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Endotoxin shock is associated with severe impairments in cardiovascular and respiratory functions. We showed previously that choline or cytidine-5′-diphosphocholine (CDP-choline) provides beneficial effects in experimental endotoxin shock in dogs. The objective of the present study was to determine the effects of choline or CDP-choline on endotoxin-induced cardiovascular and respiratory dysfunctions. Dogs were treated intravenously (i.v.) with saline or endotoxin (LPS, 0.1 mg/kg) 5 min before i.v. infusion of saline, choline (20 mg/kg) or CDP-choline (70 mg/kg). Blood pressure, cardiac rate, myocardial and left ventricular functions, respiratory rate, blood gases, serum electrolytes and cardiac injury markers were determined before and at 0.5-48 h after endotoxin. Plasma tumor necrosis factor alpha (TNF-α), high mobility group box-1 (HMGB1), catecholamine and nitric oxide (NO) levels were measured 2 h and 24 h after the treatments. Endotoxin caused immediate and sustained reductions in blood pressure, cardiac output, pO2 and pH; changes in left ventricular functions, structure and volume parameters; and elevations in heart rate, respiratory rate, pCO2 and serum electrolytes (Na, K, Cl, Ca and P). Endotoxin also resulted in elevations in blood levels of cardiac injury markers, TNF-α, HMGB1, catecholamine and NO. In choline- or CDP-choline-treated dogs, all endotoxin effects were much smaller in magnitude and shorter in duration than observed values in controls. These data show that treatment with choline or CDP-choline improves functions of cardiovascular and respiratory systems in experimental endotoxemia and suggest that they may be useful in treatment of endotoxin shock in clinical setting.

Purpose: This study aims to evaluate the effect of citicoline administration in suppressing retinal damage due to methanol intoxication. This study hypothesizes that citicoline will minimize the lo...

Background Cytidine-5′-diphosphate choline (CDP-choline) has been suggested to exert neuroprotective and neuroreparative effects and may be beneficial for patients with stimulant dependence. This randomized, double-blind, placebo-controlled study in methamphetamine (MA) dependence investigated effects of CDP-choline on the brain structures and their associations with craving and MA use. Methods MA users (n = 44) were randomized to receive 2 g/day of CDP-choline (n = 22) or placebo (n = 22) for 8 weeks. Patients underwent brain magnetic resonance imaging (MRI) at baseline and 8-week follow-up. Healthy individuals (n = 27) were also examined using brain MRI at the same interval. Voxel-based morphometry analysis was conducted to examine changes in gray matter (GM) volumes and their associations with craving and MA use. Results Craving for MA was significantly reduced after the 8 week-treatment with CDP-choline (p = 0.01), but not with the placebo treatment (p = 0.10). There was no significant difference in the total number of MA-negative urine samples between the two groups (p = 0.19). With CDP-choline treatment, GM volumes in the left middle frontal gyrus (p = 0.001), right hippocampus (p = 0.009), and left precuneus (p = 0.001) were significantly increased compared to the placebo and control groups. Increased GM volumes in the left middle frontal gyrus with CDP-choline treatment were associated with reduced craving for MA (Spearman's ρ = −0.56, p = 0.03). In addition, the right hippocampal volume increases were positively associated with the total number of MA-negative urine results in the CDP-choline group (Spearman's ρ = 0.67, p = 0.006). Conclusion Our findings suggest that CDP-choline may increase GM volumes of MA-dependent patients, which may be related to decreases in MA use and craving.

Background Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations. Objective The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI). Methods A total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons. Results A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052). Conclusions Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was registered at clinicaltrials.gov as NCT03369925.

Objectives Amblyopia is a decrease of visual acuity that cannot be attributed to any structural abnormality of the eye or visual system, causing a partial or complete loss of vision due to inadequate stimulation in early life. Citicoline has been reported to improve visual acuity in amblyopic eyes as adjuvant treatment. This study was aimed to determine the effectiveness of citicoline in pediatric patients with refractive amblyopia in ophthalmology daily practices. Methods This was a retrospective–descriptive study with a time limited sampling method. This study was conducted at Surabaya Eye Clinic, East Java, Indonesia, by reviewing medical records for the period of January 2018 to December 2019. Results A total of 34 eyes were included in the study with the majority aged five years (41.2%) and six years (35.3%). The severity of amblyopia varied among patients, 21 eyes (61.76%) had mild amblyopia, seven eyes (20.59%) had moderate amblyopia, and two eyes (5.88%) had severe amblyopia. The duration of given therapy also varied, 18 eyes (52.94%) were given 3 months therapy, two eyes were given 4 months therapy, 12 eyes were given 6 months therapy, and two eyes were given 8 months therapy. Citicoline was found effective in mild and moderate amblyopia and for the duration of 3 and 6 months (p Conclusions Citicoline therapy resulted in a clinically and statistically improvement in refractive amblyopia patients.

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5’-diphospho)-choline (100 μg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 μg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.

Background:: Citicoline is a drug used both in degenerative and in vascular cognitive decline; memantine is a drug used for the treatment of mild to moderate Alzheimer’s disease (AD). Our hypothesis is that their combined use could have enhanced action in patients having AD and mixed dementia (MD). We report the main tips from a recent study on the use of these drugs, the CITIMEM study. Methods:: The study was retrospective and was performed on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old) who had been visited between 2015 and 2017 in four different centers for dementia all over Italy. Neuropsychological and functional tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The effects of combined treatment versus memantine alone on cognitive functions assessed by Mini Mental State Examination (MMSE) and the possible onset of side effects or adverse events, as well as the influence on daily life functions and behavioral symptoms were investigated. Results:: Patients undergoing combined treatment showed a significant increase in MMSE vs memantine alone, both at T1 (p=0.003) and T2 (p =0.000). Conclusions:: The CITIMEM study confirms our hypothesis that combined administration of memantine plus citicoline is safe and more effective than memantine alone on cognition in patients suffering from AD or MD.

Background: Background: Citicoline has been proven to have beneficial effects in patients with cognitive impairment. In previous studies, combined treatment with memantine and acetylcholinesterase inhibitors (AChEIs) maintained cognitive function in patients with Alzheimer’s disease (AD) better than memantine or AChEIs alone. Objective: To evaluate the effectiveness and safety of a combination therapy of oral citicoline, memantine, and an AChEI in AD when compared with memantine and an AChEI without citicoline. Methods: This was a retrospective multi-centric case-control study, conducted in Italian Centers for Cognitive Impairment and Dementia. Overall, 170 patients were recruited (34.11%of men, mean age 76,81±4.93 years): 48.8%treated with memantine and donepezil; 48.2%with memantine and rivastigmine; 2.9%with memantine and galantamine. 89 patients (control-group) were treated with memantine and an AChEI, whereas 81 patients (case-group) were treated with oral citicoline 1000 mg/day added to memantine and an AChEI given orally. Cognitive functions, activities of daily living, instrumental activities of daily living, comorbidities, mood and behavioral disturbances were assessed at baseline, month 6, and month 12. Results: In the case group, MMSE score had a statistically significant increasing trend between T0 and T2 (14.88±2.95 versus 15.09±3.00; p = 0.040), whereas in the control group, MMSE score showed a statistically significant decrease trend (14.37±2.63 versus 14.03±2.92 p = 0.024). Conclusion: In older patients with AD, a triple therapy with citicoline, memantine, and AChEI was more effective than memantine and AChEI without citicoline in maintaining the MMSE total score after 12 months.

