Le traitement par BRAF-inhibiteur (BRAFi) et MEK-inhibiteur (MEKi) en association a permis d’améliorer significativement la survie des patients atteints de mélanome métastatique muté BRAFV600. Cette mutation est présente chez 50 % des patients. Les BRAFi et MEKi sont des inhibiteurs de protéines kinase, dont le métabolisme fait intervenir le CYP 3A4, à l’origine de grandes variabilités des concentrations plasmatiques inter-patients pour une même dose administrée. La moitié des patients répondent au traitement, et 90% des patients présentent des effets indésirables, nécessitant une diminution de la posologie dans 33% des cas. Dans ce contexte, nous avons décrit les effets indésirables de chacun des BRAFi et MEKi et, pour ceux qui sont dose-dépendants, nous avons cherché à établir un lien entre concentration plasmatique et survenue d’effet indésirable. Grace à la mise au point d’une méthode analytique en chromatographie liquide couplée à la spectrométrie de masse, nous avons mesuré prospectivement les concentrations plasmatiques des BRAFi et MEKi chez les patients bordelais. Ces données permis de définir un seuil de toxicité de 48 ng/ml pour le dabrafenib. La définition de ce seuil constitue une étape essentielle à la conduite d’une étude randomisée visant à évaluer l’intérêt du suivi thérapeutique pharmacologique. / The combination of BRAF-inhibitors (BRAFi) and MEK-inhibitors (MEKi) has significantly improved the survival of patients with metastatic melanoma with BRAFV600 mutation. About 50% of patients harbour BRAFV600 mutation. BRAFi and MEKi are kinase inhibitors, metabolized by CYP 3A4, responsible for large between-patients variability in plasma concentrations for the same administered dose. About half of patients respond to treatment, and 90% of patients present adverse drug reactions (ADR), requiring dose reduction in 33% of cases. In this context, we described ADR profiles of each of the BRAFi and MEKi in the global pharmacovigilance database, and for ADR that are dose-dependent; we looked for the link between plasma exposure to the drug and the occurrence of ADR. Using the assay method developed, we prospectively measured the plasma concentrations of BRAFi and MEKi in Bordeaux patients, which allowed us to define a toxicity threshold of 48 ng / ml for dabrafenib. This work allowed to deepen the knowledge on the profiles and the occurrence of the ADR for each BRAFi and MEKi. The definition of a toxicity threshold for dabrafenib is a prerequisite for a randomized study to evaluate the value of therapeutic drug monitoring.

nÃo hà / A Anfotericina B Desoxicolato (ANB-D) à uma droga que possui a capacidade de produzir muitos efeitos adversos. à uma substÃncia fungicida de escolha no tratamento da maioria das micoses sistÃmicas e uma alternativa importante para o tratamento da leishmaniose visceral. O Instituto de DoenÃas Tropicais Natan Portela à o Ãnico hospital de referÃncia para o tratamento de doenÃas infecciosas e parasitÃrias no Estado do PiauÃ. Participa da Rede Sentinela da ANVISA, e atravÃs do Sistema de FarmacovigilÃncia, monitora o uso dos fÃrmacos notificando qualquer reaÃÃo adversa a medicamentos (RAM). Partindo desse pressuposto, realizou-se este estudo, observacional, retrospectivo e quantitativo, a partir do qual foram analisados os prontuÃrios de todos os pacientes que utilizaram o fÃrmaco no perÃodo de janeiro a marÃo de 2009, um total de 60 pacientes, considerando sempre as reaÃÃes adversas a medicamentos, as queixas tÃcnicas e as interaÃÃes medicamentosas do fÃrmaco com outros medicamentos presentes nas prescriÃÃes mÃdicas. A anÃlise estatÃstica for realizadapelo programa Stata/SE 10.0 for Windows (CollegeStation, Texas, USA). Entre os pacientes analisados no presente estudo, 63,3% eram do sexo masculino. A faixa etÃria com maior nÃmero de pacientes foi a de â41 ou mais anosâ com 36%. A patologia presente na grande parte dos pacientes em uso de ANB-D foi a Leishmaniose visceral com 75,0%. 