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Objective: This network meta-analysis aims to explore the efficacy and safety of neuroprotective agents in patients with ischemic stroke and attempts to identify which drug is the most effective in improving outcomes for patients with acute ischemic stroke (AIS) through a ranking method. Methods: We comprehensively searched the PubMed, Medline, Embase, Web of Science, and Cochrane library databases from their establishment to 30 June 2024. Data were extracted from the studies identified, and their quality was assessed using the Cochrane risk-of-bias tool or the Newcastle–Ottawa Scale (NOS). The outcome measures were for a favorable prognosis, based on the modified Rankin Scale score (mRS) or National Institutes of Health Stroker Scale (NIHSS) score, mortality, and adverse effect with different drug regimens. We utilized Stata version 16.0 and Review Manager (RevMan) version 5.3.0 for statistical analysis. Results: A total of 35 studies were included: 25 randomized control trials, eight retrospective studies, and two prospective studies. The total sample size was 18,423 cases and included nine interventions: citicoline, edaravone (EDV), edaravone dexborneol, cinepazide maleate, cerebrolysin, minocycline, ginkgolide, ginkgo diterpene lactone meglumine (GDLM), and conventional (CON) treatment. Our analysis revealed that, except for edaravone dexborneol, the ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM treatment schemes reduced the mortality of patients with AIS compared with CON. Each drug regimen significantly improved the neural function of these patients compared with CON, which from highest to lowest was citicoline + vinpocetine, GDLM, citicoline, edaravone dexborneol, cinepazide maleate, ginkgolide, EDV, and CON. Moreover, we also found that, except for citicoline, the ginkgolide, EDV, edaravone dexborneol, GDLM, and cinepazide maleate treatment schemes had a high total treatment effective rate in these patients, the order from highest to lowest being ginkgolide, EDV, edaravone dexborneol, GDLM, cinepazide maleate, CON, and citicoline. In terms of the ineffective rate, we found that, compared with CON, the edaravone dexborneol, EDV, citicoline, GDLM, ginkgolide, and cinepazide maleate treatment schemes all had a lower ineffective rate. Finally, our analysis revealed that, except for cinepazide maleate and ginkgolide, the EDV, minocycline, edaravone dexborneol, GDLM, citicoline, and cerebrolysin schemes all had a higher rate of adverse effect on patients compared to CON. Based on the impact of the adverse effect with different surgical interventions, we further analyzed the effect of these drug treatments by the total treatment effective rate combined with adverse effect, revealing that EDV, ginkgolide, and edaravone dexborneol were the safest and most effective treatments. Conclusion: In patients with AIS, ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM were associated with a reduction in mortality rate. Moreover, ginkgolide, EDV, edaravone dexborneol, and GDLM treatment schemes revealed not only a high total treatment effective rate but also a low rate of treatment inefficacy. When considering the combination of the total treatment effective rate with adverse effect, EDV, ginkgolide, and edaravone dexborneol were revealed as the safest and most effective. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti‐apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies. [ABSTRACT FROM AUTHOR]

Stroke is a sudden cerebral root neurologic collapse, a major cause for global morbidity and death, necessitates the use of neuroprotectants to prevent further damage to ischemic decline. Citicoline and piracetam are widely used as neuro-protectives, however their benefits in Acute Ischemic Stroke have not yet been established. This prospective, quasi-experimental study compared the effectiveness of citicoline (Group A) and citicoline with piracetam combination (Group B) in moderate-to-severe patients. 75 patients were divided into two groups (25 in Group A and 50 in Group B) and followed for a period of 90 days. Their cognitive and functioning events were examined using National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI). There is no discernible difference (p > 0.05) amongst the two groups by NIHSS whereas, there was a significant difference (p<0.05) in mRS and BI. After 90 days, Group A patients significantly progressed in terms of overall functional and cognitive improvement. The administration of citicoline within the first 24 hours of a stroke helps to prevent further sequelae and minimizes the severity of AIS. This study concludes that citicoline alone responds better than piracetam combination, but its neuroprotective properties have not been proven. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD), affecting over 55 million people globally, poses a substantial public health challenge. Early diagnosis and appropriate treatment are vital to slowing its progression and enhancing patient quality of life. The fixed-dose combination of citicoline with rivastigmine emerges as a promising strategy AD treatment. Methods: A real-time Delphi consensus was reached with the participation of 11 Mexican experts. Results: The combination offers neuroprotective benefits, enhancing neuronal regeneration and reducing glutamate levels linked to neuronal damage in AD. These effects translate into improved cognitive function and delayed cognitive decline in AD. Conclusions: The Mexican Consensus for the Combined Management of AD endorses this fixed-dose combination of rivastigmine with citicoline as a new therapeutic perspective. Its efficacy and safety make it a valuable option for the treatment of this neurodegenerative disease. [ABSTRACT FROM AUTHOR]

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathic pain is a result of damage/illness of the peripheral nerves. The mechanisms caused by its pathophysiology are not completely understood. Methods: Imipramine is a tricyclic antidepressant that is sometimes used to treat neuropathic pain. Moreover, citicoline is considered a novel adjuvant for painful disorders such as neuropathic pain. So, a possible interaction between imipramine and citicoline on pain behavior was examined in nerve-ligated mice using tail-flick and hot plate tests. Results: The results indicated that induction of neuropathic pain by sciatic nerve ligation caused hyperalgesia in nerve-ligated mice. On the other hand, intraperitoneal (i.p.) administration of citicoline (50, 75, and 100 mg/kg), and imipramine (2.5 and 5 mg/kg) induced anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. Furthermore, citicoline potentiated the anti-hyperalgesic and anti-nociceptive effects of imipramine when they were co-administrated in nerve-ligated mice. Interestingly, there was an additive effect between imipramine and citicoline upon induction of anti-hyperalgesic and anti-nociceptive effects in nerve-ligated mice. Conclusion: Therefore, it can be concluded that citicoline (as an adjuvant substance) enhanced the efficacy of imipramine for the modulation of pain behavior in nerve-ligated mice [ABSTRACT FROM AUTHOR]

Following an application from Egde Pharma Sp. z o.o, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Poland, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to citicoline and memory. The Panel considers that the food, citicoline (cytidine 5‐diphosphocholine, CDP‐Choline) inner salt, is sufficiently characterised. Improvement, maintenance or reduced loss of memory is a beneficial physiological effect for middle‐aged or elderly adults encountering age‐associated subjective memory impairment. The applicant identified three pertinent human intervention studies in healthy individuals that investigated the effect of citicoline on memory. In weighing the evidence, the Panel took into account that only one randomised controlled trial in healthy participants showed a beneficial effect of citicoline on episodic memory when consumed at doses of 500 mg/day for 12 weeks, whereas this effect has not been observed in another study using citicoline at doses of 1 g/day for 3 months or supported by data obtained in patients with dementia using doses of 1 g/day for 12 weeks and 12 months. No convincing evidence of a plausible mechanism by which citicoline or any of its components (in addition to their endogenous synthesis) could exert an effect on memory in humans has been provided. The Panel concludes that a cause‐and‐effect relationship has not been established between the consumption of citicoline (CDP‐Choline) inner salt and improvement, maintenance or reduced loss of memory in middle‐aged or elderly adults encountering age‐associated subjective memory impairment. [ABSTRACT FROM AUTHOR]

