Prevalencia de la prescripción de fármacos en la enfermedad de Alzheimer y uso de la terapia combinada / Prescription drug prevalence in Alzheimer's disease and use of combination therapy

Objetivo: La enfermedad de Alzheimer (EA) es la demencia más común, y se estima que alrededor de 47 millones de personas a nivel mundial sufren esta enfermedad. Los inhibidores de la acetilcolinesterasa (IACE) y la memantina están indicados en estadios leve-moderado, pero su relevancia clínica está en entredicho y el uso de la terapia combinada no se ha establecido. El objetivo es medir la prevalencia de prescripción de fármacos para la EA en un Área de Gestión Sanitaria (AGS) y analizar tanto la utilidad de la biterapia como su potencial retirada. Metodología: Estudio retrospectivo desarrollado por el Servicio de Farmacia de un AGS que abarca 408.788 pacientes. Los datos se recogieron utilizando diferentes plataformas electrónicas del Servicio Andaluz de Salud. Se incluyeron todos los pacientes con prescripción activa de algún fármaco para la EA. Resultados: El 0,6% de la población total del AGS tenía prescrito uno o más fármacos para la EA. Los más prescritos fueron memantina y donepezilo tanto en monoterapia como combinados. Aproximadamente un 40% de los pacientes con terapia combinada sufrieron un deterioro cognitivo desde la instauración de la doble terapia, pero los fármacos no se retiraron. Conclusión: La prevalencia de prescripción de fármacos para la EA en el AGS estudiada es similar a los datos de prevalencia publicados. Desde el inicio de la prescripción de la terapia combinada hasta la última consulta médica, un porcentaje relevante de pacientes sufre deterioro cognitivo, pero los fármacos no se retiran, por lo que es necesario revisar las pautas de deprescripción de estos medicamentos. (AU)

Objective: Alzheimer’s disease (AD) is the most common dementia, and it is estimated that around 47 million people worldwide suffer this disease. Acetylcholinesterase inhibitors (AChEi) and memantine are indicated in mild-moderate stages, but their clinical relevance is questioned and the use of the combination therapy has not been established. The objective is to evaluate the prevalence of drug prescription for AD in a Health Management Area (HMA) and to analyze the utility of the dual therapy and its potential withdrawal. Methodology: Retrospective study developed by the Pharmacy Service of an HMS that includes 408,788 patients. Data were collected using different electronic platforms of the Andalusian Health Service. All patients with an active prescription of some drug for AD were included. Results: 0.6% of the total population of the HMS had prescribed one or more drugs for AD. The most prescribed were memantine and donepezil, both in monotherapy and in combination. Approximately 40% of patients with combination therapy suffered cognitive decline since the introduction of dual therapy, but the drugs were not withdrawn. Conclusion: The prevalence of drug prescription for AD in the HMS studied is similar to the published prevalence data. From the start of the combination therapy prescription until the last medical consultation, a relevant percentage of patients suffer cognitive impairment, but the drugs are not withdrawn, so it is necessary to review the deprescription guidelines. (AU)

Toxicidad cardiovascular por parches transdérmicos de rivastigmina. A propósito de dos casos clínicos / Cardiovascular toxicity by rivastigmine transdermal patches. Two case report / Toxicidade cardiovascular por adesivos transdérmicos de rivastigmina. Relato de dois casos

Resumen: La rivastigmina, fármaco anticolinesterásico, mejora la neurotransmisión colinérgica y es utilizado en el tratamiento de las enfermedades de Alzheimer y de Parkinson. En el Centro de Información y Asesoramiento Toxicológico se han registrado casos de intoxicación por el uso de parches transdérmicos de rivastigmina, los cuales han aumentado en número en el último tiempo. Presentamos dos casos clínicos de intoxicación aguda por parches transdérmicos de rivastigmina en los que se constataron arritmias cardíacas graves, asociando un descenso de colinesterasa plasmática. Se destacan los riesgos del uso de esta medicación con el fin de estar atentos a los primeros síntomas de intoxicación, poder actuar en forma oportuna y prevenir nuevos eventos.