Combined therapy of memantine or acetylcholinesterase inhibitors, with cholinergic precursors such as citicoline, can be effective in Alzheimer’s disease. Indeed, they are able to increase the intrasynaptic levels of acetylcholine more than the single drug. Our aim was to evaluate the efficacy and safety of oral citicoline plus memantine plus rivastigmine in patients with Alzheimer’s disease. This was a multi-centric, retrospective case-control study conducted in Italian Centers for Cognitive Impairment and Dementia on consecutive patients aged 65 years or older affected with Alzheimer’s disease. Overall, 104 patients were recruited (27% male, mean age 76.04 ± 4.92 years); 41 (39.42%) treated with citicolin 1000 mg/day given orally + memantine + rivastigmine (Cases) and 63 (60.58%) treated with memantine + rivastigmine (Controls). At baseline (T0), month 6 (T1) and month 12 (T2), cognitive functions were assessed by the Mini Mental State Examination (MMSE), functional dependence by basal Activities (ADL) and Instrumental Activities of Daily Living (IADL), comorbidity by the Cumulative Illness Rating Scale (CIRS), mood by the Geriatric Depression Scale (GDS), and behavioural disturbances by the Neuropsychiatric Inventory (NPI). Adverse events were reported during the study. The difference in MMSE score was not significant when comparing the two groups at T0, T1 or T2. However, in the case group, the MMSE total score showed a statistically significant difference at T0 versus T1 (13.63 ± 2.46 vs. 14.17 ± 2.24; p = 0.008), and at T0 versus T2 (13.63 ± 2.46 vs. 14.32 ± 2.53; p = 0.002). In the control group, no statistical differences were found at baseline (T0), T1 and T2. ADL, IADL, GDS and NPI total score did not improve during the study in either the case or the control group. In our study we observed absence of a statistically significant difference between case and control groups for the MMSE total scores. However, in the case group in the MMSE total scores, there was a statistically significant increase between the baseline and the end of the study.

Brain hypoxia after cardiac arrest leads to damage of the neuronal cell membrane. Citicoline is necessary for the synthesis of cell membrane. We planned to assess the neuroprotective effect of citicoline in children after cardiac arrest. This randomized controlled trial was carried out at pediatric intensive care units (PICU) and surgical ICU at Tanta university hospital on 80 consecutive children surviving in-hospital cardiac arrest who were subdivided into two groups. Group I (citicoline group) included 40 children with post-cardiac arrest who received citicoline 10 mg /kg /12 h IV for 6 weeks plus other supportive measures and group II (control group) included 40 children with post-cardiac arrest who were managed with only supportive measures. All patients were evaluated for Glasgow coma score (GCS), modified Rankin scale (mRS) for children, seizures frequency, type and duration, and serum neuron-specific enolase (NSE) before and 3 months after the treatment. GCS and mRS significantly improved in citicholine group compared to the control group. Seizure frequency and duration, mortality, PICU and hospital stay significantly decreased in citicholine group compared to the control group. Serum NSE levels significantly decreased in citicholine group only. No side effects were recorded.Conclusion: Citicoline is a promising neuroprotective drug in children with post-cardiac arrest.Trial Registration: The study was registered at Pan African Clinical Trials Registry (PACTR) www.pactr.samrc.ac.za with trial number PACTR201907742119058. What is known? • Post-resuscitation brain injury is one of the major complications that can lead to death or disability. • CDP-choline has been studied for acute ischemic stroke in several adult studies because of its reparative effect. What is new? • Our study was the first in pediatrics that assessed the neuroprotective effect of CDP-choline on the brain in children after cardiac arrest. • We found that Citicoline is a promising neuroprotective drug in children with post-cardiac arrest.

Peripheral nerve injury (PNI) is a devastating condition that may result in loss of sensory function, motor function, or both. In the present study, we construct an electrospun nerve guide conduit (NGC) based on polycaprolactone (PCL) and gelatin filled with citicoline bearing platelet-rich plasma (PRP) gel as a treatment for PNI. The NGCs fabricated from PCL/Gel polymeric blend using the electrospinning technique. The characterizations demonstrated that the fabricated nanofibers were straight with the diameter of 708 ± 476 nm, the water contact angle of 78.30 ± 2.52°, the weight loss of 41.60 ± 6.94% during 60 days, the tensile strength of 5.31 ± 0.97 MPa, and the young's modulus of 3.47 ± 0.10 GPa. The in vitro studies revealed that the PCL/Gel/PRP/Citi NGC was biocompatible and hemocompatible. The in vivo studies conducted on sciatic nerve injury in rats showed that the implantation of PCL/Gel/PRP/Citi NGC induced regeneration of nerve tissue, demonstrated with histopathological assessments. Moreover, the sciatic function index (SFI) value of −30.3 ± 3.5 and hot plate latency time of 6.10 ± 1.10 s revealed that the PCL/Gel/PRP/Citi NGCs recovered motor and sensory functions. Our findings implied that the fabricated NGC exhibited promising physicochemical and biological activates favorable for PNI treatment.

Introduction This study aimed to evaluate the effect of treatment with eye drops containing citicoline and vitamin B12 on changes in function of the inner retina, morphology of the inner and outer retina, and microvascular condition in patients with type 1 diabetes (DM1) with mild signs of non-proliferative diabetic retinopathy (NPDR) during 3 years of follow-up. Methods A pilot study with prospective, randomized, and double-masked design was conducted to address the aims. Twenty patients with DM1 were enrolled and randomly divided into two groups: the DC group comprising patients treated with citicoline and vitamin B12 eye drops (10 patients; mean age ± standard deviation, 46.86 ± 8.78 years) and the DP group comprising those treated with placebo (10 patients; mean age ± standard deviation, 47.89 ± 7.74 years). In the DC group, one eye of each patient was treated with citicoline and vitamin B12 eye drops (OMK2®, Omikron Italia srl, Italy, 3 drops/day), while in the DP group, it was treated with placebo (eye drops containing hypromellose 0.3%, 3 drops/day) for a 3-year period. In both groups, Humphrey Matrix frequency doubling technology (FDT), spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA), and adaptive optics (AO) were applied at baseline and 12, 24, and 36 months of the follow-up period. Results In the results of follow-up evaluation, the DC and DP groups were significantly different: Significant reduction in function in terms of 10-2 FDT mean sensitivity and in morphology reflected by an increase in inner nuclear layer thickness and decrease in other plexiform layer thickness and foveal vessel density were observed in the DP group, while no such significant changes were observed in the DC group in the long term. Conclusions This pilot study indicated that patients with DM1 with mild signs of diabetic retinopathy (DR) who underwent treatment with citicoline and vitamin B12 eye drops for a 3-year duration achieved stabilization or decreased rate of functional impairment, neuroretinal degeneration, and microvascular damage. Trial Registration ClinicalTrials.gov identifier, NCT04009980.

Lead is a major environmental pollutant that causes serious adverse effects on biological systems and cells. In this study, we examined the effect of citicoline on lead-induced apoptosis in PC12 cells. The PC12 cells were pre-treated with citicoline and then exposed to lead for 48 h. The effect of citicoline on cell survival was examined by MTT assay. In addition, levels of lipid peroxidation (LPO), total thiol groups, total antioxidant power (TAP), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) were evaluated. The levels of Bax, Bcl-2, and caspase-3 were also measured, by Western blot analysis. Citicoline significantly increased the cell viability of PC12 cells exposed to lead. Treatment of PC12 cells with lead increased LPO levels, and citicoline effectively decreased LPO. Levels of total thiol groups and TAP, CAT, SOD, and GSH were significantly increased in citicoline-treated PC12 cells compared with the lead-treated group. Citicoline pretreatment significantly reduced Bax expression, and increased the level of Bcl-2 expression. Citicoline also reduced caspase-3 activation in PC12 cells compared with the lead-treated group. Our findings indicate 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 the mitochondria-mediated apoptotic pathway.

