The etiology of Alzheimer's disease (AD) remains unclear. The emerging view is that cerebrovascular dysfunction is a feature not only of cerebrovascular diseases, such as stroke, but also of neurodegenerative conditions, such as AD. In AD, there is impaired structure and function of cerebral blood vessels and cells in the neurovascular unit. These effects are mediated by vascular oxidative stress. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier and reduces the brain's repair capacity. Such injury can exacerbate the cognitive dysfunction exerted by incident ischemia and coexisting neurodegeneration. This article summarises data regarding cardiovascular risk factors, vascular abnormalities and brain endothelial damage in AD. In view of accumulating evidence of vascular pathology in AD, we also review the literature (MEDLINE, EMBASE) for clinical evidence of impaired endothelial function in AD. A total of 15 articles investigating endothelial dysfunction in AD were identified. 10 of these articles showed impaired endothelial function in AD patients. The current literature suggests endothelial dysfunction may be involved in the pathogenesis of AD. This aspect of AD pathology is particularly interesting in view of its potential for therapeutic intervention. Future research on endothelial function in AD should concentrate on population-based analysis and combine multiple methods to evaluate endothelial function.

ANTECEDENTES: La nicotina es un agonista colinérgico que también posee un efecto presináptico de liberación de acetilcolina. Se ha demostrado que la misma invierte los déficits de la memoria espacial producidos en las ratas por lesiones en el núcleo septal medial del cerebro, y en los monos ancianos, la administración de nicotina mejora la memoria y el alerta a los estímulos visuales. Estudios observacionales sugirieron un efecto protector del hábito de fumar contra la enfermedad de Alzheimer, pero en estudios recientes se cuestionó este hecho. El tabaco es un factor de riesgo para el accidente cerebrovascular y posiblemente también para la demencia vascular. Dado que la nicotina tiene efectos adversos es importante realizar una revisión sistemática para evaluar su eficacia y seguridad clínica en las personas con enfermedad de Alzheimer. OBJETIVOS: Evaluar la eficacia y seguridad de la nicotina, administrada por cualquier vía o forma, para las personas con enfermedad de Alzheimer. ESTRATEGIA DE BÚSQUEDA: Los ensayos se identificaron a partir de una búsqueda actualizada recientemente del Registro Especializado del Grupo Cochrane de Demencia y Trastornos Cognitivos (Cochrane Dementia and Cognitive Improvement Group) el día 12 de febrero de 2003 mediante el término "nicotine". Este Registro se actualiza regularmente con registros de las principales bases de datos de asistencia sanitaria (MEDLINE, Embase, Cinahl, PsychInfo) y varias bases de datos de ensayos. CRITERIOS DE SELECCIÓN: Todos los ensayos doble ciego, aleatorios, sin factores de confusión en los cuales se administró tratamiento con parches de nicotina o nicotina por vía intravenosa o por cualquier otra vía o forma, durante más de un día y en comparación con placebo para las personas con enfermedad de Alzheimer. RECOPILACIÓN Y ANÁLISIS DE DATOS: El único ensayo incluido no presentó resultados adecuados para la inclusión en la revisión. RESULTADOS PRINCIPALES: No hubo resultados disponibles del único estudio incluido. CONCLUSIONES DE LOS AUTORES: Esta revisión no puede proporcionar pruebas acerca de que la nicotina sea un tratamiento útil para la enfermedad de Alzheimer.

