Table I. Decrease in temperature for each batch studied relative to time zero, expressed as the mean for n = 20.
|
Batch
|
Drugs
|
Time
|
+ 30 min
|
+ 60 min
|
+ 90 min
|
A
|
Water (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
|
B
|
Citicoline (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
|
C
|
Water (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
|
D
|
Citicoline (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 versus controls.
|
Shibuya et al [303] measured, using fluorometry, striatal dopamine levels after administration of citicoline in a single dose of 500 mg/kg intraperitoneal, and found that a significant (
p < 0.05) increase occurred in striatal dopamine levels one hour after injection. On the other hand, Stanzani [304] showed citicoline to have a neuroprotective effect in substantia nigra, noting how citicoline protects this area against lesion induced by peroxydases (horse radish), achieving an increased number of surviving cells. Porceddu and Concas [305] also reported a trophic and/or stimulating effect of citicoline upon nigrostriatal dopaminergic neurons in a model of lesion induced by kainic acid. Also, there are experimental studies showing the protective effect of citicoline in cultures of dopaminergic neurons exposed to 6-hydroxydopamine [306], 1-methyl-4-phenylpyridinium [307,308], and glutamate [307]. Miwa et al [309] suggested that citicoline may act as a dopamine reuptake inhibitor after administration of a single dose, and that this drug may change the activity of dopaminergic neurons through changes in compositions of the neuronal membrane following repeated administration. In addition, these authors found citicoline to have certain muscarinic effects. In this regard, Giménez et al [310] show that chronic administration of citicoline to aged mice promotes partial recovery of the function of dopaminergic and muscarinic receptors, that normally decreases with aging, and think that this action may be explained based on mechanisms involving fluidity of neuronal membrane, in agreement with the results obtained by Petkov et al [311]. This latter investigating team, when comparing the effects of citicoline to those of the nootropic drugs adafenoxate and meclofenoxate upon the levels of the cerebral biogenic monoamines norepinephrine, dopamine, and serotonin in the frontal cortex, striate, hippocampus, and hypothalamus of rats [312], found that adafenoxate increased norepinephrine levels in striate and decreased norepinephrine levels in hypothalamus, increased dopamine levels in the cortex and hypothalamus and decreased them in the striate, and increased serotonin levels in the cortex but decreased them in the hippocampus. Meclofenoxate induced decreases in norepinephrine levels in the cortex and hypothalamus, while it increased dopamine levels in hippocampus and hypothalamus, and serotonin levels in the cortex, striate, hippocampus, and hypothalamus. Administration of citicoline has also recently been shown to increase dopamine levels in the retina [313]. Mao et al [314] showed that an intraperitoneal injection of citicoline could retard the myopic shift induced by form deprivation in guinea pigs, which was mediated by an increase in the retinal dopamine level. Citicoline increases norepinephrine levels in cortex and hypothalamus, dopamine levels in striate, and serotonin levels in cortex, striate, and hippocampus, having a slightly different profile as compared to nootropic drugs. As regards action of citicoline upon norepinephrine, a study by López-Coviella et al [315] shows that administration of citicoline increased total urinary excretion of 3-methoxy-4-hydroxyphenylglycol, reflecting noradrenergic activity, in rats and humans, suggesting that citicoline increases norepinephrine release. Recently, citicoline has also been experimentally shown to be able to influence the relationship between excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) amino acids at the brain cortex of rats [316]. A series of experiments assessed the potential of citicoline to produce a central cholinergic activation. Intracerebroventricular administration of citicoline was shown to cause an increase in levels of vasopressin [317] and other pituitary hormones [318], due mainly to central cholinergic activation. Same effect has been demonstrated after intravenous administration [319]. Citicoline has also been shown to have a pressor effect in cases of hypotensive animals [320], or even in cases of hypotension due to hemorrhagic shock [321,322]. Amín et al [323] study the effects of citicoline on cardiovascular function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated albino rats. MPTP is a chemical that changes into the neurotoxin 1-methyl-4-phenylpyridinium, which causes catecholamine depletion. In this model, citicoline increased cardiac norepinephrine and tyrosine hydroxylase and improved markers related to Reactive oxygen species scavenger, mitochondrial permeability, calcium homeostasis on the cellular level, metabolic homeostasis, and mitochondrial biogenesis. Authors conclude that citicoline improved cardiovascular dysautonomia and that was reflected on cardiac contractility, electrical activity, blood pressure, and vascular reactivity. Also, a contribution of the central histaminergic system is involved in this effect of citicoline [324]. The central cholinergic activating effect exerted by citicoline was again emphasized, involving this effect to explain the cardiovascular [325-328] and metabolic effects [329-332] of the drug. Citicoline also modulates cerebral metabolism through glutamate-linked enzyme activities [333]. Sbardella et al [334] shown that citicoline greatly affects the proteolytic activity of the 20S proteasome, functioning as a bimodal allosteric modulator, likely binding at multiple sites, suggesting its potential role as a regulator of proteostasis in nervous cells. Ilcol et al [335] observed that citicoline treatment alters serum lipid responses to endotoxin and prevents hepatorenal injury during endotoxemia through a nicotinic acetylcholine receptor mediated mechanism. CDP-choline attenuates scopolamine induced disruption of prepulse inhibition in rats thanks to the involvement of central nicotinic mechanisms [336]. Yilmaz et al [337] show that citicoline administration restores the abnormalities in the primary, secondary, and tertiary hemostasis and prevents the development of disseminated intravascular coagulation during experimental endotoxemia in dogs probably by increasing both neuronal and nonneuronal cholinergic activity. Kocaturk et al [338] show that treatment with citicoline improves functions of cardiovascular and respiratory systems in experimental endotoxemia in dogs and suggest that they may be useful in treatment of endotoxin shock in clinical setting. Doolittle et al [339] demonstrated that citicoline corrects alveolar type II cell mitochondrial dysfunction in influenza-infected mice through preventing the declines in oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis.
