthy volunteers receiv-ing the drug by the oral or intravenous route andin rats treated by the intravenous route. wo hoursollowing the administration o a single oral doseo 2 g citicoline, choline plasma levels increased48% and cytidine plasma levels increased 136%

(Figure 11). In individuals receiving three 2-g dosesat 2-hour intervals, choline plasma levels reached apeak, representing approximately 30% o the base-line value, 4 hours ater the administration o theinitial citicoline dose, whereas cytidine plasma lev-els increased or up to 6 hours (Figure 12) and were5-old higher than the baseline value ( p < 0.001).Citicoline administered intravenously was rapidly hydrolysed in humans and rats [319]. In healthy in-dividuals receiving a citicoline inusion o 3 g in500 mL o physiological saline over 30 minutes,citicoline levels were virtually undetectable imme-diately ater the end o the inusion period, when

plasma levels o cytidine and choline reached apeak, although their concentrations remained sig-nicantly increased up to 6 hours ater the start o the inusion (Figure 13). Tese observations show that citicoline, administered by both oral and in-travenous routes, is converted into two major cir-culating metabolites, cytidine and choline. How-ever, in humans, plasma cytidine is converted touridine, its circulating orm, which is transormedin the brain to uridine phosphate, which will beconverted into cytidine triphosphate at the neu-ronal level [320].

Tissue difusion and distribution.Transport and metabolism

issue diusion o citicoline and its componentshas been studied in rats that were intravenously administered (methyl 14C, 5-3H) citicoline that waslabelled in the choline and the cytidine ractions[321,322]. In the same battery test, plasma radioac-tivity levels were measured or 30 minutes ollow-ing administration. Renal and aecal excretion val-ues o labelled metabolites were also measured or48 hours. As early as 2 minutes ollowing injection,less than 10% o the administered radioactivity wasound in the plasma. In addition, the radioactivity excreted by the kidney during the rst 48 hours

only accounted or 2.5% o the14

C administeredand 6.5% o the 3H administered. In the same timeinterval, aecal excretion did not exceed 2% o theadministered dose. Tese results suggest that citi-coline rapidly diuses to the tissues ollowing ad-ministration and is actively used by tissues. Figure14 shows the radioactivity levels that were ound inthe liver, brain and kidney at dierent time pointsollowing intravenous administration o dually la-belled citicoline. Tere is a special interest inchanges in brain levels o radioactivity. Radioactiv-ity uptake by the brain gradually increases or the

Table II. Blood kinetics o the total radioactivity o 4 mg/g methyl 14C-citicoline ater oral or intravenousadministration to male rats. The percentages o radioactivity (mean ± SD) with respect to the total ad-ministered are shown.

Time Oal oute Intavenous oute

10 min 0.26 ± 0.12 3.05 ± 0.24

20 min 0.40 ± 0.02 2.59 ± 0.31

30 min 0.74 ± 0.01 1.47 ± 0.22

1 h 1.32 ± 0.40 1.40 ± 0.02

2 h 2.33 ± 0.63 2.84 ± 0.02

3 h 3.31 ± 0.86 2.50 ± 0.05

4 h 3.57 ± 0.88 2.77 ± 1.00

5 h 4.17 ± 0.83 3.37 ± 0.31

6 h 4.18 ± 0.03 3.68 ± 0.02

7 h 3.81 ± 0.73 –

24 h 2.48 ± 0.40 3.12 ± 0.19




J.J. Secades

rst 10 hours ater drug administration, and theselevels achieved remain unchanged at 48 hours.

In a group o animals, the radioactivity levels o

labelled compounds were measured in the brain at0.5, 1, 4 and 48 hours ater the administration o dually labelled citicoline. Radioactivity corre-sponding to 3H in the brain was primarily concen-trated in cytidine nucleotides at the beginning o the experiment but was subsequently concentrat-ed in nucleic acids. With regard to compounds la-belled with 14C, the highest levels initially corre-sponded to betaine, choline and phosphorylcho-line, whereas at 4 hours, 14C-methionine and 14C-phospholipids accounted or 26.4% and 24.2%, re-spectively, o the total cerebral radioactivity cor-responding to 14C. At 48 hours, this radioactivity

was primarily concentrated in phospholipids andproteins. Tereore, the levels o labelled phospho-lipids continuously increased in the 48 hours ol-lowing the administration o dually labelled citi-coline. As shown in Figure 15, this increase is rap-id in the rst 5 hours but then becomes slowerover time.

In another test battery, the presence o the drugin various brain areas and its distribution in cere-bral ultrastructures were measured ollowing theadministration o (methyl 14C) citicoline [323-327].In a study perormed with high-perormance auto-radiography in mouse brains, the radioactive

marker was widely incorporated into the dierentcerebral areas studied, including the brain cortex,white matter and central grey nuclei, at 24 hoursollowing the administration o labelled citicoline[323]. It was ound in both intra- and extracellularspaces, with a particularly strong presence in cellmembranes. In the same experimental model but10 days ollowing the administration o the labelleddrug [324], a concentration o radioactivity wasseen in the more myelinated areas, as well asmarked uptake by cerebellar Purkinje cells. Usinglow-perormance autoradiography, the distributiono radioactivity o labelled citicoline in rat brains

was analysed 5 and 24 hours ater drug adminis-tration [325]. At 24 hours, most radioactivity wasdetected at the intracellular level. In another study,the incorporation o radioactivity rom (methyl14C) citicoline ater oral administration to maleSprague-Dawley rats was analysed in dierent ce-rebral phospholipid ractions [326]. O the total ra-dioactivity measured in the brain, 62.8% was oundto be part o brain phospholipids, particularly phosphatidylcholine and sphingomyelin, showingthat citicoline administered by the oral route hasan eect on the synthesis o structural phospholip-

Figure 12. Plasma concentrations o choline and cytidine immediatelyater administration o three consecutive oral doses (2 g) in humans.

30

25

20

15

10

5

0

P l a s m a c o n c e n t r a t i o n ( µ M )

Time (h)

Choline

Cytidine

0 2 4 6 8

Figure 11. Plasma concentrations o choline and cytidine immediatelyater administration o a single oral dose o 2 g citicoline in humans.

30

25

20

15

10

5

P l a s m

a c o n c e n t r a t i o n ( µ M )

Time (h)

Choline

Cytidine

0 2 4 6 8 10 12





ids o cell membranes. Tese results agree with thoseobtained by Aguilar et al [327], who showed thatradioactivity rom labelled citicoline is associatedwith cytoplasmic and mitochondrial membranesin brain homogenate.

In conclusion, these studies show that adminis-tered citicoline is widely distributed in brain struc-tures, with a rapid incorporation o the cholineraction into structural phospholipids and o thecytosine raction into cytidine nucleotides and nu-

cleic acids. Citicoline reaches the brain and actively incorporates into the cytoplasmic and mitochon-drial cell membranes, becoming part o the struc-tural phospholipid raction [319,328,329].

Elimination route and kinetics

When labelled citicoline is administered by eitherthe oral or intravenous route, radioactivity is elim-inated very slowly by the urinary or aecal routeand in expired CO2 [330].

Figure 16 shows total radioactivity excretion or5 days ollowing the oral administration o 14C

-citicoline to healthy volunteers. able III providesthe primary data on the elimination kinetics o thecompound.

wo phases are dierentiated in urinary elimi-nation o the drug: a rst phase, lasting approxi-mately 36 hours, in which the excretion rate de-creases rapidly, and a second phase, in which theexcretion rate decreases much more slowly. Tesame phenomenon occurs with expired CO2, whoseelimination rate decreases rapidly or approxi-mately the rst 15 hours, ater which a slower de-crease occurs.

Clinical experience

Head injury and sequelae

Te above-reported experimental studies show that the administration o citicoline leads to a sig-nicant regression o brain oedema and improve-ments in electroencephalographic tracing, impair-ment o consciousness and survival quality. Teeect on consciousness level is attributable to the

acilitating action o the electroencephalographicarousal reaction, induced by stimulation o the as-cending reticular activating system at the level o the brain stem.

Based on these experimental assumptions, many clinical trials have been conducted to veriy wheth-er these eects have implications or the treatmento patients with head injury.

In 1967, Moriyama et al [331] published a study on the eects o citicoline in 25 patients with headinjuries and depressed consciousness. Te drugwas eective, leading to recovery rom neurologi-cal clinical symptoms and a return to a conscious

state in 70% o cases, and was very well tolerated,causing no side eects.Ayuso and Saiz [332] conducted a double-blind

study on the value o citicoline in mnesic dysunc-tion induced by bilateral electroshock in a series o 22 patients admitted to the hospital or endogenousdepression. Te group receiving the active drughad a lower reduction in memory perormance a-ter our electroshock sessions compared to thecontrol group, showing the value o citicoline ortreating patients with memory disorders as resulto an injury or lesion.

Table III. Most signicant parameters in the elimination kinetics o 14C-citicoline ater oral administration. Data show the means o six individuals.

Paametes CO2 Uine Faeces

Maximum ate o excetion (% dose/h) 1.22 ± 0.59 0.159 ± 0.084 0.021 ± 0.008

Time o maximum excetion (h) 1.60 ± 0.73 1.3 ± 0.8 56 ± 18

Fist phase o elimination

Apparent hal-lie

Apparent rate o elimination (% dose/h)

2.58 ± 0.60

0.279 ± 0.055

6.62 ± 1.28

0.107 ± 0.017

–

–

Second phase o elimination

Apparent hal-lie (h)

Apparent rate o elimination (% dose/h)

56.22 ± 33.39

0.030 ± 0.049

71.08 ± 58.16

0.013 ± 0.006

19.39 ± 6.63

0.039 ± 0.014




J.J. Secades

De la Herrán et al [333] compared the eects o citicoline administration in a series o 50 patientswith impaired levels o consciousness (o traumat-ic origin in 32 cases) to another series o patientswith similar characteristics who were receivingstandard treatment. Tirty-our percent o pa-tients recovered consciousness within 48 hours.Ater a ew days, 66% o patients had recoveredconsciousness. Tese results were better than those

achieved in the control group. Tese results showedthat citicoline reactivates and accelerates normali-sation o the consciousness stated in patients withhead injuries.

Carcassonne and Leourneau [334] conducted adouble-blind study in a series o 43 children with atrue consciousness disorder o traumatic origin,ater excluding severe cases and cases requiringsurgical treatment. Ater analysing the results,these authors concluded that citicoline is very welltolerated, both locally and systemically: it signi-cantly accelerates the recovery o a normal con-

sciousness state, it accelerates the disappearance o neuropsychological disorders and cerebral electro-genesis disorders and it coners a better quality o the evolution o patients.

Espagno et al [335] compared the eects o citi-coline and placebo in a series o 46 patients whohad sustained head injuries. Te authors conduct-ed a double-blind study in which 22 patients re-ceived 250 mg/d citicoline intraperitoneally or 20

days, and 24 patients were given placebo. Te re-sults showed that, or patients in mild comas, citi-coline signicantly accelerated ( p < 0.05) the re-covery o consciousness, whereas or patients inmore severe comas and at the administered dose(currently considered to be highly inadequate), cit-icoline improved the prognosis. In the placebogroup, 75.2% o patients showed late recovery (>15days) o consciousness and/or progressed to death.In contrast, in the group treated with the citicoline,recovery rom coma beyond day 15 occurred in31% o cases and the incidence o prolonged coma

Figure 13. Concentrations o choline, cytidine and CDP-choline in human plasma ater intravenous inusion o a solution o citicoline (3 g/500 mLphysiological saline solution).

