Introdução: Na fase pré-comercialização, os ensaios clínicos randomizados (ECRs) constituem-se em ferramenta primordial no acúmulo de informação sobre a segurança de um medicamento. Recomendações têm sido publicadas no sentido de que a informação sobre eventos adversos seja adequadamente descrita nesses estudos. Na fase pós-comercialização, vigilância ativa e passiva complementam-se e relatos de caso de reações adversas a medicamentos (RAMs) publicados em revistas médicas deveriam contribuir no processo de geração de sinal, alertando o meio científico e auxiliando na adoção de medidas pelas agências regulatórias de medicamentos. Seu impacto, no entanto, é incerto, seja na geração de estudos confirmatórios ou incorporação das RAMs em fontes de informação sobre medicamentos utilizadas na prática médica. Objetivo: avaliar, em revistas de alto impacto da área médica: 1) a adoção das recomendações da versão do CONSORT “Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement” e das recomendações propostas por outros autores em ECRs envolvendo medicamentos publicados em 2009; 2) o impacto de relatos de caso de RAMs novas publicados em 1998, através da geração de estudos controlados confirmatórios e inclusão na base de dados MICROMEDEX e no British National Formulary (BNF). Metodologia: Através de buscas no Medline, foram selecionados todos os ECRs envolvendo medicamentos publicados em 2009 nas revistas British Medical Journal, The Journal of The American Medical Association, The Lancet e The New England Journal of Medicine e os relatos de caso publicados em 1998 nas revistas Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association e New England Journal of Medicine. Baseando-se nas recomendações propostas por Ioannidis e Lau e na versão ampliada do CONSORT, as informações sobre eventos adversos foram extraídas dos ECRs. O impacto dos relatos de caso foi avaliado através da geração de estudos controlados confirmatórios publicados em revistas indexadas no Medline e/ou EMBASE e da incorporação da informação na base de dados MICROMEDEX e no BNF. Resultados: Dos 122 ECRs analisados, 32,8% objetivaram avaliar desfechos de segurança do medicamento em questão (posicionando-se a este respeito na introdução), 72,1% mencionaram riscos no título ou resumo; 10,7% esclareceram como a informação sobre riscos foi coletada; 46,7% apresentaram as frequências dos eventos adversos, separando-os por tipo e braço do estudo e especificando se algum tipo de evento adverso não ocorreu; e 18,0% apresentaram discussão balanceada sobre riscos e benefícios. Dos 32 relatos de caso de RAMs novas avaliados, verificou-se a inclusão da RAM em questão no MICROMEDEX em 16 (50%) relatos de caso e, no BNF, em 10 (32,1%). Observou-se geração de estudos controlados confirmatórios para 4 (12,5%) relatos. Conclusões: Informações importantes sobre eventos adversos permanecem insuficientemente atendidas em ECRs. Relatos de caso publicados em revistas médicas desempenham papel importante no processo de geração de sinal, impactando relativamente na geração de estudos confirmatórios e em fontes de informação da prática médica. / Introduction: In pre-commercialization phase, randomized clinical trials (RCTs) represent an essential tool for obtaining information on drug safety. Recommendations have been published so that the information about adverse events is properly described in these studies. In the pre-commercialization phase, active and passive vigilance complement one another, and case reports of adverse reactions to drugs (ADRs) published in medical journals should contribute for the process of sign generation, making the scientific world alert and supporting the adoption of measures by the regulatory drug agencies. Its impact, nonetheless, remains uncertain, both regarding the generation of confirmation studies and the ADR acceptance in the drug information sources used in the medical practice. This study aims at assessing, in highly-impacting medical journals: the compliance with the recommendations from the CONSORT version ‘Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement’ , as well as with the ones proposed by other authors in RCTs involving drugs, published in 2009; the impact of new ADR case reports published in 1998, through carrying out controlled confirmation studies and including them in the MICROMEDEX databank and in the British National Formulary (BNF). Methodology: Through Medline search, all the RCTs involving drugs published in 2009 in the journals British Medical Journal, The Journal of The American Medical Association, The Lancet and The New England Journal of Medicine were chosen. The same was done for the case reports published in 1998 in the Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association and New England Journal of Medicine. Based on the recommendations proposed by Ioannidis and Lau and in the CONSORT comprehensive version, the information on adverse events was extracted from the RCTs. The impact of the case reports was assessed through carrying out controlled confirmation studies published in journals indexed in the Medline and/or EMBASE and the inclusion of this information in the MICROMEDEX databank and the BNF. Outcomes: Among the 122 RCTs analyzed, 72.1% mentioned risks in the title or abstract; 10.7% explained how information on risks had been collected; 46.7% presented adverse event frequency, sorting them by kind and study ramification, and also specifying whether some kind of adverse event had not occurred; and 18.0% presented a balanced discussion on risks and benefits. Among the 32 new ADR case reports analyzed, it was verified that these ADRs were included in the MICROMEDEX in 16 (50%) of the case reports, and in the BNF in 10 (32.1%). It was observed that controlled confirmation studies were designed for 4 (12.5%) of these studies. Conclusions: Relevant information on adverse events remains insufficient in RCTs. Case reports published in medical journals play an important part in the sign generating process, and they also relatively impact the carrying out of confirmation studies and the information sources of the medical practice.

