Η ΒΥΠ διαθέτει αντίτυπο της διατριβής σε έντυπη μορφή στο βιβλιοστάσιο διδακτορικών διατριβών που βρίσκεται στο ισόγειο του κτιρίου της. / Ο ιππόκαμπος στον αρουραίο είναι μια δομή σε C-σχήμα που εκτείνεται από τον διαφραγματικό πυρήνα προσθιοραχιαία έως τον κροταφικό λοβό οπισθιοκοιλιακά. Παρόλο που από παλιά θεωρείτο ως ομοιογενής δομή, έχουν παρατηρηθεί πολλές διαφορές σε όλα τα επίπεδα οργάνωσης μεταξύ του διαφραγματικού και του κροταφικού ιππόκαμπου. Οι βενζοδιαζεπίνες δρουν στις θέσεις δέσμευσης των βενζοδιαζεπινών, οι οποίες είναι αλλοστερικά συνδεδεμένες με το σύμπλοκο του GABAA, όπου ενισχύουν την δράση του GABA στους GABAA υποδοχείς, αυξάνοντας τη συχνότητα ανοίγματος του διαύλου των ιόντων χλωρίου (Cl-) και έχοντας μικρή μόνο επίδραση στο χρόνο ανοίγματος ή στην αγωγιμότητα του διαύλου. Προηγούμενη μελέτη υποδεικνύει ότι η έκφραση των α1-, β2- και γ2-υπομονάδων ήταν μικρότερη, ενώ αντίθετα η έκφραση των α2-, α5- και β1-υπομονάδων ήταν μεγαλύτερη στον κροταφικό ιπποκάμπο σε σύγκριση με τον διαφραγματικό ιππόκαμπο. Σύμφωνα με προηγούμενες μελέτες που αφορούν την συνέκφραση των υπομονάδων στο σύμπλοκο του GABAA υποδοχέα τα αποτελέσματα μας υποδηλώνουν ότι ο α1β2-υποτύπος του GABAA υποδοχέα επικρατεί στον διαφραγματικό ιππόκαμπο (ΔΙ), ενώ ο α2β1-υπότυπος κυριαρχεί στον κροταφικό ιππόκαμπο (ΚΙ). Επιπλέον, φαρμακολογικές μελέτες έχουν δείξει ότι η καταπραϋντική δράση της diazepam πραγματοποιείται μέσω των GABAA υποδοχέων, που περιέχουν την α1-υπομονάδα, ενώ η αγχολυτική δράση της πραγματοποιείται μέσω των υποδοχέων που φέρουν την α2-υπομονάδα. Επομένως, η μελέτη των φαρμακολογικών ιδιοτήτων των υποτύπων του GABAΑ υποδοχέα δίνει την δυνατότητα στο να σχεδιαστούν ειδικά φάρμακα τα οποία θα βελτιώνουν το κλινικό προφίλ ασθενειών, όπως το άγχος, η αϋπνία ή η επιληψία, δρώντας σε εξειδικευμένους υποτύπους του GABAΑ υποδοχέα. Ο στόχος της συγκεκριμένης εργασίας ήταν να μελετηθούν οι φαρμακολογικές ιδιότητες των υποτύπων του συμπλόκου του GABAA υποδοχέα/βενζοδιαζεπινών στον διαφραγματικό σε σύγκριση με τον κροταφικό ιππόκαμπο επίμυος. Έτσι, για τη μελέτη των θέσεων δέσμευσης των βενζοδιαζεπινών μεταξύ του διαφραγματικού και κροταφικού ιπποκάμπου χρησιμοποιήθηκε ο ευρέως φάσματος αγωνιστής των θέσεων δέσμευσης των βενζοδιαζεπινών, [3H]-flunitrazepam, σε μια αυτοραδιογραφική μελέτη. Επιπλέον, χρησιμοποιήθηκαν εξειδικευμένα φάρμακα, που δεσμεύονται σε συγκεριμένους υποτύπους του GABAA υποδοχέα, όπως το zolpidem (ειδικός αγωνιστής των GABAA υποδοχέων, που περιέχουν την α1-υπομονάδα), το etomidate (ειδικός θετικός αλλοστερικός ρυθμιστής των GABAA υποδοχέων, που περιέχουν τη β2-υπομονάδα) και το L-655,708 (ειδικός αντίστροφος αγωνιστής των GABAA υποδοχέων, που περιεχούν την α5-υπομονάδα) σε μια αυτοραδιγραφική κινητική μελέτη. Τα αποτελέσματα μας έδειξαν ότι οι τομές που προέρχονταν από τον ΚΙ συγκρινόμενες με αυτές από τον ΔΙ είχαν: Α) μειωμένη δέσμευση της [3H]-flunitrazepam στις CA1, CA3 και DG περιοχές, Β) μικρότερη χημική συγγένεια της δέσμευση της [3H]-flunitrazepam στη CA1 περιοχή, Γ) καμία διαφορά στον αριθμό των θέσεων δέσμευσης, Δ) μεγαλύτερες τιμές IC50 και EC50 για το zolpidem και το etomidate, αντίστοιχα και Ε) μικρότερες τιμές IC50 για το L-655,708. Συμπερασματικά, τα αποτελέσματά μας υποδεικνύουν διαφορετικές φαραμκολογικές ιδιότητες των υποτύπων του GABAΑ/ΒΖ υποδοχέα μεταξύ του ΔΙ και ΚΙ, ενώ επιβεβαιώνεται και ενισχύεται προηγούμενη μελέτη που υποδηλώνει ότι ο α1β2-υποτύπος του GABAA υποδοχέα επικρατεί στον διαφραγματικό ιππόκαμπο (ΔΙ), ενώ ο α2β1-υπότυπος κυριαρχεί στον κροταφικό ιππόκαμπο (ΚΙ). Η μελέτη αυτή είναι πιθανό να τυγχάνει ιδιαίτερης κλινικής αξίας, στην κατεύθυνση της ακριβέστερης ρύθμισης των αποτελεσματικών δόσεων των διάφορων μορίων που δρουν στις θέσεις δέσμευσης των βενζοδιαζεπινών των α1- και α2-υποτύπων του GABAA υποδοχέα. / The hippocampus in the rat appears grossly as an elongated structure with its long axis bending in a C-shaped manner from the septal nuclei rostrodorsally to the incipient temporal lobe caudoventrally. The long axis of the hippocampal formation is referred as the dorsoventral axis. Although hippocampus has been traditionally thought as a homogeneous structure, several studies have been demonstrated differences at several organization levels (from the behavioural to the cellular) between its dorsal (DH) and ventral (VH) pole. Pharmacological studies have shown that the