160

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Choline (µM) Cytidine (µM) CDP-choline (µM)





and/or death was 12.5%. In conclusion, citicolineresulted in earlier recovery o consciousness andan increased number o clinical and electroen-

cephalographic improvements and was very welltolerated.Richer and Cohadon [336] conducted a double-

blind study in a group o 60 patients with comas o traumatic origin who were distributed into two ho-mogeneous groups, one o which was given the ac-tive drug and the other given a placebo. With re-gard to coma duration, the number o patients whorecovered consciousness at 60 days was signi-cantly greater ( p < 0.01) in the group treated withciticoline. Ater 90 days, greater recovery ( p < 0.04)rom motor decits was observed in the citicoline-treated group. Gait recovery was also signicantly

accelerated in the active drug group. As a result,greater social and occupational reinsertion wasound at 60 days in the group treated with citico-line ( p < 0.06). Tis nding demonstrates the lim-iting eect o the duration o posttraumatic comao citicoline and its participation in the restorationo decits related to the brain lesions associatedwith such comas. Tere were no changes in mor-tality associated with the treatments.

In a double-blind trial, Lecuire and Duplay [337]compared the eects o a 750-mg/d intravenousdose o citicoline to those o mecloenoxate at 3 g/di.v. in a group o 25 patients. Tere was signicant

improvement in the patient group treated with cit-icoline, particularly with respect to the recovery o consciousness, electroencephalographic changesand unctional recovery. Te mean coma durationwas 10 days in the citicoline group, compared to 20days in the mecloenoxate group. At 10 days, elec-troencephalographic tracings improved in 50% o the citicoline-treated patients and in 18% o themecloenoxate-treated patients. Tereore, citico-line was shown to be superior to mecloenoxate,and its main characteristic was accelerated recov-ery o the consciousness level, which is related toan improvement in electroencephalographic trac-

ing. Tese same authors carried out an open-labelstudy in a series o 154 patients with head injuries[338]. Teir study assessed the eects o citicolinetreatment and ound that the drug accelerates pa-tient arousal and recovery rom decit syndromesand improves the quality o survival. Lecuire [339]subsequently perormed a double-blind study com-paring piracetam (6 g/d) vs. citicoline (750 mg/d)in a group o 40 patients who sustained head inju-ries and ound a avourable evolution in 75% o pa-tients in the citicoline group, compared to 33% inthe piracetam group.

Cohadon et al [16,340] showed the clinical ef-cacy o citicoline in a double-blind study conduct-ed on a series o 60 patients with severe head inju-

ries. A standard treatment was used in both groups,and surgery was perormed when required. Onegroup o patients was given 750 mg/d citicoline in-travenously or the rst 6 days and by the intra-muscular route or an additional 20 days. Te othergroup was administered a placebo. Clinical evalua-tion was continued up to 6 months. At 15 days, theresponse to painul stimuli was superior in thegroup o citicoline-treated patients ( p < 0.01), andan earlier recovery o consciousness was seen inthis group (Figure 17). Te authors also noted agreater recovery rom neurological decits in thegroup having the active treatment. Ater 120 days,

autonomous ambulation was seen in 84% o the pa-tients in the citicoline group, compared to 62.5% o the patients in the placebo group. Tis dierencewas statistically signicant rom day 60 ( p < 0.01).able IV shows the nal outcomes obtained inboth groups, as assessed using the Glasgow Out-come Scale (GOS). Te mortality rate was similarin both groups. Data reported in this study show that citicoline shortens the time elapsed to recov-ery o consciousness and accelerates recovery romneurological decits in patients with severe headinjury.

Deleuze et al [341] reported that citicoline de-

creases serum creatine phosphokinase (CPK) levelsand lactate levels in cerebrospinal uid (CSF), witha decrease in the lactate/pyruvate ratio, in patientswith severe brain distress and coma. Tey empha-sised that the product was very well tolerated.

Ogashiwa et al (102) conducted a clinical trial in101 patients with consciousness disorders romdierent causes (20% o traumatic origin) and showedthe eectiveness o citicoline or improving theGeneral Recovery Rate, which is closely related tothe Principal Component Analysis Score. Te au-thors ound that citicoline is more eective initems related to the executive actor than in items

related to the verbal actor and that the greatest e-ect was achieved in patients under 60 years o ageand with a stabilised period o impaired conscious-ness o no longer than 3 weeks. Tey emphasisedthe excellent tolerability o the product and evenadministered it by the intrathecal route in somecases [342,343].

At the Department o Neurosurgery o the‘Ramón y Cajal’ Special Centre in Madrid, a serieso 100 patients with head injuries treated with citi-coline until discharge were studied, and their re-sults were compared to those o another series o




J.J. Secades

100 patients with similar characteristics but whodid not receive citicoline [344]. reatment withciticoline was started at doses o 600-1,200 mg/d

intraperitoneally and switched to 300-900 mg/dorally in the rehabilitation phase. Te course wasmonitored by assessing the mean coma duration,the persistence o neurological and psychic symp-toms, the WAIS test, and electrophysiologicalstudies o muscle tension. Te results suggestedthat the addition o citicoline to the treatment regi-men caused a decrease in the duration o posttrau-matic coma and the rate o both neurological andpsychic sequelae and achieved a better response inrecovery rom intellectual disorders and motordecits.

In a national survey conducted in France, Rag-

gueneau et al [345] recorded 921 cases o severehead injury, i.e., those with an initial score on theGlasgow Coma Scale (GCS) o 8 or less. O these,219 patients had been treated with citicoline, whichallowed or their distribution into two groups tocompare the results obtained. No signicant di-erences were ound in mortality, but dierenceswere seen in the number o dependent states, andthe greatest eect was ound in patients with aninitial GCS score o 6-7 (Figure 18). Citicoline im-proved the quality o survival, allowing or morerequent social and amiliar reinsertion, as well asa return to work or school. Mortality in head inju-

ries essentially depends on the initial lesions,which, with the exception o epidural haematoma,are beyond any real therapeutic resolution.

Calatayud et al [346] reported the results o theinuence o citicoline administration in the treat-ment o head injury. A total o 216 patients withinitial GCS scores ranging rom 5 to 10 were re-ported. O these, 115 patients received treatmentwith citicoline. Te mean citicoline dose adminis-tered was 4 g/d. Te results showed that citicolinetreatment decreased hospital stays ( p < 0.05) andthe duration o outpatient ollow-up ( p < 0.001),with the dierences that were more marked in the

group o patients with initial GCS scores rangingrom 5 to 7), promoted the recovery o memory,motor disorders, higher neurological unctions,and mood changes and improved global unctionaloutcome (able V).

Lozano [347] reported the impact o citicolinetherapy on the course o posttraumatic cerebraloedema in a study conducted in 78 cases o headinjury with initial GCS scores ranging rom 5 to 7.In all cases, a computerised tomograph o the headwas collected at the start and end o the study toassess changes in the tomographic image o cere-

Figure 14. Concentrations o radioactivity in the liver (a), brain (b) and kidneys (c) o rats at dierent timepoints ater injecting double-labelled citicoline at a dose o 2 mg/kg. All values represent the means ob-tained rom 10 animals.

30

20

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0 10 20 30 40 50 h

0 20 40 h

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3H

3 H / 1 4 C

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o s e a d m i n i s t e r e d ( % )

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/ 1 4 C

D o s e a d m i n i s

t e r e d ( % )

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b

c





bral oedema. Other parameters investigated in-cluded the duration o hospital stay and the extento autonomy at hospital discharge. Citicoline was

administered to 39 patients or the rst 2 weeks atdoses ranging rom 3 to 6 g/d by intravenous inu-sion. Ater 14 days o citicoline treatment, theimages o cerebral oedema evolved as shown inFigure 19. Cerebral oedema had been reduced ornormalised in a higher number o patients treatedwith citicoline compared to control patients, withthe dierences being highly signicant ( p < 0.005).No signicant dierences were observed betweengroups in the therapeutic requirements or treat-ments received. Te mean hospital stay was 28.718± 21.6 days or the group receiving active treatmentand 37.323 ± 35.22 days or the control group,

which was a statistically signicant dierence ( p <0.001). Dierences in the nal outcomes, assessedaccording to the GOS, did not reach statistical sig-nicance due to the small number o cases andspecial characteristics o this type o patient. How-ever, a trend was seen toward a more avourableresolution in the group o patients that were treat-ed with citicoline (able VI).

Levin [348] conducted a study in 14 patientswith postconcussional syndrome ollowing a mildto moderate head injury. Tis syndrome is charac-terised by symptoms such as headache, dizziness,mnesic disorders and sleep disturbances. In this

study, patients treated with citicoline or onemonth experienced improvements in memory tests, particularly recognition tests, that were sta-tistically signicant compared to a placebo. Figure20 shows the changes in symptoms ater onemonth o treatment. Greater improvements wereachieved in patients that were treated with citico-line compared to placebo patients, with the excep-tion o gastrointestinal discomort. Dizziness wassignicantly more common in patients rom theplacebo group ater one month o study. However,in a simple-blind study in patients with mild headinjuries [349], the authors were unable to demon-

strate dierences between citicoline and controlwith regard to the evolution o postconcussionalsymptoms.

León-Carrión et al [350-352] investigated theeects o citicoline on posttraumatic memory dis-orders in a series o studies. In a group o 7 pa-tients with severe memory decits, these authorsinvestigated the eects o administering 1 g citico-line on cerebral blood ow (CBF), as measured by the 133Xe inhalation technique. wo measure-ments were made, one at baseline and the other at48 hours, under the same conditions, except that

patients had taken the drug one hour beore thetest. All patients showed a signicant hypoper-usion in the ineroposterior area o the let emo-

Figure 16. Total excretion o radioactivity (percentage o total administered) or 5 days ater oral admin-istration o 14C -Citicoline. The mean values o six individuals are shown.

CO2

Urine Faeces Total

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20

15

10

5

0

( % )

Figure 15. Evolution o 14C-phospholipid concentrations in rat brains ater intravenous administration o double-labelled citicoline. The concentrations represent the means o three animals and are expressed asa percentage o the total radioactivity corresponding to 14C in the brain.

40

20

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(%)

0 20 40 Time (h)

1 4 C r

a d i o a c t i v i t y

i n

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J.J. Secades

ral lobe in the rst measurement that disappearedollowing citicoline administration. In a second

study, 10 patients with severe memory decitswere randomised into two groups. Both patientgroups were subjected to a short memory rehabili-tation program. One group received 1 g/d p.o. citi-coline or the 3 months that the neuropsychologi-cal treatment program lasted, whereas the othergroup was given a placebo. Te results obtainedare shown in able VII. Neuropsychological reha-bilitation associated with citicoline resulted in im-provements in al l evaluated areas and reached sta-tistical signicance in verbal uency and the wordrecall Luria test.

As a nal conclusion, it has been widely shownthat patients who have sustained a head injury,particularly those with an initial GCS score o 5-7,

benet rom the addition o citicoline into theirtherapeutic regimen because this drug acceleratescerebral oedema reabsorption and recovery o bothconsciousness and neurological disorders, result-ing in a shorter hospital stay and improved quality o survival [353]. Moreover, in cases o mild tomoderate head injury, citicoline signicantly de-creases the duration and severity o the so-calledpostconcussional syndrome and improves memory decits. A Cochrane review o citicoline or thetreatment o head injury will soon be available[354]. In addition, there is a new, ongoing clinicaltrial in the United States, the COBRI trial, to

evaluate the eects o citicoline in patients withhead injuries [355].

Acute cerebrovascular disease and sequelae

Te neurobiological processes involved in thepathophysiology o cerebral ischaemia are ex-tremely complex [356]. For this reason, some au-thors postulate that multiunctional treatments[357-362] are needed or this disease. As has beenshown experimentally, citicoline is a drug that haspleiotropic actions, including the activation o neu-ronal metabolism, stabilisation o neuronal mem-

branes and their unction and normalisation o neurotransmission [15,34-36,148,221,222]. Variousstudies with citicoline that were conducted inthe 1960s suggested its efcacy to reduce neuro-logical symptoms in patients with cerebral ischae-mia [363,364].