BACKGROUND: Current treatments for Alzheimer's disease (AD) provide modest symptomatic relief but do not slow the progression of the disease. Latrepirdine may modulate several targets involved in AD pathology, including lipid peroxidation, mitochondrial permeability, voltage-gated calcium ion channels as well as neurotransmitter receptor activity, and thus potentially represents both a symptomatic and disease-modifying intervention. Several randomized, placebo-controlled trials have sought to evaluate the effect of latrepirdine on cognition, function and behaviour in patients with AD. OBJECTIVES: To evaluate the efficacy and safety of latrepirdine for the treatment of AD. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 4 June 2014 using the terms: latrepirdine OR dimebon OR dimebolin OR 2,3,4,5-tetrahydro-2,8-dimethyl-5- (2-(6-methyl-3-pyridyl)ethyl)-1H-pyrido(4,3-b)indole. SELECTION CRITERIA: We included all randomized, double-blind, placebo-controlled trials where latrepirdine was administered to patients with mild, moderate or severe AD. DATA COLLECTION AND ANALYSIS: We assessed the quality of studies and two authors extracted data. We calculated mean difference (MD), risk ratio (RR) and 95% confidence interval (CI) on an intention-to-treat (ITT) basis for all relevant outcome measures. MAIN RESULTS: Seven trials involving a total of 1697 participants were found and six were included in the quantitative analyses. No data were available from the seventh trial. Three trials involving 1243 patients were included in analyses of efficacy outcomes, and four trials involving 1034 patients were included in analyses of safety and tolerability outcomes. We judged five trials to be at high risk of bias due to selective outcome reporting and three to be at high risk of attrition bias. There was low quality evidence favouring latrepirdine on the Clinician's Interview - Based Impression of Change Plus Caregiver Input after 26 weeks (CIBIC-Plus) (MD -0.60, 95% CI -0.89 to -0.31, 1 study, P < 0.001). Due to imprecision in the results, it was not possible to determine whether latrepirdine had any effect on cognition measured with the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog) (MD -1.49, 95% CI -3.47 to 0.49, 3 studies, P = 0.14) or the Mini-Mental State Examination (MMSE) (MD 0.59, 95% CI -0.94 to 2.11, 3 studies, P = 0.45), or on function measured with the Alzheimer's Disease Co-operative Study - Activities of Daily Living scale (ADCS-ADL) (MD 1.00, 95% CI -1.15 to 3.15, 3 studies, P = 0.36) at study endpoint (26 or 52 weeks). We considered the evidence provided on these outcomes to be of overall low quality. However, there was some high quality evidence showing a very small benefit of latrepirdine on the Neuropsychiatric Inventory (NPI) (MD -1.77, 95% CI -3.09 to -0.45, 3 studies, P = 0.009) at study endpoint (26 or 52 weeks). Additionally, moderate quality evidence suggested that latrepirdine and placebo were comparable in adverse events (RR 1.03, 95% CI 0.93 to 1.14, P = 0.51), serious adverse events (RR 0.86, 95% CI 0.55 to 1.35, P = 0.52), dropouts (RR 0.91, 95% CI 0.65 to 1.27, P = 0.57) and dropouts due to adverse events (RR 0.98, 95% CI 0.57 to 1.67, P = 0.93). AUTHORS' CONCLUSIONS: Our meta-analysis is limited by the small number of studies, imprecision, inconsistencies between studies and likelihood of bias. Nevertheless, the evidence to date suggests that while not associated with an increased risk of adverse events compared with placebo, there is no effect of latrepirdine on cognition and function in mild-to-moderate AD patients, though there appears to be a modest benefit for behaviour. Further studies should investigate the potential benefit of latrepirdine on neuropsychiatric symptoms in AD.