Roohi-Azizi et al [340] concluded that administration of citicoline, as an adjuvant drug, in combination with citalopram, enhanced the effectiveness of selective serotonin reuptake inhibitors drugs for depression treatment in a mice model of depression. Khakpai et al [341] concluded that the administration of citicoline, as an adjuvant drug, in combination with imipramine increased the efficacy of tricyclic antidepressant drugs for modulation of pain and depression behaviors in mice.
Also, citicoline has antinociceptive effects involving the cholinergic system [342-344], opioid and gamma-aminobutyric acid receptors [345,346], the arginine-vasopressin system [347], and the Na
+/K
+ ATPase activity [348].
Citicoline, administered prior to thiopental sodium anesthesia, can improve brain function by decreasing the duration of lack of response to corneal reflex and also increasing the effect on analgesia duration [349], and a significant increase in heart and respiration rate, an insignificant increase in oxygen saturation and an insignificant decrease of rectal temperature in animals [350]. Citicoline also has a protective effect in models of epilepsy induced by xylocaine [351] and pentylenetetrazol [352,353], but not when the epilepsy is induced by pilocarpine [354]. Bekhet et al [355] aimed to formulate citicoline-loaded niosomes for efficient brain delivery via the intranasal route to improve management of epilepsy. The protection against pentylenetetrazol-induced generalized seizures and mortality were determined in rats and compared with the oral drug solution at the exact dosage. The in vivo results revealed that a low dose of citicoline-loaded niosomes in situ gel had a powerful protective effect with delayed the latency for the start of convulsions and this can be considered as a method to boost the efficacy of citicoline in epilepsy management.
Nashine and Kenney [356] characterized the cytoprotective effects of purified citicoline in transmitochondrial age-related macular degeneration retinal pigment epithelium cybrid cells which carry diseased mitochondria from clinically characterized age-related macular degeneration patients and demonstrated that citicoline downregulates apoptosis-associated genes and reduces caspase-3 and caspase-7-mediated apoptosis in this model, together with a reduction of the oxidative stress.
In reference to the intracellular signaling systems, it has been demonstrated an effect of citicoline on the following systems:
- Platelet- activating factor [357, 358].
- MAP kinase [271].
- ERK1/2 [232,246].
- Rho/Rho-kinase [359].
- Calpain [142].
- Phospholipase-thromboxane [360].
- Phospholipase-prostaglandin [361].
- Proinflammatory cytokines [143,362-366].
To sum up, the effects of citicoline in the experimental models used to reveal pharmacological actions upon the dopaminergic system have been studied. Citicoline has been shown to act as a dopaminergic agonist and has a particularly significant effect upon levels of dopamine and its metabolites in the corpus striatum. The results obtained suggest that, with citicoline administration, striatal dopamine synthesis is increased, probably through tyrosine hydroxylase activation. Increase in dopamine levels would partly result from inhibition of dopamine reuptake, possibly related to citicoline action upon phospholipids synthesis. In addition, citicoline also has some effects upon the other monoamines, serotonin and norepinephrine, muscarinic and nicotinic receptors, and glutamate, opioids and gamma-aminobutyric acid, together to important modulating effects on several intracellular signaling processes.
Learning performance, memory, and brain aging
It has been shown that hypobaric hypoxia decreases learning performance in rats undergoing sound avoidance conditioning, and that this effect may be antagonized by pretreatment with apomorphine or other dopaminergic agonists. These effects of hypoxia appear in relation to an inhibition of metabolism of cerebral catecholamines that would be ultimately responsible for an understimulation of central postsynaptic dopaminergic receptors. Based on these assumptions, Saligaut and Boismare [206] conducted a study on the effects of citicoline administration upon learning performance in rats subjected to hypobaric hypoxia. Under hypoxic conditions, citicoline was administered at 300 mg/kg/day for 12 days to a group of rats that underwent learning tests of a sound avoidance conditioning in the last five days of treatment. Effects seen in this group were compared to those seen in another group receiving apomorphine 0.5 mg/kg 30 minutes before each daily conditioning session and to those recorded in animals receiving both treatments. A group of animals acted as control and received an ascorbic acid solution under the same experimental conditions. Citicoline partially restored learning performance. The same effect, but to a lesser extent, was seen with administration of apomorphine and with combined administration of both drugs. These results suggest that administration of citicoline counteracts, as with dopaminergic agonists, the effects of hypoxia. Previously we commented the protective effect of citicoline against the cognitive impairment induced by chronic cerebral hypoperfusion [253].
Drago et al [367] administered citicoline 10-20 mg/kg/day intraperitoneal for 20 days to 24-month-old Sprague-Dawley male rats from a strain showing cognitive and motor deficits. The drug was also given to rats with behavioral changes induced by a single injection of scopolamine, a cholinergic antagonist, by prenatal exposure to methylazoxymethanol, or by bilateral injections of kainic acid into the magnocellular basal nuclei. In all cases, citicoline improved learning and memory performance, evaluated using active and passive avoidance tests. In the old rat group, improved motor capacity and coordination was also seen. For these authors, these results suggest that citicoline affects the central mechanisms involved in cognitive behavior, probably through a cholinergic action.
