Introduction : La douleur chronique non cancéreuse (DCNC) est prévalente, notamment en première ligne où l’on traite la plupart des maladies chroniques. Cette étude de cohorte vise à décrire l’usage des analgésiques, la prévalence et le traitement des effets secondaires des analgésiques utilisés, la satisfaction ainsi que les croyances et attitudes face à la douleur et son traitement chez des patients souffrant de DCNC et suivis en première ligne. Méthodologie : Des patients souffrant de DCNC (douleur qui dure depuis six mois et plus), ressentie au minimum deux fois par semaine avec une intensité d’au moins 4 sur une échelle de 0 à 10 (10 = la pire douleur possible) et qui possèdent une ordonnance active d’un médecin de famille pour un médicament contre la douleur, ont été recrutés à travers le Québec. Ils ont complété une entrevue téléphonique et un questionnaire auto-administré afin de documenter les caractéristiques de leur douleur, son impact psychosocial et émotionnel ainsi que leur satisfaction et croyances face à la douleur et son traitement. L’information concernant la pharmacothérapie reçue a été collectée en utilisant les banques de données administratives de la Régie d’assurance maladie du Québec et les dossierspatients des pharmacies communautaires. Résultats : Les 486 patients qui ont participé à l’étude avaient une moyenne d’âge de 58,4 ans. Ils ont rapporté une douleur qui dure en moyenne depuis 11,7 ans évaluée à 6,5 sur une échelle de 0 à 10. Sur la période d’une année, 52,9% des patients ont reçu des analgésiques prescrits par deux ou trois médecins de famille. Les analgésiques les plus dispensés étaient les anti-inflammatoires non stéroïdiens (72,2%) et les opioïdes (65,6%). Bien que 90% des patients ont rapporté des effets gastro-intestinaux, les proportions de ceux n’ayant pas reçu de médicaments pour soulager la constipation ou les nausées et/ou vomissements étaient respectivement 36,4% et 54,4%. Le niveau de satisfaction était faible, notamment face à l’information reçue concernant la douleur et son traitement. La peur des effets néfastes des analgésiques constitue la barrière face à l’optimisation de la pharmacothérapie de la douleur la plus souvent rapportée par les patients. Conclusion : En première ligne, la prise en charge de la douleur chronique non cancéreuse modérée à sévère paraît sous-optimale. Elle implique différents médecins de famille suggérant un manque de cohérence et de continuité. Les effets secondaires aux analgésiques sont prévalents et souvent non traités; la satisfaction est faible et les patients paraissent réticents à prendre les médicaments contre la douleur. Ces résultats indiquent clairement la nécessité d’optimiser la pharmacothérapie de ces patients. / Background: Chronic non-cancer pain (CNCP) is highly prevalent and mostly managed in primary care. This study sought to describe the use of analgesics in primary care, the prevalence and management of adverse reactions, as well as patients’ satisfaction with treatment and their barriers to pain management. Methods: Patients reporting CNCP (pain for six months and more), present at least twice weekly, with an average pain intensity of at least 4 on a 0-10 scale(10=worst pain possible) and having an active analgesic prescription from a primary-care physician were recruited in a cohort study conducted in Quebec (Canada). They completed a telephone interview and a self-administered questionnaire to document the characteristics and impact of their pain, their emotional well-being, their satisfaction with pain treatment and beliefs/attitudes about pain and its management using validated measurement instruments. Information on pharmacotherapy was retrieved using an administrative provincial database and pharmacies’ charts. Results: A total of 486 patients participated in this study. Their mean age was 58.4 years(SD=12.5) and they had pain for 11.7 years (SD=11.1) with an average pain intensity of 6.5. Over a one year period, 52.9% of patients had analgesics prescriptions from two or three primary-care physicians. The most commonly dispensed analgesics were nonsteroidal anti-inflammatory drugs (72.2%) and opioids (65.6%). Though 90% reported adverse gastrointestinal effects, 36.4% and 54.4% of these patients took no medication for constipation or nausea, respectively. Patient satisfaction was low, particularly regarding information about pain and its treatment The most important patients’ barriers to optimal management included fear of harmful effects of analgesics. Conclusions: In primary care, the management of moderate to severe CNCP is not always optimal. It involves several primary-care physicians indicating that the management is presently complex and lack of coherence and continuity. The prevalence of adverse effects of pain medication is high and often left untreated, patients’ satisfaction is low, and patients are reluctant to take pain medication.

