4 Advice to Choose a Citicoline Sodium And Stroke Prevention

Adibhatla, R. M., Hatcher JF, and Dempsey RJ. Effects of citicholine on phospholipid and glutathione levels in transient cerebral ischemia. Stroke ;32(10):-.

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Agnoli A, Fioravanti M, and Lechner H. Efficacy of CDP-Choline in chronic cerebral vascular diseases (CCVD). In: Zappia V, Kennedy EP, Nilsson BI, and Galletti PV. Novel Biochemical, Pharmacological, and Clinical Aspects of Cytidinediphosphocholine. New York: Elsevier Science;.

Aizawa, K., Kanai, T., Saikawa, Y., Takabayashi, T., Kawano, Y., Miyazawa, N., and Yamamoto, T. A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Surg.Today. ;32(4):310-314. View abstract.

Alvarez, X. A., Laredo, M., Corzo, D., Fernandez-Novoa, L., Mouzo, R., Perea, J. E., Daniele, D., and Cacabelos, R. Citicoline improves memory performance in elderly subjects. Methods.Find.Exp.Clin.Pharmacol. ;19(3):201-210. View abstract.

Alvarez, X. A., Mouzo, R., Pichel, V., Perez, P., Laredo, M., Fernandez-Novoa, L., Corzo, L., Zas, R., Alcaraz, M., Secades, J. J., Lozano, R., and Cacabelos, R. Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods.Find.Exp.Clin.Pharmacol. ;21(9):633-644. View abstract.

Angeli G. Clinical study on Asonic (provisional name) [Sperimentazione clinica sul prodotto denominato provvisoriamente Asonic]. Rivista di Neuropsichiatria e Scienze Affini ;31:13-24.

Arranz, J. and Ganoza, C. Treatment of chronic dyskinesia with CDP-choline. Arzneimittelforschung. ;33(7A):-. View abstract.

Ataus S, Onal M, Zulkuf M, and et al. The effects of citicholine and lamotrigine alone and in combination following permanent middle cerebral artery occlusion in rats. International Journal of Neuroscience ;114(2):183-196.

Babb, S. M., Wald, L. L., Cohen, B. M., Villafuerte, R. A., Gruber, S. A., Yurgelun-Todd, D. A., and Renshaw, P. F. Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study. Psychopharmacology.(Berl.) ;161(3):248-254. View abstract.

Barbagallo-Sangiorgi G, Ceruso D, Cuzzupoli MF, and et al. Double-blind, multicenter study on CDP-choline in patients with primary senile mental deterioration [Studio multicentrico in doppio cieco con Citicolina nel deterioramento mentale senile primitivo]. Invecchiamento Cerebrale e Cerebrovasculopatie Croniche ;

Berggren, D., Gustafson, Y., Eriksson, B., Bucht, G., Hansson, L. I., Reiz, S., and Winblad, B. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth.Analg. ;66(6):497-504. View abstract.

Bettini, R. and Gorini, M. [Reaction times during citicoline treatment]. Clin.Ter. ;153(4):247-250. View abstract.

Bonavita E, Chioma V, Dall'Oca P, and et al. Double-blind study on CDP-choline activity in primitive mild cognitive deterioration cases [Studio in doppio cieco sull'azione della citicolina nel cervello senile]. Minerva Psichiatrica ;24:53-62.

Bonavita, E. [Neuropsychological study of the senile brain during and after single and combined treatment with deanol and citicoline]. Clin.Ter. 6-15-;117(5):387-398. View abstract.

Brown, E. S., Gorman, A. R., and Hynan, L. S. A randomized, placebo-controlled trial of citicoline add-on therapy in outpatients with bipolar disorder and cocaine dependence. J Clin.Psychopharmacol. ;27(5):498-502. View abstract.

Campos, E. C., Schiavi, C., Benedetti, P., Bolzani, R., and Porciatti, V. Effect of citicoline on visual acuity in amblyopia: preliminary results. Graefes.Arch Clin.Exp.Ophthalmol. ;233(5):307-312. View abstract.

Capurso A, Capurso S, Panza F, and et al. Efficacy of cytidine diphosphate choline in patients affected by chronic cerebrovascular disease. Clinical Drug Investigation ;12(1):26-38.