There is evidence that both omega-3 polyunsaturated fatty acids (n-3 PUFAs) and choline can influence sports performance, but information establishing their combined effects when given in the form of krill oil during power training protocols is missing. The purpose of this study was therefore to characterize n-3 PUFA and choline profiles after a one-hour period of high-intensity physical workout after 12 weeks of supplementation. Thirty-five healthy power training athletes received either 2.5 g/day of Neptune krill oilTM (550 mg EPA/DHA and 150 mg choline) or olive oil (placebo) in a randomized double-blind design. After 12 weeks, only the krill oil group showed a significant HS-Omega-3 Index increase from 4.82 to 6.77% and a reduction in the ARA/EPA ratio (from 50.72 to 13.61%) (p < 0.001). The krill oil group showed significantly higher recovery of choline concentrations relative to the placebo group from the end of the first to the beginning of the second exercise test (p = 0.04) and an 8% decrease in total antioxidant capacity post-exercise versus 21% in the placebo group (p = 0.35). In conclusion, krill oil can be used as a nutritional strategy for increasing the HS-Omega-3 Index, recover choline concentrations and address oxidative stress after intense power trainings.

Objective To compare selective serotonin reuptake inhibitors (SSRIs) and nootropic drugs in the reduction of anxiety and depressive symptoms in post-stroke patients. Methods This retrospective cohort study included patients diagnosed with post-stroke depression that were treated with either SSRIs or nootropic drugs (i.e. citicoline or choline alphoscerate). Depression and anxiety were assessed using the Hamilton Rating Scales. Statistical associations between the use of nootropic drugs and mood disorder improvements were determined by measuring assessment scores at 6-months. Results A total of 44 post-stroke patients with depression (aged 45–75 years) were enrolled in the study: 20 were treated with SSRIs and 24 received nootropic drugs. From baseline to follow-up, the SSRI group showed a large effect size with regard depression (success rate difference [SRD] 0.57; 95% confidence interval [CI] 0.21, 0.79) and anxiety (SRD 0.49; 95% CI 0.14, 0.74), whereas the nootropic group showed a small effect size for depression (SRD 0.16; 95% CI –0.17, 0.46) and a small effect size for anxiety (SRD 0.36; 95% CI –0.03, 0.62). Conclusion The administration of nootropic drugs could be a valid therapeutic strategy to manage post-stroke patients suffering from mild–moderate anxiety or anxious-depressive syndrome, but this requires further research.

An observational cohort study was performed at Neonatal Intensive Care Units of two military hospitals to see the effects of citicoline in neonates diagnosed to have moderate to severe hypoxic ischemic encephalopathy. Twenty newborns fulfilling the inclusion criteria were selected for the study and were given injection citicoline via the IV route. The outcomes in the immediate newborn period, including neurological features and mortality, were studied. Only one baby, who was given injection citicoline, died during the study period and 19 babies were discharged and sent home after establishment of oral feeds. Citicoline was found promising in treatment of newborns with moderate to severe birth asphyxia. Key Words: Hypoxia, Ischemia, Birth asphyxia, HIE.

Introduction Our aim was to evaluate the effects of 36 months of treatment with citicoline and vitamin B12 eye drops on macular function in patients with type 1 diabetes (DM1) with mild signs of non-proliferative diabetic retinopathy (NPDR). Methods A prospective, randomized, interventional, monocentric, double-masked study was conducted. Twenty patients with DM1 were enrolled and randomly divided into two groups: the DC group (10 patients; mean age ± standard deviation 46.86 ± 8.78 years) in which one eye of each patient was treated with citicoline and vitamin B12 eye drops (OMK2®, Omikron Italia srl, Italy, one drop thrice daily) for a period of 36 months; the DP group (10 patients; mean age ± standard deviation 47.89 ± 7.74 years) in which one eye of each patient was treated with placebo (eye drops containing hypromellose 0.3%, one drop thrice daily) for a period of 36 months. A total of 18 eyes (10 from the DP and 8 from the DC group, respectively) completed the study. In both groups, multifocal electroretinogram (mfERG) recordings were assessed at baseline and after 36 months. In mfERG analysis, the N1–P1 response amplitude density (RAD) evaluated in the 0–2.5° (ring 1), in the 2.5–5° (ring 2), in the 5–10° (ring 3), and in the 0–10° (ring 1 + ring 2 + ring 3) were considered. Results With respect to baseline, after 36 months of follow-up, the mfERG RADs recorded in R1, R2, R3, and R1 + R2 + R3 were significantly increased (i.e., R1 + R2 + R3 RAD from 21.552 ± 2.522 nV/degree2 at baseline to 26.912 ± 2.850 nV/degree2 at 36 months) in DC eyes, whereas in DP eyes they were significantly reduced (i.e., R1 + R2 + R3 RAD from 21.033 ± 3.574 nV/degree2 at baseline to 16.151 ± 3.571 nV/degree2 at 36 months). Conclusions This study indicates that patients with NPDR treated with citicoline and vitamin B12 eye drops for a 36-month period achieved an improvement of the macular bioelectrical responses detectable by mfERG recordings. By contrast, during the same period of follow-up, patients with NPDR treated with placebo showed a worsening of the macular function.

Background Prospects for recovery after traumatic brain injury (TBI) are often underestimated, potentially leading to withdrawal of care in the comatose TBI patient who may ultimately have a favorable outcome with aggressive care. Outcomes and trajectories of recovery in a large series of patients with TBI were evaluated at 30, 90, and 180 days postinjury. Methods A secondary analysis of the phase 3 Citicoline Brain Injury Treatment (COBRIT) trial was performed analyzing recovery trajectories and long-term outcomes at 30, 90, and 180 days postinjury. A Glasgow Outcome Scale-Extended (GOS-E) score of 5 or higher was considered favorable. Pearson χ2 analysis was used, and a P value of 0.05 was considered significant. A locally weighted, polynomial regression model was used to model recovery trajectories in a nonlinear fashion. Results Subjects with TBI in the COBRIT trial had high rates of favorable outcome (57% of severe TBI, 86% of moderate TBI, and 93% of complicated mild TBI) at 6-month follow-up. These favorable outcomes often converted from high rates of unfavorable outcome at initial 1-month follow-up (85% of severe TBI, 57% of moderate TBI, and 21% of complicated mild TBI). Recovery trajectories had not plateaued at 6 months, suggesting that further improvement occurs beyond 6 months postinjury. Conclusions In this secondary analysis of the COBRIT trial, most patients had favorable outcomes by the GOS-E at 6 months postinjury in all complicated mild and moderate TBI groups, with over half of patients with severe TBI achieving a favorable outcome as well. Of subjects in a vegetative state (GOS-E score 2) at 1 month postinjury, 18% improved to a favorable outcome by 6 months postinjury. There was substantial improvement in all groups from 1 to 6 months, and this improvement may continue beyond 6 months. Clinical trials in TBI should consider recovery curves with repeated measures to assess outcomes because arbitrary single-moment outcome determination likely underestimates treatment effect in TBI care.

