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Beyond neuroprotection:
neurorepair
When a stroke occurs,
what if besides protection...
it could be repaired?
PROVED NEUROPROTECTIVE PROPERTIES
STROKE, a catastrophic disease
	 Cerebrovascular disease is the second most frequent
cau...
PROVED EFFICACY IN STROKE
	 Recovery at
3 months was 25.2%
in citicoline-treated
patients and 20.2% in
placebo-treated pat...
A formal metaanalysis of trials of citicoline in acute and subacute ischemic stroke7
	 10 controlled trials enrolling 4420...
ENHANCES NEUROREPAIR IN STROKE RECOVERY
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Base
Functional evaluation score8
24 hours
Time (M...
Citicoline increases dendritic complexity11
	 Citicoline increases spine density11
ENHANCES NEUROREPAIR IN STROKE RECOVERY...
CAN IMPROVE POST-STROKE VASCULAR COGNITIVE IMPAIRMENT
	 Six months after stroke, 44% to 74% of patients present some
degre...
IS EFFECTIVE IN MILD VASCULAR
COGNITIVE IMPAIRMENT
MMSEc* Citicoline group n = 265 Controls n = 84 t p
T0 22.4 ± 4 21.5 ± ...
HAS A POSSITIVE EFFECT IN CHRONIC
CEREBRAL DISORDERS IN ELDERLY
In a Cochrane review based on 14 clinical trials, citicoli...
IS SAFE
In a drug surveillance study carried out in 4191 patients
with a diagnosis of Acute Ischemic Stroke (AIS), oral
ci...
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT SOMAZINA 1000 mg oral solution 2.
QUALITATIVE AND QUAN...
Stroke. Acute phase and its neurological sequelae
Traumatic brain injury and its neurological sequelae
Cognitive and behav...
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LA SOMAZINA Y SUS USOS...

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LA SOMAZINA Y SUS USOS...

  1. 1. Beyond neuroprotection: neurorepair When a stroke occurs, what if besides protection... it could be repaired?
  2. 2. PROVED NEUROPROTECTIVE PROPERTIES STROKE, a catastrophic disease Cerebrovascular disease is the second most frequent cause of mortality in the world1 1 in 6 people worldwide will have a stroke in their lifetime2 Restores the activity of mitochondrial ATPase and membrane Na+/K+ ATPase4 Inhibits activation of certain phospholipases4 Decreases the volume of ischemic lesion4 Accelerates reabsortion of cerebral edema4 Inhibits mechanisms of apoptosis4 Citicoline has demonstrated neuroprotective effects in acute stroke3 Citicoline acts in the ischemic cascade process4 :
  3. 3. PROVED EFFICACY IN STROKE Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (OR: 1.33; 95% CI: 1.10-1.62) The dose showing the largest difference with placebo was 2000 mg, with 27.9% of patients achieving recovery (OR: 1.38; 95% CI: 1.10-1.72) 0 30 60 90 PLACEBO C500 %infarctgrowthincrease C2000 Citicoline shows a dose-dependent reduction on infarct growth5 Citicoline increases the probability of complete recovery at 3 months in stroke patients6 Intent-to-Treat set: GEE-Estimated Probabilities of Global Recovery at week 12 Of Follow-Up Citicoline % Placebo % OR 95% CI P Citicoline vs. placebo (4 trials, 1.372 patients) 25.2 20.2 1.33 1.10-1.62 0.0034 Doses Citicoline 500 mg vs placebo Study 001a 27.7 11.4 2.98 1.25-7.02 0.0129 Study 007 24.2 16.6 1.61 0.93-2.78 0.0890 Study 010 17.1 24.0 0.65 0.28-1.48 0.3078 Overall 20.8 15.7 1.42 0.96-2.093 0.0782 Citicoline 1000 mg vs placebo Study 001a 9.1 10.7 0.84 0.35-2.15 0.7096 Citicoline 2000 mg vs placebo Study 001a 25.19 9.8 3.098 1.18-8.12 0.0214 Study 018 28.47 23.25 1.314 1.0-1.65 0.0183 Overall 27.9 21.9 1.38 1.10-1.72 0.0043 84.7 34 1.8 p<0.05