Centrone, G., Ragno, G., and Calicchio, G. [Use of citicoline in high dosages in acute cerebrovascular disease]. Minerva Med 3-17-;77(11):371-373. View abstract.

Clark, W. M., Warach, S. J., Pettigrew, L. C., Gammans, R. E., and Sabounjian, L. A. A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology. ;49(3):671-678. View abstract.

Clark, W. M., Wechsler, L. R., Sabounjian, L. A., and Schwiderski, U. E. A phase III randomized efficacy trial of mg citicoline in acute ischemic stroke patients. Neurology. 11-13-;57(9):-. View abstract.

Clark, W. M., Williams, B. J., Selzer, K. A., Zweifler, R. M., Sabounjian, L. A., and Gammans, R. E. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke. ;30(12):-. View abstract.

Cubells, J. M. and Hernando, C. Clinical trial on the use of cytidine diphosphate choline in Parkinson's disease. Clin.Ther ;10(6):664-671. View abstract.

D'Orlando, K. J. and Sandage, B. W., Jr. Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. Neurol.Res ;17(4):281-284. View abstract.

Di, Trapani G. and Fioravanti, M. [Citicoline in the treatment of cognitive and behavioral disorders in pathologic senile decline]. Clin.Ter. 6-30-;137(6):403-413. View abstract.

Diaz, V., Rodriguez, J., Barrientos, P., Serra, M., Salinas, H., Toledo, C., Kunze, S., Varas, V., Santelices, E., Cabrera, C., Farias, J., Gallardo, J., Beddings, M. I., Leiva, A., and Cumsille, M. A. [Use of procholinergics in the prevention of postoperative delirium in hip fracture surgery in the elderly. A randomized controlled trial]. Rev.Neurol. 10-16-;33(8):716-719. View abstract.

Dinsdale, J. R., Griffiths, G. K., Castello, J., Maddock, J., Ortiz, J. A., and Aylward, M. CDP-choline: repeated oral dose tolerance studies in adult healthy volunteers. Arzneimittelforschung. ;33(7A):-. View abstract.

Dinsdale, J. R., Griffiths, G. K., Rowlands, C., Castello, J., Ortiz, J. A., Maddock, J., and Aylward, M. Pharmacokinetics of 14C CDP-choline. Arzneimittelforschung. ;33(7A):-. View abstract.

Eberhardt, R., Birbamer, G., Gerstenbrand, F., Rainer, E., and Traegner, H. Citicoline in the treatment of Parkinson's disease. Clin.Ther ;12(6):489-495. View abstract.

Falchi Delitata G, Falchi Delitata N, Casali R, and et al. Intermediate term, double-blind vs. placebo study of CDP-choline in cases with cognitive senile deterioration. Gazzetta Medica Italiana - Archivio Scienze Mediche ;143:789-810.

Fioravanti, M. and Yanagi, M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database.Syst.Rev. ;(2):CD. View abstract.

Fridman, E. A., Ottaviano, F., Fiol, M., Javelier, A., Perea, J. E., and Ameriso, S. F. [Neuroprotection in acute ischemic stroke. Practicability of guidelines for treatment]. Rev.Neurol. 5-1-;32(9):818-821. View abstract.

Iranmanesh, F. and Vakilian, A. Efficiency of citicoline in increasing muscular strength of patients with nontraumatic cerebral hemorrhage: a double-blind randomized clinical trial. J Stroke.Cerebrovasc.Dis. ;17(3):153-155. View abstract.

Kalisvaart, K. J., de Jonghe, J. F., Bogaards, M. J., Vreeswijk, R., Egberts, T. C., Burger, B. J., Eikelenboom, P., and van Gool, W. A. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am.Geriatr Soc ;53(10):-. View abstract.

León-Carrión J, Dominguez-Roldán JM, Murillo-Cabezas F, Dominguez-Morales MR, and Munoz-Sanchez MA. The role of citicholine in neuropsychological training after traumatic brain injury. NeuroRehabilitation ;14(1):33-40.

Liptzin B, Laki A, Garb, and et al. Donepezil in the Prevention and Treatment of Post-Surgical Delirium. American Journal of Geriatric Psychiatry ;13:-.

Lozano, Fernandez R. Efficacy and safety of oral CDP-choline. Drug surveillance study in cases. Arzneimittelforschung. ;33(7A):-. View abstract.

