Morphological investigation of protective effects of CDP-choline on liver and small intestine in an experimental sepsis model in rats / Investigación morfológica de los efectos protectores de la CDP-colina en el hígado y el intestino delgado en un modelo experimental de sepsis en ratas

SUMMARY: Fifty male Wistar albino rats were divided into 5 groups; Group 1 as a sham group. Group 2 as a control group, Group 3 as 100 mg/kg CDP-choline administered group, Group as 200 mg/kg CDP-choline administered group, and Group 5 as sepsis group. The sepsis model was performed by ligating and perforating the caecum of rats. Liver and small intestine tissues were assessed either histologically or quantitatively and qualitatively. There was a significant difference between the sepsis and CDP-choline groups for liver and intestinal damage evaluated in tissue samples. (p <0.001). CDP-choline treatment partially improved dose-dependent the clinical parameters of sepsis and septic shock, reversed micro-anatomical damage caused by sepsis.

Cincuenta ratas albinas Wistar macho se dividieron en 5 grupos; Grupo 1 como grupo control simulador, el grupo 2 como grupo de control, el grupo 3 como grupo al que se administró 100 mg/kg de CDP-colina, el grupo 4 como grupo al que se administró 200 mg/kg de CDP-colina y el grupo 5 como grupo con sepsis. El modelo de sepsis se realizó ligando y perforando el intestino ciego de las ratas. Los tejidos del hígado y del intestino delgado se evaluaron histológicamente o cuantitativa y cualitativamente. Hubo una diferencia significativa entre los grupos de sepsis y CDP-colina para el daño hepático e intestinal evaluado en muestras de tejido (p<0,001). El tratamiento con CDP-colina mejoró parcialmente, según la dosis, los parámetros clínicos de sepsis y shock séptico y revirtió el daño micro anatómico causado por la sepsis.

A Retrospective Study on the Benefits of Combined Citicoline, Memantine, and Acetylcholinesterase Inhibitor Treatments in Older Patients Affected with Alzheimer's Disease.

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

Effects of Citicoline, Homotaurine, and Vitamin E on Contrast Sensitivity and Visual-Related Quality of Life in Patients with Primary Open-Angle Glaucoma: A Preliminary Study.

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

Natural Products: Evidence for Neuroprotection to Be Exploited in Glaucoma.

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

CDP-choline and galantamine, a personalized α7 nicotinic acetylcholine receptor targeted treatment for the modulation of speech MMN indexed deviance detection in healthy volunteers: a pilot study.

RATIONALE: The combination of CDP-choline, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, with galantamine, a positive allosteric modulator of nAChRs, is believed to counter the fast desensitization rate of the α7 nAChRs and may be of interest for schizophrenia (SCZ) patients. Beyond the positive and negative clinical symptoms, deficits in early auditory prediction-error processes are also observed in SCZ. Regularity violations activate these mechanisms that are indexed by electroencephalography-derived mismatch negativity (MMN) event-related potentials (ERPs) in response to auditory deviance. OBJECTIVES/METHODS: This pilot study in thirty-three healthy humans assessed the effects of an optimized α7 nAChR strategy combining CDP-choline (500 mg) with galantamine (16 mg) on speech-elicited MMN amplitude and latency measures. The randomized, double-blinded, placebo-controlled, and counterbalanced design with a baseline stratification method allowed for assessment of individual response differences. RESULTS: Increases in MMN generation mediated by the acute CDP-choline/galantamine treatment in individuals with low baseline MMN amplitude for frequency, intensity, duration, and vowel deviants were revealed. CONCLUSIONS: These results, observed primarily at temporal recording sites overlying the auditory cortex, implicate α7 nAChRs in the enhancement of speech deviance detection and warrant further examination with respect to dysfunctional auditory deviance processing in individuals with SCZ.

Effects of Citicoline as an Adjunct Treatment for Alzheimer's Disease: A Systematic Review.

