Orientador: Rosana Teresa Onocko Campos / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T05:20:12Z (GMT). No. of bitstreams: 1 Borges_LuanaRibeiro_M.pdf: 2473330 bytes, checksum: 50bd6ca2b36684691d7608b9329a30b3 (MD5) Previous issue date: 2014 / Resumo: No Brasil a prescrição de psicofármacos pode ser considerada uma prática ainda não reformada, tendo em vista que, pesquisas recentes apontam para o baixo empowerment dos usuários em relação a seus tratamentos medicamentosos, deixando o poder desta decisão a critério apenas dos profissionais de saúde. Considerando isso, utilizamos o "medicamento" como gatilho para analisar o conflito de forças existentes em toda escolha clínica, inclusive na gestão da medicação. Conduzimos desta forma, por entender que ele ocupa um lugar importante quando se pretende problematizar as relações de poder existentes entre pacientes e profissionais de saúde. Assim, o objeto desse estudo está pautado nas inter-relações usuário/trabalhador/serviço de saúde, a quais tornam-se reveladoras dos desafios colocados a atual Política Nacional de Saúde Mental. Adotamos como base a estratégia de gestão autônoma de medicamentos (GAM), pois esse dispositivo tem se mostrado um intercessor potente para trabalhar tais questões. Então, buscando reconhecer seus efeitos naqueles que vivem a experiência GAM, desenvolvemos um estudo hermenêutico-narrativo de caráter qualitativo. Esse estudo fundamentou-se no tripé avaliação, participação e intervenção e teve como sujeitos-participantes trabalhadores da rede de assistência à saúde mental e estudantes de especialização em saúde da Unicamp. Foram realizados 9 Grupos de Intervenção GAM (GIs), sendo 4 em Unidades Básicas de Saúde (UBS) e 5 em Centros de Atenção Psicossocial (CAPS). Cada grupo contava com 2 operadores GAM (1 trabalhador e 1 estudante) e 10 usuários de psicotrópicos. Os GIs foram realizados nos serviços de saúde, com encontros semanais e duração média de 7 meses, atingindo nesse período 51 usuários e 29 operadores GAM. A fase de colheita dos dados ocorreu de Julho de 2011 à maio de 2012. Metodologicamente a pesquisa foi construída a partir da triangulação de métodos (entrevista semiestruturada, diário de bordo e oficinas de debate e aprofundamento). As entrevistas foram transcritas e transformadas em metanarrativas através da extração dos núcleos argumentais e após foram validadas por diferentes pesquisadores. O material foi analisado sob a perspectiva Gadameriana. Essa dissertação irá discutir os resultados obtido pelas entrevistas e irá considerar apenas a voz dos trabalhadores da Atenção Básica (8 metanarrativas). A escolha de trabalhar com esse segmento da atenção básica deu-se por entender que a mudança paradigmática resultante da Reforma Psiquiátrica brasileira vem solicitando cada vez mais a atuação desse nível de atenção nos cuidados à saúde mental de sua população adscrita. As falas desses trabalhadores trouxeram à tona a supervalorização do saber científico em detrimento do saber da experiência. Também, desvelaram a existência de modos de restrição da autonomia tanto do usuário como dos profissionais de saúde e as armadilhas que conduzem a medicalização e a restrição da liberdade e do cuidado de si. Ao mesmo tempo, foi possível observar o surgimento de um devir hermenêutico nos participantes do estudo, um movimento de colocar em questão as próprias verdades e as relações de saber/poder existente na clínica / Abstract: In Brazil psychotropic prescription can be considered a practice not yet reformed, given that recent studies show low empowerment of users regarding their drug treatments, letting this important decision only to the health professionals. Considering this, we use "drug" as a start to review the existing conflict of forces across clinical choice, including the management of medication. We conducted this way, understanding that it plays an important role when we intend to analyze the existing power relations between patients and health professionals. Thus, the object of this study is based in the interrelationships user / worker / health care service, which reveal the challenges to the current National Mental Health Policy. We adopt as a basis the strategy of Autonomous Medication Management (GAM), because this device has proved to be a powerful intercessor to work such issues. So, trying to recognize their effects on those living GAM experience, we developed a hermeneutic-narrative qualitative study. This study was based on tripod evaluation/ participation/ intervention, and had as participating subjects, mental healthcare staff and health specialization students of Unicamp. We performed 9 GAM Intervention Groups (GIs), 4 in Basic Health Units (UBS) and 5 in Psychosocial Care Centers (CAPS). Each group had 2 GAM operators (1 worker and 1 student) and 10 users of psychotropic drugs. The GIs were performed at services with weekly meetings and mean duration of 7 months, reaching in total 51 users and 29 GAM operators. The collection of data occurred from July 2011 to May 2012. The survey was constructed from the triangulation of methods (semi-structured interviews, logbook and workshops for discussion and deepening). The interviews were transcribed and processed in metanarratives through the extraction of argumentation nuclei, and then validated by different researchers. The material was analyzed under the Gadamerian perspective. This dissertation will discuss the results obtained by interviews and will consider only the voice of the Primary Care workers (8 metanarratives). The reason for choosing to work with primary care is related to the fact that it is increasingly being requested in the context of Brazilian psychiatric reform with regard to mental health care for its enrolled population The discourses of these workers have brought to light the overvaluation of scientific knowledge at the expense of learning from experience. Also unveiled the existence of modes of restricting the autonomy for both the users and the healthcare professionals and the pitfalls that lead to medicalization and freedom and self-care restrictions. At the same time, we observed the emergence of a hermeneutic becoming in the study participants, a movement to put into question the very truths and knowledge/power relations existing in the clinic / Mestrado / Política, Planejamento e Gestão em Saúde / Mestra em Saúde Coletiva