Hazama et al [365] conducted a double-blindstudy to assess the eect o citicoline on unctionalrecovery rom hemiplegia in 165 patients with cer-ebrovascular disease. Tese authors showed thatciticoline, at a dose o 1,000 mg/d or 8 weeks, wassuperior to a placebo, particularly or motor recov-ery in the lower limbs, and concluded that citico-

line promotes natural recovery rom hemiplegia.Goas et al [366] conducted a double-blind study comparing citicoline (750 mg/d/10 d i.v.) to placeboin 64 patients with cerebral inarction starting lessthan 48 hours prior to the stroke onset. Te assess-ments at 3 months showed citicoline to be superiorto placebo or improving motor decit ( p < 0.05),hypertonia ( p < 0.03), gait recovery ( p < 0.02),changes over time in electroencephalographic trac-ings ( p < 0.01) and psychometric tests ( p < 0.05),achieving a higher number o independent states(51.6% with citicoline; 24.24% with placebo) (Fig-

Figure 17. Normalisation o the state o consciousness in relation to time and treatment; p < 0.01 atday 60.

Placebo

25

20

15

10

5

01 6 15 60 90 120

Days

(n)

Citicoline

Table IV. Final results according to treatment.

Glasgo Outcome Scale

I II III IV V

Placebo goup 12 5 4 3 6

Citicoline goup 11 9 3 2 5





ure 21). In a study with the same characteristics,Boudouresques et al [367] achieved similar results.Tis study included 52 patients, 27 o whom re-

ceived citicoline (750 mg/d/10 d i.v.), and 25 o whom received a placebo. An assessment was madeat 10 days, and the assessment showed that citico-line-treated patients had a better course with re-gard to consciousness disorders. Recovery o con-sciousness occurred in 66.7% o the citicoline casescompared to 32.0% o the placebo group ( p < 0.01),and decit syndromes (82.6% and 54.5% o patientsrecovered with citicoline and placebo, respectively;

p < 0.04) and electroencephalographic tracings(83.3% with citicoline vs. 35.3% with placebo; p <0.01) were improved in the citicoline group. In bothstudies, citicoline tolerability was rated as excel-

lent by investigators.In a double-blind study o citicoline (1 g/d/30 di.v.) vs. placebo in a sample o 33 patients, Corso etal [368] noted that at the end o the study, the de-cit syndrome ater acute stroke had improved in76.5% o the patients treated with citicoline ( p <0.01 vs. placebo), and improved electroencephalo-graphic tracings were seen in 70.6% o patients ( p <0.01 vs. placebo).

azaki et al [369] perormed a double-blind,prospective, multicenter, placebo-controlled study on the value o citicoline or the treatment o acutecerebral inarction. Sixty-three Japanese academic

centres participated in this study, in which a totalo 272 patients were enrolled, ollowing strict in-clusion criteria. Patients were randomised to re-ceive 1 g/d i.v. o citicoline or saline (placebo) or 14days. At the end o the treatment, citicoline wasshown to signicantly improve consciousness (51%vs. 33% or placebo; p < 0.05), as well as overall im-provement (52% vs. 26%; p < 0.01) and overall use-ulness rates (47% vs. 24%; p < 0.001). In addition,ewer complications occurred in the citicoline-treated patient group (1%) compared to the placebogroup (8.1%). Tese authors concluded that citico-line is an eective and sae drug or the treatment

o acute cerebral inarction. Tese results agreewith those reported by others [370-373].Guillén et al [374] reported a comparative, ran-

domised study on the efcacy o citicoline ortreating acute ischaemic stroke compared to con-

ventional therapy and showed a signicantly high-er improvement in the citicoline group comparedto the control group. In open-label studies by Bruh-wyler et al [375] and Fridman et al [376], better re-sults avouring citicoline were also achieved, withsignicant clinical improvements in patients andan excellent saety prole o the drug. Álvarez and

González [377] reported the benecial eects o citicoline in a double-blind study conducted inVenezuela. León-Jiménez et al [378] evaluated thecorrelation between citicoline exposure and unc-tional outcome at discharge and at 30 and 90 dayspost-stroke in a retrospective, case-controlled de-sign on systematic descriptive databases rom threereerral hospitals in Mexico. Clinical records o 173consecutively registered patients were analysed, 86o whom were treated with citicoline within the

Figure 18. Eect o treatment with c iticoline on nal results. Results are expressed as percentages. a p <0.001 vs. patients not treated with citicoline.

With citicoline (n = 219)

Independent

state

Dependent

state

Vegetative

state

Death

a

a

0 10 20 30 40 50

Without citicoline (n = 702)

Table V. Final result, evaluated with the Glasgow Outcome Scale (GOS),in relation to treatment ( p < 0.05).

Citicoline Contol

GOS I 77 51

GOS II 19 31

GOS III 1 7

GOS IV 0 2

GOS V 18 10




J.J. Secades

Figure 19. Evolution o the tomographic image o cerebral oedema ater 14 days o treatment ( p < 0.005).

Citicoline

No change

30

25

20

15

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5

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(n)

Reduction

Control

rst 48 h ater acute ischaemic stroke. Te remain-ing 87 were untreated, randomly selected controlsmatched or age (± 5 years), gender and NIHSS (± 1point) at hospital admission. Pretreatment condi-tions were similar between groups. Comparedwith controls, exposure to citicoline was associat-ed with a signicantly lower 30-day mean and me-dian modied Rankin score (or both, p < 0.05).Ater paired multivariate analyses (controlled orNIHSS, age, gender, hospital arrival in < 24 h,thrombolysis and comorbidities) citicoline was in-

dependently associated with a lower 90-day mor-tality risk ( p = 0.047) and ewer in-hospital com-plications (mainly inections and sepsis, p = 0.001).

In this observational study, citicoline use was as-sociated with a better unctional status and lowerrates o short-term mortality, possibly due to ewerin-hospital systemic complications.

In 1997, a study on oral citicoline or the treat-ment o acute ischaemic stroke was started in theUnited States. Te rst clinical trial was a ran-domised, dose-response study [379]. Tis double-blind, randomised, multicenter study compared 3citicoline doses (500 mg, 1,000 mg and 2,000 mg,given orally) to a placebo to document drug saety,determine the optimum dose and collect data onthe efcacy o citicoline or the treatment o acute

ischaemic stroke. A total o 259 patients with is-chaemic strokes in the territory o the middle cer-ebral artery were recruited within 24 hours o symptom onset. Te patients were randomisedinto our groups: administration o placebo or 500,1,000 or 2,000 mg/d o oral citicoline or 6 weeks.Patient recovery was assessed at the end o the6-week treatment period and ater a subsequentollow-up period o 6 weeks. Te main efcacy endpoint was the Barthel Index (BI) at 12 weeks.Secondary endpoints included the modied RankinScale (mRS), the National Institutes o HealthStroke Scale (NIHSS), the Mini-Mental State Ex-

amination (MMSE), hospital stay duration andmortality. A signicant dierence avouring citi-coline was ound between groups in unctionalstatus (BI, mRS), neurological assessment (NIHSS)and cognitive unction (MMSE). A signicant e-ect o citicoline treatment was ound at 12 weeks( p < 0.05) in a regression analysis o the BI, includ-ing the baseline NIHSS score as a covariate. Teproportions o patients who achieved a BI scoreranging rom 85 to 100 were 39.1% or the placebo,61.3% or the 500 mg dose, 39.4% or the 1,000 mgdose and 52.3% or the 2,000 mg dose. Te oddsratios or an improved outcome were 2.0 or the

500 mg dose and 2.1 or the 2,000 mg dose. Telack o efcacy seen in the 1,000 mg group couldhave been due to the inclusion o patients into thisgroup that were more overweight and had poorerneurological status at baseline. Te mean score inthe mRS was 3.1 with the placebo, 2.5 with 500 mgciticoline, 3.1 with 1,000 mg and 2.6 with 2,000 mg,and a signicant dierence was ound betweenthe 500 mg and placebo groups ( p < 0.03). No citi-coline-related serious adverse events or deathswere seen. According to these results, oral citi-coline treatment achieves better unctional out-

Table VI. Final result, evaluated with the Glasgow Outcome Scale (GOS),in relation to treatment (n.s.).

Citicoline Contol

GOS I 15 11

GOS II 8 8

GOS III 6 7

GOS IV 4 6

GOS V 6 7





comes, and 500 mg is the most eective dose o citicoline.

A second multicenter, double-blind, placebo-controlled, randomised study [380] recruited 394

patients with acute ischaemic stroke arising in themiddle cerebral artery less than 24 hours beoreand with a NIHSS score o 5 or higher. Te patientswere assigned oral administration o a placebo (n =127) or 500 mg/d citicoline (n = 267). reatmentwas continued or 6 weeks, and ollow-up was sub-sequently conducted or 6 weeks. Mean entry timeinto the study was 12 hours ater stroke onset, andthe mean patient age was 71 years in the placebogroup and 71 years in the citicoline group. Al-though the mean baseline NIHSS scores were sim-ilar in both groups, a greater proportion o patients

in the citicoline group had a baseline NIHSS < 8(34% vs. 22%; p < 0.01) in the placebo group. Teplanned primary endpoint (logistic regression or5 BI categories) did not meet the proportional odd

assumption and was thereore not reliable. No sig-nicant between-group dierences were seen inany o the planned secondary variables, including aBI o 95 or higher at 12 weeks (placebo 40%, citico-line 40%) and the mortality rate (placebo 18%, citi-coline 17%). However, a post hoc subgroup analysisshowed that, in patients with moderate to severestroke dened by a baseline NIHSS score o 8 orhigher, treatment with citicoline conerred a great-er chance o achieving complete recovery, denedas a BI = 95 at 12 weeks (21% placebo, 33% citico-line; p = 0.05), whereas no dierences were ound

Figure 20. Evolution o post-concussional symptoms ater one month o treatment with citicoline or placebo. The number o patients reportingeach symptom is shown.

Citicoline

Gastrointestinal

Insomnia

Vision

Tinnitus

Vertigo

Headache

1 month

Baseline

0 1 2 3 4 5 6

(n)

Gastrointestinal

Insomnia

Vision

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Control




J.J. Secades

in patients with mild stroke (i.e., with a baselineNIHSS score < 8). No serious adverse events attrib-utable to the drug were detected, which attests toits saety. Based on these data, citicoline may beconsidered a sae drug that may induce avourableeects in patients with moderate to severe acute is-chaemic stroke.

Te last clinical study conducted in the UnitedStates was the ECCO 2000 study [381]. Tis study had similar characteristics to the previous ones andenrolled 899 patients with moderate to severe acuteischaemic stroke (baseline NIHSS score = 8) aris-

ing in the middle cerebral artery within the past 24hours. Te patients were randomised to receive2,000 mg/d citicoline (n = 453) or placebo (n = 446)orally or 6 weeks, with a subsequent ollow-up or6 weeks. Te primary study endpoint was the pro-portion o patients that had a reduction in theNIHSS scale by 7 or more points at 12 weeks. Atthe end o the study, 51% o the patients in the pla-cebo group and 52% o the patients in the citicolinegroup achieved reductions in the NIHSS scale o 7or more points, with no signicant between-groupdierences. In contrast, there was a trend avour-

ing citicoline in the achievement o complete neu-rological recovery, as dened by a score o 1 or lesson the NIHSS scale (40% with citicoline vs. 35%

with placebo; p = 0.056), and in complete unction-al recovery, as dened by a BI score o 95 or higher(40% with citicoline vs. 35% with placebo; p = 0.108).With regard to the mRS, 20% o patients in the pla-cebo group achieved complete recovery (mRS ≤ 1),as compared to 26% o patients in the citicolinegroup, a dierence that is statistically signicant( p = 0.025). Tere were no dierences in mortality or incidence o serious adverse events betweentreatments, but a signicant decrease was seen inthe worsening o stroke (3% with citicoline vs. 6%with placebo; p = 0.02). However, the occurrence o a new stroke was decreased in patients treated with

citicoline (2.9% with placebo vs. 1.8% with citico-line (i.e., 62.1% risk reduction). A post hoc analysisusing the Generalized Estimating Equations (GEE)method dened by illey et a l [382] assessed the e-ects o citicoline in a multiple outcome global as-sessment and considered the proportion o patientswho had achieved complete recovery in all 3 scalesused (i.e., achieved scores o 0-1 on the NIHSS, 0-1on the mRS and ≥ 95 in the BI at 12 weeks). Citico-line was signicantly superior to the placebo andachieved this complete recovery in 19% o the cas-es, compared to 14% in the placebo group (OR =1.32; 95% CI = 1.03-1.69; p = 0.03).