ObjectiveThis network meta-analysis aims to explore the efficacy and safety of neuroprotective agents in patients with ischemic stroke and attempts to identify which drug is the most effective in improving outcomes for patients with acute ischemic stroke (AIS) through a ranking method.MethodsWe comprehensively searched the PubMed, Medline, Embase, Web of Science, and Cochrane library databases from their establishment to 30 June 2024. Data were extracted from the studies identified, and their quality was assessed using the Cochrane risk-of-bias tool or the Newcastle–Ottawa Scale (NOS). The outcome measures were for a favorable prognosis, based on the modified Rankin Scale score (mRS) or National Institutes of Health Stroker Scale (NIHSS) score, mortality, and adverse effect with different drug regimens. We utilized Stata version 16.0 and Review Manager (RevMan) version 5.3.0 for statistical analysis.ResultsA total of 35 studies were included: 25 randomized control trials, eight retrospective studies, and two prospective studies. The total sample size was 18,423 cases and included nine interventions: citicoline, edaravone (EDV), edaravone dexborneol, cinepazide maleate, cerebrolysin, minocycline, ginkgolide, ginkgo diterpene lactone meglumine (GDLM), and conventional (CON) treatment. Our analysis revealed that, except for edaravone dexborneol, the ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM treatment schemes reduced the mortality of patients with AIS compared with CON. Each drug regimen significantly improved the neural function of these patients compared with CON, which from highest to lowest was citicoline + vinpocetine, GDLM, citicoline, edaravone dexborneol, cinepazide maleate, ginkgolide, EDV, and CON. Moreover, we also found that, except for citicoline, the ginkgolide, EDV, edaravone dexborneol, GDLM, and cinepazide maleate treatment schemes had a high total treatment effective rate in these patients, the order from highest to lowest being ginkgolide, EDV, edaravone dexborneol, GDLM, cinepazide maleate, CON, and citicoline. In terms of the ineffective rate, we found that, compared with CON, the edaravone dexborneol, EDV, citicoline, GDLM, ginkgolide, and cinepazide maleate treatment schemes all had a lower ineffective rate. Finally, our analysis revealed that, except for cinepazide maleate and ginkgolide, the EDV, minocycline, edaravone dexborneol, GDLM, citicoline, and cerebrolysin schemes all had a higher rate of adverse effect on patients compared to CON. Based on the impact of the adverse effect with different surgical interventions, we further analyzed the effect of these drug treatments by the total treatment effective rate combined with adverse effect, revealing that EDV, ginkgolide, and edaravone dexborneol were the safest and most effective treatments.ConclusionIn patients with AIS, ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM were associated with a reduction in mortality rate. Moreover, ginkgolide, EDV, edaravone dexborneol, and GDLM treatment schemes revealed not only a high total treatment effective rate but also a low rate of treatment inefficacy. When considering the combination of the total treatment effective rate with adverse effect, EDV, ginkgolide, and edaravone dexborneol were revealed as the safest and most effective.

Cytidine-5’-diphosphocholine (CDP-choline) is a key precursor for the intracellular synthesis of phosphatidylcholine and other phospholipids. Following either intravenous or oral application citicoline (CDP-choline of exogenous origin) undergoes quick decomposition to cytidine and choline, and for this reason it is frequently considered a prodrug. However, upon acute intravenous application in mice citicoline is, on a molar basis, 20 times less toxic than choline. To find out whether cytidine may attenuate toxicity of choline, in the present experiments we compared maximum tolerated doses of single intravenous injections of choline and equimolar mixture of choline and cytidine. We assumed that, if after oral intake a substantial part of citicoline is catabolised already in the intestine and its catabolites enter blood separately, intravenously applied equimolar mixture of cytidine and choline will be markedly less toxic than an equivalent molar dose of choline. However, the maximum tolerated single doses determined in our experiment for choline and equimolar mixture of choline and cytidine were similar. These data suggest that citicoline taken orally is not significantly decomposed in the intestinal lumen, but absorbed to blood as the intact molecule.

OBJECTIVE. To evaluate the effect of citicoline on cerebral blood flow and microembolic signals (MES) after 6 months of treatment in patients with coronary artery disease combined with coronavirus disease (COVID-19). MATERIALS AND METHODS. A prospective study of 68 patients with coronary artery disease with confirmed COVID-19 by PCR was conducted. Group I (n=35) included patients with coronary artery disease in combination with COVID-19, who, in addition to standard therapy of cerebrovascular disease, received citicoline (500 mg twice daily) for 6 months after discharge from the hospital. The comparison group (group II; n=33) consisted of patients who did not receive citicoline. Cerebral blood flow, peak systolic velocity in extracranial and intracranial vessels were determined, and 1-hour transcranial monitoring to detect MES were performed. Patients were re-examined in 6 months. RESULTS. At the initial examination of patients, cerebral blood flow and the number of MES did not differ significantly. After 6 months, there was an increase in cerebral blood flow in the cerebral arteries, as well as a decrease in MES in patients taking citicoline, whereas in group II there was no positive dynamics of this ratio. A direct correlation between plasma C-reactive protein, D-dimer and MES was found in patients of both groups. After 6 months of treatment, C-reactive protein and D-dimer decreased in both groups equally. CONCLUSIONS. The obtained results of improvement of cerebral perfusion, blood rheology, due to the anti-inflammatory effect, stabilising function of citicoline on phospholipid membranes of cerebral vascular endothelium, neurons and glial elements allow the use of citicoline in patients with coronary artery disease in combination with COVID-19 to reduce the negative impact of COVID-19 on the central nervous system.

The management of patients with cognitive impairment (CI) is one of the urgent problems of modern medicine. Vascular CI (VCI) is the second most common cause of dementia after Alzheimer's disease. The diagnosis of VCI is based on the results of a neuropsychological examination, the presence of clinical and neuroimaging signs of cerebrovascular disease, and the absence of data for other causes of CI. Socio-psychological methods, stroke prevention, correction of vascular risk factors, and stimulation of patients to regular physical and mental activity are of leading importance in the management of patients with VCI. The effectiveness and safety of citicoline in VCI are discussed.

What is expected from neuroprotection is to inhibit neuronal death and halt or decelerate the neuronal loss to lower the mortality rates, decrease disability, and improve the quality of life following an acute ischemic stroke. Several agents were described as neuroprotective up to date; however, there is still debate which to use in the neurorehabilitation of stroke patients, in terms of both efficacy and also safety. In this review, we discuss the agents, citicoline, cerebrolysin and MLC901 (NeuroAiD II), the three agents which have started to be used frequently in neurorehabilitation clinics recently in the light of the current literature. [ABSTRACT FROM AUTHOR]

Cytidine-5’-diphosphocholine (CDP-choline) is a key precursor for the intracellular synthesis of phosphatidylcholine and other phospholipids. Following either intravenous or oral application citicoline (CDP-choline of exogenous origin) undergoes quick decomposition to cytidine and choline, and for this reason it is frequently considered a prodrug. However, upon acute intravenous application in mice citicoline is, on a molar basis, 20 times less toxic than choline. To find out whether cytidine may attenuate toxicity of choline, in the present experiments we compared maximum tolerated doses of single intravenous injections of choline and equimolar mixture of choline and cytidine. We assumed that, if after oral intake a substantial part of citicoline is catabolised already in the intestine and its catabolites enter blood separately, intravenously applied equimolar mixture of cytidine and choline will be markedly less toxic than an equivalent molar dose of choline. However, the maximum tolerated single doses determined in our experiment for choline and equimolar mixture of choline and cytidine were similar. These data suggest that citicoline taken orally is not significantly decomposed in the intestinal lumen, but absorbed to blood as the intact molecule. [ABSTRACT FROM AUTHOR]

Abstract Following an application from Egde Pharma Sp. z o.o, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Poland, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to citicoline and memory. The Panel considers that the food, citicoline (cytidine 5‐diphosphocholine, CDP‐Choline) inner salt, is sufficiently characterised. Improvement, maintenance or reduced loss of memory is a beneficial physiological effect for middle‐aged or elderly adults encountering age‐associated subjective memory impairment. The applicant identified three pertinent human intervention studies in healthy individuals that investigated the effect of citicoline on memory. In weighing the evidence, the Panel took into account that only one randomised controlled trial in healthy participants showed a beneficial effect of citicoline on episodic memory when consumed at doses of 500 mg/day for 12 weeks, whereas this effect has not been observed in another study using citicoline at doses of 1 g/day for 3 months or supported by data obtained in patients with dementia using doses of 1 g/day for 12 weeks and 12 months. No convincing evidence of a plausible mechanism by which citicoline or any of its components (in addition to their endogenous synthesis) could exert an effect on memory in humans has been provided. The Panel concludes that a cause‐and‐effect relationship has not been established between the consumption of citicoline (CDP‐Choline) inner salt and improvement, maintenance or reduced loss of memory in middle‐aged or elderly adults encountering age‐associated subjective memory impairment.

