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Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86–1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. Ferrer Grupo.

To evaluate whether treatment with Citicoline in oral solution (OS-Citicoline) would increase visual function, retinal ganglion cells (RGCs) function, and neural conduction along visual pathways (neuroenhancement), and/or induce preservation of RGCs fibers' loss (neuroprotection) in non-arteritic ischemic optic neuropathy (NAION), a human model of neurodegeneration. Thirty-six patients with NAION and 20 age-matched controls were enrolled. Nineteen NAION patients received 500 mg/day of OS-Citicoline for a 6-month period followed by 3-month of wash-out (NC Group); 17 NAION patients were not treated (NN Group) from baseline to 9 months. In all subjects at baseline, and in NC and NN eyes at 6 and 9 months of follow-up, we assessed Visual Acuity (VA), Pattern Electroretinogram (PERG), Visual Evoked Potentials (VEP), retinal nerve fiber layer thickness (RNFL-T), and Humphrey 24-2 visual field mean deviation (HFA MD). Mean differences were statistically evaluated with ANOVA between Groups, and linear correlations were analysed with Pearson's test. At 6 months, significant differences between groups for all parameters were observed (ANOVA, p<0.01). In NC eyes, VA increased, PERG responses increased, VEP recordings improved and were significantly correlated with increases in HFA MD (p<0.01), and RNFL-T was unmodified or improved. In contrast, in NN eyes, VA, PERG, VEP responses, RNFL-T, and HFA MD were further worsened. Significant differences were still present at 9-month follow-up in the NN Group and after 3 months of OS-Citicoline wash-out in NC eyes. OS-Citicoline treatment induced neuroenhancement (improvement in RGCs function and neural conduction along visual pathways related to improvement of visual field defects) and neuroprotection (unmodified or improved RNFL morphological condition) in a human model of NAION involving fast RGCs degeneration. ClinicalTrials.gov NCT03758118.

The aim of the present study was to evaluate the effects of supplementation with a fixed combination of citicoline 500 mg, homotaurine 50 mg, and vitamin E 12 mg (CIT/HOMO/VITE) on contrast sensitivity and visual-related quality of life in patients with primary open-angle glaucoma (POAG) in mild stage. This was a multicenter, observational, cross-over, short-term, pilot study on POAG patients with stable controlled intraocular pressure (IOP). Patients were randomly assigned to Group 1 (current topical therapy for 4 months and then current topical therapy plus CIT/HOMO/VITE for 4 months) or Group 2 (CIT/HOMO/VITE in addition to current topical therapy for 4 months and then topical therapy alone for 4 months). Best-corrected visual acuity, IOP, visual field, and the Spaeth/Richman contrast sensitivity (SPARCS) test score were recorded at baseline and after 4 and 8 months. The Glaucoma Quality of Life-15 (GQL-15) questionnaire was administered at each check time. Forty-four patients were assigned to Group 1 and 65 to Group 2. Over the follow-up period, there were no significant changes in IOP or visual field findings, whereas SPARCS and GQL-15 findings significantly varied from baseline, both being improved in subjects treated with CIT/HOMO/VITE fixed combination. These results demonstrate that a daily intake of a fixed combination of citicoline, homotaurine, and vitamin E in addition to the topical medical treatment significantly increased the total score of the contrast sensitivity test and the quality of life in patients with POAG.

This study evaluated the early structural and functional effects of combined citicoline and coenzyme Q10 (CoQ10) (CitiQ10) treatment in a laser-induced ocular hypertension (OHT) model in Swiss albino mice, focusing on retinal inflammation and neuroprotection. Sixty male CD-1 mice were assigned to four groups: vehicle, CitiQ10, OHT, and OHT + CitiQ10. OHT was induced by laser photocoagulation of limbal and episcleral veins, and CitiQ10 was administered orally starting 15 days before induction. Intraocular pressure (IOP) was measured by rebound tonometry, retinal structure was assessed by spectral domain optical coherence tomography (SD-OCT), and function was evaluated using full-field electroretinography (ffERG). At 3 days post-induction, OHT eyes exhibited significant retinal nerve fiber layer (RNFL) thickening, increased vitreous particles, and early functional impairment, particularly reduced scotopic b-wave and oscillatory potentials. CitiQ10 treatment mitigated these changes, reducing vitreous particles, moderating RNFL alterations, and not exhibiting significant changes in ERG amplitudes. At 7 days post-induction, structural and functional deficits persisted but were less pronounced in treated eyes. These findings suggest that CitiQ10 treatment may attenuate early retinal damage in glaucoma, with OCT and ffERG serving as reliable monitoring tools, supporting the therapeutic potential of this approach in early stage disease.

PurposeThis study aims to evaluate whether the use of citicoline oral solution could improve quality of life in patients with chronic open-angle glaucoma (OAG).DesignRandomized, double-masked, placebo-controlled, cross-over study was used. Patients were randomized to one of the two sequences: either citicoline 500 mg/day oral solution-placebo or placebo-citicoline 500 mg/day oral solution. Switch of treatments was done after 3 months; patients were then followed for other 6 months. Follow-up included 3-month, 6-month, and 9-month visits.OutcomesThe primary outcome was the mean change of “intra-patient” composite score of the Visual Function Questionnaire-25 (VFQ-25). after citicoline oral solution vs placebo at 6-month visit as compared with baseline.MethodsThe trial was multicenter, conducted at 5 European Eye Clinics. OAG patients with bilateral visual field damage, a mean deviation (MD) ranging from − 5 to − 13 dB in the better eye, and controlled IOP were included. VFQ-25 and SF-36 questionnaires were administered at baseline and at 3-, 6-, and 9-month visits. A mixed effect model, with a random effect on the intercept, accounted for correlations among serial measurements on each subject.ResultsThe primary pre-specified outcome of the analysis reached statistical significance (p = 0.0413), showing greater improvement after citicoline oral solution. There was an increase in the composite score in both arms compared to baseline, but it was significant only for the placebo-citicoline arm (p = 0.0096, p = 0.0007, and p = 0.0006 for the three time-points compared to baseline). The effect of citicoline was stronger in patients with vision-related quality of life more affected by glaucoma at baseline.ConclusionsThis is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related quality of life in glaucomatous patients.