Introdução: Na fase pré-comercialização, os ensaios clínicos randomizados (ECRs) constituem-se em ferramenta primordial no acúmulo de informação sobre a segurança de um medicamento. Recomendações têm sido publicadas no sentido de que a informação sobre eventos adversos seja adequadamente descrita nesses estudos. Na fase pós-comercialização, vigilância ativa e passiva complementam-se e relatos de caso de reações adversas a medicamentos (RAMs) publicados em revistas médicas deveriam contribuir no processo de geração de sinal, alertando o meio científico e auxiliando na adoção de medidas pelas agências regulatórias de medicamentos. Seu impacto, no entanto, é incerto, seja na geração de estudos confirmatórios ou incorporação das RAMs em fontes de informação sobre medicamentos utilizadas na prática médica. Objetivo: avaliar, em revistas de alto impacto da área médica: 1) a adoção das recomendações da versão do CONSORT “Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement” e das recomendações propostas por outros autores em ECRs envolvendo medicamentos publicados em 2009; 2) o impacto de relatos de caso de RAMs novas publicados em 1998, através da geração de estudos controlados confirmatórios e inclusão na base de dados MICROMEDEX e no British National Formulary (BNF). Metodologia: Através de buscas no Medline, foram selecionados todos os ECRs envolvendo medicamentos publicados em 2009 nas revistas British Medical Journal, The Journal of The American Medical Association, The Lancet e The New England Journal of Medicine e os relatos de caso publicados em 1998 nas revistas Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association e New England Journal of Medicine. Baseando-se nas recomendações propostas por Ioannidis e Lau e na versão ampliada do CONSORT, as informações sobre eventos adversos foram extraídas dos ECRs. O impacto dos relatos de caso foi avaliado através da geração de estudos controlados confirmatórios publicados em revistas indexadas no Medline e/ou EMBASE e da incorporação da informação na base de dados MICROMEDEX e no BNF. Resultados: Dos 122 ECRs analisados, 32,8% objetivaram avaliar desfechos de segurança do medicamento em questão (posicionando-se a este respeito na introdução), 72,1% mencionaram riscos no título ou resumo; 10,7% esclareceram como a informação sobre riscos foi coletada; 46,7% apresentaram as frequências dos eventos adversos, separando-os por tipo e braço do estudo e especificando se algum tipo de evento adverso não ocorreu; e 18,0% apresentaram discussão balanceada sobre riscos e benefícios. Dos 32 relatos de caso de RAMs novas avaliados, verificou-se a inclusão da RAM em questão no MICROMEDEX em 16 (50%) relatos de caso e, no BNF, em 10 (32,1%). Observou-se geração de estudos controlados confirmatórios para 4 (12,5%) relatos. Conclusões: Informações importantes sobre eventos adversos permanecem insuficientemente atendidas em ECRs. Relatos de caso publicados em revistas médicas desempenham papel importante no processo de geração de sinal, impactando relativamente na geração de estudos confirmatórios e em fontes de informação da prática médica. / Introduction: In pre-commercialization phase, randomized clinical trials (RCTs) represent an essential tool for obtaining information on drug safety. Recommendations have been published so that the information about adverse events is properly described in these studies. In the pre-commercialization phase, active and passive vigilance complement one another, and case reports of adverse reactions to drugs (ADRs) published in medical journals should contribute for the process of sign generation, making the scientific world alert and supporting the adoption of measures by the regulatory drug agencies. Its impact, nonetheless, remains uncertain, both regarding the generation of confirmation studies and the ADR acceptance in the drug information sources used in the medical practice. This study aims at assessing, in highly-impacting medical journals: the compliance with the recommendations from the CONSORT version ‘Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement’ , as well as with the ones proposed by other authors in RCTs involving drugs, published in 2009; the impact of new ADR case reports published in 1998, through carrying out controlled confirmation studies and including them in the MICROMEDEX databank and in the British National Formulary (BNF). Methodology: Through Medline search, all the RCTs involving drugs published in 2009 in the journals British Medical Journal, The Journal of The American Medical Association, The Lancet and The New England Journal of Medicine were chosen. The same was done for the case reports published in 1998 in the Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association and New England Journal of Medicine. Based