Projeto de mestrado para implementação de um sistema de gestão da qualidade em farmácia comunitária

Nos últimos anos, a Qualidade em Instituições de saúde tem sido um tema relevante. O conceito de qualidade tem várias definições, sendo um conceito difícil de medir e definir. A Qualidade é uma ferramenta cada vez mais almejada pelas instituições que prestam cuidados de saúde e neste caso particular pela Farmácia Comunitária. Essa procura advém da necessidade de garantir um atendimento aos utentes cada vez mais eficaz e eficiente, capaz de satisfazer as suas reais necessidades e expectativas, por meio da otimização de processos e economização de recursos, tornando-se, por isso, uma prioridade nas áreas onde os farmacêuticos operam. O objetivo deste projeto é clarificar e explicar as etapas para a implementação de um Sistema de Gestão da Qualidade, com base na Norma ISO 9001:2008, numa Farmácia Comunitária, encorajando toda a equipa e promovendo o empenho e envolvência de todos nas práticas de gestão integrada da qualidade e nas estratégias de melhoria contínua. A Implementação de um Sistema de Gestão da Qualidade com base na norma ISO 9001:2008 poderá ter um impacto muito positivo, contribuindo não apenas para a melhoria da qualidade interna da organização, nas suas diversas vertentes, como também para a focalização nos seus clientes, melhorando ainda mais a qualidade dos serviços prestados, demonstrando ser relevante para a saúde, para a forma como os recursos humanos se organizam em torno do trabalho e para racionalização dos recursos. Desta forma se demonstra o valor desta ferramenta na gestão, eficácia e segurança no sistema de utilização do medicamento em Farmácia Comunitária.

Familial amyloid polyneuropathy: TTR sequencing and "in silico" analysis

Familial amyloid polyneuropathy (FAP) or paramiloidosis is an autosomal dominant neurodegenerative disease with onset on adult age that is characterized by mutated protein deposition in the form of amyloid substance. FAP is due to a point alteration in the transthyretin (TTR) gene and until now more than 100 amyloidogenic mutations have been described in TTR gene. FAP shows a wide variation in age-at-onset (AO) (19-82 years, in Portuguese cases) and the V30M mutation often runs through several generation of asymptomatic carriers, before expressing in a proband, but the protective effect disappear in a single generation, with offspring of late-onset cases having early onset. V30M mutation does not explain alone the symptoms and AO variability of the disease observed in the same family. Our aim in this study was to identify genetic factors associated with AO variability and reduced penetrance which can have important clinical implications. To accomplish this we genotyped 230 individuals, using a directautomated sequencing approach in order to identify possible genetic modifiers within the TTR locus. After genotyping, we assessed a putative association of the SNPs found with AO and an intensive in silico analysis was performed in order to understand a possible regulation of gene expression. Although we did not find any significant association between SNPs and AO, we found very interesting and unreported results in the in silico analysis since we observed some alterations in the mechanism of splicing, transcription factors binding and miRNAs binding. All of these mechanisms when altered can lead to dysregulation of gene expression, which can have an impact in AO and phenotypic variability. These putative mechanisms of regulation of gene expression within the TTR gene could be used in the future as potential therapeutical targets, and could improve genetic counselling and follow-up of mutation carriers.

The evolving profile, role and relevance of the medical director in a pharmaceutical company

Over the last years, operations in Pharmaceutical Companies have become more complex, trying to adapt to new demands of the market environment. Overall, the observed change of paradigm requires adapting, mainly by the setting of new priorities, diversification of investments, cost containment strategies, exploring new markets and developping new sets of skills. In this context, new functions have been created, the relevance of some has diminished, and the importance of others has arisen. Amongst these, the medical structure within a Pharmaceutical Company, increased to meet demands, with companies adopting different models to respond to these needs, and becoming a pillar to the business. Assuming the leading role within a medical department, the medical director function often lies in the shadow. It is a key function within Pharma Industry, either on a country or on a Global basis. It has evolved and changed in the past years to meet the constant demands of a changing environment. The Medical Director is a highly skilled and differeniated professional who provides medical and scientific governance within a Pharmaceutical company, since early stages of drug development and up to loss of exclusivity, not only but also by leading a team of other physicians, pharmacists or life scientists whose functions comprise specificities that the medical director needs to understand, provide input to, oversee and lead. As the organization of Pharmaceutical Companies tends to be different, in accordance to values, culture, markets and strategies, the scope of activities of a Medical Director can be broader or may be limited, depending on size of the organization and governance model, but they must fulfil a large set of requirements in order to leverage impact on internal and internal customers. Key technical competencies for medical directors such as an MD degree, a strong clinical foundation, knowledge of drug development, project and team management experience and written and verbal skills are relatively easy to define, but underlying behavioural competencies are more difficult to ascertain, and these are more often the true predictors of success in the role. Beyond seamless proficiency in technical skills, at this level interpersonal skills become far more important, as they are the driver and the distinctive factor between a good and an excelent medical director. And this has impact in the business and in the people doing it.

