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Efficacy of the different baclofen enantiomers on the reduction of binge drinking in a rodent model: a gender study
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Atualmente, de entre os problemas de saúde mundial encontra-se o consumo excessivo de álcool, principalmente decorrente de Binge Drinking, que é o consumo de grandes quantidades de álcool num curto espaço de tempo. Além dos 4 tratamentos farmacológicos possíveis, muitos estudos têm sido realizados de forma a aumentar as possibilidades terapêuticas, de onde se destaca o fármaco baclofeno, a mais recente adição aos fármacos autorizados na França para este tratamento. Nos últimos anos, vários estudos sobre a eficácia do baclofeno foram realizados, principalmente sobre a forma racémica RS(±)-baclofeno, mas resultados divergentes foram encontrados. Após o isolamento dos 2 enantiómeros deste fármaco, o R(+)-baclofeno e o S(-)-baclofeno, descobriu-se que a eficácia reside no enantiómero ativo R, o que levantou a questão se realmente o melhor tratamento seria com a forma racémica RS. Assim, neste estudo procurou-se caracterizar os efeitos enantiosseletivos do baclofeno num modelo animal de consumo crónico binge-like em ratos Long Evans machos e fêmeas, sendo o foco as diferenças entre os 2 géneros, uma vez que ainda não existem estudos neste sentido. R(+)-baclofeno, S(-)-baclofeno e a forma racémica, que é a única ainda administrada aos pacientes, foram avaliados quanto à sua eficácia na diminuição do consumo de álcool. De seguida, avaliou-se o efeito do RS(±)-baclofeno no sistema dopaminérgico, uma vez que a libertação de dopamina na via mesolímbica sofre alterações com o consumo de álcool e o baclofeno, agonista dos recetores GABA-B, atua nas mesmas vias. Os resultados obtidos sugerem que a variabilidade da resposta à forma racémica é devido aos diferentes efeitos dos 2 enantiómeros, sendo que uma diminuição no consumo de álcool e uma reposta positiva à terapêutica são devido à sensibilização do enantiómero R, e, pelo contrário, um aumento do consumo pode ser devido ao enantiómero S. Estas diferenças aparentam resultar de uma resposta diferencial do sistema dopaminérgico. Mais interessante ainda, foi demonstrado que a forma racémica RS não tem efeito nas fêmeas e o efeito do enantiómero R é ainda baixo comparado com os machos. Estes resultados sugerem que o tratamento com baclofeno atualmente disponível origina resposta terapêutica variável nas mulheres.
Currently, among the world's health problems is excessive alcohol consumption, especially Binge Drinking, which is the consumption of large amounts of alcohol in a short time. In addition to the 4 possible pharmacological treatments, many studies have been conducted to increase the therapeutic possibilities, with the highlight in the drug baclofen, the latest addition to the list of drugs authorized in France for this treatment. In recent years, several studies to determine the efficacy of baclofen have been performed, mainly on the racemic form RS (±)-baclofen, but divergent results have been found. After the isolation of the 2 enantiomers of this drug, R (+)-baclofen and S (-)-baclofen, it was found the efficacy of the drug lies in the active enantiomer R. That raised the question if really the best treatment would be with the racemic form RS. Thus, this study sought to characterize the enantioselective effects of baclofen in an animal model of chronic binge-like consumption in male and female Long Evans rats, focusing on the differences between the two genders, since there are no studies in this regard. R (+)-baclofen, S (-)-baclofen and the racemic form, which is the only one still administered to patients, were evaluated for their effectiveness. Then, the relation of the dopaminergic system was also evaluated, since the release of dopamine in the mesolimbic pathway changes with alcohol consumption and baclofen, being a GABA-B receptor agonist, acts in the same pathways. The results provide important evidence, as they suggest that the variability of patients' response to racemic form is due to the different effects of the 2 enantiomers and a decrease in alcohol consumption with response to therapy are due to sensitization to the R enantiomer and, on the contrary, an increase in consumption may be due to S enantiomer. A differential response of the dopaminergic system seems to be the reason their differences appear. More interestingly, it has been shown that the racemic form RS has no effect on females and the R enantiomer has little effect compared to males. These results suggest the currently available treatment leads to variable therapeutic response in women.
Currently, among the world's health problems is excessive alcohol consumption, especially Binge Drinking, which is the consumption of large amounts of alcohol in a short time. In addition to the 4 possible pharmacological treatments, many studies have been conducted to increase the therapeutic possibilities, with the highlight in the drug baclofen, the latest addition to the list of drugs authorized in France for this treatment. In recent years, several studies to determine the efficacy of baclofen have been performed, mainly on the racemic form RS (±)-baclofen, but divergent results have been found. After the isolation of the 2 enantiomers of this drug, R (+)-baclofen and S (-)-baclofen, it was found the efficacy of the drug lies in the active enantiomer R. That raised the question if really the best treatment would be with the racemic form RS. Thus, this study sought to characterize the enantioselective effects of baclofen in an animal model of chronic binge-like consumption in male and female Long Evans rats, focusing on the differences between the two genders, since there are no studies in this regard. R (+)-baclofen, S (-)-baclofen and the racemic form, which is the only one still administered to patients, were evaluated for their effectiveness. Then, the relation of the dopaminergic system was also evaluated, since the release of dopamine in the mesolimbic pathway changes with alcohol consumption and baclofen, being a GABA-B receptor agonist, acts in the same pathways. The results provide important evidence, as they suggest that the variability of patients' response to racemic form is due to the different effects of the 2 enantiomers and a decrease in alcohol consumption with response to therapy are due to sensitization to the R enantiomer and, on the contrary, an increase in consumption may be due to S enantiomer. A differential response of the dopaminergic system seems to be the reason their differences appear. More interestingly, it has been shown that the racemic form RS has no effect on females and the R enantiomer has little effect compared to males. These results suggest the currently available treatment leads to variable therapeutic response in women.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Palavras-chave
Binge drinking Consumo de álcool Sistema dopaminérgico Diferenças entre sexos Mestrado Integrado - 2019