Lukas, S. E., Kouri, E. M., Rhee, C., Madrid, A., and Renshaw, P. F. Effects of short-term citicoline treatment on acute cocaine intoxication and cardiovascular effects. Psychopharmacology.(Berl.) ;157(2):163-167. View abstract.

Madariaga Aguirre L. A double-blind evaluation on a group of senile female patients, treated with CDP-choline. Revista de Psiquiatría y Psicología Médica ;13(5):331-342.

Marcantonio, E. R., Flacker, J. M., Wright, R. J., and Resnick, N. M. Reducing delirium after hip fracture: a randomized trial. J Am.Geriatr Soc ;49(5):516-522. View abstract.

Marti Masso, J. F. and Urtasun, M. Citicoline in the treatment of Parkinson's disease. Clin.Ther ;13(2):239-242. View abstract.

Motta L, Fichera G, Tiralosi G, and et al. CDP-choline in the treatment of chronic cerebrovasculopaties [La citicolina nel tratta mento delle cerebrovasculopatie croniche]. Unpublished Lederle (Cyanamid Italia) report. ;

Parisi, V., Coppola, G., Centofanti, M., Oddone, F., Angrisani, A. M., Ziccardi, L., Ricci, B., Quaranta, L., and Manni, G. Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog.Brain.Res ;173:541-554. View abstract.

Parisi, V., Coppola, G., Ziccardi, L., Gallinaro, G., and Falsini, B. Cytidine-5'-diphosphocholine (Citicoline): a pilot study in patients with non-arteritic ischaemic optic neuropathy. Eur.J Neurol. ;15(5):465-474. View abstract.

Parisi, V., Manni, G., Colacino, G., and Bucci, M. G. Cytidine-5'-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology. ;106(6):-. View abstract.

Pecori, Giraldi J., Virno, M., Covelli, G., Grechi, G., and De, Gregorio F. Therapeutic value of citicoline in the treatment of glaucoma (computerized and automated perimetric investigation). Int Ophthalmol. ;13(1-2):109-112. View abstract.

Petkov, V. D., Stancheva, S. L., Tocuschieva, L., and Petkov, V. V. Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicholine (experiments on rats). Gen.Pharmacol. ;21(1):71-75. View abstract.

Piccoli, F., Battistini, N., Carbonin, P., Curro, Dossi B., Fiori, L., La, Bella, V, Megna, G., Salvioli, G., and Fioravanti, M. CDP-choline in the treatment of chronic cerebrovasculopathies. Arch Gerontol Geriatr ;18(3):161-168. View abstract.

Radad K, Gille G, Xiaojing J, Durany N, and Rausch W-D. CDP-choline reduces dopaminergic cell loss induced by MPP-super(+) and glutamate in primary mesencephalic cell culture. International Journal of Neuroscience ;117(7):985-998.

Renshaw, P. F., Daniels, S., Lundahl, L. H., Rogers, V., and Lukas, S. E. Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report. Psychopharmacology.(Berl.) ;142(2):132-138. View abstract.

Rossi, M. and Zanardi, M. [An open study on the clinical efficacy of citicoline in patients with chronic cerebral vasculopathy]. Clin.Ter. ;142(2):141-144. View abstract.

Salvadorini F. Clinical evaluation of CDP-choline (Nicholin): Efficacy as antidepressant treatment. Therapeutic Research ;18(3):513-520.

Secades, J. J. and Lorenzo, J. L. Citicoline: pharmacological and clinical review, update. Methods.Find.Exp.Clin.Pharmacol. ;28 Suppl B:1-56. View abstract.

Secades, J. J., Alvarez-Sabin, J., Rubio, F., Lozano, R., Davalos, A., and Castillo, J. Citicoline in intracerebral haemorrhage: a double-blind, randomized, placebo-controlled, multi-centre pilot study. Cerebrovasc.Dis. ;21(5-6):380-385. View abstract.

Senin U and Fioravanti M. Clinical controlled study vs placebo of CDPcholine in a large group of aged patients with cerebrovascular dementia. Wyeth, Italy ;

Serra, F., Diaspri, G. P., Gasbarrini, A., Giancane, S., Rimondi, A., Tame, M. R., Sakellaridis, E., Bernardi, M., and Gasbarrini, G. [Effect of CDP-choline on senile mental deterioration. Multicenter experience on 237 cases]. Minerva Med. ;81(6):465-470. View abstract.

