Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-17T12:24:07Z No. of bitstreams: 1 tiagobaessomonteirodecastro.pdf: 1669524 bytes, checksum: 9a14116f51037cbccac895a4f9c011a8 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-28T14:04:30Z (GMT) No. of bitstreams: 1 tiagobaessomonteirodecastro.pdf: 1669524 bytes, checksum: 9a14116f51037cbccac895a4f9c011a8 (MD5) / Made available in DSpace on 2016-06-28T14:04:30Z (GMT). No. of bitstreams: 1 tiagobaessomonteirodecastro.pdf: 1669524 bytes, checksum: 9a14116f51037cbccac895a4f9c011a8 (MD5) Previous issue date: 2015-11-05 / Introdução: A maioria dos protocolos para o tratamento do mieloma múltiplo (MM) é composto pelo bortezomibe e/ou talidomida, associados a outras drogas, como agentes alquilantes e corticóides. A farmacovigilância mostra-se uma importante ferramenta durante o tratamento, pois é grande a chance dos pacientes apresentarem algum tipo de efeito adverso (EA). Objetivo: Avaliar as principais toxicidades dos protocolos que utilizam bortezomibe e/ou talidomida para o tratamento do MM. Materiais e Métodos: Foi realizado um estudo prospectivo de farmacovigilância, em que esta foi exercida através de entrevistas realizadas a cada retorno do paciente, observação clínica e consultas aos exames laboratoriais e prontuários. Os critérios National Cancer Institute versão 4.0 foram utilizados para identificação e graduação de EA. Os dados foram coletados em 3 instituições, no período de 28 meses. Resultados: Foram incluídos no estudo 59 pacientes (tendo sido avaliados 62 tratamentos). Houve uma predominância do sexo feminino, 36 (61%), versus 23 (39%) do sexo masculino, e de brancos, 49 (83,1%) versus 10 (16,9%) da raça negra. A idade dos pacientes variou de 40 a 94 anos, com mediana de 65 anos de idade (DP = 11,6). Em relação ao estadiamento ao diagnóstico, 27 (45,7%) pacientes se encontravam no estádio III-A, sendo 12 (20,3%) pacientes com creatinina ≥ 2. Os principais EA do grupo tratado com bortezomibe (n = 40) foram: neutropenia (42,5%), diarreia (47,5%) e neuropatia periférica (NP) em 60% dos casos, sem diferença (p = 0,343) da administração endovenosa do bortezomibe (n = 26) em relação a utilizacao subcutânea (n = 14). No grupo tratado com talidomida (n = 19), 31,6% apresentaram neutropenia, 47,4% constipação e 68,4% NP. A neutropenia esteve associada ao uso de alquilantes (p = 0,038). Dos 3 pacientes que receberam bortezomibe associado a talidomida apenas 1 apresentou NP (33,3%). Conclusão: A NP foi o principal EA dos protocolos que utilizaram bortezomibe ou talidomida, com maior risco de neutropenia naqueles que utilizaram agentes alquilantes. Aprimorar a identificação de EA é fundamental para o cuidado com o paciente portador de MM que apresenta melhoras progressivas no tratamento e requer um uso racional e seguro dos medicamentos. / Introduction: Most protocols for the treatment of multiple myeloma (MM) consist of bortezomib and/or thalidomide, combined with other drugs such as alkylating agents and corticosteroids. Pharmacovigilance proves to be an important tool during treatment, as there is a high likelihood of patients having some type of adverse effect (AE). Objective: To assess the major adverse effects of the protocols that use bortezomib and/or thalidomide for the treatment of MM. Materials and methods: A prospective study of pharmacovigilance, carried out through interviews at each appointment with the patient, clinical observation, and by consulting laboratory tests and medical records. The National Cancer Institute criteria, version 4.0, were used for the identification and grading of AEs. Data were collected at three institutions, over 28 months. Results: A total of 59 patients (with 62 treatments being evaluated) were included in the study. There was a predominance of females, 36 (61%), versus 23 (39%) males, and Whites, 49 (83.1%), versus Blacks, 10 (16.9%). Patient age ranged from 40 to 94 years, with a median of 65 years (SD = 11.6). Regarding staging at diagnosis, 27 (45.7%) of the patients were in stage III-A, with 12 (20.3%) patients having creatinine ≥ 2. The main AEs for the bortezomib treatment group (n = 40) were: neutropenia (42.5%), diarrhea (47.5%), and peripheral neuropathy (PN) in 60% of cases, with no difference (p = 0.343) between intravenous administration of bortezomib (n = 26) and subcutaneous use (n = 14). In the group treated with thalidomide (n = 19), 31.6% had neutropenia, 47.4% constipation, and 68.4% PN. Neutropenia was associated with the use of alkylating agents (p = .038). Of the 3 patients who received bortezomib combined with thalidomide, only 1 presented NP (33.3%). Conclusion: NP was the main AE of the protocols that used bortezomib or thalidomide, with increased risk of neutropenia in those using alkylating agents. Improving the identification AEs is critical in caring for the patient with MM, which shows progressive improvements in treatment, and requires a rational and safe use of medicines.