Orientador: Rosana Teresa Onocko Campos / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T00:00:56Z (GMT). No. of bitstreams: 1 Santos_DeivissonViannaDantasdos_D.pdf: 4666096 bytes, checksum: 747ecbfd3091d236f7eeb842b855abe6 (MD5) Previous issue date: 2014 / Resumo: No contexto atual, onde o saber científico se sobrepõe ao saber experiencial, a inclusão das posições dos usuários de serviços de saúde no direcionamento dos seus tratamentos ainda está distante da realidade. Esta tese reporta aspectos de uma pesquisa qualitativa que teve a oportunidade de intervir em práticas de cuidado em 10 serviços de saúde de dois municípios do Estado de São Paulo (Campinas e Amparo). Seguindo o princípio da Reforma Psiquiátrica brasileira da defesa dos direitos do usuário em participar das decisões sobre seu tratamento, utilizou-se a estratégia da gestão autônoma da medicação, de 2011 a 2012. Tal estratégia tem como proposta "empoderar" os usuários quanto ao uso de medicamentos em seus projetos terapêuticos. A partir de entrevistas semi-estruturadas com os moderadores destes grupos, antes e depois da intervenção, construiu-se narrativas sob os preceitos da hermenêutica gadameriana. Os trabalhadores que experimentaram a estratégia assumiram um papel mais crítico quanto suas próprias práticas clínicas. Identificaram na metodologia horizontal, grupal e direcionada para uma escuta não filtrada pelas categóricas científicas do campo da saúde uma ferramenta para a valorização da voz dos usuários. Relataram que a individualidade de cada sujeito foi fonte de um saber capaz de promover uma clínica mais flexível e propícia para uma construção conjunta de ações de saúde. Perceberam também que os usuários puderam repensar o papel dos medicamentos em suas vidas e, apesar das resistências institucionais, autorizaram-se a negociar seus tratamentos com seus prescritores / Abstract: In a context where scientific knowledge overlaps the experiential knowledge, the practice of sharing decisions with patients is still far from reality, despite the consensus that physicians must base their recommendations on the patient¿s values rather than on their own. This study reports aspects of a qualitative research that had the opportunity to intervene in care practices in 10 health facilities at two Brazilian cities (Campinas and Amparo). Following the principle of Brazilian Psychiatric Reform, defending users' rights to participate in decisions about their treatment, we worked with the gaining autonomy and medication (GAM) guide in order to seek the empowerment of the users regarding the use of psychotropic medication in their therapeutic projects. Semi-structured interviews were conducted with the GAM Group¿s moderators before and after the intervention, the material collected was transformed in narratives according Gadamer¿s hermeneutic principles. From the analysis, among other things, the workers attested the difficulty of avoiding the exercise of power over users via administration of psychotropic drugs. Besides, the health workers began to take a more critical approach to their own clinical practices. They also reported to practice a more flexible clinic, making shared decisions with their patients regarding their treatments / Doutorado / Política, Planejamento e Gestão em Saúde / Doutor em Saude Coletiva

Malgré la fréquence d’utilisation des psychotropes chez les personnes plus âgées et leur propension aux événements indésirables liés aux médicaments, peu d’études se sont intéressées au respect des règles de bon usage des psychotropes dans cette population. L’objectif de ce travail était d’évaluer les modalités d’utilisation des psychotropes et le respect des recommandations de bon usage publiées en France. Deux types de population ont été inclus : un échantillon clinique constitué de patients âgés d’au moins 65 ans hospitalisés dans deux Pôles de psychiatrie à Bordeaux, et un échantillon de la population générale âgée d’au moins 65 ans, à partir d’une base de données de l’assurance maladie française. En population clinique, les règles de bon usage étaient plutôt bien respectées, avec, pour les benzodiazépines, la prescription d’une produit à demi-vie courte dans près de trois quarts des prescriptions et une posologie adéquate dans près de deux tiers des cas. Toutefois, un arrêt de traitement n’était jamais prévu dès l’initiation du traitement et le rythme de prescription était discontinu dans seulement un tiers des cas. Dans la population générale âgée, la durée et la surveillance biologique des traitements antidépresseurs étaient conformes chez moins de 20% des sujets, alors que près des trois quarts des sujets initiant un traitement par benzodiazépine recevaient une durée adéquate. En revanche moins de la moitié des délivrances concernaient une benzodiazépine anxiolytique à demi-vie courte. L’étude de l’impact de la publication des recommandations n’a pas montré qu’elle permettait une amélioration de l’utilisation des psychotropes. Il est nécessaire d’accompagner la publication des recommandations d’autres mesures, afin d’insister sur le bon usage des psychotropes, notamment la durée nécessaire de traitement antidépresseur et le choix d’un anxiolytique à demi-vie courte. / Despite a high frequency of use and a tendency to present with adverse events of drugs, few studies assessed compliance with guidelines related to proper use of psychotropic drugs in the older population. The aim was to assess the patterns of psychotropic drugs use in this population, as well as the compliance with French guidelines. Two population samples were included, a clinical sample of older psychiatric inpatients and a sample of the older general population using claims database of the national health insurance. In clinical population, compliance with guidelines