Siddiqi, N., Stockdale, R., Britton, A. M., and Holmes, J. Interventions for preventing delirium in hospitalised patients. Cochrane Database.Syst.Rev. ;(2):CD. View abstract.

Sinforiani E, Trucco M, Pacchetti C, and et al. Assessment of CDPcholine effects in patients with chronic cerebrovascular disease [Valutazione degli effetti della citicolina nella malattia cerebro-vascolare cronica]. Minerva Medica ;77(51):57.

Sinforiani, E., Trucco, M., Pacchetti, C., and Gualtieri, S. [Evaluation of the effects of citicoline in chronic cerebrovascular diseases]. Minerva Med 1-14-;77(1-2):51-57. View abstract.

Stramba-Badiale, M. and Scillieri, E. [Citicoline activity in senile mental decay]. Minerva Med 4-7-;74(14-15):819-821. View abstract.

Suryani L, Adnjana T, and Jensen G. Citicholine treatment of memory deficits in elderly people. International Journal of Geriatric Psychiatry ;3(3):235-236.

Tanaka, Y., Minematsu, K., Hirano, T., Hayashida, K., and Yamaguchi, T. [Effects of CDP-choline on dynamic changes in LCBF and cognitive function in demented subjects--an H2 15O-PET study]. Rinsho.Shinkeigaku. ;34(9):877-881. View abstract.

Trovarelli, G., de Medio, G. E., Dorman, R. V., Piccinin, G. L., Horrocks, L. A., and Porcellati, G. Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil. Neurochem.Res ;6(8):821-833. View abstract.

Virno, M., Pecori-Giraldi, J., Liguori, A., and De, Gregorio F. The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow-up). Acta Ophthalmol.Scand.Suppl ;(232):56-57. View abstract.

Warach, S., Pettigrew, L. C., Dashe, J. F., Pullicino, P., Lefkowitz, D. M., Sabounjian, L., Harnett, K., Schwiderski, U., and Gammans, R. Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators. Ann.Neurol. ;48(5):713-722. View abstract.

Xiong, Y., Liu, X., Wang, Y., and Du, Y. Cloning of cytidine triphosphate: phosphocholine cytidylyltransferase mRNA upregulated by a neuropeptide arginine-vasopressin((4-8)) in rat hippocampus. Neurosci.Lett. 4-7-;283(2):129-132. View abstract.

Yashima, K., Takamatsu, M., and Okuda, K. Intestinal absorption of cytidine diphosphate choline and its changes in the digestive tract. J Nutr Sci Vitaminol.(Tokyo) ;21(1):49-60. View abstract.

Adibhatla RM, Hatcher JF. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res ;73:308-15. View abstract.

Adibhatla RM, Hatcher JF. Citicoline mechanisms and clinical efficacy in cerebral ischemia. J Neurosci Res ;70:133-9. View abstract.

Aidelbaum R, Labelle A, Baddeley A, Knott V. Assessing the acute effects of CDP-choline on sensory gating in schizophrenia: a pilot study. J Psychopharmacol. ;32(5):541-51. View abstract.

Babb SM, Appelmans KE, Renshaw PF, et al. Differently effect of CDP-choline on brain cytosolic choline levels in younger and older subjects as measured by magnetic resonance spectroscopy. Psychopharmacology (Berl) ;127:88-94. View abstract.

Barrachina M, Dominguez I, Ambrosio S, et al. Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells. J Neurol Sci ;215:105-10. View abstract.

Brown ES, Todd JP, Hu LT, et al. A randomized, double-blind, placebo-controlled trial of citicoline for cocaine dependence in bipolar I disorder. Am J Psychiatry ;172(10):-21. View abstract.

Castagna A, Manzo C, Fabbo A, Lacava R, Ruberto C, Ruotolo G. The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer's Disease. Clin Drug Investig. Feb;41(2):177-182. View abstract.

Cinar E, Yuce B, Aslan F, Erbakan G. Neuroprotective effect of citicoline eye drops on corneal sensitivity after LASIK. J Refract Surg. Dec 1;35(12):764-770. View abstract.