In a model of scopolamine-induced memory impairment, Petkov et al [368] showed citicoline to be able to prevent amnesia induced by scopolamine. Subsequently, Mosharrof and Petkov [369] showed that citicoline 100 mg/kg completely prevented amnesia induced by scopolamine, as did the association of citicoline 50 mg/kg and piracetam 500 mg/kg, also causing a significant increase in retention. Authors suggested that this effect is mediated by drug actions on neurotransmission. Takasaki et al [370] suggest that citicoline has ameliorative effect on the impairment of spatial memory induced by scopolamine, reducing the neuronal death and improving the impaired cholinergic signal. Citicoline acts as a memory-enhancing drug, and this effect is particularly marked in animals with memory deficits [371]. On the other hand, Álvarez et al [372] showed that citicoline antagonized amnesia induced by bromazepam in rats. Bruhwyler et al [373] found that chronic administration of citicoline has facilitating effects on learning and memory processes in dogs, but does not affect the established capacities and does not show, in this model, any effect on the motor, neurovegetative, or motivational systems. According to these authors, this represents an argument in favor of the selectivity of drug action in memory processes. Citicoline has even been shown to have a protective effect against mnesic disorders in aged animals [374] and in animals in isolation conditions [375] when administered as a dietary supplement, as well as in spontaneously hypertensive rats [376]. Ahmad et al [377] compare the relative efficacy of nootropics like piracetam, modafinil and citicoline on learning and memory in rats using the Morris water maze test. A total of 30 Wistar rats were used for the study. The animals were divided into five groups (
n = 6). The groups I to V received gum acacia orally, scopolamine 2 mg/kg intraperitoneally, piracetam (52.5 mg/kg), modafinil (2.5 mg/kg), citicoline (25 mg/kg) respectively orally for 20 days. Learning and memory was evaluated using the Morris water maze test. The animals were trained in the Morris water maze on the last five days of dosing. Scopolamine 2 mg/kg was administered intraperitoneally to the above groups of animals (except groups I and II) for induction of amnesia, 45 minutes before the behavioural test. Scopolamine induced marked impairment of memory evidenced by significant reduction (
p < 0.01) in the number of entries and time spent in the target quadrant when compared to the control group. There was significant (
p < 0.05) increase in the number of entries and time spent in target quadrant of the Morris water maze in the animals who were pre-treated with piracetam, modafinil and citicoline, in comparison to the scopolamine treated group. Amongst the three nootropics, modafinil and citicoline showed significant (
p < 0.05) memory enhancement in comparison to piracetam. Abdel-Zaher et al [378] investigated the potential protective effect of citicoline on aluminum chloride-induced cognitive deficits in rats, and demonstrated, for the first time, that citicoline can protect against the development of these cognitive deficits through inhibition of aluminum-induced elevation of glutamate level, oxidative stress, and nitric oxide overproduction in the hippocampus. Hosseini-Sharifabad et al [379] showed that magnesium increases the protective effect of citicoline on aluminum chloride-induced cognitive impairment in mice.
Cakir et al [380] investigated the effects of citicoline on the well-known negative effects of rapid eye movements sleep deprivation on learning and memory in adult male Wistar albino rats, and the results obtained suggest that citicoline reduces rapid eye movements sleep deprivation-induced impairment in memory, at least in part, by counteracting the disturbances in biochemical and molecular biological parameters.
Safavi et al [381] compare the individual effects of benfotiamine and citicoline and their co-administration on memory impairments in diabetic mice. Diabetes was induced by a single dose of streptozotocin (140 mg/kg, intraperitoneal) and benfotiamine and/or citicoline were administered for three weeks. Memory was evaluated using the object recognition task and passive avoidance test. In passive avoidance test, co-administration of benfotiamine and citicoline was more effective than either alone in improving memory. Regarding object recognition task, although benfotiamine added to citicoline improved memory notably, the difference between combination therapy and single-drug therapy was not considerable.
There are multiple morphological, neurochemical, and physiological changes characterizing brain aging in mammals. General agreement exists between investigators on the existence of aged-related changes in certain neurochemical parameters, such as enzyme activity, receptor binding, and neurotransmission. Biochemical evidence is available of the existence of a component of cholinergic dysfunction and impaired cerebral phospholipids metabolism in the pathophysiology of brain aging [1,4,5]. De Medio et al [382] investigated the effects of citicoline upon changes in lipid metabolism in the brain during aging. Thus, they measured in vivo lipid synthesis in different brain areas from 12-month-old male rats. For this, they administered, by injection in the lateral cerebral ventricle, a mixture of (2-
3H)glycerol and (Me-
14C)choline, as lipid precursors, and measured, one hour after isotope administration, incorporation of these precursors into the fractions of total lipids, water-soluble intermediates, and choline phospholipids. In another series of experiments, citicoline was injected intraventricularly to aged rats 10 minutes before killing, and the same radioactivity tests as described above were performed. Distribution of the radioactivity contained in citicoline in the brain 10 minutes following administration showed enrichment, in the studied areas, of nucleotides and related water-soluble compounds. Incorporation of labelled glycerol, that is greatly decreased in aged rats, increased in all areas. Incorporation of labelled choline also decreases with aging, and citicoline was able to increase such incorporation in the cortex. As a result, the
3H/
14C ratio was increased in total lipids and in phosphatidylcholine and choline plasmalogens following citicoline treatment. Following this line of research, López-Coviella et al [383] studied the effects of oral citicoline on phospholipids content in mouse brain. These authors supplemented animal diet with citicoline 500 mg/kg/day for 27 months in 3-month-old mice, and for 90, 42, and 3 days in 12-month-old mice, after which phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine levels, and contents of phosphatidylinositol plus phosphatidic acid were measured in brain cortex. After 27 months of treatment, phosphatidylcholine and phosphatidylethanolamine levels significantly increased by 19 and 20% respectively, while phosphatidylserine levels increased by 18%, but statistical significance was not reached (Fig. 10). Similar increases were noted when 12-month-old animals were treated for three months, but not with shorter treatment periods. These results suggest that chronic administration of citicoline may have significant effects on phospholipid composition of the brain that may partly be responsible for the reported therapeutic efficacy of this drug. Wang and Lee [384] obtained similar results in their study. Plataras et al [385] showed citicoline to be able to restore activity of hippocampal acetylcholinesterase and Na
+/K
+ pumps, involving these mechanisms in the improvement of memory performance exerted by citicoline. Zhang et al [386] suggest the citicoline could play a role in improving memory performance and exert protective effects against Alzheimer’s disease by increasing expression or activity of Na
+/K
+-ATPase. Giménez et al [387] showed that citicoline, administered for two months to aged rats, caused a significant activation of cytidine triphosphate:phosphocholine cytidyltransferase, which according to authors would explain the reparative effects of the drug on damaged membranes of aged animals. This same investigating team made a more extensive study of the effects of citicoline on the activity of this enzymatic system and showed that, in addition to its effect on phospholipid metabolism, citicoline also has a regulatory effect upon platelet activating factor levels in the brain [357,358]. All such effects occur with no changes in plasma levels of homocysteine, a known risk factor [388]. However, citicoline also offers beneficial actions on brain metabolism of nucleic acids and proteins [385,389-391], on dopaminergic, nicotinic and muscarinic receptors [324], and on neuroendocrine and neurosecretory changes [392-394] in experimental aging models, as well as a neuroprotective effect against neurotoxic aggressions [394-402], an immunomodulatory effect [403], and an antiapoptotic effect [404,405] in various models of neurodegeneration and cerebrovascular dementia. Sahraiian and Khazali [406] showed that citicoline, as ghrelin, improves passive avoidance learning by altering the N-methyl-D-aspartate receptor (NMDAR1) and the serotonin receptor 1A (HTR1a) expression in the hippocampus in adult male rats.