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

Open-label pilot clinical trial of citicoline for fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that is characterized by tremor, cerebellar ataxia, frequent falls, cognitive decline, and progressive loss of motor function. There are currently no approved treatments for this disorder. The purpose of this study was to determine if citicoline was safe for the treatment of tremor and balance abnormalities and to stabilize cognitive decline in patients with FXTAS. Ten participants with diagnosed FXTAS were administered 1000 mg of citicoline once daily for 12 months. Outcome measures and neurological examination were performed at baseline, 3 months, 6 months, and 12 months. The primary outcome was the FXTAS Rating Scale score. Secondary outcomes included change in a battery of neuropsychological tests, an instrumented Timed up and go test, computerized dynamic posturography, 9-hole pegboard test, and balance confidence and psychiatric symptom questionnaires. Safety was also evaluated. Citicoline treatment resulted in minimal adverse events in all but one subject over the course of the study. There was a significant improvement in the Beck Anxiety Inventory (p = 0.03) and the Stroop Color-Word test (p = 0.03), with all other measures remaining stable over the course of 12 months. This open-label pilot trial of citicoline for individuals with FXTAS showed that it is safe and well tolerated in this population. Registration: This trial was registered at ClinicalTrials.gov. Identifier: NCT0219710.

The neuroprotective role of citicoline treatment in glaucoma - 6 months results of a prospective therapeutic trial.

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

Human vitreous concentrations of citicoline following topical application of citicoline 2% ophthalmic solution.

PURPOSE: To evaluate the presence and concentration of citicoline and its metabolites (choline, cytidine and uridine) in the vitreous body in human eyes after topical application of an ophthalmic solution of citicoline 2%, in vivo. METHODS: Twenty-one subjects affected by epiretinal membrane with surgical indication for pars-plana vitrectomy underwent treatment with 1 drop 3 times/day of a solution of citicoline 2%, 0.2% high molecular weight hyaluronic acid and 0.01% benzalkonium chloride (OMK1, Omikron Italia s.r.l., Rome, Italy) 14 days before surgery and 2 hours prior to surgery. Five additional patients served as controls and received an OMK1 vehicle solution without citicoline. The vitreous samples were taken at the beginning of the pars-plana vitrectomy and analyzed for qualitative/quantitative determination of vitreous concentration of citicoline and its metabolites by means of high performance liquid chromatography. RESULTS: The overall mean concentration of citicoline in patients treated with citicoline 2% solution was 406.72 ± 52.99 µg/mL, while the mean concentration of choline, cytidine and uridine was 180.88 ± 41.49 µg/mL, 44.45 ± 10.19 µg/mL and 330.41 ± 75.8 µg/mL, respectively. The concentration of citicoline in phakic eyes (n = 13, 366.61 ± 129.61 µg/mL) was lower compared to that found in pseudophakic eyes (n = 8, 435.89 ± 131.42 µg/mL) and the difference was not statistically significant. The concentration of citicoline in the control eyes was 45.66 ± 26.36 µg/mL, while the concentration of choline, cytidine and uridine were 17.21 ± 9.93 µg/mL, 6.24 ± 3.6 µg/mL and 172.80 ± 99.76 µg/mL, respectively. CONCLUSION: Citicoline can reach the human vitreous in high concentration when administered in ophthalmic solution. This evidence contributes to the build-up of the pyramid of the evidences required for determining the role of citicoline administered in ophthalmic formulation in retinal and optic nerve neurodegenerative diseases.

Dendrimer grafted albumin nanoparticles for the treatment of post cerebral stroke damages: A proof of concept study.

Stroke is the second largest disease of mortality. The biggest hurdle in designing effective brain drug delivery systems is offered by the blood-brain barrier (BBB), which is highly impermeable to many drugs. Albumin nanoparticles (NP) have gained attention due to their multiple ligand binding sites and long circulatory half-life. Citicoline (CIT) is reported to enhance the acetylcholine secretion in the brain and also helps in membrane repair and regeneration. However, the poor BBB permeation of CIT results in lower levels of CIT in the brain. This demands the development of a suitable delivery platform to completely realize the therapeutic benefit of CIT in stroke therapy. This investigation reports the synthesis and characterization of second generation (2.0 G) dendrimer Amplified Albumin (dAA) biopolymer by FTIR, MALDI-TOF, and surface charge (mV). Further, the synthesized biopolymer has been utilized to develop a CIT nanoformulation using a commercially translatable one-pot process. Release of CIT from biopolymer was performed within an acetate buffer at pH 5 and Phosphate buffer at pH 7.4. Further, we investigated the ability of biopolymer to permeate BBB by in vitro permeability assay in bEnd.3 cells. MTT assay of CIT-dAA-NP, CIT-ANP, and 2.0 G PAMAM dendrimers was performed in bEnd.3 cells. Therapeutic efficacy of the synthesized biopolymer was determined by VEGF gene expression within an in vitro hypoxia model in PC12 cells. Thus, this investigation resulted in biopolymers that can be used to deliver any therapeutic agent by altering the permeability of the BBB. Also, cationization by dendrimer grafting is one such strategy that may be used to cationize any other negatively charged polymer, such as albumin. The synthesized biopolymer is not limited to deliver molecules to the brain, but can also be used to increase the loading of negatively-charged drug molecules, siRNA, or any other oligonucleotide.

