Potentiation of Imipramine-Induced Anti-hyperalgesic and Anti-Nociceptive Effects by Citicoline in the Sciatic Nerve Ligated Mice.

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.

Unveiling citicoline's mechanisms and clinical relevance in the treatment of neuroinflammatory disorders.

Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti-inflammatory effects. This review aims to elucidate citicoline's anti-inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age-associated memory impairment. Citicoline's anti-inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate-a pro-inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF-κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age-related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti-inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration.

Use of Citicoline in Attention-Deficit/Hyperactivity Disorder: A Pilot Study.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurobehavioral disorder in school-aged children. Although there are several drug treatment options, some patients do not have adequate therapeutic responses to conventional medications or experience considerable adverse effects. Citicoline is an endogenous molecule that has beneficial effects on attention, impulsivity, and memory and is a potential treatment for ADHD. This study aimed to evaluate the effect of citicoline in pediatric patients diagnosed with ADHD. METHODS: This randomized, crossover, double-blind, placebo-controlled clinical trial included with patients aged 7-12 years diagnosed with ADHD. RESULTS: As a result, no statistically significant difference was noted between the use of citicoline and placebo in the evaluated parameters. The treatment had no adverse effects. CONCLUSIONS: Citicoline seems to be a safe molecule to be administered in the pediatric age group. Further studies are required to assess the therapeutic potential of citicoline in ADHD.

The additive effect between bupropion and citicoline upon induction of anti-nociceptive effect in nerve-ligated mice.

OBJECTIVES: Bupropion is an atypical antidepressant that shows robust efficacy in the regulation of neuropathic pain. Citicoline is a dietary supplement which is used as a neuroprotective agent for central nervous system (CNS) disorders. The probable interaction between bupropion and citicoline on neuropathic pain was assessed in male mice. METHODS: Neuropathic pain was induced by sciatic nerve ligation. Neuropathic pain was examined in nerve-ligated mice using tail-flick and hot-plate tests. RESULTS: The results indicated that intraperitoneal (i.p.) administration of citicoline (50 and 100 mg/kg) induced an anti-nociceptive effect in nerve-ligated animals. Similarly, i.p. injection of bupropion (2.5 and 5 mg/kg) induced anti-nociceptive effects in nerve-ligated mice. Co-administration of different doses of bupropion (2.5 and 5 mg/kg) along with a low dose of citicoline (25 mg/kg) caused an anti-nociceptive effect by enhancement of tail-flick and hot plate latencies. Interestingly, there is an additive effect between bupropion and citicoline upon the induction of the anti-nociceptive effect. CONCLUSIONS: Based on these results, it can be concluded that there is an interaction between bupropion and citicoline upon induction of an anti-nociceptive effect in nerve-ligated mice.

[Recognan (citicoline) in the correction of asthenic and anxiety-depressive disorders]. / Rekognan (tsitikolin) v korrektsii astenicheskikh i trevozhno-depressivnykh narushenii.

The article reflects the results of a number of studies that demonstrate the therapeutic effectiveness of Recognan (citicoline) in anxiety-depressive and asthenic disorders against the background of somatic and neurological diseases, in the correction of post-stroke depression. Recent experimental animal studies prove the effect of citicoline on anxiety and depression. In the complex effect, Recognan potentiates the main pharmacological effect of antidepressants and anxiolytics. In some studies, a dose-dependent change in animal behavior has been observed in response to the analgesic and antidepressant effects of citicoline. The effectiveness of citicoline in combination with transcranial direct current stimulation in the treatment of depression has been shown. The analysis of these research materials allows us to recommend Recognan in the complex therapy of asthenic and anxiety-depressive disorders in response to such pathological conditions as anxiety, asthenia, depression.

Citicoline: A Cholinergic Precursor with a Pivotal Role in Dementia and Alzheimer's Disease.