BACKGROUND: Metrifonate is a long-acting irreversible cholinesterase inhibitor, originally used to treat schistosomiasis. Its potential to enhance central nervous system cholinergic neurotransmission led to clinical trials for the treatment of people with Alzheimer's disease (AD). Although low incidence of serious side effects occurred during short-term use as an antihelmintic, in studies of the treatment of AD extending over six months, 20 patients experienced respiratory paralysis and problems with neuromuscular transmission. These findings have led to a halt to trials of metrifonate for AD and Bayer, the pharmaceutical company, has withdrawn its FDA application. OBJECTIVES: 1) To establish the efficacy of metrifonate for patients with Alzheimer's disease, in terms of cognition, global impression, functional activity, non cognitive symptoms, rate of institutionalization and mortality. 2) To assess the safety and tolerability of metrifonate. SEARCH METHODS: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 29 February 2008 using the term metrifonat*. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources. One of the authors (LS), as member of the Metrifonate Study Group, has had the opportunity to contact other metrifonate trialists to obtain data from potentially non published data of metrifonate clinical trials. SELECTION CRITERIA: All unconfounded, randomized double-blind clinical controlled trials comparing metrifonate to placebo in people with AD. DATA COLLECTION AND ANALYSIS: Data were extracted by the two reviewers, cross-checked, and pooled when appropriate and possible. MAIN RESULTS: Most studies assessed changes in cognitive function, global function, activities of daily living, behavioural problems, severity of disease and adverse events. Occasionally the results were not reported in sufficient detail to allow extraction of data for the meta-analyses. The treatment regimens were varied: loading doses were used in some trials. The range of maintenance doses and studies were not pooled unless the treatment regimens were considered comparable. The lengths of treatment varied from 6 to 26 weeks and studies were not pooled unless the treatment duration was similar. The results are derived from the ITT populations. Metrifonate at various doses, fixed and loading doses, was associated with significant cognitive improvement compared to placebo, except for weekly doses where there was no difference from placebo: MMSE (metrifonate 60-80 mg/day with initial loading at 26 weeks; metrifonate 50 mg/day fixed dose with no initial loading at 26 weeks MD 1.85, 95% CI 1.06 to 2.64, p<0.00001); ADAS-Cog (metrifonate 60-80 mg/day with initial loading at 26 weeks MD -3.24, 95% CI -4.40 to -2.08, p<0.00001) In most trials, there was improvement in clinical global impression: CIBIC-Plus (metrifonate 30-55 mg/day, approximately 0.65 mg/kg body weight, with initial loading at 26 weeks MD -0.25, 95% CI -0.41 to -0.09 p=0.002; metrifonate 50 mg/day fixed dose with no initial loading at 26 weeks MD -0.20, 95% CI -0.39 to -0.01, p=0.04). There were generally-significant drug-placebo differences in activities of daily living but this often depended on sample size and the characteristics of the instrument used: DAD (metrifonate 30-55 mg/day, 0.65 mg/kg body weight, with initial loading at 26 weeks MD 2.72, 95% CI 0.66 to 4.77, p=0.01; metrifonate 50 mg/day fixed dose with no initial loading at 26 weeks MD 4.07, 95% CI 0.29 to 7.85, p=0.03) Also there were differences associated with metrifonate compared with placebo for different doses of metrifonate in scores on a behavioural symptom scale, caregiver burden scale, and severity of disease scale. Adverse events occurring more often with metrifonate included abdominal pain, bloating, bradycardia, diarrhoea, leg cramps, nausea and rhinitis and were described as mostly mild and transient, but occasionally moderately severe, and infrequently severe and serious. Analysis of the number of patients suffering at least one mild, moderate, severe or serious adverse event before the end of treatment showed that there was usually no difference between placebo and metrifonate. AUTHORS' CONCLUSIONS: Metrifonate given once per day appears to be related to clinical response in cognition, global improvement, and activities of daily living in patients with mild to moderate Alzheimer's disease. Tolerability is good with adverse events as expected from a cholinesterase inhibitor, but with a low incidence of neuromuscular dysfunction and respiratory failure, too low to be detected in this review. It has been withdrawn from further development.