Neuroenhancement and neuroprotection by oral solution citicoline in non-arteritic ischemic optic neuropathy as a model of neurodegeneration: A randomized pilot study.

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

Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats.

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5'-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 µM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

Combined citicoline and docosahexaenoic acid treatment improves cognitive dysfunction following transient brain ischemia.

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

Enhancement of Retinal Function and of Neural Conduction Along the Visual Pathway Induced by Treatment with Citicoline Eye Drops in Liposomal Formulation in Open Angle Glaucoma: A Pilot Electrofunctional Study.

INTRODUCTION: To evaluate the retinal function and the relative neural conduction along the visual pathway after treatment with citicoline in liposomal formulation (CLF) eye drops in patients with open angle glaucoma (OAG). METHODS: Twelve OAG patients (mean age ± standard deviation 52.58 ± 11.39 years, intraocular pressure < 18 mmHg under topical hypotensive treatment, Humphrey field analyzer mean deviation - 4.49 ± 2.46 dB) were enrolled. Only one eye of studied patients was treated with CLF eye drops (OMK1-LF®, Omikron Italia, 3 drops/day) (CLF group, 12 eyes) over a period of 4 months. In CLF eyes, pattern electroretinogram (PERG), visual evoked potentials (VEP), and visual field test were assessed at baseline and at the end of treatment (month 4). RESULTS: After treatment with CLF eye drops, a significant increase of PERG P50-N95 amplitude and a significant shortening of VEP P100 implicit time were found. In CLF eyes, the shortening of VEP P100 implicit time was significantly correlated with the increase of PERG P50-N95 amplitude. CONCLUSION: Data from this pilot study suggest that treatment with CLF eye drops induces an enhancement of the retinal bioelectrical responses (increase of PERG amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex (shortening of VEP implicit time). FUNDING: Omikron Italia S.r.l. and Opko Health Europe.

In vivo effects of single or combined topical neuroprotective and regenerative agents on degeneration of retinal ganglion cells in rat optic nerve crush model.

To determine the effectiveness of a single or a combination of topical neurotrophic factors (NFs) in protecting retinal ganglion cells (RGCs) in the rat optic nerve crush (ONC) model, the left ONC was performed to induce the death of the RGCs in adult Sprague-Dawley rats. The NFs studied were tauroursodeoxycholic acid (TUDCA), citicoline, neurotrophin-4 (NT-4), combined TUDCA/citicoline (Doublet-1), combined TUDCA/NT-4 (Doublet-2), combined TUDCA/citicoline/NT-4 (Triplet), and PBS. After 2 weeks, the number of RGCs was determined by Brn3a immunostaining. The optic nerves were immunostained for anti-Growth Associated Protein-43(GAP-43) and -200kD neurofilament heavy antibody to study optic nerve regeneration. Two weeks after the ONC, the densities of RGCs in all treated eyes were significantly higher than that of the PBS treated eyes. In the Triplet group, the number of RGC axons after ONC was significantly higher than that in all of the single treatment groups and the number of TUNEL positive cells was significantly reduced and the number of GAP-43 immunopositive axons was significantly greater than those in the PBS group. Neovascularization was observed only in the Doublet-1 group. We conclude that the combination of the three NFs was the most effective way to protect RGCs after the ONC.

Effects of Liposomal Formulation of Citicoline in Experimental Diabetes-Induced Retinal Neurodegeneration.

Diabetic retinopathy (DR) has been classically considered a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is also an early event in the pathogenesis of DR. Citicoline has been successfully used as a neuroprotective agent in the treatment of glaucoma but their effects on DR remain to be elucidated. On this basis, the main aim of the present study was to evaluate the effect of topical administration of citicoline in liposomal formulation on retinal neurodegeneration in db/db mouse and to investigate the underlying mechanisms of action. The treatment (citicoline or vehicle) was topically administered twice daily for 15 days. Retinal analyses were performed in vivo by electroretinography and ex vivo by using Western blot and immunofluorescence measurements. We found that the liposomal formulation of citicoline prevented glial activation and neural apoptosis in the diabetic retina. The main mechanism implicated in these beneficial effects were the inhibition of the downregulation of synaptophysin and its anti-inflammatory properties by means of preventing the upregulation of NF-κB and TNF-α (Tumor Necrosis Factor α) induced by diabetes. Overall, these results suggest that topical administration of citicoline in liposomal formulation could be considered as a new strategy for treating the early stages of DR.

