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  • Pharmacometric Evaluation of the Intranasal Administration of New Antiepileptic Drugs Loaded in Lipidic Nanosystems: Focus on Perampanel and Stiripentol
    Publication . Meirinho, Sara Alexandra; Alves, Gilberto Lourenço; Rodrigues, Márcio José de Abreu Marques; Ferreira, Amílcar Celta Falcão Ramos
    Even though there are numerous options for epilepsy treatment, the effective control of all epileptic patients continues to be unsatisfactory. Besides the available therapeutics only provide the management of epileptic seizures, a high number of patients never respond to any of the established treatments or ends up developing pharmacoresistance and/or serious longstanding adverse effects. That commonly results in a noncompliance to the therapeutics and in the need of changing disease control strategies. Therefore, it is urgent to broaden the available therapeutic options in order to successfully provide a complete control of seizures, always maintaining acceptable tolerability and safety profiles. However, the ideal antiepileptic drug capable of preventing, delaying or modifying epilepsy has not yet emerged. Thus, the development of alternative therapeutic options able to improve the efficacy/safety binomial of the already available antiepileptic drugs may be a very attractive approach. In this context, the intranasal (IN) administration of antiepileptics formulated in state-of-the-art lipidic nanosystems is presented as a promising strategy. In addition of providing greater comfort to patients, IN administration can increase brain bioavailability of drugs and decrease their peripheral systemic exposure, which may result in a better therapeutic efficacy and safety profile even using lower doses than the currently used. In fact, there are two clinically available benzodiazepines formulated for IN administration that already proved to be as effective as their intravenous administration for the treatment of acute epileptic seizures, demonstrating this route viability to be clinically applied in epilepsy management. This primarily relies on the unique anatomic connection between the olfactory region and the central nervous system that allows a partial direct delivery of drugs to brain, bypassing the blood-brain barrier. That offers a great opportunity for intranasally administered drugs to gain quick and easy access to the brain, minimizing their systemic exposure. Still, since the nasal epithelium is highly vascularized, part of the intranasally administered drugs is unavoidably absorbed to bloodstream. However, the anatomical characteristics of the nasal blood supply also allow drugs to circumvent the hepatic first-pass metabolism, particularly increasing the systemic bioavailability of drugs subject to extensive metabolism and/or drug interactions. Nonetheless, the IN route is also associated with some disadvantages as the restricted volume of nasal cavity, which requires the administration of small volumes of highly concentrated formulations. So, to increase the prospect of achieving brain therapeutic concentrations using compatible instillation volumes, the use of relatively potent drugs should be considered. Nevertheless, there are also less potent drugs that could greatly benefit from being intranasally delivered. For that, a viable alternative is to formulate them into safe lipidic nanosystems as the case of nanometric emulsions. These formulations are usually lipophilic, biocompatible, easy to prepare and with a high solubilization capacity of poorly water-soluble drugs, attributes that make them a promising strategy for nose-to-brain delivery of neurotherapeutics as antiepileptic drugs. With that in mind, the main purpose of this work was to evaluate the potential of the IN route to administrate two third-generation antiepileptics – perampanel (PER) and stiripentol (STP). Fundamentally, PER is a very potent antiepileptic drug that acts through a unique mechanism of action, making it a very attractive molecule to be formulated in a nanosystem for nose-to-brain delivery. With that, it is expected that PER quickly attains higher brain concentrations, which could be highly beneficial in chronic therapeutic schedules and, mainly, as a rescue therapy in emergency situations. On the other hand, STP does not present a favourable oral pharmacokinetic profile – it is not a potent drug, it is chemically unstable in gastric acid, it follows a non-linear pharmacokinetics, an extensive hepatic metabolism, and it is highly likely to be involved in drug-drug interactions. Thus, it seems possible that a nanometric emulsion of STP for IN delivery could potentially favour its pharmacokinetics and therapeutic efficacy even using lower doses than the currently used by oral route. So, in order to understand whether PER and STP could benefit from being intranasally administered, pharmacokinetic and pharmacodynamic studies were performed after its IN dosing, being the obtained results compared with the ones obtained after oral and intravenous administration. To support the execution of whole project, the work started by developing and validating an appropriate bioanalytical technique for the simultaneous quantification of PER and STP in mice plasma, brain, liver and kidney. In essence, the developed high performance liquid chromatographic method coupled with fluorescence detection revealed to be simple, fast, precise, accurate, selective and highly sensitive. Additionally, the salting-out assisted liquid-liquid extraction technique optimized by a design of experiments allowed to maximize the recovery values of both antiepileptics after samples’ extraction and quickly prepare the high number of samples expected from the pharmacokinetic experiments. With the purpose of administering PER intranasally, the developed self-microemulsifying drug