on the recommendations proposed by Ioannidis and Lau and in the CONSORT comprehensive version, the information on adverse events was extracted from the RCTs. The impact of the case reports was assessed through carrying out controlled confirmation studies published in journals indexed in the Medline and/or EMBASE and the inclusion of this information in the MICROMEDEX databank and the BNF. Outcomes: Among the 122 RCTs analyzed, 72.1% mentioned risks in the title or abstract; 10.7% explained how information on risks had been collected; 46.7% presented adverse event frequency, sorting them by kind and study ramification, and also specifying whether some kind of adverse event had not occurred; and 18.0% presented a balanced discussion on risks and benefits. Among the 32 new ADR case reports analyzed, it was verified that these ADRs were included in the MICROMEDEX in 16 (50%) of the case reports, and in the BNF in 10 (32.1%). It was observed that controlled confirmation studies were designed for 4 (12.5%) of these studies. Conclusions: Relevant information on adverse events remains insufficient in RCTs. Case reports published in medical journals play an important part in the sign generating process, and they also relatively impact the carrying out of confirmation studies and the information sources of the medical practice.

Made available in DSpace on 2014-12-17T14:13:51Z (GMT). No. of bitstreams: 1 RodrigoSD_DISSERT_partes.pdf: 44411 bytes, checksum: 62fe7b929c3d90fda22ce22c688f7e52 (MD5) Previous issue date: 2011-02-04 / Prescription errors are the most serious type of medication errors found in the health system. The main purpose of this study was to evaluate the quality of clonazepam prescriptions. A descriptive and observational study with retrospective data collection was conducted at 30 community pharmacies in Natal/RN, Brazil, after informed consent was obtained from the pharmacists. A sample of 313 prescription notifications was randomly collected in October 2009. They were analyzed for legible handwriting and completeness. During the study, one researcher, two pharmacists, and one pharmacy undergraduate student evaluated patient and purchaser identification, pharmaceutical form, dosing regimen, administration route, and prescription by generic name. This research was approved by the institutional Ethics Committee. Among the 313 collected notifications, only 44.1% were legible. A total of 55.91% (175/313) had at least one illegible item, 100% contained incomplete information, and 97.12% (304/313) contained one or more abbreviations. The proportion of illegible handwriting related to the patient s identification (p=0.0001) was statistically significantly greater than that related to the drug purchaser s identification (p=0.0004). Contrary to legal requirements, prescriptions with the generic name accounted for 13.42% (42/313) of the total. All the examined notifications were handwritten. Prescription errors, which potentially can have serious consequences, have been evaluated worldwide, although little is known about this subject as it relates to community pharmacies. This study showed high percentages of prescribing problems, which justifies the development of future research about medication errors in community pharmacies and education activities for prescribers / Os erros de prescri??o s?o os mais s?rios tipos de erros de medica??o encontrados no sistema de sa?de. Sendo assim, o principal objetivo desse estudo foi avaliar a qualidade das notifica??es de receita de clonazepam. Um estudo descritivo e observacional, com coleta retrospectiva de dados, foi conduzido em 30 farm?cias comunit?rias no munic?pio de Natal/RN, Brasil. Ap?s a obten??o do termo de consentimento livre e esclarecido por parte dos farmac?uticos comunit?rios, uma amostra de 313 notifica??es de receita de clonazepam foi aleatoriamente coletada em Outubro de 2009. As notifica??es foram analisadas quanto ? legibilidade e completude de informa??es. Durante o estudo, uma comiss?o, constitu?da por um dos pesquisadores, dois farmac?uticos e um estudante de gradua??o em farm?cia, avaliou os seguintes par?metros: identifica??o do paciente e comprador do medicamento, forma farmac?utica, posologia, via de administra??o e prescri??o pela denomina??o gen?rica. A pesquisa foi aprovada pelo Comit? de ?tica em pesquisa da Universidade Federal do Rio Grande do Norte. Dentre 313 notifica??es de receita de clonazepam coletadas, apenas 44,1% apresentaram-se leg?veis. Um total de 55,91% (175/313) demonstrou pelo menos um dado ileg?vel, 100% continham informa??es incompletas e 97,12% (304/313) possu?am uma ou mais abreviaturas. A propor??o de ilegibilidade relacionada ? caligrafia da identifica??o do paciente (p=0,0001) foi estatisticamente mais significante que a relacionada ? caligrafia da identifica??o do comprador do medicamento (p=0,0004). Contrariando dispositivos legais, a prescri??o pela denomina??o gen?rica ocorreu em apenas 13,42% (42/313) do total. Todas as notifica??es de receita examinadas estavam escritas ? m?o. Os erros de prescri??o, que potencialmente podem levar a s?rias consequ?ncias, t?m sido mundialmente estudados, embora pouco seja conhecido no ?mbito da farm?cia comunit?ria. Esse estudo mostrou elevados percentuais de problemas relacionados ? prescri??o, o que justifica o desenvolvimento de pesquisas futuras sobre erros de medica??o em farm?cias comunit?rias e de atividades de ensino para os prescritores