Summary: Rivastigmine, an anticholinesterase drug, improves cholinergic neurotransmission and is used in the treatment of Alzheimer's and Parkinson's diseases. In the Center for Information and Toxicological Advice there have been cases of intoxication due to the use of transdermal rivastigmine patches, which have increased in recent times. We present two clinical cases of acute intoxication by transdermal patches of rivastigmine in which serious cardiac arrhythmias were found, associating a decrease in plasma cholinesterase. The risks of the use of this medication are highlighted in order to be attentive to the first symptoms of intoxication, to be able to act timely and to prevent new events.

Resumo: A rivastigmina, um anticolinesterásico, melhora a neurotransmissão colinérgica e é usada no tratamento das doenças de Alzheimer e Parkinson. No Centro de Informação e Conselhos Toxicológicos, houve casos de intoxicação devido ao uso de adesivos transdérmicos de rivastigmina, que aumentaram nos últimos tempos. Se apresentam dois relatos de caso de intoxicação aguda por adesivos transdérmicos de rivastigmina. Em ambos os casos, foram encontradas arritmias cardíacas graves, associando uma diminuição na colinesterase plasmática. Os riscos do uso desse medicamento são destacados para estar atento aos primeiros sintomas de intoxicação, para poder atuar de forma oportuna e prevenir novos eventos.

From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease.

INTRODUCTION: Rivastigmine, a treatment for mild to moderate Alzheimer disease (AD), is the first cholinesterase inhibitor to be available in the transdermal format. We aim to describe user experience and satisfaction with the rivastigmine patch, as well as any clinical changes perceived in patients. METHODS: Observational, cross-sectional, multicentre study with 239 investigators and 1851 informal caregivers of patients with mild to moderate AD. Patients were treated with transdermal rivastigmine patches for ≥ 6 months and had previously received high doses of oral rivastigmine. RESULTS: Mean caregiver age was 59.8±14.4 years and 70.9% were women. They spent 10.0±7.1hours per day providing care and 79.8% lived with the patient. Patch instructions were described as easy to follow by 97.1% of the caregivers and 92.1% of them rated patch application as easy or very easy. The most commonly cited disadvantage was adhesion problems (26.8%). Discontinuation of treatment was due to cutaneous reactions in most cases. Overall, 76.5% of the caregivers were satisfied or very satisfied with transdermal treatment and 77.4% considered that its interference with daily activities was minimal or null. The patch was preferred to oral treatment by 94.3% of caregivers. Clinical Global Impression of Change ratings improved according to 61.3% of the caregivers and 53% of the investigators. Few caregivers reported medication forgetfulness. CONCLUSIONS: Most caregivers of patients with mild to moderate AD preferred the transdermal format of rivastigmine to the oral format. Caregivers also reported overall satisfaction, ease of use, and reduced impact on daily activities for transdermal rivastigmine format, in addition to patient improvement compared to their condition under the previous treatment.

[Rivastigmine as treatment for patients with mild to moderately severe Alzheimer disease under normal clinical practice conditions. The ENTERPRISE study]. / Manejo terapéutico con rivastigmina en pacientes con enfermedad de Alzheimer de leve a moderadamente grave en condiciones de práctica clínica habitual. Estudio ENTERPRISE.