Te eects o citicoline on the reduction o cer-ebral inarct volume were investigated at the sametime o other clinical study based on clinical out-comes. Te rst analysis was a pilot study to assessciticoline eects on lesion volume, as measured by diusion-weighted magnetic resonance imaging(MRI) in patients with acute cerebral inarction[383]. Tis study recruited 12 patients rom therst clinical study on citicoline in the United States[379]. Lesion growth was seen in 3 o the 4 patientstreated with a placebo, whereas a decrease in lesion

volume was noted in 7 o the 8 patients treatedwith citicoline ( p < 0.01, with the baseline NIHSS

as a covariate). A second, double-blind study de-signed or this purpose (i.e., to measure changes inlesion volume using diusion-weighted techniques)recruited 100 patients who were randomised to re-ceive 500 mg/d citicoline or placebo orally or 6weeks [384]. Tese patients were enrolled within24 hours o symptom onset and had a baselineNIHSS o 5 points or more and a lesion volume inthe cerebral grey matter o 1-120 cm3 in diusion-weighted MRI. Neuroimaging techniques (diu-sion-weighted MRI, 2-weighted MRI, perusion-weighted MRI and MRI angiography) were per-

Figure 21. Outcome in relation to treatment, highlighting the number o good results achieved with citi-coline compared to the control group.

Citicoline

Minimal or

no sequelae

Moderate

sequelae

Vegetative

state

Death

0 5 10 15 20

Patients (n)

Placebo





ormed at baseline and at weeks 1 and 12. Te pri-mary endpoint was progression o the ischaemiclesion rom baseline to the nal assessment at 12weeks, as measured by MRI. Te primary analysisplanned could be perormed in 41 patients treatedwith citicoline and 40 patients treated with place-bo, and no signicant dierences were ound. Frombaseline to 12 weeks, the ischaemic lesion volumeexpanded by 180 ± 107% in the placebo group and34 ± 19% in the citicoline group. A secondary anal-

ysis showed that rom week 1 to week 12, the lesion volume decreased by 6.9 ± 2.8 cm3 in the placebogroup and increased by 17.2 ± 2.6 cm3 in the citico-line group ( p < 0.01). Te high correlation betweenthe lesion volume reduction and clinical improve-ment, regardless o treatment, was a signicantnding and supported the idea o using this meth-odology or assessing stroke treatments. In theECCO 2000 study [381], a substudy was conductedto assess the eects o citicoline on lesion volume[385]. Tis substudy had three objectives. Te rstobjective was to assess the eects o the drug onchronic lesion volume, as measured using MRI 2

sequences in the entire patient sample, althoughthis assessment could only be made in 676 patients.Te second objective was to analyse the eects o citicoline on the change in lesion volume using di-usion-weighted MRI perormed at baseline and atweek 12. A total o 181 patients were recruited orthis second objective, out o which 134 patientswere evaluable. Te third objective was methodo-logical in nature, that is, an attempt was made tocorrelate clinical changes to volume changes andto determine whether lesion volume reduction wasassociated with clinical improvement. No signi-

cant dierences were ound in the assessment o chronic lesion volume (median o 25.0 cm3 or citi-coline and 31.3 cm3 or placebo). Te diusion-weighted study showed that lesions increased 30.1± 20.5%, with a median o –8.7%, in the placebogroup (n = 71), whereas the change in the citicolinegroup (n = 63) was 1.3 ± 14.3%, with a median o –22.9%, a non-signicant dierence ( p = 0.077).However, the dierence was signicant ( p = 0.02)when the logarithm o the change was analysed

and the baseline NIHSS was introduced as a cov-ariate. In this diusion-weighted substudy, 54% o the patients in the placebo group and 67 % o theciticoline-treated patients were shown to have adecreased lesion volume compared to baseline, al-though the dierence was not signicant ( p =0.122). In patients with cortical lesions with vol-umes ranging rom 1-120 cm3 that were analysedat baseline, a lesion increase by 40.5 ± 28.7%, witha median o 4.5%, was seen in patients treated withplacebo (n = 47), whereas in patients receivingtreatment with citicoline (n = 43), the lesion in-creased by 7.3 ± 19.9%, with a median o –23.9%.

Te dierence between groups was statistically signicant ( p = 0.006, median comparison). In thepatient subgroup with initial cortical lesions with

volumes o 1-120 cm3, a decrease in lesion volumeoccurred in 47% o the patients in the placebogroup and in 70% o the patients in the citicolinegroup. Tis dierence was signicant, with a p-

value o 0.028. Te decrease in volume was alsosignicantly correlated with clinical improvementsin patients.

Although the results obtained in studies con-ducted in the United States with oral citicoline or

Table VII. Scores (mean ± SD) obtained by patients beore and ater treatment.

Goup A (placebo + ehabilitation) Goup B (citicoline + ehabilitation)

Beoe Ate Beoe Ate

Attention 95.60 ± 5.73 97.60 ± 2.19 82.00 ± 33.79 90.80 ± 20.57

Alertness 88.40 ± 8.65 96.80 ± 1.79 89.60 ± 17.74 98.80 ± 1.79

Verbal fuency 22.40 ± 9.91 23.60 ± 11.01 24.80 ± 14.65 31.80 ± 9.36 a

Benton test 8.20 ± 3.63 9.40 ± 6.95 8.80 ± 5.45 7.20 ± 3.70

Luria test 62.80 ± 13.24 62.00 ± 11.58 63.20 ± 17.31 71.00 ± 12.98 a

a p < 0.05 vs. beore treatment.




J.J. Secades

the treatment o acute ischaemic stroke were in-conclusive regarding citicoline efcacy or saety improving the outcome o the patients, there was a

trend toward improved prognosis o treated pa-tients. Because there was no neuroprotective drugthat had been shown to be eective in the treat-ment o this severe condition [386] at that time, ameta-analysis was conducted o the results ob-tained with oral citicoline in the treatment o acuteischaemic stroke to examine the eects o the drugon neurological and unctional recovery in patients[387]. Following the methods o the Cochrane Li-brary [388] and the guidelines o the InternationalConerence on Harmonization [389], a compre-hensive literature search was perormed in bothMedline and our own literature database. Tis

search ound that only our double-blind, ran-domised clinical studies had been conducted withoral citicoline or the treatment o acute ischaemicstroke, namely, the our trials that were perormedin the United States [379-381,384]. Te total sam-ple comprised 1652 patients, 686 patients in theplacebo group and 966 patients in the citicolinegroup (381 with 500 mg/d, 66 with 1,000 mg/d and519 with 2,000 mg/d). Te rst analysis was per-ormed in the total patient sample, regardless o dose. With regard to complete neurological recov-ery (NIHSS ≤ 1) at 3 months, the odds ratio was1.22 (95% CI = 0.98-1.52), which did not reach sta-

tistical signicance ( p = 0.07). In contrast, signi-cant dierences avouring citicoline were obtainedin the analysis o patients who achieved virtually complete recovery in activities o daily living (BI ≥95) at 3 months (OR = 1.26; 95% CI = 1.02-1.55; p =0.01) and unctional recovery at 3 months, denedas a score o 1 or less in the mRS (OR = 1.36; 95%CI = 1.06-1.74; p = 0.01). Because the experiencegathered in the above clinical studies suggestedthat the drug is more eective in patients withmoderate to severe acute ischaemic stroke (base-line NIHSS ≥ 8), databases rom the original stud-ies were obtained, and patients who met this crite-

rion and had optimum unctional status prior tothe stroke (mRS ≤ 1) were selected. Out o the en-tire sample, 1372 patients met these criteria andunderwent the same assessment. In this case, themeta-analysis ound statistically signicant dier-ences or all variables analysed (able VIII).

o continue the analysis o these data, a poolingdata analysis was perormed [390] using individualdata rom each patient. Tis additional analysis in-cluded a sample o 1372 patients who met the es-tablished criteria o severity (baseline NIHSS ≥ 8),prior unctional status (mRS ≤ 1), a therapeutic

window not longer than 24 hours and consistentneuroimaging. Te efcacy endpoint selected wastotal recovery at 3 months in the three scales ana-

lysed (mRS ≤ 1 + NIHSS ≤ 1 + BI ≥ 95), using thepreviously described GEE analysis [382]. Amongthese 1372 patients, 583 received a placebo and 789received citicoline (264 patients received 500 mg,40 patients received 1,000 mg and 485 patients re-ceived 2,000 mg). otal recovery at 3 months wasachieved in 25.2% o the patients treated with citi-coline and 20.2% o the patients in the placebogroup (OR = 1.33; 95% CI = 1.10-1.62; p = 0.003),and the most eective dose was 2,000 mg. Tisdose resulted in complete recovery at 3 months in27.9% o the patients who received the drug (OR =1.38; 95% CI = 1.10-1.72; p = 0.004) (Figure 22). In

addition, citicoline saety was similar to that o theplacebo.Te preliminary results o a Cochrane review

on the eects o choline precursors, including citi-coline, in the treatment o acute and subacutestroke were reported in 2002 [391]. Tis meta-anal-

ysis collected data rom 8 double-blind studiesconducted with citicoline at doses ranging rom500 to 2,000 mg daily, administered both orally and intravenously. Despite study heterogeneity,citicoline treatment was associated with decreasesin late mortality and disability rates: citicoline611/1119 (64.6%) vs. placebo 561/844 (54.4%) (OR =

0.64; 95% CI = 0.53-0.77; p < 0.00001). o decreasethe heterogeneity, the analysis was restricted to the4 studies with large sample sizes (n > 100), andthe positive eect persisted: citicoline 574/1048(54.58%) vs. placebo 500/773 (64.7%) (OR = 0.70;95% CI = 0.58-0.85; p < 0.0003). In the saety anal-

ysis, no dierences were ound in the mortality rate between citicoline and the placebo. Te au-thors concluded that the ormal meta-analysis o citicoline studies in acute and subacute stroke sug-gests a benecial and substantial eect o the drug,with absolute reductions by 10-12% in the long-term disability and mortality rate (i.e., the number

o patients with scores o 3 or higher in the mod-ied Rankin scale was signicantly decreased).Tese results agree with those previously reportedor the pooled data analysis [390].

A pooled data analysis that evaluated the eecto citicoline on the increase in cerebral inarct sizeis also available [392]. Data used in this analysiscame rom two studies in which neuroimaging datahad been obtained using MRI techniques [381,384].Te primary endpoint in this analysis was the per-cent change in inarct size rom the start o thestudy to the end o the study, 3 months later. Data





were available or 111 patients receiving a placebo,41 patients treated with citicoline 500 mg/d/6 weeksand 62 patients treated with citicoline 2,000 mg/d/

6 weeks. Patients receiving the placebo experienceda mean increase o 84.7 ± 41.2%, and a dose-de-pendent eect was associated with citicoline: amean increase o 34.0 ± 18.5% was observed with500 mg citicoline, and an increase o 1.8 ± 14.5%was observed with 2,000 mg citicoline.