Orientador: Patrícia Moriel / Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T03:57:40Z (GMT). No. of bitstreams: 1 Carvalho_IndiraValade_M.pdf: 1267534 bytes, checksum: de03a91e0914a3ff437fe44fca10a9e9 (MD5) Previous issue date: 2013 / Resumo: A segurança na utilização de medicamentos tornou-se um tema altamente discutido nas políticas de saúde, em parte devido a pesquisas que demonstram a ocorrência de importantes eventos adversos aos medicamentos (EAM) causados por fármacos comumente utilizados. Poucos estudos em pediatria quantificam os EAM, o que demonstra a necessidade da condução de mais estudos com esta faixa etária. O objetivo deste trabalho foi realizar uma análise prospectiva sobre a incidência de EAM e estabelecer o perfil de adesão à farmacoterapia de uso contínuo em pacientes pediátricos admitidos em uma unidade de emergência. Trata-se, portanto, de um estudo transversal, com duração de um ano (julho/2011 a junho/2012), conduzido na Unidade de Emergência Referenciada Pediátrica do Hospital de Clínicas da (HC) da Universidade Estadual de Campinas (UNICAMP). Os EAM foram identificados, quantificados e caracterizados em 7 categorias (reação adversa ao medicamento; não adesão; inefetividade terapêutica; uso inadequado do medicamento; interação medicamentosa; intoxicação e queixa técnica) e classificados segundo a gravidade obedecendo aos critérios do CTCAE (Common Terminology Criteria for Adverse Events). As reações adversas aos medicamentos foram classificadas pela causalidade, segundo Algoritmo de Naranjo. Para os pacientes em tratamento medicamentoso em regime contínuo, foi avaliado o grau de adesão à terapia proposta utilizando o Teste de Morisky-Green. No período de estudo foram admitidos na unidade de emergência 20.441 pacientes e 1723 (8,4%) foram atendidos pela farmacêutica responsável pelo projeto. Destes, 199 (11,5%) foram admitidos em decorrência de pelo menos um EAM e fazem parte da "População EAM" e 226 (13,2%) relataram o uso de pelo menos um medicamento em regime contínuo e por isso foram incluídos na "População Adesão". O evento de maior frequência foi uso inadequado do medicamento, identificado em 39,3% dos casos. O principal medicamento envolvido nos casos de reação adversa ao medicamento, não adesão e uso inadequado foi a Amoxicilina (26,0%). Nos casos em que mais de um medicamento estava envolvido em um ou mais eventos, notou-se que a maioria dos medicamentos causadores dos EAM provinha de medicamentos prescritos (85,8%). Foi observada maior ocorrência de EAM de gravidade leve (62,9%) e, ao estudo da causalidade das reações adversas, apenas 1 caso foi classificado como definido (2,4%). Quanto às características do perfil de adesão à farmacoterapia prescrita, houve predomínio de alta adesão (62,2%) principalmente entre crianças de 0 a 9 anos. Este trabalho demonstra uma alta incidência de EAM relacionados à admissão de pacientes pediátricos em unidade de emergência. A carência de informações e de estudos publicados na área demonstra a necessidade de estímulo a pesquisas nos grandes pólos de saúde no Brasil os quais poderão demonstrar o real problema de eventos adversos aos medicamentos na pediatria, podendo com isso estabelecer propostas de ações mais efetivas para o uso racional de medicamentos nesta faixa etária o que ressalta a importância da atuação do farmacêutico clínico através da atenção farmacêutica, para orientar e intervir no uso correto dos medicamentos / Abstract: The safety drug utilization has became a highly visible topic in health politics, due in part to research suggesting that there are important adverse drug events (ADE) caused by commonly used medications. Few pediatric studies quantify the ADE; this fact demonstrates the necessity of conducting further research with this age group. The objective of this study was to realize a prospective analysis on the incidence of ADE and to establish the profile of adherence to pharmacotherapy of continuous use in pediatric patients admitted to an emergency unit. This study was transversal with lasting one year (July/2011 to June/2012), conducted at the Emergency Pediatric Unit, Hospital de Clinicas (HC), State University of Campinas (UNICAMP). The ADE were identified, quantified and