93,3% dos pacientes analisados apresentaram RAMs e 11,7% dos pacientes foram a Ãbitos, os quais apresentaram uma mÃdia de 5,6 RAMs/paciente. Evidenciou-se o maior numero de RAMs no grupo etÃrio de â21 à 40 anosâ. 6,0 RAMs/paciente foi o nÃmero mÃdio observado nos pacientes que nÃo receberam a prÃ-medicaÃÃo. Dentre as RAMs com maior freqÃÃncia estiveram: febre (76,7%), calafrios (45,0%), vÃmitos (40,0%), tosse (27,0%) e cefalÃia (25,0%). Observou-se que em um total de 221 RAMs, houve predominÃncia de RAMs de gravidade moderada (57%). Visualizou-se que nÃo houve interaÃÃo medicamentosa dos medicamentos prescritos quando utilizados em associaÃÃo à ANB-D. A maior letalidade ocorreu em pacientes com idade de 21 a 40 anos. Pacientes com AIDS tinham idade entre 21 e 40 anos principalmente. Conclui-se, portanto, que sÃo muitas as RAMs provocadas pela ANB-D. InformaÃÃes incompletas/ou ausentes sobre RAMs registradas nos prontuÃrios mostrou que pode existir subnotificaÃÃo dessas reaÃÃes. Dentre os grupos etÃrios, os que mais sofrem com o aparecimento dessas reaÃÃes sÃo adultos jovens (entre 21 e 40 anos).Acredita-se que, a maior freqÃÃncia de RAMs nos pacientes que vieram a Ãbito pode ter contribuÃdo para o agravamento do quadro clÃnico dos mesmos. Pacientes com AIDS tinham idade entre 21 e 40 anos principalmente, esta doenÃa pode ter sido a razÃo da maior letalidade. / Amphotericin B Desoxicolate (AmB-D) is a drug that possesses the capacity to produce many adverse effects. It is a fungicide substance of choice in the treatment of the majority of the systemic mycosis and an important alternative for the treatment of visceral leishmaniosis. The institute of tropical diseases Natan Portela is the only hospital of reference for the treatment of parasite and infectious diseases in the state of PiauÃ. Participate of the sentinel web ANVISA, and through the farmacovigilance system, monitors the use of drugs notifying any adverse reaction to drugs. This observing, retrospective and quantitative study, was carried out in which the records of all the patients Who used the drug between january and march 2009, a total of 60 patients were analyzed, considering at all times adverse reactions to drugs, the technical complaints and the interactions of the drug with other drugs present in the medical prescription. The statistic analysis was carried out by the program Stata/SE 10.0 for Windows (College Station, Texas, USA). Among the patients analyzed in the present study, 63,3% were male. The age group with greater number of patients was â41 or overâ with 36%.The presnet pathology in most patients using AmB-D was visceral Leishmaniosis with 75,0%. 93,3% of the patients analyzed presented RAMs and 11,7% of the patients passed away. These patients presented an average of 5,6 RAMs/pacient. It was evident the greater number of RAMs in the age group from â21 to 40 yearsâ. 6,0 RAMs/pacient was the average number observed in the patients Who did not receive pre-medication. Among the RAMs with greater frequence were: fever (76,7%), chills (45,0%), vomit (40,0%), cough (27,0%) and headache (25,0%). It was observed that in a total of 221 RAMs, there was the predominance of RAMs of moderate seriousness (57%). It was observed that there was no drug interaction of the prescribed drugs when administered in association with AmB-D. Thegreater lethality happened in patients with age between 21 and 40 years. Patients with AIDS were aged between 21 and 40 years, mainly. It was concluded, therefore, that there are many RAMs caused by AmB-D. Incomplete or absent Information about RAMs registered in the records have shown that there may exist sub-notifications of these reactions. Among the age groups, the ones who suffers most with the appearing of these reactions are Young adults (between 21 and 40 years). It is believed that, the greater frequency of RAMs in the patients who passed away could have contributed for the worsening the clinical picture of these patients. Patients with AIDS were aged between 21 and 40 years mainly, this could have been the reason of greater lethality.