delivery system (SMEDDS) demonstrated to be the most promising strategy. This nanometric emulsion type not only presented good pharmaceutical characteristics to promote nose-to-brain delivery of PER, but also revealed to be safe, not causing local or systemic histopathological changes nor variations in the olfactory sense of mice. By using it, the IN administration resulted in a substantially higher and prolonged brain exposure of PER comparatively with its oral and intravenous administration. Additionally, the maximum plasmatic and brain concentrations of PER attained with IN delivery were significantly higher and reached faster than the obtained after the oral administration of the same dose. An uneven distribution profile of PER, with the highest drug concentration levels being attained in olfactory bulbs, was found after PER IN dosing, strongly suggesting a rostral-caudal drug distribution with a possible involvement of a direct transport pathway from nose to brain. Comparatively with same oral dose, the IN administration of PER resulted in an improved anticonvulsant activity, also showing some anxiolytic potential at longer times after a single IN dose. After IN dosing, PER only caused a slight neuromotor impairment when maximum concentrations were attained, a condition that was normalized after a once a day IN administration for seven consecutive days. In terms of neurochemical evaluation, IN PER decreased the brain levels of L-glutamate and nitric oxide, without changing the levels of gamma-aminobutyric acid. Contrary to PER, the most promising formulation for STP IN delivery was a high strength microemulsion containing a high proportion of external aqueous phase. That allowed the addition of chitosan and albumin, excipients that may increase formulation residence time in nasal cavity, promote drug permeation through nasal epithelium and potentiate the direct delivery of STP, particularly at longer times post IN dosing. Like PER SMEDDS, this microemulsion strategy also fulfilled the critical quality attributes for being intranasally administered. Compared with the administration of an 8-fold higher oral dose, the STP maximum concentrations values in plasma and brain after IN administration were reached faster and were significantly higher using the developed formulation strategies. Still, a pronounced decrease in STP concentrations at early times post-dosing was obtained despite the route used for its administration. Only the IN mucoadhesive microemulsion containing albumin resulted in a second brain concentration peak 8 hours after IN dosing, with no reflection on STP plasmatic concentrations. That can be a proof of concept regarding the benefit of including albumin in IN formulations to promote a delayed direct brain delivery. Nonetheless, the brain concentrations of STP between 3 and 6 hours post-IN dosing continued to be low. Still, the bioavailability of IN STP using the three tested microemulsions revealed to be surprisingly higher than the reference values obtained with intravenous and oral routes, demonstrating that the concentration of STP available to reach brain and perform it therapeutic effects can be highly improved with an IN administration of a dose at least 8-fold lower than the oral one. According to the obtained results, it seems that the IN route using state-of-the-art nanometric emulsions can be assumed as a suitable and valuable strategy for brain delivery of PER and STP, gathering favourable conditions to be either used in acute convulsive emergencies and potentially in chronic conditions after administrating lower doses than the oral ones. Even though there is still a long road to travel, all the set of evidence resulting from our work can support the design of future clinical trials to fully demonstrate the usefulness of the IN administration of PER and STP to humans, so that its delivery to the brain can be improved with lower peripheral systemic exposure, possibly resulting in an improved clinical efficacy/safety binomial in epilepsy treatment and possibly in related comorbidities.
    2024-01-12Doctoral thesis Embargoed access Show more
  • Aplicação de Ferramentas Lean no Sector Logístico: Estudo de Caso
    Publication . Inocêncio, Guilherme Chimbaia; Morais, Flávio Daniel Correia
    A filosofia Lean Thinking e as ferramentas associadas têm se tornado prevalentes na busca por soluções que visem minimizar desperdícios, assegurar a qualidade e promover o constante aprimoramento dos processos logísticos. A presente dissertação tem como objetivo analisar a implementação de ferramentas Lean no setor logístico. Em particular, procurou-se examinar as principais motivações e desafios enfrentados na implementação das ferramentas Lean nas atividades logísticas, identificar os desperdícios combatidos pelas ferramentas aplicadas, verificar e avaliar os ganhos obtidos com a implementação desta filosofia e avaliar a situação atual para possíveis melhorias. Através de um estudo de caso no departamento logístico de uma empresa do setor automóvel que opera em Portugal, utilizando várias técnicas de recolha de dados, foi analisada a implementação da filosofia Lean. A motivação interna foi identificada como o principal impulsionador para a sua aplicação neste departamento. A resistência ao Lean foi observada entre colaboradores e na alta administração. A implementação de ferramentas como o Kanban, JIT e Gestão Visual neste setor, resultou em benefícios notáveis, como redução de tempos de espera, melhor gestão de stock e aumento da produtividade. A introdução de quadros visuais facilitou as atividades diárias dos funcionários, e de igual modo aprimorou-se o abastecimento de materiais nas linhas de produção. Essas práticas contribuíram significativamente para a melhoria geral dos processos logísticos da empresa.
    2024-01-12Master thesis Open access Show more