characterized in seven categories: (adverse drug reaction, non-compliance, and treatment ineffectiveness, inappropriate use of medication, drug interactions, toxicity, and technical defect) and classified by severity according to the criteria of the CTCAE (Common Terminology Criteria for Adverse Events). The adverse drug reactions were classified by causality, second to Naranjo algorithm, and type (organ involved). For patients under treatment in continuous, the degree of adherence to therapy proposal was evaluated using the Morisky-Green test. During the study period 20,441 patients were admitted and 1,723 (8.4%) were attended by the pharmaceutical responsible for the project. Of these, 199 (11.5%) were admitted with at least one ADE and form part of the "Population ADE"; and 226 (13.2%) were evaluated because of administering at least one drug in continuous and so were included in the "Population Adherence". The most frequent event was inappropriate use of the drug, identified in 39.3% of cases. The main drug involved in cases of adverse reaction to medication, non-compliance and inappropriate use was Amoxicillin (26.0%). In cases where more than one drug was involved in one or more events, it was noted that most of the drugs that cause ADE came from prescription drugs (85.8%). There was higher occurrence of ADE mild severity (62.9%), and the study of causality of adverse events, only 1 case was classified as definite (2.4%). Regarding the characteristics of the profile of adherence to pharmacotherapy prescribed, were higher in adherence (62.2%) mainly children aged 0 to 9 years. This work demonstrates a high incidence of ADE related to admission of pediatric patients in emergency unit. The lack of information and studies published in the area demonstrates the need to stimulate research in major health centers in Brazil which will demonstrate the real problem of adverse drug events in pediatric, and this may establish proposals for more effective actions for rational drug use in this age group which emphasizes the importance of the role of the clinical pharmacist through pharmaceutical care to guide and intervene in the correct use of medicines / Mestrado / Ciencias Biomedicas / Mestra em Ciências Médicas

L'utilisation de termes équivalents ou sémantiquement proches est nécessaire pour augmenter la couverture et la sensibilité d'une application comme la recherche et l'extraction d'information ou l'annotation sémantique de documents. Dans le contexte de l'identification d'effets indésirables susceptibles d'être dûs à un médicament, la sensibilité est aussi recherchée afin de détecter plus exhaustivement les déclarations spontanées et de mieux surveiller le risque médicamenteux. C'est la raison qui motive notre travail. Dans notre travail de thèse, nous cherchons ainsi à détecter des termes sémantiquement proches et à les regrouper en utilisant plusieurs méthodes : des algorithmes de clustering non supervisés, des ressources terminologiques exploitées avec le raisonnement terminologique et des méthodes de Traitement Automatique de la Langue, comme la structuration de terminologies, où nous visons la détection de relations hiérarchiques et synonymiques. Nous avons réalisé de nombreuses expériences et évaluations des clusters générés, qui montrent que les méthodes proposées peuvent contribuer efficacement à la tâche visée. / The use of equivalent terms or semantically close is necessary to increase the coverageand sensitivity of applications such as information retrieval and extraction or semanticannotation of documents. In the context of the adverse drug reactions identification, sensitivityis also sought to detect more exhaustively spontaneous reports and better monitordrug risk. This is the reason that motivates our work. In our work, we thus seek to detectsemantically close terms and the together using several methods : unsupervised algorithms, terminological resources exploited with terminological reasoning and methodsof Natural Language Processing, such as terminology structuring, where we aim to detecthierarchical and synonymous relations. We conducted many experiments and evaluations of generated, which show that the proposed methods can efficiently contribute tothe task in question.