OBJECTIVE To determine the comparative effect of monosialoganglioside versus citicoline on the content changes of serum apoptotic factors (PDCD5, sFas and sFasL), neurological function indices (BDNF, NSE, S100-β and NGF) and oxidative stress indices (SOD, MDA and GSH-PX) in newborns with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN An experimental study. PLACE AND DURATION OF STUDY Emergency Department, Affiliated Children's Hospital of Zhengzhou University, China, from October 2016 to February 2018. METHODOLOGY A total of 90 newborns with HIE were randomly divided into a treatment group and a control group, with 45 cases in each group. In addition to the conventional treatment, the treatment group was given monosialoganglioside treatment, while the control group was given citicoline treatment. Both groups were treated for 10 days. After treatment, the content differences of serum apoptosis factors (PDCD5, sFas and sFasL), neurological function indices (BDNF, NSE, S100-β and NGF) and oxidative stress indices (SOD, MDA and GSH-PX) were observed in the two groups. RESULTS After treatment, the levels of serum PDCD5, sFas, sFasL, MDA, NSE and S100-β in the treatment group were lower than those in the control group (all p

Phospholipids are structural components of cellular membranes that play important roles as precursors for various signaling pathways in modulating neuronal membrane function and maintenance of the intracellular environment. Phosphatidylcholine (PtdCho) is the most abundant cellular phospholipid. Citicoline and docosahexaenoic acid (DHA) are essential intermediates in the synthesis of PtdCho. Both PtdCho intermediates have independently shown neuroprotective effects in cerebral ischemia, but their combined effect is unknown. This study aimed to investigate the combined effect of oral citicoline and DHA treatment on improvement of cognitive deficits following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. BCCAO ischemic mice were treated for a total of 11 days with a combination of citicoline (40 mg/kg body weight/day) and DHA (300 mg/kg body weight/day) or each alone. Combined citicoline and DHA synergistically and significantly improved learning and memory ability of ischemic mice compared with either alone. Further, citicoline and DHA treatment significantly prevented neuronal cell death, and slightly increased DHA-containing PtdCho in the hippocampus, albeit not significantly. Taken together, these findings suggest that combined citicoline and DHA treatment may have synergistic benefits for partially improving memory deficits following transient brain ischemia. Keywords: Citicoline, DHA, Bilateral common carotid artery occlusion, Neuroprotection, Memory

To evaluate the retinal function and the relative neural conduction along the visual pathway after treatment with citicoline in liposomal formulation (CLF) eye drops in patients with open angle glaucoma (OAG). Twelve OAG patients (mean age ± standard deviation 52.58 ± 11.39 years, intraocular pressure

Objective: To evaluate the effectiveness of acupuncture in patients with vascular cognitive impairment no dementia (VCIND) in comparison with citicoline, an agent for cognitive disturbances associated with chronic cerebral disorders. Design: A randomized controlled multicenter trial. Setting: In three hospitals in Beijing, China. Subjects: A total of 216 patients with VCIND were recruited. Interventions: Patients with VCIND (mean age of 65.4 years) were randomized to receive acupuncture (two sessions per week) or oral citicoline (100 mg three times daily) over three months. Main measures: The primary outcome was the change from baseline to three months in cognitive symptom, measured by Alzheimer’s disease Assessment Scale, cognitive subscale (ADAS-cog). Secondary outcomes included changes from baseline to six months in ADAS-cog, executive function measured by the Clock Drawing Test (CDT), and functional disability measured by the Ability of Daily Living (ADL) scale at three and six months. Results: At three months, the acupuncture group had a greater decrease in mean ADAS-cog score (−2.33 ± 0.31) than the citicoline group (−1.38 ± 0.34) with a mean difference of −0.95 (95% CI, −1.84 to −0.07, P = 0.035). The mean change from baseline to six months in ADAS-cog also significantly favored acupuncture treatments (acupuncture change −2.61 vs citicoline −1.25, difference: −1.36 points; 95% CI, −2.20 to −0.51; P = 0.002). There was no difference between the two groups on CDT and ADL scores at either time point. Conclusion: Compared with citicoline, acupuncture has comparable and even superior efficacy with improved cognitive and daily living performance as a complementary and alternative medicine treatment for VCIND.

The detection of deviant auditory features is empirically supported as impaired in schizophrenia and has been shown to associate with functional outcome. Modulated by glutamate neurotransmission, this sensory process has also been shown to relate to the α7 nicotinic acetylcholine receptor (nAChR) system, a prioritized molecular target for the development of novel cognition targeted pharmacological treatments. This pilot study assessed the acute effects of CDP-Choline, a choline supplement with α7 nAChR agonist properties, on the mismatch negativity (MMN), an event-related potential index of the detection of an acoustic change, in a sample of individuals diagnosed with chronic schizophrenia. Utilizing a randomized, placebo-controlled, double-blind design, the dose-dependent (500 mg, 1,000 mg, 2,000 mg), baseline amplitude-dependent (low vs. high), and deviant feature-dependent effects of CDP-Choline on the MMN were examined. CDP-choline's effects interacted with dosage, deviance feature, and baseline amplitude with low baseline amplitude patients demonstrating enhanced MMNs, and high baseline amplitude patients demonstrating suppressed MMNs in response to CDP-Choline. These findings offer tentative support for the involvement of the α7 nAChR system in auditory MMN abnormalities in schizophrenia and supports further research assessing the effects of long-term treatment with CDP-Choline in the personalized treatment of auditory deviance processing impairments. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01033-6.

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.

Optimization of the choice of neuroprotective treatment regimens in patients with chronic cerebral ischemia that takes into account the synergy of drug interactions gives the doctor an opportunity for personalized approach that increases the effectiveness of treatment.Differential chemoreactomic analysis of the synergism of ethyl methyl hydroxypyridine succinate (EMHPS) and a number of monocomponent neuroprotective agents (piracetam, vinpocetine, citicoline, choline alfoscerate); proteomic analysis of polypeptide neuroprotectors (cerebrolysin, etc.); an expert analysis of multicomponent neuroprotector Cytoflavin.Piracetam, citicoline (Neupilept) and choline alfoscerate (Cereton) effectively enhance the pharmacological properties of EMHPS and vice versa. Expert assessments of the synergism between the properties of EMHPS, polypeptide neuroprotectors (cerebrolysin) and other multicomponent drugs (cytoflavin), which are also used in adjuvant therapy with EMHPS, are presented.In real clinical practice, of particular interest is the objectification of the appointment of combined therapy regimens. This study indicates that EMHPS can provide a favorable background for maximizing the effectiveness of therapy when used with other drugs.Оптимизация выбора схем нейропротективной терапии у пациентов с хронической ишемией головного мозга с учетом синергизма лекарственных взаимодействий для возможности индивидуального, персонифицированного подхода, повышающего эффективность лечения.Дифференциальный хемореактомный анализ синергизма этилметилгидроксипиридин сукцината (ЭМГПС) и ряда монокомпонентных нейропротекторных средств (пирацетам, винпоцетин, цитиколин, холина альфосцерат); протеомный анализ полипептидных нейропротекторов (церебролизин и др.); экспертный анализ состава многокомпонентного нейропротектора (Цитофлавин).Пирацетам, цитиколин (Нейпилепт) и холина альфосцерат (Церетон) эффективно усиливают фармакологические свойства ЭМГПС. Представлены экспертные оценки синергизма между свойствами ЭМГПС, полипептидных нейропротекторов (церебролизин) и других многокомпонентных препаратов (цитофлавин), которые также используются в адъювантной терапии совместно с ЭМГПС.В реальной клинической практике особый интерес вызывает объективизация назначения комбинированных схем терапии. ЭМГПС может обеспечивать благоприятный фон для достижения максимальной эффективности терапии при использовании с другими препаратами.

