Rafael Lozano

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 ≤1, modified Rankin Scale score ≤1, and Barthel Index ≥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 ≤1. Four clinical trials using various doses of oral citicoline (500, 1000, and 2000 mg) were identified. Results— Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62;P =0.0034). 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 to 1.72;P =0.0043). The overall safety of citicoline was similar to placebo. Conclusions— Treatment with oral citicoline within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months.

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 ≤ 2) in comparison with 5 patients in the citicoline group (OR, 5.38; 95% CI, 0.55–52). Conclusions: Citicoline seems to be a safe drug in human intracerebral haemorrhage with a positive trend regarding efficacy. These data should be confirmed in a larger trial.

CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons

Cytidine 5′-diphosphocholine (CDP-choline) has been shown to reduce neuronal degeneration induced in central nervous system (CNS) injury. However, the precise mechanism underlying the neuroprotective properties of this molecule is still unknown. Excitotoxicity causes cell death in CNS injury (trauma or ischemia) and has also been involved in neurodegenerative diseases. We have examined whether CDP-choline prevents glutamate-mediated cell death, determined by trypan blue exclusion and lactate dehydrogenase activity assays. Pretreatment of rat cerebellar granule cells (CGCs) with CDP-choline causes a dose- and time-dependent reduction of glutamate-induced excitotoxicity. Cell death is prevented >50% when 100 µM CDP-choline is added 6 d before the glutamate excitotoxic insult but less than 20% when added concomitantly with glutamate. Pretreatment of CGCs with CDP-choline reduces almost completely (>80%) the number of apoptotic cells analyzed by flow cytometry, suggesting that CDP-choline exerts a neuroprotective effect by inhibiting the apoptotic pathway induced by glutamate.

A Method to Select an Instrument for Measurement of HR-QOL for Cross-Cultural Adaptation Applied to Dermatology

AbstractObjective: The objective of this study was to develop a process to obtain an instrument to measure dermatology specific health-related quality of life (HRQOL), and to adapt it into another culture, namely the Spanish-speaking community Design and Setting: By consensus, a multi-disciplinary team determined the qualities of an ‘ideal’ questionnaire as follows: need (absence of any such instrument), utility, multi-dimensionality, psychometric development, simplicity, high degree of standardisation, and accessibility.A bibliographic search was conducted on Medline, EMBASE and IME (Spanish Medical Index), using ‘dermatology’ and ‘quality of life’ as the key words, from January 1990 through to September 1997, supplemented by a second level reference search, to identify the instruments already in existence. Rather than develop a questionnaire ex novo, it was decided to make a cultural adaptation of an existing one. The questionnaires identified in the literature search were classified according to their generic or specific scope and it was decided to adapt a dermatology specific instrument. To select and compare the instruments, a model was developed which would provide an Adaptation Index (ADAPT), which includes the degree of development of psychometric properties, the formal design and the degree of standardisation at a given moment in time. Results: Six dermatology specific scales were identified: Impact of Skin Disease Scale (IMPACT), Dermatology Life Quality Index (DLQI), Skindex, Dermatology Quality-of-Life Scales (DQOLS), Dermatology Specific Quality of Life (DSQL) and Qualita di Vita Italiana in Dermatologia (QUAVIDERM). The ADAPT Index for each of the above was determined at the time of the study and the DLQI was chosen for adaptation (ADAPT = 77, October 1997). Results: Six dermatology specific scales were identified: Impact of Skin Disease Scale (IMPACT), Dermatology Life Quality Index (DLQI), Skindex, Dermatology Quality-of-Life Scales (DQOLS), Dermatology Specific Quality of Life (DSQL) and Qualita di Vita Italiana in Dermatologia (QUAVIDERM). The ADAPT Index for each of the above was determined at the time of the study and the DLQI was chosen for adaptation (ADAPT = 77, October 1997). Conclusions: The study showed the utility of ADAPT Index to assist in the selection process of the questionnaire to adapt. The results of the analysis indicate that in order to introduce and systematically use dermatology specific HR-QOL instruments, the indices require consolidation and improvement. There is a special need for an effort to be made in developing transculturally equivalent instruments suitable for international research.