Te benets shown in these systematic reviewswere also associated with reductions in the costs o integral treatment o patients with acute ischaemicstroke [393], with an average cost savings o €101.2-126.4 per patient treated. In patients with acute is-chaemic stroke, treatment with placebo was moreexpensive and less eective in the scenarios o in-

patient care and inpatient plus outpatient care a-ter hospital discharge.Sobrino et al [394] investigated whether admin-

istration o citicoline, started in the acute phase o stroke, could increase the endothelial progenitorcell (EPC) concentration in patients with ischaemicstroke. Forty-eight patients with rst-ever non-lac-unar ischaemic strokes were prospectively includ-ed in the study within 12 hours o symptom onset.Patients received treatment (n = 26) with oral citi-coline (2,000 mg/day/6 week or no treatment (n = 22).EPC colonies were quantied as early outgrowthcolonies orming a unit-endothelial cell (CFU-EC)

at admission (previous to citicoline treatment) andday 7. Te EPC increment during the rst week wasdened as the dierence in the number o CFU-ECbetween day 7 and admission. Te CFU-EC weresimilar at baseline between patients treated withciticoline and non-treated (7.7 ± 6.1 vs. 9.1 ± 7.3CFU-EC; p = 0.819). However, patients treated withciticoline and recombinant tissue-plasminogen ac-tivator (rt-PA) had a higher EPC increment thanpatients treated with citicoline only or those whowere not treated (35.4 ± 15.9 vs. 8.4 ± 8.1 vs. 0.9 ±10.2 CFU-EC; p < 0.0001). In a logistic model, citi-coline treatment (OR = 17.6; 95% CI = 2.3-137.5;

p = 0.006) and co-treatment with citicoline andrt-PA (OR = 108.5; 95% CI = 2.9-1094.2; p = 0.001)were independently associated with an EPC incre-ment ≥ 4 CFU-EC. Te authors concluded that citi-coline administration and citicoline and rt-PA co-administration increase the EPC concentration inacute ischaemic stroke. However, the molecularmechanism by which citicoline increases the con-centration o EPCs remains to be claried.

Regarding saety, a drug surveillance study involving 4191 acute stroke patients treated with citi-coline was conducted in South Korea [395]. Te

aim o this study was to determine the efcacy andsaety o oral citicoline in Korean patients withacute ischaemic stroke. Oral citicoline (500-4,000mg/day) was administered within 24 h ater acuteischaemic stroke in 3,736 patients (early group) andlater than 24 h ater acute ischaemic stroke in 455patients (late group), and the treatments continuedor at least 6 weeks. For the efcacy assessment, theprimary outcomes were the patients’ scores ob-tained with a short orm o the National Institutes

Table VIII. Results obtained ater three months on individual scales.

Studies (n) Patients (n) Peto odds atio (95% CI) p

NIHSS ≤ 1 4 1,372 1.34 (1.05-1.71) 0.020

mrS ≤ 1 4 1,351 1.45 (1.11-1.90) 0.007

BI ≥ 95 4 1,372 1.28 (1.03-1.59) 0.003

95% CI: 95% condence interval; NIHSS: National Institutes o Health Stroke Scale; mRS: modied Rankin Scale;BI: Barthel index.

Figure 22. Estimated probabilities (GEE analysis) o overall recovery three months ater onset o symp-toms. Overall recovery is dened as a consistent and persuasive dierence in the proportion o patientswho achieve scores o NIHSS ≤ 1, BI ≥ 95 and mRS ≤ 1 at the same time.

0 5 10 15 20 25 30

(%)

Placebo

Citicoline 2000 mg

Placebo

Citicoline 500 mg

Placebo (total)

Citicoline (total)

21,9

p = 0.0043

p = 0.0782

p = 0.0034

27,9

15,7

20,8

20,2

25,2




J.J. Secades

o Health Stroke Scale (s-NIHSS), a short orm o the Barthel Index o activities o daily living (s-BI)and a modied Rankin Scale (mRS) at enrolment,

ater 6 weeks and at the end o therapy or thosepatients with extended treatment. All adverse re-actions were monitored during the study periodor saety assessment. All measured outcomes, in-cluding the s-NIHSS, s-BI and mRS, were improvedater 6 weeks o therapy ( p < 0.05). Further im-provements were observed in 125 patients whocontinued citicoline therapy or more than 12weeks compared with those who ended therapy atweek 6. Improvements were more signicant in thehigher dose group (≥ 2,000 mg/day) ( p < 0.001).Te s-BI scores showed no dierences between theearly and late groups at the end o therapy. Citico-

line saety was excellent; 37 side eects were ob-served in 31 patients (0.73%). Te most requentside eects were nervous system-related symptoms(8 o 37, 21.62%), ollowed by gastrointestinal symp-toms (5 o 37, 13.5%). Oral citicoline improved neu-rological, unctional and global outcomes in pa-tients with acute ischaemic stroke without signi-cant saety concerns.

A pilot study has been published on the saety and efcacy o citicoline or the treatment o pri-mary intracerebral haemorrhage [396]. Tis study recruited 38 patients, aged 40 to 85 years, who werepreviously independent and were enrolled within 6

hours o symptom onset caused by primary intrac-erebral haemorrhage, as diagnosed by neuroimag-ing tests (C or MRI). Patients had a baseline se-

verity categorised by a score higher than 8 in theGlasgow Coma Scale and a score higher than 7 inthe NIH stroke scale. Te patients were randomisedto 1 g/12 h o citicoline or placebo i.v. or orally or 2weeks. Te primary study objective was to assesstreatment saety based on the occurrence o ad-

verse events. Te efcacy endpoint selected wasthe proportion o patients who had scores o 0-2 onthe modied Rankin scale at 3 months. Nineteenpatients were included in each group, and the

groups were perectly matched with regard to base-line characteristics. Te adverse event rate did notdier between groups (4 cases each). With respectto efcacy, one patient rom the placebo group wasrated as independent (mRS < 3), compared to 5 pa-tients rom the citicoline group (OR = 5.38; 95% CI= 0.55-52; ns). In conclusion, citicoline appears tobe a sae drug or patients with primary intracere-bral haemorrhage, which may allow citicoline to begiven to patients with clinical signs suggestive o stroke beore neuroimaging tests are perormedand at an earlier time than usual. With respect to

efcacy, very promising data or a avourable out-come have been obtained, but they should be con-rmed in a larger study. Recently, Eribal et al [397]

communicated the results o the RICH trial per-ormed in the Philippines. Tis study was con-ceived to investigate the role o neuroprotectants,particularly citicoline, in intracerebral supratento-rial haemorrhage, which, to date, has a paucity o data on proven eective therapies. Tis trial was arandomised, double-blind, placebo-controlled, multi-centre, parallel group study on patients with rst-time supratentorial intracerebral haemorrhages.Te patients were given either 4 g citicoline or aplacebo or 14 days rom the index stroke. A totalo 182 patients were enrolled in the study. Temean age was similar or both groups (56.90 ±

11.45 or citicoline and 57.61 ± 11.83 or placebo).Te comorbidities were similar, except or the sig-nicantly higher number o diabetic patients in theciticoline group. Te results showed that therewere more patients with avourable Barthel Indexscores (2.2% vs. 0%, 9.2% vs. 8.5% and 50.8% vs.31.9%) in the citicoline group than in the placebogroup, respectively. However, the dierence wasonly clinically signicant ater day 90. Patients hadmore avourable mRS scores (7.9% vs. 13.4%, 18.2%

vs. 20.3% and 46.1% vs. 33.8%) in the citicolinegroup than in the placebo group; however, this di-erence occurred only on day 90 and was not statis-

tically signicant. Te NIHSS did not dier be-tween groups, with scores o 76.3% vs. 75.6%, 93.9% vs. 91.9% and 96.8% vs. 94.3%, respectively. Mortal-ity was slightly higher in the citicoline group (11 pa-tients) than in the placebo group (10 patients), butthis dierence was not statistically signicant. Teincidence o adverse events in both groups was notsignicantly dierent. For these authors, citicolinewas eective in improving BI and mRS scores onthe attainment o unctional independence begin-ning on day 90 post-stroke compared to the place-bo. Iranmanesh and Vakilian demonstrated the e-ciency o citicoline in increasing the muscular

strength o patients with nontraumatic cerebralhaemorrhages in a double-blind, randomised clini-cal trial [398]. Tus, citicoline could play a role inthe pharmacological treatment o patients with in-tracerebral haemorrhages [399].

In a new meta-analysis study that included alldouble-blind studies perormed with citicoline inacute stroke patients, Saver [400] suggested that citi-coline has benecial eects on long-term death anddisability rates in this type o patient (Figure 23).

Ortega et al [401] planned a study with the goalo assessing the efcacy and saety o a citicoline





treatment rom the rst stroke event until thesixth month to preserve neurocognitive unctions.Tey included 347 patients with rst stroke events.Cognitive unctions were evaluated by a completeneuropsychological battery six weeks (± 3 days)and six months (± 7 days) ater the strokes. Allsubjects received citicoline treatment (2 g/d) untilthe sixth week. Randomly, approximately hal o thesample continued the citicoline treatment (1 g/d)until the sixth month. Tose patients who were

not treated with citicoline showed statistical ly sig-nicant higher cognitive impairment in attentionand executive unctions (OR = 1.725; 95% CI =1.090-2.729; p = 0.019) and temporal orientation(OR = 1.728; 95% CI = 1.021-2.927; p = 0.042). Teauthors concluded that citicoline treatment untilthe sixth month in patients with rst ischaemicstroke events is sae and efcient in improvingneurocognitive unctions.

In conclusion, it has been adequately shown thatpatients with acute stroke and sequelae may benetrom citicoline treatment by achieving better unc-

tional and neurological recovery and that this is asae and well-tolerated treatment, as recognised by

various studies [402-411] and some agencies [412-413]. Tere is also a new, ongoing trial in Europe,the ICUS trial [414-416], to corroborate the dataobtained with citicoline.

Cognitive disorders

Various investigations in recent years on brain age-

ing have led to the increased importance o chang-es in neuronal metabolism as a actor that is involved in the pathophysiology o this process. Inthe senile brain, there is a general decrease in en-zyme activities related to energy metabolism andmore specic biochemical changes aecting lipidand nucleic acid metabolism. It has also beenshown that specic changes in certain neurotrans-mitters (dopamine, acetylcholine) and hormones(growth hormone, prolactin) are associated in bothageing processes and certain presenile and senilediseases [417].

Figure 23. Death or dependency at long-term ollow-up. Forest plot meta-analysis o the eect o citicoline vs. control in trials enrolling patientswith ischaemic stroke, intracerebral haemorrhage and stroke without imaging conrmation o subtype. C010: citicoline 010 trial; CI: condenceinterval; CSSG: Citicoline Stroke Study Group; d: degree o reedom; Fixed: xed-eects model; M-H: Mantel-Haenszel estimate. Reprinted with

permission rom J.L. Saver. Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair . Rev Neurol Dis 2008;5: 167-77.




J.J. Secades

As shown in the aorementioned experimentalstudies, citicoline increases phospholipid synthesisand glucose uptake in the brain in conditions inwhich these activities are decreased. Citicoline also

inuences the metabolism o neurotransmittersand increases dopamine synthesis in certain brainregions. Based on these acts, many clinical trialshave been conducted to assess the efcacy o citi-coline in the treatment o cognitive disorders as-sociated with brain ageing, chronic cerebral vascu-lar disease and dementia [418]. Using magneticresonance spectroscopy techniques, citicoline hasbeen shown to stimulate phosphatidylcholine syn-thesis in the brain [419-421] and improve the ener-getic cerebral metabolism o elderly subjects [422],which is related to improvements in their cognitivecapacities [423], particularly memory [424-426]

and reaction time [427]. In addition, an eect onpreventing cognitive impairment ater a rst-everischaemic stroke has been described [401].