was rather good, with prescription of a short half-life benzodiazepine in nearly three quarters of prescriptions and adequate dosage in nearly two third of cases. However, treatment discontinuation was never specified at the time of treatment initiation and rhythm of prescription was discontinuous in only one third of cases. In the older general population, duration of antidepressant treatment and biological monitoring was appropriate in only 20 % of patients, whereas nearly three quarters of subjects initiating a benzodiazepine treatment were treated over an appropriate duration. However, less than half of them had received a benzodiazepine anxiolytic of short half-life. The assessment of the impact of practice guidelines publication found no improvement of psychotropic drugs use. Other interventions should accompany guidelines publication in order to underline the importance of proper use of drugs, particularly antidepressant treatment duration and use of short half-life benzodiazepine drugs.

Background: The Probation and Mediation Service plays an essential role in the execution of alternative sanctions for offenders who are often addictive users. During my practice I was intrigued by the scope and breadth of activities and the necessary knowledge of probation workers. Objectives: The aim of the thesis was describing the possibilities of using addictological knowledge and specialization of probation officers to work with clients using narcotic and psychotropic substances and to compare possible changes compared to the situation described by Gabrhelíková in her dissertation in 2010. Sample: The research sample consisted of probation officers and assistants of the Probation and Mediation Service Prague; 36 respondents were participated in the research. Methods: The research methods were a questionnaire survey, semi-structured interviews and also a case report of the Probation and Mediation Service client. The analysis of available documentation was used in the case report. Ethical principles were observed. Results: Surveys showed that the number of users of narcotic drugs and psychotropic substances among clients continues to increase. Official statistics underestimate this situation. Probation workers positively perceive the contribution of addictological knowledge to their client work while...

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Cette thèse a pour but de mieux comprendre le recours aux médicaments psychotropes chez les enfants hébergés en Centre jeunesse, une population qui compte parmi les plus médicalisées. Afin d’y parvenir, les caractéristiques sociodémographiques, anamnestiques et psychopathologiques des enfants placés qui reçoivent des psychopharmacoprescriptions ont été analysées. L’échantillon se compose de 101 enfants de 6 à 12 ans placés en foyer de groupe ou centre de réadaptation, dont 71 recevant des médicaments psychotropes. Les données ont été obtenues par le biais de questionnaires remplis par les éducateurs, par une entrevue semi-structurée réalisée auprès des enfants et une analyse du dossier. Sur le plan de la structure, cet ouvrage comprend une introduction, quatre articles et une conclusion. Le premier article comporte une recension des écrits sur l’usage de la psychopharmacothérapie chez les jeunes placés dans les services de la protection de la jeunesse. Il a été constaté que les taux de prescriptions peuvent varier entre 13% et 77%, selon le type de placement et les régions à l’étude. La symptomatologie des enfants placés qui reçoivent des médicaments psychotropes est caractérisée par des problèmes extériorisés et des troubles psychotiques. Les corrélats du recours à la prescription concernent à la fois la sévérité du tableau clinique, mais aussi le type et l’instabilité du placement, l’âge et le sexe de l’enfant ainsi que la formation des intervenants. Enfin, les écrits recensés font état de l’influence des neurosciences dans les milieux médicaux sur les décisions de prescrire. Le deuxième article présente la prévalence des psychopharmacoprescriptions chez les enfants de 6 à 12 ans placés hors d’un milieu familial. Les résultats indiquent que 70,3% des jeunes reçoivent au moins une prescription, le plus souvent signées par des médecins spécialistes. La plupart se composent de psychostimulants et d’antipsychotiques atypiques, prescrits pour des troubles de l’attention avec hyperactivité. Le troisième article cherche à préciser les caractéristiques sociodémographiques et anamnestiques des enfants placés qui prennent des médicaments psychotropes. Les résultats indiquent que les sujets médicamentés et non médicamentés ont vécu des stresseurs psychosociaux similaires. Par contre, les enfants placés qui reçoivent une psychopharmacothérapie ont été retirés de leur milieu familial à un plus jeune âge. Le quatrième article consiste à cibler leur portrait psychopathologique et à connaître leur niveau de fonctionnement global. Il s’intéresse également aux connaissances et aux perceptions des éducateurs sur la psychopharmacothérapie. Les résultats révèlent que les enfants médicamentés ont plus souvent un diagnostic de trouble mental inscrit à leur dossier. Selon les éducateurs, ils présentent davantage de problèmes extériorisés et intériorisés. À partir de données autorévélées, aucune distinction ne peut être établie entre les sujets, puisque les uns et les autres rapportent un niveau comparable de symptômes et de signes diagnostiques. Enfin, les symptômes de stress post-traumatique et l’opinion favorable des éducateurs sur la psychopharmacothérapie constituent des prédicteurs significatifs de la probabilité de recourir à un traitement médicamenteux. En conclusion, l’apport des résultats de cette recherche est analysé à la lumière des études antérieures. Les retombées cliniques sont discutées et des pistes de recherche futures sont suggérées. . / Summary The present thesis aims to better understand the use of psychotropic medication among children in foster care, a population, which appears to be particularly subject to psychopharmacotherapy. In order to achieve