Tikslas: Išanalizuoti Lietuvos visuomenės vaistinėse dirbančių farmacijos specialistų požiūrį į pacientams suteikiamą informaciją apie galimus vaistų nepageidaujamus poveikius. Darbo metodika: Tyrimui atlikti buvo taikomas analizės metodas – anketavimas. Apklausta 230 farmacijos specialistų dirbančių visuomenės vaistinėse. Tyrimo duomenys apdoroti naudojant SPSS 17.0 versiją. Darbe pateikiami grafikai ir lentelės sudaryti MS Excel 2007 programa. Rezultatai: Daugumos farmacijos specialistų (98,2%) nuomone, teikti informaciją apie NRV yra būtina. Pagrindiniai veiksmai, pacientui pasireiškus NRV, yra paciento nukreipimas pas gydytoją (93,8%) arba konsultavimas (73,0%). Tik 4 proc. respondentų nesusiduria su problemomis teikiant informaciją susijusią su NRV. Pagrindiniai barjerai iš farmacijos specialisto pusės yra laiko (83,7%) bei žinių (57,2%) trūkumas, o iš paciento pusės – nenoras išklausyti suteikiamos informacijos (63,9%), nedrąsa klausti (44,6%), konfidencialumo (42,1%) bei išsilavinimo (41,6%) trūkumas. Nustatyta, kad ne visos vaistų grupės yra vienodai svarbios suteikiant informaciją apie NRV (p<0,05). Pagrindinės vaistų grupės yra antidepresantai (82,4%), krešumo sistemą veikiantys vaistai (82,4%), antibiotikai (79,4%), antipsichoziniai vaistai (73,5%) bei NVNU (67,6%). Išvados: 1. Farmacijos specialistų nuomone, informacijos apie NRV teikimas pacientams yra būtinas, tačiau ne visi sutinka, kad jis yra pagrindinis asmuo, galintis suteikti šią informaciją. Daugiau nei... [toliau žr. visą tekstą] / Objective: To analyze the attitude of pharmaceutical professionals working in Lithuanian community pharmacies towards providing information about adverse drug reactions. Methods: A questionnaire method was aplied during this research. 230 of 264 pharmacists working in community pharmacies participated in the survey (response rate 87,1%). Results: The majority of pharmaceutical professionals (98,2%) believed that the provision of information about adverse drug reactions (ADRs) is necessary. 97,8% of respondents said that they spoke to patients about reported adverse effects to drugs.The main pharmacists actions after receiving information that patients experienced ADRs were consulting (93,8%) or reffering the patient to a doctor (73,0%). Almost all (96%) respondents told that they have problems when providing information about ADRs. 3 out of 4 specialists point out that the main problem is the lack of time. Approximately half of them think that they lack of knowledge to provide such information. Problems encountered from the patient‘s side is their unwillingness to listen to the information provided (63,9%), timidity to ask for such information (44,6%), lack of privacy (42,1%) and education (41,6%).It was found that not all drug groups are equally important in providing information about ADRs (p<0,05). The main groups of medicines are antidepressants (82.4%), coagulation system drugs (82.4%), antibiotics (79.4%), antipsychotics (73.5%) and NSAIDs (67.6%). Conclusion: According... [to full text]

Objetivos: Investigar o padrão de uso de medicamentos, incluindo prescritos e nãoprescritos e classificar polifarmácia em idosos do município de Porto Alegre, RS, Brasil; verificar a existência de trocas ou alterações no esquema posológico dos medicamentos usualmente utilizados e descrever a prevalência de eventos adversos relatados por idosos. Métodos: A pesquisa seguiu um modelo de estudo transversal. O instrumento de coleta de dados foi um questionário preenchido durante uma visita domiciliar. Questões discursivas foram analisadas através da técnica do Discurso do Sujeito Coletivo. Os medicamentos foram classificados de acordo com o Anatomical Therapeutic Chemical (ATC). As reações adversas relatadas foram classificadas através da Classificação Internacional de Doenças 10ª edição (CID-10). Resultados: Dos 215 entrevistados, 141 (66%) eram mulheres; 117 (54%) na faixa etária entre 60 e 70 anos; 157 (73%) brancos e 115 (53%) tinham cônjuge. Houve uma prevalência de uso de medicação em 195 (91%) idosos e 697 (84%) medicamentos haviam sido utilizados na semana anterior à entrevista. Do total da amostra, 71 (33%) responderam ter usado medicamento sem prescrição médica e 57 (27%) relataram polifarmácia na última semana. As classes terapêuticas mais comuns foram aquelas referentes ao aparelho cardiovascular 224 (32%), sistema nervoso 150 (22%) e aparelho digestivo e metabolismo 124 (18%). Dos entrevistados, 106 (49%) relataram já ter esquecido o horário de tomar o medicamento e 22 (10%) já haviam trocado as quantidades de medicamentos para mais ou para menos. Conclusões: Os dados mostram que existe uma tendência em consumir elevado número de medicamentos entre pessoas de faixa etária igual ou superior a 60 anos que vivem na comunidade. De grande importância é a detecção dos eventos adversos preveníveis para educação e prevenção. / Objectives: To investigate the patterns of medication use, including both prescription and non-prescription drugs and to describe the presence of polypharmacy for older people in Porto Alegre, Brazil. To determine whether elderly patient’s changes drug regimens and to describe the prevalence of self-reported adverse drugs events in older people. Methods: A cross-sectional study whose data were collected by questionnaire, which was answered during home visits. For qualitative data was employed thematic discourse analysis technique. Drugs were classified according to the Anatomic Therapeutic Classification codes (ATC). The self-reported adverse drugs events were described by CID-10, 1999. Results: From 215 interviewed, 141 (66%) were women; 117 (54%) were between 60 and 70 years old; 157 (73%) were white and 115 (53%) had lived with a partner. Last year, 74 (35%) had had one hospital admission and 187 (87%) had had at least one doctor visit. There was a prevalence of use of 195 (91%) medications by elderly people and 697 (84%) were used on the week before the interview. From the total, 71 (33%) confirmed the use of drugs without prescription and 57 (27%) had polypharmacy one week before. Cardiovascular 224 (32%) and central nervous system 150 (22%) and gastrointestinal drugs 124 (18%) were the most common classification. Female gender, old age and live without a partner was associated with drug utilization. 106 (49%) said they had forgotten the time of their medication intake and 22 (10%) said they had changed the drug’s quantities. Conclusions: There is a pattern of increased medication use by elderly people who live at this community. To evaluate the preventable adverse drug events in older people who live at this community is very important for designing preventive and educational programs.

