Consumption of drugs for Alzheimer's disease on the Brazilian private market / Consumo de medicamentos para doença de Alzheimer no mercado privado brasileiro

ABSTRACT OBJECTIVE To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020. METHODS National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels. RESULTS Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020. CONCLUSION The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

RESUMO OBJETIVO Analisar o consumo de medicamentos para a doença de Alzheimer no mercado privado brasileiro e sua distribuição geográfica entre os anos de 2014 e 2020. MÉTODOS Foram utilizados dados do Sistema Nacional de Gerenciamento de Produtos Controlados relativos às vendas de donepezila, galantamina, rivastigmina e memantina, entre janeiro de 2014 a dezembro de 2020, em todo o território nacional. Os dados de venda foram utilizados como proxy para o consumo dos medicamentos, avaliado em dose diária definida (DDD)/1.000 habitantes/ano em nível nacional, regional, por unidade federativa e microrregião. RESULTADOS O consumo dos medicamentos passou de 5.000 DDD/1.000 habitantes em 2014 para mais de 16.000 DDD/1.000 habitantes em 2020, e todas as unidades de federação apresentaram variação positiva. A região Nordeste apresentou o maior consumo acumulado no período, porém exibiu disparidades microrregionais. A região Norte apresentou o menor consumo. Os medicamentos mais consumidos foram donepezila e memantina, os quais também apresentaram maior crescimento do consumo no intervalo de tempo entre os anos de 2014 e 2020. CONCLUSÃO O consumo de medicamentos para o tratamento da doença de Alzheimer triplicou no Brasil entre os anos de 2014 e 2020, o que pode estar relacionado ao aumento da prevalência da doença no país e/ou maior acesso a serviços de saúde, assim como estar ligado, também, à utilização inapropriada destes medicamentos. Este é um desafio para gestores e profissionais de saúde num cenário de envelhecimento populacional e aumento da prevalência de doenças crônico-degenerativas.

Eficácia e segurança de Pregabalina, Gabapentina, Memantina, Amitriptilina, treinamento físico com exercícios em solo ou aquáticos para tratamento de Fibromialgia: revisão rápida de evidências / Effectiveness and safety of Pregabalin, Gabapentin, Memantine, Amitriptyline, exercises on land or aquatic exercises for Fibromyalgia treatment: rapid evidence review

Tecnologia: Pregabalina, drogas não-opioides disponíveis no SUS, treinamento físico no solo ou em meio aquático. Indicação: Tratamento da fibromialgia. Pergunta: Há diferenças de eficácia e segurança entre a Pregabalina e as outras drogas não opioides ou terapias disponíveis no SUS para tratamento da dor crônica relacionada à fibromialgia? Métodos: Levantamento bibliográfico foi realizado nas bases eletrônicas PUBMED e Cochrane Database, seguindo estratégias de buscas predefinidas, com busca adicional na página eletrônica da Comissão Nacional de Incorporação de Tecnologias em Saúde. Avaliou-se a qualidade metodológica das revisões sistemáticas com Assessing the Methodological Quality of Systematic Reviews versão 2 (AMSTAR-II). Resultados: Foram selecionadas e incluídas 6 revisões sistemáticas. Conclusão: A afirmação de eficácia da Gabapentina, Amitriptilina e Memantina para tratamento da fibromialgia é pouco confiável, pois as evidências são de nível 3, provenientes de ensaios clínicos de baixa qualidade metodológica. Pregabalina é eficaz para reduzir a dor em curto prazo (risco absoluto é 50%, nível 1 de evidência), mas não em longo prazo. O treinamento físico, relatado como única estratégia eficaz para tratamento da fibromialgia nas diretrizes do SUS, não tem efeito clinicamente importante sobre a dor

Technology: Pregabalin, non-opioid drugs available in Brazilian Public Health System, aquatic exercise or exercise on land. Indication: Treatment of fibromyalgia. Question: Are there differences in efficacy and safety between Pregabalin and other non-opioid drugs or therapies available in the SUS for the treatment of chronic pain related to fibromyalgia? Methods: A bibliographic survey was carried out in the electronic databases PUBMED and Cochrane Database, following pre-defined search strategies, with an additional search on the website of the National Commission for the Incorporation of Health Technologies. The methodological quality of systematic reviews was evaluated with Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-II). Results: Six systematic reviews were selected and included. Conclusion: There is not confidence about effectiveness of Gabapentin, Amitriptyline and Memantine for fibromyalgia treatment (level 3 of evidence, from clinical trials of low methodological quality). Pregabalin, in the short term, is effective for reducing pain (absolut risk is 50%, level 1 of evidence), but not in the long term. Physical training, reported as the only effective strategy for treating fibromyalgia in Brazilian Public Health System guidelines, has no clinically important effect on pain.