In one early study conducted in this eld, Ma-dariaga et al [428] showed that, in a group o emalesenile patients, citicoline treatment induced im-provements in memory, cooperation and the ca-pacity or a relationship with the environment.Fassio et al [429] discussed the value o citicolinein psychogeriatrics and stressed that the use o cit-icoline as background treatment allows the reduc-tion o the dosages o psychoactive drugs that are

routinely used in psychogeriatrics. Many studieshave shown the value o citicoline or treating thesenile cerebral involution, decreasing its character-

istic symptoms [430-439]. In an open-label, con-trolled study conducted on a group o 30 patientswith senile involutive brain disease, Lingetti et al[430] achieved symptomatic improvements in83.3% o cases and emphasised the absence o treat-ment-related side eects. Stramba-Badiale and Sci-llieri [431] showed signicant improvements inscores o the Fishback Mental Status Questionnairein a group o 24 elderly subjects ater 20 days o treatment with 500 mg/d i.m. citicoline. Bonavita etal [432] emphasised the efcacy o citicoline in pro-moting changes in certain neuropsychiatric symp-toms, including memory and attention, in senile

patients without causing side eects. Lozano et al[433] reviewed a series o 2067 elderly patients whowere treated with citicoline at doses o 300-600mg/d or 2 months. able IX gives the results ob-tained based on the remission and improvement o certain neuropsychic symptoms. Palleschi and Ca-pobianco [434] showed signicant improvementsin scores o the SCAG and Mini-Mental State Ex-amination scales in patients with pathological brainageing ollowing citicoline treatment. In a multi-centre study with 502 senile patients, Schergna andLupo [435] showed that citicoline induced signi-cant improvements in attention, behaviour, rela-

tional lie and independence. No side eects oc-curred that were associated with this treatment.Suryani et al [436] showed that citicoline was eec-tive in the treatment o memory decits in the eld-erly, achieving signicant and progressive improve-ments in all parameters analysed (able X). Citico-line is able to improve the scores o senile patientsin various scales, such as the Plutchik scale [437],rail Making est, Randt Memory est and ou-louse-Piéron Attention est [438,439].

Te administration o citicoline to healthy adultindividuals has shown that citicoline acts on theanterior pituitary gland, inducing increased growth

hormone secretion and decreased prolactin secre-tion due to the activation o the dopaminergic sys-tem [440,441]. Ceda et al [442] showed that citico-line increases growth hormone secretion, both ba-sal hormone secretion and hormone secretion thatis stimulated by the growth hormone-releasinghormone, in elderly patients. Tis secretion is im-paired in such individuals and is impaired to aneven greater extent in patients with degenerativebrain diseases.

One o the main causes o cognitive impairmentin the elderly is chronic cerebral vascular disease,

Table IX. Percentage remission and symptomatic improvement ( p < 0.001 or each symptom in relationto the onset o treatment).

Patients (n) remission (%) Impovement (%)

State o mood 1521 38.2% 40.9%

Emotivity 1559 36.9% 39.7%

restlessness 1504 41.3% 34.1%

On initiative 1378 35.8% 32.9%

Shot-tem memoy 1614 26.0% 45.5%

Inteest in the envionment 1410 38.3% 34.5%

Appeaance 1132 40.0% 26.9%

Vetigo 1463 59.4% 31.3%

Mobility 1234 35.2% 30.5%

Headache 1425 57.7% 31.2%





also called cerebral insufciency, whose maximumdegree o clinical expression is vascular dementia.A multicentre, randomised, double-blind study o citicoline vs. placebo assessed the efcacy o citico-line or the treatment o patients with chronic vas-cular disease [443]. In this study, 33 patients re-

ceived treatment with 1 g/d citicoline or saline viaintravenous inusion or 28 days. At the end o thetreatment period, signicant improvements werenoted in the citicoline-treated group in the Bender-Gestalt test, Hamilton scale or depression, Park-side scale, neurological assessment scale and atten-tion test. Falchi Delitalia et al [444] and Moglia etal [445] noted that the observed clinical improve-ment was associated with improved EEG tracing inthese patients. Merchan et al [446] showed gradualimprovements in symptoms associated with cere-brovascular insufciency in a group o 40 elderly patients treated with citicoline at a dose o 1 g/d

i.m. or 60 days.Agnoli et al [447] conducted a double-blindstudy in 100 patients with chronic cerebral vascu-lar disease in whom the eectiveness o 1 g/d/28 di.v. citicoline administration was assessed com-pared to a placebo. Ater the treatment period, thegroup o citicoline-treated patients showed statisti-cally signicant improvements in the scores ob-tained in the Hamilton scale or depression, in themodied Parkside behaviour rating scale and inpsychometric and observational tests. It was con-cluded that citicoline improves perceptual-motor

capacity and attention in these patients in additionto having a stabilising eect on behaviour. Sinora-ni et al [448], Motta et al [449] and Rossi andZanardi [450] achieved similar results in their re-spective studies. Te best clinical and behaviouralresults in neuropsycholigical tests were observed

in patients with diuse cerebral vascular disease[451-454].Eberhardt and Derr [455] conducted a double-

blind crossover study to assess the efcacy and tol-erability o citicoline in patients with senile cere-bral insufciency. Tis study enrolled 111 patientswith a mean age o 74.6 ± 6.9 years and a clinicaldiagnosis o senile cerebral insufciency. Ater aplacebo washout period, two homogeneous groupswere ormed, one o which received treatment with600 mg/d p.o. citicoline or 5 weeks and placebo or5 additional weeks, with a placebo washout periodbetween both treatments. Te reverse administra-

tion order was used in the other group. Controlswere perormed at 2, 7, 9 and 12 weeks. Citicolinesignicantly improved the clinical status in all sixtests used (number recall, labyrinth, number con-nection, Neuropsychological Assessment Scale orNAS, Geriatric Observation Scale or NAB andSCAG) as initial treatment and provided a statisti-cally signicant additional improvement as a sec-ond treatment ater placebo, which achieved somedegree o improvement in 5 o the 6 tests. Between-subject comparisons also showed a superior efca-cy o citicoline. able XI shows the proportions o

Table X. Scores or the repetition o digits, an adaptation by Wechsler o the Stanord-Benet logical history test, the Bali image memorisation testand memory decits and physical disorders reported by patients beore and ater treatment with citicoline. Values are expressed as means ± SD.

Baseline(n = 10)

Ate teatment

1 eek(n = 10)

2 eeks(n = 10)

3 eeks(n = 6)

Diect epetition o digits 14.6 ± 4.6 19.6 ± 5.6 b 20.2 ± 4.5 b 22.8 ± 6.0 b

revese epetition o digits 5.60 ± 4.1 7.30 ± 3.4 b 11.3 ± 7.1 b 12.1 ± 7.7 b

Logic histoy test 6.10 ± 4.4 9.60 ± 3.8 b 12.7 ± 3.7 b 13.6 ± 4.8 b

Bali images test 5.20 ± 3.2 9.30 ± 3.5 b 11.7 ± 3.4 b 12.0 ± 2.4 b

Memoy defcits 2.5 ± 0.9 1.00 ± 0.9 a 0.30 ± 0.4 b 0.30 ± 0.5 b

Physical disodes 2.3 ± 0.9 1.00 ± 0.8 a 0.20 ± 0.6 b 0.10 ± 0.4 b

a p < 0.05; b p < 0.01, vs. baseline values.




J.J. Secades

patients who improved in each treatment phase inboth groups. No treatment-associated severe sideeects were seen. Te authors concluded that theseresults support the efcacy o citicoline or thetreatment o senile cerebral insufciency and dem-onstrate the excellent tolerability o the drug in

geriatric patients. Tese benets are due to the ca-pacity o citicoline to inhibit phospholipid degra-dation in neuronal membranes, increase cholineplasma levels and activate the synthesis o struc-tural phospholipids and the synthesis and releaseo catecholamines. Te eects o citicoline on testimprovement were also shown to persist aterswitching to placebo, suggesting that they are relat-ed to the neuronal metabolic process that restoresand maintains neuronal unction.

Chandra [456] reported the results o a double-blind study on the treatment o multi-inarctiondementia with citicoline. Tis study enrolled 146

patients who were randomised into two groups,one o which received treatment with 750 mg/d i.v.citicoline and the other receiving saline or 2months, although the ollow-up period was pro-longed or up to 10 months. At the end o the treat-ment period, citicoline-treated patients showedsignicant improvements in MMSE scores. Incontrast, these scores slightly worsened in the pla-cebo group. Ater 10 months, citicoline-treatedpatients achieved sustained improvement, where-as patients in the placebo group continued toworsen.

Piccoli et al [457] reported the results o a dou-ble-blind study conducted in 92 patients withchronic cerebral vascular disease treated with citi-

coline (1,000 mg/d i.m.) or placebo in 2 treatmentcycles o 4 weeks each, separated by a one-weekinterval. Forty-six patients were randomised toeach group, and both groups were ully matchedwith regard to cognitive impairment. Psychomet-ric assessments were perormed using the ou-louse-Piéron test (attention to non-verbal stimuli),Randt memory test and SCAG scale (a measure o behaviour and emotional control). A between-group comparison revealed signicant improve-ments in the citicoline group in the attention tests,with a decreased number o incorrect answers inthe oulouse-Piéron test ( p < 0.05), in mnesic ca-

pacities according to the general inormationsubtest o the Randt memory tests ( p < 0.05) andin the aective disorder score on the SCAG scale( p < 0.02). In addition to being clinically eective,citicoline was shown to be a very sae drug, as noadverse eects associated with treatment were de-tected.

Capurso et al [458] assessed the efcacy o citi-coline or treating chronic cerebrovascular diseasein a multicentre, double-blind, placebo-controlledstudy. Cognitive and behavioural unctions wereassessed using psychometric scales and tests in 31patients who were randomised to receive citicoline

(17 cases) or placebo (16 cases). Ater a 2-weekwashout period, 3 treatment periods, each lasting28 days, were started. Patients were given 1 g/d o citicoline or placebo via the intramuscular route. A1-week washout period was let between each treat-ment cycle. Various cognitive unctions improvedin the group o citicoline-treated patients, parti-cularly short-term and long-term memory. TeRandt Memory est showed constant improve-ments in several subtests, and cognitive and atten-tion efciency signicantly improved. Te GBSscale, which assesses behavioural indices, also showedimprovements associated with citicoline treatment.

Te authors concluded that patients treated withciticoline showed signicant improvements in cog-nitive unctions, whereas placebo-treated patientsshowed no avourable trends. In addition, good tol-erability o the drug was also reported.

Cohen et al [459] showed no benecial eects o citicoline in their pilot study in patients with vas-cular dementia, according to current diagnosticcriteria.

Using positron emission tomography, anaka etal [460] correlated cognitive improvement with asignicant increase in cerebral blood ow in pa-

Table XI. Percentage o patients who improved in each group in relation to treatment initiation with citi-coline or placebo.

Goup I Goup II

Citicoline Placebo Placebo Citicoline

Numeical counting 47 31 21 52

Labyinth 73 69 71 83

Numeical connection 67 76 67 87

NAS 57 41 44 69

NAB 63 57 48 67

SCAG 80 73 65 83

NAS: Neuropsychological Sel-Assessment Scale; NAB: Gerontopsychological Observation Scale; SCAG: SandozClinical Assessment Geriatric Scale.





tients with vascular dementia who received citico-line treatment (1 g/d/1 week i.v.).

Lozano [461] reported the results o a study con-

ducted by the Iberian-American Group or thestudy o Alzheimer’s disease and Longevity (GIAL),aimed at assessing the status and course, ater one

year, o a group o patients with dementia-like psy-chic and organic impairment ollowing diagnosisand classication o its cause as degenerative, vas-cular or mixed and treatment with oral citicoline.Citicoline 600 mg/d p.o. was administered or one

year to 314 patients with a mean age o 75.02 ± 7.72 years to assess the course o their dementia duringthat time. Te dementia was rated as degenerativein 41.1% o cases, whereas vascular dementia ac-counted or 39.5% o the cases and mixed dementia

accounted or 11.4% o the cases. Te MMSE andBI were used or assessment, and controls wereperormed at months 1, 3 and 12. MMSE scoressignicantly improved in vascular and mixed de-mentia and remained stable, with a trend towardimprovement, in degenerative dementia. BI scoresshowed statistically signicant improvements ineach control and or each type o dementia. Teseresults suggest that citicoline has a benecial eecton the long-term course o dementia and is a saetreatment.

Corona et al [462] pointed out that the benetso citicoline in the treatment o patients with de-

mentia could be partly due to the ability o thedrug to improve the activity o the noradrenergic,dopaminergic and serotonergic systems, as shownin a study assessing the changes over time in theCSF and urinary levels o metabolites rom themonoamines involved in these systems duringthe treatment o patients with senile dementia o the Alzheimer type.