INTRODUCTION: Alzheimer disease (AD) causes progressive cognitive decline leading to loss of independence for activities of daily living; rivastigmine is one of the drugs used for symptomatic management. OBJECTIVE: To assess the therapeutic use of different pharmaceutical forms of rivastigmine in patients with AD in normal clinical practice. PATIENTS AND METHODS: Cross-sectional, observational, multi-centre study conducted on patients with mild to moderate AD treated with rivastigmine in Spanish outpatient clinics specialising in Geriatrics, Psychiatry, and Neurology. Data regarding use of oral (OR) and transdermal (TDR) rivastigmine, compliance (degree of adherence), and caregiver satisfaction with treatment were evaluated. RESULTS: In total, 2252 patients with a mean age of 77.2 years were included; 60.2% were women. AD was moderate to moderately severe in 58.4%. Rivastigmine treatment was started orally in 54.4% of the patients and transdermally in 45.6%; 35.6% of those who started treatment by the OR route switched to TDR. A single dose adjustment was sufficient for 77.5% of patients on TDR treatment vs 11.8% of patients receiving OR treatment. More patients on TDR treatment (80.8% vs. 57.1% on OR treatment) reached the maximum therapeutic dose of rivastigmine and did so in a shorter period of time (51.6 vs 205.8 days). Compliance rates (60.5% vs 47.2%) and caregivers' satisfaction with treatment (89.4% vs 81.9%) were also higher for TDR. CONCLUSIONS: In normal clinical practice, using the TDR route of administration improves dose titration and drug compliance, allowing more patients to reach the maximum recommended dose of rivastigmine in a shorter time period.

Estudo de bioequivalência entre duas formulações de rivastigmina cápsulas de 6 mg, em voluntários sadios após administração de dose única / Study of bioequivalence between two formulations of rivastigmine 6 mg capsules, in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de rivastigmina 6 mg cápsulas (Aché Laboratórios Farmacêuticos S/A, formulação teste, e Exelon® por Novartis Biociências S/A - formulação referência, Brasil) em 56 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de 7 dias. As amostras de plasma de 46 dos 56 voluntários inicialmente incluídos foram obtidas ao longo de um intervalo de 12 horas. As concentrações de rivastigmina foram determinadas através de um equipamento LC-MS-MS, utilizando zolpidem como padrão interno. A partir dos dados obtidos calcularam-se os seguintes parâmetros farmacocinéticos: ASC0-t , ASC0-¥ e Cmax. A razão das médias geométricas de Rivastigmina/Exelon® 6 mg foi de 100,97% para ASC0-t, 101,38% para ASC0-¥ e 89,01% para Cmax; os intervalos de confiança de 90% foram de 93,20% - 109,39%, 93,65% - 109,75% e 81,10% - 97,70%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80% - 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que a cápsula de rivastigmina 6 mg foi bioequivalente ao comprimido de Exelon® de 6 mg e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica.

Influence of Rivastigmine transdermal on butyrylcholinesterase levels in patients with Alzheimers disease / A influência da rivastigmina transdérmica nos níveis de butirilcolinesterase em pacientes com doença de Alzheimer

Cholinesterase inhibitors (ChE-Is) are among the main drugs approved for the treatment of Alzheimer's disease (AD). Rivastigmine in the form of a transdermal patch is an alternative delivery method, and can give greater treatment compliance. Objectives: To conduct a preliminary assessment of the neurocognitive and biological effects of oral and transdermal Rivastigmine in patients with AD and to identify a potential biological marker and demonstrate a possible relationship between esterase levels and behavioral scores of AD patients. Methods: Forty patients with AD were treated with cholinesterase inhibitors (ChE-Is), evaluated using the MMSE and NPI, and simultaneously sampled to determine their serum levels of AChE and BuChE for 180 days. Results: The differences obtained between oral and transdermal forms, as assessed by the MMSE and NPI scores of the AD patients, were not significant at the three time points examined (0, 90, and 180 days). However, serum BuChE levels of the transdermal group differed significantly (p<0.0004) compared with those of the oral group at 90 days. Conclusion: Use of a transdermal ChE-I, rivastigmine tartrate significantly reduced BuChE levels in the AD patients studied.