Saccharomycotin transcriptomics by next-generation sequencing

The non-standard decoding of the CUG codon in Candida cylindracea raises a number of questions about the evolutionary process of this organism and other species Candida clade for which the codon is ambiguous. In order to find some answers we studied the transcriptome of C. cylindracea, comparing its behavior with that of Saccharomyces cerevisiae (standard decoder) and Candida albicans (ambiguous decoder). The transcriptome characterization was performed using RNA-seq. This approach has several advantages over microarrays and its application is booming. TopHat and Cufflinks were the software used to build the protocol that allowed for gene quantification. About 95% of the reads were mapped on the genome. 3693 genes were analyzed, of which 1338 had a non-standard start codon (TTG/CTG) and the percentage of expressed genes was 99.4%. Most genes have intermediate levels of expression, some have little or no expression and a minority is highly expressed. The distribution profile of the CUG between the three species is different, but it can be significantly associated to gene expression levels: genes with fewer CUGs are the most highly expressed. However, CUG content is not related to the conservation level: more and less conserved genes have, on average, an equal number of CUGs. The most conserved genes are the most expressed. The lipase genes corroborate the results obtained for most genes of C. cylindracea since they are very rich in CUGs and nothing conserved. The reduced amount of CUG codons that was observed in highly expressed genes may be due, possibly, to an insufficient number of tRNA genes to cope with more CUGs without compromising translational efficiency. From the enrichment analysis, it was confirmed that the most conserved genes are associated with basic functions such as translation, pathogenesis and metabolism. From this set, genes with more or less CUGs seem to have different functions. The key issues on the evolutionary phenomenon remain unclear. However, the results are consistent with previous observations and shows a variety of conclusions that in future analyzes should be taken into consideration, since it was the first time that such a study was conducted.

Product quality and compliance in the pharmaceutical industry

This thesis aims to highlight the importance of a Product Quality & Compliance department in a Pharmaceutical Industry, on the good performance of company's activities and the achievement of their goals and mission. Despite the wide activities performed by this Department, the purpose of this work will be completed by describing only some of their reponsibilities. The tasks described are specifically the ones I have been performing throughout my professional experience at Bluepharma - Pharmaceutical Industry, SA, initiated in June 2012 in the Quality Assurance Department until today in the currently named Product Quality & Compliance department. This thesis is structured into 4 parts. The first chapter is an introduction to this thesis, and includes its context and objectives, followed by a brief overview of the state-of-the art in the pharmaceutical industry, including the market environment, the regulatory environment and quality requirements. A small presentation of the company and the department where were and still are developed my professional activity is also made in this chapter. In the following chapter are described the main tasks performed, the complementary activities and key skills acquired throughout this professional experience. A discussion and conclusion is presented at the end, including an analysis of the reported activities, main difficulties encountered its role and importance in the company performance as well as the skills acquired during this work experience.

Fingolimod real world experience

Fingolimod is a Multiple Sclerosis treatment licensed in Europe since 2011. Its efficacy has been demonstrated in three large phase III trials, used in the regulatory submissions throughout the world. As usual, in these trials the inclusion and exclusion criteria were designed to obtain a homogeneous population, with interchangeable characteristics in the different treatment arms. Although this is the best strategy to achieve a robust answer to the investigation question, it does not guaranty the treatment efficacy in the clinical practice, since in the real world there are concomitant treatments, comorbidities, adherence and persistence challenges. But, to make informed treatment decision for a real life patient, we need to have evidence of the treatment efficacy, what has been called treatment effectiveness. This work aims to review fingolimod effectiveness, using as source of information abstracts, posters and manuscripts. This unorthodox strategy was developed because more than half of the published experience with fingolimod is still on abstracts and posters. Only a small part of the studies reviewed are already published in peer reviewed journals. Fingolimod seems to be, at least, as effective and safe as it was on clinical trials, and with its long term experience no new safety signals were observed. In the Portuguese hospital perspective, early treatment with fingolimod is expected to result in better clinical outcomes associated with a more efficient healthcare resources allocation.