Introdução: Na fase pré-comercialização, os ensaios clínicos randomizados (ECRs) constituem-se em ferramenta primordial no acúmulo de informação sobre a segurança de um medicamento. Recomendações têm sido publicadas no sentido de que a informação sobre eventos adversos seja adequadamente descrita nesses estudos. Na fase pós-comercialização, vigilância ativa e passiva complementam-se e relatos de caso de reações adversas a medicamentos (RAMs) publicados em revistas médicas deveriam contribuir no processo de geração de sinal, alertando o meio científico e auxiliando na adoção de medidas pelas agências regulatórias de medicamentos. Seu impacto, no entanto, é incerto, seja na geração de estudos confirmatórios ou incorporação das RAMs em fontes de informação sobre medicamentos utilizadas na prática médica. Objetivo: avaliar, em revistas de alto impacto da área médica: 1) a adoção das recomendações da versão do CONSORT “Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement” e das recomendações propostas por outros autores em ECRs envolvendo medicamentos publicados em 2009; 2) o impacto de relatos de caso de RAMs novas publicados em 1998, através da geração de estudos controlados confirmatórios e inclusão na base de dados MICROMEDEX e no British National Formulary (BNF). Metodologia: Através de buscas no Medline, foram selecionados todos os ECRs envolvendo medicamentos publicados em 2009 nas revistas British Medical Journal, The Journal of The American Medical Association, The Lancet e The New England Journal of Medicine e os relatos de caso publicados em 1998 nas revistas Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association e New England Journal of Medicine. Baseando-se nas recomendações propostas por Ioannidis e Lau e na versão ampliada do CONSORT, as informações sobre eventos adversos foram extraídas dos ECRs. O impacto dos relatos de caso foi avaliado através da geração de estudos controlados confirmatórios publicados em revistas indexadas no Medline e/ou EMBASE e da incorporação da informação na base de dados MICROMEDEX e no BNF. Resultados: Dos 122 ECRs analisados, 32,8% objetivaram avaliar desfechos de segurança do medicamento em questão (posicionando-se a este respeito na introdução), 72,1% mencionaram riscos no título ou resumo; 10,7% esclareceram como a informação sobre riscos foi coletada; 46,7% apresentaram as frequências dos eventos adversos, separando-os por tipo e braço do estudo e especificando se algum tipo de evento adverso não ocorreu; e 18,0% apresentaram discussão balanceada sobre riscos e benefícios. Dos 32 relatos de caso de RAMs novas avaliados, verificou-se a inclusão da RAM em questão no MICROMEDEX em 16 (50%) relatos de caso e, no BNF, em 10 (32,1%). Observou-se geração de estudos controlados confirmatórios para 4 (12,5%) relatos. Conclusões: Informações importantes sobre eventos adversos permanecem insuficientemente atendidas em ECRs. Relatos de caso publicados em revistas médicas desempenham papel importante no processo de geração de sinal, impactando relativamente na geração de estudos confirmatórios e em fontes de informação da prática médica. / Introduction: In pre-commercialization phase, randomized clinical trials (RCTs) represent an essential tool for obtaining information on drug safety. Recommendations have been published so that the information about adverse events is properly described in these studies. In the pre-commercialization phase, active and passive vigilance complement one another, and case reports of adverse reactions to drugs (ADRs) published in medical journals should contribute for the process of sign generation, making the scientific world alert and supporting the adoption of measures by the regulatory drug agencies. Its impact, nonetheless, remains uncertain, both regarding the generation of confirmation studies and the ADR acceptance in the drug information sources used in the medical practice. This study aims at assessing, in highly-impacting medical journals: the compliance with the recommendations from the CONSORT version ‘Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement’ , as well as with the ones proposed