Background: Citicoline is a naturally occurring compound with pleiotropic effects on neuronal function and cognitive processes. Objective: Based on previous studies, which shed light on the positive effects of citicoline 1 g when combined with acetylcholinesterase inhibitors (AChEIs) and/or memantine, we further investigated the benefits of citicoline in combination therapy in Alzheimer's disease and mixed dementia. Methods: We integrated the datasets of CITIMEM and CITIDEMAGE, increasing the overall sample size to enhance statistical power. We analyzed data from these two investigator-initiated studies involving 295 patients. The primary outcome was the assessment over time of the effects of combined treatment versus memantine given alone or AChEI plus memantine on cognitive functions assessed by Mini-Mental State Examination (MMSE). The secondary outcomes were the influence of combined treatment on daily life functions, mood, and behavioral symptoms assessed by activities of daily life (ADL) and instrumental ADL, Geriatric Depression Scale, and Neuropsychiatric Inventory Scale. One-hundred-forty-three patients were treated with memantine and/or AChEI (control group), and 152 patients were treated with memantine and/or AChEI plus citicoline 1 g/day orally (Citicoline group). Results: A significant difference in MMSE score was found in the average between the two groups of treatment at 6 and 12 months. Conclusions: This study confirmed the effectiveness of combined citicoline treatment in patients with mixed dementia and Alzheimer's disease, with a significant effect on the increase of MMSE score over time. The treated group also showed a significant reduction in the Geriatric Depression Scale and a significant increase in the instrumental ADL scale.

Cytoprotection as an Innovative Therapeutic Strategy to Cardiogenic Shock: Exploring the Potential of Cytidine-5-Diphosphocholine to Mitigate Target Organ Damage.

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

SCARLET (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial): study protocol for a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 trial of i.v. citicoline (CDP-choline) in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure.

BACKGROUND: The SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improved gas exchange and reduced pulmonary inflammation without altering viral replication. In unpublished studies, we found that treatment of SARS CoV-2-infected K18-hACE2-transgenic mice with CDP-choline prevented development of hypoxemia. We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure (HARF) and that we will obtain preliminary evidence of clinical benefit to support a larger Phase 3 trial using one or more citicoline doses. METHODS: We will conduct a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 dose-ranging and safety study of Somazina® citicoline solution for injection in consented adults of any sex, gender, age, or ethnicity hospitalized for SARS CoV-2-associated HARF. The trial is named "SCARLET" (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). We hypothesize that SCARLET will show that i.v. citicoline is safe at one or more of three doses (0.5, 2.5, or 5 mg/kg, every 12 h for 5 days) in hospitalized SARS CoV-2-infected patients with HARF (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the SpO2:FiO2 ratio on study day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined. DISCUSSION: Citicoline has many characteristics that would be advantageous to any candidate COVID-19 therapeutic, including safety, low-cost, favorable chemical characteristics, and potentially pathogen-agnostic efficacy. Successful demonstration that citicoline is beneficial in severely ill patients with SARS CoV-2-induced HARF could transform management of severely ill COVID patients. TRIAL REGISTRATION: The trial was registered at www. CLINICALTRIALS: gov on 5/31/2023 (NCT05881135). TRIAL STATUS: Currently enrolling.

Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

Thromboelastographic evaluation of the effectiveness of choline or CDP-choline treatment on endotoxin-induced hemostatic alterations in dogs.

Sepsis/endotoxemia associates with coagulation abnormalities. We showed previously that exogenous choline treatment reversed the changes in platelet count and function as well as prevented disseminated intravascular coagulation (DIC) in endotoxemic dogs. The aim of this follow-up study was to evaluate the effect of treatment with choline or cytidine-5'-diphosphocholine (CDP-choline), a choline donor, on endotoxin-induced hemostatic alterations using thromboelastography (TEG). Dogs were randomized to six groups and received intravenously (iv) saline, choline (20 mg/kg) or CDP-choline (70 mg/kg) in the control groups, whereas endotoxin (0.1 mg/kg, iv) was used alone or in combination with choline or CDP-choline at the same doses in the treatment groups. TEG variables including R- and K-time (clot formation), maximum amplitude (MA) and α-angle (clot stability), G value (clot elasticity), and EPL, A, and LY30 (fibrinolysis), as well as overall assessment of coagulation (coagulation index - CI), were measured before and at 0.5-48 h after the treatments. TEG parameters did not change significantly in the control groups, except for CI parameter after choline administration. Endotoxemia resulted in increased R-time and A value (P < 0.05), decreased K-time (P < 0.05), α-angle (P < 0.001) and CI values (P < 0.01) at different time points. Treatment with either choline or CDP-choline attenuated or prevented completely the alterations in TEG parameters in endotoxemic dogs with CDP-choline being more effective. These results confirm and extend the effectiveness of choline or CDP-choline in endotoxemia by further demonstrating their efficacy in attenuating or preventing the altered viscoelastic properties of blood clot measured by TEG.

