Loading...
Publication
O Recetor Histamínico H3: um novo alvo terapêutico no tratamento de doenças do Sistema Nervoso Central
| Name: | Description: | Size: | Format: | |
|---|---|---|---|---|
| 4.55 MB | Adobe PDF |
Authors
Advisor(s)
Abstract(s)
A histamina é uma amina endógena sintetizada por várias células do organismo
humano tendo, por isso, um papel de extrema importância em vários processos
fisiológicos. No organismo, atua como um potente vasodilatador que leva ao aumento da
permeabilidade vascular, exibe caraterísticas de mediador inflamatório com capacidades
quimiotáxicas, e ainda intervém como estimulante da secreção ácida ao nível do trato
gastrointestinal. Mais concretamente no Sistema Nervoso Central, a histamina comporta se como um neurotransmissor, pelo que o sistema histaminérgico pode intervir de igual
modo na fisiopatologia de algumas doenças do foro neurológico, como a narcolepsia,
doença de Alzheimer, esquizofrenia, perturbação da hiperatividade e défice de atenção, e
a obesidade. Contudo, a eficácia limitada da terapêutica atual para os sintomas cognitivos
destas patologias, tem direcionado a indústria farmacêutica para a investigação e
desenvolvimento de novos compostos anti-histamínicos com futura aplicação na prática
clínica.
Desta forma, esta monografia apresenta uma revisão bibliográfica acerca da
fisio(patologia) da histamina nos diferentes sistemas de órgãos, assim como uma
introdução aos recetores histamínicos conhecidos, e os respetivos anti-histamínicos já
comercializados. O foco principal incide sobre o estudo dos compostos anti-histamínicos
H3 que integraram recentemente os ensaios pré-clínicos e clínicos com indicações
terapêuticas para as patologias supramencionadas.
No caso da narcolepsia, os dados existentes na literatura não permitem retirar
conclusões rigorosas acerca dos compostos estudados. Já na doença de Alzheimer,
espera-se que os agentes anti-histamínicos H3, S 38093, SAR-110894, e AZD 5213, GSK-189254, GSK-239512, MK-3134 avancem num futuro próximo para ensaios
clínicos de fase 1 e fase 2, respetivamente. Contudo, no caso da esquizofrenia e da
perturbação da hiperatividade e défice de atenção, nenhum dos compostos avaliados
promoveu benefício terapêutico em ensaios clínicos de fase 1 e fase 2, pelo que estes
necessitarão de ser estudados em maior pormenor. Por último, e no que respeita à
obesidade, aguarda-se a aplicação da betahistina, do pitolisant e do KSK-19 em ensaios
clínicos de fase 1, face à evidência de propriedades anorexígenas em modelos animais.
Até ao momento, os resultados obtidos permitem sustentar a possibilidade da exploração do recetor H3 como potencial alvo terapêutico no tratamento de algumas doenças do
Sistema Nervoso Central.
Histamine is an endogenous amine synthesized by several cells in the human body and therefore plays an extremely important role in various physiological processes. It acts as a potent vasodilator that leads to increased vascular permeability, exhibits characteristics of an inflammatory mediator with chemotaxic capacities, and also acts as a stimulator of acid secretion in the gastrointestinal tract. More specifically in the Central Nervous System, histamine behaves as a neurotransmitter and therefore the histaminergic system may take part in the pathophysiology of some neurological diseases such as narcolepsy, Alzheimer's disease, schizophrenia, attention deficit and hyperactivity disorder and obesity. However, the limited efficacy of current therapy for the cognitive symptoms of these pathologies, has directed the pharmaceutical industry to the research and development of new antihistamine compounds with future application in clinical practice. Thus, this monograph presents a bibliographic review on the physio(pathology) of histamine in the different organ systems as well as an introduction to known histamine receptors, and their antihistamines already marketed. The main focus is to study H3 antihistamine compounds that have recently integrated pre-clinical and clinical trials with therapeutic indications for the above-mentioned pathologies. Regarding narcolepsy, the lack of information in literature does not permit drawing rigorous conclusions about the compounds studied. In Alzheimer's disease, antihistamine agents H3, S 38093, SAR-110894, and AZD-5213, GSK-189254, GSK 239512, MK-3134 are expected to advance in the near future to phase 1 and phase 2 clinical trials, respectively. However, in schizophrenia and attention deficit and hyperactivity disorder, none of the compounds assessed resulted in therapeutic benefit neither in phase 1 or phase 2 clinical trials, so it will need to be studied in more detail. Finally, in what concerns to obesity, betahistine, pitolisant and KSK-19 are expected to be applied in phase 1 clinical trials, due to their anorectic properties evidenced in animal models. So far, the results obtained support the possibility to exploit the H3 receptor as a potential therapeutic target in the treatment of some diseases of the Central Nervous System.
Histamine is an endogenous amine synthesized by several cells in the human body and therefore plays an extremely important role in various physiological processes. It acts as a potent vasodilator that leads to increased vascular permeability, exhibits characteristics of an inflammatory mediator with chemotaxic capacities, and also acts as a stimulator of acid secretion in the gastrointestinal tract. More specifically in the Central Nervous System, histamine behaves as a neurotransmitter and therefore the histaminergic system may take part in the pathophysiology of some neurological diseases such as narcolepsy, Alzheimer's disease, schizophrenia, attention deficit and hyperactivity disorder and obesity. However, the limited efficacy of current therapy for the cognitive symptoms of these pathologies, has directed the pharmaceutical industry to the research and development of new antihistamine compounds with future application in clinical practice. Thus, this monograph presents a bibliographic review on the physio(pathology) of histamine in the different organ systems as well as an introduction to known histamine receptors, and their antihistamines already marketed. The main focus is to study H3 antihistamine compounds that have recently integrated pre-clinical and clinical trials with therapeutic indications for the above-mentioned pathologies. Regarding narcolepsy, the lack of information in literature does not permit drawing rigorous conclusions about the compounds studied. In Alzheimer's disease, antihistamine agents H3, S 38093, SAR-110894, and AZD-5213, GSK-189254, GSK 239512, MK-3134 are expected to advance in the near future to phase 1 and phase 2 clinical trials, respectively. However, in schizophrenia and attention deficit and hyperactivity disorder, none of the compounds assessed resulted in therapeutic benefit neither in phase 1 or phase 2 clinical trials, so it will need to be studied in more detail. Finally, in what concerns to obesity, betahistine, pitolisant and KSK-19 are expected to be applied in phase 1 clinical trials, due to their anorectic properties evidenced in animal models. So far, the results obtained support the possibility to exploit the H3 receptor as a potential therapeutic target in the treatment of some diseases of the Central Nervous System.
Description
Keywords
Histamina Anti-histamínicos Recetor H3 Ensaios clínicos Doenças do sistema nervoso central