Figure 10. Effect of chronic administration of citicoline on the brain titres of phospholipids in 30-month-old mice fed a dietary supplement with citicoline (500 mg/kg/day) or placebo for 27 months. a p < 0.05; b p < 0.01.
Because of such actions, various studies have shown the positive effects of citicoline on learning and memory in aged animals [373,407,408]. Based on these effects and the effects on neuroplasticity [409] and on proliferation and differentiation of astroglial cells [15,410] it has been postulated the use of citicoline in neurodegenerative diseases, but there are some exceptions, such the no protective effect of the drug in a model of Huntington’s disease [411] and in a model of amyotrophic lateral sclerosis [412]. Gromova et al [413] considered that the pharmacological effects of CDP-choline are realized via multiple molecular mechanisms contributing to the nootropic actions of this molecule in different experimental models.
Experimental withdrawal syndrome and intoxications
If citicoline 300 mg is injected by the intracarotid route to cats, effects similar to those seen with administration of 2 mg of morphine by the same route are obtained. The animal shows symptoms of anger and alertness, and the tail is placed in a rigid and upright position. This finding led to think that both substances could have some parallel effects at neuroreceptors of endogenous opiates, and that administration of citicoline could be of value in the opiate withdrawal syndrome by slowing the effects of sudden drug discontinuation [414]. Tornos et al [415] studied the effects of citicoline administration upon experimental withdrawal syndrome by analyzing various methods, such as the jumping test in mice and studies of the behavior and body temperature changes in rats. The withdrawal syndrome caused by administration of naloxone to morphine-dependent mice was assessed based on the number of jumps by the animals. A decrease in severity was seen in the group of animals treated with citicoline 2 g/kg p.o. as compared to the untreated animal group. This decreased severity of the withdrawal syndrome was demonstrated by a 39% decrease in the mean number of jumps by the animals within 10 minutes of administration of the opiate antagonist. Similarly, the behavioral study in morphine-dependent rats showed that administration of an oral dose of citicoline 2 g/kg at the same time as naloxone was able to significantly decrease the severity of manifestations that characterize the withdrawal picture provoked. As regards hypothermia caused by naloxone administration in morphine-dependent rats, administration of a single oral dose of citicoline neutralizes such effect almost completely. Nejati et al [416] studied the effects of intraperitoneal injections of citalopram and citicoline on morphine-induced anxiolytic effects in non-sensitized and morphine-sensitized mice and demonstrated a synergistic effect of citalopram and citicoline upon induction of anti-anxiety behavior in non-sensitized and morphine-sensitized mice.
Characteristic findings of fetal alcohol syndrome include delayed maturation and late development of dendrites in neocortex, hippocampus, and cerebellum. Based on these data, Patt et al [417] conducted a study to investigate the effects of citicoline on Purkinje cells from rats newborn from alcoholic dams, showing that this stabilizing agent of neuronal membranes decreases the harmful effect of alcohol on the central nervous system. Wang and Bieberich [418] demonstrated that prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development and that treatment with CDP-choline may alleviate the tissue damage caused by alcohol. Petkov et al [419] have also shown that citicoline decreases mnesic deficits in rats pre- and post-natally exposed to alcohol, which may be related with the beneficial effects upon acetylcholine synthesis and release shown using cerebral microdialysis in rats chronically exposed to alcohol [420,421]. Citicoline has also shown a protective effect in nicotine intoxication [422] and in mercury intoxication [423]. Buelna-Chontal et al [424] demonstrated that citicoline circumvents mercury-induced mitochondrial damage and renal dysfunction in a model of renal failure in rats. Laksmita et al [425] demonstrated the potential benefits of citicoline for management of ocular methanol intoxication in an experimental rat model.
Aminzadeh and Salarinejad [426] analyzed the effect of citicoline on lead-induced apoptosis in PC12 cells and their findings revealed that citicoline exerts a neuroprotective effect against lead-induced injury in PC12 cells through mitigation of oxidative stress and at least in part, through suppression of mitochondrial-mediated apoptotic pathway. Gudi et al [427] tried to confirm previous results showing that citicoline improves remyelination and to determine the potential regenerative effects of lower doses of citicoline (100 and 50 mg/kg). The effects of citicoline were investigated in the toxic cuprizone-induced mouse model of de- and remyelination. The authors found that even low doses of citicoline effectively enhanced early remyelination. The beneficial effects on myelin regeneration were accompanied by higher numbers of oligodendrocytes. They concluded that citicoline could become a promising regenerative substance for patients with multiple sclerosis and should be tested in a clinical trial. Shaffie and Shabana [428] indicated that citicoline treatment can protect against toluene-induced toxicity in rats.
Masoud et al [429], in an experimental study in mice, showed that dexamethasone and citicoline attenuate the cisplatin-induced peripheral neuropathy through an anti-inflammatory effect, improving antioxidant capacity, and inhibiting lipid peroxidation.
Zhong et al [430] concluded that citicoline can protect against neomycin-induced hair cell loss by inhibiting reactive oxygen species aggregation and thus preventing apoptosis in hair cells, and this suggests that citicoline might serve as a potential therapeutic drug in the clinic to protect hair cells and thus preventing hearing loss associated to aminoglycoside use.