ANTECEDENTES: La enfermedad de Alzheimer (EA) se ha convertido en un importante problema de salud pública en todo el mundo debido al aumento de su prevalencia, la larga duración, la carga para los cuidadores y el elevado costo económico de la atención. Se ha determinado que la degeneración de las neuronas del preencéfalo basal que contienen acetilcolina se relaciona con los síntomas de la EA. Los inhibidores de la colinesterasa pueden bloquear la degradación de la acetilcolina y aumentar así la eficacia de las neuronas colinérgicas restantes. La huperzina A es un inhibidor linealmente competitivo y reversible de la acetilcolinesterasa que se ha señalado que posee actividad central y periférica, con la capacidad de proteger las células contra el peróxido de hidrógeno, la proteína beta-amiloide (o péptido), el glutamato, la apoptosis y la isquemia y la citotoxicidad inducidas por staurosporina. Estas propiedades pueden calificar a la huperzina A como un agente prometedor para tratar la demencia (incluida la EA). OBJETIVOS: Evaluar la eficacia y la seguridad de la huperzina A para el tratamiento de los pacientes con EA. ESTRATEGIA DE BÚSQUEDA: Se realizaron búsquedas en el Registro Especializado del Grupo Cochrane de Demencia y Trastornos Cognitivos (Cochrane Dementia and Cognitive Improvement Group) el 1 de febrero de 2006 mediante el término de búsqueda: huperzin*. El registro Especializado del GCDTC contiene registros actualizados de las principales bases de datos de asistencia sanitaria (MEDLINE, EMBASE, PsycINFO, CINAHL, SIGLE, ISTP, INSIDE, LILACS) así como de muchas bases de datos de ensayos y fuentes de literaturas gris. Además, se buscó en las bases de datos CBM y AMED y los sitios web relevantes y se realizaron búsquedas manuales en algunas revistas. Se estableció contacto con especialistas en el campo en busca de material no publicado y se examinó cualquier publicación encontrada para referencias adicionales. CRITERIOS DE SELECCIÓN: Todos los ensayos controlados aleatorios (ECA) pertinentes que estudian la eficacia y la seguridad de la huperzina A para la EA. RECOPILACIÓN Y ANÁLISIS DE DATOS: Dos revisores extrajeron los datos de forma independiente mediante un formulario de obtención de datos autodesarrollado y los ingresaron en el programa informático RevMan 4.2.10. Se realizaron metanálisis cuando más de un ensayo proporcionó datos sobre un resultado susceptible de comparación en pacientes suficientemente similares. Cuando hubo heterogeneidad entre los resultados se realizaron análisis de efectos aleatorios. Para las medias de las medidas de resultado se utilizaron las diferencias estandarizadas debido al uso de diferentes escalas y períodos de tratamiento. RESULTADOS PRINCIPALES: Seis ensayos que incluyeron un total de 454 pacientes cumplieron con los criterios de inclusión. La calidad metodológica de la mayoría de los ensayos incluidos no fue alta. Se mostró que en comparación con placebo, la huperzina A tuvo efectos beneficiosos sobre la mejoría de la función cognitiva general, medida con la MMSE (DMP 2,81; IC del 95%: 1,87 a 3,76; p CONCLUSIONES DE LOS AUTORES: A partir de las pruebas disponibles, la huperzina A parece tener algunos efectos beneficiosos sobre la mejoría de la función cognitiva general, el estado clínico global, el trastorno de la conducta y el rendimiento funcional, sin eventos adversos graves evidentes para los pacientes con EA. Sin embargo, sólo un estudio fue de calidad y tamaño adecuados. Por lo tanto, no hay pruebas adecuadas para hacer alguna recomendación acerca de su uso. Se necesitan ensayos aleatorios multicéntricos con muestras grandes y diseño riguroso para evaluar adicionalmente la huperzina A para la EA.