by other authors in RCTs involving drugs, published in 2009; the impact of new ADR case reports published in 1998, through carrying out controlled confirmation studies and including them in the MICROMEDEX databank and in the British National Formulary (BNF). Methodology: Through Medline search, all the RCTs involving drugs published in 2009 in the journals British Medical Journal, The Journal of The American Medical Association, The Lancet and The New England Journal of Medicine were chosen. The same was done for the case reports published in 1998 in the Annals of Internal Medicine, Archives of Internal Medicine, The Journal of the American Medical Association and New England Journal of Medicine. Based on the recommendations proposed by Ioannidis and Lau and in the CONSORT comprehensive version, the information on adverse events was extracted from the RCTs. The impact of the case reports was assessed through carrying out controlled confirmation studies published in journals indexed in the Medline and/or EMBASE and the inclusion of this information in the MICROMEDEX databank and the BNF. Outcomes: Among the 122 RCTs analyzed, 72.1% mentioned risks in the title or abstract; 10.7% explained how information on risks had been collected; 46.7% presented adverse event frequency, sorting them by kind and study ramification, and also specifying whether some kind of adverse event had not occurred; and 18.0% presented a balanced discussion on risks and benefits. Among the 32 new ADR case reports analyzed, it was verified that these ADRs were included in the MICROMEDEX in 16 (50%) of the case reports, and in the BNF in 10 (32.1%). It was observed that controlled confirmation studies were designed for 4 (12.5%) of these studies. Conclusions: Relevant information on adverse events remains insufficient in RCTs. Case reports published in medical journals play an important part in the sign generating process, and they also relatively impact the carrying out of confirmation studies and the information sources of the medical practice.

La dématérialisation des données de santé a permis depuis plusieurs années de constituer un véritable gisement de données provenant de tous les domaines de la santé. Ces données ont pour caractéristiques d’être très hétérogènes et d’être produites à différentes échelles et dans différents domaines. Leur réutilisation dans le cadre de la recherche clinique, de la santé publique ou encore de la prise en charge des patients implique de développer des approches adaptées reposant sur les méthodes issues de la science des données. L’objectif de cette thèse est d’évaluer au travers de trois cas d’usage, quels sont les enjeux actuels ainsi que la place des data sciences pour l’exploitation des données massives en santé. La démarche utilisée pour répondre à cet objectif consiste dans une première partie à exposer les caractéristiques des données massives en santé et les aspects techniques liés à leur réutilisation. La seconde partie expose les aspects organisationnels permettant l’exploitation et le partage des données massives en santé. La troisième partie décrit les grandes approches méthodologiques en science des données appliquées actuellement au domaine de la santé. Enfin, la quatrième partie illustre au travers de trois exemples l’apport de ces méthodes dans les champs suivant : la surveillance syndromique, la pharmacovigilance et la recherche clinique. Nous discutons enfin les limites et enjeux de la science des données dans le cadre de la réutilisation des données massives en santé. / The dematerialization of health data, which started several years ago, now generates na huge amount of data produced by all actors of health. These data have the characteristics of being very heterogeneous and of being produced at different scales and in different domains. Their reuse in the context of clinical research, public health or patient care involves developing appropriate approaches based on methods from data science. The aim of this thesis is to evaluate, through three use cases, what are the current issues as well as the place of data sciences regarding the reuse of massive health data. To meet this objective, the first section exposes the characteristics of health big data and the technical aspects related to their reuse. The second section presents the organizational aspects for the exploitation and sharing of health big data. The third section describes the main methodological approaches in data sciences currently applied in the field of health. Finally, the fourth section illustrates, through three use cases, the contribution of these methods in the following fields: syndromic surveillance, pharmacovigilance and clinical research. Finally, we discuss the limits and challenges of data science in the context of health big data.