Clark BC, Georgekutty J, Berul CI. Myocardial ischemia secondary to synthetic cannabinoid (K2) use in pediatric patients. J Pediatr ;167(3):757-61.e1. View abstract.

Cohen RA, Browndyke JN, Moser DJ, et al. Long-term citicoline (cytidine diphosphate choline) use in patients with vascular dementia: Neuroimaging and neuropsychological outcomes. Cerebrovasc Dis ;16:199-204. View abstract.

Conant R, Schauss AG. Therapeutic applications of citicoline for stroke and cognitive function in the elderly: A review of the literature. Altern Med Rev ;9:17-31. View abstract.

Cotroneo AM, Castagna A, Putignano S, et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging ;8:131-7. View abstract.

Dávalos A, Alvarez-Sabín J, Castillo J, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet ;380():349-57. View abstract.

Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicoline in acute ischemic stroke: An individual patient date pooling analysis of clinical trials. Stroke ;33:-7. View abstract.

Dempsey RJ, Raghavendra Rao VL. Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg ;98:867-73. View abstract.

El Sayed I, Zaki A, Fayed AM, Shehata GM, Abdelmonem S. A meta-analysis of the effect of different neuroprotective drugs in management of patients with traumatic brain injury. Neurosurg Rev ;41(2):427-38. View abstract.

Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev ;(2):CD. View abstract.

Fogagnolo P, Melardi E, Tranchina L, Rossetti L. Topical citicoline and vitamin B12 versus placebo in the treatment of diabetes-related corneal nerve damage: a randomized double-blind controlled trial. BMC Ophthalmol. Aug 1;20(1):315.View abstract.

Ghajar A, Gholamian F, Tabatabei-Motlagh M, et al. Citicoline (CDP-choline) add-on therapy to risperidone for treatment of negative symptoms in patients with stable schizophrenia: a double-blind, randomized placebo-controlled trial. Hum Psychopharmacol. ;33(4):e. View abstract.

Jeong H, Yoon S, Sung YH, et al. Effects of cytidine-5'-diphosphate choline on gray matter volumes in methamphetamine-dependent patients: A randomized, double-blind, placebo-controlled study. J Psychiatr Res ;143:215-221. View abstract.

Licata SC, Penetar DM, Ravichandran C, et al. Effects of daily treatment with citicoline: a double-blind, placebo-controlled study in cocaine-dependent volunteers. J Addict Med ;5(1):57-64. View abstract.

Loebis R, Zulkarnain BS, Siswanto FA. Effectiveness of citicoline in pediatric patients with refractive amblyopia in Surabaya, East Java, Indonesia. J Basic Clin Physiol Pharmacol ;32(4):657-661. View abstract.

Marino PF, Rossi GCM, Campagna G, et al. 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. Molecules. Nov 29;25(23):. View abstract.

For more information, please visit Citicoline Sodium And Stroke Prevention.

Martí-Carvajal AJ, Valli C, Martí-Amarista CE, et al. Citicoline for treating people with acute ischemic stroke. Cochrane Database Syst Rev. Aug 29;8:CD. View abstract.

Nakazaki E, Mah E, Sanoshy K, Citrolo D, Watanabe F. Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Nutr ;151(8):-. View abstract.

Ottobelli L, Manni GL, Centofanti M, et al. Citicoline oral solution in glaucoma: is there a role in slowing disease progression? Ophthalmologica ;229(4):219-26. View abstract.

Parisi V, Centofanti M, Ziccardi L, et al. Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma. Graefes Arch Clin Exp Ophthalmol ;253(8):-40. View abstract.

Parravano M, Scarinci F, Parisi V, et al. Citicoline and vitamin B12 eye drops in type 1 diabetes: Results of a 3-year pilot study evaluating morpho-functional retinal changes. Adv Ther. Apr;37(4):-. View abstract.

Pawar PV, Mumbare SS, Patil MS, Ramakrishnan S. Effectiveness of the addition of citicoline to patching in the treatment of amblyopia around visual maturity: a randomized controlled trial. Indian J Ophthalmol ;62(2):124-9. View abstract.

Rejdak R, Toczolowski J, Krukowski J, et al. Oral citicoline treatment improves visual pathway function in glaucoma. Med Sci Monit ;9:PI24-8. View abstract.

Roohi-Azizi M, Arabzadeh S, Amidfar M, et al. Citicoline combination therapy for major depressive disorder: a randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol ;40(1):1-5. View abstract.