Objetivos: Investigar o padrão de uso de medicamentos, incluindo prescritos e nãoprescritos e classificar polifarmácia em idosos do município de Porto Alegre, RS, Brasil; verificar a existência de trocas ou alterações no esquema posológico dos medicamentos usualmente utilizados e descrever a prevalência de eventos adversos relatados por idosos. Métodos: A pesquisa seguiu um modelo de estudo transversal. O instrumento de coleta de dados foi um questionário preenchido durante uma visita domiciliar. Questões discursivas foram analisadas através da técnica do Discurso do Sujeito Coletivo. Os medicamentos foram classificados de acordo com o Anatomical Therapeutic Chemical (ATC). As reações adversas relatadas foram classificadas através da Classificação Internacional de Doenças 10ª edição (CID-10). Resultados: Dos 215 entrevistados, 141 (66%) eram mulheres; 117 (54%) na faixa etária entre 60 e 70 anos; 157 (73%) brancos e 115 (53%) tinham cônjuge. Houve uma prevalência de uso de medicação em 195 (91%) idosos e 697 (84%) medicamentos haviam sido utilizados na semana anterior à entrevista. Do total da amostra, 71 (33%) responderam ter usado medicamento sem prescrição médica e 57 (27%) relataram polifarmácia na última semana. As classes terapêuticas mais comuns foram aquelas referentes ao aparelho cardiovascular 224 (32%), sistema nervoso 150 (22%) e aparelho digestivo e metabolismo 124 (18%). Dos entrevistados, 106 (49%) relataram já ter esquecido o horário de tomar o medicamento e 22 (10%) já haviam trocado as quantidades de medicamentos para mais ou para menos. Conclusões: Os dados mostram que existe uma tendência em consumir elevado número de medicamentos entre pessoas de faixa etária igual ou superior a 60 anos que vivem na comunidade. De grande importância é a detecção dos eventos adversos preveníveis para educação e prevenção. / Objectives: To investigate the patterns of medication use, including both prescription and non-prescription drugs and to describe the presence of polypharmacy for older people in Porto Alegre, Brazil. To determine whether elderly patient’s changes drug regimens and to describe the prevalence of self-reported adverse drugs events in older people. Methods: A cross-sectional study whose data were collected by questionnaire, which was answered during home visits. For qualitative data was employed thematic discourse analysis technique. Drugs were classified according to the Anatomic Therapeutic Classification codes (ATC). The self-reported adverse drugs events were described by CID-10, 1999. Results: From 215 interviewed, 141 (66%) were women; 117 (54%) were between 60 and 70 years old; 157 (73%) were white and 115 (53%) had lived with a partner. Last year, 74 (35%) had had one hospital admission and 187 (87%) had had at least one doctor visit. There was a prevalence of use of 195 (91%) medications by elderly people and 697 (84%) were used on the week before the interview. From the total, 71 (33%) confirmed the use of drugs without prescription and 57 (27%) had polypharmacy one week before. Cardiovascular 224 (32%) and central nervous system 150 (22%) and gastrointestinal drugs 124 (18%) were the most common classification. Female gender, old age and live without a partner was associated with drug utilization. 106 (49%) said they had forgotten the time of their medication intake and 22 (10%) said they had changed the drug’s quantities. Conclusions: There is a pattern of increased medication use by elderly people who live at this community. To evaluate the preventable adverse drug events in older people who live at this community is very important for designing preventive and educational programs.