Cacabelos et al [463] conducted a study to as-sess the therapeutic eects o citicoline in demen-tia patients. Tis study recruited 40 patients whowere distributed into 4 groups: (1) 10 healthy eld-erly subjects; (2) 10 patients with early-onset Al-

zheimer’s disease; (3) 10 patients with late-onsetAlzheimer’s disease; and (4) 10 patients with multi-inarction dementia. Tese patients received treat-ment with citicoline at a dose o 1 g/d p.o. or 3months. Ater this treatment period, all groupsdisplayed signicant improvements in MMSEscores (Figure 24) and a signicant antidepressanteect, as assessed by the Hamilton scale or de-pression (Figure 25). Patients with early-onsetAlzheimer’s disease were ound to have signi-cantly higher interleukin 1β (IL-1β) plasma levelsat baseline compared to all other groups, revealing

the participation o a neuroimmune change in thepathophysiology o Alzheimer’s disease. Ater citi-coline treatment, IL-1β plasma levels were normal-

ised, which suggests that this drug has a certainimmunomodulatory action. In a subsequent phaseo their study, this group showed that in patientswith Alzheimer’s disease, citicoline not only im-proved cognitive unction but also improved cere-brovascular unction, as assessed using transcra-nial Doppler ultrasonography [464]. Te neuroim-mune eect o the drug was demonstrated by thendings that citicoline therapy decreased hista-mine plasma levels that are abnormally elevated inpatients with Alzheimer’s disease [465] and in-creases the plasma levels o tumour necrosis actoralpha or NFα [466].

Tis same group recently published the resultso a double-blind, randomised, placebo-controlled,pilot study where citicoline (1 g/d/12 weeks p.o.) orplacebo was administered to 30 patients with mildto moderate senile dementia o the Alzheimer type[467]. As compared to the 17 patients treated withplacebo, patients receiving citicoline who had apositive APOE ε4 genotype showed a signicantimprovement in their cognitive capacity, as as-sessed with the ADAS scale ( p < 0.05). As seen pre-

viously, citicoline was shown to increase cerebralblood ow and improve bioelectric activity in thebrain.

Soto et al [468] showed the value o the thera-peutic association o citicoline, piracetam and a di-hydropyridine calcium channel blocker, either ni-cardipine or nimodipine, or the treatment o se-nile dementia o the Alzheimer type. Cacabelos etal [469] also advocated a multiactorial treatmentthat would include citicoline or Alzheimer’s dis-ease in genotyped patients or this disease.

In a systematic review published by the Co-chrane Library, Fioravanti et al [470] examined theeects o citicoline in the treatment o cognitive,emotional and behavioural decits associated withchronic brain disorders in the elderly. Fourteen

studies were included in this review. Some o theincluded studies did not present numerical datathat were suitable or analysis. Te description o participants varied over the years, the type and se-

verity o the disorders varied and the participantsranged rom aged individuals with subjectivememory disorders to patients with vascular cogni-tive impairment (mild to moderate), vascular de-mentia, or senile dementia (mild to moderate).Seven studies observed subjects or a period o 20-30 days, one study had a duration o 6 weeks, ourstudies used periods extending over 2 and 3 months,




J.J. Secades

one study observed continuous administrationover 3 months and one study was prolonged, with12 months o observation. Te studies were hetero-geneous in dose, modalities o administration, in-clusion criteria or subjects and outcome measures.Results were reported or the domains o attention,memory testing, behavioural rating scales, globalclinical impression and tolerability. Te reactiontime was used as a measure o attention, and re-

sults were obtained rom seven o the includedstudies with a total o 790 subjects, 384 in the citi-coline group and 406 in the placebo group. Usingthe standardised mean dierence (SMD) and axed-eect model, the summary eect size was–0.09 (95% CI = –0.23 to 0.05), and there was littleeect o CDP-choline on attention. Te meta-anal-

ysis o memory tests rom ten studies included atotal o 924 subjects, 456 in the citicoline groupand 468 in the placebo group. Te size o the eecton memory was 0.38 (95% CI = 0.11-0.65], whichwas statistically signicant. Using six studies that

reported memory test results in 675 participantswith cognitive decits associated with cerebrovas-cular disorders, the meta-analysis o memory unc-tion revealed homogeneous results, and there wasevidence o a statistically signicant positive eecton memory (SMD = 0.22; 95% CI = 0.07-0.37). Be-haviour was measured using ve dierent scales ineight studies with 844 subjects, 412 in the citico-line group and 432 in the placebo group. Tere was

evidence o a positive eect o citicoline on behav-iour (SMD = –0.60; 95 CI = –1.05 to –0.15) usingthe random-eects model. Te evidence o benetrom global impression was stronger using a xed-eect model, and the Peto odds ratio or improve-ment in subjects treated with citicoline as opposedto subjects treated with placebo was 8.89 (95% CI =5.19-15.22). Te nding that citicoline tended to beassociated with ewer adverse eects than the pla-cebo was relevant, but this nding was not statisti-cally signicant. According to the authors, urtherresearch with citicoline should ocus on longer-

Figure 24. Eects o citicoline on cognitive unction assessed using the MMSE in healthy older subjects (control), patients with early-onset Al-zheimer’s disease (EOAD) or late-onset Alzheimer’s disease (LOAD) and patients with multi-inarct dementia (MID). a p < 0.02; b p < 0.01.

Baseline

40

35

30

25

20

15

10

5

0 M i n i - M e n t a l S t a

t e E x a m i n a t i o n ( M M S E )

Control EOAD LOAD MID

Final

a

a

a

b





term studies in subjects who have been diagnosedwith currently accepted standardised criteria, es-pecially or vascular mild cognitive impairment or

vascular dementia.Tere are many studies on the use o citicolineor the treatment o cognitive disorders and de-mentia, and all have shown that this drug inducesimprovements in cognitive and behavioural im-provements. Deutsch et al [471] are studying theassociation o citicoline plus galantamine in schizo-phrenia. Te drug may be more eective or mildcognitive disorders [452-454,472,473] and cases o chronic cerebral vascular disease [474,475]. In ad-dition, citicoline has benecial eects on neuro-physiological and neuroimmune changes.

Other clinical experiences

Parkinson’s disease

Although levodopa continues to be the centraltherapeutic agent in Parkinson’s disease, it haswell-known limitations, the main limitation beinga progressive loss o efcacy that is oten evidentater 3-5 years o treatment. Tereore, it seemswarranted to use other drugs that can be adminis-tered in association with levodopa to allow or adecrease in the dosage o levodopa or even admin-istered as the only medication in the early stages o the disease. Te use o citicoline has been tested

or this purpose because o its previously analysedcapacity to increase dopamine availability in thestriatum and act as a dopaminergic agonist. Citico-line is eective in various experimental models,and its use in Parkinson’s disease is thereore ac-cepted [476].

In a double-blind crossover study conducted on28 Parkinsonian patients comparing 600 mg/d/10 d i.v. citicoline to a placebo, Ruggieri et al [477]showed that citicoline is an eective treatment orthese patients by achieving improvements in as-sessments o bradykinesia, rigidity and tremor andin scores o the Webster scale and the Northwest-

ern University Disability Scale (NUDS). Te sameinvestigators later obtained similar results in anextension o the aorementioned study [478]. Tey subsequently tested the eects o citicoline in twogroups o patients with Parkinson’s disease [479].Te rst group included 28 patients who had notpreviously received treatment, and the secondgroup included 30 patients who were already re-ceiving treatment with levodopa and carbidopa orat least 2 months beore the study and in whom thedosage had been stabilised at the minimum eec-tive level. Te same methods were used as in previ-

ous studies by these investigators, that is, a double-blind crossover study comparative to a placebo.reatment was administered or 20 days at a dose

o 500 mg/d by a parenteral route. Clinical assess-ments were perormed on days 10 and 20, coincid-ing with the change in treatment, according tothe study design. reatment with citicoline pro-

vided statistically signiicant improvements inthe Webster scale, NUDS and the assessment o bradykinesia in both patient groups. Rigidity alsoimproved in both groups, although this improve-ment only reached statistical signicance in thepreviously treated group o patients. remor alsoimproved in both groups, but statistical signi-cance was not reached.

Eberhardt et al [480-482] showed that combin-

ing citicoline with levodopa treatment allows a 50%reduction in the dose o levodopa, minimising theside eects associated with levodopa therapy. Tus,or this group o investigators, citicoline representsa useul alternative in patients requiring a reduc-tion in levodopa doses and, moreover, the additiono citicoline to a treatment with levodopa may re-lieve decompensation states in the course o par-kinsonism [483].

Loeb et al [484] conducted a multicentre, dou-ble-blind study with citicoline or the treatment o Parkinsonian patients. In this study, 65 patientswere randomised to a group to which citicoline 1

g/d i.v. was added to their treatment or to a placebogroup. reatment lasted 21 days. All patients con-tinued their underlying treatments with levodopaplus mianserin or benserazide or at least 8 weeks.Te authors ound signicant dierences betweenciticoline and the placebo ater 14 and 21 days o treatment in all parameters assessed by the Websterand NUDS scales. Tey also noted that patientstreated with citicoline experienced signicantworsening 45 days ater the medication was dis-continued, thus showing the efcacy o citicolineas an adjuvant treatment to levodopa in patientswith Parkinson’s disease.

Acosta et al [485] treated 61 Parkinsonian pa-tients with citicoline. Out o 61 patients, 48 werealready receiving treatment with levodopa. Eachpatient received two treatment courses. In the rst10-day phase, 500 mg citicoline was administereddaily by intramuscular injection. Te rst phase o the treatment was ollowed by a second phase o oraltreatment at the same dose or 14 weeks. Patientstreated with levodopa continued taking this medi-cation at the same dose in the rst period, aterwhich an attempt was made to decrease it. Parkin-sonian symptoms were assessed using the Webster




J.J. Secades

scale. Among the patients receiving levodopa, 36%improved when citicoline was added, with greaterpercent improvements obtained in bradykinesia,rigidity, posture, gait and limb sway. In patientswho had been treated with levodopa or less than 2

years, percent improvements amounted to 42.12%,compared to 19.08% o improvements in patientswith more than 2 years o levodopa therapy.Levodopa doses could be decreased by 20-100% in

35.3% o patients with less than 2 years o treat-ment. In patients with more than 2 years o levodo-pa treatment, levodopa dose could be reduced by 25-33% in 10% o the cases. Te authors concludedthat citicoline treatment allows or delaying thestart o levodopa therapy in the early disease stagesand or decreasing or maintaining the levodopadosage in previously treated subjects.

Cubells and Hernando [486] tested citicoline in30 parkinsonian patients who were already beingtreated with levodopa. Te dose administered was500 mg/d by intramuscular injection or 2 months

and was reduced to a third at the end o the rstmonth o treatment. Changes in parkinsoniansymptoms, according to the Yahr scale, were evi-dent ater the rst month o treatment. Moderateimprovements in acial expression and digital skillsand obvious improvements in postural stability,motor changes and bradykinesia were observed. Agreater stabilisation o the therapeutic responsewas also seen, with a decreased incidence o ‘wear-

ing-o’ and ‘on-o’ phenomena, although dyskine-sia increased. When the levodopa dose was de-creased during the second study month, clinicalimprovements were maintained and the incidenceo dyskinesia was decreased. Measurements o var-ious electrophysiological parameters using an orig-inal technique revealed recovery rom hyporeexiaand hypotonia ater one month o treatment withciticoline. Te authors ound a major improvementin active muscle contraction, decreased muscle a-tigue and an obvious recovery o contractile speed,a parameter that was greatly decreased beore the

Figure 25. Antidepressive eects o citicoline in healthy older subjects (control) and in patients with Alzheimer’s disease or multi-inarct dementia(MID), evaluated with the Hamilton Depression Scale. EOAD: early-onset Alzheimer’s disease; LOAD: late-onset Alzheimer’s disease. a p < 0.02;b p < 0.01; c p < 0.05.