α1-GABAA receptor subtype is associated with the sedative and anticonvulsant effects of benzodiazepines (BZs), whereas the α2-subtype is associated with the anxiolytic effects of BZs. Recent data have demonstrated a differential distribution of the GABAA receptor subunits between DH and VH, with the α1/β2 GABAA receptor subtype dominating in the DH and the α2/β1 subtype prevailing in the VH. We therefore study possible differences in the pharmacological properties and receptor binding parameters of the GABAA/BZ receptor subtypes between DH and VH, by examining: 1a) the specific binding of [3H]-flunitrazepam (BZ sites agonist), by using quantitative autoradiography, b) the kinetic parameters of [3H]-flunitrazepam specific binding, by using the “wipe off” technique and 2) the competitive displacement of [3H]-flunitrazepam binding by using zolpidem (a specific agonist of α1-subtype) and L-655,708 (a specific inverse agonist of α5-subtype) and the enhancement of [3H]-flunitrazepam binding by using etomidate (a selective positive modulator of β2- subunit), in an autoradiographical saturation kinetic study. Our results showed in VH compared to the DH: A) lower level of [3H]-flunitrazepam binding in CA1, CA3 and DG regions, B) higher KD value for [3H]-flunitrazepam specific binding in CA1 region and no differences in the Bmax value, C) higher IC50 and EC50 values for zolpidem and etomidate, respectively and D) lower IC50 values for L-655,708. In conclusion, the lower affinity of GABAA receptors for [3H]-flunitrazepam binding, the higher IC50 and EC50 values for zolpidem and etomidate, respectively, as well as the lower IC50 values for L-655,708 observed in VH compared to DH, support the evidence that the α1/β2-GABAA receptor subtype dominates in DH and the α2/β1-subtype prevails in VH and suggest differential pharmacological effects of the benzodiazepines in DH compared to VH, which could be of clinical relevence for the more accuate adjustment of the effective dose of α1- and α2-subtype specific BZ binding sites’ ligands.

Many epidemiological studies assess the effects of time-dependent exposures, where both the exposure status and its intensity vary over time. The analysis of such studies poses the challenge of modelling the association between complex time-dependent drug exposure and the risk, especially given the uncertainty about the etiological relevance of doses taken in different time periods. / To address this challenge, I developed a flexible method for modelling cumulative effects of time-varying exposures, weighted by recency, represented by time-dependent covariates in the Cox proportional hazards model. The function that assigns weights to doses taken in the past is estimated using cubic regression splines. Models with different number of knots and constraints are estimated. Bootstrap techniques are used to obtain pointwise confidence bands around the weight functions, accounting for both the sampling variation of the regression coefficients, and the uncertainty at the model selection stage, i.e. the additional variance due to a posteriori selection of the number of knots. / To assess the method in simulations, I had to develop and validate a novel algorithm to generate event times conditional on time-dependent covariates and compared it with the algorithms available in the literature. The proposed algorithm extends a previously proposed permutational algorithm to include a rejection sampler. While all the algorithms generated data sets that, once analyzed, provided virtually unbiased estimates with comparable variances, the algorithm that I proposed reduced the computational time by more than 50 per cent relative to alternative methods. I used simulations to systematically investigate the properties of the weighted cumulative dose method. Six different weight functions were considered. Simulations showed that in most situations, the proposed method was able to capture the shape of the true weight functions and to produce estimates of the magnitude of the exposure effect on the risk that were close to those used to generate the data. I finally illustrated the use of the weighted cumulative dose modelling by reassessing the association between the use of selected benzodiazepines and fall-related injuries, using administrative data on a cohort of elderly who initiated their use of benzodiazepines between 1990 and 2004.