The submitted thesis deals with the theme of a neurodegenerative autoimmune disease, the sclerosis multiplex. Although this serious disease has become an object of intensive research in recent decades and there is an inexhaustible quantity of literature available, we haven't yet fully identified the causes of this disease as well as we haven't found such kind of effective treatment that would lead to the permanent recovery of patients. I focused my interest on two main spheres: first, the description and comparison of practices in terms of pharmacotherapy giving priority to its benefits to patients, second, the view of another important but not always appreciated part of therapy, physiotherapy or rehabilitation; the main point is studying of processes and actions from the pedagogical point of view.

This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function. The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry. As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core. A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.

Introdução: No âmbito da epidemiologia nos serviços de saúde, este estudo avaliou a adesão ao tratamento medicamentoso de pacientes portadores de hipertensão arterial em uma situação de pleno acesso farmacológico, verificando sua associação com aspectos sócio demográficos, comportamentais e características clínicas. Metodologia: estudo transversal com aplicação de questionário junto a usuários do Programa Remédio em Casa da Secretaria Municipal de Saúde de São Paulo. A variável dependente foi a adesão e as variáveis independentes, as características sociodemográficas, comportamentais e clínicas. Foram calculadas as razões de prevalência e a análise multivariada foi realizada por regressão de Poisson. Principais resultados: portadores de hipertensão arterial com pleno acesso aos medicamentos apresentaram alta adesão terapêutica. Os poucos participantes não aderentes não diferiram dos demais do ponto de vista das características sócio demográficas, comportamentais e clínicas. Conclusão: em situação de adequada assistência, os fatores relacionados aos aspectos individuais perdem influência na determinação da adesão, sendo superados pela oferta efetiva de atenção à saúde e pelo pleno acesso aos medicamentos / Background: This study evaluated the medication adherence of hypertensive patients who had full access to medicines and the association with sociodemographic, behavioral and clinical characteristics. Methods: Cross-sectional study using a questionnaire applied to users of Programa Remédio em Casa [Home Medicine Program], a program of distribution of medicines from the city of São Paulo-Brazil. The dependent variable was adherence and the independent variables were sociodemographic, behavioral and clinical characteristics. Prevalence ratios were calculated and multivariate analyses were performed using Poisson Regression. Results: The study population showed high adherence. The non-adherent participants did not differ from the adherent participants in sociodemographic, behavioral or clinical characteristics. Conclusions: with effective provision of health care and full access to medicine, sociodemographic, behavioral and clinical factors lose influence in the determination of adherence to medicine

<p>Population pharmacokinetic-pharmacodynamic (PK-PD) models can be fitted using nonlinear mixed effects modelling (NONMEM). This is an efficient way of learning about drugs and diseases from data collected in clinical trials. Identifying covariates which explain differences between patients is important to discover patient subpopulations at risk of sub-therapeutic or toxic effects and for treatment individualization. Stepwise covariate modelling (SCM) is commonly used to this end. The aim of the current thesis work was to evaluate SCM and to develop alternative approaches. A further aim was to develop a mechanistic PK-PD model describing fasting plasma glucose, fasting insulin, insulin sensitivity and beta-cell mass.</p><p>The lasso is a penalized estimation method performing covariate selection simultaneously to shrinkage estimation. The lasso was implemented within NONMEM as an alternative to SCM and is discussed in comparison with that method. Further, various ways of incorporating information and propagating knowledge from previous studies into an analysis were investigated. In order to compare the different approaches, investigations were made under varying, replicated conditions. In the course of the investigations, more than one million NONMEM analyses were performed on simulated data. Due to selection bias the use of SCM performed poorly when analysing small datasets or rare subgroups. In these situations, the lasso method in NONMEM performed better, was faster, and additionally validated the covariate model. Alternatively, the performance of SCM can be improved by propagating knowledge or incorporating information from previously analysed studies and by population optimal design.</p><p>A model was also developed on a physiological/mechanistic basis to fit data from three phase II/III studies on the investigational drug, tesaglitazar. This model described fasting glucose and insulin levels well, despite heterogeneous patient groups ranging from non-diabetic insulin resistant subjects to patients with advanced diabetes. The model predictions of beta-cell mass and insulin sensitivity were well in agreement with values in the literature.</p>