ABSTRACT. The review describes some pathogenetic mechanisms of central nervous system lesions in patients with coronary artery disease in combination with coronavirus disease (COVID-19) and presents the current possibilities of their pharmacotherapy. The analysis of experimental and clinical trials has shown that the multifactorial effect of citicoline on the main pathogenic links of brain damage in COVID-19 and numerous positive clinical effects make it a promising drug in the treatment of patients with coronary artery disease in combination with COVID-19 and post-COVID syndrome.

Aim. To study changes in the electrical and viscoelastic parameters of erythrocytes using the method of dielectrophoresis in patients with manifestations of the metabolic syndrome who underwent COVID-19, when exposed to the drug citicoline in an in vitro experiment to reduce the severity of microcirculatory disorders. Materials and methods. 31 men were examined with manifestations of metabolic syndrome (50.6±9.9 years), COVID-19 convalescences, within 8 to 12 months after the disease, the diagnosis was confirmed by PCR, ELISA. The electrical and viscoelastic parameters of erythrocytes were studied by dielectrophoresis twice: the initial levels of indicators were determined and after 30 minutes of exposure with after 30 minutes of exposure to a solution of the drug Ronocyte (oral solution with the active substance citicoline sodium – 104.50 mg., which is equivalent to 100.00 mg citicoline at a concentration of 0.01 µl per 0.3 µl of red blood cell suspension in 0.3M sucrose solution (pH 7.36). Results. Exposure of erythrocyte suspension of patients with Ronocyte solution led to change in the levels of electrical, viscoelastic parameters: an increase in the average cell diameter (p=0.0003), the proportion of discocytes (p=0.0004), the amplitude of cell deformation at high frequencies of the electric field (p=0.000002), cell capacity (p=0.000007), the velocity of erythrocytes to the electrodes (p=0.003), dipole moment (p=0.002), polarizability at 106 and 0.5×106 Hz (p=0.000019 and p=0.0015, respectively), relative polarizability (p0.05) and, conversely, to reduce summarized rigidity (p=0.000003), viscosity (p=0.000002), electrical conductivity (p0.000001), aggregation indices (p=0.00003), destruction at frequencies of 106 Hz (p=0.003), 0.5x106 Hz (p=0.00002), 0.1×106 Hz (p0.00001), polarizability at low frequencies of the electric field (p=0.02). Under the influence of the drug, the equilibrium frequency of erythrocytes shifted to the low-frequency range compared to the initial values (p0.0000001). The revealed changes indicate an increase in the surface charge of erythrocytes, their ability to deform, and cell resistance under the action of citicoline. Conclusion. For the first time, the effect of the drug with the active substance citicoline, improving the rheological properties of erythrocytes, was discovered. Preparations with the active substance - citicoline should be considered promising for conducting a full-fledged clinical study to study the reduction of circulatory disorders at the microcirculatory level in patients with manifestations of metabolic syndrome who have undergone COVID-19 coronavirus infection.

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application.

Introduction. Citicoline is an endogenous nucleoside consisting of cytidine and choline linked by a diphosphate bridge that is involved in the synthesis of membrane phospholipids. Drugs containing citicoline have neuroprotective and neurometabolic effects and are used for the treatment of a wide range of neurological disorders. In its turn, bioequivalence study is a pathway to register a generic citicoline drug in Russian Federation.Aim. The aim of the study was to investigate the comparative pharmacokinetics (PK) and bioequivalence of two citicoline-containing drugs GP30121 and Ceraxon® in healthy male volunteers when taken on an empty stomach.Materials and methods. We evaluated the pharmacokinetics of citicoline-containing drugs corrected for endogenous analyte (uridine) level using an adaptive design. We determined uridine concentration by high-performance liquid chromatography with mass spectrometric detection. We used R Project software, version 3.6.3. for performing statistical analysis for the study.Results and discussion. GP30121 and Ceraxon® exhibited similar PK profiles. It was shown that the values of 94.12 % confidence interval (CI) at α = 0.0294 for the geometric mean ratios for the primary PK parameters of the main metabolite of the active ingredient of the investigated drugs were fully contained within the predefined equivalence limits of 80.00–125.00 %.Conclusion. The study demonstrates bioequivalence of GP30121 and Ceraxon® proving the approach with the correction for endogenous analyte could be considered in studies of other drugs.

Cardiovascular factors significantly increase the risk of vascular cognitive impairment (VCI). Currently, there are no specific treatments for VCI. A promising therapeutic strategy is the administration of citicoline, which has a neuroprotective effect.Objective: to evaluate the effect of treatment with citicoline (Noocil®) on cognitive function and quality of life (QoL)in patients with mild cognitive impairment (MCI) developed in a background of arterial hypertension and cerebral arteriosclerosis.Material and methods. An open-label prospective observational study enrolled 32 patients with neuroimaging-confirmed vascular cognitive impairment who received baseline therapy (antihypertensive, lipid-lowering, and antiplatelet therapy) and achieved target blood pressure and low-density lipoprotein cholesterol levels. All patients were assessed with a neuropsychological status assessment (MoCA-test). The efficacy of therapy was assessed by the Short Form-36 Quality of Life Questionnaire (SF-36).Results. The most common complaints of the patients were poor concentration, fatigue, forgetfulness, mood lability, sleep disturbances, more often in the form of early waking, and headaches. After 3 months of taking the drug Noocil®, all patients noted an increase in the ability to work, an improvement in concentration, memory and reproduction of the information received, both physical and mental indicators of QoL improved. The positive dynamics in terms of cognitive status (especially the functions of attention, short-term memory, several aspects of executive functions), QoL of patients, which was associated with the effect of Noocil® therapy, was accompanied by the absence of adverse events. A distinctive feature of domestic citicoline (Noocil®) is the presence of an original dosage form – a 240 ml bottle for oral administration, which improves adherence to long-term therapy.Conclusion. The efficacy, safety and good tolerability of Noocil® therapy in patients with predemental VCI was demonstrated.

