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Novel pharmacological strategies for neuroprotection in stroke: from bench to bedside
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O acidente vascular cerebral (AVC) é uma das principais causas de mortalidade e morbilidade a longo prazo no mundo. Esta doença tem uma forte repercussão não apenas nos doentes, mas também nos seus cuidadores, visto que os sobreviventes se tornam frequentemente incapazes de realizar tarefas diárias básicas de forma independente. O AVC pode ser dividido em duas grandes categorias: isquémico ou hemorrágico, sendo que o AVC isquémico é responsável por cerca de 87% da totalidade de casos. O grande impacto negativo provocado por esta doença justifica a necessidade de desenvolver novas e melhores estratégias que permitam melhorar a qualidade de vida dos sobreviventes. Atualmente o “gold standard” para tratamento do AVC é a trombólise através da administração intravenosa de trombolíticos (tPA e derivados recombinantes). Quando administrado nas primeiras horas após o AVC, estes fármacos permitem aumentar a probabilidade de recuperação dos doentes. Infelizmente, muitos doentes não cumprem os critérios necessários para realizar este tratamento, o que justifica a necessidade de desenvolver novas estratégias. Nas últimas décadas, o conceito de neuroprotecção tem recebido muita atenção por parte dos investigadores, e inúmeros agentes têm sido testados em contexto pré-clínico, e alguns em ensaios clínicos. A melhor compreensão da cascata isquémica que leva ao dano neuronal permitiu a identificação de novos alvos para estratégias de neuroprotecção. Muitos dos ensaios pré-clínicos com estes compostos têm tido resultados encorajadores, mas que falham em demonstrar benefício na translação para contexto clínico. Alguns autores têm identificado razões para esta falha de translação. Apesar dos desafios que têm surgido neste campo, muitos compostos foram testados em ensaios clínicos nos últimos 5 anos, alguns dos quais ainda estão a decorrer. Independentemente das falhas que ocorreram no passado, a neuroprotecção tem um futuro promissor, e novas terapêuticas têm emergido como a adropina, a tirosina fosfatase STEP, o verapamilo e os microRNAs. A terapêutica combinada tem também um grande potencial, visto que poderia aumentar o número de doentes elegíveis para tratamento com trombolíticos. É muito provável que nos próximos anos surjam descobertas no tratamento do AVC, e os investigadores devem manter em mente os erros que foram cometidos no passado de forma a prevenir que se voltem a repetir no futuro.
Stroke is among the main causes of death worldwide and it is a serious cause of long-term disability. This disease has an important impact not only in patients, but also in care providers, since often stroke survivors become unable to perform basic daily tasks on their own. Stroke can be divided into two major categories: ischemic and hemorrhagic. Ischemic stroke is the most common, being responsible for around 87% of all stroke cases. The huge burden associated with this disease, justifies the need to develop new and better therapeutic strategies that can improve survivor’s quality of life. Currently, the gold standard for treatment of stroke is recombinant tissue plasminogen activator (rtPA) administered intravenously. Given within the first hours of symptoms onset, rtPA can considerably increase the chances of stroke recovery. Unfortunately, a lot of patients do not meet the criteria to be eligible for this treatment, thus the need to develop new therapeutic strategies. In the last decades, a lot of attention has been drawn to the concept of neuroprotection and numerous agents were tested in preclinical studies and some of them in clinical trials. A better understanding of the ischemic cascade that leads to neuronal damage has enabled the development of novel therapeutic targets for neuroprotective strategies. Numerous compounds have undergone preclinical trials with exciting results but have failed to translate into clinical benefit. Some reasons behind the gap between bench and bedside have been identified by authors. Despite the challenges of translation, multiple compounds have been tested in clinical trials in the last 5 years, some of which are still ongoing. Regardless of the failures that occurred in the past, neuroprotection has a promising future with new emergent treatments such as adropin, tyrosine phosphatase STEP, verapamil, and microRNAs. Combination therapy holds great potential, since it could amplify the number of patients eligible for treatment with rtPA. In the next years, is likely that new discoveries arise in stroke research, and investigators must keep in mind the failures that happened in the past, to prevent them from happening in the future.
Stroke is among the main causes of death worldwide and it is a serious cause of long-term disability. This disease has an important impact not only in patients, but also in care providers, since often stroke survivors become unable to perform basic daily tasks on their own. Stroke can be divided into two major categories: ischemic and hemorrhagic. Ischemic stroke is the most common, being responsible for around 87% of all stroke cases. The huge burden associated with this disease, justifies the need to develop new and better therapeutic strategies that can improve survivor’s quality of life. Currently, the gold standard for treatment of stroke is recombinant tissue plasminogen activator (rtPA) administered intravenously. Given within the first hours of symptoms onset, rtPA can considerably increase the chances of stroke recovery. Unfortunately, a lot of patients do not meet the criteria to be eligible for this treatment, thus the need to develop new therapeutic strategies. In the last decades, a lot of attention has been drawn to the concept of neuroprotection and numerous agents were tested in preclinical studies and some of them in clinical trials. A better understanding of the ischemic cascade that leads to neuronal damage has enabled the development of novel therapeutic targets for neuroprotective strategies. Numerous compounds have undergone preclinical trials with exciting results but have failed to translate into clinical benefit. Some reasons behind the gap between bench and bedside have been identified by authors. Despite the challenges of translation, multiple compounds have been tested in clinical trials in the last 5 years, some of which are still ongoing. Regardless of the failures that occurred in the past, neuroprotection has a promising future with new emergent treatments such as adropin, tyrosine phosphatase STEP, verapamil, and microRNAs. Combination therapy holds great potential, since it could amplify the number of patients eligible for treatment with rtPA. In the next years, is likely that new discoveries arise in stroke research, and investigators must keep in mind the failures that happened in the past, to prevent them from happening in the future.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Stroke Neuroprotection Translation Mestrado integrado - 2021