Background Stroke is one of the leading causes of long-lasting disability and mortality and its global burden has increased in the past two decades. Several therapies have been proposed for the recovery from, and treatment of, ischemic stroke. One of them is citicoline. This review assessed the benefits and harms of citicoline for treating patients with acute ischemic stroke. Objectives To assess the clinical benefits and harms of citicoline compared with placebo or any other control for treating people with acute ischemic stroke. Search methods We searched in the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS until 29 January 2020. We searched the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. Additionally, we also reviewed reference lists of the retrieved publications and review articles, and searched the websites of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Selection criteria We included randomized controlled trials (RCTs) in any setting including participants with acute ischemic stroke. Trials were eligible for inclusion if they compared citicoline versus placebo or no intervention. Data collection and analysis We selected RCTs, assessed the risk of bias in seven domains, and extracted data by duplicate. Our primary outcomes of interest were all-cause mortality and the degree of disability or dependence in daily activities at 90 days. We estimated risk ratios (RRs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We conducted our analyses using the fixed-effect and random-effects model meta-analyses. We assessed the overall quality of evidence for six pre-specified outcomes using the GRADE approach. Main results We identified 10 RCTs including 4281 participants. In all these trials, citicoline was given either orally, intravenously, or a combination of both compared with placebo or standard care therapy. Citicoline doses ranged between 500 mg and 2000 mg per day. We assessed all the included trials as having high risk of bias. Drug companies sponsored six trials. A pooled analysis of eight trials indicates there may be little or no difference in all-cause mortality comparing citicoline with placebo (17.3% versus 18.5%; RR 0.94, 95% CI 0.83 to 1.07; I² = 0%; low-quality evidence due to risk of bias). Four trials found no difference in the proportion of patients with disability or dependence in daily activities according to the Rankin scale comparing citicoline with placebo (21.72% versus 19.23%; RR 1.11, 95% CI 0.97 to 1.26; I² = 1%; low-quality evidence due to risk of bias). Meta-analysis of three trials indicates there may be little or no difference in serious cardiovascular adverse events comparing citicoline with placebo (8.83% versus 7.77%; RR 1.04, 95% CI 0.84 to 1.29; I² = 0%; low-quality evidence due to risk of bias). Overall, either serious or non-serious adverse events - central nervous system, gastrointestinal, musculoskeletal, etc. - were poorly reported and harms may have been underestimated. Four trials assessing functional recovery with the Barthel Index at a cut-off point of 95 points or more did not find differences comparing citicoline with placebo (32.78% versus 30.70%; RR 1.03, 95% CI 0.94 to 1.13; I² = 24%; low-quality evidence due to risk of bias). There were no differences in neurological function (National Institutes of Health Stroke Scale at a cut-off point of ≤ 1 points) comparing citicoline with placebo according to five trials (24.31% versus 22.44%; RR 1.08, 95% CI 0.96 to 1.21; I² = 27%, low-quality evidence due to risk of bias). A pre-planned Trial Sequential Analysis suggested that no more trials may be needed for the primary outcomes but no trial provided information on quality of life. Authors' conclusions This review assessed the clinical benefits and harms of citicoline compared with placebo or any other standard treatment for people with acute ischemic stroke. The findings of the review suggest there may be little to no difference between citicoline and its controls regarding all-cause mortality, disability or dependence in daily activities, severe adverse events, functional recovery and the assessment of the neurological function, based on low-certainty evidence. None of the included trials assessed quality of life and the safety profile of citicoline remains unknown. The available evidence is of low quality due to either limitations in the design or execution of the trials.

The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single-gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease.

Citicoline is a chemical compound involved in the synthesis of cell membranes. It also has other, not yet explained functions. Research on the use of citicoline is conducted in neurology, ophthalmology, and psychiatry. Citicoline is widely available as a dietary supplement. It is often used to enhance cognitive functions. In our article, accessible databases were searched for articles regarding citicoline use in neurological diseases. This article has a systemic review form. After rejecting non-eligible reports, 47 remaining articles were reviewed. The review found that citicoline has been proven to be a useful compound in preventing dementia progression. It also enhances cognitive functions among healthy individuals and improves prognosis after stroke. In an animal model of nerve damage and neuropathy, citicoline stimulated regeneration and lessened pain. Among patients who underwent brain trauma, citicoline has an unclear clinical effect. Citicoline has a wide range of effects and could be an essential substance in the treatment of many neurological diseases. Its positive impact on learning and cognitive functions among the healthy population is also worth noting.

Precis Citicoline eyedrops in patients with progressing glaucoma. Purpose This study aimed to test whether the additional therapy with citicoline eyedrops to intraocular pressure (IOP)-lowering treatment could slow glaucoma progression in patients with worsening of damage and IOP 18 mm Hg or less. Design This was a randomized, double-masked, placebo-controlled, multicenter 3-year study. Outcomes The outcomes studied were difference in the visual field (mean deviation, MD, of 24-2; MD of 10-2) rates of progression and difference in retinal nerve fiber layer (RNFL) thickness change between the 2 study groups at 3 years. Methods Patients with mild to moderate open-angle glaucoma (OAG) showing damage progression of at least -0.5 dB/y in the 2 years before enrollment despite IOP ≤18 mm Hg were randomized to receive citicoline eyedrops or placebo 3 times daily for 3 years. Patients were followed every 3 months and underwent a visual field examination with 24-2 and 10-2 strategies and RNFL assessment. Analysis of variance and linear models were used to test the differences between groups. Results Eighty patients were randomized in the trial. The mean 3-year rates of progression were -1.03 (2.14) dB in the citicoline group and -1.92 (2.23) dB in the placebo group (P=0.07) for 24-2 MD and -0.41 (3.45) dB in the citicoline group and -2.22 (3.63) dB in the placebo group (P=0.02) for 10-2 MD. On average, patients receiving citicoline eyedrops lost 1.86 μm of RNFL in 3 years, versus 2.99 μm in the placebo group (P=0.02). Conclusions Additional treatment with citicoline eyedrops to IOP-lowering treatment might reduce disease progression in patients with progressing glaucoma despite IOP ≤18 mm Hg.

Background To evaluate the effects of topical citicoline and vitamin B12 (Cit-B12: OMK2, Omikron Italia srl, Italy) on corneal innervation of patients with diabetic neuropathy. Methods This prospective, randomized, double blind, placebo-controlled study included 30 patients randomised with a 2:1 ratio to Cit-B12 or placebo 3 times daily for 18 months. At baseline and at months 4, 8, 12, 18 patients underwent the Ocular Surface Disease Index questionnaire (OSDI), tear break-up time, evaluation of corneal and conjunctival staining, Schirmer I test, Cochet-Bonnet esthesiometry, and confocal biomicroscopy of corneal sub-basal plexus (SBP). Fiber lenght density (FLD) was calculated using NeuronJ and expressed in mm/mm2. Raw data and differences from baseline were analysed in the two groups. Results 29/30 patients concluded the study. The two groups had similar FLD at baseline; it progressively improved up to month 18 in both groups (Cit-B12, p p = 0.04). A progressive amelioration of corneal sensitivity (baseline, 28 ± 18 mm; month 18, 52 ± 10 mm, p P = 0.04) and OSDI questionnaire (P = 0.05) were shown on Cit-B12 group alone. Both treatments were well tolerated and adherence during the study was high. Conclusions Cit-B12 ameliorated both morphology and function of corneal nerves in patients with diabetes, thus suggesting a neuroregenerative effect. Trial registration Trial registration NCT03906513, retrospectively registered on 08 April 2019.