this goal, the sociodemographic, anamnestic and psychopathological characteristics of children who receive psychopharmacotherapy will be analyzed. The sample consists of 101 children in care, including 71 children receiving psychotropic medications. These data were obtained through questionnaires completed by the educators responsible for these youths. In terms of structure, this work of research consists of an introduction, four articles, and a conclusion. The first article includes a review of the literature on the use of psychopharmacotherapy in children placed in youth protection care. It has been found that prescription rates can vary between 13% and 77%, depending on the type of placement and geographical areas studied. The symptomatology of children receiving psychotropic medication is mainly characterized by externalizing problems and psychotic disorders. The correlates of prescription rates involve the severity of the clinical portrait, the type and instability of placement, child age and gender, and workers’ training. Finally, the literature review shows the influence of neuroscience on the medical community’s decisions to prescribe. The second article presents the prevalence of psychopharmacological prescriptions in children ages 6 to 12 years, who are placed in foster group homes or rehabilitation centers. It also identifies the classes of molecules used, the reasons for prescribing and the training of the prescribing physician. The results indicate that 70.3% of young people receive at least one prescription, most often signed by specialized physicians. These data mostly consist of psycho-stimulant and antipsychotic drugs prescribed for Attention Deficit Disorder with Hyperactivity (ADHD). The third article seeks to identify the sociodemographic and anamnestic characteristics of children receiving psychotropic medication. Medicated youths (n = 71) were compared to non-medicated ones (n = 30). The results indicate that both groups experienced psychosocial stressors prior to their placement. However, foster children who received psychopharmacotherapy were removed from their home at a younger age, and experienced more family life changes before the age of 6, in comparison to non-medicated children. The fourth article aimed to target the psychopathology portrait of children receiving psychotropic medication, and to clarify their overall level of functioning. It also focuses on educators’ knowledge and perceptions of psychopharmacotherapy. The results showed that medicated had a mental disorder diagnosis recorded in their files more often than non-medicated children. As perceived by educators, these children had more externalized and internalized problems. However, according to self-reported data, no distinction can be made between medicated and non-medicated children, since both groups reported comparable levels of symptoms and diagnostic signs. Finally, the results indicate that post-traumatic stress symptoms and educators’ favorable opinion concerning pharmacotherapy are significant predictors of the probability of medication use. In conclusion, the inputs of these research findings are analyzed in light of previous studies. The clinical implications are discussed and future research directions will be suggested

Les objectifs de ce travail étaient d’évaluer la prévalence vie entière des traitements à visée psychotrope et les caractéristiques associées à cet usage dont l’adéquation avec l’existence de troubles psychiatriques. Les travaux ont été réalisés à partir des données issues de l’enquête Santé Mentale en Population Générale sur un échantillon de 36 785 adultes représentatifs de la population générale française. Un tiers des sujets a rapporté avoir fait usage d’au moins un traitement psychotrope au cours de la vie. L’inadéquation diagnostic-traitement est retrouvée dans le sens « usage en l’absence de trouble psychiatrique » aussi bien que dans le sens « absence d’usage en présence de trouble identifié ». Ainsi, seul un tiers des sujets avec un diagnostic de trouble dépressif récurrent a fait usage d’un traitement antidépresseur ou thymorégulateur. Concernant l’utilisation de traitements alternatifs, seuls 1,3 % des personnes rapportent un usage de traitement homéopathique à visée psychotrope. Ces traitements sont principalement utilisés par des personnes présentant un trouble anxieux en association avec un traitement psychotrope conventionnel. Des études ultérieures documentant l’ensemble des traitements à visée psychotrope utilisé dans le traitement des symptômes psychiques permettraient d’affiner les résultats sur l’adéquation diagnostic-traitement et d’estimer le nombre de sujets évitant le recours aux traitements conventionnels par l’utilisation d’alternatives thérapeutiques. / The aims of this work were to assess the lifetime prevalence of psychotropic drug use and the characteristics associated with use, particularly the congruence with psychiatric diagnoses. The studies were performed using the database from the survey Mental Health in the General Population including 36 785 persons representative of the French general population. One out of three subjects reported a lifetime use of psychotropic treatment. The non-congruence between diagnosis and psychotropic drug was observed in the pattern “use without psychiatric disorders” as well as in the pattern “no use with psychiatric disorders”. So, only one out of three persons with recurrent major depressive disorder reported having used an antidepressant or a mood stabilizer. Regarding complementary and alternative medicine use, only 1,3% of persons reported use of homeopathic treatment for psychiatric symptoms. These treatments were mainly used by persons with anxiety symptoms in association with conventional psychotropic drugs. Further studies assessing the all the treatments used for psychiatric symptoms would allow to refine the results on the congruence between diagnosis and psychotropic drug and to estimate the number of persons avoiding use of conventional psychotropic drugs by using complementary and alternative medicine.