Marta Almeria,1,2 Ignacio Alvarez,2 Jessica Molina-Seguin,1 Sarah Besora,1 Mariateresa Buongiorno,1,2 Silvia Romero,1 Laura Casas,1 Cristina Cano,2 Judith Castejon,2 Sonia Arribas,2 Jerzy Krupinski1,3 1Departament de Neurologia, Fundació Assistencial Hospital Universitari MútuaTerrassa, Terrassa, Barcelona, Spain; 2Fundació per a la Recerca Biomèdica i Social MútuaTerrassa, Terrassa, Barcelona, Spain; 3Healthcare Sciences, Manchester Metropolitan University, Manchester, UKCorrespondence: Marta Almeria, Fundació Assistencial Hospital Universitari MútuaTerrassa, Departament de Neurologia, plaça dels drets humans n 1 (planta -3, despatx. 324), Terrassa, Barcelona, 08222, Spain, Tel +34 937365050, Email malmeria@mutuaterrassa.catIntroduction: Neuroprotective drugs such as citicoline could improve cognitive performance and quality of life. We studied the effect of citicoline treatment and its association with Vascular Risk Factors (VRF) and APOE on cognition in patients with Subjective Cognitive Complaints (SCC) and Mild Cognitive Impairment (MCI).Methods: This is an observational and prospective study with citicoline during 12 months follow-up. Eighty-one subjects who met criteria for SCC/MCI, aged 50– 75 years with VRF were included and prescribed citicoline 1g/day. Subjects with previous cognitive impairment and any other central nervous system affection were excluded. Wilcoxon Signed Ranks test and paired samples t-test were used to analyze the change in neuropsychological performance.Results: Mean age of the sample was 68.2 (SD 6.8) years and 26 (32.09%) were females. Fifteen subjects (24.6%) were APOE-&epsiv;4 carriers, fifty-six (76.7%) had hypertension, fifty-eight (79.5%) had dyslipidemia, twenty-one (28.8%) had diabetes mellitus and twenty-six (35.6%) had cardiopathy. Thirty-two (43.8%) subjects were diagnosed as SCC and forty-one (56.16%) as MCI. During the follow-up, Tweny-six patients (81.25%) in the group of SCC remained stable, six subjects (18.8%) converted to MCI. Twelve patients (29.9%) with MCI reverted to SCC and twenty-nine patients (70.7%) remained stable. At follow-up, SCC subjects had an improvement in the global language domain (p=0.03), naming (p< 0.001), attention (p=0.01) and visuospatial abilities (p< 0.01). MCI group showed an improvement in the screening test (p=0.03), delayed memory (p< 0.01), global cognition (p=0.04) and in cognitive flexibility (p=0.03). Presence of APOE-&epsiv;4 had no impact on the above findings.Discussion: SCC subjects showed an improvement in language and attention domains, while those with MCI performed better after 12 months in total scores of MoCA and RBANS domains, some converting back to SCC. This supports the idea that citicoline may prevent cognitive decline in patients with cognitive deficits.Keywords: cerebrovascular disease, cognitive decline, citicoline

Introduction: Citicoline has therapeutic and beneficial effects in a variety of neurologic disorders and neurodegenerative diseases. The aim of this study was to examine the beneficial effects of low doses of citicoline for the early period of administration in rat sciatic nerve crush injury by using electrophysiological and biochemical approaches. Methods: Thirty-two adult male Wistar rats were divided into four groups (n = 8 in each) and treated as follows: sham-operated (intact, saline), control (crushed sciatic nerve, saline), 50C (crushed sciatic nerve, 50 mg/kg citicoline), and 250C (crushed sciatic nerve, 250 mg/kg citicoline). At the end of the 7-day experimental period, motor nerve conduction velocities (MNCVs) were determined using in vivo electrodes and fresh rat blood was collected for biochemical analysis. Results: MNCVs were significantly reduced in crushed sciatic nerve of rats but significantly increased after 7 days of citicoline administration. Improved electrophysiological recovery in the citicoline groups was significant when compared to the control group. In addition, citicoline exacerbated the decrease in total glutathione level and glutathione reductase and catalase activities but decreased malondialdehyde levels compared to the control group. Conclusion: Results presented in this paper suggest that low doses of citicoline for the early period of administration have a promotional effect on improving the electrical conduction function of the sciatic nerve.

Glaucoma represents a group of neurodegenerative diseases characterized by optic nerve damage and the slowly progressive death of retinal ganglion cells. Glaucoma is considered the second leading cause of irreversible blindness worldwide. Pharmaceutical treatment of glaucoma is critical because of the properties of the ocular barrier that limit the penetration of drugs, resulting in lower systemic bioavailability. This behavior causes the need of frequent drug administration, which leads to deposition of concentrated solutions on the eye, causing toxic effects and cellular damage to the eye. To overcome these drawbacks, novel drug-delivery systems, such as liposomes, can play an important role in improving the therapeutic efficacy of antiglaucomatous drugs. In this work, liposomes were synthesized to improve various aspects, such as ocular barrier penetration, bioavailability, sustained release of the drug, targeting of the tissue, and reduction in intraocular pressure. Citicoline (CDP-choline; cytidine 5′-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids, with neuroprotective and neuroenhancement properties, and it was used in the treatment on retinal function and neural conduction in the visual pathways of glaucoma patients. In this study, citicoline was loaded into the 1,2-dioleoyl-sn-glycerol-3-phosphocholine and cholesterol liposomal carrier to enhance its therapeutic effect. The citicoline encapsulation efficiency, drug release, and size analysis of the different liposome systems were investigated using dynamic light scattering, nuclear magnetic resonance, infrared spectroscopy, and ToF-SIMS experiments. [ABSTRACT FROM AUTHOR]

Alzheimer's disease manifests as a complex pathological condition, with neuroinflammation, oxidative stress and cholinergic dysfunction being a few of the many pathological changes. Due to the complexity of the disease, current therapeutic strategies aim at a multitargeted approach, often relying on a combination of substances with versatile and complementary effects. In the present study, a unique combination of α-lipoic acid, citicoline, extracts of leaves from olive tree and green tea, vitamin D3, selenium and an immune-supporting complex was tested in scopolamine-induced dementia in rats. Using behavioral and biochemical methods, we assessed the effects of the combination on learning and memory, and elucidated the mechanisms of these effects. Our results showed that, compared to its components, the experimental combination was most efficient in improving short- and long-term memory as assessed by the step-through method as well as spatial memory as assessed by T-maze and Barnes maze underlined by decreases in AChE activity (p < 0.05) and LPO (p < 0.001), increases in SOD activity in the cortex (p < 0.05) and increases in catalase (p < 0.05) and GPx (p < 0.01) activities and BDNF (p < 0.001) and pCREB (p < 0.05) levels in the hippocampus. No significant histopathological changes or blood parameter changes were detected, making the experimental combination an effective and safe candidate in a multitargeted treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract Non-alcoholic steatohepatitis (NASH) is a more dangerous form of chronic non-alcoholic fatty liver disease (NAFLD). In the current investigation, the influence of citicoline on high-fat diet (HFD)-induced NASH was examined, both alone and in combination with Lactobacillus (probiotic). NASH was induced by feeding HFD (10% sugar, 10% lard stearin, 2% cholesterol, and 0.5% cholic acid) to rats for 13 weeks and received single i.p. injection of streptozotocin (STZ, 30 mg/kg) after 4 weeks. Citicoline was given at two dose levels (250 mg and 500 mg, i.p.) at the beginning of the sixth week, and in combination with an oral suspension of Lactobacillus every day for eight weeks until the study’s conclusion. HFD/STZ induced steatohepatitis as shown by histopathological changes, elevated serum liver enzymes, serum hyperlipidemia and hepatic fat accumulation. Moreover, HFD convinced oxidative stress by increased lipid peroxidation marker (MDA) and decreased antioxidant enzymes (GSH and TAC). Upregulation of TLR4/NF-kB and the downstream inflammatory cascade (TNF-α, and IL-6) as well as Pentaraxin, fetuin-B and apoptotic markers (caspase-3 and Bax) were observed. NASH rats also had massive increase in Bacteroides spp., Fusobacterium spp., E. coli, Clostridium spp., Providencia spp., Prevotella interrmedia, and P. gingivalis while remarkable drop in Bifidobacteria spp. and Lactobacillus spp. Co-treatment with citicoline alone and with Lactobacillus improve histopathological NASH outcomes and reversed all of these molecular pathological alterations linked to NASH via upregulating the expression of Nrf2/HO-1 and downregulating TLR4/NF-kB signaling pathways. These results suggest that citicoline and lactobacillus may represent new hepatoprotective strategies against NASH progression.