Proton pump inhibitors (PPIs) are commonly coadministered with clopidogrel, an antiplatelet agent, to patients with acute coronary syndrome (ACS). Mechanistic studies suggest that PPIs have the potential to competitively inhibit the bioactivation of clopidogrel and may attenuate its antiplatelet action in the body. The clinical implications of this drug-drug interaction have been extensively studied; however reported findings are inconsistent. More recently, several studies have questioned whether PPIs are associated with adverse cardiovascular events independent of clopidogrel. Given that PPIs and clopidogrel are widely used, it is critical to better understand the clinical impact of the concomitant treatment with both drugs. This thesis includes four studies that investigate the clinical effects of the drug-drug interaction between clopidogrel and PPIs. Chapter 2, a systematic review and meta-analysis, summarizes findings from 118 studies. Findings do not provide strong evidence for an association between adverse cardiovascular events and the use of PPIs when used alone, in combination with clopidogrel, or in combination with other antiplatelets. Chapters 3, 4, and 5 present analyses of real-world data comprised of electronic medical records. Results of these analyses demonstrate 1) that the concomitant use of clopidogrel and PPIs among inpatients was consistent with clinical guidelines suggested by the FDA (Chapter 3); 2) a lack of association between PPI use vs nonuse and four adverse cardiovascular outcomes among clopidogrel users (Chapter 4); and 3) a lack of association between PPI use vs nonuse and adverse cardiovascular outcomes among prasugrel users or ticagrelor users (Chapter 5). Collectively, our findings do not provide evidence of an elevated risk of adverse cardiovascular outcomes with the combined use of PPIs and clopidogrel. Although pharmacodynamic and pharmacokinetic studies have demonstrated an interaction between these two drugs, our findings support the opinion that the biological interaction does not translate into adverse clinical events among patients with acute coronary syndrome.

Les quatre principales activités de la gestion de risque thérapeutique comportent l’identification, l’évaluation, la minimisation, et la communication du risque. Ce mémoire aborde les problématiques liées à l’identification et à la minimisation du risque par la réalisation de deux études dont les objectifs sont de: 1) Développer et valider un outil de « data mining » pour la détection des signaux à partir des banques de données de soins de santé du Québec; 2) Effectuer une revue systématique afin de caractériser les interventions de minimisation de risque (IMR) ayant été implantées. L’outil de détection de signaux repose sur la méthode analytique du quotient séquentiel de probabilité (MaxSPRT) en utilisant des données de médicaments délivrés et de soins médicaux recueillis dans une cohorte rétrospective de 87 389 personnes âgées vivant à domicile et membres du régime d’assurance maladie du Québec entre les années 2000 et 2009. Quatre associations « médicament-événement indésirable (EI) » connues et deux contrôles « négatifs » ont été utilisés. La revue systématique a été faite à partir d’une revue de la littérature ainsi que des sites web de six principales agences réglementaires. La nature des RMIs ont été décrites et des lacunes de leur implémentation ont été soulevées. La méthode analytique a mené à la détection de signaux dans l'une des quatre combinaisons médicament-EI. Les principales contributions sont: a) Le premier outil de détection de signaux à partir des banques de données administratives canadiennes; b) Contributions méthodologiques par la prise en compte de l'effet de déplétion des sujets à risque et le contrôle pour l'état de santé du patient. La revue a identifié 119 IMRs dans la littérature et 1,112 IMRs dans les sites web des agences réglementaires. La revue a démontré qu’il existe une augmentation des IMRs depuis l’introduction des guides réglementaires en 2005 mais leur efficacité demeure peu démontrée. / The four main components of therapeutic risk management (RM) consist of risk detection (identification), evaluation, minimisation, and communication. This thesis aims at addressing RM methodologies within the two realms of risk detection and risk minimisation, through the conduct of two distinct studies: i) The development and evaluation of a data mining tool to support signal detection using health care claims databases, and ii) A systematic review to characterise risk minimisation interventions (RMIs) implemented so far. The data mining tool is based on a Maximised Sequential Probability Ratio Test (MaxSPRT), using drug dispensing and medical claims data found in the Quebec health claims databases (RAMQ). It was developed and validated in a cohort of 87,389 community-dwelling elderly aged 66+, randomly sampled from all elderly drug plan members between 2000 and 2009. Four known drug-AE associations and two "negative" controls were used. The systematic review on RMIs is based on a literature search as well as a review of the websites of six main regulatory agencies. Types of RMIs have been summarized and implementation gaps identified. The data mining tool detected signals in one of four of the known drug-AE associations. Major contributions are: a) The first signal detection data mining tool applied to a Canadian claims database; b) Methodological improvements over published methods by considering the depletion of susceptibles effect and adjusting for overall health status to control for prescription channelling. The review yielded 119 distinct RMIs from the literature and 1,112 from the websites. The review demonstrated that an increase in RMI numbers among websites occurred since the introduction of guidances in 2005, but their effectiveness remains insufficiently examined.