Background A critical strategy in the management of Alzheimer's disease (AD) is optimizing the effects of currently available pharmacologic therapies such as citicoline (CC). Objective The purpose of this study was to determine the effects of CC as adjunct therapy to cholinesterase inhibitors (AChEI) in the treatment of AD. Methods We identified relevant studies by electronic search until April 2020. We considered studies with a comparator group that enrolled elderly patients with a diagnosis of AD and employed CC as an adjunct therapy to AChEIs compared to AChEI monotherapy or comparisons of different AChEIs combined with CC. Methodological quality assessment was done using the Newcastle-Ottawa Scale. Results Out of 149 articles identified, two retrospective cohort studies involving 563 elderly patients affected with AD were included. After 3 months and 9 months, better Mini-Mental Status Examination scores were observed in the "AChEIs + CC" group versus "AChEIs alone" group. CC combined with donepezil may be better in improving cognition than when combined with rivastigmine. No significant difference was noted in terms of activities of daily living (ADL) and instrumental-ADL. Neuropsychiatric Inventory and Geriatric Depression Scale-short form scores appeared to be lower in the combination treatment versus monotherapy. The adverse events of combined treatment were self-limiting and included occasional excitability, gastric intolerance, and headache. Conclusion Limited evidence from pooled data of two observational studies suggests that CC used in adjunct with AChEIs in the treatment of AD was well-tolerated and showed improvement in cognition, mood, and behavioral symptoms compared to treating with AChEIs alone.

Purpose Parkinson disease (PD) medications are not readily available in all countries. Citicoline increases dopamine synthesis and inhibits dopamine uptake. This systematic review aims to synthesize current existing evidence on the efficacy of citicoline adjunctive therapy in improving PD symptoms. Methods An extensive literature search of Scopus, Embase, PubMed, Cochrane Library, and Google Scholar was conducted for articles published on or before December 31, 2019. The studies were screened and selected by 2 independent reviewers. We included all studies that explored the efficacy of citicoline as an adjunct therapy in PD. Findings A total of 7 studies (2 crossover, 3 randomized controlled, and 2 open prospective studies) were included. Despite the varied outcome tools, this review found that patients with PD who were taking citicoline had significant improvement in rigidity, akinesia, tremor, handwriting, and speech. Citicoline allowed effective reduction of levodopa by up to 50%. Significant improvement in cognitive status evaluation was also noted with citicoline adjunctive therapy. Implications Citicoline adjuvant therapy has beneficial effects as an adjuvant therapy in patients with PD. However, due to the heterogeneity of the studies, there is a need for more high-quality studies.

Background: Citicoline represents a dietary source of choline, an essential nutrient, and precursor of cell membrane components, highly required during development and post-injury recovery. Objectives: We previously showed that perinatal asphyxia (PA) induces hippocampal neuroinflammation and injury that are subject to epigenetic change by maternal diet. The present study investigates maternal citicoline-supplemented diet (CSD) impact on offspring hippocampal response to PA. Methods: Six-day-old Wistar rats from mothers with standard-diet or CSD were exposed to PA. The hippocampal inflammation and injury were assessed by interleukin-1 beta (IL-1b), tumor necrosis factor-alpha (TNFα), and S-100B protein (S-100B), 24–48 h post-asphyxia. The microRNAs species miR124, miR132, miR134, miR146, and miR15a were measured from the hippocampus 24 h post-asphyxia, to investigate its epigenetic response to PA and maternal diet. At maturity, the offspring’s behavior was analyzed using open field (OFT), T-maze (TMT), and forced swimming (FST) tests. Results: Our data show that the maternal CSD decreased IL-1b (p = 0.02), TNFα (p = 0.007), and S100B (p = 0.01) at 24 h postexposure, upregulated miR124 (p = 0.03), downregulated miR132 (p = 0.002) and miR134 (p = 0.001), shortened the immobility period in FST (p = 0.01), and increased the percentage of passed trials in TMT (p = 0.01) compared to standard-diet. Conclusions: Maternal CSD reduces hippocampal inflammation and S100B level, triggers epigenetic changes related to homeostatic synaptic plasticity, memory formation, and neuronal tolerance to asphyxia, decreases the depressive-like behavior, and improves the lucrative memory in offspring subjected to PA. Thus, citicoline could be valuable as a maternal dietary strategy in improving the brain response to PA.

A simple, sensitive, and precise spectrofluorimetric method has been developed and validated for quantitation of citicoline in its pharmaceutical formulations. The proposed method based on quantitative quenching effect of citicoline on the native fluorescence of Eosin Y via developing of a binary complex reaction between the cited drug and Eosin Y in acidic medium using acetate buffer pH = 3.6. The quenching of the fluorescence of eosin was measured at 540 nm after excitation at 518 nm. Calibration graph was achieved in the range of 300–3000 ng/mL with 0.9996 as correlation coefficient and 291.0 and 93.86 ng/mL as quantitation and detection limits, respectively. The developed method considered as the first developed spectrofluorimetric one for quantitation of citicoline with high sensitivity and validated according to ICH guidelines. The selectivity of the proposed method was investigated by studying the interference of piracetam as co-formulated drug with CIT in pharmaceutical formulation, therefore the developed method could be used for routine quality control of citicoline in its pharmaceutical formulations either alone or in combination with piracetam.

BACKGROUND Lipid metabolism in pregnancy delivers PUFAs from maternal liver to the developing fetus. The transition at birth to diets less enriched in PUFA is especially challenging for immature, extremely preterm infants who are typically supported by total parenteral nutrition. OBJECTIVE The aim was to characterize phosphatidylcholine (PC) and choline metabolism in preterm infants and demonstrate the molecular specificity of PC synthesis by the immature preterm liver in vivo. METHODS This MS-based lipidomic study quantified the postnatal adaptations to plasma PC molecular composition in 31 preterm infants

To assess the formation of positive personality phenomena in patients with mild cognitive impairment and asthenic syndrome during the treatment with recognan (citicoline).Thirty-eight patients (17 men and 21 women), aged 18 to 45 years (mean age 27.8±12.1 years), with asthenic syndrome with mild cognitive impairment (ICD-10 F06.7) were examined. Patients were divided into two groups: 20 people in the main group and 18 people in the comparison group. The main group received recognan (orally, in solution, 100 mg in 1 ml) for 30 days, the daily dosage of the drug was 0.5 g (5 ml solution). The comparison group did not receive any medications. Adapted methods of positive personality psychology were used: the Fordyce Emotions Questionnaire, the Subjective Happiness Scale (SHS), the Adult Hope Scale (AHS), the Satisfaction with Life Scale (SWLS), M. Atkinson's Scale of Emotional Maturity, the projective technique 'Map of experiences'. The follow-up period was 30 days. All subjects were examined three times (at baseline, 15 and 30 days after treatment).After a month of treatment with recognan, there was an improvement of positive personality traits and a significant decrease in negative experiences, indicating the positive impact of the drug on the formation of positive personality manifestations and compensation for emotional disorders in patients with mild cognitive impairment and asthenic syndrome.Цель исследования. Оценка особенностей формирования позитивных личностных феноменов у пациентов с легкими когнитивными нарушениями и астеническим синдромом, а также их динамики в процессе использования препарата Рекогнан (цитиколин). Материал и методы. Обследовали 38 пациентов,17 мужчин и 21 женщину, в возрасте от 18 до 45 лет (средний возраст 27,8±12,1 года), у которых диагностирован астенический синдром с легкими когнитивными расстройствами (рубрика F06.7 по МКБ-10). Больные были разделены на две группы: 20 человек в основной группе и 18 человек в группе сравнения. Основная группа получала лечение препаратом Рекогнан (перорально, в растворе, 100 мг в 1 мл) в течение 30 дней, суточная дозировка препарата составляла 0,5 г (5 мл раствора). В группе сравнения лекарственную терапию не проводили. Для оценки состояния больных и личностных изменений применяли следующие психологические тесты и шкалы: 'Эмоциональный тест Фордайса', 'Шкала субъективного счастья', 'Шкала надежды', 'Шкала эмоциональной зрелости М. Аткинсона', 'Шкала удовлетворенности жизнью', проективная методика 'Карта переживаний'. Период наблюдения составил 30 дней. Все испытуемые были обследованы 3 раза (до начала исследования, на 15-й и 30-й дни). Результаты и заключение. После месячного курса лечения Рекогнаном отмечено улучшение показателей по шкалам, направленным на оценку позитивных изменений личности, а также достоверное уменьшение негативных переживаний, что свидетельствовало о положительном влиянии препарата на формирование у больных с легкими когнитивными нарушениями при астеническом синдроме позитивных личностных проявлений и компенсацию эмоциональных нарушений.

