Neuroprotective and neuroregenerative drugs after severe traumatic brain injury : A narrative review from a clinical perspective.

Traumatic brain injuries cause enormous individual and socioeconomic burdens. Survivors frequently struggle with motor handicaps as well as impaired cognition and emotion. In addition to the primary mechanical brain damage, complex secondary mechanisms are the main drivers of functional impairment. Many of these pathophysiological mechanisms are now well known: excitotoxic amino acids, breakdown of the blood-brain barrier, neuroinflammation with subsequent damage to cell organelles and membranes, cerebral edema, and apoptotic processes triggering neuronal death; however, paracrine resilience factors may counteract these processes. Specific neuroprotective and neuroregenerative intensive care therapies are few. This review highlights medical approaches aimed at mitigating secondary damage and promoting neurotrophic processes in severe traumatic brain injury. Some pharmacologic attempts that appeared very promising in experimental settings have had disappointing clinical results (progesterone, cyclosporine A, ronopterin, erythropoietin, dexanabinol). Thus, the search for drugs that can effectively limit ongoing posttraumatic neurological damage is ongoing. Some medications appear to be beneficial: N­methyl-D-aspartate receptor (NMDA) antagonists (esketamine, amantadine, Mg++) reduce excitotoxicity and statins and cerebrolysin are known to counteract neuroinflammation. By supporting the impaired mitochondrial energy supply, oxidative processes are inhibited and neuroregenerative processes, such as neurogenesis, angiogenesis and synaptogenesis are promoted by citicoline and cerebrolysin. First clinical evidence shows an improvement in cognitive and thymopsychic outcomes, underlined by own clinical experience combining different therapeutic approaches. Accordingly, adjuvant treatment with neuroprotective substances appears to be a promising option, although more randomized prospective studies are still needed.

Role of Citicoline in the Management of Traumatic Brain Injury.

Head injury is among the most devastating types of injury, specifically called Traumatic Brain Injury (TBI). There is a need to diminish the morbidity related with TBI and to improve the outcome of patients suffering TBI. Among the improvements in the treatment of TBI, neuroprotection is one of the upcoming improvements. Citicoline has been used in the management of brain ischemia related disorders, such as TBI. Citicoline has biochemical, pharmacological, and pharmacokinetic characteristics that make it a potentially useful neuroprotective drug for the management of TBI. A short review of these characteristics is included in this paper. Moreover, a narrative review of almost all the published or communicated studies performed with this drug in the management of patients with head injury is included. Based on the results obtained in these clinical studies, it is possible to conclude that citicoline is able to accelerate the recovery of consciousness and to improve the outcome of this kind of patient, with an excellent safety profile. Thus, citicoline could have a potential role in the management of TBI.

Citicolina: revisión farmacológica y clínica, actualización 2016 / Citicoline: pharmacological and clinical review, 2016 update

Esta revisión se basa en la publicada en 2010 -Secades JJ. Citicolina: revisión farmacológica y clínica, actualización 2010. Rev Neurol 2011; 52 (Supl 2): S1-62- e incorpora 183 nuevas referencias aparecidas desde entonces, con lo que se organiza toda la información disponible para facilitar el acceso a dicha información en un único documento. La revisión se centra en las principales indicaciones del fármaco, como son los accidentes cerebrovasculares agudos y sus secuelas, incluyendo el deterioro cognitivo, y los traumatismos craneoencefálicos y sus secuelas. Se recogen los principales aspectos experimentales y clínicos en estas indicaciones (AU)

This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications (AU)

Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials.

