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- ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms and antidepressant response phenotypes: results from a portuguese major depressive disorder cohortPublication . Santos, Marlene; Lima, Luís; Carvalho, Serafim; Brandão, Andreia; Barroso, Fátima; Cruz, Agostinho; Medeiros, RuiP-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood–Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T, G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T, C3435T and G2677TA polymorphisms were genotyped with TaqMan® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms (C1236T, C3435T and G2677TA) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself.
- Uma abordagem à avaliação de ambientes virtuais de aprendizagemPublication . Jesus, Ângelo; Gomes, Maria JoãoA avaliação de ambientes de aprendizagem é um tema complexo e multifatorial. No presente trabalho apresenta-se a proposta de avaliação de um ambiente virtual de aprendizagem utilizado para o ensino da farmacoterapia baseado em casos clínicos. Utilizou-se a versão portuguesa reduzida do WEBLEI assim como a Evaluative Assertion Analysis para a recolha de dados. Os resultados obtidos são abonatórios ao nível do acesso aos materiais, interação com os conteúdos e a plataforma, interação com o docente assim como na estruturação e design. Foram reveladas algumas fragilidades nomeadamente ao nível da interação entre estudantes e gestão de tempo. As inferências obtidas serão alvo de reflexão pela equipa de desenvolvimento da UC no processo contínuo de melhoria da iniciativa.
- Acetonitrile adducts of tranexamic acid as sensitive ions for quantification at residue levels in human plasma by UHPLC-MS/MSPublication . Silva, Eduarda M. P.; Barreiros, Luísa; Fernandes, Sara R.; Sá, Paula; Ramalho, João P. Prates; Segundo, Marcela A.The quantitative analysis of pharmaceuticals in biomatrices by liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) is often hampered by adduct formation. The use of the molecular ion resulting from solvent adducts for quantification is uncommon, even if formed in high abundance. In this work, we propose the use of a protonated acetonitrile adduct for the quantitative analysis of tranexamic acid (TXA) by LC-MS/MS. The high abundance of the protonated acetonitrile adduct [M + ACN + H]+ was found to be independent of source-dependent parameters and mobile phase composition. The results obtained for TXA analysis in clinical samples were comparable for both [M + ACN + H]+ and [M + H]+ , and no statistically significant differences were observed. The relative stability and structure of the [M + ACN + H]+ ions were also studied by analyzing probable structures from an energetic point of view and by quantum chemical calculations. These findings, and the studied fragmentation pathways, allowed the definition of an acetimidium structure as the best ion to describe the observed acetonitrile protonated adduct of TXA.
- Adaptive design: A review of the technical, statistical, and regulatory aspects of implementation in a clinical trialPublication . Cerqueira, Franck Pires; Jesus, Ângelo; Cotrim, Maria DulceIn an adaptive trial, the researcher may have the option of responding to interim safety and efficacy data in a number of ways, including narrowing the study focus or increasing the number of subjects, balancing treatment allocation or different forms of randomization based on responses of subjects prior to treatment. This research aims at compiling the technical, statistical, and regulatory implications of the employment of adaptive design in a clinical trial. Review of adaptive design clinical trials in Medline, PubMed, EU Clinical Trials Register, and ClinicalTrials.gov. Phase I and seamless phase I/II trials were excluded. We selected variables extracted from trials that included basic study characteristics, adaptive design features, size and use of independent data-monitoring committees (DMCs), and blinded interim analysis. The research retrieved 336 results, from which 78 were selected for analysis. Sixty-seven were published articles, and 11 were guidelines, papers, and regulatory bills. The most prevalent type of adaptation was the seamless phase II/III design 23.1%, followed by adaptive dose progression 19.2%, pick the winner / drop the loser 16.7%, sample size re-estimation 10.3%, change in the study objective 9.0%, adaptive sequential design 9.0%, adaptive randomization 6.4%, biomarker adaptive design 3.8%, and endpoint adaptation 2.6%. It is possible to infer that the use of Adaptive Design is an ethical and scientific advantage when properly planned and applied, since it increases the flexibility of the trial, shortens the overall clinical investigation time of a drug, and reduces the risk of patient exposure to adverse effects related to the experimental drug. Its greater methodologic and analytic complexity requires an adequate statistical methodology. The application of “adaptive clinical designs” for phase II/III studies appear to have been limited to trials with a small number of study centers, with smaller extensions of time and to experimental drugs with more immediate clinical effects that are amenable to risk/benefit decisions based on interim analyses. According to the reviewed studies, simple adaptive trial designs—such as early study terminations due to futility and sample size re-estimation—are becoming widely adopted throughout the pharmaceutical industry, especially in phase II and III studies. The pharmaceutical industry and contract research organizations (CROs) are implementing simple adaptations more frequently and the more complex adaptations—biomarker adaptive design, endpoint adaptation—are more sporadic.