ANTECEDENTES: Los medicamentos antiinflamatorios no esteroideos, tales como el ibuprofeno, pudieran tener un papel en el tratamiento de las enfermedades caracterizadas por procesos inflamatorios. El ibuprofeno pudiera atenuar los efectos de los moduladores de la inflamación que han sido implicados en la patogénesis de la enfermedad de Alzheimer. OBJETIVOS: INVESTIGAR LA EFICACIA DEL TRATAMIENTO CON IBUPROFENO PARA PERSONAS CON ENFERMEDAD DE ALZHEIMER ESTRATEGIA DE BÚSQUEDA: Los ensayos fueron identificados en una búsqueda realizada en el Registro Especializado del Grupo Cochrane de Demencia y Trastornos Cognitivos (GCDTC)(Cochrane Dementia and Cognitive Improvement Group), el 10 de diciembre del 2002, en la que se usaron los términos listados en el texto principal de la revisión. El Registro del GCDTC se actualiza regularmente y contiene información de todas las bases de datos importantes sobre asistencia sanitaria y de muchas bases de datos sobre ensayos en curso. Además, las bases de datos informatizadas y los sitios de Internet relacionados con el ibuprofeno y la enfermedad de Alzheimer fueron examinados sistemáticamente por dos revisores de forma independiente. También se revisaron los datos sobre ensayos en curso del ibuprofeno para el tratamiento de personas con EA. CRITERIOS DE SELECCIÓN: Se eligieron para su inclusión en esta revisión todos los ensayos con asignación aleatoria, únicos o multicéntricos, controlados con placebo, que examinaron la eficacia del tratamiento con ibuprofeno en personas a las que el diagnóstico de la enfermedad de Alzheimer se realizó de acuerdo con criterios aceptados internacionalmente. Los criterios de inclusión y exclusión se especificaron para asegurar la ausencia de sesgos en la selección y la calidad metodológica de los ensayos seleccionados. RECOPILACIÓN Y ANÁLISIS DE DATOS: El objetivo de los dos revisores NT y HF fue obtner los datos de forma independiente. Los datos seleccionados pueden reflejar aspectos cognoscitivos, conductuales, físicos y fisiológicos de enfermedad de Alzheimer (EA). RESULTADOS PRINCIPALES: Una búsqueda sistemática en todas las bases de datos disponibles y de otras fuentes no pudo identificar ensayos completamente con asignación aleatoria, doble ciegos y controlados con placebo, que evaluaran la eficacia del ibuprofeno en la EA, y fueran elegibles para su inclusión en la revisión. Se identificó un ensayo doble ciego, controlado con placebo, que investiga el tratamiento con ibuprofeno para mejorar los defectos de la memoria asociados con la edad, pero todavía no está terminado ni hay datos disponibles. Están en curso otros ensayos que evalúan el efecto del ibuprofeno sobre el betaamiloide del líquido cefalorraquídeo en los individuos sin deficiencia cognoscitiva y el efecto de otros AINE, tales como el naproxeno y el rofecoxib en personas con EA. CONCLUSIONES DE LOS AUTORES: No hay todavía pruebas provenientes de ensayos con asignación aleatoria, doble ciegos y controlados con placebo de que el tratamiento con ibuprofeno es eficaz en los pacientes con diagnóstico de enfermedad de Alzheimer. El ibuprofeno, al igual que otros AINE, tiene un perfil de efectos secundarios identificable, que en algunas ocasiones pudiera ser grave e incluir la hemorragia gastrointestinal. Por lo tanto, es necesario demostrar que los beneficios de tal tratamiento sobrepasan el riesgo de los efectos secundarios antes de que el ibuprofeno pueda ser recomendado para el tratamiento de las personas con enfermedad de Alzheimer.

BACKGROUND: Alzheimer's disease is the most common cause of dementia in older people accounting for some 60% of cases with late-onset cognitive deterioration. It is now thought that several neurotransmitter dysfunctions are involved from an early stage in the pathogenesis of Alzheimer's disease-associated cognitive decline. The efficacy of selegiline for symptoms of Alzheimer's disease remains controversial and is reflected by its low rate of prescription and the lack of approval by several regulatory authorities in Europe and elsewhere. Reasons for this uncertainty involve the modest overall effects observed in some trials, the lack of benefit observed in several trials, the use of cross-over designs which harbour methodological problems in a disease like dementia and the difficulty in interpreting results from trials when a variety of measurement scales are used to assess outcomes. OBJECTIVES: The objective of this review is to assess whether or not selegiline improves the well-being of patients with Alzheimer's disease. SEARCH METHODS: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'selegiline', 'l-deprenyl', ''eldepryl" and "monamine oxidase inhibitor-B" on 9 October 2002. This Register contains records from all major health care databases and many trials databases and is updated regularly. SELECTION CRITERIA: All unconfounded, double-blind, randomized controlled trials in which treatment with selegiline was administered for more than a day and compared to placebo in patients with dementia. DATA COLLECTION AND ANALYSIS: An individual patient data meta-analysis of selegiline, Wilcock 2002 provides much of the data that are available for this review. Seven studies provided individual patient data and this was pooled with summary statistics from the published papers of the other nine studies. Where possible, intention-to-treat data were used but usually the meta analyses were restricted to completers' data (data on people who completed the study). MAIN RESULTS: There are 17 included trials. There were very few significant treatment effects and these were all in favour of selegiline; cognition at 4-6 weeks and 8-17 weeks, and activities of daily living at 4-6 weeks . There is little evidence