Memantine for episodic migraine: A systematic review and meta-analysis

@#<p style="text-align: justify;"><strong>Introduction.</strong> Migraine is a common, debilitating primary headache. Memantine is a non-competitive N-methyl D-aspartate (NMDA) antagonist that lowers neuronal excitability that could prevent migraine attacks. This study aimed to determine the efficacy and safety of memantine in patients with episodic migraine attacks using a systematic review and meta-analysis.</p><p style="text-align: justify;"><strong>Methods.</strong> We searched CENTRAL, MEDLINE, Scopus, Cochrane, LILACS, ClinicalTrials.gov, HERDIN and Google Scholar for relevant studies until July 31, 2020. Prespecified screening and eligibility criteria for inclusion were applied. Included studies underwent methodological quality assessment. Study design, patient characteristics, interventions given, and relevant outcomes were extracted and synthesized.</p><p style="text-align: justify;"><strong>Results.</strong> This review included five relevant articles - two randomized controlled trials (RCT) and three non randomized studies (one retrospective records review and survey, two prospective open-label single-arm trials). There were 109 patients included in the RCTs and 197 patients reported in the non-randomized studies. Pooled data from the two RCTs showed that memantine at 10 mg/day significantly decreased the monthly number of migraine days at 12 weeks compared to placebo with a mean difference of -1.58 [95% confidence interval (CI) -1.84, -1.32]. Non-randomized studies also showed a decrease in migraine days per month with memantine (5 to 20 mg/day) after 12 weeks [95% CI]: -9.1 [-11, -7.23], -7.2 [-8.85, -5.55], and -4.9 [-6.29, -3.51]. Adverse drug events (ADE) did not differ significantly between patients treated with memantine compared to placebo.</p><p style="text-align: justify;"><strong>Conclusion.</strong> Memantine may be effective and well-tolerated as prophylaxis for episodic migraine.</p>

The role of NMDA receptor antagonists, amantadine and memantine, in schizophrenia treatment: a systematic review

Abstract Objective Schizophrenia is a complex and chronic psychiatric disorder. In recent years, studies have found glutamatergic system participation in its etiopathogenesis, especially through aberrant NMDA receptors functioning. Thus, drugs that modulate this activity, as amantadine and memantine, could theoretically be used in its treatment. To perform a systematic literature review about memantine and amantadine use as adjunct in schizophrenia treatment. Methods A systematic review of papers published in English indexed in the electronic database PubMed ® using the terms "memantine", "amantadine" and "schizophrenia" published until October 2016. Results We found 144 studies, 8 selected for analysis due to meet the objectives of this review. Some of these have shown benefits from such drug use, especially in symptoms measured by PANSS and its subdivisions, while others do not. Discussion: The data in the literature about these drugs use for schizophrenia treatment is still limited and have great heterogeneity. Thus, assay with greater robustness are needed to assess real benefits of these drugs as adjuvant therapy.

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat

Memantine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, suppresses the release of excessive levels of glutamate that may induce neuronal excitation. Here we investigated the effects of memantine on salicylate-induced tinnitus model. The expressions of the activity-regulated cytoskeleton-associated protein (ARC) and tumor necrosis factor-alpha (TNF α)genes; as well as the NMDA receptor subunit 2B (NR2B) gene and protein, were examined in the SH-SY5Y cells and the animal model. We also used gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and noise burst prepulse inhibition of acoustic startle, and the auditory brainstem level (electrophysiological recordings of auditory brainstem responses, ABR) and NR2B expression level in the auditory cortex to evaluate whether memantine could reduce salicylate-mediated behavioral disturbances. NR2B was significantly upregulated in salicylate-treated cells, but downregulated after memantine treatment. Similarly, expression of the inflammatory cytokine genes TNFα and immediate-early gene ARC was significantly increased in the salicylate-treated cells, and decreased when the cells were treated with memantine. These results were confirmed by NR2B immunocytochemistry. GPIAS was attenuated to a significantly lesser extent in rats treated with a combination of salicylate and memantine than in those treated with salicylate only. The mean ABR threshold in both groups was not significant different before and 1 day after the end of treatment. Additionally, NR2B protein expression in the auditory cortex was markedly increased in the salicylate-treated group, whereas it was reduced in the memantine-treated group. These results indicate that memantine is useful for the treatment of salicylate-induced tinnitus.

Memantine Improves Cognitive Function and Alters Hippocampal and Cortical Proteome in Triple Transgenic Mouse Model of Alzheimer's Disease

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer's disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.