[Multicenter observational program for evaluation of the effectiveness of the recognan (citicoline) in the correction of cognitive impairment in patients with chronic cerebrovascular pathology]. / Mnogotsentrovaia nabliudatel'naia programma po otsenke éffektivnosti preparata rekognan (tsitikolin) v korrektsii kognitivnykh narushenii u patsientov s khronicheskoi tserebrovaskuliarnoi patologiei.

AIM: To study the efficacy and safety of recognan (citicoline) in the treatment of cognitive and depressive disorders in chronic cerebrovascular pathology (chronic brain ischemia) developed in patients with arterial hypertension and/or atherosclerosis. MATERIAL AND METHODS: Seven hundred and thirty-six patients with cerebrovascular pathology, cognitive impairment and mild dementia were examined. The sample included 279 (37.9%) men and 457 (62.1%) women aged from 35 to 80 years (mean age 64.5±8.7 years). The drug recognan ('Gerofarm', Russia) was administered in the dose of 1000 mg daily during 30 days. Recovery of cognitive functions was assessed with MSSE, correction of visual/spatial coordination with CDT, depression severity with MGDS. RESULTS: The improvement of cognitive function, memory and visual/spatial coordination, decrease in depression severity were observed during the treatment. CONCLUSION: Recognan reduced cognitive dysfunction and disturbances of visual/spatial coordinationas well as had a positive effect on the emotional sphere decreasing the level of depression.

Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.

Citicoline (CDPC) is a natural supplement with well-documented neuroprotective effects in the treatment of neurodegenerative diseases. In the present study, we sought to exploit citicoline as a theranostic agent with its inherent chemical exchange saturation transfer (CEST) MRI signal, which can be directly used as an MRI guidance in the citicoline drug delivery. Our in vitro CEST MRI results showed citicoline has two inherent CEST signals at +1 and +2 ppm, attributed to exchangeable hydroxyl and amine protons, respectively. To facilitate the targeted drug delivery of citicoline to ischemic regions, we prepared liposomes encapsulating citicoline (CDPC-lipo) and characterized the particle properties and CEST MRI properties. The in vivo CEST MRI detection of liposomal citicoline was then examined in a rat brain model of unilateral transient ischemia induced by a two-hour middle cerebral artery occlusion. The results showed that the delivery of CPDC-lipo to the brain ischemic areas could be monitored and quantified by CEST MRI. When administered intra-arterially, CDPC-lipo clearly demonstrated a detectable CEST MRI contrast at 2 ppm. CEST MRI revealed that liposomes preferentially accumulated in the areas of ischemia with a disrupted blood-brain-barrier. We furthermore used CEST MRI to detect the improvement in drug delivery using CDPC-lipo targeted against vascular cell adhesion molecule (VCAM)-1 in the same animal model. The MRI findings were validated using fluorescence microscopy. Hence, liposomal citicoline represents a prototype theranostic system, where the therapeutic agent can be detected directly by CEST MRI in a label-free fashion.

Early application of citicoline in the treatment of acute stroke: A meta-analysis of randomized controlled trials.

This study was to evaluate the efficacy and safety of early application of citicoline in the treatment of patients with acute stroke by meta-analysis. Randomized controlled trials published until May 2015 were electronically searched in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, WHO International Clinical Trial Registration Platform, Clinical Trial.gov, and China Biology Medicine disc. Two reviewers independently screened the articles and extracted the data based on the inclusion and exclusion criteria. The quality of included articles was evaluated by using Revman5.0, and meta-analysis was performed. The results showed that 1027 articles were obtained in initial retrieval, and finally 7 articles, involving a total of 4039 cases, were included for analysis. The meta-analysis showed that no significant differences were found in the long-term mortality (OR=0.91, 95% CI 0.07 to 1.09, P=0.30), the rate of dependency (OR=1.02, 95% CI 0.87 to 1.24, P=0.85), and the effective rate (OR=0.98, 95% CI 0.84 to 1.14, P=0.82) between citicoline group and control group. The overall rate of adverse events in citicoline group was not significantly different from that in control group (P=0.30). The quality of included articles reached moderate-low level. In conclusion, citicolne cannot reduce long-term mortality and dependence rate in the treatment of acute stroke, and the effective rate of citivoline may be not better than that of controls but with reliable safety.