Objetivos: Investigar o padrão de uso de medicamentos, incluindo prescritos e nãoprescritos e classificar polifarmácia em idosos do município de Porto Alegre, RS, Brasil; verificar a existência de trocas ou alterações no esquema posológico dos medicamentos usualmente utilizados e descrever a prevalência de eventos adversos relatados por idosos. Métodos: A pesquisa seguiu um modelo de estudo transversal. O instrumento de coleta de dados foi um questionário preenchido durante uma visita domiciliar. Questões discursivas foram analisadas através da técnica do Discurso do Sujeito Coletivo. Os medicamentos foram classificados de acordo com o Anatomical Therapeutic Chemical (ATC). As reações adversas relatadas foram classificadas através da Classificação Internacional de Doenças 10ª edição (CID-10). Resultados: Dos 215 entrevistados, 141 (66%) eram mulheres; 117 (54%) na faixa etária entre 60 e 70 anos; 157 (73%) brancos e 115 (53%) tinham cônjuge. Houve uma prevalência de uso de medicação em 195 (91%) idosos e 697 (84%) medicamentos haviam sido utilizados na semana anterior à entrevista. Do total da amostra, 71 (33%) responderam ter usado medicamento sem prescrição médica e 57 (27%) relataram polifarmácia na última semana. As classes terapêuticas mais comuns foram aquelas referentes ao aparelho cardiovascular 224 (32%), sistema nervoso 150 (22%) e aparelho digestivo e metabolismo 124 (18%). Dos entrevistados, 106 (49%) relataram já ter esquecido o horário de tomar o medicamento e 22 (10%) já haviam trocado as quantidades de medicamentos para mais ou para menos. Conclusões: Os dados mostram que existe uma tendência em consumir elevado número de medicamentos entre pessoas de faixa etária igual ou superior a 60 anos que vivem na comunidade. De grande importância é a detecção dos eventos adversos preveníveis para educação e prevenção. / Objectives: To investigate the patterns of medication use, including both prescription and non-prescription drugs and to describe the presence of polypharmacy for older people in Porto Alegre, Brazil. To determine whether elderly patient’s changes drug regimens and to describe the prevalence of self-reported adverse drugs events in older people. Methods: A cross-sectional study whose data were collected by questionnaire, which was answered during home visits. For qualitative data was employed thematic discourse analysis technique. Drugs were classified according to the Anatomic Therapeutic Classification codes (ATC). The self-reported adverse drugs events were described by CID-10, 1999. Results: From 215 interviewed, 141 (66%) were women; 117 (54%) were between 60 and 70 years old; 157 (73%) were white and 115 (53%) had lived with a partner. Last year, 74 (35%) had had one hospital admission and 187 (87%) had had at least one doctor visit. There was a prevalence of use of 195 (91%) medications by elderly people and 697 (84%) were used on the week before the interview. From the total, 71 (33%) confirmed the use of drugs without prescription and 57 (27%) had polypharmacy one week before. Cardiovascular 224 (32%) and central nervous system 150 (22%) and gastrointestinal drugs 124 (18%) were the most common classification. Female gender, old age and live without a partner was associated with drug utilization. 106 (49%) said they had forgotten the time of their medication intake and 22 (10%) said they had changed the drug’s quantities. Conclusions: There is a pattern of increased medication use by elderly people who live at this community. To evaluate the preventable adverse drug events in older people who live at this community is very important for designing preventive and educational programs.

Les effets indésirables médicamenteux (EIM) ont des répercussions considérables tant sur la santé que sur l'économie. De 1,9% à 2,3% des patients hospitalisés en sont victimes, et leur coût a récemment été estimé aux alentours de 400 millions d'euros pour la seule Allemagne. De plus, les EIM sont fréquemment la cause du retrait d'un médicament du marché, conduisant à des pertes pour l'industrie pharmaceutique se chiffrant parfois en millions d'euros.De multiples études suggèrent que des facteurs génétiques jouent un rôle non négligeable dans la réponse des patients à leur traitement. Cette réponse comprend non seulement les effets thérapeutiques attendus, mais aussi les effets secondaires potentiels. C'est un phénomène complexe, et nous nous tournons vers l'apprentissage statistique pour proposer de nouveaux outils permettant de mieux le comprendre.Nous étudions différents problèmes liés à la prédiction de la réponse d'un patient à son traitement à partir de son profil génétique. Pour ce faire, nous nous plaçons dans le cadre de l'apprentissage statistique multitâche, qui consiste à combiner les données disponibles pour plusieurs problèmes liés afin de les résoudre simultanément.Nous proposons un nouveau modèle linéaire de prédiction multitâche qui s'appuie sur des descripteurs des tâches pour sélectionner les variables pertinentes et améliorer les prédictions obtenues par les algorithmes de l'état de l'art. Enfin, nous étudions comment améliorer la stabilité des variables sélectionnées, afin d'obtenir des modèles interprétables. / Adverse drug reaction (ADR) is a serious concern that has important health and economical repercussions. Between 1.9%-2.3% of the hospitalized patients suffer from ADR, and the annual cost of ADR have been estimated to be of 400 million euros in Germany alone. Furthermore, ADRs can cause the withdrawal of a drug from the market, which can cause up to millions of dollars of losses to the pharmaceutical industry.Multiple studies suggest that genetic factors may play a role in the response of the patients to their treatment. This covers not only the response in terms of the intended main effect, but also % according toin terms of potential side effects. The complexity of predicting drug response suggests that machine learning could bring new tools and techniques for understanding ADR.In this doctoral thesis, we study different problems related to drug response prediction, based on the genetic characteristics of patients.We frame them through multitask machine learning frameworks, which combine all data available for related problems in order to solve them at the same time.We propose a novel model for multitask linear prediction that uses task descriptors to select relevant features and make predictions with better performance as state-of-the-art algorithms. Finally, we study strategies for increasing the stability of the selected features, in order to improve interpretability for biological applications.