A nifedipina atua como bloqueador de canais de cálcio inibindo o fluxo transmembrânico de ions Ca2+ no interior das células do músculo cardíaco e células do músculo liso vascular, o qual induz ao relaxamento do músculo liso e diminuição da resistência vascular periférica. É utilizado no Brasil no tratamento de hipertensão arterial sistêmica (HAS), faz parte da Relação Nacional de Medicamentos Essenciais do Ministério da Saúde e vem sendo distribuída pela Secretaria da Saúde do Estado de São Paulo. Uma vez que a determinação plasmática do fármaco contribui para maior segurança de seu uso, o objetivo deste trabalho se prendeu em padronizar e validar um método analítico em cromatografia em fase gasosa com detecção por captura de elétrons, sensível, específico e reprodutível para a quantificação das concentrações plasmáticas com a finalidade de avaliar a relação entre a dose diária de 60mg e a concentração plasmática versus a resposta da pressão arterial sistêmica, observando a ocorrência de possíveis reações adversas, alterações bioquímicas e hematológicas, em pacientes portadores de HAS, submetidos à farmacoterapia. O método apresentou linearidade na faixa de 10 a 200 ng.mL-1 , com coeficiente de correlação (r) igual a 0,9977. Coeficientes de variação de precisão intra e interensaio menor que 10% e recuperação absoluta da nifedipina de 74,47 a 75,97%. Os limites de detecção e quantificação do método foram de 1,0 e 2,0 ng.mL-1, respectivamente e o fármaco demonstrou ser estável por 90 dias quando armazenado a -70°C ao abrigo da luz. Os dados observados no presente estudo permitiram evidenciar que os pacientes apresentaram concentrações plasmáticas no intervalo terapêutico preconizado, as quais foram efetivas na redução da pressão arterial sistólica e diastólica. Estas concentrações não acarretaram efeitos adversos em nível do sistema hematológico e bioquímico estatisticamente significativos e em relação às reações adversas relacionadas ao medicamento, tais como: cefaléia, edema periférico vascular, tontura, hipotensão arterial, rubor, tosse e cãibras, apesar de relatadas de forma significativa pelos pacientes no inicio do tratamento, foram ao longo do mesmo minimizadas e pouco relatadas. / Nifedipine, a compound of dihydropyridine class, is a calcium-channel antagonists drug that inhibits the transmembrane influx of Ca+2 into cardiac muscle cells and vasculas smooth muscle cells throught specific ion channels. It induces smooth muscle relaxation and decreases peripheral vascular resistance. It is widely used for the treatment of high blood pressure, and is considered as a essencial medicine by the Brazilian government. In Sao Paulo state, this drug has been distributed to hypertensive patients in treatment. Since the drug quantification in plasma contributes for a drug safety use, the objective of the present study was to develop and validate a accurate, specific and reproducible method for the determination of nifedipine in plasma by gas chromatography with eletron capture detection. The validated method was applied in samples of hipertensive patients on 60 mg daily dose of nifedipine with the purpose to evaluate the relation between drug plasma concentration and it\'s daily dose versus the hemodymamic effects, possible side effects and biochemical and hematologic alterations. The method was linear over a concentration range of 10 -200 ng.mL-1 (r2>0,99). The coefficient of variation of intra- and inter-assay precision less than 10% and the recovery was higher than 74%. The limit of detection and quantification were 1,0 and 2,0 ng.mL-1, respectively. Nifedipine was found to be stable in samples stored at -70ºC for 90 days and protect from light. The result showed that patients with drug plasma concentration within therapeutics levels also showed systolic and diastolic blood pressure succesfully controled. Therefore, these patients do not manifested any adverse effects specially in biochemical and hematologic systems. Other adverse efects of nifedipine such as headache, peripheral edema, hypotension, redness, cramp and cough reported by the patients at the beggining of thetreatment, were gradually diminishing and rarely related.