Interventions for preventing delirium in hospitalised non-ICU patients.

BACKGROUND: Delirium is a common mental disorder, which is distressing and has serious adverse outcomes in hospitalised patients. Prevention of delirium is desirable from the perspective of patients and carers, and healthcare providers. It is currently unclear, however, whether interventions for preventing delirium are effective. OBJECTIVES: To assess the effectiveness of interventions for preventing delirium in hospitalised non-Intensive Care Unit (ICU) patients. SEARCH METHODS: We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 4 December 2015 for all randomised studies on preventing delirium. We also searched MEDLINE (Ovid SP), EMBASE (Ovid SP), PsycINFO (Ovid SP), Central (The Cochrane Library), CINAHL (EBSCOhost), LILACS (BIREME), Web of Science core collection (ISI Web of Science), ClinicalTrials.gov and the WHO meta register of trials, ICTRP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of single and multi- component non-pharmacological and pharmacological interventions for preventing delirium in hospitalised non-ICU patients. DATA COLLECTION AND ANALYSIS: Two review authors examined titles and abstracts of citations identified by the search for eligibility and extracted data independently, with any disagreements settled by consensus. The primary outcome was incidence of delirium; secondary outcomes included duration and severity of delirium, institutional care at discharge, quality of life and healthcare costs. We used risk ratios (RRs) as measures of treatment effect for dichotomous outcomes; and between group mean differences and standard deviations for continuous outcomes. MAIN RESULTS: We included 39 trials that recruited 16,082 participants, assessing 22 different interventions or comparisons. Fourteen trials were placebo-controlled, 15 evaluated a delirium prevention intervention against usual care, and 10 compared two different interventions. Thirty-two studies were conducted in patients undergoing surgery, the majority in orthopaedic settings. Seven studies were conducted in general medical or geriatric medicine settings.We found multi-component interventions reduced the incidence of delirium compared to usual care (RR 0.69, 95% CI 0.59 to 0.81; seven studies; 1950 participants; moderate-quality evidence). Effect sizes were similar in medical (RR 0.63, 95% CI 0.43 to 0.92; four studies; 1365 participants) and surgical settings (RR 0.71, 95% CI 0.59 to 0.85; three studies; 585 participants). In the subgroup of patients with pre-existing dementia, the effect of multi-component interventions remains uncertain (RR 0.90, 95% CI 0.59 to 1.36; one study, 50 participants; low-quality evidence).There is no clear evidence that cholinesterase inhibitors are effective in preventing delirium compared to placebo (RR 0.68, 95% CI, 0.17 to 2.62; two studies, 113 participants; very low-quality evidence).Three trials provide no clear evidence of an effect of antipsychotic medications as a group on the incidence of delirium (RR 0.73, 95% CI, 0.33 to 1.59; 916 participants; very low-quality evidence). In a pre-planned subgroup analysis there was no evidence for effectiveness of a typical antipsychotic (haloperidol) (RR 1.05, 95% CI 0.69 to 1.60; two studies; 516 participants, low-quality evidence). However, delirium incidence was lower (RR 0.36, 95% CI 0.24 to 0.52; one study; 400 participants, moderate-quality evidence) for patients treated with an atypical antipsychotic (olanzapine) compared to placebo (moderate-quality evidence).There is no clear evidence that melatonin or melatonin agonists reduce delirium incidence compared to placebo (RR 0.41, 95% CI 0.09 to 1.89; three studies, 529 participants; low-quality evidence).There is moderate-quality evidence that Bispectral Index (BIS)-guided anaesthesia reduces the incidence of delirium compared to BIS-blinded anaesthesia or clinical judgement (RR 0.71, 95% CI 0.60 to 0.85; two studies; 2057 participants).It is not possible to generate robust evidence statements for a range of additional pharmacological and anaesthetic interventions due to small numbers of trials, of variable methodological quality. AUTHORS' CONCLUSIONS: There is strong evidence supporting multi-component interventions to prevent delirium in hospitalised patients. There is no clear evidence that cholinesterase inhibitors, antipsychotic medication or melatonin reduce the incidence of delirium. Using the Bispectral Index to monitor and control depth of anaesthesia reduces the incidence of postoperative delirium. The role of drugs and other anaesthetic techniques to prevent delirium remains uncertain.