Determinação da estabilidade química e ex-vivo de compostos da série LINS01 e derivados do levetiracetam com potencial aplicação nos Transtornos Centrais
Carregando...
Data
2021-12-13
Autores
Domingues, Regina Helena Munhoz
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
O processo de envelhecimento populacional está associado ao desenvolvimento de transtornos do sistema nervoso central que acometem processos cognitivos e também doenças neurodegenerativas como Alzheimer e Parkinson, cujos tratamentos consistem na terapia com fármacos nootrópicos. À vista disso, os pesquisadores da Universidade Federal de São Paulo (UNIFESP) e do grupo de pesquisa Milagre Research Group (IQ/UNESP) sintetizaram compostos com potencial nootrópico, com diferentes abordagens farmacológicas, denominados compostos da série LINS01 (diidrobenzofuranil-piperazinas e diidroindol-piperazinas) e derivados do levetiracetam, respectivamente. Contudo, a avaliação da eficácia e segurança de um candidato a fármaco engloba uma série de estudos de investigação farmacológica para fundamentar a seleção dos compostos mais promissores para a continuidade do desenvolvimento do produto farmacêutico, como por exemplo os estudos de estabilidade. O presente trabalho teve como objetivo realizar estudos de estabilidade química e em plasma dos compostos LINS01 e derivados do levetiracetam. A determinação da estabilidade química e ex vivo fornece informações que permitem verificar o período de tempo na qual um composto se mantém estável e também em quais condições é provável que ocorra a geração de metabólitos tóxicos devido ao comprometimento da estrutura, que por sua vez podem influenciar parâmetros farmacocinéticos, fornecendo assim subsídios para a seleção da via de administração mais adequada à finalidade e também para a tomada de decisões ao longo do processo de desenvolvimento. Os compostos foram então submetidos a três diferentes pHs (1,2; 7,4 e 8,8) e plasma de rato por 720 minutos, sob aquecimento a 37°C e agitação constante, e avaliou-se a estabilidade dos compostos através de métodos analítico e bioanalítico, previamente desenvolvidos e validados no presente estudo. Os métodos analítico e bioanalítico forneceram reprodutibilidade e efetividade, de forma a quantificar os compostos com precisão e exatidão e os resultados dos estudos de estabilidade proporcionaram resultados satisfatórios para os compostos, classificando-os como aptos a prosseguir para os estudos pré-clínico e clínico.
The ageing population process is associated with the development of central nervous system disorders that affect cognitive processes and also neurodegenerative diseases such as Alzheimer’s and Parkinson’s, whose treatments consist of therapy with nootropic drugs. For this reason, researchers from the Federal University of São Paulo (UNIFESP) and from the Miracle Research Group (IQ / UNESP) synthesized compounds with nootropic potential, with different pharmacological approaches, called LINS01 series compounds (dihydrobenzofuranyl-piperazines and dihydroindole-piperazines) and levetiracetam derivatives, respectively. However, the evaluation of the efficacy and safety of a drug candidate includes a series of pharmacological investigation studies to support the selection of the most promising compounds to continue the development of the pharmaceutical product, for example stability studies. This present study aimed realize chemical and plasma (ex vivo) stability studies of LINS01 compounds and levetiracetam derivatives. The determination of chemical and ex vivo stability provides important informations that allows to verify the period of time in which a compound remains stable and also under which conditions is likely to occour the generation of toxic metabolites, due to the compromised structure, which can influence pharmacokinetic parameters, thus providing support for the selection of the most adequate administration routes for the purpose and also for decision-making throughout the development process. So, the compounds were subjected to three different pHs (1,2; 7,4 and 8,8) and rat plasma for 720 minutes, under heating at 37°C and constant agitation, and the stability of the compounds was evaluated through analytical and bioanalytical methods, previously developed and validated, in the present study. The analytical and bioanalytical methods provided reproducibility and effectiveness, in order to quantify the compounds with precision and accuracy, and the results of the stability studies provided satisfactory results for the compounds, classifying them as suitable for proceeding to pre-clinical and clinical studies.
The ageing population process is associated with the development of central nervous system disorders that affect cognitive processes and also neurodegenerative diseases such as Alzheimer’s and Parkinson’s, whose treatments consist of therapy with nootropic drugs. For this reason, researchers from the Federal University of São Paulo (UNIFESP) and from the Miracle Research Group (IQ / UNESP) synthesized compounds with nootropic potential, with different pharmacological approaches, called LINS01 series compounds (dihydrobenzofuranyl-piperazines and dihydroindole-piperazines) and levetiracetam derivatives, respectively. However, the evaluation of the efficacy and safety of a drug candidate includes a series of pharmacological investigation studies to support the selection of the most promising compounds to continue the development of the pharmaceutical product, for example stability studies. This present study aimed realize chemical and plasma (ex vivo) stability studies of LINS01 compounds and levetiracetam derivatives. The determination of chemical and ex vivo stability provides important informations that allows to verify the period of time in which a compound remains stable and also under which conditions is likely to occour the generation of toxic metabolites, due to the compromised structure, which can influence pharmacokinetic parameters, thus providing support for the selection of the most adequate administration routes for the purpose and also for decision-making throughout the development process. So, the compounds were subjected to three different pHs (1,2; 7,4 and 8,8) and rat plasma for 720 minutes, under heating at 37°C and constant agitation, and the stability of the compounds was evaluated through analytical and bioanalytical methods, previously developed and validated, in the present study. The analytical and bioanalytical methods provided reproducibility and effectiveness, in order to quantify the compounds with precision and accuracy, and the results of the stability studies provided satisfactory results for the compounds, classifying them as suitable for proceeding to pre-clinical and clinical studies.
Descrição
Palavras-chave
estabilidade, HPLC-MS, transtornos centrais, nootrópicos, stability, central disorders, nootropics