- Adverse reactions by radiopharmaceuticals: Retrospective analysis of the Portuguese National Pharmacovigilance SystemPublication . Martins, Sara; Jesus, Ângelo; Andrade, Ricardo; Rocha, Mariana; Martín-Suarez, Ana; Jesus, ÂngeloRadiopharmaceuticals are essential in the field of nuclear medicine, but like any other medicinal product, radiopharmaceuticals can potentially cause adverse reactions in patients. To describe the adverse reactions to radiopharmaceuticals reported to the Portuguese National Pharmacovigilance System (SNF). Methods: We performed a retrospective, observational study by examining individual case safety reports (ICSRs) provided by the SNF related to all radiopharmaceuticals commercially available in Portugal from 2010 to 2023. The SNF received a total of 84 ICSRs. These reports resulted in a total of 224 adverse drug reactions (ADR), which involved a total of 15 different radiopharmaceuticals. The mean age of patients was 61.9 years old. Twenty-one different system organ classes (SOCs) were identified, with the most prevalent situations being “Gastrointestinal Disorders” (18.3%; n = 41) followed by “General disorders and administration site conditions” (16.5%; n = 37), “Skin and subcutaneous tissue disorders” (11.2%; n = 25) and “Blood and lymphatic system disorders” (10.3%; n = 23). Fifty-seven reports (67.85%) showed at least 1 serious ADR. Most notified radiopharmaceuticals were, respectively, radium—223 (n = 36, 41.4%), lutetium-177 oxotreotide (n = 12, 13.8%) and iodide—131 (n = 9, 10.3%). Although the number of notifications is limited, these findings provide valuable insights into the types and frequencies of adverse reactions associated with radiopharmaceuticals used in Portugal between 2010 and 2023. The data highlight the importance of continued pharmacovigilance efforts to monitor the safety of these specialized medical products and inform clinical decision-making.
- Adverse reactions mediated by 99mTc-tetrofosmin: Literature review and analysis of post-marketing reportsPublication . Martins, Sara; Costa, Sara Poças; Sousa, Mariana; Moreira, Fernando; Martín-Suaréz, A.; Jesus, Ângelo; Jesus, Ângelo; Moreira, Fernando99mTc-tetrofosmin is a diagnostic radiopharmaceutical used to evaluate cardiac pathologies. Despite the lower incidence of reactions compared to other drugs, radiopharmaceuticals can still cause adverse reactions. For this reason, pharmacovigilance plays a crucial role in detecting, understanding, evaluating and preventing them. This study aims to review the available literature,on the safety of99mTc-tetrofosmin, and to analyze spontaneous adverse drug reaction reports from the European EudraVigilance database. A literature review was conducted according to PRISMA methodology. An analysis of spontaneous notifications was carried out in EudraVigilance, until 2022. The review identified a selection of 7 articles. The most reported adverse reactions were skin irritation, strange taste in the mouth and nausea. Regarding the EudraVigilance analysis, 220 notifications were identified, accounting for 477 adverse reactions. The majority belong to males (51%), between 18-64 years (45%). Health professionals were the main reporters (84%). The most prevalent System Organ Class was “general disorders and administration site conditions” (21%) and the most reported adverse reaction was pruritus (10%). Approximately 67% of reactions were considered serious, with 6 fatal cases recorded. The results demonstrated that adverse reactions associated with99mTc-tetrofosmin do occur and should not be minimized. Over a period of 17 years, only 220 notifications were recorded, which may highlight potential challenges in pharmacovigilance for radiopharmaceuticals. Therefore, raising awareness about the importance of reporting adverse reactions is crucial.
- Allergic rhinitis characterization in community pharmacy customers: a cross-sectional studyPublication . Hélio, Guedes; Morgado, Manuel; Rodrigues, Márcio; Cruz, Agostinho; Fonseca, Cecília; Costa, Elísio; Araújo, André R. T. S.Allergic rhinitis represents a public health problem that is signifcantly prevalent in the global population and has been associated with asthma, a strong desire to sleep and a low quality of life. Objective This study aims to evaluate the prevalence, symptoms, control strategies and treatment, as well as the control of this condition and its impact on the quality of life of customers of community pharmacies with allergic rhinitis.
