Erschienen:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2022
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, 2022
Anmerkungen:
Beschreibung:
Tese de Doutoramento em Ciências Farmacêuticas apresentada à Faculdade de Farmácia da Universidade de Coimbra. ; Epilepsy has a major negative impact on the quality of life of the patients and their families. With an increasing incidence, mortality and morbidity, epilepsy dictates the need for developing new safe and effective therapeutic strategies namely due to the significant percentage of patients who do not respond to the current marketed antiepileptic drugs (AEDs). The blood-brain barrier (BBB) and the efflux transporters therein expressed, including the Breast Cancer Resistance Protein (BCRP), are well-known barriers that must be overcome when an AED is administered by classic systemic routes. Furthermore, the overexpression of efflux transporters has already demonstrated to contribute to the development of pharmacoresistant epilepsy. The current scientific knowledge regarding BCRP interactions with AEDs remains scarce even though this information is extremely important to predict AEDs distribution into the central nervous system (CNS). Ideally, the administration of AEDs through alternative routes that would allow the direct access of the drug to the brain would be desirable. In this context, the present PhD thesis was planned to investigate the potential of the intranasal (IN) route to directly deliver three AEDs of new generation into the CNS. Through neural and olfactory epithelial pathways, their direct nose-to-brain delivery is expected to occur, circumventing the BBB and efflux transporters. To attain this main objective, comparative pharmacokinetic studies were carried out for lacosamide, levetiracetam and zonisamide after their administration through IN, intravenous (IV) and oral routes to male CD-1 mice. Firstly, a high performance liquid chromatography (HPLC) with diode array detection (DAD) method was developed and validated to accurately quantify the AEDs in mouse plasma, brain, lung and kidney tissues collected from the in vivo pharmacokinetic studies. Furthermore, the interaction of the ...