  4. 4. A formal metaanalysis of trials of citicoline in acute and subacute ischemic stroke7 10 controlled trials enrolling 4420 patients were identified7 Under the random-effects model, the meta-analysis shows an OR of 1,56 (95% CI, 1,12; 2,16) in favour of citicoline in the rates of death and disability, using as measure the mRS 0-27 PROVED EFFICACY IN STROKE Study Experimental Control Odds Ratio Events Total Events Total OR 95%-CI W(fixed) W(random) Boudouresques 1980 11 23 2 22 9.17 (1.73; 48.60) 0.2% 3.2% Goas 1980 16 31 8 33 3.33 (1.15; 9.65) 0.9% 6.4% Corso 1982 7 17 0 16 23.57 (1.21; 457.36) 0.1% 1.2% Tazaki 1988 68 136 35 136 2.89 (1.73; 4.81) 4.0% 13.0% USA 1 1997 80 193 22 64 1.35 (0.75; 2.44) 4.4% 11.8% USA 2 1999 116 267 50 127 1.18 (0.77; 1.82) 8.8% 14.3% USA 3 2000 20 52 19 48 0.95 (0.43; 2.13) 2.8% 8.9% USA 4 2001 185 452 156 446 1.29 (0.98; 1.69) 21.3% 16.8% Alviarez 2007 13 29 10 30 1.62 (0.57; 4.66) 1.2% 6.4% ICTUS 2012 329 1148 343 1150 0.95 (0.79; 1.13) 56.2% 17.9% Fixed effect model 2348 2072 1.20 (1.06; 1.36) 100% -- Random effects model 1.56 (1.12; 2.16) -- 100% Heterogeneity: I-squared = 72,1%, tau-squared = 0.149, p = 0.0002 0.01 0.1 1 10 100 Cumulative Meta-Analysis Added Study Confidence interval Boudouresques (1980) 9,167 (1,729, 48,596) Goas (1980) 4,469 (1,818, 10,987) Corso (1982) 5,277 (2,136, 13,041) Tazaki (1988) 3,562 (2,085, 6,084) USA 1 (1997) 2,928 (1,520, 5,640) USA 2 (1999) 2,337 (1,308, 4,174) USA 3 (2000) 2,011 (1,196, 3,383) USA 4 (2001) 1,762 (1,189, 2,612) Alviarez (2007) 1,733 (1,207, 2,940) ICTUS (2012) 1,556 (1,119, 2,162) 0.1 1 10 NEW EVIDENCE
  5. 5. ENHANCES NEUROREPAIR IN STROKE RECOVERY 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Base Functional evaluation score8 24 hours Time (MCAO) Scores(±SD) 14 days Infarct CDP choline * * Functional evaluation at baseline, 24 h and 14 days after pMCAO. All animals presented a 0 score at baseline. CDP-choline treatment significantly improved functional outcome compared with the Infarct group at 24 h and 14 days after stroke (p < 0.05 vs. Infarct). Image of Infarct group. Functional testing: (A) somatosensory recovery was assessed by the adhesive-tape removal test. Animals treated with citicoline showed enhanced somatosensory recovery compared with the control group. Note the significant improvement starting on Day 10 until Day 28 after ischemia. B, Motor recovery was assessed by the cylinder test. Note the significant improvement in motor function of the animals treated with citicoline compared to controls, starting on Day 21 until Day 28 after ischemia. (means_SEM; *P_0.05, Fisher protected least significant difference post hoc test after significant 2-way repeated-measures analysis of variance). A. adhesive tape removal test -1.00 -0.80 -0.60 -0.40 -0.20 0.00 Baseline Control Citicoline d1 d10 d21 d28 Recoveryindex * * * B. cylinder test Control Citicoline * * -0.40 -0.50 -0.30 -0.20 -0.10 0.00 0.10 Baseline d1 d10 d21 d28 Recoveryindex Treatment with CDP- Choline significantly improved functional recovery associated with a decrease in lesion volume by MRI and cell death in an experimental animal model8 Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells in an experimental animal model9 Citicoline enhances neuroregenerative processes after experimental stroke in rats10
  6. 6. Citicoline increases dendritic complexity11 Citicoline increases spine density11 ENHANCES NEUROREPAIR IN STROKE RECOVERY SPINE DENSITY Effect of a chronic treatment with CDP-choline on neuronal plasticity. CDP-choline (MCAO+CDP) and saline (MCAO+SAL) were administered 24 h after pMCAO and for 28 days. Neuronal plasticity was studied by determining dendritic morphology of layer V pyramidal cells in the undamaged motor cortex using a Golgi-Cox procedure). Data are mean ± S.E. M., n = 10: *p<0.05 vs. MCAO+SAL. Citicoline increases neuronal plasticity and contributes to sensorimotor function recovery after experimental stroke11 The administration of citicoline increases endothelial progenitor cells (EPC) concentration and improves functional recovery in patients with acute ischemic stroke12 C. Spine density 0.0 2.5 5.0 10.0 7.5 MCAO+SAL MCAO+CDP Numberofspines/10µm MCAO+SAL MCAO+CDP *