Introduction :Les anticoagulants oraux soulèvent des problématiques majeures en termes de risque hémorragique et de bon usage. L’informatisation du dossier médical offre la possibilité d’accéder à de grandes bases de données que l’on peut exploiter de manière automatisée. L’objectif de ce travail est de montrer comment la réutilisation de données peut permettre d’étudier des problématiques liées aux anticoagulants et accompagner une démarche d’assurance de la qualité des soins. MéthodesCe travail a été réalisé sur les données informatisées (97 355 séjours) d’un centre hospitalier général. Pour chaque séjour nous disposons des données diagnostiques, biologiques, médicamenteuses, administratives et des courriers de sortie. Ce travail est organisé autour de 3 axes :Axe I. L’objectif est d’évaluer la qualité de la détection des facteurs pouvant majorer l’effet anticoagulant des antivitamines K (AVK), à l’aide de règles développées au cours de du projet européen PSIP (convention de subvention n° 216130). Une revue des cas sur une année a permis de calculer la valeur prédictive positive et la sensibilité des règles. Axe II. Nous avons réalisé une étude de cohorte historique sur les données de 2007 à 2012 pour déterminer les éléments majeurs impliqués dans l’élévation du risque hémorragique sous AVK dans la réalité clinique. Les cas étaient les séjours présentant une élévation de l’INR au-delà de 5, les témoins n’en présentaient pas. Axe III. Nous avons mis la réutilisation de données au service de l’étude de la qualité des prescriptions. D’une part nous avons évalué le suivi des recommandations de traitement du risque thromboembolique dans la fibrillation atriale (FA) chez la personne âgée, d’autre part nous avons étudié les modalités de prescription des anticoagulants oraux directs (AOD).Résultats : Axe I : La valeur prédictive positive des règles de détection des facteurs favorisant l’élévation de l’INR sous AVK est de 22,4%, leur sensibilité est de 84,6%. Les règles les plus contributives sont les règles de détection d’un syndrome infectieux et de l’administration d’amiodarone. Axe II : Les facteurs majeurs d’élévation du risque hémorragique sous AVK mis en évidence par l’étude de cohorte sont le syndrome infectieux, le cancer, l’hyprotidémie et l’insuffisance hépatique. Axe III : Le taux de suivi des recommandations dans la fibrillation atriale chez le sujet âgé est de 47.8%. Seuls 45% des patients reçoivent des anticoagulants oraux, 22,9% ne reçoivent aucun traitement antithrombotique et 32,1% reçoivent des antiagrégants plaquettaires. Les AOD sont quant à eux prescrits à des posologies inadaptées chez 15 à 31,4% des patients, respectivement pour le dabigatran et le rivaroxaban. Ces erreurs sont principalement des sous-dosages en AOD dans la FA de la personne âgée (82.6%). Discussion : L’informatisation des dossiers médicaux a permis la constitution de grandes bases de données médico-administratives, qui peuvent être utilisées à des fins variées comme nous le montrons dans ce travail. Dans le premier axe nous avons montré que des systèmes d’aide à la décision à base de règles permettent de caractériser les facteurs impliqués dans les surdosages en AVK avec une bonne sensibilité mais avec une faible valeur prédictive positive. Le second axe a montré que l’on pouvait utiliser ces données à des fins exploratoires pour identifier les facteurs liés à l’élévation de l’INR chez les patients recevant des AVK en pratique réelle. Le troisième axe montre que les systèmes à base de règles peuvent aussi être utilisés pour identifier des prescriptions inappropriées à des fins d’amélioration de la qualité des soins. Dans le domaine de l’anticoagulation ce travail ouvre des perspectives innovantes en vue de l’amélioration de la qualité des soins. / Introduction :Oral anticoagulants raise major issues in terms of bleeding risk and appropriate use. The computerization of medical records offers the ability to access large databases that can be explored automatically. The objective of this work is to show how routinely collected data can be reused to study issues related to anticoagulants in a supportive approach to quality of care.MethodsThis work was carried out on the electronic data (97,355 records) of a community hospital. For each inpatient stay we have diagnostic, biological, drug and administrative data, and the discharge letters. This work is organized around three axes:Axis I. The objective is to evaluate the accuracy of the detection of factors that may increase the anticoagulant effect of vitamin K antagonists (VKA), using rules developed in the PSIP european project (grant agreement N° 216130). A case review on one year enabled the calculation of the positive predictive value and sensitivity of the rules. Axis II. We conducted a cohort study on data from 2007 to 2012 to determine the major elements involved in raising the risk of bleeding related to VKA in clinical reality. Cases were the stays with an elevation of the INR beyond 5, the controls did not have.Axis III. We made data reuse serve a