Curricular training report: 7 months as a study coordinator at Blueclinical LTD

The present report describes in detail the activities undertaken under the coordination of clinical and observational studies during the curricular internship at Blueclinical Ltd., inserted in the Master of Pharmaceutical Biomedicine. Blueclinical Ltd.company operates in three different areas: R&D consultancy, management and coordination of trial centers, and a phase I unit. The curricular internship had the duration of seven months during which I was able to perform different tasks relating to coordination of clinical trials in Centro Hospitalar do Baixo Vouga, E.P.E., (CHBV) in Aveiro, Portugal. This academic internship allowed me to develop theoretical and practical skills in the field of clinical trials and observational studies. I also had the opportunity to further the knowledge I gained throughout my academic journey. During this internship, I had the opportunity to interact with different health professionals and develop my knowledge in the field of several therapeutic indications. I also could interact with distinct monitors and sponsors. This experience allowed me to improve time management, communication and problems resolution skills.

Agentes etiológicos de infecções urinárias em ambulatório

As infeções do trato urinário (ITU), depois das infeções respiratórias, são as mais comuns na comunidade, sendo a Escherichia coli o principal agente etiológico. Afeta predominantemente o sexo feminino e, anualmente, estima-se que ocorram em todo o Mundo cerca de 150 milhões de episódios de ITU, sendo responsável por 15% dos antibióticos prescritos em ambulatório. Os objetivos deste estudo foram caracterizar os agentes etiológicos das ITU e determinar o seu padrão de resistência aos antimicrobianos na região litoral norte de Portugal, de modo a contribuir para o uso racional na terapêutica empírica. Foi realizado um estudo observacional, descritivo e transversal, sendo obtidos 80 967 resultados de uroculturas de um Laboratório de Análises Clínicas de prestação de serviços à comunidade, relativos ao período entre Abril de 2007 e Março de 2015. Registaram-se 13 541 bacteriúrias positivas (16,72%). Escherichia coli foi o microrganismo mais isolado (71,62%), seguida de Klebsiella pneumoniae (12,41%), Proteus mirabilis (7,84%), Enterococcus. faecalis (3,97%) e Pseudomonas aeruginosa (1,42%), tendo-se observado diferenças estatisticamente significativas entre sexos e idades. Verificou-se uma diminuição da resistência aos antimicrobianos a partir do ano de 2012. E. coli apresentou em 2015 a menor taxa de resistência respetivamente de 4,46% e 12,37% para a fosfomicina e nitrofurantoína. A combinação de amoxicilina+ácido clavulânico registou uma taxa de resistência superior a 20% (22,03%). O baixo nível de resistência à fosfomicina permite que este antibiótico se apresente como a opção terapêutica de primeira linha no tratamento empírico de ITU não complicada na mulher em ambulatório, pelo que, estes resultados permitem corroborar as indicações de 2011 da Direção Geral de Saúde sobre a substituição de fluoroquinolonas por fosfomicina.

Curricular training report: clinical studies coordination in a clinical research organization vs an investigational site perspective