Benzodiazepines have been widely prescribed since the 1960s for the management of adverse symptoms related to anxiety, depression, and sleep problems. They were regarded as an efficacious medication when compared with their predecessor, barbiturates. Within 10 years of their introduction, concerns began to be raised regarding their potential to produce dependence and withdrawal symptoms when ceased, including symptoms not present prior to their being prescribed. Subsequent research focussed on establishing effective strategies to ameliorate the adverse symptoms experienced even when the daily intake was slowly reduced. The aim of the work undertaken for this doctorate was to establish whether there was a role for cognitive behaviour therapy (CBT) in benzodiazepine cessation. The initial step in conducting the research for this doctorate was to obtain a detailed understanding of the current state of research on benzodiazepine cessation. Study 1 therefore focussed on establishing the effectiveness of treatment approaches used to assist individuals to cease benzodiazepine use. A Meta-analysis of treatment strategies undertaken in general practice and outpatient settings established that brief intervention resulted in superior cessation rates at post-treatment than routine care. Gradual dose reduction plus CBT was slightly superior to gradual dose reduction alone. However, substitutive pharmacotherapies in combination with gradual dose reduction did not result in a superior outcome to gradual dose reduction alone, and substitutive pharmacotherapy plus abrupt benzodiazepine cessation was less effective than gradual dose reduction. While, providing CBT in conjunction with gradual dose reduction offered a superior outcome than gradual dose reduction alone, current evidence does not identify the CBT strategies that contributed to the superior outcome. The next step in the development of the CBT intervention involved obtaining a deep appreciation of the issues relating to cessation from the perspective of General Practitioners (GPs) and Benzodiazepine Users (BzUs). Accordingly, Study 2 administered semi-structured interviews about benzodiazepine use and its cessation to 28 GPs and 23 BzUs. Responses were analysed using the Consensual Qualitative Research approach, as it enabled comparisons to be made between the views of the two groups of interviewees. The study identified commonality between GPs and BzUs on reasons for commencing use, the role of dependence in continued use, and the importance of lifestyle change in its cessation. BzUs felt there was greater need for GPs to routinely advise patients about non-pharmacological management of their problems and potential adverse consequences of long-term use before prescribing benzodiazepines. Few GPs had assisted a patient to cease use reportedly due to the required time and the expectation of a poor outcome. There was a perception that patients wanted a pharmacological solution to their problems. A critical gap in assessment instruments that are needed for a comprehensive assessment of the outcomes from a treatment trial was identified. In particular, there was no measure of benzodiazepine expectancy or self-efficacy concerning maintenance of benzodiazepine dose reduction. Therefore, Study 3 adapted existing expectancy and self-efficacy measures form other substance domains to verify their applicability to benzodiazepines. Current BzUs (n = 155) were invited to complete two questionnaires either online or via hard copy. Principal component analysis (PCA) of a newly developed Benzodiazepine Expectancy Questionnaire (BEQ) resulted an 18-item, 2-factor scale, while a Benzodiazepine Refusal Self Efficacy Questionnaire (BRSEQ) formed a 16-item, 4-factor scale, Confirmatory factor analysis (CFA) in a second sample (n = 139) confirmed these internal structures, reducing the BEQ to 12 items and the BRSEQ to 14 items respectively. The qualitative study suggested that many GPs would be reluctant to engage in psychological support for benzodiazepine cessation and it was evident that specialist services would be unable to provide substantial support especially in rural and remote areas. Accordingly, it was decided to develop a treatment that was remotely delivered. The initial pilot used a correspondence-based approach, delivered via the postal service. Study 4 comprised a small pilot comparing GP managed gradual dose reduction, plus CBT via mail (M-CBT), which was either delivered immediately (IM-CBT) or after 3 months (DM-CBT). Despite substantial efforts over a 2 year period to recruit GPs and BzUs, only 6 received the allocated intervention. It was decided to trial the intervention as an internet-delivered program to enhance its accessibility to BzUs. Access to the program was promoted through the project website and links from high profile support websites. Study 5 was an uncontrolled trial of internet-based CBT (I-CBT). Access was provided to all newsletters, although, participants were given a suggested sequence for access. Despite placement on the internet and cross-listing on several key websites, the study still only recruited 35 participants (3 of which received the program by mail). Of the 32 undertaking the program via the internet, 21 completed the 3-month assessments and 14 the 6-month assessments. Eight participants reduced their weekly benzodiazepine intake by at least 50%, by 3 months, with five ceasing use at 6 months. A significant increase in self-efficacy, and a decrease in depressive symptoms and dependence were seen. Providing CBT either via mail or the internet assisted some participants to reduce or cease long-term benzodiazepine use. Recruitment to both M-CBT and I-CBT was limited, despite substantial attempts to market the intervention. The studies undertaken for this doctorate make a unique contribution to improving treatment outcomes for people wishing to cease long-term benzodiazepine use. They also provide direction for more extensive studies to definitively establish the nature of effective treatment. The current evidence clearly supports the importance of gradual dose reduction and the role of CBT in further improving treatment outcomes. However, engagement of both BzUs and GPs remains challenging. Remote delivery of CBT via mail or the internet may assist with improving access to CBT, but it does not solve the problem of GP and BzU engagement. An effective system-wide program to address long-term benzodiazepine use will require that incentives for GP involvement (a disincentive for long-term prescription) are in place.