Citicoline increases glutathione redox ratio and reduces caspase-3 activation and cell death in staurosporine-treated SH-SY5Y human neuroblastoma cells

Citicoline, or CDP-choline, is an essential endogenous intermediate in the biosynthesis of phosphatidylcholine that may act as a neuroprotector in several models of neurodegeneration. The present study analyses the effects of citicoline in the paradigm of staurosporine-induced cell death in human SH-SY5Y neuroblastoma cells. Citicoline reduces apoptosis induced by 100 nM staurosporine for 12 h in SH-SY5Y cells. This effect is higher with pre-treatment of 60 mM citicoline for 24 h after staurosporine challenge. Moreover, citicoline treatment restores glutathione redox ratio diminished after staurosporine challenge. Finally, citicoline also reduces the expression levels of active caspase-3 and specific PARP-cleaved products of 89 kDa resulting from staurosporine exposure when citicoline is added to the culture medium 24 h before staurosporine. These findings demonstrate that citicoline affects the staurosporine-induced apoptosis cell-signalling pathway by interacting with the glutathione system and by inhibiting caspase-3 in SH-SY5Y human neuroblastoma cells.

Prednicarbate versus fluocortin for inflammatory dermatoses. A cost-effectiveness study.

SummaryThe purpose of this study was to compare, from a societal perspective, the cost effectiveness of topical prednicarbate 0.25% and fluocortin 0.75% in the treatment of inflammatory dermatoses, such as dermatitis and eczema, in Spain.Effectiveness and tolerability were determined by means of a meta-analysis of 17 randomised double-blind controlled clinical trials, using a MEDLINE search and a second-level reference search. The data were obtained on the basis of a per-protocol assessment system, and the Mantel-Haenszel method (as modified by Peto) was used to make the statistical analysis.In terms of economic assessment, a model was developed in which the expected total cost was determined by the cost of the medicine (adjusted to the recommended dosage) plus the costs derived from the ineffectiveness and/or adverse effects associated with the different treatments. A sensitivity analysis was carried out on the basis of changes in: (i) clinical effectiveness; (ii) price of prednicarbate; (iii) incidence of adverse reactions; (iv) costs associated with ineffectiveness and/or adverse effects; and (v) the regimen under which prednicarbate was administered.The meta-analysis showed that there was a statistically significant difference between the 2 alternatives (p = 0.001). The value of a combined odds ratio [and 95% confidence interval (95% CI)] for the combined studies of prednicarbate was 1.54 (95% CI 1.10 to 2.15), compared with 0.73 (95% CI 0.60 to 0.89) for fluocortin relative to moderate or moderate-to-high potency corticosteroids. Effectiveness was 84.9% for prednicarbate and 69.7% for fluocortin, while frequency of adverse effects was 3.5% for prednicarbate and 4.9% for fluocortin.The total expected cost per patient treated was found to be 4600 Spanish pesetas (Pta) [

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

US37.10; 1996 values] for prednicarbate and Pta5778 (

Adaptación transcultural al español del cuestionario Dermatology Life Quality Index (DLQI): El Índice de Calidad de Vida en Dermatología

US46.60; 1996 values) for fluocortin. The total expected cost per patient successfully treated was Pta5608 (

Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells

US45.20) for prednicarbate and Pta8680 (

Use of CDP-choline for the prophylactic treatment of cerebral ischemia

US70) for fluocortin.Prednicarbate has been shown to have a favourable cost-effectiveness ratio, when compared with fluocortin, for the treatment of dermatitis and eczema in Spain. Additional pharmacoeconomic studies on topical corticosteroids are required, including the use of new variables, long term analysis and/or the measurements of the effect of the drug on patients’ quality of life.