Rossetti L, Iester M, Tranchina L, et al. Can treatment with citicoline eyedrops reduce progression in glaucoma? The results of a randomized placebo-controlled clinical trial. J Glaucoma. Jul;29(7):513-520. View abstract.

Salamah A, Mehrez M, Faheem A, El Amrousy D. Efficacy of Citicoline as a Neuroprotector in children with post cardiac arrest: a randomized controlled clinical trial. Eur J Pediatr. Apr;180(4):-. View abstract.

Savci V, Goktalay G, Cansev M, et al. Intravenously injected citicoline increases blood pressure and reverses hypotension in haemorrhagic shock: effect is mediated by central cholinergic activation. Eur J Pharmacol ;468:129-39. View abstract.

Secades JJ, Alvarez-Sabín J, Castillo J, et al. Citicoline for acute ischemic stroke: a systematic review and formal meta-analysis of randomized, double-blind, and placebo-controlled trials. J Stroke Cerebrovasc Dis ;25(8):-96. View abstract.

Shi PY, Zhou XC, Yin XX, Xu LL, Zhang XM, Bai HY. Early application of citicoline in the treatment of acute stroke: a meta-analysis of randomized controlled trials. J Huazhong Univ Sci Technolog Med Sci ;36(2):270-7. View abstract.

Sobrado M, Lopez MG, Carceller F, et al. Combined nipodimine and citicoline reduce infarct size, attenuate apoptosis, and increase BCL-2 expression after focal cerebral ischemia. Neuroscience ;118:107-13. View abstract.

Spiers PA, Myers D, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol ;53:441-8. View abstract.

Teather LA, Wurtman RJ. Dietary cytidine (5)-diphosphocholine supplementation protects against development of memory deficits in aging rats. Prog Neuropsychopharmacol Biol Psychiatry ;27:711&#;17. View abstract.

Trimmel H, Majdan M, Wodak A, Herzer G, Csomor D, Brazinova A. Citicoline in severe traumatic brain injury: indications for improved outcome: a retrospective matched pair analysis from 14 Austrian trauma centers. Wien Klin Wochenschr. ;130(1-2):37-44. View abstract.

Weiss GB. Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci ;56:637-60. View abstract.

Zemel MB, Thompson W, Milstead A, et al. Calcium and dairy acceleration of weight and fat loss during energy restriction in obese adults. Obes Res ;12:582&#;90. View abstract.

Zweifler RM. Membrane stabilizer: Citicoline. Curr Med Res Opin ;18:s14-s17. View abstract.

The timing of outcome measures indicates the approximate target for the review. It is based on the conventional timing used in the assessment of these outcomes.

Neurological function assessed with the National Institutes of Health Stroke Scale (NIHSS) ( Harrison ). We assessed this at the first 24 hours (acute phase), at 72 hours, and at discharge. See Appendix 3 for details.

Degree of disability or dependence in daily activities according to the modified Rankin scale (at 90 days) ( Harrison van Swieten ). See Appendix 1

Citicoline administered at any dose, by any route, and for any duration of treatment, versus no intervention, placebo, or other interventions. Since acute ischemic stroke requires a variety of medical treatments (that is, primary interventions), we considered citicoline as a supplementary intervention. Thus, for the purpose of this review, eligible RCTs were those that compared the same primary interventions with and without citicoline supplementation.

People (children or adults) with acute ischemic stroke, irrespective of etiology. We used clinical diagnosis with imaging as an eligibility criterion.

We included randomized controlled trials (RCTs) irrespective of publication status. We did not apply any limitation by language, country, or duration of follow&#;up. We only included parallel&#;design trials.

We screened the reference lists of relevant studies and use Cited Reference Search within Web of Science to identify further studies for potential inclusion in the review, and we contacted trialists and companies for further information.

In order to identify unpublished information submitted for the marketing approval of citicoline, we also searched the following sites.

With the assistance of the Cochrane Stroke Group's Information Specialist, we designed the search strategy in MEDLINE and adapted it to all other databases ( Appendix 5 ). We combined all search strategies deployed with subject strategy adaptations of the Highly Sensitive Search Strategy designed by Cochrane for identifying randomized controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Chapter 6: Lefebvre ).