Made available in DSpace on 2015-12-06T23:46:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2013 / Associação Fundo de Incentivo à Psicofarmacologia (AFIP) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: O uso nao prescrito de medicamentos psicotropicos entre jovens tem crescido mundialmente e se tornado objeto de preocupacao nos ultimos anos. Os tranquilizantes estao entre os medicamentos mais utilizados, com grande potencial para uso inadequado, abuso e dependencia, especialmente em populacoes mais vulneraveis como os adolescentes. Este estudo descreve o padrao de uso de tranquilizantes sem receita medica por estudantes brasileiros e identifica caracteristicas dos adolescentes e da exposicao a essas substancias que estao associadas ao consumo nao prescrito. Metodos: As analises foram realizadas a partir de uma amostra randomizada e estratificada de 47979 estudantes de 10 a 18 anos de nivel fundamental e medio da rede publica e privada de ensino nas 27 capitais brasileiras. Os dados foram obtidos por meio da aplicacao de um questionario de autopreenchimento sobre uso de tranquilizantes sem receita medica e demais substancias psicotropicas (alcool, tabaco, maconha, cocaina/crack, ecstasy, Benflogin®, anabolizantes, anfetaminas e opioides), variaveis sociodemograficas (idade, genero, classe socioeconomica, tipo de escola e regiao do pais), indicadores de acesso (ja ter recebido prescricao medica e uso de tranquilizantes por familiar ou amigo) e tambem percepcao de risco. Modelos de regressao logistica foram realizados para verificar associacao entre uso na vida nao prescrito de tranquilizantes e os fatores previamente mencionados. Resultados: O uso na vida de tranquilizantes sem receita medica foi relatado por 3,9% dos participantes, sendo o diazepam o medicamento mais consumido. O principal motivo de uso foi automedicacao e mais de 80% mencionou ter obtido o medicamento atraves da familia ou disponivel em ambiente familiar. O consumo foi duas vezes mais prevalente entre meninas e alunos provenientes de classes socioeconomicas mais favorecidas e escolas privadas. Houve associacao entre uso nao prescrito de tranquilizantes e uso na vida de alcool, de tabaco, de drogas ilicitas e de outros medicamentos sem receita medica. O uso sem prescricao medica de tranquilizantes pelos adolescentes tambem foi associado ao uso de tranquilizantes por algum parente ou amigo, ja ter recebido uma prescricao medica anterior de tranquilizantes e a uma baixa percepcao de risco de uso regular da substancia. A prescricao medica tambem esteve associada a uma baixa percepcao de risco do adolescente ao uso regular nao prescrito. Conclusao: O uso de tranquilizantes sem receita medica por adolescentes pode indicar o consumo de outras substancias, incluindo combinacoes de risco, como o uso concomitante com alcool. Ha influencia direta (oferta) e indireta (acesso e uso) da familia, e a prescricao medica tem um papel reforcador sobre o uso nao prescrito, inclusive reduzindo a percepcao de risco dos adolescentes. Os riscos decorrentes do uso de tranquilizantes sem prescricao medica devem ser abordados em fases iniciais de programas preventivos sobre drogas, e maior atencao pode ser dada aos grupos de maior risco ao consumo, como meninas e adolescentes com maior poder aquisitivo. Os medicos devem ser alertados sobre o efeito da prescricao medica de tranquilizantes acerca de um eventual uso nao prescrito entre adolescentes, sendo judiciosos ao prescrever para esta faixa etaria. Da mesma forma, adultos devem ser orientados quanto a importancia de nao compartilhar seus psicotropicos ou deixa-los acessiveis para adolescentes / Background: The use of a psychotropic medication without a prescription among young people appears to be a growing global problem. Tranquilizers are used in large scale, with great potential of misuse, abuse and dependence, especially in more vulnerable populations such as adolescents. This study aims to describe the patterns of nonprescribed use of tranquilizers by Brazilian students and to identify these adolescents' characteristics as well as the exposure variables (characteristics) that may lead to (may imply) the use of tranquilizers without a proper prescription. Methods: Analyses were made from a dataset of a randomized and stratified sample of 47979 students aged 10 to 18, attending middle and high school in private and public schools, from the 27 Brazilian state capitals. We used a self-report questionnaire to obtain information regarding the nonprescribed use of tranquilizers and other substances (alcohol, tobacco, marijuana, cocaine/ crack, ecstasy, Benflogin®, amphetamines and opioids), sociodemographic variables (age, gender, socioeconomic status, type of school and country region), access indicators (having received a medical prescription for tranquilizers and use of these substances by a relative or a close friend) and risk perception. Logistic regression models were performed to verify association between nonprescribed lifetime use and the factors we mention above. Results: Nonprescribed lifetime use of tranquilizers was reported by 3.9% of respondents and diazepam was the most cited drug. The main reason to use tranquilizers without a prescription was self-medication and more than 80% of adolescents had obtained them within their own home or by means of a relative. Girls were twice more likely than boys to report the use, as well as adolescents from private schools and higher socioeconomic status. Nonprescribed lifetime use of