Citicoline or CDP-choline is a drug, made up by a cytidine 5′-diphosphate moiety and choline, which upon adsorption is rapidly hydrolyzed into cytidine 5′-diphosphate and choline, easily bypassing the blood–brain barrier. Once in the brain, these metabolites are used to re-synthesize citicoline in neurons and in the other cell histo-types which uptake them. Citicoline administration finds broad therapeutic application in the treatment of glaucoma as well as other retinal disorders by virtue of its safety profile and neuro-protective and neuroenhancer activity, which significantly improves the visual function. Further, though supported by limited clinical studies, this molecule finds therapeutic application in neurodegenerative disease, delaying the cognitive decline in Alzheimer's Disease (AD) and Parkinson's Disease (PD) subjects. In this work we show that citicoline greatly affects the proteolytic activity of the 20S proteasome on synthetic and natural substrates, functioning as a bimodal allosteric modulator, likely binding at multiple sites. In silico binding simulations identify several potential binding sites for citicoline on 20S proteasome, and their topology envisages the possibility that, by occupying some of these pockets, citicoline may induce a conformational shift of the 20S proteasome, allowing to sketch a working hypothesis for the structural basis of its function as allosteric modulator. In addition, we show that over the same concentration range citicoline affects the distribution of assembled proteasome populations and turn-over of ubiquitinated proteins in SH-SY5Y and SK-N-BE human neuroblastoma cells, suggesting its potential role as a regulator of proteostasis in nervous cells.

PubMed: 32388671 BACKGROUND AND OBJECTIVE: To use optical coherence tomography (OCTA) examination of the retinal microvascular structures to evaluate the effect of neuroprotective eye drops (citicoline, OMK1®) administered for laser in situ keratomileusis (LASIK) surgery. PATIENTS AND METHODS: This prospective study included 45 patients treated with citicoline after LASIK and 48 patients not treated with citicoline after LASIK as a control group. In both groups, the foveal avascular zone (FAZ), retinal superficial vascular density (SVD), and deep vascular density (DVD) in the foveal and parafoveal areas were measured preoperatively and at 1 and 3 months postoperatively using OCTA. RESULTS: No significant difference was detected between the groups in terms of preoperative SVD or DVD in the foveal and parafoveal zones and all quadrants (superior, inferior, temporal, and nasal) (P?>?0.05). Similarly, no significant difference was detected between the citicoline group and control group in terms of SVD or DVD in the foveal and parafoveal zones at 1 and 3 months after LASIK (P?>?0.05). CONCLUSIONS: Despite their neuroprotective effect, topical citicoline drops had no significant effect on the superficial and deep microvascular structures of the retina or choriocapillaris.

Glaucoma, a leading cause of irreversible blindness worldwide, is an optic neuropathy characterized by the progressive death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is recognized as the main risk factor. Despite effective IOP-lowering therapies, the disease progresses in a significant number of patients. Therefore, alternative IOP-independent strategies aiming at halting or delaying RGC degeneration is the current therapeutic challenge for glaucoma management. Here, we review the literature on the neuroprotective activities, and the underlying mechanisms, of natural compounds and dietary supplements in experimental and clinical glaucoma.

Glaucoma, a heterogeneous set of progressively degenerative optic neuropathies characterized by a loss of retinal ganglion cells (RGCs) and typical visual field deficits that can progress to blindness, is a neurodegenerative disease involving both ocular and visual brain structures. Although elevated intraocular pressure (IOP) remains the most important modifiable risk factor of primary open-angle glaucoma (POAG) and is the main therapeutic target in treating glaucoma, other factors that influence the disease course are involved and reaching the optimal IOP target does not stop the progression of glaucoma, as the visual field continues to narrow. In addition to a managed IOP, neuroprotection may be beneficial by slowing the progression of glaucoma and improving the visual defects. Citicoline (cytidine 5′-diphosphocholine) is a naturally occurring endogenous compound that has been investigated as a novel therapeutic agent for the management of glaucoma. Citicoline has demonstrated activity in a range of central neurodegenerative diseases, and experimental evidence suggests a it performs a neuromodulator and neuroprotective role on neuronal cells, including RGCs, associated with improvement in visual function, extension of the visual field and central benefits for the patient. This review aims to critically summarize the current evidence for the neuroprotective properties of citicoline in glaucoma.

Purpose Glycogen synthase kinase 3 (GSK3) is a key controlling element of many cellular processes including cell-cycle progression and recent studies suggest that GSK3 is a potential anticancer target. Changes in glucose metabolism associated with GSK3 inhibition may impact on lipid synthesis, whilst lipid metabolites can act as molecular response markers. Methods Here, SKBr3 breast and HCT8 colorectal cancer cells were treated with the GSK3 inhibitor SB216763, and [14C (U)] glucose and [3H] choline incorporation into lipids was determined. Cell extracts from treated cells were subject to 31P NMR spectroscopy. Results SB216763 treatment decreased choline incorporation into lipids and caused an accumulation of CDP-choline which was accompanied by decreased conversion of glucose into lipid components. Conclusion SB216763 profoundly inhibits phospholipid synthesis in cancer cells which demonstrate accumulation of CDP-choline detectable by 31P NMR spectroscopy. Metabolic changes in lipid metabolism present potential response markers to drugs targeting GSK3.

Zwitterion-modification, as a bioinspired strategy, provides greatly promising platforms for biological detection and sensor applications. A green, low-cost and straight-forward method for synthesis of highly fluorescent biomimetic carbon quantum dots (BCQDs) has been developed via pyrolysis of cytidine diphosphate choline (CDPC) and ethylenediamine. The BCQDs with a strong emission at wavelength of 450 nm shows ultrasensitive sensing capability for vitamin B12 with high selectivity. Using the fluorometric assay, the detection limit (DL) for vitamin B12 was found to be as low as 81 nM. Meanwhile, the results of 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), hemolysis measuring and morphological characterization of Red blood cells (RBCs) confirms the excellent biocompatibility of BCQDs. The imaging experiments of human cervical cancer cells (HeLa) certify that BCQDs could be served as an effective fluorescent sensing probe for label-free sensitive and selective detection of vitamin B12 in biological samples on account of their low toxicity and good biocompatibility. The BCQDs, further, were successfully applied to probe vitamin B12 in living cells, which broaden its potential application in vivo system.

