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- Síntese de derivados da estrona funcionalizados nos anéis C e D como potenciais agentes anti-cancerígenosPublication . Pires, Patrícia Sofia Cabral; Canário, Catarina; Silvestre, Samuel MartinsNa presente dissertação é apresentada informação relativa à experiência adquirida no estágio curricular em farmácia comunitária, assim como ao trabalho de investigação experimental efetuado paralelamente. O estágio em farmácia comunitária, realizado maioritariamente na farmácia Holon Covilhã, permitiu-me efetuar tarefas e adquirir conhecimentos no âmbito das várias áreas de intervenção farmacêutica: aprovisionamento, atendimento, gestão de documentação, gestão de qualidade e ações perto da comunidade. Permitiu-me não só perceber um pouco melhor qual a extensão do contributo do farmacêutico para a saúde pública, como também adquirir e aprofundar o meu conhecimento das ciências farmacêuticas. A investigação experimental, levada a cabo no Centro de Investigação em Ciências da Saúde da Universidade da Beira Interior, incidiu sobre o desenvolvimento e a avaliação biológica de derivados da molécula de estrona funcionalizados nos anéis C e D com potencial atividade anti-tumoral. Com este objetivo, foram sintetizadas algumas moléculas e efetuou-se a avaliação da sua atividade anti-proliferativa em várias linhas celulares humanas. Os resultados desta avaliação biológica parecem demonstrar que o derivado com a substituição 9a-hidroxi-11ß-nitrooxi tem elevada ação anti-proliferativa nas várias linhas celulares estudadas. Adicionalmente, a introdução de uma dupla ligação entre os carbonos 9 e 11 levou também a um marcado efeito anti-proliferativo, principalmente em células HepaRG. Esta modificação estrutural, bem como a introdução de uma lactona no anel D, têm potencial interesse, uma vez que têm sido associadas a uma redução da estrogenicidade, o que poderá ser benéfico na seletividade da sua ação. São necessários, no entanto, estudos mais aprofundados para confirmação e melhoria dos resultados obtidos.
- The promise of prodrugs and nanosystems in nose-to-brain delivery of poorly soluble drugsPublication . Pires, Patrícia Sofia Cabral; Santos, Adriana Oliveira dos; Alves, Gilberto Lourenço; Rodrigues, Márcio José de Abreu MarquesIn brain-targeted drug delivery, the intranasal route can be a good alternative to parenteral administration. In addition to being associated with a greater comfort for the patient, intranasal drug delivery can reduce systemic drug distribution, resulting in an increased safety, and can allow direct drug transport to the brain, resulting in an increased therapeutic efficacy. For example, benzodiazepines administration for the treatment of acute epileptic episodes has been proven to be at least as effective as their intravenous administration. Nevertheless, their solubilization requires substantial amounts of organic solvents, which can cause lacrimation and nose and throat irritation. Additionally, benzodiazepines can cause somnolence, deleterious cognitive effects and dependence/tolerance. Phenytoin is also an antiepileptic drug, being non-inferior in efficacy, while not having these adverse effects. Although its systemic administration can cause other adverse events (such as cardiovascular complications or liver toxicity), its intranasal administration could increase its safety and even efficacy compared to other non-invasive routes in the treatment of status epilepticus. Yet, phenytoin has low aqueous solubility, being difficult to formulate at a high strength. However, its hydrophilic prodrug, fosphenytoin, has high water solubility. Hence, aqueous liquid water-based formulations of fosphenytoin for intranasal administration were developed. Pharmacokinetic results in mice showed that a fosphenytoin formulation containing hydroxypropyl methylcellulose and albumin prolonged drug concentration in the brain, also producing a high absolute drug bioavailability. The study demonstrated that phosphate ester prodrugs (such as fosphenytoin) can be an efficient strategy to increase the intranasal bioavailability of low solubility drugs (such as phenytoin). In addition, we hypothesized that if there was phenytoin in the formulation, in the active and diffusible form, brain drug delivery could be increased and/or made faster. Thus, nano and microemulsions containing phenytoin (internalized in the oil droplets) and fosphenytoin (solubilized in the aqueous phase) in combination were developed. A microemulsion having good characteristics (reasonably homogeneous, with small droplet size and physically stable for at least 1 week) was selected for pharmacokinetic evaluation in mice. In addition to the intranasal administration of this selected microemulsion, containing both phenytoin and fosphenytoin, a second microemulsion was also administered intranasally, having an identical composition but without phenytoin (with fosphenytoin only), for comparison purposes. Despite the existence of a small amount of phenytoin in the formulation not inducing accelerated brain drug delivery, it led to prolonged and increased drug levels. Moreover, the intranasal administration of the microemulsion containing both drugs led to a maximum brain concentration that was similar to that obtained with the intravenous fosphenytoin solution, also leading to prolonged drug retention. The microemulsion containing both drugs also had a higher bioavailability than any of the intranasally administered formulations containing fosphenytoin only (microemulsion without phenytoin, and simple fosphenytoin formulations). Furthermore, both microemulsions (the one containing both drugs and the one containing fosphenytoin only) led to higher drug concentrations at initial time points than those obtained with the simple intranasal fosphenytoin solution, which suggests that the microemulsion had a drug permeation enhancement effect. Thus, in general this work allowed to prove that the use of phosphate ester prodrugs can be an effective strategy in increasing the intranasal bioavailability of low solubility drugs, albumin is a good strategy to prolong brain targeting, the existence of a small amount of active drug (in addition to the prodrug), in an emulsified form, can increase drug levels at longer time points, and the use of microemulsions can increase brain drug delivery at shorter time points.