Abstract Background Hypoxic-ischemic encephalopathy (HIE) is one of the major complications that can lead to death or disability in neonates. We assessed the effect of citicoline as a neuroprotector in neonates with moderate and severe HIE. Methods This clinical trial was carried on 80 neonates with moderate to severe HIE who were not candidates for therapeutic cooling. They were subdivided randomly into two groups; citicoline treatment group which included 40 neonates who received citicoline 10 mg / kg /12 h IV for 4 weeks plus other supportive measures and the control group which included 40 neonates who were managed with placebo and the same supportive measures. All patients were evaluated for duration of mechanical ventilation (MV), need for inotropes, seizures (type, frequency, and duration), and duration of NICU. Cranial ultrasounds and brain magnetic resonance image (MRI) were performed for all included neonates after 4 weeks of treatment. Follow- ups of all neonates for the neurodevelopmental outcomes were done at 3, 6, 9, and 12 months. Results There was a significant reduction in the number of neonates having seizures after discharge in the citicoline-treated group (2 neonates) compared to the control group (11 neonates). Cranial ultrasound and MRI findings at 4 weeks were significantly better in the treatment group compared to the control group. Moreover, neurodevelopmental outcome showed significant improvement at 9 and 12 months in the citicoline treated neonates compared to the control group. There was statistically significant reduction in the duration of seizures, NICU stay, inotrope use, and MV in the treatment group compared to the control group. Citicoline was well tolerated with no remarkable side effects. Conclusion Citicoline could be a promising neuroprotector drug in neonates with HIE. Trial registration The study was registered at ClinicalTrials.gov (NCT03949049). Registered at 14 May 2019, https://clinicaltrials.gov/ct2/show/NCT03949049

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is characterized by severe flu-like symptoms, which can progress to life-threatening systemic inflammation and multiorgan dysfunction. The nervous system is involved in over one-third of patients, and the most common neurological manifestations concern the central nervous system, such as headache, fatigue, and brain fog. The activation of innate, humoral, and cellular immune responses, resulting in a cytokine storm and endothelial and mitochondrial dysfunctions, are the main pathophysiological mechanisms of SARS-CoV-2 infection. Citicoline is an exogenous source of choline and cytidine involved in intracellular phospholipid synthesis, which improves blood flow, brain activity, and mitochondrial dysfunction. This report will present the case of a non-hospitalized, 59-year-old female. After a mild form of SARS-CoV-2 infection, the patient developed cognitive disturbances such as forgetfulness and anomia. The multidimensional neuropsychological assessment revealed an impairment in episodic memory with borderline performance in executive and visuospatial functioning. Cognitive rehabilitation and treatment with citicoline 1000 mg/daily led to a marked improvement in symptoms after six months. Early identification of the neurological sequelae of the Coronavirus Disease 2019 (COVID-19) and timely rehabilitation interventions are required in non-hospitalized long-hauler patients with COVID-19. Long-term treatment with citicoline should be considered as potentially effective in improving cognitive functioning in subjects with Post COVID-19 Neurological Syndrome. [ABSTRACT FROM AUTHOR]

Citicoline is the generic name of CDP-choline, a natural metabolite presents in all living cells. Used in medicine as a drug since the 1980-s, citicoline was recently pronounced a food ingredient. When ingested, citicoline breaks down to cytidine and choline, which become incorporated into their respective normal metabolic pathways. Choline is a precursor of acetylcholine and phospholipids; these is a neurotransmitter pivotal for learning and memory and important constituents of neuronal membranes and myelin sheaths, respectively. Cytidine in humans is readily converted to uridine, which exerts a positive effect on synaptic function and supports the formation of synaptic membranes. Choline deficiency has been found to be correlated with memory dysfunction. Magnetic resonance spectroscopy studies showed that citicoline intake improves brain uptake of choline in older persons, suggestive of that it shall help in reversing early age-related cognitive changes. In randomized, placebo-controlled trials of cognitively normal middle-aged and elderly persons, positive effects of citicoline on memory efficacy were found. Similar effects of citicoline on memory indices were also found in patients suffering from mild cognitive impairment and some other neurological diseases. Altogether, the aforementioned data provide complex and unambiguous evidence supporting the claim that oral citicoline intake positively influences memory function in humans who encounter age-related memory impairment also in the absence of any detectable neurological or psychiatric disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Citicoline is the exogenous form of the nootropic, Cytidine 5'-diphosphate-choline that exerts its neuroprotective effects in the brain as well as in the eye. The current study characterized the cytoprotective effects of purified Citicoline in transmitochondrial AMD (Age-related Macular Degeneration) RPE cybrid cells which carry diseased mitochondria from clinically characterized AMD patients. The effects of Citicoline were examined via flow cytometry analysis of AnnexinV/ PI-stained cells, IncuCyte live-cell imaging analysis to quantify cells undergoing caspase-3/7-mediated apoptosis, analyses of gene expression profiles of apoptosis, hypoxia, and angiogenesis markers, and measurement of ROS levels and cell viability. Our results demonstrated that Citicoline when added exogenously alleviates apoptotic effects as evidenced by diminished AnnexinV/PI and Caspase-3/7 staining, downregulation of apoptosis genes, enhanced cell viability, and reduced oxidative stress in AMD RPE cybrid cells. In conclusion, our study identified Citicoline as a protector in AMD RPE cybrid cells in vitro. However, further studies are required to establish the merit of Citicoline as a cytoprotective molecule in AMD and to decipher the molecular underpinnings of its mechanism of action in AMD.

The development of dementia is preceded by mild cognitive impairment (MCI), the treatment of which can slow down the transformation of MCI into dementia. The article discusses drug and non-drug therapies for MCI. Multiple pharmacological effects of citicoline on cognitive functions of patient’s with MCI and mild vascular dementia or Alzheimer's disease are analyzed. The need for long-term therapy with citicoline is actualized, increasing adherence to therapy by prescribing a convenient form of the drug Noocil (240 ml bottle, liquid form of citicoline for oral administration).

Non-alcoholic steatohepatitis (NASH) is a more dangerous form of chronic non-alcoholic fatty liver disease (NAFLD). In the current investigation, the influence of citicoline on high-fat diet (HFD)-induced NASH was examined, both alone and in combination with Lactobacillus (probiotic). NASH was induced by feeding HFD (10% sugar, 10% lard stearin, 2% cholesterol, and 0.5% cholic acid) to rats for 13 weeks and received single i.p. injection of streptozotocin (STZ, 30 mg/kg) after 4 weeks. Citicoline was given at two dose levels (250 mg and 500 mg, i.p.) at the beginning of the sixth week, and in combination with an oral suspension of Lactobacillus every day for eight weeks until the study's conclusion. HFD/STZ induced steatohepatitis as shown by histopathological changes, elevated serum liver enzymes, serum hyperlipidemia and hepatic fat accumulation. Moreover, HFD convinced oxidative stress by increased lipid peroxidation marker (MDA) and decreased antioxidant enzymes (GSH and TAC). Upregulation of TLR4/NF-kB and the downstream inflammatory cascade (TNF-α, and IL-6) as well as Pentaraxin, fetuin-B and apoptotic markers (caspase-3 and Bax) were observed. NASH rats also had massive increase in Bacteroides spp., Fusobacterium spp., E. coli, Clostridium spp., Providencia spp., Prevotella interrmedia, and P. gingivalis while remarkable drop in Bifidobacteria spp. and Lactobacillus spp. Co-treatment with citicoline alone and with Lactobacillus improve histopathological NASH outcomes and reversed all of these molecular pathological alterations linked to NASH via upregulating the expression of Nrf2/HO-1 and downregulating TLR4/NF-kB signaling pathways. These results suggest that citicoline and lactobacillus may represent new hepatoprotective strategies against NASH progression. [ABSTRACT FROM AUTHOR]