Le système nerveux central est un organe privilégié et protégé, notamment grâce à l’existence des barrières histologiques entre le sang et les tissus nerveux. La barrière-hémato encéphalique (BHE) et la barrière hémato-rétinienne (BHR) séparent respectivement le parenchyme cérébral et la rétine des composés contenus dans l’espace vasculaire, grâce à l’expression de jonctions serrées et de transporteurs membranaires permettant une régulation spécifique des échanges entre le sang et le parenchyme nerveux. Ce travail a porté sur l’étude d’un nouveau transporteur de cations organiques mis en évidence fonctionnellement à la BHE de la souris. Ce transporteur appartenant très probablement à la superfamille des solute carrier (SLC), fonctionne comme un antiport proton. Actuellement, sa présence ne peut être démontrée que de façon fonctionnelle car son identité moléculaire est encore inconnue. Cet antiport proton constitue un nouvel acteur de la perméabilité cérébrale et ouvre une nouvelle voie d’accès au cerveau. Nous nous sommes tout d’abord attachés à approfondir les connaissances fonctionnelles de ce transporteur en étudiant de nouveaux substrats et tissus d’expression. Le transport cérébral de psychotropes a été étudié in vivo par la technique de perfusion carotidienne in situ chez la souris et in vitro grâce à une lignée de cellules endothéliales cérébrales humaines immortalisées (hCMEC/D3). Nous avons démontré que la haute perméabilité cérébrale de la cocaïne fait intervenir à la fois une diffusion passive et surtout une diffusion médiée par un antiport proton. La vitesse d’entrée des substances d’abus dans le cerveau est associée à un plus fort risque d’addiction et fait de ce transporteur un nouvel acteur critique de la régulation du passage cérébral. En effet, d’autres substances comme la nicotine et certaines amphétamines comme le MDPV et l'ecstasy sont également des substrats de cet antiport. Ce transporteur apparaît comme une cible pharmacologique potentielle dans la prise en charge de toxicomanies. Malgré la diversité chimique et pharmacologique d’interactions des composés avec cet antiport, les concentrations nécessaires pour l’inhiber dépassent celles retrouvées dans le sang. Pour aider l’identification d’inhibiteurs sélectifs et efficaces nous avons développé un modèle pharmacophorique d’inhibiteurs du transporteur à partir de données générées in vitro et de l’approche FLAPpharm. Ce modèle semble prédictif de nouveaux composés pouvant constituer de meilleurs inhibiteurs de ce transporteur. L’étude des échanges in vivo au niveau du tissu nerveux nous a menés à étudier l’impact de transporteurs ABC et de l’antiport-proton au niveau cérébral et rétinien à l’aide de substances spécifiques ou de substrats mixtes comme le vérapamil. L’antiport proton est fonctionnel au niveau de la BHR et transporte notamment la clonidine, le DPH et le vérapamil. Cependant, dans le cas d’un substrat mixte P-gp et SLC (ex : vérapamil), ce transport d’influx n’est visible à la BHE que lorsque la P-gp est neutralisée. Au contraire, à la BHR l’influx lié à cet SLC est visible naturellement. L’impact de la P-gp à la BHR étant 6.3-fois plus faible ce processus est probablement moins masqué. Cette étude illustre la difficulté actuelle de prédire l’impact fonctionnel d’un transporteur pour des substrats multi-spécifiques et l’existence d’une priorisation du transport. Enfin, nous avons essayé d’identifier l’antiport proton au niveau moléculaire par une méthode de photo-activation à l’aide d’un composé adapté. Cette méthode s’est avérée efficace pour fixer une molécule sur le transporteur, permettant par la suite de l’isoler plus facilement. En conclusion, ce travail a permis de mettre en évidence l’importance de l’antiport proton dans la distribution cérébrale de psychotropes et d’ouvrir de nouvelles perspectives dans l’addiction et la compréhension du transport de substrats multi-spécifiques. / The central nervous system is a privilege organ protected by histological barriers between the blood and the nervous tissue. The blood-brain barrier (BBB) and the blood-retinal barrier (BRB) separate cerebral parenchyma and retina from the circulating blood and both express tight junctions and membrane transporters, allowing a precise regulation of the exchanges between the blood and nervous tissues. We studied a new cationic transporter functionally evidenced at the mouse BBB. This molecularly unknown transporter belong to the solute carrier super family (SLC) and is a