Toxicity
Acute toxicity
Acute toxicity from single citicoline administration has been studied in various animal species and using different administration routes. The intravenous LD
50 in mice, rats, and rabbits is 4.6, 4.15, and 1.95 g/kg, respectively [431,432]. Oral LD
50 is 27.14 g/kg in mice and 18.5 g/kg in rats [433]. The intravenous LD
50 of citicoline is approximately 44 times higher than the LD
50 of choline hydrochloride at equivalent doses, and it has been shown that choline doses inducing cholinergic crises do not cause any toxicity sign when equivalent doses of citicoline are administered [434,435]. This suggests that administration of choline has metabolic implications clearly different from those of exogenous choline administration. The administration of 2,000 mg/kg of citicoline p.o. during 14 days was well tolerated [436].
Subacute toxicity
Intraperitoneal administration to rats of doses up to 2 g/kg/day of citicoline for 4.5 weeks did not results in clinical toxicity signs or significant changes in the hematological, biochemical, or histological parameters analyzed. A slight decrease in intake and weight gain was only seen from two weeks of the study [433]. Similar results were seen following subcutaneous administration to male rats of up 1 g/kg for four weeks [432]. Oral administration of 1.5 g/kg/day to rats for 30 days did not cause weight, hematological, biochemical, or histological changes [437].
Chronic toxicity
Chronic oral (1.5 g/kg/day for 6 months in dogs) and intraperitoneal (1 g/kg/day for 12 weeks in rats) toxicity studies did not reveal either significant abnormalities related to drug administration [432,438]. Intravenous administration of citicoline 300-500 mg/kg/day for three months in dogs only caused toxic signs immediately after injection, including vomiting and occasional diarrhea and sialorrhea [435]. In a 90-day study in rats, 100, 350, and 1,000 mg/kg/day oral doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1,000 mg/kg/day) and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1,000 mg/kg/day), and blood urea nitrogen (100 and 350 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1,000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result [436].
Teratogenicity
Citicoline was administered to albino rabbits at a dose of 800 mg/kg during the organogenesis phase, i.e., from days 7
th to 18
th of pregnancy. Animals were killed on day 29
th, and a detailed examination was made of fetuses and their mothers. No signs of maternal or embryofetal toxicity were seen. Effects on organogenesis were imperceptible, and only a slight delay in cranial osteogenesis was seen in 10% of treated fetuses (unpublished data).
Pharmacokinetics
Plasma level curves. Bioavailability
Labelled citicoline (methyl
14C) was administered to rats at a dose of 4 mg/kg by jugular vein injection and by the oral route using a nasogastric tube [439]. The results obtained, expressed as percent radioactivity in 10 mL of blood for each administration route, are shown in table II. From these data, the ratio between bioavailability of the oral and the intravenous administration route was estimated and found to be virtually one, which agrees with the fact, demonstrated in the same study, that no residual radioactivity is found in feces excreted in the 72 hours following oral administration.
Table II. Blood kinetics of the total radioactivity of 4 mg/g methyl 14C-citicoline after oral or intravenous administration to male rats. The percentages of radioactivity (mean ± SD) with respect to the total administered are shown.
|
Time
|
Oral route
|
Intravenous route
|
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
|
López-Coviella et al [440] studied the effects of citicoline on plasma levels of cytidine, choline, and CDP-choline in healthy volunteers receiving the substance by the oral or intravenous route and in rats treated by the intravenous route. Two hours following administration of a single oral dose of citicoline 2 g, choline plasma levels increased 48%, and cytidine plasma levels 136% (Fig. 11). In individuals receiving three 2 g doses at two-hour intervals, choline plasma levels reached a peak, representing approximately 30% of baseline value, four hours after administration of the initial citicoline dose, while cytidine plasma levels increased up to six hours (Fig. 12) and were five-fold higher than the baseline value (
p < 0.001). Citicoline administered by the intravenous route was rapidly hydrolyzed in both humans and rats [441]. In healthy individuals receiving a citicoline infusion of 3 g in 500 mL of physiological saline over 30 minutes, CDP-choline levels were virtually undetectable just after the end of the infusion period, when plasma levels of cytidine and choline reached a peak, though their concentrations remained significantly increased up to six hours after the start of infusion (Fig. 13). These observations show that citicoline, administered by both the oral and intravenous routes, is converted into two major circulating metabolites, cytidine and choline. However, plasma cytidine is converted in humans to uridine, its circulating form, that is transformed in the brain to uridine phosphate, that will in turn be converted to cytidine triphosphate at neuronal level [442].
Figure 11. Plasma concentrations of choline and cytidine immediately after administration of a single oral dose of 2 g citicoline in humans.
Figure 12. Plasma concentrations of choline and cytidine immediately after administration of three consecutive oral doses (2 g) in humans.
Figure 13. Concentrations of choline, cytidine and CDP-choline in human plasma after intravenous infusion of a solution of citicoline (3 g/500 mL physiological saline solution).
Tissue diffusion and distribution. Transport and metabolism
Tissue diffusion of citicoline and its components has been studied in rats intravenously administered (methyl
14C, 5-
3H) citicoline, labelled in the choline and the cytidine fraction [443,444]. In the same battery test, plasma radioactivity levels were measured for 30 minutes following administration. Renal and fecal excretion of labelled metabolites was also measured for 48 hours. As early as two minutes following injection, less than 10% of administered radioactivity was found in plasma. In addition, radioactivity excreted by the kidney during the first 48 hours only accounted for 2.5% of
14C and 6.5 % of
3H administered. In the same time interval, fecal excretion did not exceed 2% of the administered dose. These results suggest that citicoline rapidly diffuses to tissue following administration and is actively used by tissues. Figure 14 shows the radioactivity levels found in liver, brain, and kidney at different time points following intravenous administration of dually labelled citicoline. There is a special interest in changes in brain levels. Radioactivity uptake by the brain gradually increases for the first 10 hours after drug administration, and the levels achieved remain unchanged at 48 hours.
Figure 14. Concentrations of radioactivity in the liver (a), brain (b) and kidneys (c) of rats at different time points after injecting double-labelled citicoline at a dose of 2 mg/kg. All values represent the means obtained from 10 animals.