  7. 7. CAN IMPROVE POST-STROKE VASCULAR COGNITIVE IMPAIRMENT Six months after stroke, 44% to 74% of patients present some degree of cognitive disturbance13 Half of the patients with VCI have dementia develop within 5 years13 Citicoline treatment within 24 hours of stroke onset (2 g/day) for 6 weeks; followed by continuous treatment for up to 12 months (1 g/day) showed excellent tolerability, safety, and continued improvement in post-stroke vascular cognitive impairment (VCI), especially in temporal orientation, executive functions, and attention3 In a study with 347 patients13 Patients with cognitive sequelae from acute cerebral infarction may benefit from long-term citicoline treatment (1 g/day) and achieve better functional, cognitive, and neurological recovery13 10 10 10 10 10 10 1 month 1 month 1 month 1 month 1 month 1 month Atention, executive function Spatial perception Language Motor speed Memory Citicoline No citicoline Temporal orientation 6 months 6 months 6 months 6 months 6 months 6 months 12 months 12 months 12 months 12 months 12 months 12 months 20 20 20 20 20 20 30 30 30 30 30 30 40 40 40 40 40 40 50 50 50 50 50 50 60 60 60 60 60 60 70 70 70 70 70 70 % % % % % % * * * * Cognitive impairment in the 1st, 6th and 12th months evaluations in both treatment group. *p<0.05
  8. 8. IS EFFECTIVE IN MILD VASCULAR COGNITIVE IMPAIRMENT MMSEc* Citicoline group n = 265 Controls n = 84 t p T0 22.4 ± 4 21.5 ± 6.9 1.422 0.156 T1 22.7 ± 4 20.4 ± 6.6 3.728 0.0001 T2 22.9 ± 4 19.6 ± 6.3 5.437 0.0001 Comparison of corrected MMSE levels between citicoline group and controls. Notes: *MMSEc = MMSE corrected according to age and education. T0 = baseline; T1 = 3 months; T2 = 9 months. Abbreviations: MMSE, mini mental state examination; MMSEc, mini mental state examination corrected (for age and education). 21 17 19 21.2 18 19.5 21.4 19 20 21.8 21 21 22 22 21.5 22.2 23 22 22.4 24 22.5 22.6 23 22.4 22.9 22.7P=0.156 P=0.0001 P = 0.0001 21.5 19.6 20.4 21.6 20 20.5 Citicotine group Citicotine group Citicotine group MMSE T0 MMSE T2 MMSE T1 Control group Control group Control group ScoreScore Score MMSE Citicoline group MMSE controls T0-T1 T0-T2 T0-T1 T0-T2 t 0.863 1.439 1 1.792 p 0.388 0.151 0.319 0.075 Citicoline was effective and well tolerated in elderly patients with mild vascular cognitive impairment14 Prospective, multicenter study performed in 349 elderly patients with mild vascular cognitive impairment14 The active or citicoline group (265 patients) was treated with 1 g/day of citicoline during 9 months and compared with the control group (84 patients), who was not treated with citicoline14 At 9 months, the MMSE score in the treated group had a mild improvement of 0.5 on average, while the untreated group showed a decline of 1.914 NEW EVIDENCE: IDEALE Study14
  9. 9. HAS A POSSITIVE EFFECT IN CHRONIC CEREBRAL DISORDERS IN ELDERLY In a Cochrane review based on 14 clinical trials, citicoline has been shown to have a positive effect on memory, behaviour and clinical global impression15 Heterogeneity Tau2 = 0.11; Chi2 = 27.70, df = 9 (P = 0.001); 12 =68% Test for overall effect: Z = 2.74 (P = 0.0062) Comparison I CDP-choline vs. Placebo, Outcome 2 Memory Measures15 Study or subgroup CDP-choline Placebo Std. Mean Difference IV, Random, 95% CI Weight Std. Mean Difference IV, Random, 95% CIN Mean (SD) N Mean (SD) 1 Recall Production Alvarez 1999 12 0.33 (2.84) 16 -0.31 (2.04) 5.6 % 0.26 (-0.49,1.01) Barbagallo 1988 44 6.97 (25.45) 47 6.79 (23.06) 12.8 % 0.01 (-0.40,0.42) Bonavita 1983 20 1.45 (0.69) 20 0.3 (0.2) 5.0 % 2.22 (1.41,3.02) Capurso 1996 17 11.45 (31.5) 14 -5.21 (23.45) 6.0 % 0.58 (-0.15,1.30) Cohen 2003 15 -2.7 (5.4) 15 -4.6 (5.6) 6.0 % 0.34 (-039,1.06) Motta 1985 25 0.52 (2.09) 25 -0.2 (2.19) 8.8 % 0.33 (-0.23,0.89) Piccoli 1994 35 3.74 (10.78) 34 2.21 (10.8) 10.9 % 0.14 (-0.33,0.61) Senin 2003 216 3.87 (12.24) 221 2.07 (11.29) 22.6 % 0.15 (-0.04,0.34) Sinforiani 1986 26 0.7 (0.83) 32 0.16 (1.22) 9.5 % 0.50 (-0.03,1.03) Spiers 1996 46 3.16 (3.41) 44 2.76 (2.47) 12.7 % 0.13 (-0.28,0.55) Subtotal (95% CI) 456 468 100.0% 0.38 [0.11,0.65]
  10. 10. IS SAFE In a drug surveillance study carried out in 4191 patients with a diagnosis of Acute Ischemic Stroke (AIS), oral citicoline improved neurological, functional and global outcomes without significant safety concerns16 37 side effects were observed in 31 patients (0,73%)16 The most frequent findings were nervous system-related symptoms followed by gastrointestinal symptoms16 Citicoline shows a good safety profile
  11. 11. SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT SOMAZINA 1000 mg oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION SOMAZINA 1000 mg oral solution is supplied in sachets containing 10 ml of solution. Each ml contains100mg of citicoline (as sodium salt). Excipients: Per ml of solution: 0.005 mg of Ponceau 4-R red colour; 0.4 mg of propyl parahydroxybenzoate; 1.6 mg of methyl parahydroxybenzoate; 200 mg of sorbitol and other excipients in q.s. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Oral solution.SOMAZINA 1000 mg oral solution: Sachets containing 10 ml of a transparent and pink-colored liquid with strawberry smell and taste. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications • Stroke, Acute phase and its neurological sequela. • Traumatic Brain injury and its neurological sequela. • Cognitive and behavioral impairment secondary to chronic vascular and degenerative cerebral disorders. 4.2 Posology and method of administration Adults: The recommended dose is 1 or 2 sachets per day, depending on the severity of the symptoms to be treated. It may be taken directly or dissolved in half a glass of water (120 ml), with the meals or between them. See the instructions for preparation in section 6.6.Elderly: SOMAZINA does not need any specific dose adjustment for this age group. Children: The experience in children is limited; therefore it may only be administeredwhentheexpectedtherapeuticalbenefitishigherthananypossiblerisk. 4.3 Contraindications In case of allergy to Citicoline or any excipient It must not be administeredtopatientswithhypertoniaoftheparasympathetic.4.4SpecialWarnings and precautions for use Due to Ponceau 4-R red colour, it may cause allergic reactions. It may cause asthma, especially in patients with allergy to acetylsalicylic acid.Due to Sorbitol,patientswithrarehereditaryproblemsoffructoseintoleranceshouldnottake this medicine. Due to Propyl parahydroxybenzoate and Methyl parahydroxybenzoate it may cause allergic reactions (possibly delayed). 4.5 Interaction with other medicinal products and other forms of interaction Citicoline potentiates the effects of L-Dopa. It must not be administered in conjunction with medicines containing Meclofenoxate. 4.6 Pregnancy and lactation There are no adequate data from the use of Citicoline in pregnant women. SOMAZINA should not be used during pregnancy unless clearly necessary. That is, only when the expected therapeutic benefit is higher than any possible risk (see section 5.3). 