study of the quality of the prescriptions. On the one hand we assessed treatment of the thromboembolic risk recommendations in atrial fibrillation (AF) in the elderly, on the other hand we investigated the prescription of direct oral anticoagulants.Results : Axis I : The positive predictive value of the rules intended to detect the factors favoring the elevation of INR in case of treatment with VKA is 22.4%, the sensitivity is 84.6%. The main contributive rules are the ones intended to detect an infectious syndrome and amiodarone.Axis II : The major factor increasing the INR with VKA treatment highlighted by the cohort study are infectious syndrome, cancer, hepatic insufficiency and hypoprotidemia. The recommendations compliance rate in atrial fibrillation in the elderly is 47.8%. Only 45% of patients receive oral anticoagulants, 22.9% do not receive antithrombotic treatment at all and 32.1% received platelet aggregation inhibitors. Direct oral anticoagulants are prescribed at inadequate dosages in 15 to 31.4% of patients, respectively for dabigatran and rivaroxaban. These errors are mainly underdosages in the elderly with atrial fibrillation (82.6%).Discussion : The computerization of medical records has led to the creation of large medical databases, which can be used for various purposes as we show in this work. In the first work axis we have shown that rule-based decision support systems detect the contributing factors for VKA overdose with a good sensitivity but a low positive predictive value. The second line shows that we could use the data for exploratory purposes to identify factors associated with increased INR in patients receiving VKA in “real life practice”. The third line shows that the rule-based systems can also be used to identify inappropriate prescribing for the purpose of improving the quality of care. In the field of anticoagulation this work opens up innovative perspectives for improving the quality of care.

Nesta pesquisa foram avaliados 186 idosos hospitalizados quanto ao aparecimento de reações adversas a medicamentos (RAM). Encontrou-se 199 RAM (1,07 por paciente). Para 11,3% dos idosos a RAM constituiu a causa da internação, para 17,2% estava presente à internação mas não como causa e 46,2% apresentaram RAM durante a hospitalização. As RAM sérias mais comuns foram a insuficiência renal aguda, a hipercalemia e a hipotensão postural. Concluiu-se que houve uma prevalência importante de RAM nesses pacientes, encontrando-se como fatores de risco significativos o número de diagnósticos, o número de medicamentos e o uso de medicamento inapropriado para idosos / The present study evaluated the prevalence of adverse drug reactions (ADR) among 186 hospitalized elderly. A total of 199 ADR were founded (1.07 per patient). For 11.3% of the patients the ADR was the cause of hospitalization, for 17.2% the ADR was present at hospitalization but not as the cause and for 46.2% it was presented during hospitalization. The most common serious ADR were acute renal insufficiency, hyperkalemia and postural hypotension. We concluded that a significant prevalence of ADR was found among that patients, with the number of diagnosis, the number of drugs and the use of a drug considered to be inappropriate as risk factors

Os sistemas de farmacovigilância fundamentam as decisões sobre segurança no uso de medicamentos regulamentados por autoridades de saúde. Estudá-los e propor estratégias de melhorias contribuem para fortalecer os sistemas de saúde, aperfeiçoando a qualidade da assistência à saúde e assegurando a segurança do paciente e coletividade. A Tese objetivou analisar a evolução e desempenho do sistema brasileiro de farmacovigilância, denominado de SINAF, e as notificações dos pacientes com suspeitas de reações adversas a medicamentos (RAMs) registradas no Notivisa-medicamento no período de 2008 a 2013 e propor uma lista-referência de códigos da CID-10 para vigilância de RAMs e intoxicações medicamentosas (IMs). A Tese compreende seis artigos científicos organizados para publicação. No primeiro, uma revisão de escopo apresentou uma perspectiva histórica para caracterizar a evolução do SINAF e lacunas identificadas no processo, como a ausência de comissão de farmacovigilância que atenda aos requisitos mínimos de um sistema de farmacovigilância propostos pela Organização Mundial da Saúde. Os artigos 2, 3 e 4 analisaram características relacionadas com o desempenho do SINAF. O artigo 2 revelou que não há preferência digital da idade na base de dados das notificações de eventos adversos a medicamentos (EAMs) do Notivisa-medicamento. Mediante uma análise comparativa, o artigo 3 mostrou diferenças entre o formulário para notificação de EAMs utilizado no SINAF e de outros doze países latinoamericanos (Argentina, Bolívia, Chile, Colômbia, Costa Rica, Cuba, Guatemala, México, Panamá, Peru, Uruguai e Venezuela), sobretudo na quantidade de variáveis para preenchimento, podendo contribuir com a subnotificação de casos. No artigo 4 – um estudo de avaliação de sistemas de vigilância de saúde