BACKGROUND: Citicoline is a drug approved for the treatment of acute ischemic stroke. Although evidence of its efficacy has been reported, recently published results of a large placebo-controlled clinical trial did not show differences. This study aims to assess whether starting citicoline treatment within 14 days after stroke onset improves the outcome in patients with acute ischemic stroke, as compared with placebo. METHODS: A systematic search was performed to identify all published, unconfounded, randomized, double-blind, and placebo-controlled clinical trials of citicoline in acute ischemic stroke. RESULTS: Ten randomized clinical trials met our inclusion criteria. The administration of citicoline was associated with a significant higher rate of independence, independently of the method of evaluation used (odds ratio [OR] 1.56, 95% confidence interval [CI] = 1.12-2.16 under random effects; OR 1.20, 95% CI = 1.06-1.36 under fixed effects). After studying the cumulative meta-analysis, and with the results obtained with the subgroup of patients who were not treated with recombinant tissue plasminogen activator (rtPA) (OR 1.63, 95% CI = 1.18-2.24 under random effects; OR 1.42, 95% CI = 1.22-1.66 under fixed effects), our hypothesis of dilution of the effect of citicoline was confirmed. When we analyzed the effect of citicoline in patients who were not treated with rtPA and were receiving the highest dose of citicoline started in the first 24 hours after onset, based on more recent trials, there was no heterogeneity, and the size of the effect has an OR of 1.27 (95% CI = 1.05-1.53). CONCLUSIONS: This systematic review supports some benefits of citicoline in the treatment of acute ischemic stroke. But, on top of the best treatment available (rtPA), citicoline offers a limited benefit.

Metanálisis de estudios clínicos controlados sobre el tratamiento del traumatismo craneoencefálico / Meta-analysis of controlled clinical studies on treating cranioencephalic traumatism

La citicolina es un fármaco neuroprotector-neurorrestaurador que se utiliza en diversos países para el tratamiento de los traumatismos craneales. Tras la publicación del estudio COBRIT, muy controvertido metodológicamente, se ha visto cuestionado el uso de la citicolina en esta indicación, por lo que ha sido necesario realizar una revisión sistemática de cara a evaluar si realmente el tratamiento en fase aguda con citicolina supone algún beneficio al paciente afectado de una lesión cerebral traumática. Métodos: Se realizó una búsqueda sistemática en Medline, En base y la base de datos del Grupo Ferrer para identificar todos los estudios comparativos con citicolina en esta indicación. Resultados: Se encontraron 12 estudios válidos para su inclusión en el metanálisis, con 2 706 pacientes tratados en la fase aguda. Bajo el modelo de efectos aleatorios, el metanálisis demuestra que el uso de citicolina se asocia con una mejor tasa de independencia, valorada con la escala de recuperación de Glasgow o equivalente,con un odds ratio (OR) de 1.815 (IC 95%: 1.302-2.530). Con el uso de la técnica del metanálisis acumulado se pone de manifiesto que el efecto del tratamiento con citicolina se ha podido ir diluyendo a lo largo del tiempo, en paralelo con las mejorías adquiridas en el tratamiento basal estándar de este tipo de pacientes. Conclusión: El metanálisis formal de citicolina para el traumatismo craneo encefálico demuestra un efecto beneficioso del tratamiento, sin que haya que considerar problemas de seguridad asociados...

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial).

BACKGROUND: Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS: We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS: 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION: Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING: Ferrer Grupo.

Posible papel de la citicolina en la rehabilitación tras un ictus: revisión de la bibliografía / Probably role of citicoline in stroke rehabilitation: review of the literature

El ictus es una de las causas más importantes de muerte y la causa principal de incapacidad grave y duradera en adultos. Tras el tratamiento durante la fase aguda de la enfermedad, persiste la necesidad de continuar el tratamiento de los pacientes durante la fase de rehabilitación, de cara a mejorar la recuperación y las actividades de la vida diaria. Éste es el papel de los programas de rehabilitación. La rehabilitación se centra e incrementar la plasticidad cerebral con el fin de recuperar algunas de las funciones perdidas o disminuidas basándose en diferentes metodologías, que incluyen el tratamiento farmacológico. En este contexto, se revisa el posible papel que pudiera desempeñar la citicolina en la rehabilitación de pacientes afectos de un ictus (AU)

Stroke is a leading cause of mortality and the main cause of severe and long-term disability in adults. Following treatment during the acute phase, there is a need to continue the treatment of the patients in the rehabilitation phase, in order to improve the outcome and daily life activities. This is the role of rehabilitation programs. Rehabilitation is focused on increasing brain plasticity to recover some of the lost functions, based on different methodologies, including pharmacotherapy. In this context, the role of citicoline in the rehabilitation of patients with stroke is reviewed (AU)

Probably role of citicoline in stroke rehabilitation: review of the literature.