In a group of animals, radioactivity levels of the labelled compounds were measured in the brain at 0.5, 1, 4, and 48 hours of administration of dually labelled citicoline. Radioactivity corresponding to
3H in the brain was mainly concentrated in cytidine nucleotides at the beginning, but subsequently concentrated in nucleic acids. As regards compounds labelled with
14C, the highest levels initially corresponded to betaine, choline, and phosphorylcholine, while at four hours
14C-methionine and
14C -phospholipids accounted for 26.4 and 24.2% respectively of total cerebral radioactivity corresponding to
14C. At 48 hours, this radioactivity mainly concentrated in phospholipids and proteins. Thus, labelled phospholipids were seen to continuously increase in the 48 hours following administration of dually labelled citicoline. As shown in figure 15, such increase is fast in the first five hours, but then becomes slower.
Figure 15. Evolution of 14C-phospholipid concentrations in rat brains after intravenous administration of double-labelled citicoline. The concentrations represent the means of three animals and are expressed as a percentage of the total radioactivity corresponding to 14C in the brain.
In another test battery, the presence of the drug in various brain areas and its distribution in cerebral ultrastructures was measured following administration of (methyl
14C) citicoline [445-449]. In a study performed with high-performance autoradiography in mouse brain 24 hours following administration of labelled citicoline [445], the radioactive marker was seen to be widely incorporated into the different cerebral areas studied, brain cortex, white matter, and central grey nuclei. It was found in both intra and extracellular spaces, with a particular presence in cell membranes. In the same experimental model, but 10 days following administration of the labelled drug [446], concentration of radioactivity in the more myelinated areas was seen, as well as a marked uptake by the cerebellar Purkinje cells. Using low-performance autoradiography, distribution of radioactivity of labelled citicoline in rat brain was analyzed five and 24 hours after drug administration [447]. At 24 hours, most radioactivity was detected at intracellular level. In another study, incorporation of radioactivity from (methyl
14C) citicoline after oral administration to male Sprague-Dawley rats was analyzed in the different cerebral phospholipid fractions [448]. Of total radioactivity measured in brain, 62.8% was found to be part of brain phospholipids, particularly phosphatidylcholine and sphingomyelin, showing that citicoline administered by the oral route influences the synthesis of structural phospholipids of cell membranes. These results agree with those obtained by Aguilar et al [449], who showed radioactivity from labelled citicoline to be associated to cytoplasmic and mitochondrial membranes in brain homogenate.
In conclusion, these studies show that the citicoline administered is widely distributed in brain structures, with a rapid incorporation of the choline fraction into structural phospholipids, and of the cytosine fraction into cytidine nucleotides and nucleic acids. Citicoline reaches the brain and incorporates actively into the cytoplasmic and mitochondrial cell membranes, being part of the structural phospholipid fraction [441,450,451].
Elimination route and kinetics
When labelled citicoline is administered by either the oral or intravenous route, radioactivity is eliminated very slowly by the urinary or fecal route and in expired CO
2 [452].
Figure 16 shows total radioactivity excretion for the five days following oral administration of
14C citicoline to healthy volunteers. Table III gives the main data on the elimination kinetics of the product.
Figure 16. Total excretion of radioactivity (percentage of total administered) for 5 days after oral administration of 14C -Citicoline. The mean values of six individuals are shown.
Table III. Most significant parameters in the elimination kinetics of 14C-citicoline after oral administration. Data show the means of six individuals.
|
| |
CO2
|
Urine
|
Faeces
|
Maximum rate of excretion (% dose/h)
|
1.22 ± 0.59
|
0.159 ± 0.084
|
0.021 ± 0.008
|
Time of maximum excretion (h)
|
1.60 ± 0.73
|
1.3 ± 0.8
|
56 ± 18
|
First phase of elimination
Apparent half-life
Apparent rate of elimination (% dose/h)
|
2.58 ± 0.60
0.279 ± 0.055
|
6.62 ± 1.28
0.107 ± 0.017
|
–
–
|
Second phase of elimination
Apparent half-life (h)
Apparent rate of 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
|
Two phases are differentiated in urinary elimination of the drug: a first phase, lasting approximately 36 hours, in which excretion rate decreases rapidly, and a second phase in which excretion rate decreases much more slowly. The same occurs with expired CO
2, whose elimination rate decreases rapidly for the first 15 hours, approximately, after which a slower decrease is seen.
Clinical experience
Head injury and sequelae
The above reported experimental studies showed that administration of citicoline led to a significant regression of brain edema and improvements in the electroencephalographic tracing and impairment of consciousness, as well as in survival quality. The effect on consciousness level is attributable to the facilitating action of the electroencephalographic arousal reaction, induced by stimulation of the ascending reticular activating system at brain stem level.
Based on these experimental assumptions, many clinical trials have been conducted to verify if these effects have some implications for treatment of patients with traumatic brain injury.
In 1967, Moriyama et al [453] published their study on the effects of citicoline in 25 patients with head injury and depressed consciousness. The drug was shown to be effective, leading to recovery from neurological clinical symptoms and return to a conscious state, in 70% of cases, and was very well tolerated, causing no side effects.
Ayuso and Saiz [454] conducted a double-blind study on the value of citicoline in mnesic dysfunction induced by bilateral electroshock in a series of 22 patients admitted to hospital for an endogenous depression. The group receiving active drug had a lower reduction in memory performance after four electroshock sessions as compared to the control group, thus showing the value of citicoline for treatment of patients with memory disorders of an organic base.
De la Herrán et al [455] compared the effects of citicoline administration in a series of 50 patients with an impaired level of consciousness, of a traumatic origin in 32 cases, to another series of patients with similar characteristics who were receiving standard treatment. 34% of patients recovered consciousness within 48 hours. After a few days, 66% of patients had recovered consciousness. These results were better than those achieved in the control group. With these results, authors showed that citicoline reactivates and accelerates normalization of the consciousness stated in patients with head injury.