proton antiporter. It could constitute a new actor in the cerebral permeability and may be a new brain access pathway. First, we worked on the functional identification studying new substrates and new localization. Psychotropic brain transport was studied in vivo by brain in situ perfusion on mouse and in vitro with human immortalized endothelial cells (hCMEC/D3). We showed that cocaine brain entry depends on passive diffusion but also mainly on a proton antiporter. Brain entry rate of drugs of abuse is associated with modulation of addiction liability, making this transporter a new component of brain entry of cocaine, and also nicotine and some amphetamines such as ecstasy and MDPV. This proton antiporter appears to be a new potential target in addiction. Various chemical entities interact with this transporter; however concentrations used to inhibit the transporter are much higher than the one possibly found in the blood. In order to help find or design new selective and potent inhibitors, we developed a pharmacophore model of the proton antiporter inhibitors using in vitro data and the FLAPpharm approach. The model predicts well new possible inhibitors of this transporter. We also studied the impact of the ABC transporters and the proton antiporter at the BBB and the BRB using specific or multi-specific substrates such as verapamil. The proton antiporter is functionally expressed at the BRB and transports clonidine, DPH and verapamil. However, for the multi-specific (P-gp and SLC) compound verapamil, influx transport by the proton antiporter is visible at the BBB only when P-gp efflux is neutralized. On the contrary, at the BRB, the proton antiporter influx is always visible. This is certainly due to the lower impact (by 6.3 fold) of P-gp at the BRB compared to the BBB. These results show the difficulty to predict the functional impact of a transporter for multi-specific compounds and a probable transport prioritization. Finally we worked on the molecular identification of the proton antiporter using a photolabeling method. This work evidenced the importance of the proton antiporter in the brain distribution of psychotropic and drugs of abuse and opened toward new perspectives in addiction and transport comprehension.

Le système nerveux central est un organe privilégié et protégé, notamment grâce à l’existence des barrières histologiques entre le sang et les tissus nerveux. La barrière-hémato encéphalique (BHE) et la barrière hémato-rétinienne (BHR) séparent respectivement le parenchyme cérébral et la rétine des composés contenus dans l’espace vasculaire, grâce à l’expression de jonctions serrées et de transporteurs membranaires permettant une régulation spécifique des échanges entre le sang et le parenchyme nerveux. Ce travail a porté sur l’étude d’un nouveau transporteur de cations organiques mis en évidence fonctionnellement à la BHE de la souris. Ce transporteur appartenant très probablement à la superfamille des solute carrier (SLC), fonctionne comme un antiport proton. Actuellement, sa présence ne peut être démontrée que de façon fonctionnelle car son identité moléculaire est encore inconnue. Cet antiport proton constitue un nouvel acteur de la perméabilité cérébrale et ouvre une nouvelle voie d’accès au cerveau. Nous nous sommes tout d’abord attachés à approfondir les connaissances fonctionnelles de ce transporteur en étudiant de nouveaux substrats et tissus d’expression. Le transport cérébral de psychotropes a été étudié in vivo par la technique de perfusion carotidienne in situ chez la souris et in vitro grâce à une lignée de cellules endothéliales cérébrales humaines immortalisées (hCMEC/D3). Nous avons démontré que la haute perméabilité cérébrale de la cocaïne fait intervenir à la fois une diffusion passive et surtout une diffusion médiée par un antiport proton. La vitesse d’entrée des substances d’abus dans le cerveau est associée à un plus fort risque d’addiction et fait de ce transporteur un nouvel acteur critique de la régulation du passage cérébral. En effet, d’autres substances comme la nicotine et certaines amphétamines comme le MDPV et l'ecstasy sont également des substrats de cet antiport. Ce transporteur apparaît comme une cible pharmacologique potentielle dans la prise en charge de toxicomanies. Malgré la diversité chimique et pharmacologique d’interactions des composés avec cet antiport, les concentrations nécessaires pour l’inhiber dépassent celles retrouvées dans le sang. Pour aider l’identification d’inhibiteurs