of adverse effects caused by selegiline, and few withdrew from trials, apart from the Sano trial. The analyses were conducted on data available. There was no attempt to correct for missing patients because there were so few and withdrawal was probably unconnected with treatment. All trials examined the cognitive effects of selegiline, and in addition 12 trials examined the behavioural and mood effects. The meta-analysis revealed benefits on memory function, shown by improvement in the memory tests from several cognitive tests. The combined memory tests, and overall the combined cognitive tests, analysed using standardised mean differences, showed an improvement due to selegiline compared with placebo at 4-6 weeks and 8-17 weeks. The meta-analyses of emotional state show no treatment effects. Several studies assessed activities of daily living using several different scales. The combined tests, analysed using the standardised mean difference, showed an improvement due to selegiline at 4-6 weeks. The global rating scales analysed using standardised mean differences showed no effect of selegiline. A variety of adverse effects were recorded, but very few patients left a trial as a direct result. The meta-analyses of the numbers suffering adverse effects, and of the numbers of withdrawals before the end of the trial show no difference between control and selegiline. AUTHORS' CONCLUSIONS: Despite its initial promise, i.e. the potential neuroprotective properties, and its role in the treatment of Parkinson's disease sufferers, selegiline for Alzheimer's disease has proved disappointing. Although there is no evidence of a significant adverse event profile, there is also no evidence of a clinically meaningful benefit for Alzheimer's disease sufferers. This is true irrespective of the outcome measure evaluated, i.e. cognition, emotional state, activities of daily living, and global assessment, whether in the short, or longer term (up to 69 weeks), where this has been assessed. There would seem to be no justification, therefore, to use it in the treatment of people with Alzheimer's disease, nor for any further studies of its efficacy in Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared. DATA COLLECTION AND ANALYSIS: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies). AUTHORS' CONCLUSIONS: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Velnacrine is a derivative of tacrine. OBJECTIVES: To determine the clinical efficacy and safety of velnacrine for patients with dementia of Alzheimer's type. SEARCH METHODS: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2004 using the terms velnacr* and 'HP 029'. The CDCIG SR is regularly updated and contains records from all major health care databases and a great many ongoing trial databases. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with velnacrine was administered for more than two weeks to patients with dementia of the Alzheimer's type and its effects compared with those of placebo in a parallel group of patients. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: Four trials, involving 899 participants, were included. Cutler 1990 reported only the adverse events, and omitted the results for the placebo group. Medication was stopped for all in the highest dose group after the fourth day because one member suffered a tonic seizure. It is not possible to report any comparisons with placebo. Antuono 1995 reported benefit for velnacrine at endpoint for the CGI-C, and the Physical Self-maintenance Scale (PGIR), but not for the Carers Assessment of Time Activity (CATS). These results could not be checked because the relevant information was not reported, and we cannot assess the effect on the results of the higher number of non-completers from the velnacrine group. Treatment was discontinued because of safety reasons in 135 patients, mostly due to an abnormal liver function tests. There was a significant difference in favour of placebo compared with the combined treatment group for the number with an abnormal liver function test before the end of treatment at 24 weeks [105/297 vs 4/152, OR =20.23, 95% CI 7.29 to 56.18, p<0.00001]. There was a significant difference in favour of placebo compared with the combined treatment group for the number of withdrawals before the end of treatment at 24 weeks [130/297 vs 39/152, OR =2.26, 95% CI 1.47 to 3.47, p=0.0002]. Results are available for the dose replication phases of Zemlan 1996a and Zemlan 1996b. All the patients had taken velnacrine within two weeks prior to this phase and were identified as responders to velnacrine defined by improvement on the ADAS-Cog. Both studies reported a significant benefit for velnacrine compared with placebo for the ADAS-cog, but the results could not be checked because the relevant information was not reported. Neither study reported any benefit for velnacrine for the other efficacy measures. There was a significant difference in favour of placebo compared with the treatment group for the number with elevated liver transaminases before the end of treatment at 6 weeks [45/153 vs 29/156, OR =1.82, 95% CI 1.07 to 3.11, p=0.03]. There was a significant difference in favour of placebo compared with the treatment group for the number of withdrawals before the end of treatment at 6 weeks [68/211 vs 47/215, OR =1.70, 95% CI 1.10 to 2.62, p=0.02]. AUTHORS' CONCLUSIONS: There has been no research into the use of velnacrine as a cognitive enhancer in the treatment of Alzheimer's disease since 1994. The FDA peripheral and CNS drug advisory board voted unanimously against recommending approval. This review shows the toxic nature of velnacrine, and provides no evidence of efficacy. There are no grounds for further research into velnacrine.