See the methods for the Cochrane Stroke Group Specialised register. We searched for trials in all languages and arranged for translation of relevant articles where necessary.

Data collection and analysis

We conducted data collection and analysis of data according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins a; Higgins b).

Selection of studies

Two review authors (AMC, CV) independently screened titles and abstracts of the references obtained as a result of our searching activities, and excluded obviously irrelevant reports. We retrieved the full&#;text articles for the remaining references and, independently, two or more review authors (AMC, CV, IS) screened the full&#;text articles and identified studies for inclusion. They also identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreements through discussion or, if required, we consulted a third review author (JMF). We collated multiple reports of the same study so that each study, not each reference, was the unit of interest in the review. We recorded the selection process and completed a PRISMA flow diagram.

Data extraction and management

Two review authors (AMC, CV) independently extracted data from included studies. We developed an Excel spreadsheet based on the 'Data extraction template for included studies' from the Consumers and Communication Group resources for authors. We planned to describe the details of the intervention following recommendations from Hoffmann and Hoffmann .

Assessment of risk of bias in included studies

Two review authors (AMC, CV) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins c). We resolved any disagreements by discussion or by involving another review author (JMF, XB). We assessed the risk of bias according to the following domains.

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessment

• Incomplete outcome data

• Selective outcome reporting

• Other bias

We graded the risk of bias for each domain as high, low, or unclear and provide information from the study report together with a justification of our judgment in the 'Risk of bias' tables.

We included company funding, bias in the presentation of the data, design bias, measurements and confounding biases under 'Other bias'. See Porta for definitions of the examples of biases.

See Appendix 12 for details of domains.

Measures of treatment effect

For binary outcomes in this review, such as all&#;cause mortality and adverse events, we calculated the risk ratio (RR) with 95% confidence intervals (CIs).

For future updates we will follow this approach: for continuous outcomes, such as functional outcome, degree of disability or dependence in daily activities, and neurological, behavioral and cognitive function, we plan to calculate the mean difference (MD) with 95% CI. If ordinal data are reported, we will use a proportional odds model as a measure of treatment effect with Stata statistical software (STATA) (Bath : Deeks ; Scott ). If different scales are used for measuring the same outcome, for example quality of life, we plan to use the standardized mean difference (SMD) with 95% CI. We will also estimate ratio of means (RoM) with 95% CI from mean difference (Friedrich ). Due to practitioners' understanding and preferring dichotomous presentations of continuous outcomes, which they perceive to be the most useful (Johnston ), we will estimate odds ratios (OR) with 95% CI and the number needed to treat for an additional beneficial outcome (NNTB) from SMD with Furukawa's method (Furukawa ; Furukawa ).

As recommended in section 9.2.3.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins a), if necessary we will multiply the mean values from one set of studies by &#;1 to ensure that all the scales point in the same direction (Deeks ).

If statistical information is missing (such as standard deviations), we will try to extract them from other relevant information in the paper, such as P values and CIs.

We will calculate the NNTB if the RR was significant (P value < 0.05). NNTB is a measure of assessment of clinical useful of the consequences of treatment (Laupacis ). We will estimate NNTB with GraphPad software and with the Cochrane Stroke Group NNT calculator. If ordinal data are reported, we will estimate NNTB according to Bath .

Unit of analysis issues

The unit of analysis was participants. We excluded cluster RCTs.

As recommended in the Cochrane Handbook for Systematic Reviews of Interventions, we conducted the following plan to assess the outcomes with multiple observations.

• For primary outcomes (all&#;cause mortality and degree of disability or dependence in daily activities according to the modified Rankin scale) and secondary outcomes (adverse events, functional recovery and quality of life), we selected a single time point and analyzed only data at this time for trials in which it will be presented.

• Neurological function assessed with the National Institutes of Health Stroke Scale (secondary outcome): we planned to define different periods of follow&#;up (short&#;term, medium&#;term, and long&#;term follow&#;up) ( Deeks ), and perform separate analyses.

Dealing with missing data

We assessed the percentage of dropouts for each intervention group for each included trial, and evaluated whether an intention&#;to&#;treat (ITT) analysis was performed or could have been performed from the available published information. We contacted study authors to resolve any questions arising from this issue.