Carcassonne and LeTourneau [456] conducted a double-blind study in a series of 43 children with a true consciousness disorder of a traumatic origin, after excluding severe cases and those requiring surgical treatment. After analyzing the results obtained, these authors arrived to the following conclusions:
- Citicoline is very well tolerated, both locally and systemically.
- Citicoline significantly accelerates recovery of a normal consciousness state.
- Citicoline accelerates disappearance of neuropsychological disorders and cerebral electrogenesis disorders.
- Citicoline confers a better quality to the course of patients.
Espagno et al [457] compared the effects of citicoline versus placebo in a series of 46 patients who had sustained a head injury. For this, authors conducted a double-blind study in which 22 patients received citicoline 250 mg/day by the parenteral route for 20 days, while 24 patients were given placebo. The results obtained showed that, in mild coma, citicoline significantly accelerated (
p < 0.05) recovery of consciousness, while in more severe coma and at the administered dose, that is currently considered to be highly inadequate, citicoline improved prognosis, so that 75.2% of patients in the placebo group showed a late recovery (>15 days) of consciousness and/or progressed to death. By contrast, in the group treated with the active product, recovery from coma beyond the 15
th day occurred in 31% of cases, and incidence of prolonged coma and/or death was 12.5%. In conclusion, citicoline resulted in an earlier recovery of consciousness and an increased number of clinical and electroencephalographic improvements and was also very well tolerated.
Richer and Cohadon [458] conducted a double-blind study in a group of 60 patients with coma of a traumatic origin who were distributed into two homogeneous groups, one of which was given the active drug, and the other placebo. As regards coma duration, the number of patients who had recovered consciousness at 60 days was significantly greater (
p < 0.01) in the group treated with citicoline. After 90 days, a greater recovery (
p < 0.04) from the motor deficit was found in the citicoline-treated group. Gait recovery was also shown to be significantly accelerated in the active drug group. As a result, a greater social and occupational reinsertion was found at 60 days in the group treated with citicoline (
p < 0.06). This demonstrated the limiting effect of duration of posttraumatic coma of citicoline, as well as its participation in restoration of deficits related to the brain lesions associated to such coma. However, there were no changes in mortality associated to the treatments.
Lecuire and Duplay [459], in a double-blind trial, compared the effects of citicoline, at an intravenous dose of 750 mg/day, to those of meclofenoxate at 3 g/day intravenous in a group of 25 patients. An analysis of the results showed a significant improvement in the patient group treated with citicoline, particularly as regarded recovery of consciousness, electroencephalographic changes, and functional recovery. Mean coma duration was 10 days in the citicoline group, as compared to 20 days in the meclofenoxate group. At 10 days, electroencephalographic tracings had improved in 50% of citicoline-treated patients and in 18% of patients given meclofenoxate. Citicoline was therefore shown to be superior to meclofenoxate, and its main characteristic was accelerated recovery of the consciousness level, that is related to improvement in the electroencephalographic tracing. These same authors carried out an open label study in a series of 154 patients with head injury [460]. This study assessed the effects of citicoline treatment and found the drug to accelerate patient arousal and recovery from deficit syndromes, and to improve the quality of survival. Lecuire [461] subsequently performed a double-blind study comparing piracetam (6 g/day) versus citicoline (750 mg/day) in a group of 40 patients sustaining head injury and found a favorable course in 75% of patients in the citicoline group, as compared to 33% in the piracetam group.
Cohadon et al [21,462] showed the clinical efficacy of citicoline in a double-blind study conducted on a series of 60 patients with severe head injury. A standard treatment was used in both groups, and surgery was performed when required. A group of patients was given citicoline 750 mg/day by the intravenous route for the first six days, and subsequently by the intramuscular route for an additional 20 days. The other group was administered placebo. Clinical evaluation was continued up to six months. At 15 days, response to painful stimuli was already superior in the group of citicoline-treated patients (
p < 0.01), in which an earlier recovery of consciousness was also seen (Fig. 17). Authors also noted a greater recovery from neurological deficits in the active group. After 120 days, autonomous ambulation was seen in 84% of patients in the citicoline group, as compared to 62.5% of patients in the placebo group. This difference was statistically significant from day 60
th (
p < 0.01). Table IV shows the final outcome obtained in both groups, as assessed using the Glasgow Outcome Scale. The mortality rate was similar in both groups. Data reported in this study show that citicoline shortens the time elapsed to recovery of consciousness and accelerates recovery from neurological deficits in patients with severe head injury.
Figure 17. Normalisation of the state of consciousness in relation to time and treatment; p < 0.01 at day 60.
Table IV. Final results according to treatment.
|
| |
Glasgow Outcome Scale
|
I
|
II
|
III
|
IV
|
V
|
Placebo group
|
12
|
5
|
4
|
3
|
6
|
Citicoline group
|
11
|
9
|
3
|
2
|
5
|
Deleuze et al [463] reported that citicoline is able to decrease serum creatine phosphokinase levels and lactate levels in cerebrospinal fluid, with a decrease in the lactate/pyruvate ratio, in patients with severe brain distress and coma. They also emphasized that the product was very well tolerated.
Ogashiwa et al [115] conducted a clinical trial in 101 patients with disorders of consciousness from different causes (20% of traumatic origin), showing the effectiveness of citicoline for improving the General Recovery Rate, closely related to the Principal Component Analysis Score. Authors found citicoline to be more effective in items related to the executive factor than in those related to the verbal factor, and that the greatest effect was achieved in patients less than 60 years of age and with a stabilized period of impaired consciousness not longer than three weeks. They also emphasized the excellent tolerability of the product, and even administered it by the intrathecal route in some cases [464,465].
At the Department of Neurosurgery of Centro Especial Ramón y Cajal in Madrid, a series of 100 patients with head injury treated with citicoline until discharge were studied, and their results were compared to those of another series of 100 patients with similar characteristics, but who did not receive citicoline [466]. Treatment with citicoline was started at doses of 600-1,200 mg/day by the parenteral route, switched to 300-900 mg/day by the oral route in the rehabilitation phase. The course was monitored by assessing mean coma duration, persistence of neurological and psychic symptoms, the Wechsler Adult Intelligence Scale test, and electrophysiological studies of muscle tension. Results achieved suggested that citicoline addition to the treatment regimen caused a decrease in duration of posttraumatic coma and rate of both neurological and psychic sequelae and achieved a better response in recovery from intellectual disorders and motor deficits.