The studio di intervento nel decadimento vascolare lieve (IDEALE study) was an open multicenter Italian study, the aim of which was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment. The study was performed in 349 patients. The active or citicoline group was composed of 265 patients and included 122 men and 143 women of mean age 79.9 ± 7.8 years selected from six Italian regions. Inclusion criteria were age ≥ 65 years, Mini-Mental State Examination (MMSE) score ≥ 21, subjective memory complaints but no evidence of deficits on MMSE, and evidence of vascular lesions on neuroradiology. Those with probable Alzheimer's disease were excluded. The control group consisted of 84 patients, including 36 men and 48 women of mean age 78.9 ± 7.01 (range 67-90) years. Patients included in the study underwent brain computed tomography or magnetic resonance imaging, and plasma dosage of vitamin B12, folate, and thyroid hormones. Functional dependence was investigated by scores on the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales, mood was assessed by the Geriatric Depression Scale (GDS), and behavioral disorders using the Neuropsychiatric Inventory scale. Comorbidity was assessed using the Cumulative Illness Rating Scale. An assessment was made at baseline (T0), after 3 months (T1), and after 9 months (T2, ie, 6 months after T1). The main outcomes were an improvement in MMSE, ADL, and IADL scores in the study group compared with the control group. Side effects were also investigated. The study group was administered oral citicoline 500 mg twice a day throughout the study. MMSE scores remained unchanged over time (22.4 ± 4 at T0; 22.7 ± 4 at T1; 22.9 ± 4 at T2), whereas a significant difference was found between the study and control groups, both in T1 and in T2. No differences were found in ADL and IADL scores between the two groups. A slight but not statistically significant difference was found in GDS score between the study and control groups (P = 0.06). No adverse events were recorded. In this study, citicoline was effective and well tolerated in patients with mild vascular cognitive impairment. Citicoline activates biosynthesis of phospholipids in neuronal membranes, increases brain metabolism as well as norepinephrine and dopamine levels in the central nervous system, and has neuroprotective effects during hypoxia and ischemia. Therefore, citicoline may be recommended for patients with mild vascular cognitive impairment.

Medicines containing citicoline (cytidine-diphosphocholine) as an active principle have been marketed since the 1970s as nootropic and psychostimulant drugs available on prescription. Recently, the inner salt variant of this substance was pronounced a food ingredient in the major world markets. However, in the EU no nutrition or health claim has been authorized for use in commercial communications concerning its properties. Citicoline is considered a dietetic source of choline and cytidine. Cytidine does not have any health claim authorized either, but there are claims authorized for choline, concerning its contribution to normal lipid metabolism, maintenance of normal liver function, and normal homocysteine metabolism. The applicability of these claims to citicoline is discussed, leading to the conclusion that the issue is not a trivial one. Intriguing data, showing that on a molar mass basis citicoline is significantly less toxic than choline, are also analyzed. It is hypothesized that, compared to choline moiety in other dietary sources such as phosphatidylcholine, choline in citicoline is less prone to conversion to trimethylamine (TMA) and its putative atherogenic N-oxide (TMAO). Epidemiological studies have suggested that choline supplementation may improve cognitive performance, and for this application citicoline may be safer and more efficacious.

Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5′-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.

Abstract Background: Preservation of organ function and viability is a crucial factor for survival in cardiogenic shock (CS) patients. There is not information enough on cytoprotective substances that may delay organs damage in CS. We hypothesize that cytidine-5-diphosphocholine (CDP-choline) can act as a cytoprotective pharmacological measure that diminishes the target organ damage. So, we aimed to perform a review of works carried out in our institution to evaluate the effect of therapeutic cytoprotection of the CDP-choline. Summary: CDP-choline is an intermediate metabolite in the synthesis of phosphatidylcholine. It is also a useful drug for the treatment of acute ischaemic stroke, traumatic brain injury, and neurodegenerative diseases and has shown an excellent pharmacological safety profile as well. We review our institution’s work and described the cytoprotective effects of CDP-choline in experimental models of heart, liver, and kidney acute damage, where this compound was shown to diminish reperfusion-induced ventricular arrhythmias, oxidative stress, apoptotic cell death, inflammation, lactic acid levels and to preserve mitochondrial function. Key Messages: We propose that additional research is needed to evaluate the impact of cytoprotective therapy adjuvant to mitigate target organ damage in patients with CS.

INTRODUCTION: Traumatic brain injury (TBI) is a paramount factor in mortality and morbidity. The clinical trials conducted to investigate the efficacy of neuroprotective agents, such as citicoline, as a therapeutic alternative for TBI have presented divergent findings. Therefore, this study aimed to evaluate and compare citicoline's effect on the Barthel Index in patients with severe and moderate brain injury. MATERIALS AND METHODS: The study is a randomized clinical trial. Patients in the case group (35 patients) were treated with citicoline and the control group (34 patients) received a placebo. Data were analyzed using SPSS 16 software. RESULTS: The results showed that changes in the Glasgow Coma Scale, changes in quadriceps muscle force score, Barthel Index score changes, achieving the status without intubation, and spontaneous breathing in patients treated with citicoline were not a statistically significant difference in the two groups (P > 0.05). CONCLUSION: Findings revealed that citicoline did not impact the recovery process of severe and moderate TBI patients.