An Analysis on Prescribing Patterns of Alzheimer's Dementia Treatment and Choline Alfoscerate using HIRA Claims Data

BACKGROUND: Alzheimer's dementia is the most common dementia. However, recently, choline alfoscerate is prescribed for treating Alzheimer's dementia, although it is not a treatment for this disease. PURPOSE: To analyze the prescription patterns of choline alfoscerate as a dementia treatment for patients with Alzheimer's disease and to analyze, as well as the factors affecting choline alfoscerate prescription. METHOD: The 2016 HIRA-NPS data was used in this study. The code of Alzheimer's dementia is F00 in the ICD-10 disease classification code. We analyzed the demographic, clinical, and regional characteristics associated with donepezil, rivastigmine, galantamine, memantine, and choline alfoscerate prescriptions. All statistical and data analyse were conducted by SAS 9.4 and Excel. RESULTS: For patients with Alzheimer's disease, choline alfoscerate was the second most prescribed after donepezil. Analysis results showed that choline alfoscerate was more likely to be prescribed to men than to women, and more likely to be prescribed by local health centers than by medical institutions. Moreover, choline alfoscerate was highly likely to be prescribed at neurosurgical departments, among medical departments. CONCLUSION: This study confirmed that choline alfoscerate was prescribed considerably for patients with Alzheimer's dementia. Further studies valuating its clinical validity should be performed to clarify whether choline alfoscerate prescription is appropriate for treating Alzheimer's dementia.

Uso da memantina na doença de Alzheimer grave: análise de custo-efetividade na perspectiva do Sistema Único de Saúde / Use of memantine in severe Alzheimer's disease: a cost-effectiveness analysis from the perspective of the Brazilian Health System

A Doença de Alzheimer (DA) representa a causa mais comum de demência, sendo uma doença neurodegenerativa progressiva e incurável, expressa por uma diversidade de sintomas neuropsiquiátricos. É a principal responsável pelas taxas de mortalidade e de dependência funcional entre os idosos, representando um impacto econômico importante para as famílias e sistemas universais de saúde. Apesar da literatura observar que os efeitos da memantina na DA são pequenos, o fármaco foi incorporado ao Sistema Único de Saúde (SUS) em 2017. No entanto, ao contrário do preconizado pela normativa legal acerca da incorporação de tecnologias no SUS, este processo não foi acompanhado de uma avaliação econômica completa que demonstrasse a custo-efetividade deste fármaco. Este estudo examinou a custo-utilidade da memantina para a DA grave em comparação a nenhum tratamento farmacológico específico, sob a perspectiva do SUS como financiador da assistência. Foi conduzida uma revisão sistemática de estudos de avaliação econômica que usaram a memantina isolada ou combinada com doenepezilpara a DA moderada a grave. A revisão permitiu conhecer o estado da arte das avaliações econômicas e possibilitou levantar aspectos gerais relacionados às modelagens utilizadas nos estudos de forma a auxiliar na construção do modelo de decisão analítico conduzido no estudo de custo-efetividade. Foi construído um modelo de Markov para modelar a progressão da doença com base nos estados de gravidade da DA (leve, moderado e grave), definidos pelo Mini- Exame do Estado Mental (MEEM), acrescidos do estado morto. Foram considerados ciclos de 1 ano e o horizonte temporal adotado foi de 5 anos. Os custos da memantina foram considerados por 2 anos, porém os efeitos observados apenas ao longo do primeiro ano. Custos e benefícios foram descontados em 5%. Comparado com nenhum tratamento específico, a memantina representou um aumento nos custos do cuidado e nos ganhos obtidos em QALY. Os pacientes que usaram memantina tiveram um ganho de 3,080 QALY ao longo dos 5 anos simulados a um custo incremental de R$ 351.500,00 em valores já descontados, resultando em uma RCEI de R$ 114.205,75 por QALY, para o caso de referência. Os resultados encontrados são de difícil comparação com estudos realizados fora do país. Desta forma, sua incorporação não seria justificada no contexto nacional, dados seus custos elevados e um benefício pequeno e circunscrito ao tempo