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the major complications that can lead to death or disability in neonates. We assessed the effect of citicoline as a neuroprotector in neonates with moderate and severe HIE. Methods: This clinical trial was carried on 80 neonates with moderate to severe HIE who were not candidates for therapeutic cooling. They were subdivided randomly into two groups; citicoline treatment group which included 40 neonates who received citicoline 10 mg / kg /12 h IV for 4 weeks plus other supportive measures and the control group which included 40 neonates who were managed with placebo and the same supportive measures. All patients were evaluated for duration of mechanical ventilation (MV), need for inotropes, seizures (type, frequency, and duration), and duration of NICU. Cranial ultrasounds and brain magnetic resonance image (MRI) were performed for all included neonates after 4 weeks of treatment. Follow- ups of all neonates for the neurodevelopmental outcomes were done at 3, 6, 9, and 12 months. Results: There was a significant reduction in the number of neonates having seizures after discharge in the citicoline-treated group (2 neonates) compared to the control group (11 neonates). Cranial ultrasound and MRI findings at 4 weeks were significantly better in the treatment group compared to the control group. Moreover, neurodevelopmental outcome showed significant improvement at 9 and 12 months in the citicoline treated neonates compared to the control group. There was statistically significant reduction in the duration of seizures, NICU stay, inotrope use, and MV in the treatment group compared to the control group. Citicoline was well tolerated with no remarkable side effects. Conclusion: Citicoline could be a promising neuroprotector drug in neonates with HIE. Trial registration: The study was registered at ClinicalTrials.gov (NCT03949049). Registered at 14 May 2019, https://clinicaltrials.gov/ct2/show/NCT03949049 [ABSTRACT FROM AUTHOR]

Background: Globally, stroke is the second leading cause of death and disability. In different studies conducted previously, the choline-containing phospholipids citicoline and choline alphoscerate have been proposed as adjuvants in the treatment of acute strokes. A systematic review was conducted to provide updated information on the effects of citicoline and choline alphoscerate in patients with acute and hemorrhagic strokes. Methods: PubMed/Medline, Scopus, and Web of Science were searched to identify relevant materials. Data were pooled, and odds ratios (OR) were reported for binary outcomes. Using mean differences (MD), we evaluated continuous outcomes. Results: A total of 1460 studies were reviewed; 15 studies with 8357 subjects met the eligibility criteria and were included in the analysis. In our study, citicoline treatment did not result in improved neurological function (NIHSS < 1, OR = 1.05; 95% confidence interval (CI): 0.87–1.27) or functional recovery (mRS < 1, OR = 1.36; 95% CI: 0.99–1.87) in patients with acute stroke. Choline alphoscerate improved neurological function and functional recovery in stroke patients based on the Mathew's scale and the Mini-Mental State Examination (MMSE). Conclusion: Citicoline did not improve the neurological or functional outcomes in acute stroke patients. In contrast, choline alphoscerate improved neurological function and functional recovery and reduced dependency in stroke patients. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy and safety of Citicoline in acute stroke. Study Design: Comparative cross-sectional study. Place of Study and Duration: Combined Military Hospital, Jhelum Pakistan, from Dec 2017 to May 2018. Methodology: Thirty patients with a new onset of stroke, either ischemic or hemorrhagic, were included in the study. This sample of the population was further categorized into four Groups based on the National Institute of Health Stroke Scale scoring system. Half of the patients were medicated with Citicoline and standard stroke treatment and were examined as cases. The rest of the patients were treated with standard stroke management alone and were examined as Controls. The baseline guidelines of the patients were assessed by the Canadian Neurological Stroke Scale. However, for ease of comparison, the CNSS was converted into the National Institute of Health Stoke Scale using the following formula: NIHSS=23-2xCNSS. Results: In our study, baseline improvement in NIHSS score was higher in the Citicoline Group than in the Control Group(68% in the case Group vs. 53% in the Control Group). There was a 30% drop in NIHSS score in Cases compared to the ControlGroup (p>0.05). Conclusion: This study could not prove the effectiveness of Citicoline despite a favourable improvement in NIHSS score in cases. Though Citicoline is a well-tolerated and safe drug, it is ineffective in improving neurological outcomes in patients with acute stroke.

Ocular neurodegenerative diseases such as glaucoma, diabetic retinopathy, and age-related macular degeneration are common retinal diseases responsible for most of the blindness causes in the working-age and elderly populations in developed countries. Many of the current treatments used in these pathologies fail to stop or slow the progression of the disease. Therefore, other types of treatments with neuroprotective characteristics may be necessary to allow a more satisfactory management of the disease. Citicoline and coenzyme Q10 are molecules that have neuroprotective, antioxidant, and anti-inflammatory properties, and their use could have a beneficial effect in ocular neurodegenerative pathologies. This review provides a compilation, mainly from the last 10 years, of the main studies that have been published on the use of these drugs in these neurodegenerative diseases of the retina, analyzing the usefulness of these drugs in these pathologies. [ABSTRACT FROM AUTHOR]

Background: Citicoline or CDP-choline is a neuroprotective/neurorestorative drug used in several countries for the treatment of traumatic brain injury (TBI). Since the publication of the controversial COBRIT, the use of citicoline has been questioned in this indication, so it was considered necessary to undertake a systematic review and meta-analysis to evaluate whether citicoline is effective in the treatment of patients with TBI. Methods: A systematic search was performed on OVID-Medline, EMBASE, Google Scholar, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ferrer databases, from inception to January 2021, to identify all published, unconfounded, comparative clinical trials of citicoline in the acute phase of head-injured patients— that is, treatment started during the first 24 h. We selected studies on complicated mild, moderate, and severe head-injured patients according to the score of the Glasgow Coma Scale (GCS). The primary efficacy measure was independence at the end of the scheduled clinical trial follow-up. Results: In total, 11 clinical studies enrolling 2771 patients were identified by the end. Under the random-effects model, treatment with citicoline was associated with a significantly higher rate of independence (RR, 1.18; 95% CI = 1.05–1.33; I2, 42.6%). The dose of citicoline or the administration route had no effect on outcomes. Additionally, no significant effects on mortality were found, and no safety concerns were noticed. Conclusions: This meta-analysis indicates some beneficial effects of citicoline's increasing the number of independent patients with TBI. The most important limitation of our meta-analysis was the presumed heterogeneity of the studies included. Registration: PROSPERO CRD42021238998 [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is a staggering personal and societal burden; accordingly, there is a strong interest in potential strategies for its prevention and treatment. Nutritional supplements have been extensively investigated, and citicoline seems to be a promising agent; its role in clinical practice, however, has not been established. We systematically reviewed studies on the effect of citicoline on cognitive performance. Methods: We searched the PubMed and Cochrane Library databases for articles published between 2010 and 2022. Relevant information was extracted and presented following the PRISMA recommendations. Data were pooled using the inverse-variance method with random effects models. Results: We selected seven studies including patients with mild cognitive impairment, Alzheimer's disease or post-stroke dementia. All the studies showed a positive effect of citicoline on cognitive functions. Six studies could be included in the meta-analysis. Overall, citicoline improved cognitive status, with pooled standardized mean differences ranging from 0.56 (95% CI: 0.37–0.75) to 1.57 (95% CI: 0.77–2.37) in different sensitivity analyses. The overall quality of the studies was poor. Discussion: Available data indicate that citicoline has positive effects on cognitive function. The general quality of the studies, however, is poor with significant risk of bias in favor of the intervention. Other: PubMed and the Cochrane Library. [ABSTRACT FROM AUTHOR]

Aim: The rehabilitation of children who experience stroke is hampered by the lack of proven treatments and the choice of drugs and dosages. We compared clinical and neurological parameters in children receiving citicoline. Materials & methods: We assessed 199 children (128 boys, 64.3%) with stroke using the Pediatric Stroke Outcome Measure–Short Neurological Exam. Results: Hemorrhagic infarction was diagnosed more often than ischemic stroke, most often owing to the child's early age (before and after 3 months). The presence of disorders of consciousness in the most acute and acute periods is noteworthy. Conclusion: The Pediatric Stroke Outcome Measure–Short Neurological Exam scale can be used to predict adverse outcomes. Citicoline can be administered early and is especially effective during the first year of life. [ABSTRACT FROM AUTHOR]