pública –, revelou que o desempenho do Notivisa-medicamento foi considerado satisfatório para três atributos (flexibilidade, validade e erro preditivo positivo) e deficitário para a maioria deles (simplicidade, aceitabilidade, representatividade, completude, consistência, oportunidade e clareza metodológica). O artigo 5, mediante estudo descritivo e retrospectivo, encontrou uma taxa de notificação de RAMs de 22,8/ 1 milhão de habitantes/ano. Trata-se de taxa bastante inferior a países de alta renda como Nova Zelândia, Suécia, Austrália e Suíça que possuem mais de 300 notificações por milhão, como em relação a países de média renda, como a África do Sul, com taxa de 77 por milhão de habitantes. A população feminina (60,5%) prevaleceu no total de pacientes (26.554), assim como, a raça/cor branca (58,1%). A idade variou de 0 a 112 anos (mediana = 46 anos). Quase 1/3 (32,5%) das suspeitas de RAMs ocorreram em populações vulneráveis (idosos e crianças). Foram avaliados 54.288 pares de medicamento-reação adversa, onde prevaleceram as reações adversas graves (59,2%), com destaque para as que resultaram em efeito clinicamente importante (83,1%). O estudo 6 propôs uma lista-referência com 691 códigos da CID-10, sendo 360 (52,1%) relacionados com RAMs e 331 (47,9%) com IMs. Um total de 511 (73,9%) códigos estão relacionados com casos de admissão hospitalar e/ou óbito. Os achados da Tese evidenciam a necessidade de mudanças em diferentes aspectos estudados do SINAF, como forma de contribuir na produção de informações completas, fidedignas e mais representativas sobre danos ocasionados por medicamentos comercializados no país. / The pharmacovigilance systems support the decisions on safety when using medications regulated by health authorities. Analyzing them and proposing improvement strategies are ways to make healthcare systems stronger, improving the quality of healthcare assistance, making sure the patient is safe and that the population is ensured. The dissertation was aimed at analyzing the evolution and performance of the Brazilian pharmacovigilance system, SINAF, and the notification of patients with suspected adverse drug reactions (ADRs) registered with the notification system NOTIVISA/medication from 2008 through 2013, as well as proposing a reference list of ICD-10 codes for surveillance of ADRs and intoxication due to medication (IDM). The dissertation is comprised of six scientific articles ready to be published. The first one, a scoping review, presents a historical perspective to demonstrate the development process of SINAF and the gaps identified during the process, such as the absence of a pharmacovigilance commission that complies with the minimum requirements of a pharmacovigilance system as proposed by World Health Organization. Articles 2, 3 and 4 presents an analysis of the performance-related characteristics of SINAF. Article 2 reveals that there is no digital age preference in the adverse drug events (ADEs) database belonging to NOTIVISA/medication. Using a comparative analysis, article 3 shows differences between the form for ADEs notification using SINAF and in other twelve Latin-American countries (Bolivia, Chile, Colombia, Costa Rica, Cuba, Guatemala, Mexico, Panama, Peru, Uruguay and Venezuela), highlighting the number of variables to complete, and it may collaborate with the sub-notification of cases. Article 4 – a study on the evaluation of public health surveillance systems over time – reveal that the performance of NOTIVISA/medication was considered satisfactory regarding three attributes (flexibility, validity and positive predictive error) and deficient regarding most of the others (simplicity, acceptability, representability, integrality, consistency, opportunity and methodological clarity). Article 5, by means of a descriptive and retrospective study, found an ADR notification rate of 22.8/million inhabitants/year. This is a much lower rate than in high income countries, such as New Zealand, Sweden, Australia and Switzerland, which have over 300 notifications per million, when compared against average income, such as South Africa, with a rate of 77/million inhabitants. Female population (60.5%) prevailed in the total number of patients (26,554), as well as white race/color (58.1%). Age was between 0 - 112 years old (median = 46 years). Almost 1/3 (32.5%) of the suspected ADRs occurred in vulnerable populations (elderly and children). 54,288 pairs of medication/adverse reactions were assessed. Severe adverse reactions prevailed (59.2%), and attention is drawn to those resulting in clinically important effect (83.1%). Study 6 proposes a reference list with 691 ICD-10 codes; 360 (52.1%) out of them are ADRs-related and 331 (47.9%) out of them are IDM. A total of 511 (73.9%) codes are related to cases of hospital admission and/or death. The dissertation findings prove the need of changes across different aspects in SINAF as a way to contribute to production of complete, reliable and representative information on damages caused by commercially available drugs in Brazil.