tranquilizers was associated with lifetime use of alcohol, tobacco, illicit drugs and nonprescribed use of other medications. The nonprescribed use was also associated with having received a medical prescription in the past, the use of tranquilizers by a relative or close friend, as well as low risk perception to the regular nonprescribed use of tranquilizers. Medical prescription was likewise associated with low risk perception among those who ever used tranquilizers. Conclusions: Adolescents’ non-medical use of prescription tranquilizers might indicate the use of other substances including risky combinations such as prescription tranquilizers and alcohol. Family may act directly, by offering, or indirectly, by allowing access and self use. Prior medical prescription might reinforce this behaviour, as well as reduce adolescents’ risk perception. The risks that result from nonmedical use of prescription anxiolytics should be addressed during the early stages of drug prevention programs, and more attention should be given to high risk groups, including girls and adolescents with higher purchasing power. Physicians should be warned about the effect of prescription tranquilizers regarding possible misuse among adolescents, and ought to be judicious when prescribing for this age group. Likewise, adults should be counselled about the importance of not sharing their psychotropic drugs and not leaving them accessible to adolescents. / BV UNIFESP: Teses e dissertações

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Introdução: A preocupação em torno do uso irracional de psicofármacos tem sido observada em diversos países, constituindo-se uma questão importante para a saúde pública mundial. No Brasil, a promoção do uso racional de psicofármacos é um desafio para a atenção primária, sendo importante caracterizar sua dimensão psicossocial. Objetivos. O artigo 1, com características descritivas, tem como objetivo caracterizar o uso de psicofármacos em unidades de saúde da família segundo a presença de transtornos mentais comuns (TMC) e segundo as principais características socioeconômicas e demográficas. O artigo 2, com um caráter analítico, tem como objetivo avaliar o papel da rede social no uso de cada um destes psicofármacos segundo a presença de TMC. Métodos O estudo utiliza um delineamento seccional e abarca a primeira fase de coleta de dados de dois estudos em saúde mental na atenção primária. Esta se deu em 2006/2007 para o estudo 1 (Petrópolis, n= 2.104) e em 2009/2010 para o estudo2 (São Paulo, n =410, Rio de Janeiro, n= 703, Fortaleza , n=149 e Porto Alegre, n= 163 participantes). Ambos os estudos possuem o mesmo formato no que se refere à coleta de dados, seu processamento e revisão, resultando em uma amostra de 3.293 mulheres atendidas em unidades de saúde da família de cinco diferentes cidades do país. Um questionário objetivo com perguntas fechadas foi utilizado para a coleta de informações socioeconômicas e demográficas. O uso de psicofármacos foi avaliado através de uma pergunta aberta baseada no auto-relato do uso de medicamentos. A presença de TMC foi investigada através do General Health Questionnaire, em sua versão reduzida (GHQ-12). O nível de integração social foi aferido através do índice de rede social (IRS), calculado a partir de perguntas sobre rede social acrescentado ao questionário geral. No estudo descritivo (artigo 1), a frequência do uso de antidepressivos e o uso de benzodiazepínicos na população de estudo foram calculadas para cada cidade, tal como a frequência do uso destes psicofármacos entre as pacientes com transtornos mentais comuns. A distribuição do uso de cada um destes psicofármacos segundo as principais características socioeconômicas, demográficas e segundo transtornos mentais comuns foi avaliada através do teste de qui-quadrado de Pearson. No estudo analítico (artigo 2), a associação entre o nível de integração social e o uso exclusivo de cada um dos psicofármacos foi analisada através da regressão logística multivariada, com estratificação segundo a presença de TMC. Resultados: A frequência do uso de psicofármacos foi bastante heterogênea entre as cidades, destacando-se, porém, a importância do uso de benzodiazepínicos frente ao uso de antidepressivos em sua maioria. A proporção do uso de psicofármacos, sobretudo antidepressivos, foi predominantemente baixa entre as pacientes com TMC. Entre elas, o uso de antidepressivos mostrou-se positivamente associado ao isolamento social, enquanto o uso de benzodiazepínicos associou-se negativamente a este. Conclusão: Os resultados colaboram para a caracterização do uso de psicofármacos em unidades de saúde da família e para a discussão acerca de sua racionalidade. Destaca-se a importância de avaliar a dimensão psicossocial que envolve o uso destas substâncias com vistas ao desenvolvimento de estratégias de cuidado mais efetivas / Introduction: Concerns about irrational use of psychotropic drugs has been observed in many countries, becoming an important issue for global public health. In Brazil, the promotion of rational use of psychotropic drugs is a challenge for primary care, therefore it is important to characterize its psychosocial dimension. Objectives This dissertation consists of two articles. Article 1, with descriptive characteristics, aims to characterize the use of psychotropic drugs in family health units, according to major socioeconomic and demographic characteristics and according to the presence of common mental disorders (CMD). Article 2, with an analytical