Objective(s): Sleep has a pivotal role in learning-memory and sleep deprivation (SD) negatively affects synaptic functioning. Cytidine-5-diphosphocholine (Citicoline) has been known to improve learning and memory functions. Our objective was to explore the effects of Citicoline on hippocampal and cortical synaptic proteins in rapid eye movement (REM) sleep-deprived rats.Materials and Methods: Rats (n=36) were randomly divided into 6 groups. Environmental control or sleep deprivation was done by placing the rat on a 13 cm diameter platform (Large Platform [LP] group) or on a 6.5 cm diameter platform (REMSD group), respectively, for 96 hours. Rats randomized for controls (Home Cage [HC] group) were followed up in home cages. Rats in each of the REMSD, LP or HC group were randomized to receive either saline (0,9%NaCl) or Citicoline (600 μmol/kg) intraperitoneally twice a day for four days. After the experiments, rats were sacrificed; their cerebral cortices and hippocampi were dissected for analyzing the levels of pre-synaptic proteins synaptophysin and synapsin I, and the post-synaptic density protein-95 (PSD-95) by Western-blotting. Results: Hippocampal levels of PSD-95, but not the pre-synaptic proteins, were reduced by REM sleep deprivation. Citicoline treatment ameliorated the reduction in PSD-95 levels in REM sleep-deprived rats. On the other hand, REM sleep deprivation was not found to be significantly effective on pre- or post-synaptic proteins in cerebral cortex.Conclusion: REM sleep deprivation reduces hippocampal PSD-95 levels which are enhanced by Citicoline treatment. These data propose that Citicoline may ameliorate the adverse effects of SD on hippocampal synaptic functioning.

Alzheimer’s disease manifests as a complex pathological condition, with neuroinflammation, oxidative stress and cholinergic dysfunction being a few of the many pathological changes. Due to the complexity of the disease, current therapeutic strategies aim at a multitargeted approach, often relying on a combination of substances with versatile and complementary effects. In the present study, a unique combination of α-lipoic acid, citicoline, extracts of leaves from olive tree and green tea, vitamin D3, selenium and an immune-supporting complex was tested in scopolamine-induced dementia in rats. Using behavioral and biochemical methods, we assessed the effects of the combination on learning and memory, and elucidated the mechanisms of these effects. Our results showed that, compared to its components, the experimental combination was most efficient in improving short- and long-term memory as assessed by the step-through method as well as spatial memory as assessed by T-maze and Barnes maze underlined by decreases in AChE activity (p < 0.05) and LPO (p < 0.001), increases in SOD activity in the cortex (p < 0.05) and increases in catalase (p < 0.05) and GPx (p < 0.01) activities and BDNF (p < 0.001) and pCREB (p < 0.05) levels in the hippocampus. No significant histopathological changes or blood parameter changes were detected, making the experimental combination an effective and safe candidate in a multitargeted treatment of AD.

AIM: To evaluate the short-term effects of oral citicoline therapy on the retinal nerve fiber layer (RNFL) and the macular ganglion cell-inner plexiform layer (mGCIPL) in patients with primary open angle glaucoma (POAG). METHODS: Fifty-four eyes of 54 patients with POAG glaucoma included in the study. In addition to a topical hypotensive, 250-mg oral citicoline was administered to 27 patients, while 27 patients were assigned as the control group. RNFL and mGCIPL values were measured using optical coherence tomography (OCT) at 1d before treatment and 3mo after the initiation of treatment. At the third month visit, citicoline treatment was discontinued and drug-free control (wash-out) measurements were obtained at the fourth month in citicoline group. RESULTS: The average RNFL thickness was significantly higher at month 3 than the baseline (P=0.038) in citicoline group. However, this improvement partially regressed after a 1-month wash-out period. No statistically significant changes in RNFL were observed in the superior, nasal, temporal and inferior quadrants at months 3 and 4 (P>0.05). The change in the average and inferior quadrant RNFL thickness in the citicoline group at 3mo was significantly greater than the control group (P=0.006 and P=0.014, respectively). There were no significant differences between the groups according to the change in mGCIPL thickness and the superior, nasal and temporal quadrant RNFL thickness (P>0.05). CONCLUSION: With oral citicoline treatment, the loss in the average RNFL is prevented in POAG patients in the short-term. Study data show that citicoline may have a significant impact on slowing glaucoma progression, which could have a potential neuroprotective effect.

Hussein M Eid,1 Adel A Ali,1 Ahmed M Abdelhaleem Ali,2 Essam M Eissa,1 Randa M Hassan,3 Fatma I Abo El-Ela,4 Amira H Hassan1 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; 3Department of Cytology and Histology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62511, Egypt; 4Department of Pharmacology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62511, EgyptCorrespondence: Adel A AliDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511, Egypt, Tel +20822317958, Email adel.ali@pharm.bsu.edu.eg; dr_adelahmedali@yahoo.comPurpose: This study aimed to formulate citicoline-loaded chitosan-coated liposomes (CT-CS-LPs) for topical administration and evaluated for wound healing in a diabetic animal model.Methods: CT-LPs were formulated via a thin-film hydration approach and coated with chitosan (CS). Box-Behnken statistical design investigated the effects of lipid amount, chitosan concentration, and cholesterol amount on vesicle diameter, surface charge, and entrapment efficiency. The potential of the optimized CT-CS-LPs gel for wound healing was further evaluated in streptozocin-induced diabetic rats. The different healing stages were evaluated by several techniques, including general and special staining techniques, in addition to antibody immunohistochemistry.Results: The optimized CT-CS-LPs obtained had a mean size of 211.6 nm, a 50.7% entrapment efficiency, and a positive surface charge of 32.1 mV. In addition, the optimized CT-CS-LPs exhibited in vitro sustained release behavior. The in vivo experiments revealed that treatment with the optimized CT-CS-LPs boosts the healing process of the skin wound in diabetic rats by reducing inflammation, accelerating re-epithelization, angiogenesis, fibroblast proliferation, and connective tissue remodeling, leading to rapid wound closure.Conclusion: Chitosan-coated liposomes containing citicoline have emerged as a potential approach for promoting the healing process in diabetic rats. However, the therapeutic effectiveness of the suggested approach in diabetic patients needs to be investigated.Keywords: citicoline, chitosan, liposomes, diabetes mellitus, wound healing

Severe traumatic brain injury (sTBI) is a major cause of death and disability worldwide, resulting in a significant individual and socioeconomic burden. Current treatment guidelines do not include any recommendations for neuroprotective or neuoregenerative drugs. Here, we present a combined treatment with Cerebrolysin and Citicoline in two cases. Both drugs are experimentally better than clinically proven in their own effectiveness, but there is almost no clinical data on the combination of the two. Our case study hints at a promising approach that may improve neurological outcome after sTBI. The first patient was a 29 years male motorcyclist suffered polytrauma in a high‐speed accident. He had severe bilateral chest trauma and fractures in both thighs and an sTBI. In addition to surgical and standard neurocritical care according to the evidence‐based guidelines, he was given neuroprotective therapy with Cerebrolysin (50 ml/day) and Citicoline (3 g/day), by continuous intravenous infusion (IV), for 21 days. The second patient was a 30 years male ski mountaineer who had suffered a fall over 300 m in open terrain. In addition to the sTBI, he had fractures in the cervical spine, ribs, pelvis, and lower extremities, as well as lung contusions and massive soft tissue trauma. After initial treatment in a local hospital, he was transferred to our department and received the same neuroprotective drugs, like all of our patients with sTBI. Considering the severity of the injuries (Injury Severity Score [ISS]: 43/50, Revised Trauma Score [RTS: 5.0304, 2.7794]) and the unfavorable outcome probability (Hukkelhoven Score) of 93.1% and 82.6%, the outcomes of both patients are surprisingly encouraging 1 year after the accident. They achieved a Glasgow Outcome Score of 6 and 5 and grades 2 and 4 on the modified Rankin Scale, respectively. Currently, both are able to take care of themselves in activities of daily life to a large extent. Neuroprotective drugs may improve the regeneration of cell membranes, improve blood brain barrier integrity, and reduce neuroinflammation leading to secondary damage to the injured brain. Our clinical experience and data suggest that the combined administration of Citicoline and Cerebrolysin may contribute to better recovery, without relevant side effects. However, it would be important to validate these results by means of a controlled, prospective study. Citicoline and Cerebrolysin can improve the regeneration of cell membranes, reduce the permeability of the blood–brain barrier, neuroinflammation, and neuronal degeneration. Neurotrophic stimulation increases the survival of highly differentiated neuronal cells; neuromodulation enhances neuronal and synaptic plasticity. Both drugs should be given intravenously and continuously as soon as possible after severe traumatic brain injury. [ABSTRACT FROM AUTHOR]