This report describes my experience of nine months as a trainee of a CRO (Eurotrials, Scientific Consultants), as well as a trainee of a clinical research site (Clinical Academic Center – Braga, Association). This document describes the European framework about clinical research and the Portuguese situation compared to similar countries. The activities developed during this internship are also described. These activities are divided in two phases. The first one occurred in Eurotrials, Scientific Consultants, a CRO specialized in clinical research and scientific advice. The first weeks were dedicated to intensive self-training needed to perform CTA tasks. These tasks included qualification, initiation and monitoring activities related to clinical trials, as well as the development of a quality management system. The second phase took place on 2CA-Braga, a clinical research center located in Hospital of Braga. Clinical studies coordination was the main focus of this second phase of my internship, as well as negotiation of clinical studies agreements. I had also the opportunity to participate in “1as Jornadas de Investigação Clínica e Inovação” (1st Clinical Investigation and Innovation Conference) organized by 2CA-Braga. Globally, this internship was a great opportunity to get knowledge and experience in the implementation and management of clinical trials, in a CRO and clinical research site perspectives. These two perspectives provided an interesting overview about the scientific needs of different players involved in clinical research. To conclude, this internship strengthened the knowledge acquired from my academic background, which make me able to face and overcome new challenges in the clinical research area.

O médico na indústria farmacêutica: contributo para o enquadramento da atividade

Ao longo desta dissertação de mestrado pretendemos analisar e discutir o papel do Médico na Indústria Farmacêutica, contribuindo para um melhor enquadramento de uma atividade ainda não muito conhecida. A partir da análise da implementação da Indústria Farmacêutica em Portugal, descrevemos o seu contributo para a Sociedade aliado ao valor do medicamento. Descrevemos a Medicina Farmacêutica, o treino da atividade e alguns dos órgãos relevantes nesta área, como a Competência em Medicina Farmacêutica da Ordem dos Médicos e a Associação dos Médicos Portugueses da Indústria Farmacêutica. De uma forma detalhada caraterizamos as atividades e competências do Médico nesta indústria que reforçamos com uma análise de um questionário efetuado com as opiniões de colegas Portugueses e estrangeiros com experiência nesta área do conhecimento. Concluímos, reconhecendo a importância da atividade, da sua caraterização e dos seus desafios futuros.

Optimization of a multielectrode array (MEA)-based approach to study the impact of Aβ on the SH-SY5Y cell line

The human brain stores, integrates, and transmits information recurring to millions of neurons, interconnected by countless synapses. Though neurons communicate through chemical signaling, information is coded and conducted in the form of electrical signals. Neuroelectrophysiology focus on the study of this type of signaling. Both intra and extracellular approaches are used in research, but none holds as much potential in high-throughput screening and drug discovery, as extracellular recordings using multielectrode arrays (MEAs). MEAs measure neuronal activity, both in vitro and in vivo. Their key advantage is the capability to record electrical activity at multiple sites simultaneously. Alzheimer’s disease (AD) is the most common neurodegenerative disease and one of the leading causes of death worldwide. It is characterized by neurofibrillar tangles and aggregates of amyloid-β (Aβ) peptides, which lead to the loss of synapses and ultimately neuronal death. Currently, there is no cure and the drugs available can only delay its progression. In vitro MEA assays enable rapid screening of neuroprotective and neuroharming compounds. Therefore, MEA recordings are of great use in both AD basic and clinical research. The main aim of this thesis was to optimize the formation of SH-SY5Y neuronal networks on MEAs. These can be extremely useful for facilities that do not have access to primary neuronal cultures, but can also save resources and facilitate obtaining faster high-throughput results to those that do. Adhesion-mediating compounds proved to impact cell morphology, viability and exhibition of spontaneous electrical activity. Moreover, SH-SY5Y cells were successfully differentiated and demonstrated acute effects on neuronal function after Aβ addition. This effect on electrical signaling was dependent on Aβ oligomers concentration. The results here presented allow us to conclude that the SH-SY5Y cell line can be successfully differentiated in properly coated MEAs and be used for assessing acute Aβ effects on neuronal signaling.

Curricular trainig report as study coordinator in Blueclinical Ltd.

The present report describes in detail the activities and knowledge aquired during my internship as study coordinator in Blueclinical – Investigação e Desenvolvimento em Saúde, Ltd., in order to obtain the master degree in Pharmaceutical Biomedicine. According to the type of services provided, Blueclinical is formed by three business units: Blueclinical Clinical Research Partnership, Blueclinical Phase I and Blueclinical Research and Development. The fact of belonging to such a company gave me the opportunity to be in touch with different areas of pharmaceutical development and to contact with different research teams, which for me was an added advantage to the integration and consolidation of knowledge, as well as in the development and improvement of soft and hard skills. The main activity developed was the coordination of clinical studies, in Unidade Local de Saúde de Matosinhos, E.P.E., which was one of the institutions that established a partnership with Blueclinical, Ltd. During my internship I was able to contact with various stages of development and coordination of clinical trials, which will be reported in this report.