Cytidine-5'-diphosphocholine (CDP-choline) participates as an intermediary in the synthesis of phosphatidylcholine, an essential component of cellular membranes. Citicoline treatment has shown beneficial effects in cerebral ischemia, but its potential to diminish reperfusion damage in liver has not been explored. In this work, we evaluated the hepatoprotective effect of citicoline and its possible association with inflammatory/oxidative stress and mitochondrial function because they are the main cellular features of reperfusion damage. Ischemia/reperfusion (I/R) in rat livers was performed with the Pringle's maneuver, clamping the 3 elements of the pedicle (hepatic artery, portal vein, and biliary tract) for 30 minutes and then removing the clamp to allow hepatic reperfusion for 60 minutes. The I/R + citicoline group received the compound before I/R. Liver injury was evaluated by measuring aspartate aminotransferase and alanine aminotransferase as well as lactic acid levels in serum; proinflammatory cytokines, proresolving lipid mediators, and nuclear factor kappa B content were determined as indicators of the inflammatory response. Antioxidant effects were evaluated by measuring markers of oxidative stress and antioxidant molecules. Oxygen consumption and the activities of the respiratory chain were used to monitor mitochondrial function. CDP-choline reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as lactic acid levels in blood samples from reperfused rats. Diminution in tumor necrosis factor alpha (TNF-α) and increase in the proresolving lipid mediator resolvin D1 were also observed in the I/R+citicoline group, in comparison with the I/R group. Oxidative/nitroxidative stress in hepatic mitochondria concurred with deregulation of oxidative phosphorylation, which was associated with the loss of complex III and complex IV activities. In conclusion, CDP-choline attenuates liver damage caused by ischemia and reperfusion by reducing oxidative stress and maintaining mitochondrial function. Liver Transplantation XX XX-XX 2018 AASLD.

Imipramine is a tricyclic antidepressant (TCA) drug that is sometimes used to treat neuropathic pain. Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders. Probable interaction between imipramine and citicoline on pain and depression behaviors was examined in mice using a tail-flick test, open field test (OFT), forced swimming test (FST), and tail suspension test (TST). The results indicated that the intraperitoneal (i.p.) administration of citicoline (50 mg/kg) induced analgesic and antidepressant-like behaviors in mice. Similarly, i.p. injection of imipramine (5 mg/kg) induced dose-dependent anti-nociceptive and anti-depressive effects. Co-administration of different doses of imipramine (1.25, 2.5, and 5 mg/kg) along with an ineffective dose of citicoline (6.25 mg/kg) increased tail-flick latency and decreased immobility time in the FST, suggesting an analgesic and antidepressant-like behaviors. Interestingly, there is a synergistic effect between imipramine and citicoline upon the induction of analgesic and antidepressant effects. All doses of the drugs had no significant effect on the locomotor activity. Based on these results, it can be concluded that the administration of citicoline (as an adjuvant drug) in combination with imipramine increased the efficacy of TCA drugs for modulation of pain and depression behaviors.

Background: Spinal cord injury results in disruption of brain-spinal cord fibre connectivity, leading to progressive tissue damage at the site of injury and resultant paralysis of varying degrees. The current study investigated the role of autologous bone marrow modulated with neurotransmitters and neurotransmitter stimulating agent, Citicholine, in spinal cord of spinal cord injured rats. Methods: Radioreceptor assay using [3H] ligand was carried out to quantify muscarinic receptor. Gene expression studies were done using Real Time PCR analysis. Results: Scatchard analysis of muscarinic M1 receptor showed significantly decreased Bmax (p

Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid β peptide (Aβ42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and Aβ42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP (p

Objectives. Neuroprotective treatment, including citicoline, is a new perspective in glaucoma management, having the role of progression delay. The purpose of the present study was to observe the evolution of the different parameters in patients with glaucoma treated with citicoline. Methods. 22 patients with GPUD were enrolled in the study, and they received oral citicoline in addition to the ocular hypotensive therapy. Investigations were performed at the beginning of the current study, then at 3 months and 6 months, and included, besides full ophthalmologic checkup and IOP determination, optic nerve and RGCs OCT, and visual evoked potentials, pattern and flash. The data we obtained were statistically analyzed with the SPSS (Microsoft) program. Results. The outcomes of the study following VEP wave analysis indicated variations in P100 wave amplitude, but after 6 months period, an increase was found. Also, the P2 wave amplitude recorded statistically insignificant variations. The increase in P2 latency at 6 months was noted as statistically significant. Negative correlations were also met between the thickness of the RGC layer and the P100 latency, but also between the amplitude and the latency of this wave. At 6 months, a positive correlation between the RGC layer and the P100 amplitude was observed. The RNFL thickness at the optical disc had higher values at the 6 months visit, it was statistically significant, and a slight increase in the thickness of the RGC layer between successive visits was noted. These might be an examination artifact because clinically they are not possible. The RNFL thickness showed a positive correlation with the amplitude of P100 and P2 waves. Conclusions. The study of the parameters and their correlations demonstrated that citicoline had positive effects in glaucoma on certain aspects, data confirmed by literature.

In the present study, the effects of intraperitoneal (i.p.) injections of citalopram and citicoline on morphine-induced anxiolytic effects were investigated in non-sensitized and morphine-sensitized mice using elevated plus-maze (EPM). Subcutaneous (s.c.) administration morphine (5 mg/kg) increased the percentage of open arm time (%OAT, in morphine-sensitized mice), and open arm entries (%OAE, in non-sensitized mice), but not a locomotor activity, indicating an anxiolytic response to morphine. On the other hand, i.p. administration of naloxone decreased %OAT (morphine-sensitized mice), and %OAE (non-sensitized and morphine-sensitized mice), but not a locomotor activity, showing an anxiogenic effect to naloxone. Moreover, i.p.co-administration of citalopram (5 and 10 mg/kg) and citicoline (75 mg/kg) induced the anxiolytic effect. Interestingly, i.p. co-administration of low doses of citalopram (0.5, 1 and 2.5 mg/kg) and citicoline (25 mg/kg) significantly increased %OAT and %OAE in non-sensitized as well as %OAT in morphine-sensitized mice, indicating an anxiolytic effect. An isobolographic analysis of data was performed, presenting a synergistic interaction between citalopram and citicoline upon the production of anxiolytic effect in non-sensitized and morphine-sensitized mice. In conclusion, it seems that (1) morphine sensitization affects the anxiety behavior in the EPM, (2) μ-opioid receptors play an important role in morphine anxiolytic effect, (3) citalopram and citicoline induced anti-anxiety effect, (4) a synergistic effect of citalopram and citicoline upon induction of anti-anxiety behavior in non-sensitized and morphine-sensitized mice.

Cytidine 5-diphosphocholine (CDP-choline) administration has been shown to improve learning and memory deficits in different models of brain disorders. In this study, effects of CDP-choline on the well known negative effects of Rapid Eye Movements (REM) sleep deprivation on learning and memory were investigated. Sleep deprivation was induced by placing adult male Wistar albino rats on 6.5 cm diameter platforms individually for 96 h according to flower pot method. Learning and memory performances were evaluated using Morris Water Maze (MWM) test during the same period of time. Saline or CDP-choline (100 µmol/kg, 300 µmol/kg or 600 µmol/kg) was administered intraperitoneally 30 min prior to the onset of MWM experiments. On completion of behavioral tests, rats were decapitated and hippocampi were assayed for total and phosphorylated Ca2+/calmodulin-dependent protein kinase II (tCaMKII and pCaMKII, respectively) and total antioxidant capacity. We observed that while REM sleep deprivation had no effect on learning, it diminished the memory function, which was associated with decreased levels of pCaMKII and total antioxidant capacity in the hippocampus. CDP-choline treatment blocked the impairment in memory function of sleep-deprived rats and, increased pCaMKII levels and total antioxidant capacity. These data suggest that CDP-choline reduces REM sleep deprivation-induced impairment in memory, at least in part, by counteracting the disturbances in biochemical and molecular biological parameters.