The role of nutraceuticals in the treatment of glaucoma remains controversial. The aim of this study was to evaluate the effect of citicoline, vitamin C, and docosahexaenoic acid (DHA) in patients with glaucoma. Methods: This was a prospective, randomized study. Patients with glaucoma were randomized to one of four groups and treated for 3 months with vitamin C, DHA, citicoline, or a combination of DHA and citicoline. We conducted a complete ophthalmic examination and visual fields each month and calculated the slopes of field indices. Changes in visual field indices (VFIs) and their slopes were assessed in each group and compared. Results: Seventy-three persons were included in the study. Mean defect (MD) significantly improved (p = 0.001) from −9.52 ± 4.36 to −7.85 ± 4.36 dB during the study period in persons taking DHA + citicoline. Similarly, the mean VFI significantly improved (p = 0.001) in this group. The only treatment group showing a statistically significant improvement (p = 0.006) in the MD (from −0.1041 ± 0.2471 to 0.1383 ± 0.2544 dB/month) and VFI slope was the group treated with DHA+citicoline. Conclusions: The combination of oral treatment with DHA + citicoline significantly improved VF indices and their slopes in patients with glaucoma after 3 months of treatment. [ABSTRACT FROM AUTHOR]

Objectives: Given the rising prevalence of cisplatin-induced peripheral neuropathy (CisIPN), investigations to alleviate its adverse effects are required. Oxidative stress and free radical development are essential pathways of CisIPN. Specifically, dexamethasone and citicoline are characterized by anti-inflammatory and antioxidant activities that might reduce CisIPN incidence and severity. The current study assessed the possible impacts of novel interventions, dexamethasone, and, citicoline on CisIPN. Materials and Methods: Seventy-two male mice were randomly allocated into nine groups (n: 8/each group). Different doses of dexamethasone (7.5, 15, 30 mg/kg, i.p.), citicoline (10, 20, 40 mg/kg, i.p.), and the combination (dexamethasone 7.5 mg/kg + citicoline 10 mg/kg, i.p.) were injected in the first three days and one day before receiving cisplatin (2 mg/kg, i.p.). The tail-flick method was used for assessing nociception. Besides, malondialdehyde (MDA), interleukin-1 beta (IL-1ß), tumor necrosis factor-a (TNF-a), total antioxidant capacity (TAC), and mice weight differences (ΔW) were measured. Results: Different doses of dexamethasone and citicoline enhanced latency time (p<0.05). Moreover, dexamethasone 15 mg/kg diminished the level of MDA and increased TAC (p<0.05) and in 30 mg/kg, MDA was reduced (p<0.05). Besides, 20 and 40 mg/kg of citicoline reduced MDA and elevated TAC (p<0.05), and 10 mg/kg merely reduced MDA (p<0.05). Dexamethasone in all doses declined IL-1ß and TNF-a levels, and citicoline only at 40 mg/kg lessened their levels (p<0.05). Interestingly, ΔW declined more in the dexamethasone and citicoline groups than the cisplatin group (p<0.05). Conclusion: Dexamethasone and citicoline attenuate CisIPN through anti-inflammatory activity, improving the antioxidant capacity, and inhibiting lipid peroxidation. [ABSTRACT FROM AUTHOR]

Citicoline, presumed to be involved in the dopaminergic pathway, might play a role as a candidate agent in controlling myopia. However, its study with respect to myopia is limited. The aim of this study is to demonstrate the effect of citicoline on the expression of MMP-2, TGF-β1, and Ki-67, and on the thickness of scleral tissue of a rat myopia model. Immunohistochemistry was performed to evaluate the expression of MMP-2, TGF-β1, and Ki-67 as the markers for fibroblast proliferation. Hematoxylin and eosin staining were used to evaluate scleral thickness. An electronic digital caliper was used to evaluate the axial length. The treatment group administered with 200 mg/kg BW/day had the lowest mean MMP-2 expression, axial elongation, and fibroblast proliferation, but it had the highest mean scleral thickness. The treatment group administered with 300 mg/kg BW/day had the highest mean TGF-β1 expression. Citicoline is able to decrease MMP-2 expression and fibroblast proliferation and increase TGF-β1 expression and scleral tissue thickness significantly in the scleral tissue of rat models for myopia. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain is a usual condition followed by nerve injury. Experimental neuropathy is linked with delayed behavioral variations correlated to anxiety and depression behaviors. Imipramine is a tricyclic antidepressant that can diminish anxiety- and depressive-like behaviors. Also, citicoline as a dietary supplement has antidepressant and anxiolytic effects., Methods: We sought to investigate citicoline's effect on anxiety-like (by elevated plus-maze (EPM)) and depression-like (by tail suspension test (TST)) responses as well as its potential to increase imipramine antidepressant properties in nerve-ligated mice., Results: The results showed that induction of neuropathic pain through sciatic nerve ligation caused anxious- and depressant-like behaviors in male mice. On the other hand, intraperitoneal (i.p.) injections of moderate (50 mg/kg) and high (100 mg/kg) doses of citicoline and high dose of imipramine (5 mg/kg) significantly reduced anxiety- and depression-like behaviors induced by sciatic nerve ligation in male mice. Additionally, a low (25 mg/kg) dose of citicoline potentiated the anxiolytic- and antidepressant-like effects of different doses of imipramine when they co-injected in nerve-ligated mice. Isobolographic analysis indicated an additive effect of imipramine and citicoline on the occurrence of anxiolytic- and antidepressant-like behaviors in nerve-ligated mice. Our results showed that citicoline alone reduces anxiety- and depression-like behaviors. Furthermore, when co-administered with imipramine, citicoline potentiates imipramine effects., Conclusions: Injection of citicoline (as a dietary supplement) along with imipramine improved the effectiveness of imipramine for the management of anxiety- and depressive-like responses in nerve-ligated mice., Competing Interests: No financial or other conflicts of interest are declared., (© 2024 The Authors.)

Glaucoma is the leading cause of irreversible blindness worldwide. Several risk factors have been involved in the pathogenesis of the disease. By now, the main treatable risk factor is elevated intraocular pressure. Nevertheless, some patients, whose intraocular pressure is considered in the target level, still experience a progression of the disease. Glaucoma is a form of multifactorial ocular neurodegeneration with complex etiology, pathogenesis, and pathology. New evidence strongly suggests brain involvement in all aspects of this disease. This hypothesis and the need to prevent glaucomatous progression led to a growing interest in the pharmacological research of new neuroprotective, non-IOP-lowering, agents. The aim of this paper is to report evidence of the usefulness of Coenzyme Q10 and Citicoline, eventually combined, in the prevention of glaucomatous neurodegeneration.