This thesis applied a novel interdisciplinary approach for pharmacovigilance to examine the use of complementary and integrative medicine (CIM), focusing on herbal remedies, to manage pediatric attention-deficit hyperactivity disorder (ADHD). The safety and potential risk of herb-drug interactions in ADHD management were first evaluated through an assessment of available information on the safety and efficacy of natural health products (NHPs) commonly used by ADHD patients as a means of identifying knowledge gaps. A clinical questionnaire was administered to caregivers of pediatric patients with ADHD to determine the factors and related outcomes of CIM use, including adverse events. A systematic search was conducted to further identify clinical adverse events involving herbal remedies and ADHD drugs to determine causal links to herb-drug interactions. In vitro analysis of identified herbal remedies was conducted to determine their potential for pharmacokinetic interactions, specifically on carboxylesterase-1 (CES1) mediated metabolism. The presented research builds on otherwise scarce evidence of the safety of herbal remedies for ADHD, particularly with respect to herb-drug interactions and adverse events (AEs) associated with concurrent use of NHPs and ADHD prescription drugs. Beyond studies conducted on the pharmacokinetic safety of herbal remedies through the cytochrome P450 pathways that metabolize some ADHD drugs, including amphetamine, atomoxetine and guanfacine, few data were available for CES1, which metabolizes methylphenidate, the first line of drug used to manage ADHD. The clinical questionnaire revealed that 40% of patients had used CIM and confirmed the use of a variety of CIM. Moreover, the majority of CIM users were also concurrently taking ADHD medication, and eight mild adverse events were self-reported. The systematic search on the adverse event reporting system highlighted a potential NHP-drug interaction between methylphenidate and St. John’s wort, and the overall poor quality of NHP-related adverse event reports. As a follow-up from the adverse event results, various commercial St. John’s wort products showed variable inhibition of recombinant human CES1 in vitro. Although the concentration of marker phytochemicals was not correlated to inhibition, hyperforin showed stronger activity than hypericin and quercetin. The preliminary in vitro investigation revealed that the herbal remedies used by ADHD patients have the potential to interact with CES1 mediated metabolism, with Rhodiola rosea identified as the most potent inhibitor. Further investigation on various commercial products of Rhodiola rosea revealed both reversible and irreversible inhibition of recombinant CES1. However, the inhibition was not dependent on the concentration of marker phytochemicals, and rosarin, rosavin, rosin, and salidroside were not potent inhibitors of recombinant CES1. Moreover, a commercial Rhodiola rosea extract showed concentration-dependent inhibition of human liver microsome meditated metabolism of methylphenidate. Overall, results from this thesis suggest potential risk from use of NHPs concurrently with conventional medicine used to manage ADHD. Improved evidence and pharmacovigilance for the use of NHPs in a pediatric population is warranted.