Baseline

18

16

14

12

10

8

6

4

2

0

H a m i l t o n

Control EOAD LOAD MID

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c

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start o citicoline treatment. Te authors statedthat the increase in levodopa plasma levels was sosignicant that it could not be interpreted as due

only to the increased release o dopamine stored inpresynaptic vesicles. Tereore, they assumed thatciticoline exerts an action on the synthetic mecha-nism o dopamine, acting through the tyrosine hy-droxylase enzymatic system. In addition, the in-crease in dopamine receptors that were quantiedin lymphocytes suggests, according to the authors,a promoting role o citicoline on the availability o postsynaptic dopamine receptors.

Martí-Massó and Urtasun [487] examined theeects o citicoline in 20 parkinsonian patientstreated with levodopa or more the 2 years. Tesepatients were administered 1 g/d/15 d i.m. citico-

line and then continued with 500 mg/d or 15 ad-ditional days. Progressive improvements in symp-toms was achieved. Tus, 4.16% and 7.26% overallimprovements were achieved in the Columbia Uni-

versity scale at 15 days and at the end o treatment,respectively. Te partial improvements that wereachieved in ambulation, turning time in bed andwriting time should be noted. In assessments con-ducted by relatives, improvements in agility, am-bulation and general patient status deserve specialmention.

García-Mas et al [488] conducted a study withquantied electroencephalography (qEEG) using

ast Fourier transorms in two groups o patientswith idiopathic Parkinson’s disease, one o whichshowed cortical cognitive impairment. A study o specic qEEG indices allowed the establishmento some parameters that dierentiate patients withand without cortical impairment. Specically, di-erences were ound in global potencies o deltaand alpha rhythms, the alpha/theta index, posteri-or activities, anteriorisation index o delta and al-pha rhythms and nally, spatialisation index o al-pha rhythm. Te administration o 2 g i.v. citicolinein these patients achieves a global increase in po-tencies corresponding to posterior rhythms, par-

ticularly the alpha rhythm, which is a marker o cognitive activity in dementia processes.Based on the aorementioned studies, it may be

stated that citicoline represents an eective treat-ment or Parkinson’s disease in both untreated pa-tients and patients who have already been treatedwith levodopa, in whom it also allows a reductionin the dose o levodopa. In patients with Parkin-son’s disease and cognitive impairment, citicolineadministration induces a trend toward normalisa-tion o the main altered electrophysiological pa-rameters.

Alcoholism and drug addiction

Clinical experience with citicoline in alcoholismand drug addictions is not extensive, but there is

some evidence o its efcacy in these applications.Chinchilla et al [489] conducted a randomiseddouble-blind study on the eects o citicoline in 20patients with alcohol withdrawal syndrome. At theend o the study (at 2 months), there were signi-cant improvements in attention-concentration andtime and space orientation in the group o patientsreceiving citicoline. According to the authors, thisnding suggests that the drug may be useul ortreating chronic alcoholism.

Renshaw et al [490-492] published a double-blind pilot study o patients addicted to cocaineshowing that ater 14 days o treatment with

500 mg/12 h o citicoline or a placebo, the patientsin the citicoline group experienced reductions incravings or cocaine. Consequently, citicoline ap-pears to be a promising therapy or this type o a-iction. Furthermore, positive eects have beenreported in patients with memory problems relatedwith the use o cocaine [493]. Tere is a clear impli-cation or cerebral metabolism in drug addictionpathophysiology [494,495]. Tere are also data sug-gesting the potential useulness o citicoline inmodulating appetite [496].

Amblyopia and glaucoma

Tere is clinical evidence that citicoline improvesthe visual acuity o patients with amblyopia [497-503] and visual unction in patients with glaucoma[504-509] or non-arteritic ischaemic optic neuro-pathy [510].

Saety

Dinsdale et al [511] administered citicoline or aplacebo to 12 healthy volunteers in two oral regi-mens that were repeated at short-term intervals(600 mg/day and 1 g/day) every day or 5 days. Teonly adverse eects that appeared were sel-limit-

ing headaches in our and ve subjects with highand low doses, respectively, and in one subject whowas given the placebo. Te results o haematologi-cal and clinical analyses showed no abnormality associated with citicoline administration. No clini-cally signicant ECG and EEG abnormalities wereregistered. Empirical neurological tests, tendon re-exes, blood pressures and heart rates were not a-ected by any dose o the drug or placebo.

In addition to excellent tolerability in healthy individuals, as demonstrated in the aorementionedstudy, all o the authors o the clinical trials using




J.J. Secades

Table XII. Saety analysis in the pooling data analysis o acute ischaemic stroke patients treated with citicoline. The table shows adverse eventsthat were reported in more than 5% o cases. n.s.: no signicative.

Placebo Citicoline

n % n % p

Advese events ith incidence > 5% in the citicoline goup

Anxiety 58 9.95 108 13.69 0.036

Leg oedema 38 6.52 77 9.76 0.032

Advese events ith incidence > 5%

Accidental injury 86 14.75 135 17.11 n.s.

Agitation 78 13.38 113 14.32 n.s.

Constipation 228 39.11 286 36.25 n.s.

Coughing 81 13.89 105 13.31 n.s.

Diarrhoea 81 13.89 117 14.83 n.s.

Dizziness 46 7.89 72 9.13 n.s.

ECG abnormality 57 9.78 74 9.38 n.s.

Fever 182 31.22 241 30.54 n.s.

Auricular brillation 65 11.15 92 11.66 n.s.

Headache 186 31.90 261 33.08 n.s.

Haematuria 53 9.09 91 11.53 n.s.

Hypertension 88 15.09 131 16.60 n.s.

Hypokalemia 71 12.18 119 15.08 n.s.

Hypotension 55 9.43 90 11.41 n.s.

Urinary tract inection 235 40.31 298 37.77 n.s.

Insomnia 103 17.67 145 18.38 n.s.

Joint pain 48 8.23 78 9.89 n.s.

Nausea 111 19.04 157 19.90 n.s.

Pain 180 30.87 227 28.77 n.s.

Back pain 45 7.72 74 9.38 n.s.

Chest pain 55 9.43 82 10.39 n.s.

Rash 79 13.55 112 14.20 n.s.

Restlessness 49 8.40 74 9.38 n.s.

Shoulder pain 75 12.86 105 13.31 n.s.

Vomiting 89 15.27 111 14.07 n.s.

Advese events ith incidence > 5% in the placebo goup

Depression 160 27.44 178 22.56 0.038

Falling down 109 18.70 99 12.55 0.002

Urinary incontinence 82 14.07 83 10.52 0.047





citicoline that have been reviewed in this articleagree in rating the saety o this drug as excellentand without serious reported side eects. In some

cases, the appearance o digestive intolerance andoccasional excitability or restlessness have been re-ported in the rst days o treatment. For instance,Lozano [512] monitored a study o the efcacy andsaety o citicoline in 2,817 patients o all ages, witha predominance o patients between 60 and 80

years who had dierent neurological conditions,mostly cognitive disorders o diverse origin. Teduration o citicoline treatment ranged rom 15to 60 days, and the mean dose administered was600 mg/day orally. Only 5.01% o the patients hadcollateral eects associated with citicoline treat-ment, most oten digestive intolerance (3.6%). In

no case was it necessary to interrupt treatment dueto the side eects attributable to citicoline use.In the pooled analysis o citicoline in the treat-

ment o acute ischaemic stroke [390], there wereew adverse events that were reported in more than5% o patients in the saety analysis. Tese adverseevents are listed in able XII.

In the South Korean drug surveillance study [395], the saety o the product was considered ex-cellent, with only 37 side eects in 31 cases among4191 patients treated, giving a rate o 0.73%.

In addition, in the Cochrane Library review [470], a lower incidence rate o adverse events was

demonstrated related to citicoline compared toplacebo.In conclusion, the tolerability o citicoline is ex-

cellent, and the side eects that are attributable tothis drug are rare. Te side eects are never severeand consist mainly o gastrointestinal discomortand restlessness.

Conclusions

Cytidine 5’-diphosphocholine, CDP-choline, orciticoline is an essential intermediate in the bio-

synthetic pathway o structural phospholipids incell membranes, particularly phosphatidylcholine.Following administration by both oral and paren-teral routes, citicoline releases its two main com-ponents, cytidine and choline. Absorption by theoral route is virtually complete, and bioavailability by the oral route is approximately the same as by the intravenous route. Once absorbed, citicoline iswidely distributed throughout the body, crossesthe blood-brain barrier and reaches the central

nervous system (CNS), where it is incorporatedinto the membrane and microsomal phospholipidraction. Citicoline activates the biosynthesis o

structural phospholipids o neuronal membranes,increases brain metabolism and aects the levelso dierent neurotransmitters. Tus, citicoline hasbeen experimentally shown to increase norepi-nephrine and dopamine levels in the CNS. Owingto these pharmacological mechanisms, citicolinehas a neuroprotective eect in hypoxic and ischae-mic conditions and improves learning and memory perormance in animal models o brain ageing. Inaddition, citicoline has been shown to restore theactivity o mitochondrial APase and membraneNa+/K+ APase, to inhibit activation o phospholi-pase A2 and to accelerate reabsorption o cerebral

oedema in various experimental models. Citicolineis a sae drug, as shown by toxicological tests, thathas no signicant systemic cholinergic eects andis a well-tolerated product. Tese pharmacologicalcharacteristics and the action mechanisms o citi-coline suggest that this product may be indicatedor the treatment o cerebral vascular disease, headinjury o varying severity and cognitive disorderso dierent causes. In studies conducted in thetreatment o patients with head injuries, citicolineaccelerated recovery rom post-traumatic comaand improved gait, achieving an improved nalunctional outcome and shortening hospital stays

in these patients. Citicoline also improved themnesic and cognitive disorders seen ater head injuries o minor severity that constitute the so-called postconcussional syndrome. In the treat-ment o patients with acute ischaemic cerebral vas-cular disease, citicoline accelerates the recovery o consciousness and motor decit, achieves a betternal outcome and acilitates the rehabilitation o these patients. Te other major indication or citi-coline is the treatment o senile cognitive impair-ment, secondary to either degenerative diseases(e.g., Alzheimer’s disease) or either chronic cere-bral vascular disease. In patients with chronic ce-

rebral ischaemia, citicoline improves scores in cog-nitive rating scales, whereas in patients with seniledementia o the Alzheimer type, it stops the courseo the disease and neuroendocrine, neuromodula-tory and neurophysiological benets have been re-ported. Moreover, citicoline has been shown to beeective as adjuvant therapy in Parkinson’s disease.No serious side eects have occurred in any serieso patients treated with citicoline, which attests tothe saety o this treatment.




J.J. Secades

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Citicolina: revisión armacológica y clínica, actualización 2010

Resumen. Esta revisión se basa en la publicada en el año 2006 –Secades JJ, Lorenzo JL. Citicoline: pharmacological and

clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56– e incorpora las nuevas reeren-cias aparecidas desde entonces, con lo que se organiza toda la inormación disponible para acilitar el acceso a dicha in-

ormación en un único documento. La revisión se centra en las principales indicaciones del ármaco, como son los acci-

dentes cerebrovasculares agudos y sus secuelas, incluyendo el deterioro cognitivo, y los traumatismos craneoenceálicos y

sus secuelas. Se recogen los principales aspectos experimentales y clínicos en estas indicaciones.

Palabras clave. Alcoholismo. Ambliopía. Apoptosis. CDP-colina. Citicolina. Demencia senil. Drogodependencia. Edema

cerebral. Enermedad de Alzheimer. Enermedad de Parkinson. Fosatidilcolina. Fosolipasa. Fosolípidos estructurales.

Glaucoma. Ictus. Isquemia cerebral. Lesión cerebral traumática. Membrana neuronal. Memoria. Neuroplasticidad. Neuro-

protección. Neurorreparación. Neurotransmisión. Trastorno cognitivo. Traumatismo craneoenceálico.

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