sélectifs et efficaces nous avons développé un modèle pharmacophorique d’inhibiteurs du transporteur à partir de données générées in vitro et de l’approche FLAPpharm. Ce modèle semble prédictif de nouveaux composés pouvant constituer de meilleurs inhibiteurs de ce transporteur. L’étude des échanges in vivo au niveau du tissu nerveux nous a menés à étudier l’impact de transporteurs ABC et de l’antiport-proton au niveau cérébral et rétinien à l’aide de substances spécifiques ou de substrats mixtes comme le vérapamil. L’antiport proton est fonctionnel au niveau de la BHR et transporte notamment la clonidine, le DPH et le vérapamil. Cependant, dans le cas d’un substrat mixte P-gp et SLC (ex : vérapamil), ce transport d’influx n’est visible à la BHE que lorsque la P-gp est neutralisée. Au contraire, à la BHR l’influx lié à cet SLC est visible naturellement. L’impact de la P-gp à la BHR étant 6.3-fois plus faible ce processus est probablement moins masqué. Cette étude illustre la difficulté actuelle de prédire l’impact fonctionnel d’un transporteur pour des substrats multi-spécifiques et l’existence d’une priorisation du transport. Enfin, nous avons essayé d’identifier l’antiport proton au niveau moléculaire par une méthode de photo-activation à l’aide d’un composé adapté. Cette méthode s’est avérée efficace pour fixer une molécule sur le transporteur, permettant par la suite de l’isoler plus facilement. En conclusion, ce travail a permis de mettre en évidence l’importance de l’antiport proton dans la distribution cérébrale de psychotropes et d’ouvrir de nouvelles perspectives dans l’addiction et la compréhension du transport de substrats multi-spécifiques. / The central nervous system is a privilege organ protected by histological barriers between the blood and the nervous tissue. The blood-brain barrier (BBB) and the blood-retinal barrier (BRB) separate cerebral parenchyma and retina from the circulating blood and both express tight junctions and membrane transporters, allowing a precise regulation of the exchanges between the blood and nervous tissues. We studied a new cationic transporter functionally evidenced at the mouse BBB. This molecularly unknown transporter belong to the solute carrier super family (SLC) and is a proton antiporter. It could constitute a new actor in the cerebral permeability and may be a new brain access pathway. First, we worked on the functional identification studying new substrates and new localization. Psychotropic brain transport was studied in vivo by brain in situ perfusion on mouse and in vitro with human immortalized endothelial cells (hCMEC/D3). We showed that cocaine brain entry depends on passive diffusion but also mainly on a proton antiporter. Brain entry rate of drugs of abuse is associated with modulation of addiction liability, making this transporter a new component of brain entry of cocaine, and also nicotine and some amphetamines such as ecstasy and MDPV. This proton antiporter appears to be a new potential target in addiction. Various chemical entities interact with this transporter; however concentrations used to inhibit the transporter are much higher than the one possibly found in the blood. In order to help find or design new selective and potent inhibitors, we developed a pharmacophore model of the proton antiporter inhibitors using in vitro data and the FLAPpharm approach. The model predicts well new possible inhibitors of this transporter. We also studied the impact of the ABC transporters and the proton antiporter at the BBB and the BRB using specific or multi-specific substrates such as verapamil. The proton antiporter is functionally expressed at the BRB and transports clonidine, DPH and verapamil. However, for the multi-specific (P-gp and SLC) compound verapamil, influx transport by the proton antiporter is visible at the BBB only when P-gp efflux is neutralized. On the contrary, at the BRB, the proton antiporter influx is always visible. This is certainly due to the lower impact (by 6.3 fold) of P-gp at the BRB compared to the BBB. These results show the difficulty to predict the functional impact of a transporter for multi-specific compounds and a probable transport prioritization. Finally we worked on the molecular identification of the proton antiporter using a photolabeling method. This work evidenced the importance of the proton antiporter in the brain distribution of psychotropic and drugs of abuse and opened toward new perspectives in addiction and transport comprehension.