El presente documento es un trabajo de investigación, cuya finalidad es la de entender la situación actual del sistema de farmacovigilancia en Lima Metropolitana y comprender que, es necesario promover y concientizar sobre el reporte de sospecha de reacciones adversas para fortalecer el sistema de farmacovigilancia; en vista de que el tema que nos ocupa es nuevo y de vanguardia se ha optado por usar la metodología de entrevista profunda a expertos especialistas en el tema. La entrevista profunda tiene la finalidad de conocer la situación real y actualizada de la farmacovigilancia en Lima Metropolitana y las diferentes perspectivas de los actores que pertenecen al sistema, perspectivas respecto al estado de farmacovigilancia, sobre la concientización, sobre las capacitaciones y la opinión de los expertos respecto a las estrategias del Ministerio de Salud y su órgano adscrito DIGEMID. Es así como mediante estas entrevistas, se ha realizado un acercamiento profundo a logrando respaldar la hipótesis y estableciendo cuáles serían los principales objetivos para concientizar sobre el impacto a nivel preventivo que se tendría en la Salud colectiva fortalecimiento del sistema de farmacovigilancia. Finalmente, se propone la creación de una asociación de grupo de personas que trabajen sin fines de lucro para trabajar objetivos claves que engranen actividades aisladas, lograr romper paradigmas en la atención primaria en relación al reporte de sospecha de reacciones adversas, cambios de actitud, a través de programas, talleres de reporte y actividades que promuevan contribuir con el fortalecimiento del sistema de farmacovigilancia. / The following document is a research within the purpose of understand the current situation of the pharmacovigilance system in Metropolitan Lima, then understand that it is necessary to promote and generate awareness about the suspect adverse reaction notification to strengthen the pharmacovigilance system, after review the fact that the area at hand is new and advance-guard, it has been decided to use as methodology, experts in-depth interviews. In-depth interview has a purpose of knowing the real and updated situation of pharmacovigilance in Metropolitan Lima and the different perspectives of actors that belong to the system, within perspectives regarding to pharmacovigilance status, about physician awareness, about training and opinion about Health authority strategies, both Ministry of health and its attached DIGEMID. Finally, a community or associations whom work non-profit is proposed in order to work on key objectives that engage isolated activities, achieve breaking paradigms in primary care due to suspected adverse reactions notification, changes in attitude through programs, workshops and others activities, to strengthening the pharmacovigilance system. / Trabajo de investigación

Indiana University-Purdue University Indianapolis (IUPUI) / Adverse drug events (ADEs) are injuries resulting from drug-related medical interventions. ADEs can be either induced by a single drug or a drug-drug interaction (DDI). In order to prevent unnecessary ADEs, many regulatory agencies in public health maintain pharmacovigilance databases for detecting novel drug-ADE associations. However, pharmacovigilance databases usually contain a significant portion of false associations due to their nature structure (i.e. false drug-ADE associations caused by co-medications). Besides pharmacovigilance studies, the risks of ADEs can be minimized by understating their mechanisms, which include abnormal pharmacokinetics/pharmacodynamics due to genetic factors and synergistic effects between drugs. During the past decade, pharmacogenomics studies have successfully identified several predictive markers to reduce ADE risks. While, pharmacogenomics studies are usually limited by the sample size and budget. In this dissertation, we develop statistical methods for pharmacovigilance and pharmacogenomics studies. Firstly, we propose an empirical Bayes mixture model to identify significant drug-ADE associations. The proposed approach can be used for both signal generation and ranking. Following this approach, the portion of false associations from the detected signals can be well controlled. Secondly, we propose a mixture dose response model to investigate the functional relationship between increased dimensionality of drug combinations and the ADE risks. Moreover, this approach can be used to identify high-dimensional drug combinations that are associated with escalated ADE risks at a significantly low local false discovery rates. Finally, we proposed a cost-efficient design for pharmacogenomics studies. In order to pursue a further cost-efficiency, the proposed design involves both DNA pooling and two-stage design approach. Compared to traditional design, the cost under the proposed design will be reduced dramatically with an acceptable compromise on statistical power. The proposed methods are examined by extensive simulation studies. Furthermore, the proposed methods to analyze pharmacovigilance databases are applied to the FDA’s Adverse Reporting System database and a local electronic medical record (EMR) database. For different scenarios of pharmacogenomics study, optimized designs to detect a functioning rare allele are given as well.

No description available.