4.7 Effects on the ability to drive and use machines SOMAZINAhasnoinfluenceontheabilitytodriveanduseofmachines.4.8Undesirable effects Very rare (<1/10,000) (include individual notifications) Psychiatric disorders: hallucinations Nervous system disorders: cephalea, vertigo Vascular disorders: arterial hypertension, arterial hypotension Respiratory, thoracic and mediastinal disorders: dyspnoea Gastrointestinal disorders: nausea, vomiting, occasional diarrhea Skin and subcutaneous tissue disorders: blush, hives, exanthemas, purple General disorders and administration site conditions: shiver, edema 4.9 Overdose No case of overdose has been reported 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Psychostimulants, agents used for Attention- Deficit Hyperactivity Disorder (ADHD) and nootropics. ATC code: N06BX06. Citicoline stimulates the biosynthesis of structural phospholipids of the neuronal membrane as it is demonstrated in the magnetic resonance spectroscopy studies. Citicoline, through this action, improves the function of the membrane mechanisms, such as the functioning of the ionic exchange pumps and receptors inserted in the latter, the modulation of which is indispensable in the neurotransmission. Citicoline due to its membrane stabilizing activity has properties which favor brain edema reabsorption. Experimental studies have shown that Citicoline inhibits the activation of some phospholipases (A1, A2, C and D), reducing the formation of free radicals, avoiding the destruction of membranous systems and preserving antioxidant defense systems as glutation. Citicoline preserves the neuronal energetic reserve, inhibits apoptosis and stimulates acetylcholine synthesis. It has been experimentally shown that Citicoline alsoexertsaprophylacticneuroprotectiveeffectinfocalbrainischemicmodels.Clinical trials have shown that Citicoline significantly increases the functional evolution of patients with acute ischemic cerebrovascular accident, coinciding with a lower growth of the brain ischemic injury in neuroimagen tests. In patients with craniocerebral traumatisms, citicoline speeds up their recuperation and reduces the duration and intensity of the post-concussional syndrome. Citicoline improves the level of attention and consciousness and acts favorably over amnesia and cognitive and neurological disorders associated to brain ischemia. 5.2 Pharmacokinetic properties Citicoline is well absorbed after oral, intramuscular or intravenous administration. Plasma choline levels significantly increase after the aforementioned routes. Oral absorption is nearly complete and its bioavailability is approximately the same as the intravenous route. The drug product is metabolized in the intestine and in the liver to choline and cytidine. The administered citicoline is widely distributed in brain structures, with a quickincorporationofthecholinefractioninstructuralphospholipidsandthecytidine fraction in cytidinic nucleotides and nucleic acids. Citicoline reaches the brain and it is actively incorporated to cellular, cytoplasmatic and mitochondrial membranes, taking part of the structural phospholipids fraction. Only a small amount of the dose appears in urine and feces (less than 3%). Approximately 12 % of the dose is eliminated via expired CO2. In the urinary excretion of the drug, two phases can be distinguished: a first phase, around 36 hours, where the excretion speed rapidly decreases, and a second phase where excretion speed decreases much slower. The same happens with expired CO2, the elimination speed rapidly decreases after approximately 15 hours and later it decreases much slower. 5.3 Preclinical safety data Oral and intraperitoneal chronictoxicitystudies(1.5g/kg/dayduring6monthsindogs)didnotshowsignificant abnormalities related with the administration of the drug. Intravenous administration of 300-500 mg/kg/day of citicoline during 3 months in dogs, only produced toxic signs immediately after the injection, such as occasional vomiting, diarrhea and hyper-salivation. 