- Altered NRF2 signalling in systemic redox imbalance: Insights from non-communicable diseasesPublication . Santos, Marlene; Morgenstern, Christina; Santos, MarleneThe balanced activity of the cytoprotective transcription factor NRF2 is central for maintaining redox, metabolic-energetics, and proteome homeostasis, as well as for regulating inflammatory responses, among other functions. Activated NRF2 regulates the expression of hundreds of genes containing antioxidant response elements (AREs) or electrophile response elements (EpRE) in their regulatory regions, often promoting cytoprotection under stress conditions and contributing to defence against various pathologies and non-communicable diseases (NCDs). The products of increased NRF2 activity, detected systemically, may originate from either the white blood cells, the cells of the vasculature or tissue-derived products that could be secreted into biological fluids. Therefore, assessing basal and inducible NRF2 activity in blood or other biofluids is crucial for inferring NRF2 responses in local and often inaccessible tissues. In previous work, we identified a panel of six biomarkers - Glutamate-cysteine ligase catalytic subunit (GCLC), Glutamate-cysteine ligase modifier subunit (GCLM), Haem oxygenase 1 (HMOX1), NAD(P)H quinone dehydrogenase 1 (NQO1), Sulfiredoxin 1 (SRXN1), and Thioredoxin reductase 1 (TXNRD1) - as indicators of NRF2 activity. In the current study, we assess their utility in a clinical setting to measure NRF2 activation in a disease context. Here we discuss findings on how NRF2 activity in accessible human samples can reveal its involvement in various NCDs and its connection to clinical aspects such as diagnosis, disease progression and response to therapy.
- An overview of the recent advances in antimicrobial resistancePublication . Oliveira, Manuela; Antunes, Wilson; Mota, Salete; Carvalho, Áurea Madureira; Oliveira, Ricardo Jorge Dinis; Silva,Diana Dias daAntimicrobial resistance (AMR), frequently considered a major global public health threat, requires a comprehensive understanding of its emergence, mechanisms, advances, and implications. AMR’s epidemiological landscape is characterized by its widespread prevalence and constantly evolving patterns, with multidrug-resistant organisms (MDROs) creating new challenges every day. The most common mechanisms underlying AMR (i.e., genetic mutations, horizontal gene transfer, and selective pressure) contribute to the emergence and dissemination of new resistant strains. Therefore, mitigation strategies (e.g., antibiotic stewardship programs—ASPs—and infection prevention and control strategies—IPCs) emphasize the importance of responsible antimicrobial use and surveillance. A One Health approach (i.e., the interconnectedness of human, animal, and environmental health) highlights the necessity for interdisciplinary collaboration and holistic strategies in combating AMR. Advancements in novel therapeutics (e.g., alternative antimicrobial agents and vaccines) offer promising avenues in addressing AMR challenges. Policy interventions at the international and national levels also promote ASPs aiming to regulate antimicrobial use. Despite all of the observed progress, AMR remains a pressing concern, demanding sustained efforts to address emerging threats and promote antimicrobial sustainability. Future research must prioritize innovative approaches and address the complex socioecological dynamics underlying AMR. This manuscript is a comprehensive resource for researchers, policymakers, and healthcare professionals seeking to navigate the complex AMR landscape and develop effective strategies for its mitigation.
- Análise da rotulagem de suplementos alimentares utilizados no Sistema Nervoso CentralPublication . Ferreira, Liliana; Cruz, Agostinho; Oliveira, Ana Isabel; Ferraz Oliveira, Rita; Pinho, CláudiaOs suplementos alimentares têm diversos benefícios demonstrados. No entanto, a crença errónea por parte dos consumidores de que estes são isentos de risco e as obrigações legais requeridas para a sua entrada no mercado têm servido de alerta para a necessidade de mais investigação. Analisar, do ponto de vista legal e científico, a informação disponibilizada na rotulagem de suplementos alimentares à base de plantas utilizados para problemas associados ao Sistema Nervoso, comercializados em Portugal. Estudo descritivo, observacional, transversal com a recolha de 44 rótulos de suplementos comercializados em Farmácias Comunitárias e em Ervanárias/Lojas Dietéticas da cidade de Vila Nova de Famalicão, entre julho e agosto de 2019, em formulário próprio. Do ponto de vista legal, a maioria dos SA analisados cumpriu as menções obrigatórias na rotulagem. Do ponto de vista científico, o nome científico das plantas foi a informação que mais frequentemente está presente na rotulagem, com 97,7%. A padronização dos extratos (29,5%), as interações (11,4%) e as reações adversas (11,4%) foram as informações menos mencionadas. Os resultados obtidos realçam a necessidade de uma maior atenção quanto às informações existentes na rotulagem dos suplementos, no sentido de permitir aos consumidores um uso informado e seguro dos produtos.