character, aims to evaluate the role of social networks in the use of each of these psychotropic drugs, according to the presence of CMD. Methods The study has a cross-sectional design and integrates baseline data from two previous studies on mental health in primary care . Data collection took place in 2006/2007 for the study 1 (Petropolis, n = 2.104) and in 2009/2010 for the study2 (São Paulo, n = 410, Rio de Janeiro, n = 703, Fortaleza - n = 149 and Porto Alegre, n = 163 participants). Although performed in different periods, both studies have the same format as regards data collection, processing and review, resulting in a sample of 3293 women attending family health units from five different cities. An objective questionnaire with closed questions was used to collect socioeconomic and demographic information. Psychotropic use was assessed through an open-ended question based on self-reporting of drug use. The presence of CMD was investigated by the General Health Questionnaire in its reduced version (GHQ-12). The level of social integration was evaluated through the social network index (IRS), calculated from questions about social network added to the general questionnaire. In the descriptive study (Article 1), the frequency of antidepressants and benzodiazepines use in the study population were calculated for each city, such as the frequency of the use of psychotropic drugs among patients with common mental disorders. The distribution of the use of each of these psychoactive drugs according to major socioeconomic and demographic characteristics and according to the presence of common mental disorders was assessed by Pearsons chi-square test. In the analytical study (Article 2), the association between the level of social integration and the exclusive use of each of psychotropic drugs was analyzed by multivariate logistic regression, stratified according to the presence of TMC. Results: The frequency of psychotropic medication use was quite heterogeneous among cities, emphasizing, however, the importance of the use of benzodiazepines against the use of antidepressants in most of the cities. The proportion of use of psychotropic medication, particularly antidepressants, was predominantly low among patients with CMD. Among these, antidepressants use was positively associated with social isolation, while benzodiazepines use was negatively associated. Conclusion: This study collaborates to characterize the use of antidepressants and benzodiazepines in family health units and to discuss about their rationality. The results highlight the importance of assessing the psychosocial dimension that involves the use of these substances in order to develop strategies to promote its rational use in primary care.

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O protocolo de teste/reteste no labirinto em cruz elevado (LCE) mostra que a experiência prévia no labirinto produz alterações duradouras nas respostas comportamentais de roedores. Nesse contexto, ratos submetidos ao LCE pela primeira vez apresentam um aumento característico na exploração dos braços abertos e uma redução dos comportamentos de avaliação de risco após a administração de drogas ansiolíticas. Na reexposição ao labirinto, porém, essas drogas tornam-se ineficazes em alterar as medidas tradicionais do LCE. Esse fenômeno foi inicialmente observado com o benzodiazepínico clordiazepóxido e referido como one-trial tolerance (tolerância de um ensaio OTT). A proposta do presente estudo é compreender a OTT por meio do exame dos fatores hormonais, cognitivos e neuroanatômicos envolvidos nesse fenômeno. A administração sistêmica do benzodiazepínico midazolam ou de metirapona, um bloqueador da síntese de glicocorticóides, reduziu a frequência dos comportamentos de avaliação de risco e dos níveis plasmáticos de corticosterona quando injetados antes das sessões teste ou reteste. Além disso, a reexposição de ratos ao LCE foi caracterizada por uma avaliação de risco mais proeminente, de acordo com a análise fatorial, e pela ativação de estruturas límbicas envolvidas com aspectos cognitivos do medo, como a região ventral do córtex pré-frontal medial (CPFm) e a amígdala, mostrada por meio da distribuição da proteína Fos. Midazolam administrado antes da primeira exposição ao LCE produziu uma redução significativa do número de neurônios Fos-positivos no córtex cingulado anterior, área 1 (Cg1) e nos núcleos anterior e pré-mamilar dorsal do hipotálamo. Por outro lado, midazolam causou uma redução no número de neurônios Fos-positivos no CPFm, amígdala, núcleo dorsomedial do hipotálamo e núcleos da rafe em ratos reexpostos ao LCE. Cg1 foi a única estrutura-alvo do benzodiazepínico em ambas as sessões. Resultados comportamentais similares aos produzidos pelo tratamento sistêmico foram obtidos com infusões de midazolam intra-Cg1. Esses resultados apontam para um papel crucial dos comportamentos de avaliação de risco no desenvolvimento da OTT e indicam o Cg1 como um importante sítio de ação ansiolítica dos benzodiazepínicos em roedores. / The elevated plus maze (EPM) test/retest protocol has shown that prior experience to the maze produces enduring changes in behavioral responses of rodents. In this context, rats submitted for the first time to the EPM display a characteristic increase in open arm exploration and reduced risk assessment behaviors after the administration of anxiolytic drugs. Upon re-exposure to the maze, however, these drugs become unable to change the traditional measures of the EPM. This