Alzheimer's disease (AD) represents the most common cause of dementia, being a progressive and incurable neurodegenerative disease, expressed by a variety of neuropsychiatric symptoms. It the main responsible for mortality rates and functional dependence among the elderly, representing an economic impact important for families and universal health systems. Although the literature observes that the effects of memantine on AD are small, the drug was incorporated into the Brazilian Health System in 2017. However, contrary to the legal norm regarding the incorporation of technologies in SUS, this process was not accompanied by an economic evaluation that would demonstrate the cost-effectiveness of this drug. This study examined the cost-utility of memantine for severe AD compared to no specific pharmacological treatment, from the perspective of the SUS as a care funder. A systematic review of economic evaluation studies using memantine alone or in combination with donepezil for moderate to severe AD has been conducted. The review allowed to know the state of the art of economic evaluations and made it possible to raise general aspects related to the modeling used in the studies to assist in the construction of the analytical decision model conducted in the cost-effectiveness study. A Markov model was constructed to model the progression of AD based on the severity states of AD (mild, moderate and severe), defined by the MEEM, plus the dead state. Cycles of 1 year were considered and the adopted time horizon was 5 years. The costs of memantine were considered for 2 years, but the effects observed only during the first year. Costs and benefits were discounted at 5%. Compared with no specific treatment, memantine represented an increase in care costs and gains in QALY. Patients who used memantine had a gain 3,080 QALY over the simulated 5 years at an incremental cost of $ 351.500,00 and an ICER of $ 114.205,75 in amounts already discounted for the reference case. The results found are difficult to compare with studies conducted outside the country. If the cost-effectiveness threshold adopted in Brazil was previously recommended by the WHO, memantine would be considered a non-cost-effective technology based on the analysis of the reference case. In this way, its incorporation would not be justified in the national context, given its high costs and a small benefit and circumscribed to the time

A systematic review of economic evaluations of the use of memantine alone or combined with donepezil for moderate to severe Alzheimer's disease / Revisão sistemática de avaliações econômicas acerca do uso da memantina isolada ou combinada com o donepezil para a doença de Alzheimer moderada a grave

OBJECTIVE: To synthesize the available evidence and state of the art of economic evaluations which evaluate the use of memantine, whether alone or combined with donepezil, for moderate to severe Alzheimer's disease (AD), focusing on the analytical decision models built. METHOD: The electronic databases MEDLINE, EMBASE, NHS EED, CEA Registry and LILACS were searched for references. After duplicates were removed, two independent reviewers evaluated the titles and abstracts and subsequently the full texts. The Drummond M. tool was used to evaluate the quality of the studies. RESULTS: After the application of the eligibility criteria, twelve complete economic evaluations were included. One evaluation was a clinical trial, two involved simulations and nine used Markov models. The main outcome measure adopted was dominated by cost per quality adjusted life year (QALY). The use of memantine was considered cost-effective and dominant in eight studies; while in a single study, its use was dominated when compared to donepezil for moderate AD. Sensitivity analyzes were systematically performed, with robust results. The quality assessment indicated that the methodological quality of the studies was good. CONCLUSION: Although there is some controversy regarding the benefits derived from the use of memantine, whether combined or not with donepezil, the evidence collected suggests that it is cost-effective in the countries where the studies were performed. However, local economic studies need to be performed, given the significant variability derived from the different parameters adopted in the evaluations.

OBJETIVO: Sintetizar as evidências disponíveis e o estado da arte das avaliações econômicas que avaliaram a memantina isolada ou combinada com donepezil para a Doença de Alzheimer (DA) moderada a grave, com foco nos modelos de decisão analíticos elaborados. MÉTODO: As bases eletrônicas MEDLINE, EMBASE, NHS EED, CEA Registry e LILACS foram usadas para busca de referências. Após a remoção de duplicatas, dois revisores independentes avaliaram os títulos e resumos e, posteriormente, os textos completos. A ferramenta de Drummond M. foi utilizada para avaliação da qualidade dos estudos. RESULTADO: Após a aplicação dos critérios de elegibilidade, foram incluídas doze avaliações econômicas completas. Quanto aos desenhos de estudo, uma avaliação foi conduzida ao longo de ensaio clínico, duas fizeram simulação e nove utilizaram modelos de Markov. A principal medida de desfecho adotada foi custo por ano de vida ajustado por qualidade (QALY). O uso da memantina foi considerada custo-efetivo e dominante em oito estudos; em um único estudo, seu uso foi dominado quando comparado ao donepezil para a DA moderada. Análises de sensibilidade foram sistematicamente realizadas, evidenciando resultados robustos. A avaliação de qualidade apontou boa qualidade metodológica dos trabalhos. CONCLUSÃO: Apesar de existirem controvérsias quanto aos benefícios derivados do uso da memantina associada ou não ao donepezil, o levantamento das evidências sugere que ela é custo-efetiva nos países onde os estudos foram elaborados. No entanto, estudos econômicos locais necessitam ser realizados, dada a grande variabilidade derivada dos diferentes parâmetros adotados nas avaliações.