Health care systems in Saudi Arabia and elsewhere play a significant role in the lives of individuals as well as society at large. Although healthcare aims at enhancing the quality of life it can sometimes happen that treatment itself can lead to a diminution of the quality of life due to unexpected adverse effects. These problems may cause therapeutic failures or even drug-related morbidity and mortality. Consequently there is a need to have in place a system, conventionally known as Pharmacovigilance. The aims of Pharmacovigilance are to identify, quantify and continuously monitor all drug use through a system which would enable all health care professionals such as physicians, pharmacists, dentists and nurses to contribute. This thesis investigated the present knowledge of and use of, the Pharmacovigilance system in Makkah, in the Kingdom of Saudi Arabia. A mixed method yielded data that provided depth and breadth to the findings of this study. A questionnaire was designed for 170 community pharmacists and 310 respondents drawn from different medical roles across the seven hospitals in Makkah yielded some useful results. Resistance to change was identified in some groups but it was of interest to discover that 72% of respondents who admitted that their knowledge was insufficient were, nevertheless, agreed about its importance. Key issues from the analysis of the questionnaire were used to design the second phase of the sequential mixed method which involved semi structured interviews with seven senior pharmacists, one from each of the seven hospitals. Analysis yielded three overarching categories: Technology, Internalisation and Motivation. A follow up feedback survey at the end of a lecture, of a group of pharmacy students enhanced the overall findings of the study and revealed a very high degree of interest and acceptance of Pharmacovigilance reporting systems and an expressed desire for its inclusion as a subject in its own right in their training programme. Conflicting epistemological positions inherent in a mixed method are candidly admitted and no attempt is made to circumvent this difficulty. Rather, the enhanced nature of the findings is highlighted despite the opposing knowledge claims of both approaches. A key finding was that 59% of the respondents were unaware of the Saudi National Pharmacovigilance centre (NPC) and reporting arrangements. The problems of lack of internet access and of suitable reporting forms were important contributory reasons for the under-usage of the system. There is a need to raise awareness of all pharmacists of the importance of the knowledge and practice of Pharmacovigilance. Technological solutions should be implemented to facilitate reporting at all levels. Continuing professional development should include Pharmacovigilance. Resistance to change can be addressed by identifying the motivational factors that can lead to a more wholehearted acceptance of the importance of Pharmacovigilance for patient care and well-being. Indeed, these could well be the focus of future studies. / Ministry of Interior, KSA

Quinolones are a group of antibiotics that have gained significant popularity on a global scale since the end of the last century. This popularity was predominantly based on their proven potency, broad coverage against a wide range of bacteria, in addition to possessing a favorable pharmacologic profile. Whereas quinolone-associated adverse reactions are generally tolerable and self-limiting, some reactions have generated heightened concerns due to their serious nature, which have resulted in label changes or even market withdrawal in some instances. This thesis investigates the association between quinolone antibiotics and two adverse reactions of an acute and serious nature: acute liver failure and retinal detachment. Each adverse reaction is investigated through integrating evidence from three studies utilizing different designs based on data from different sources, with each source offering a unique perspective on this issue. The first study type (chapter 2 for acute liver failure ‘ALF’ and Chapter 5 for retinal detachment ‘RD’) analyzes spontaneous reports submitted to the US Food & Drug Administration (FDA) adverse event reporting system database. Chapters 3 and 6 systematically identified all relevant (published and unpublished) clinical trials for occurrences of ALF and RD, respectively, among trial participants. Finally, chapters 4 (ALF) and 7 (RD) involved case-control analysis of a major US database of electronic health records for nearly 70 million inpatients admitted to more than 500 hospitals between 2000 and 2016. The FAERS analysis revealed a positive ALF signal with ciprofloxacin and a marginal signal for RD with moxifloxacin. Examination of the evidence from clinical trials revealed only two cases of ALF, one associated with gemifloxacin and one with moxifloxacin. No cases of RD were reported in any of the identified clinical trials. Primary analyses of the Health Facts® data revealed no overall association between quinolones and the risk of ALF or RD. However, elevated risk was identified in some subgroups, including African Americans (ALF, RD), Caucasians (ALF), women (ALF, RD), men (ALF), those ≤60 years of age (ALF) or 56-70 years of age (RD), and those with no or few comorbidities (ALF). Evidence from analyses of data from spontaneous reports and clinical trials provided some evidence for an elevated risk of ALF or RD following the systemic administration of quinolone antibiotics. Some evidence of elevated risk was also identified in the case-control analyses of inpatient EHR records. Findings from our six epidemiologic studies are in line with current advisories by FDA and Health Canada.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.