Raggueneau and Jarrige [467], in a national survey conducted in France, recorded 921 cases of severe head injury, i.e., with an initial score in the Glasgow Coma Scale of 8 or less. Of these, 219 patients had been treated with citicoline, which allowed for distribution into two groups to compare the results obtained. No significant differences were found in mortality, but differences were seen in the number of dependent states, and the greatest effect was found in patients with an initial Glasgow Coma Scale score of 6-7 (Fig. 18). Citicoline improved quality of survival, allowing for more frequent social and familiar reinsertion, as well as return to work or school. Mortality in head injuries essentially depends on initial lesions which, except for epidural hematoma, are beyond any real therapeutic resolution.
Figure 18. Effect of treatment with citicoline on final results. Results are expressed as percentages. a p < 0.001 versus patients not treated with citicoline.
Calatayud et al [468] reported the results of the influence of citicoline addition to the treatment of head injury. Two hundred and sixteen patients with an initial Glasgow Coma Scale score ranging from 5 and 10 were reported. Of these, 115 patients received treatment with citicoline. Mean citicoline dose administered was 4 g/day. Analysis of the results showed that citicoline:
- Decreased hospital stay (p < 0.05) and duration of outpatient follow-up (p < 0.001), with differences being more marked in the group of patients with an initial Glasgow Coma Scale score ranging from 5 and 7.
- Promoted the recovery of memory, motor disorders, higher neurological functions, and mood changes.
- Improved global functional outcome (Table V).
Table V. Final result, evaluated with the Glasgow Outcome Scale (GOS), in relation to treatment (p < 0.05).
|
| |
Citicoline
|
Control
|
GOS I
|
77
|
51
|
GOS II
|
19
|
31
|
GOS III
|
1
|
7
|
GOS IV
|
0
|
2
|
GOS V
|
18
|
10
|
Lozano [469] reported the impact of citicoline therapy on the course of posttraumatic cerebral edema in a study conducted in 78 cases of head injury with an initial Glasgow Coma Scale score ranging from 5 and 7. In all cases, a computerized tomography of the head was performed at the start and end of the study to assess changes in the tomographic image of cerebral edema. Other parameters investigated included duration of hospital stay and the extent of autonomy at hospital discharge. Citicoline was administered to 39 patients for the first two weeks at a dose ranging from 3 and 6 g/day by intravenous infusion. After 14 days of treatment with citicoline, image of cerebral edema evolved as shown in figure 19. Cerebral edema had been reduced or normalized in a higher number of patients treated with citicoline as compared to control patients, with differences being highly significant (
p < 0.005). No significant differences were seen between both groups in therapeutic requirements or treatments received. Mean hospital stay was 28.718 ± 21.6 days for the group receiving active treatment and 37.323 ± 35.22 days for the control group, with statistically significant differences (
p < 0.001). Differences in final outcomes assessed according to the Glasgow Outcome Scale did not reach statistical significance due to the low number of cases and the special characteristics of this type of patients. However, a trend was seen to a more favorable resolution in the group of patients treated with citicoline (Table VI).
Figure 19. Evolution of the tomographic image of cerebral oedema after 14 days of treatment (p < 0.005).
Table VI. Final result, evaluated with the Glasgow Outcome Scale (GOS), in relation to treatment (n.s.).
|
| |
Citicoline
|
Control
|
GOS I
|
15
|
11
|
GOS II
|
8
|
8
|
GOS III
|
6
|
7
|
GOS IV
|
4
|
6
|
GOS V
|
6
|
7
|
Levin [470] conducted a study in 14 patients with postconcussional syndrome following a mild to moderate head injury. This syndrome is characterized by the occurrence of symptoms such as headache, dizziness, mnesic disorders, and sleep disturbances mainly. In this study, patients treated with citicoline for one month experienced an improvement in memory tests, particularly recognition tests, that was statistically significant as compared to placebo. Figure 20 shows changes in symptoms after one month of treatment. Greater improvements were achieved in patients treated with citicoline as compared to placebo patients, except for gastrointestinal discomfort. Dizziness was significantly more common in patients from the placebo group after one month of study. However, in a simple-blind study in patients with mild head injury [471], the authors were unable to evidence differences between citicoline and control with regards to the evolution of the postconcussional symptoms. Despite that, CDP-choline is considered a therapeutic option for postconcussional syndrome [472].
Figure 20. Evolution of post-concussional symptoms after one month of treatment with citicoline or placebo. The number of patients reporting each symptom is shown.
León-Carrión et al [473-475] investigated in a series of studies the effects of citicoline on post-traumatic memory disorders. In a group of seven patients with severe memory deficits, these authors investigated the effects of administration of citicoline 1 g on cerebral blood flow, as measured by the
133Xe inhalation technique. Two measurements were made, one at baseline and the other at 48 hours, under the same conditions, except those patients had taken the drug one hour before the test. All patients showed a significant hypoperfusion at the inferoposterior area of the left femoral lobe in the first measurement, that disappeared following citicoline administration. In a second study, 10 patients with severe memory deficits were randomized into two groups. Both patient groups were subjected to a short memory rehabilitation program. A group received citicoline 1 g/day p.o. for the three months the neuropsychological treatment program lasted, while the other group was given placebo. The results obtained are shown in table VII. Neuropsychological rehabilitation associated to citicoline achieved improvements in all evaluated areas, reaching statistical significance in verbal fluency and the word recall Luria test. Citicoline is considered as a valid therapeutic option for the treatment of post-traumatic cognitive impairments [476], improving also the quality of survival [477].
Table VII. Scores (mean ± SD) obtained by patients before and after treatment.
|
| |
Group A (placebo + rehabilitation)
|
Group B (citicoline + rehabilitation)
|
Before
|
After
|
Before
|
After
|
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 fluency
|
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 versus before treatment.
|
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