phenomenon was initially observed with the benzodiazepine chlordiazepoxide and referred to as one-trial tolerance (OTT). The purpose of the present study is to understand the OTT through the exam of the hormonal, cognitive and neuroanatomical factors involved in this phenomenon. The systemic administration of the benzodiazepine midazolam or metyrapone, a glucocorticoids synthesis blocker, reduced the frequency of risk assessment behaviors and the corticosterone levels when injected before the test or retest sessions. Moreover, the re-exposure of rats to the EPM was characterized by more prominent risk assessment behaviors, according to the factor analysis, and by activation of limbic structures involved with cognitive aspects of fear, such as the ventral regions of the medial prefrontal cortex (mPFC) and amygdala, as shown through the distribution of the Fos protein. Midazolam injected before the first exposure to the EPM produced a significant decrease in the number of Fos-positive neurons in the anterior cingulate cortex, area 1 (Cg1), anterior and dorsal premammillary nuclei of hypothalamus. On the other hand, midazolam caused a decrease in the number of Fos-positive neurons in the mPFC, amygdala, dorsomedial nucleus of hypothalamus and raphe nuclei in rats re-exposed to the EPM. Cg1 was the only structure targeted by the benzodiazepine in both sessions. Behavioral results similar to those produced by systemic treatment were obtained with intra-Cg1 infusions of midazolam. These results point to a crucial role of the risk assessment behaviors in the development of the OTT and indicate the Cg1 as an important locus for the anxiolytic-like action of benzodiazepines in rodents.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Introdução: A preocupação em torno do uso irracional de psicofármacos tem sido observada em diversos países, constituindo-se uma questão importante para a saúde pública mundial. No Brasil, a promoção do uso racional de psicofármacos é um desafio para a atenção primária, sendo importante caracterizar sua dimensão psicossocial. Objetivos. O artigo 1, com características descritivas, tem como objetivo caracterizar o uso de psicofármacos em unidades de saúde da família segundo a presença de transtornos mentais comuns (TMC) e segundo as principais características socioeconômicas e demográficas. O artigo 2, com um caráter analítico, tem como objetivo avaliar o papel da rede social no uso de cada um destes psicofármacos segundo a presença de TMC. Métodos O estudo utiliza um delineamento seccional e abarca a primeira fase de coleta de dados de dois estudos em saúde mental na atenção primária. Esta se deu em 2006/2007 para o estudo 1 (Petrópolis, n= 2.104) e em 2009/2010 para o estudo2 (São Paulo, n =410, Rio de Janeiro, n= 703, Fortaleza , n=149 e Porto Alegre, n= 163 participantes). Ambos os estudos possuem o mesmo formato no que se refere à coleta de dados, seu processamento e revisão, resultando em uma amostra de 3.293 mulheres atendidas em unidades de saúde da família de cinco diferentes cidades do país. Um questionário objetivo com perguntas fechadas foi utilizado para a coleta de informações socioeconômicas e demográficas. O uso de psicofármacos foi avaliado através de uma pergunta aberta baseada no auto-relato do uso de medicamentos. A presença de TMC foi investigada através do General Health Questionnaire, em sua versão reduzida (GHQ-12). O nível de integração social foi aferido através do índice de rede social (IRS), calculado a partir de perguntas sobre rede social acrescentado ao questionário geral. No estudo descritivo (artigo 1), a frequência do uso de antidepressivos e o uso de benzodiazepínicos na população de estudo foram calculadas para cada cidade, tal como a frequência do uso destes psicofármacos entre as pacientes com transtornos mentais comuns. A distribuição do uso de cada um destes psicofármacos segundo as principais características socioeconômicas, demográficas e segundo transtornos mentais comuns foi avaliada através do teste de qui-quadrado de Pearson. No estudo analítico (artigo 2), a associação entre o nível de integração social e o uso exclusivo de cada um dos psicofármacos foi analisada através da regressão logística multivariada, com estratificação segundo a presença de TMC. Resultados: A frequência do uso de psicofármacos foi bastante heterogênea entre as cidades, destacando-se, porém, a importância do uso de benzodiazepínicos frente ao uso de antidepressivos em sua maioria. A proporção do uso de psicofármacos, sobretudo antidepressivos, foi predominantemente baixa entre as pacientes com TMC. Entre elas, o uso de antidepressivos mostrou-se positivamente associado ao isolamento social, enquanto o uso de benzodiazepínicos associou-se negativamente a este. Conclusão: Os resultados colaboram para a caracterização do uso de psicofármacos em unidades de saúde da família e para a discussão acerca de sua racionalidade. Destaca-se a importância de avaliar a dimensão psicossocial que envolve o uso destas substâncias com vistas ao desenvolvimento de estratégias de cuidado mais efetivas / Introduction: Concerns about irrational use of psychotropic drugs has been observed in many countries, becoming an important issue for global public health. In Brazil, the promotion of rational use of psychotropic drugs is a challenge for primary care, therefore it is important to characterize its psychosocial dimension. Objectives This dissertation consists of two articles. Article 1, with descriptive characteristics, aims