Pharmacotherapy for dementia

Dementia is a clinical syndrome characterized by a cluster of symptoms and signs that manifest as difficulties in cognitive functions such as memory, psychological and psychiatric changes, and impairments in activities of daily living. As a result of worldwide trends of population aging, dementia has had a huge impact on public health in almost all countries. Disease modification therapies for dementia have not yet been developed. However, pharmacotherapy is essential in patients with dementia to combat delays in their cognitive and functional decline. In this article, we review the current pharmacotherapy for dementia. Three acetylcholinesterase inhibitors—donepezil, rivastigmine, galantamine—and memantine are the only medications that have been approved for the treatment of dementia. We present the indications, dose recommendations, side effects, and criteria for National Health Insurance coverage in Korea of these medications for dementia treatment. Although the Ministry of Food and Drug Safety in Korea has not approved any medications for managing the behavioral and psychological symptoms of dementia, some antipsychotics and antidepressants have been studied and used clinically for those purposes. Clinicians may consider vitamin E, Ginkgo biloba extract, choline alfoscerate, or omega-3 fatty acids as additional treatment options. Non-steroid anti-inflammatory drugs, estrogen hormone therapy, and statins are not generally recommended for dementia treatment. We believe that our findings will aid clinicians in the treatment of patients with cognitive decline.

Memantina para doença de Alzheimer / Memantine for Alzheimer's disease

CONTEXTO: A doença de Alzheimer (DA) é uma afecção crônica e progressiva que leva à neurodegeneração gradual e demência e se caracteriza por perda cognitiva progressiva, sintomas neuropsiquiátricos (comportamentais) e prejuízo das atividades da vida diária (funcionais) dos doentes. Por meio do Protocolo Clínico e Diretrizes Terapêuticas (PCDT) da DA o Ministério da Saúde preconiza tratamento com inibidores das colinesterases ­ donepezila, galantamina e rivastigmina - para melhorar a função cognitiva e o estado clínico geral de pacientes com doença de gravidade leve a moderada. O presente relatório foi elaborado como parte da conduta de revisão do PCDT da DA e tem por objetivo avaliar as evidências de segurança e eficácia de memantina como tratamento da DA leve, moderada e grave. TECNOLOGIA: Cloridrato de memantina. INDICAÇÃO: Doença de Alzheimer (CID-10 G30). PERGUNTA: Memantina é eficaz e segura no tratamento de pacientes com doença de Alzheimer leve, moderada e grave quando comparada a inibidores da colinesterase ou placebo na evolução de sintomas cognitivos, sintomas comportamentais ou neuropsiquiátricos, atividades da vida diária, impressão clínica global e efeitos adversos? EVIDÊNCIAS CIENTÍFICAS: Foram realizadas buscas nas bases de dados Medline/PubMed, Embase e Cochrane Library por meio de estratégias elaboradas com termos específicos para cada base. Foram avaliadas 10 metanálises e 1 revisão sistemática da Cochrane. Dentre os 11 estudos incluídos, sete se referiam ao uso de memantina em monoterapia versus placebo e em 4 se avaliou a combinação de memantina com inibidores da acetilcolinesterase versus inibidores em monoterapia. Entre os estudos nos quais se avaliou a monoterapia com memantina, há um deles no qual se incluem somente participantes com DA leve à moderada, não havendo evidência de eficácia na DA leve, mas pequeno benefício na DA moderada nos desfechos de cognição e impressão clínica global. Em dois destes estudos se avaliou apenas o desfecho de sintomas comportamentais, com benefício em um deles. Dos 4 estudos restantes houve evidência de benefício em todos os desfechos da pergunta PICO, com exceção de 1 estudo em que não houve evidência de benefício em desfechos comportamentais e na impressão clínica global. A avaliação da combinação de memantina com inibidores da acetilcolinesterase versus monoterapia com inibidores da acetilcolinesterase, nos 4 estudos incluídos, mostra evidência de benefício em todos os desfechos (cognição, comportamento, funcional e impressão clínica global); benefício apenas para sintomas comportamentais em 1 e sem benefício para sintomas funcionais em 2 estudos. Sugere-se, dessa forma, a incorporação de memantina combinada a inibidores da acetilcolinesterase nos casos moderados e de memantina em monoterapia nos casos graves de DA. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário estimou quais seriam os gastos decorrentes de uma possível incorporação da memantina no SUS. Foram contemplados os pacientes com a forma moderada da doença além de um aumento da população elegível referente aos pacientes com a forma grave da doença. No primeiro ano, a estimativa foi de aproximadamente R$ 10 milhões, enquanto a estimativa para os 5 primeiros anos após a incorporação foi de aproximadamente R$ 73 milhões. A análise de sensibilidade apontou que os gastos para os 5 primeiros anos podem variar entre aproximadamente, R$ 50 milhões e R$ 131 milhões. RECOMENDAÇÃO DA CONITEC: Apesar do tamanho do efeito ser pequeno, ele é significativo e influencia favoravelmente a qualidade de vida dos doentes e cuidadores. Assim a CONITEC, em sua 57ª reunião ordinária realizada nos dias 05 e 06 de julho de 2017, recomendou preliminarmente a incorporação no SUS da memantina combinada aos inibidores da acetilcolinesterase nos casos moderados e da memantina em monoterapia nos casos graves de Doença de Alzheimer conforme Protocolo Clínico e Diretrizes Terapêuticas. A matéria será disponibilizada em Consulta Pública com recomendação preliminar favorável à incorporação. CONSULTA PÚBLICA: A consulta pública nº 34, de 02 de agosto de 2017 referente à recomendação inicial da CONITEC favorável à incorporação de memantina para doença de Alzheimer apresentada pela Secretaria de Ciência, Tecnologia e Insumos Estratégicos (SCTIE/MS) nos autos do processo MS/SIPAR nº 25000.063591/2017-11 ficou disponível para contribuições entre os dias 04/08 e 23/08/2017. Ao todo, foram recebidas 22 contribuições, sendo 4 do formulário "experiência ou opinião" e 18 do formulário "técnico-científico". Entre as contribuições recebidas 2 do formulário técnico-científico foram excluídas (9%); 4 apresentavam posicionamento contra ou parcialmente contra a recomendação (18% - 3 técnicas e 1 opinião) e 16 a favor ou parcialmente a favor da recomendação (73% - 13 técnicas e 3 opiniões). Em posicionamentos contrários reforçou-se o baixo efeito do medicamento nos desfechos apresentados nos estudos, mas não foram apresentadas novas evidências que pudessem modificar o parecer inicial, no qual se considerou como relevante o efeito na qualidade de vida dos pacientes e cuidadores como observados nos estudos selecionados para análise. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na reunião do plenário do dia 31/08/2017 deliberaram, por unanimidade, recomendar a incorporação de memantina para doença de Alzheimer, conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 292/2017. DECISÃO: publicou-se a Portaria nº 49, de 8 de novembro de 2017 por meio da qual se tornou pública a decisão de aprovar a incorporação da memantina para doença de Alzheimer, conforme Protocolo Clínico e Diretrizes Terapêuticas, no âmbito do Sistema Único de Saúde - SUS.(AU)