In order to undertake an ITT analysis, we sought data from the trial authors about the number of participants in treatment groups, irrespective of their compliance and whether or not they were later thought to be ineligible, otherwise excluded from treatment, or lost to follow&#;up. If this information was not forthcoming, we performed a 'per protocol' analysis of those who completed the study, being aware that it may be biased.

We included participants with incomplete or missing data in sensitivity analyses by imputing them according to the following scenarios (Hollis ).

• Extreme case analysis favoring the experimental intervention ('best&#;worse' case scenario): none of the drop&#;outs/participants lost from the experimental arm, but all of the drop&#;outs/participants lost from the control arm experienced the outcome, including all randomized participants in the denominator.

• Extreme case analysis favoring the control ('worst&#;best' case scenario): all drop&#;outs/participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomized participants in the denominator.

• Gamble&#;Hollis analysis, which takes account of the uncertainty and generates uncertainty intervals for a trial incorporating both sampling error and the potential impact of missing data ( Gamble ). This method increases the uncertainty of the trials using the results from the best&#;case and worst&#;case analyses ( Chaimani ).

Assessment of heterogeneity

We quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error (Higgins ). We had set an I² threshold greater than 60% to consider the presence of statistical heterogeneity (Deeks ).

Assessment of reporting biases

We did not identify 10 or more RCTs to conduct the assessment of reporting biases for any outcome. For the future update, therefore, we will use the contour&#;enhanced funnel plot to differentiate asymmetry that is due to publication bias from that due to other factors (Peters ). We will assess likelihood of publication bias with Harbord's and Peters' tests (Sterne ). We will use Stata statistical software to produce conventional and contour funnel plots (STATA).

GRADE and 'Summary of findings' table

We developed a 'Summary of findings' table with the following outcomes: all&#;cause mortality; degree of disability or dependence in daily activities on the modified Rankin scale; adverse events; functional recovery (Barthel Index); neurological function (National Institutes of Health Stroke Scale: NIHSS); and quality of life ( ). We assessed the quality of the evidence for each outcome according to GRADE domains (study limitations, consistency of effect, imprecision, indirectness and publication bias) (Atkins ). We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann a), and GRADEpro GDT software (GRADEpro GDT ). We justified all decisions to downgrade the quality of the evidence using footnotes, and we made comments to aid the reader's understanding of the review where necessary. We calculated the assumed control group risks using the median control group risk (Schünemann b).

Subgroup analysis and investigation of heterogeneity

We conducted the following subgroup analysis for primary outcomes if more than five trials were included.

• Trials supported by pharmaceutical companies versus trials without support by pharmaceutical companies.

• Trials with low risk of bias versus trials with high risk of bias.

• Trials with small sample size (&#; 200 participants) versus trials with large sample size (> 200 participants).

Due to lack of data, we were not able to conduct subgroup analysis with:

• participants with diabetes mellitus versus participants without diabetes mellitus;

• participants with high blood pressure versus participants without high blood pressure.

Sensitivity analysis

We performed sensitivity analysis for primary outcomes with Stata statistical software (STATA), in order to explore the influence of particular factors on the intervention effect size: 'best&#;worst case' scenario versus 'worst&#;best case' scenario and Gamble&#;Hollis analysis (Gamble ).

Bayes factors

We estimated the threshold for clinical relevance for primary outcomes through use of Bayes factors (Jakobsen ). The Bayes factor is a likelihood ratio that indicates the relative strength of evidence for two theories (Dienes ; Dienes Goodman ; Goodman ). The Bayes factor is a comparison of how well two hypotheses (the null hypothesis &#; H0; and the alternative hypothesis &#; H1) predict the data (Goodman ). The Bayes factor provides a continuous measure of evidence for H1 over H0. When the Bayes factor is 1, evidence is insensitive, and this means that the data are equally well predicted by both models and the evidence does not favor either model over the other (1 means the data are as well predicted by H1 as H0, so it should not be interpreted as favoring H0; rather the evidence does not point either way). As the Bayes factor increases above 1 (towards infinity) the evidence favors H1 over H0. As the Bayes factor decreases below 1 (towards 0) the evidence favors H0 over H1 (Dienes ; Dienes ; Dienes ).

Despite the use of Bayes factors, we based the conclusions of this Cochrane Review on the Review Manager 5 analysis (Review Manager ).

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