Os inibidores das colinesterases estão entre as principais drogas aprovadas para tratamento da doença de Alzheimer (DA). Rivastigmina na forma de adesivo transdérmico é um método alternativo de liberação e pode fornecer uma maior aderância ao tratamento. Objetivos: Conduzir uma abordagem preliminar dos efeitos neurocognitivos e biológicos da rivastigmina oral e transdérmica em pacientes com DA e identificar um potencial marcador biológico e demonstrar uma possível relação entre níveis de esterases e escores de comportamento de pacientes com DA. Métodos: Quarenta pacientes com DA com inibidores de colinesterases foram avaliados usando o MEEM e o INP e colhidas amostras para determinar seus níveis séricos de AChE e BuChE por 180 dias. Resultados: As diferenças obtidas entre as formas oral e transdérmica, avaliadas pelo MEEM e INP não diferiram em três ocasiões (0, 90 e 180 dias). Todavia, os níveis de BuChE no grupo transdérmico diferiu significativamente (p<0.0004) comparados ao grupo de administração oral em 90 dias. Conclusão: O uso do tartarato de rivastigmina, forma transdérmica reduziu significativamente os níveis de BuChE nos pacientes estudados com DA.

A prospective study on the use of rivastigmine transdermal patch in Alzheimersdementia in a routine clinical setting

There is not much published literature on the use of rivastigmine patch in a "routine" clinical setting. Objectives: In this naturalistic longitudinal observational study we sought to evaluate the safety, tolerability and efficacy of the rivastigmine patch in patients with early and late onset moderate Alzheimer's disease in a routine clinical setting. Methods: Out of all routine clinical referrals, the first 30 patients with diagnosis of moderate Alzheimer's dementia who were started on rivastigmine patch were included in the study. Rivastigmine patch dose was titrated from 4.6 to 9.5 mg/ 24 hours as appropriate. The primary outcome measure was safety and tolerability, measured by the incidence of adverse events and discontinuation due to any reason. The secondary outcome measure was to examine improvement on global, functional and behavioral domains as demonstrated by the MMSE (Mini Mental State Examination) score, BADLS (Bristol Activities of Daily Living Skills) score, patient and carer feedback and clinical judgment. Results: Adverse events were reported in 20% of patients and 10% of total patients needed discontinuation of treatment. Improvement on global, functional and behavioral domains was observed in two thirds of patients whereas one third showed a relative decline. The most common side effect was skin irritation or erythema. Conclusions: The rivastigmine transdermal patch may provide a treatment option for those patients who require a change in their current oral cholinesterase inhibitor therapy due to safety or tolerability concerns.

Não há muita publicação na literatura sobre o uso do adesivo de rivastigmina na prática clínica. Objetivos: Em um estudo observacional longitudinal naturalístico nós tentamos avaliar a segurança, tolerabilidade e eficácia do adesivo transdérmico de rivastigmina em pacientes com doença de Alzheimer moderada de início precoce e tardio. Métodos: Os primeiros 30 pacientes ambulatoriais com DA moderada de clínicas de referência que iniciaram o uso de adesivo de rivastigmina foram incluídos no estudo. A dose foi escalonada de 4,6 a 9,5 mg/24 hs quando apropriado. As medidas de desfecho primário foram a segurança e tolerabilidade medidas pela incidência de eventos adversos e descontinuação por alguma razão. A medida de desfecho secundário foi a melhora global, funcional e comportamental, demonstrada pelos escores do Mini-Exame do Estado Mental (MEEM), escores na escala de Atividade de Vida Diária de Bristol, retorno do paciente e cuidador e julgamento clínico. Resultados: Eventos adversos foram reportados em 20% dos pacientes e 10% deles descontinuaram o tratamento. Melhora em domínios global, funcional e comportamental foi observada em dois terços dos pacientes, enquanto que, no terço restante um declínio relativo foi observado. O efeito colateral mais comum foi irritação ou eritema de pele. Conclusões: O adesivo transdérmico de rivastigmina pode ser uma opção terapêutica para aqueles pacientes que requeiram mudança na sua terapia oral com inibidor da colinesterase devido à sua segurança e tolerabilidade.