Stroke is a leading cause of mortality and the main cause of severe and long-term disability in adults. Following treatment during the acute phase, there is a need to continue the treatment of the patients in the rehabilitation phase, in order to improve the outcome and daily life activities. This is the role of rehabilitation programs. Rehabilitation is focused on increasing brain plasticity to recover some of the lost functions, based on different methodologies, including pharmaco-therapy. In this context, the role of citicoline in the rehabilitation of patients with stroke is reviewed.

Boosting the chances to improve stroke treatment.

BACKGROUND AND PURPOSE: There is a lack of agreement regarding measuring the effects of stroke treatment in clinical trials, which often relies on the dichotomized value of 1 outcome scale. Alternative analyses consist mainly of 2 strategies: use all the information from an ordinal scale and combine information from several outcome scales in a single estimate. METHODS: We reanalyzed 3 outcome scales that assessed patient recovery (modified Rankin Scale, National Institutes of Health Stroke Scale, and Barthel Index). With data collected from the 1652 patients in the Citicoline pooling data analysis, we used 2 standard techniques of exploratory multivariate analysis to analyze the distances among ranks and to isolate the common and the unique information provided by each of the 3 scales. RESULTS: The different scale values correspond to gradually different patient status, confirming that information is lost when a scale is collapsed to just 2 values, whether recovered or not. The scales shared 90.7% (95% CI, 84.5-96.9) of their information, with no individual scale contributing unique information. CONCLUSIONS: Salient stroke outcome information is lost when an ordinal scale is collapsed into fewer categories. In contrast, the full scales provide a comprehensive patient outcome estimate. Furthermore, in the context of stroke clinical trials, those scales are highly correlated, providing the rationale to pool them into a single estimate. These insights may be used to optimize the analysis of stroke trials to increase study power to detect efficacious interventions.

Evaluation of a sequential global test of improved recovery following stroke as applied to the ICTUS trial of citicoline.

The International Citicoline Trial in acUte Stroke is a sequential phase III study of the use of the drug citicoline in the treatment of acute ischaemic stroke, which was initiated in 2006 in 56 treatment centres. The primary objective of the trial is to demonstrate improved recovery of patients randomized to citicoline relative to those randomized to placebo after 12 weeks of follow-up. The primary analysis will take the form of a global test combining the dichotomized results of assessments on three well-established scales: the Barthel Index, the modified Rankin scale and the National Institutes of Health Stroke Scale. This approach was previously used in the analysis of the influential National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator in stroke.The purpose of this paper is to describe how this trial was designed, and in particular how the simultaneous objectives of taking into account three assessment scales, performing a series of interim analyses and conducting treatment allocation and adjusting the analyses to account for prognostic factors, including more than 50 treatment centres, were addressed.

Cost-effectiveness of citicoline versus conventional treatment in acute ischemic stroke.

In the framework of an integral assessment (effectiveness and cost) of the use of neuroprotection in stroke, a cost-effectiveness study was conducted to compare the potential advantages of citicoline with conventional therapy (without neuroprotection or placebo) in patients with acute ischemic stroke. The literature was searched for systematic reviews and meta-analyses evaluating the effectiveness of citicoline versus placebo in the hospital setting and during 12 weeks after discharge from hospital. Data on the use of resources were obtained from a panel of experts of four acute-care teaching hospitals in Spain. The study was performed from the perspective of the Spanish National Health System. Two meta-analyses were included (Cochrane Stroke Review Group and a pooling analysis). Treatment with citicoline resulted in 99 or 50 more patients recovered per 1000 patients treated (depending on selection criteria of the Cochrane study and the pooled analysis), with average cost savings between euro101.2 and euro126.4 per patient treated of the type of those included in the Cochrane study. In patients with acute ischemic stroke, treatment with placebo was more expensive and less effective in the scenarios of inpatient care and inpatient plus outpatient care after discharge from the hospital.

Citicoline: pharmacological and clinical review, 2006 update.

Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head trauma (HT) of varying severity, and cognitive disorders of different causes. In studies conducted in the treatment of patients with HT, citicoline was able to accelerate recovery from post-traumatic coma and neurological deficits, achieving an improved final functional outcome, and to shorten hospital stay in these patients. Citicoline also improved the mnesic and cognitive disorders seen after HT of minor severity that constitute the so-called post-concussional syndrome. In the treatment of patients with acute ischemic cerebral vascular disease, citicoline accelerates recovery of consciousness and motor deficit, achieves a better final outcome, and facilitates rehabilitation of these patients. The other major indication of citicoline is for treatment of senile cognitive impairment, either secondary to degenerative diseases (e.g. Alzheimer disease) or to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, citicoline improves scores in cognitive rating scales, while in patients with senile dementia of the Alzheimer type it stops the course of disease, and neuroendocrine, neuroimmunomodulatory, and neurophysiological benefits have been reported. Citicoline has also been shown to be effective in Parkinson disease, drug addictions, and alcoholism, as well as in amblyopia and glaucoma. No serious side effects have occurred in any series of patients treated with citicoline, which attests to the safety of treatment with citicoline.

Citicoline in intracerebral haemorrhage: a double-blind, randomized, placebo-controlled, multi-centre pilot study.

BACKGROUND: In experimental models citicoline has shown beneficial effects in intracerebral haemorrhage. Citicoline is a neuroprotectant drug with some beneficial effects in human ischaemic stroke and with an excellent safety profile. We decided to carry out a pilot study to test its safety and efficacy in human intracerebral haemorrhaging. METHODS: In this double-blind, placebo-controlled pilot study, patients had to be previously independent, aged between 40 and 85 years, and had to be admitted within 6 h after onset of symptoms of an acute primary supratentorial hemispheric cerebral haemorrhage diagnosed by neuroimaging (CT or MRI). Baseline severity was defined as patients with a score larger than 8 points on the Glasgow Coma Scale and larger than 7 on the National Institutes of Health Stroke Scale. Patients received either a placebo or 1 g/12 h citicoline for 2 weeks (orally or intravenously). The primary aim was to evaluate safety with respect to the number of adverse events that occurred. The efficacy endpoint was the percentage of patients with a modified Rankin Score (mRS) at 3 months. RESULTS: 19 patients in each group were included in the study. The incidence of serious adverse events was not different among groups (4 patients in each group). One patient in the placebo group was categorised as independent (mRS

Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport.

BACKGROUND AND PURPOSE: Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine, has shown beneficial effects in a number of CNS injury models including cerebral ischemia. Citicoline is the only neuroprotectant that has proved efficacy in patients with moderate to severe stroke. However, the precise mechanism by which citicoline is neuroprotective is not fully known. The present study was designed to search for mechanisms of citicoline neuroprotective properties using in vivo and in vitro models of brain ischemia. METHODS: Focal brain ischemia was produced in male adult Fischer rats by occluding both the common carotid and middle cerebral arteries. Brain glutamate levels were determined at fixed intervals after occlusion. Animals were then sacrificed, and infarct volume and brain ATP levels were measured. As in vitro model of ischemia, rat cultured cortical neurones or astrocytes, isolated or in co-culture, were exposed to oxygen-glucose deprivation (OGD) either in the absence or in the presence of citicoline (1-100 microM). Viability was studied by measuring LDH release. Glutamate release and uptake, and ATP levels were also determined. RESULTS: Citicoline (0.5, 1 and 2 g/kg i.p. administered 1 h before the occlusion) produced a reduction of the infarct size measured at striatum (18, 27 and 42% inhibition, respectively, n = 8, P < 0.05 vs. ischemia), effect that correlated with the inhibition caused by citicoline on ischemia-induced increase in glutamate concentrations after the onset of the ischemia. Citicoline also inhibited ischemia-induced decrease in cortical and striatal ATP levels. Incubation of cultured rat cortical neurones with citicoline (10 and 100 microM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 microM) caused an increase in glutamate uptake and in EAAT2 glutamate transporter membrane expression in cultured rat astrocytes. CONCLUSIONS: Our present findings show novel mechanisms for the neuroprotective effects of citicoline, which cooperate to decrease brain glutamate release after ischemia.

Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials.

BACKGROUND AND PURPOSE: No single neuroprotective agent has been shown to influence outcome after acute stroke. Citicoline has been studied worldwide in many clinical trials with positive findings, but only 1 trial has obtained significant results in the primary efficacy variables. Our objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials. The primary efficacy end point chosen was the common evaluation of recovery, combining National Institutes of Health Stroke Scale /=95 at 3 months using the generalized estimating equations analysis. METHODS: A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic databases) was undertaken. Individual patient data were extracted from each study and pooled in a single data file. The main inclusion criteria included compatible neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale >/=8, and prior modified Rankin Scale score