A Case of Treatment of Delayed Encephalopathy after Acute Carbon Monoxide Intoxication

Delayed carbon monoxide (CO) encephalopathy patients can show cognitive impairment, aphasia, affective and personality changes and behavioral symptoms. The prognosis of them is sometimes poor or irreversible. We present a case of 61-year-old woman who visited us at 56 days after CO intoxication and showed moderate to severe cognitive impairment and behavioral problems. We prescribed the donepezil (5 mg/d), memantine (5 mg/d), choline alfoscerate (800 mg/d) and ziprasidone (20 mg/d), based on previous case reports and performed the cognitive rehabilitation. After 30 days treatment in hospital, she showed dramatic improvement in cognitive functions and behavioral problems. This case suggests that adequate pharmacological and cognitive treatment could improve the moderate to severe symptoms of delayed CO encephalopathy even about 2 months later after CO intoxication.

Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells

OBJECTIVE: Autophagy is one of the key responses of cells to programmed cell death. Memantine, an approved anti-dementia drug, has an antiproliferative effect on cancer cells but the mechanism is poorly understood. The aim of the present study was to test the possibility of induction of autophagic cell death by memantine in glioma cell lines. METHODS: Glioma cell lines (T-98 G and U-251 MG) were used for this study. RESULTS: The antiproliferative effect of memantine was shown on T-98 G cells, which expressed N-methyl-D-aspartate 1 receptor (NMDAR1). Memantine increased the autophagic-related proteins as the conversion ratio of light chain protein 3-II (LC3-II)-/LC3-I and the expression of beclin-1. Memantine also increased formation of autophagic vacuoles observed under a transmission electron microscope. Transfection of small interfering RNA (siRNA) to knock down NMDAR1 in the glioma cells induced resistance to memantine and decreased the LC3-II/LC3-I ratio in T-98 G cells. CONCLUSION: Our study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.