Este estudo teve como objetivos identificar a frequência de interações medicamentosas (IM) potenciais do tipo fármaco-fármaco em pessoas atendidas em Estratégias de Saúde da Família (ESF) e classificá-las em relação à gravidade, à qualidade de evidências científicas e ao tempo de início; caracterizar em usuários de psicofármacos atendidos nas ESF, a adesão ao tratamento medicamentoso e a ocorrência de IM potenciais; avaliar a qualidade de vida (QV) dos pacientes atendidos nas ESF em relação ao Transtorno Mental Comum (TMC), o uso de psicofármacos e as IM; e elaborar um modelo de equações estruturais para identificar as variáveis associadas às IM, TMC, uso de psicofármacos e QV. Trata-se de estudo transversal de caráter correlacional descritivo, realizado em dez ESF de um município mineiro (n=452). Utilizou-se de questionário para coleta de dados demográficos, socieconômicos, farmacoterapêuticos, doenças clínicas e uso de psicofármacos, além de instrumento de rastreamento de TMC (SRQ-20), avaliação da adesão ao medicamento (MAT) e da QV (WHOQOL-brief). Uso de psicofármacos, IM, TMC e QV foram consideradas variáveis dependentes. Todavia, quando não ocuparam, na análise, a posição de desfecho, foram consideradas independentes. Para análise univariada foi utilizado o teste Qui-quadrado e para analisar as relações entre o conjunto de variáveis de interesse, utilizou-se Modelo de Equações Estruturais Generalizado. A IM foi prevalente em 66,59% da amostra. Em pacientes que consumiam cinco ou mais medicamentos tal prevalência foi de 85,37%. A prevalência de TMC foi de 24,56% e a de uso de psicofármacos foi de 77,65%, havendo maior frequência de IM potenciais nas prescrições dos usuários dessa classe de medicamentos. Ainda, 31,91% do total de usuários de psicofármacos utilizavam tais medicamentos sem prescrição médica. Houve maior porcentagem de IM potenciais classificadas como graves (47,47%) seguidas pelas moderadas (35,13%). As variáveis associadas à IM foram polifarmácia e renda. O uso de psicofármacos mostrou-se associado ao TMC, renda, diabetes e sexo. Na análise direta, o uso de psicofármaco e TMC influenciaram negativamente os padrões de QV em todos os domínios. A baixa renda foi indicativo de pior padrão de QV nos domínios psicológico, social e meio ambiente. A hipertensão arterial sistêmica e diabetes influenciaram de forma negativa a QV nos domínios psicológico e meio ambiente. Na análise indireta, renda, diabetes e TMC, mediado pelo uso de psicofármaco, influenciaram negativamente a QV em todos os domínios. O sexo, mediado pelo uso de psicofármaco, foi indicativo de pior padrão de QV nos domínios físico, social e meio ambiente. Os resultados apontam para a necessidade de implementação de estratégias direcionadas à segurança do paciente quanto à ocorrência de IM potenciais, prescrição racional de psicofármacos, bem como do rastreamento e intervenção para TMC, visto que este estudo identificou, na amostra investigada, que as referidas variáveis estão associadas à percepção de pior QV / The purpose of this study was to identify the frequency of drug-drug-drug interactions (DDI) in people treated in Family Health Strategies (FHS) and to classify them in relation to severity, quality of scientific evidence and the time of start; characterize in users of psychopharmaceuticals attended in FHS, adherence to drug treatment and the occurrence of potential DDI; to evaluate the quality of life (QOL) of the patients treated in the FHS in relation to the Common Mental Disorder (CMD), the use of psychotropic drugs and the DDI; and to elaborate a model of structural equations to identify the variables associated with DDI, CMD, use of psychoactive drugs and QOL. This is a cross-sectional descriptive, cross-sectional study, carried out in ten FHS of a city of Minas Gerais (n = 452). A questionnaire was used to collect demographic, socioeconomic, pharmacotherapeutic, clinical and psychopharmacological data, as well as a CMD screening tool (SRQ-20), drug adherence assessment (DDA) and QOL (WHOQOL-brief ). The use of psychoactive drugs, DDI, CMD and QOL were considered dependent variables. However, when they did not occupy the position of outcome in the analysis, they were considered independent. For univariate analysis, the Chi-square test was used and to analyze the relations between the set of variables of interest, a Generalized Structural Equation Model was used. IM was prevalent in 66,59% of the sample. In patients who consumed five or more drugs such prevalence was 85,37%. The prevalence of CMD was 24,56% and the use of psychotropic drugs was 77,65%, with a higher frequency of potential MIs in the prescriptions of users of this class of drugs. Still, 31,91% of all users of psychoactive drugs used such drugs without a prescription. There was a higher percentage of potential DDI classified as severe (47,47%) followed by moderate (35,13%). The variables associated with DDI were polypharmacy and income. The use of psychoactive drugs has been associated with CMD, income, diabetes and gender. In the direct analysis, the use of psychotropic drugs and CMD negatively influenced the QOL patterns in all domains. Low income was indicative of a worse QOL pattern in the psychological, social and environmental domains. Systemic arterial hypertension and diabetes had a negative influence on QOL in the psychological and environmental domains. In indirect analysis, income, diabetes and CMD, mediated by the use of psychoactive drugs, negatively influenced QOL in all domains. Sex, mediated by the use of psychoactive drugs, was indicative of a worse QOL pattern in the physical, social and environmental domains. The results point to the need to implement strategies directed to patient safety regarding the occurrence of potential DDI, rational prescription of psychotropic drugs, as well as the screening and intervention for CMD, since this study identified, in the sample investigated, that said variables are associated with the perception of worse QOL