El papel de la rivastigmina en la demencia de origen vascular / The definition of its role in vascular dementia

Vascular dementia represents the second most common type of dementia. The classification of vascular dementia broadly follows three clinico-pathological processes: multi-infarct dementia, single strategic infarct dementia and subcortical dementia. Currently, no established standard treatment for vascular cognitive impairment exists. Reductions in acetylcholine and acetyltransferase activity are common to both Alzheimer's disease and vascular cognitive impairment raising the possibility that cholinesterase inhibitors may also be beneficial for the latter. This review has been conducted to assess the efficacy of rivastigmine in the treatment of people with vascular cognitive impairment. From existing trial data there is some evidence of benefit of rivastigmine in vascular cognitive impairment. However, this conclusion is based on studies which had small numbers of patients, which sought to compare rivastigmine to treatments other than placebo or which used data extrapolated post hoc from large studies involving patients with Alzheimer's disease and vascular risk factors of unclear significance. From these perspectives, one can conclude that large placebocontrolled, double blind and adequately randomised trials are needed before firm conclusions can and should be drawn. The methodology of such trials should acknowledge the biological and clinical features unique to vascular cognitive impairment and its subtypes

La demencia vascular representa el segundo tipo más frecuente de demencia. La clasificación de la demencia vascular sigue tres procesos clínico-patológicos generales: demencia multiinfarto, demencia por infarto único ubicado en una zona estratégica y demencia subcortical. Actualmente no existen tratamientos estandarizados establecidos para los trastornos cognitivos de causa vascular. La disminución de la actividad de la acetilcolinesterasa es una estrategia habitualmente utilizada tanto para el tratamiento de los pacientes que presentan enfermedad de Alzheimer como para aquellos con trastornos cognitivos de causa vascular. En consecuencia, es posible que los inhibidores de la colinesterasa sean una opción conveniente. La presente revisión se llevó a cabo con el propósito de evaluar la eficacia de la rivastigmina para el tratamiento de los individuos que presentan trastornos cognitivos de origen vascular. De acuerdo con los datos provenientes de diferentes estudios, la rivastigmina sería útil para tratar pacientes con deterioro cognitivo de origen vascular. No obstante, esta conclusión se efectuó sobre la base de estudios en los cuales se incluyó un número reducido de pacientes, se buscó comparar la rivastigmina con agentes diferentes del placebo o se extrapolaron datos a partir de estudios de gran magnitud efectuados con pacientes que presentaban enfermedad de Alzheimer y factores de riesgo vasculares de relevancia poco clara. Desde ese punto de vista, se puede concluir que es necesario realizar estudios de gran tamaño, controlados con placebo a doble ciego y adecuadamente aleatorizados antes de poder alcanzar conclusiones sólidas. La metodología empleada en dichos estudios debería responder a las características biológicas y clínicas particulares del deterioro cognitivo vascular y sus subtipos

Tratamiento de las demencias / Treatment of Dementia

Introducción: el aumento en la expectativa de vida poblacional y el tratamiento médico de condiciones de alta mortalidad han facilitado que se dé, en general, un mayor envejecimiento de los pueblos. Tal es el caso de las demencias, que tienen la particularidad de afectar no sólo al paciente, sino a su entorno y muy especialmente a la familia. Objetivo: señalar, a partir del tipo de demencia, su gravedad, la presencia de otras enfermedades, entre otras, cuál podría ser la terapia más adecuada para tratarlas. Método: luego de clasifi car las demencias y sus manifestaciones clínicas, se presentan las terapias no farmacológicas, el tratamiento farmacológico sintomático, el tratamiento farmacológico específi co y los tratamientos basados en otras hipótesis fi siopatológicas. Conclusión: la intervención específi ca se ve claramente modifi cada cuando tenemos en cuenta la comorbilidad de los pacientes, entre muchos otros factores que defi nen las intervenciones integrales.

Introduction: Population is growing older due to the overall growth of life expectancy and the medical treatment now available for conditions with high mortality rate. Such is the case of dementia, an illness that affects not only the individual but also his family and his environment. Objective: To indicate the best possible treatment taking into account the type of dementia, its severity and the presence of other illnesses. Method: After classifying the type of dementia and its clinical manifestations, non-pharmacological therapies, symptomatic pharmacological treatment, specifi c pharmacological treatment and treatments based on other physiopathological hypothesis are presented. Conclusion: A specifi c intervention may be modifi ed when we take into account comorbility, among other factors defi ning an integral treatment.