[Asthenic disorders correction with Recognan]. / Korrektsiya astenicheskikh sostoyanii preparatom Rekognan.

Asthenia, asthenic syndrome, asthenic condition, asthenic reaction, asthenic disorders are terms that describe the state of «impotence¼. Fatigue that occurs against the background of habitual physical or intellectual stress for a person, and persists after rest, is asthenia. For people of the older age group, the term senile asthenia syndrome is used. Asthenia manifests itself with increased fatigue and exhaustion, mood instability, increased irritability, sleep disorders. Asthenic conditions manifest themselves along with a decrease in physical activity, increased cognitive and mental fatigue. Asthenic syndrome (AS) are considered as an integral part of cardiovascular diseases (CVD), as one of the manifestations of cerebrovascular pathology. Senile asthenia syndrome (SAS) is a geriatric syndrome characterized by an age-associated decrease in the physiological reserve and functions of many body systems, including cognitive functions. One of the drugs that has a positive effect on the severity of AS and improves the state of cognitive functions is the domestic drug Recognan (citicoline). The effectiveness of Recognan in the treatment of AS in patients with CVD, SAS, and post-COVID asthenia has been shown. It is recommended to prescribe Recognan orally at 500 mg / day for 30 days. Recognan has a nootropic and antiasthenic effect.

Liposomal Encapsulation of Citicoline for Ocular Drug Delivery.

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.

[Recognan (citicoline) efficacy and safety in cognitive impairment correction of various nosological forms]. / Effektivnost' i bezopasnost' Rekognana (tsitikolin) pri korrektsii kognitivnykh narushenii razlichnoi etiologii.

Insufficiency of a choline derivative (acetylcholine) can lead to the development of cognitive impairment (CI). One of the most well-known and well-studied medical drugs (MD) containing choline and having neuroprotective properties is citicoline (Recognan). A number of studies have demonstrated the effectiveness of Recognan in relation to mild CI, chronic cerebrovascular diseases (CVD), acute vascular disorders (including post-traumatic genesis). Recognan improves memory and other cognitive functions in healthy young people against the background of asthenia due to stress or increased cognitive and emotional stress or infection, and also has a preventive effect on fading cognitive functions in the process of age-related changes. The duration of neuroprotection can reach 6 months or more - up to 12 months, depending on the patient's condition. Therapy regimens include two-stage Recognan prescribing: with CVD intramuscularly (i/m) at 1000 mg /d for 30 days, in the acute period of ischemic stroke, i/m or intravenously (i/v) at 1000 mg every 12 hours from the first day after diagnosis, 3-5 days after the start of therapy, with preservation functions of swallowing, it is possible to switch to per oral (p/o) drug administration.

EFFECT OF INVESTIGATIONAL COMBINATIONS OF NEUROPROTECTANTS ON THE LEVEL OF S 100 AND NSE PROTEIN IN THE BLOOD SERUM OF PATIENTS WITH MODERATE AND SEVERE ISCHEMIC STROKE.

Ischemic cerebral stroke (ICS) is a devastating neurological pathology associated with enormous comorbidity and mortality. Preliminary experimental screening of cerebroprotective agents with different mechanisms of action was performed: Edaravone, Cerebrolysin, Choline alfoscerate, Citicoline, Mexidol, the most effective combinations of cerebroprotectors were identified, followed by their screening for efficacy in clinical conditions by neuron-specific enolase (NSE) and S100 protein, as one of the main biochemical markers of brain damage in acute ischemic stroke. Different combinations of neuroprotectants identified as the most effective in experimental screening differed in their ability to correct serum levels of S100 and NSE protein in ischemic stroke in clinical settings. The lowest effectiveness in the correction of neuroglioproliferative processes was recorded when using only conventional therapy (CT), which was determined according to the Order of the Ministry of Health of Ukraine of 03.08.2012 №602, without the use of neuroprotectors. Whereas, the use of a neuroprotective combination/complex (NPC) (cerebrolysin+citicoline) in the treatment of ischemic strokes in terms of the effectiveness of correction of neuroglioproliferative processes was 1,7-2,7 times (p<0.01) higher than conventional therapy, and 1,2-1,4 times (p<0.05) higher than treatment that included the use of a neuroprotective combination - cerebrolysin+mexidol.

The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway.

Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD+, nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160 mg/kg citicoline and 40 mg/kg NMN, this combination administrated at 7 days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.

CDP-choline modulates cholinergic signaling and gut microbiota to alleviate DSS-induced inflammatory bowel disease.

Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous research has revealed that IBD patients often have a deficiency of choline and its metabolites, including acetylcholine (ACh) and phosphatidylcholine (PC), within the colon. However, a comprehensive study linking these three substances and their mechanistic implications in IBD remains lacking. This study aimed to investigate the efficacy and underlying mechanism of cytidine diphosphate (CDP)-choline (citicoline), an intermediate product of choline metabolism, in a mouse model of IBD induced by dextran sulfate sodium salt (DSS). The results demonstrated that CDP-choline effectively alleviated colonic inflammation and deficiencies in choline, ACh, and PC by increasing the raw material. Further detection showed that CDP-choline also increased the ACh content by altering the expression of high-affinity choline transporter (ChT1) and acetylcholinesterase (AChE) in DSS-induced mice colon. Moreover, CDP-choline increased the expression of alpha7 nicotinic acetylcholine receptor (α7 nAChR) and activated the cholinergic anti-inflammatory pathway (CAP), leading to reduced colon macrophage activation and proinflammatory M1 polarization in IBD mice, thus reducing the levels of TNF-α and IL-6. In addition, CDP-choline reduced intestinal ecological imbalance and increased the content of hexanoic acid in short-chain fatty acids (SCFAs) in mice. In conclusion, this study elucidates the ability of CDP-choline to mitigate DSS-induced colon inflammation by addressing choline and its metabolites deficiencies, activating the CAP, and regulating the composition of the intestinal microbiome and SCFAs content, providing a potential prophylactic and therapeutic approach for IBD.

Efficacy of citicoline as a supplement in glaucoma patients: A systematic review.

PURPOSE: Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in glaucoma, leading to blindness. Elevated intraocular pressure (IOP) is the only modifiable risk factor, however, many patients progress despite excellent IOP control. Thus, alternative treatment strategies to prevent glaucoma progression are an unmet need. Citicoline has demonstrated neuroprotective properties in central neurodegenerative diseases. However, conclusive evidence of the effect of citicoline on glaucoma progression is missing. This systematic review investigates first-time the therapeutic potential of citicoline in glaucoma patients. METHODS: The present study was conducted according to the PRISMA 2020 statement. PubMed, Web of Science, Google Scholar, and Embase were accessed in July 2023 to identify all clinical studies investigating the efficacy of citicoline on IOP, the mean deviation of the 24-2 visual field testing (MD 24-2), retinal nerve fibre layer (RNFL), and the pattern electroretinogram (PERG) P50-N95 amplitude in glaucoma patients. The risk of bias was assessed using the Review Manager 5.3 software (The Nordic Cochrane Collaboration, Copenhagen) and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool. RESULTS: Ten studies were eligible for this systematic review, including 424 patients. The mean length of the follow-up was 12.1 ± 11.6 months. The overall risk of bias was low to moderate. The mean age of the patients was 56.7 years. There were no significant differences in the IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude between patients receiving citicoline and the control group. There was no improvement from baseline to the last follow-up in IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude. CONCLUSION: There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.

Citicoline on the Barthel Index: Severe and moderate brain injury.

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.

Integrating, Harmonizing, and Curating Studies With High-Frequency and Hourly Physiological Data: Proof of Concept from Seven Traumatic Brain Injury Data Sets.

Research in severe traumatic brain injury (TBI) has historically been limited by studies with relatively small sample sizes that result in low power to detect small, yet clinically meaningful outcomes. Data sharing and integration from existing sources hold promise to yield larger more robust sample sizes that improve the potential signal and generalizability of important research questions. However, curation and harmonization of data of different types and of disparate provenance is challenging. We report our approach and experience integrating multiple TBI data sets containing collected physiological data, including both expected and unexpected challenges encountered in the integration process. Our harmonized data set included data on 1536 patients from the Citicoline Brain Injury Treatment Trial (COBRIT), Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial (EPO Severe TBI), BEST-TRIP, Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial (ProTECT III), Transforming Research and Clinical Knowledge in Traumatic brain Injury (TRACK-TBI), Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II (BOOST-2), and Ben Taub General Hospital (BTGH) Research Database studies. We conclude with process recommendations for data acquisition for future prospective studies to aid integration of these data with existing studies. These recommendations include using common data elements whenever possible, a standardized recording system for labeling and timing of high-frequency physiological data, and secondary use of studies in systems such as Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR), to engage investigators who collected the original data.