Population pharmacokinetic-pharmacodynamic (PK-PD) models can be fitted using nonlinear mixed effects modelling (NONMEM). This is an efficient way of learning about drugs and diseases from data collected in clinical trials. Identifying covariates which explain differences between patients is important to discover patient subpopulations at risk of sub-therapeutic or toxic effects and for treatment individualization. Stepwise covariate modelling (SCM) is commonly used to this end. The aim of the current thesis work was to evaluate SCM and to develop alternative approaches. A further aim was to develop a mechanistic PK-PD model describing fasting plasma glucose, fasting insulin, insulin sensitivity and beta-cell mass. The lasso is a penalized estimation method performing covariate selection simultaneously to shrinkage estimation. The lasso was implemented within NONMEM as an alternative to SCM and is discussed in comparison with that method. Further, various ways of incorporating information and propagating knowledge from previous studies into an analysis were investigated. In order to compare the different approaches, investigations were made under varying, replicated conditions. In the course of the investigations, more than one million NONMEM analyses were performed on simulated data. Due to selection bias the use of SCM performed poorly when analysing small datasets or rare subgroups. In these situations, the lasso method in NONMEM performed better, was faster, and additionally validated the covariate model. Alternatively, the performance of SCM can be improved by propagating knowledge or incorporating information from previously analysed studies and by population optimal design. A model was also developed on a physiological/mechanistic basis to fit data from three phase II/III studies on the investigational drug, tesaglitazar. This model described fasting glucose and insulin levels well, despite heterogeneous patient groups ranging from non-diabetic insulin resistant subjects to patients with advanced diabetes. The model predictions of beta-cell mass and insulin sensitivity were well in agreement with values in the literature.

Introduction : La douleur chronique non cancéreuse (DCNC) est prévalente, notamment en première ligne où l’on traite la plupart des maladies chroniques. Cette étude de cohorte vise à décrire l’usage des analgésiques, la prévalence et le traitement des effets secondaires des analgésiques utilisés, la satisfaction ainsi que les croyances et attitudes face à la douleur et son traitement chez des patients souffrant de DCNC et suivis en première ligne. Méthodologie : Des patients souffrant de DCNC (douleur qui dure depuis six mois et plus), ressentie au minimum deux fois par semaine avec une intensité d’au moins 4 sur une échelle de 0 à 10 (10 = la pire douleur possible) et qui possèdent une ordonnance active d’un médecin de famille pour un médicament contre la douleur, ont été recrutés à travers le Québec. Ils ont complété une entrevue téléphonique et un questionnaire auto-administré afin de documenter les caractéristiques de leur douleur, son impact psychosocial et émotionnel ainsi que leur satisfaction et croyances face à la douleur et son traitement. L’information concernant la pharmacothérapie reçue a été collectée en utilisant les banques de données administratives de la Régie d’assurance maladie du Québec et les dossierspatients des pharmacies communautaires. Résultats : Les 486 patients qui ont participé à l’étude avaient une moyenne d’âge de 58,4 ans. Ils ont rapporté une douleur qui dure en moyenne depuis 11,7 ans évaluée à 6,5 sur une échelle de 0 à 10. Sur la période d’une année, 52,9% des patients ont reçu des analgésiques prescrits par deux ou trois médecins de famille. Les analgésiques les plus dispensés étaient les anti-inflammatoires non stéroïdiens (72,2%) et les opioïdes (65,6%). Bien que 90% des patients ont rapporté des effets gastro-intestinaux, les proportions de ceux n’ayant pas reçu de médicaments pour soulager la constipation ou les nausées et/ou vomissements étaient respectivement 36,4% et 54,4%. Le niveau de satisfaction était faible, notamment face à l’information reçue concernant la douleur et son traitement. La peur des effets néfastes des analgésiques constitue la barrière face à l’optimisation de la pharmacothérapie de la douleur la plus souvent rapportée par les patients. Conclusion : En première ligne, la prise en charge de la douleur chronique non cancéreuse modérée à sévère paraît sous-optimale. Elle implique différents médecins de famille suggérant un manque de cohérence et de continuité. Les effets secondaires aux analgésiques sont prévalents et souvent non traités; la satisfaction est faible et les patients paraissent réticents à prendre les médicaments contre la douleur. Ces résultats indiquent clairement la nécessité d’optimiser la pharmacothérapie de ces patients. / Background: Chronic non-cancer pain (CNCP) is highly prevalent and mostly managed in primary care. This study sought to describe the use of analgesics in primary care, the prevalence and management of adverse reactions, as well as patients’ satisfaction with treatment and their barriers to pain management. Methods: Patients reporting CNCP (pain for six months and more), present at least twice weekly, with an average pain intensity of at least 4 on a 0-10 scale(10=worst pain possible) and having an active analgesic prescription from a primary-care physician were recruited in a cohort study conducted in Quebec (Canada). They completed a telephone interview and a self-administered questionnaire to document the characteristics and impact of their pain, their emotional well-being, their satisfaction with pain treatment and beliefs/attitudes about pain and its management using validated measurement instruments. Information on pharmacotherapy was retrieved using an administrative provincial database and pharmacies’ charts. Results: A total of 486 patients participated in this study. Their mean age was 58.4 years(SD=12.5) and they had pain for 11.7 years (SD=11.1) with an average pain intensity of 6.5. Over a one year period, 52.9% of patients had analgesics prescriptions from two or three primary-care physicians. The most commonly dispensed analgesics were nonsteroidal anti-inflammatory drugs (72.2%) and opioids (65.6%). Though 90% reported adverse gastrointestinal effects, 36.4% and 54.4% of these patients took no medication for constipation or nausea, respectively. Patient satisfaction was low, particularly regarding information about pain and its treatment The most important patients’ barriers to optimal management included fear of harmful effects of analgesics. Conclusions: In primary care, the management of moderate to severe CNCP is not always optimal. It involves several primary-care physicians indicating that the management is presently complex and lack of coherence and continuity. The prevalence of adverse effects of pain medication is high and often left untreated, patients’ satisfaction is low, and patients are reluctant to take pain medication.