Curricular internship report in medical writing at Blueclinical, Portugal

The contents of this report are a summary of the activities carried out during the 8-month internship as an Associate Medical Writer at Blueclinical Ltd, Matosinhos, Portugal. Mainly my activities were related to medical writing, particularly writing the clinical research protocols, clinical study reports, writing manuscript and preparing poster presentations. In addition to these activities, I also participated in performance of a clinical trial from beginning to end. During the period of its realization, I was able to familiarize myself with all the steps of the Phase I clinical trial.

Influence of substrates composition on immunomodulation by MSCs

Mesenchymal stem cells (MSCs) are non-hematopoietic multipotent stem cells capable to self-renew and differentiate along different cell lineages. MSCs can be found in adult tissues and extra embryonic tissues like the umbilical cord matrix/Wharton’s Jelly (WJ). The latter constitute a good source of MSCs, being more naïve and having a higher proliferative potential than MSCs from adult tissues like the bone marrow, turning them more appealing for clinical use. It is clear that MSCs modulate both innate and adaptive immune responses and its immunodulatory effects are wide, extending to T cells and dendritic cells, being therapeutically useful for treatment of immune system disorders. Mechanotransduction is by definition the mechanism by which cells transform mechanical signals translating that information into biochemical and morphological changes. Here, we hypothesize that by culturing WJ-MSCs on distinct substrates with different stiffness and biochemical composition, may influence the immunomodulatory capacity of the cells. Here, we showed that WJ-MSCs cultured on distinct PDMS substrates presented different secretory profiles from cells cultured on regular tissue culture polystyrene plates (TCP), showing higher secretion of several cytokines analysed. Moreover, it was also shown that WJ-MSCs cultured on PDMS substrates seems to possess higher immunomodulatory capabilities and to differentially regulate the functional compartments of T cells when compared to MSCs maintained on TCP. Taken together, our results suggest that elements of mechanotransduction seem to be influencing the immunomodulatory ability of MSCs, as well as their secretory profile. Thus, future strategies will be further explored to better understand these observation and to envisage new in vitro culture conditions for MSCs aiming at distinct therapeutic approaches, namely for immune-mediated disorders.

LAP1 interactome and its functional features throughout spermatogenesis

The lamina-associated polypeptide 1 (LAP1) is a type II transmembrane protein of the inner nuclear membrane encoded by the human gene TOR1AIP1. LAP1 is involved in maintaining the nuclear envelope structure and appears be involved in the positioning of lamins and chromatin. In the nuclear envelope, LAP1 is suggested to exist as a complex with A-type and B-type lamins, torsins and emerin. The presence of such complexes suggests that LAP1 may cooperate functionally with these proteins in tissues where they play a critical role. Therefore, the identification of LAP1 binding partners and the signalling pathways where LAP1 participates, is crucial for a better understanding of LAP1 functions. The work described in this thesis addresses novel human LAP1 associated proteins found through bioinformatic tools. Public databases allowed for the discovery of the LAP1 interactome, which was manually curated, identifying several functionally relevant proteins. Subsequently, the integration of multiple bioinformatic tools established novel functions to LAP1 such as DNA damage response and telomere association. In conjunction, bioinformatic results also reinforced the association of LAP1 with mitosis, and the already identified role of LAP1 in nuclear morphology. Interestingly, this association of LAP1 with the regulation of the nuclear envelope structure and mitosis progression, shares functional elements with spermatogenesis. Therefore, this work additionally described the localization of LAP1 and some of its interactors throughout the spermatogenic cycle, in mouse and human testis. The results established that the activity of LAP1 during the mouse spermatogenic cycle is most evident from stage VIII until the end of spermiogenesis, which is characteristic of manchette development. Concomitantly, some LAP1 interactors studied in this work share a similar localization, namely, PP1γ2, Lamin B1 and Lamin A/C. The results obtained from the study of LAP1 throughout different periods of the male reproductive system attributed potential new biological functions to LAP1. Thereby, this work can be the foundation of future studies regarding LAP1 and the regulation of multiple cellular processes and disease conditions.