The effects of memantine on recovery, cognitive functions, and pain after propofol anesthesia / Efeitos da memantina sobre a recuperação, funções cognitivas e dor após a anestesia com propofol

Abstract Objectives: Postoperative cognitive dysfunction refers to the problems associated with thought and memory that are often experienced after major surgery. The aim of this study is to evaluate the effects of intraperitoneally administered memantine on recovery, cognitive functions, and pain after propofol anesthesia. Methods: The study was conducted in Gazi University Animal Research Laboratory, Ankara, Turkey in January 2012. Twenty-four adult female Wistar Albino rats weighing 170-270 g were educated for 300 s in the radial arm maze (RAM) over three days. Group P was administered 150 mg kg−1 of intraperitoneal (IP) propofol; Group M was given 1 mg kg−1 of IP memantine; and Group MP was given 1 mg kg−1 of IP memantine before being administered 150 mg kg−1 of IP propofol. The control group received only IP saline. RAM and hot plate values were obtained after recovery from the groups that received propofol anesthesia and 30 min after the administration of drugs in other two groups. Results: The duration of recovery for Group MP was significantly shorter than Group P (p < 0.001), and the number of entries and exits in the RAM by Group MP was significantly higher during the first hour when compared to Group P (p < 0.0001). Hot plate values, on the other hand, were found to be significantly increased in all groups when compared to the control values, aside from Group C (p < 0.0001). Conclusion: In this study, memantine provided shorter recovery times, better cognitive functions, and reduced postoperative pain. From this study, we find that memantine has beneficial effects on recovery, cognitive functions, and pain after propofol anesthesia.

Resumo Objetivos: A disfunção cognitiva no pós-operatório refere-se a problemas associados ao pensamento e à memória que são frequentemente manifestados após uma cirurgia de grande porte. O objetivo deste estudo foi avaliar os efeitos da memantina administrada por via intraperitoneal sobre a recuperação, as funções cognitivas e a dor após a anestesia com propofol. Métodos: O estudo foi feito no Laboratório de Pesquisa com Animais da Universidade de Gazi, Ankara, Turquia, em janeiro de 2012. Vinte e quatro ratos albinos do sexo feminino, adultos, da linhagem Wistar, com 170-270 g, foram treinados durante 300 segundos no labirinto radial de oito braços (LRB) durante três dias. O Grupo P recebeu 150 mg/kg−1 de propofol por via intraperitoneal (IP), o Grupo H recebeu 1 mg/kg−1 de memantina IP e o Grupo MP recebeu 1 mg/kg−1 de memantina IP antes da administração de 150 mg/kg−1 de propofol (IP). O grupo controle recebeu apenas solução salina IP. Os valores do LRB e da placa quente foram obtidos após a recuperação dos grupos que receberam propofol e 30 minutos após a administração dos fármacos nos outros dois grupos. Resultados: O tempo de recuperação do Grupo MP foi significativamente menor do que o do Grupo P (p < 0,001) e o número de entradas e saídas do LRB do Grupo MP foi significativamente maior durante a primeira hora, em comparação com o Grupo P (p < 0,0001). Os valores da placa quente, por outro lado, foram significativamente maiores em todos os grupos, em comparação com os valores do grupo controle, exceto pelo Grupo C (p < 0,0001). Conclusão: No presente estudo, memantina proporcionou tempos mais curtos de recuperação, funções cognitivas melhores e reduziu a dor no pós-operatório. A partir deste estudo, descobrimos que a memantina tem efeitos benéficos sobre a recuperação, as funções cognitivas e a dor após anestesia com propofol.

Rivastigmina parches sola o combinada con memantina, comparada con memantina sola en pacientes con enfermedad de Alzheimer moderada y severa: revisión sistemática de la literatura / Rivastigmine patches alone or combined with memantine compared with memantine alone in patients with moderate to severe Alzheimer's disease: Systematic review of the literature

Resumen Introducción: la enfermedad de Alzheimer (EA), una condición neurodegenerativa irreversible y progresiva, es la causa más frecuente de demencia y genera una gran carga económica anual. El objetivo de este estudio fue realizar una revisión sistemática de la literatura para determinar la seguridad y eficacia de rivastigmina parche, sola o en combinación con memantina, comparadas con la memantina en monoterapia para el tratamiento de la EA moderada y severa. Métodos: se realizó una búsqueda sistemática de la literatura. Se incluyeron estudios clínicos controlados aleatorizados de pacientes con diagnóstico de EA moderada a severa, evaluando los desenlaces de eficacia y seguridad. Resultados: los resultados de los estudios experimentales que comparan dosis de rivastigmina en parche, indican una posible diferencia en algunos desenlaces de eficacia, tales como desempeño de las actividades diarias, actividades instrumentales y funcionamiento general en pacientes con EA moderada y severa, sin diferencia significativa en los desenlaces de seguridad. Se observó una tendencia a favor de la terapia combinada en algunos desenlaces como cambio en puntuación de MMSE y actividades diarias instrumentales. Discusión: la evidencia disponible apoya el uso de rivastigmina, y la combinación con memantina parece una opción terapéutica apropiada en casos seleccionados.