The aim of this dissertation thesis was to study the factors affecting drug distribution and elimination and to use these factors to individualize dosing. The work consists of three thematic areas: estimation of the volume of distribution and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital) using body size descriptors; estimation of clearance and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital, perindopril) using renal function status markers; and the impact of drug interactions on the distribution and elimination of phenobarbital. The thesis summarizes original papers on these topics. Individual pharmacokinetic parameters were calculated for each patient based on their demographic and clinical characteristics, dosing records and measured serum drug levels. The relationships between distribution volume/drug clearance and body size descriptors/renal functional status markers were examined by regression analysis. Vancomycin volume of distribution was best predicted by the total body weight. Loading dose of 10.7 mg/kg of total body weight was optimal in patients taking continuous vancomycin and would lead to reducing of median time to reach target concentrations from 17 to 1 hour. On the contrary, amikacin volume of distribution was most associated...

Introdução: No âmbito da epidemiologia nos serviços de saúde, este estudo avaliou a adesão ao tratamento medicamentoso de pacientes portadores de hipertensão arterial em uma situação de pleno acesso farmacológico, verificando sua associação com aspectos sócio demográficos, comportamentais e características clínicas. Metodologia: estudo transversal com aplicação de questionário junto a usuários do Programa Remédio em Casa da Secretaria Municipal de Saúde de São Paulo. A variável dependente foi a adesão e as variáveis independentes, as características sociodemográficas, comportamentais e clínicas. Foram calculadas as razões de prevalência e a análise multivariada foi realizada por regressão de Poisson. Principais resultados: portadores de hipertensão arterial com pleno acesso aos medicamentos apresentaram alta adesão terapêutica. Os poucos participantes não aderentes não diferiram dos demais do ponto de vista das características sócio demográficas, comportamentais e clínicas. Conclusão: em situação de adequada assistência, os fatores relacionados aos aspectos individuais perdem influência na determinação da adesão, sendo superados pela oferta efetiva de atenção à saúde e pelo pleno acesso aos medicamentos / Background: This study evaluated the medication adherence of hypertensive patients who had full access to medicines and the association with sociodemographic, behavioral and clinical characteristics. Methods: Cross-sectional study using a questionnaire applied to users of Programa Remédio em Casa [Home Medicine Program], a program of distribution of medicines from the city of São Paulo-Brazil. The dependent variable was adherence and the independent variables were sociodemographic, behavioral and clinical characteristics. Prevalence ratios were calculated and multivariate analyses were performed using Poisson Regression. Results: The study population showed high adherence. The non-adherent participants did not differ from the adherent participants in sociodemographic, behavioral or clinical characteristics. Conclusions: with effective provision of health care and full access to medicine, sociodemographic, behavioral and clinical factors lose influence in the determination of adherence to medicine

TITLE: Self- inflicted trauma in young people with in the context of behavioral disturbance AUTHOR: Bc. Katarína Kolaříková DEPARTMENT: Department of special education SUPERVISOR: Doc. PaeDr. Eva Šotolová, Ph.D. ABSTRACT: This thesis solves two serious topics of special pedagogic. Behavioural disorders and self-harming behaviour. Self-harming behaviour is deliberate, conscious and often repetitive violation of physical integrity without intent to die. The work is divided into 11 chapters. The first are focused on behavioural disorders, self-harming behaviours, and crisis intervention. Other chapters deal with the goals, research questions and chosen method of treatment. The aim was to map the occurrence, factors and methods of self-harming and describe alternative techniques of reducing this behaviour. Qualitative research is used in this work - analysing the anamneses of individuals with behavioural disorders and interviews with ethopedic workers. The inquiry of documentation shows that self-harming behaviour is caused by negative effects of family and social environment. The most common methods include self-cutting of girls, fists and head pounding against the wall of boys. For alternative methods of reducing this behaviour, the staff of orphanages with schools agreed that the preferred method is...