A nifedipina atua como bloqueador de canais de cálcio inibindo o fluxo transmembrânico de ions Ca2+ no interior das células do músculo cardíaco e células do músculo liso vascular, o qual induz ao relaxamento do músculo liso e diminuição da resistência vascular periférica. É utilizado no Brasil no tratamento de hipertensão arterial sistêmica (HAS), faz parte da Relação Nacional de Medicamentos Essenciais do Ministério da Saúde e vem sendo distribuída pela Secretaria da Saúde do Estado de São Paulo. Uma vez que a determinação plasmática do fármaco contribui para maior segurança de seu uso, o objetivo deste trabalho se prendeu em padronizar e validar um método analítico em cromatografia em fase gasosa com detecção por captura de elétrons, sensível, específico e reprodutível para a quantificação das concentrações plasmáticas com a finalidade de avaliar a relação entre a dose diária de 60mg e a concentração plasmática versus a resposta da pressão arterial sistêmica, observando a ocorrência de possíveis reações adversas, alterações bioquímicas e hematológicas, em pacientes portadores de HAS, submetidos à farmacoterapia. O método apresentou linearidade na faixa de 10 a 200 ng.mL-1 , com coeficiente de correlação (r) igual a 0,9977. Coeficientes de variação de precisão intra e interensaio menor que 10% e recuperação absoluta da nifedipina de 74,47 a 75,97%. Os limites de detecção e quantificação do método foram de 1,0 e 2,0 ng.mL-1, respectivamente e o fármaco demonstrou ser estável por 90 dias quando armazenado a -70°C ao abrigo da luz. Os dados observados no presente estudo permitiram evidenciar que os pacientes apresentaram concentrações plasmáticas no intervalo terapêutico preconizado, as quais foram efetivas na redução da pressão arterial sistólica e diastólica. Estas concentrações não acarretaram efeitos adversos em nível do sistema hematológico e bioquímico estatisticamente significativos e em relação às reações adversas relacionadas ao medicamento, tais como: cefaléia, edema periférico vascular, tontura, hipotensão arterial, rubor, tosse e cãibras, apesar de relatadas de forma significativa pelos pacientes no inicio do tratamento, foram ao longo do mesmo minimizadas e pouco relatadas. / Nifedipine, a compound of dihydropyridine class, is a calcium-channel antagonists drug that inhibits the transmembrane influx of Ca+2 into cardiac muscle cells and vasculas smooth muscle cells throught specific ion channels. It induces smooth muscle relaxation and decreases peripheral vascular resistance. It is widely used for the treatment of high blood pressure, and is considered as a essencial medicine by the Brazilian government. In Sao Paulo state, this drug has been distributed to hypertensive patients in treatment. Since the drug quantification in plasma contributes for a drug safety use, the objective of the present study was to develop and validate a accurate, specific and reproducible method for the determination of nifedipine in plasma by gas chromatography with eletron capture detection. The validated method was applied in samples of hipertensive patients on 60 mg daily dose of nifedipine with the purpose to evaluate the relation between drug plasma concentration and it\'s daily dose versus the hemodymamic effects, possible side effects and biochemical and hematologic alterations. The method was linear over a concentration range of 10 -200 ng.mL-1 (r2>0,99). The coefficient of variation of intra- and inter-assay precision less than 10% and the recovery was higher than 74%. The limit of detection and quantification were 1,0 and 2,0 ng.mL-1, respectively. Nifedipine was found to be stable in samples stored at -70ºC for 90 days and protect from light. The result showed that patients with drug plasma concentration within therapeutics levels also showed systolic and diastolic blood pressure succesfully controled. Therefore, these patients do not manifested any adverse effects specially in biochemical and hematologic systems. Other adverse efects of nifedipine such as headache, peripheral edema, hypotension, redness, cramp and cough reported by the patients at the beggining of thetreatment, were gradually diminishing and rarely related.

No description available.