to characterize the use of psychotropic drugs in family health units, according to major socioeconomic and demographic characteristics and according to the presence of common mental disorders (CMD). Article 2, with an analytical character, aims to evaluate the role of social networks in the use of each of these psychotropic drugs, according to the presence of CMD. Methods The study has a cross-sectional design and integrates baseline data from two previous studies on mental health in primary care . Data collection took place in 2006/2007 for the study 1 (Petropolis, n = 2.104) and in 2009/2010 for the study2 (São Paulo, n = 410, Rio de Janeiro, n = 703, Fortaleza - n = 149 and Porto Alegre, n = 163 participants). Although performed in different periods, both studies have the same format as regards data collection, processing and review, resulting in a sample of 3293 women attending family health units from five different cities. An objective questionnaire with closed questions was used to collect socioeconomic and demographic information. Psychotropic use was assessed through an open-ended question based on self-reporting of drug use. The presence of CMD was investigated by the General Health Questionnaire in its reduced version (GHQ-12). The level of social integration was evaluated through the social network index (IRS), calculated from questions about social network added to the general questionnaire. In the descriptive study (Article 1), the frequency of antidepressants and benzodiazepines use in the study population were calculated for each city, such as the frequency of the use of psychotropic drugs among patients with common mental disorders. The distribution of the use of each of these psychoactive drugs according to major socioeconomic and demographic characteristics and according to the presence of common mental disorders was assessed by Pearsons chi-square test. In the analytical study (Article 2), the association between the level of social integration and the exclusive use of each of psychotropic drugs was analyzed by multivariate logistic regression, stratified according to the presence of TMC. Results: The frequency of psychotropic medication use was quite heterogeneous among cities, emphasizing, however, the importance of the use of benzodiazepines against the use of antidepressants in most of the cities. The proportion of use of psychotropic medication, particularly antidepressants, was predominantly low among patients with CMD. Among these, antidepressants use was positively associated with social isolation, while benzodiazepines use was negatively associated. Conclusion: This study collaborates to characterize the use of antidepressants and benzodiazepines in family health units and to discuss about their rationality. The results highlight the importance of assessing the psychosocial dimension that involves the use of these substances in order to develop strategies to promote its rational use in primary care.

Objectives Main objectives of this doctoral thesis were to review available information on pharmacological properties of benzodiazepines and their age-related changes; to evaluate the prevalence of benzodiazepine use in older patients residing in long term care facilities; to investigate the association between use of benzodiazepines and occurrence of falls in acutely hospitalized older patients; and to describe utilization of benzodiazepines in the Czech Republic. Methods A narrative review of literature focused on pharmacokinetics, pharmacodynamics, adverse effects and association of benzodiazepines with falls in older population was conducted. The evaluation of benzodiazepine use in long term care facilities was analysed in a retrospective cross-sectional study using data from the EC 7th Framework Program SHELTER project (Service and Health in the Elderly in Long Term Care). A prospective cohort study data of acutely hospitalized patients in Australia were used to evaluate association between benzodiazepines and falls. To describe utilization of benzodiazepines in the Czech Republic, data from the State Institute for Drug Control and from databases of General Health Insurance Fund were used. This dissertation thesis is a summary of published articles from above stated works and analyses. Results...

The aim of this diploma thesis was the development of a screening method for analysis of 17 benzodiazepines in urine samples using ultra high-performance liquid chromatography with tandem mass spectrometric detection. The partial task was to optimize the conditions for the enzymatic hydrolysis of benzodiazepine glucuronides present in urine using design of experiments (DOE). The optimized chromatographic system consisted of a Zorbax Eclipse Plus Phenyl-Hexyl RRHD column (100 × 2.1 mm, 1.8 μm) and mobile phase consisting of water with 0.1 % acetic acid (component A) and acetonitrile with 0.1 % acetic acid (component B) in various ratios according to the gradient program. Flow rate was 0.2 ml/min, column temperature was 40 řC, and total analysis time was 12 min. Calibration curves for all analytes were measured under optimized conditions in methanol and urine. After optimal detection conditions for oxazepam-glucuronide were found, oxazepam glucuronide was hydrolysed using β-glucuronidase from the abalone to confirm the functionality of the enzyme within the pilot experiment. Optimization of enzymatic hydrolysis conditions via 27 experiments proposed by program Minitab 16 using the Box-Behnken design will be realized later.