ANTECEDENTES: La deficiencia de vitamina B1 (tiamina) desempeña una función importante en el síndrome de Wernicke-Korsakoff. Este síndrome es un tipo de daño cerebral que se presenta en alcohólicos crónicos que dependen principalmente del alcohol para su nutrición. El síndrome agudo (encefalopatía de Wernicke) es generalmente reversible. La evolución al síndrome amnésico profundo (psicosis de Korsakoff) puede evitarse mediante una inyección oportuna con una dosis importante de tiamina. Se ha sugerido que la tiamina puede tener un efecto beneficioso en la enfermedad de Alzheimer. OBJETIVOS: El objetivo de esta revisión sistemática es evaluar la eficacia de la tiamina en pacientes con la enfermedad de Alzheimer. ESTRATEGIA DE BÚSQUEDA: Los ensayos se identificaron en una última búsqueda actualizada del Registro Especializado de Ensayos del Grupo Cochrane de Demencia y Trastornos Cognitivos (Specialized Register of the Cochrane Dementia and Cognitive Improvement Group) el 12 de febrero de 2003 mediante el uso de los términos tiamin*, vitamina-B1, B1, "Vitamina B1". Este Registro se actualiza regularmente con los registros de las bases de datos más importantes (MEDLINE, EMBASE, CINAHL, PsycINFO) y de muchas bases de datos de ensayos. Además, los revisores realizaron búsquedas de bibliografías de revisiones y actas de congresos publicadas y establecieron contacto con las compañías farmacéuticas y los investigadores de los ensayos para obtener datos adicionales. CRITERIOS DE SELECCIÓN: Todos los ensayos aleatorios, sin factores de confusión, a doble ciego, en los que se administró el tratamiento con tiamina por más de un día y en comparación con placebo en pacientes con demencia del tipo de Alzheimer. RECOPILACIÓN Y ANÁLISIS DE DATOS: Dos revisores obtuvieron los datos de forma independiente y calcularon los odds-ratios (IC del 95%) o las diferencias promedio (IC del 95%). RESULTADOS PRINCIPALES: Se incluyeron tres estudios. Los dos estudios cruzados (cross-over) no informaron resultados de la primera fase. No fue posible combinar los resultados para un metanálisis. Nolan 1991 informa resultados que no evidencian efectos en el MMSE a los tres, seis, nueve y 12 meses para la tiamina en comparación con el placebo, para aquellos que completaron el ensayo. Meador 1993a observó que fue peor 3/8 en tiamina en comparación con 6/9 en placebo según mediciones de la ADAS-Cog (Alzheimer's Disease Assessment Scale- Cognitive Subscale) a los tres meses en comparación con el valor inicial, pero la diferencia no es estadísticamente significativa. Blass 1988 y Nolan 1991 informó que no se observaron efectos secundarios significativos durante el estudio, y Meador 1993a no mencionó efectos secundarios. Blass 1998 observó que 5/16, y Nolan 1991 que 5/15 no finalizaron el estudio, pero ninguno mencionó los grupos a los que pertenecían estas personas. CONCLUSIONES DE LOS AUTORES: No es posible establecer conclusión alguna de esta revisión. El número de personas incluidas en los estudios es menor que 50 y los resultados informados son inadecuados.