800 mg/kg of Citicoline was administered to albino rabbits during the organogenesis phase, from 7th to 18th gestation day. The animals were sacrificed the 29th day and a detailed exam of fetus and their mothers was carried out. No toxicity signs were observed neither maternal nor embryo-fetal. The effects over organogenesis were inappreciable, only 10 % of the treated fetus had a slight delay in brain osteogenesis. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sorbitol,Glycerol,Methylparahydroxybenzoate,Propylparahydroxybenzoate,Glycerol formal, Sodium citrate, Sodium saccharin, Ponceau 4-R red color, Strawberry essence, Potassium sorbate, Citric acid and Purified water. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store below 30º C. 6.5 Nature and contents of the container Carton box with 10 sachets containing 10 ml of solution each. 6.6 Special precautions for disposal and other handling It may be taken directly from the sachet or dissolved in half a glass of water (120 ml). 1. Lopez AD, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; May 27;367(9524):1747-57. 2. Seshadri S., Wolf P.A. Lifetime risk of stroke and dementia:current concepts, and estimates from the Framingham Study. The Lancet Neurology 2007; 6 (12), 1106-14. 3. Álvarez-Sabín J. et al. Citicoline in Vascular Cognitive Impairment and Vascular Dementia After Stroke. Stroke 2011; 42 (suppl 1): S 40-S43. 4. Secades J. Citicoline.Pharmacological and clinical review, 2010 update. Rev. Neurol 2011; 52 (Supl.2): S1-S62. 5. Warach S et al. Dose Dependent Reduction in Infarct Growth with Citicoline Treatment: Evidence of neuroprotection in Human. Stroke 2002; 33:354 (abstract). 6. Dávalos A. et al. Oral Citicoline in acute Ischemic Stroke: An individual patient data pooling Analysis of Clinical Trials. Stroke. 2002; 33: 2850-2857. 7. JJ Secades, J Delgadillo, N Oudovenko. “Role of citicoline on the treatment of ischemic stroke: a formal and cumulative meta-analysis”, 7th World Congress on Controversies in Neurology. Istanbul, Turkey (11-13 April 2013). 8. Gutiérrez-Fernández M et al. “CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke“ Neurochem Int. 2012 Feb;60(3):310-7. 9. Krupinski J et al. Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1. Vasc Cell. 2012 Dec 10;4(1):20. 10. Diederich K et al. Citicoline enhances neuroregenerative processes after experimental stroke in rats. Stroke. 2012 Jul;43(7):1931-40. 11. Hurtado O. et al. A chronic treatment with CDP-choline improves functional recovery and increases neuronal plasticity after experimental stroke. Neurobiology of Disease 26 (2007) 105-111. 12. Sobrino T et al. CDP-choline treatment increases circulating endothelial progenitor cells in acute ischemic stroke. Neurological Research. 2011; 33 (6): 572-577. 13. Alvarez-Sabín J. et al Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis. 2013;35(2):146-54. 14. Cotroneo AM et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging. 2013;8:131-7. 15. Fioravanti M, et al. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.The Cochrane Database of systematic reviews, Issue 3, 2009. 16. Cho HJ, Kim YJ.Efficacy and safety of oral citicoline in acute ischemic stroke: drug surveillance study in 4,191 cases. Methods Find Exp Clin Pharmacol.2009 Apr;31(3):171-6.
  12. 12. Stroke. Acute phase and its neurological sequelae Traumatic brain injury and its neurological sequelae Cognitive and behavioral impairment secondary to chronic vascular and degenerative cerebral disorders Acute phase: 2 g/day during 6 weeks Chronic Treatment: 0’5-1 g/ day Dosing: Therapeutic indications: Beyond neuroprotection: neurorepair

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