Summary Introduction: Alzheimer's disease (AD), an irreversible, progressive neurodegenerative condition, is the most common cause of dementia and generates a high economic burden. The aim of this study was to conduct a systematic review of the literature to determine the safety and efficacy of rivastigmine patch, alone or in combination with memantine, compared with memantine monotherapy for the treatment of moderate to severe AD. Methods: A systematic search of the literature was conducted. Including randomized controlled trials of patients diagnosed with moderate to severe AD, evaluating outcomes of effectiveness and safety. Results: The results of experimental studies comparing doses of rivastigmine patches indicate a possible difference in some of the outcomes of effectiveness such as performance in activities of daily living, instrumental activities, and overall functioning, in patients with moderate and severe AD, without significant difference in safety outcomes. A trend in favor of combination therapy in some of the outcomes, as change in MMSE score and instrumental daily activities, was observed. Discussion: The available evidence supports the use of rivastigmine, and the association with memantine seems an appropriate therapeutic option in selected cases.

Long-Term Efficacy of Memantine in Parkinson' Disease Dementia: An 18-Month Prospective Perfusion Single Photon Emission Computed Tomography Preliminary Study

BACKGROUND AND PURPOSE: Although the treatment efficacy of memantine in Parkinson's disease dementia (PDD) has been reported after several weeks of administration, the long-term effects on brain perfusion and clinical symptoms remain unclear. The current study aimed to follow-up PDD patients after 18 months of memantine treatment using (99m)Tc hexamethylpropylene amine oxime single photon emission computed tomography (SPECT). METHODS: A total of 15 patients with PDD and 11 healthy participants were recruited into this study and they were assessed with brain SPECT, Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), and Neuropsychiatric Inventory (NPI). Differences in regional cerebral blood flow (rCBF) between the two groups were evaluated at baseline. After 18 months of memantine administration, changes in brain perfusion, severity of dementia, cognition, and neuropsychiatric disturbances were examined in the patients with PDD. RESULTS: The PDD group showed hypoperfusion in most of the cortical, subcortical, and cerebellar areas compared to healthy controls at baseline. At the follow-up, changes in rCBF, CDR (p=0.32), sum of box of CDR (p=0.49), MMSE (p=0.61), GDS (p=0.79), and NPI (p=0.23) were not significant in the PDD patients. CONCLUSIONS: Our findings implicate that memantine may delay the progression of brain perfusion deficits and clinical symptoms of PDD in the long term.

Neonatal Administration of Memantine Enhances Social Cognition in Adult Rats Subjected to Early Maternal Deprivation

Schizophrenia is considered a neurodevelopmental disorder; however, all the available treatment options are used when the disease becomes clinically significant in adolescence or early adulthood. Using a developmental rat model of schizophrenia, we examined whether neonatal treatment with memantine, an NMDA receptor modulator, can improve schizophrenic-like symptoms in adulthood. Early maternal deprivation in rats produces deficits in social interaction behaviors in adulthood. In contrast, memantine administrated in neonatal rats subjected to early maternal deprivation significantly reduces deficits in social interaction behaviors in adulthood. These results raise the possibility that pharmacological treatment with memantine at the early developmental stage helps people with a risk to develop schizophrenic-like symptoms.

Pharmacological Treatments for Tinnitus / 한양의대학술지

Pharmacotherapy has been constantly chosen by the clinician among the available treatment options for tinnitus. Medications that have been prescribed off-label to treat tinnitus can be grouped into several categories: benzodiazepines, antidepressants, anticonvulsants, N-methyl-D-aspartate (NMDA) receptor antagonists, dopamine receptor modulators, muscle relaxants, and others. In this article, a wide variety of compounds once used in the treatment of tinnitus and evidenced by clinical trials are reviewed with respect to the mechanisms of action and the drug efficacy. Only a few of the various pharmacological interventions investigated have some beneficial effects against tinnitus: clonazepam, acamprosate, neramexan, and sulpiride. Sertraline and pramipexole were effective in subgroups of patients with psychiatric symptoms or presbycusis. However, no agents have been identified to provide a reproducible long-term reduction of tinnitus in excess of placebo effects. In rodent tinnitus models, L-baclofen, memantine, and KCNQ2/3 channel activators have been demonstrated to reduce tinnitus development. Limitation of the use of an effective high dosage during a longer treatment duration due to dose-dependent side effects of the centrally acting drugs may influence the results in clinical studies. More effective and safer innovative agents should be developed based on the further understanding of tinnitus neural mechanisms and valid animal models, and should be supported by improved clinical trial methodology. The management of tinnitus patients through a tailored treatment approach depending on the detailed classification of tinnitus subtypes will also lead to better treatment outcomes.