Im Bereich der medikamentösen antidepressiven Therapie ist die Bedeutung von erblichen Polymorphismen arzneistoffmetabolisierender Enzyme bereits in vielen Studien untersucht und gezeigt worden. Die meisten Antidepressiva werden über polymorphe Cytochrom-P450-Enzyme verstoffwechselt. Diese Arbeit befasst sich mit der Fragestellung, ob die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Allele in der an Depression erkrankten Studienpopulation sich von der in der Normalbevölkerung unterscheidet und ob Veränderungen in der Pharmakokinetik, wie sie durch Cytochrom-P450-Polymorphismen verursacht werden, unter normalen klinischen Bedingungen Auswirkungen auf die Wirksamkeit der antidepressiven Therapie, die Nebenwirkungsrate und den Verlauf der Erkrankung haben. Im Rahmen dieser Arbeit wurden 334 Patienten auf die häufigsten CYP2D6-Allele (*3,*4,*5,*6 und Duplikation) und CYP2C19- und CYP2C9-Allele *2 und *3 mittels Genotypisierung untersucht. Die Bestimmung der seltener auftretender CYP2D6-Allele (*8,*9,*10,*17,*2 und *41) erfolgte zusätzlich bei 200 Patienten. Die entsprechenden klinischen Fragebögen mit Angaben zur Anamnese, Schwere der Erkrankung, Therapieverlauf und Nebenwirkungsprofil wurden von 233 Patienten in Abhängigkeit des CYP2D6- und CYP2C19-Genotyps ausgewertet. Für die Beurteilung des Langzeittherapieverlaufs standen jedoch deutlich weniger Patientendaten zur Verfügung, so dass die Ergebnisse zum Teil nur für den CYPD6-Genotyp ausgewertet werden konnten. Die genetischen Analysen ergaben, dass die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Polymorphismen in der untersuchten Studienpopulation keine signifikante Änderung im Vergleich zur Normalbevölkerung aufwies. Während der Einfluss der CYP2D6-Genotypen auf pharmakokinetische Parameter eindeutig nachgewiesen ist, konnten die Ergebnisse dieser Arbeit weitestgehend keinen Zusammenhang zwischen der Schwere der Depression, der Therapieresponse, der Häufigkeit und Schwere der Nebenwirkungen und dem CYP2D6- und CYP2C19-Genotyp herstellen. / The importance of genetic polymorphisms of drug metablizing enzymes have been already investigated und proved in many studies before. Most of antidepressants are metabolized by cytochrome P450 enzymes. The aim of this study was to determine if there is a difference in the distribution of CYP2D6-, CYP2C19- and CYP2C9-allels in inpatients with major depression in comparison to the healthy population and if changes in the pharmacokinatic, created by cytochrome P450 polymorphisms, can be have effects on the efficacy of antidepressant therapy, rate of intolerable side effects and development of the depression. We examined 334 patients by genotyping for the most important CYP2D6-allels (*3,*4,*6,*5 und duplication) and the CYP2C19- and CYP2C9-allels *2 and *3. Further 200 patients were tested for the more infrequent CYP2D6-allels (*8,*9,*10,*17,*2 and *41). The corresponding clinical questionnaires containing informations about the anamnesis, severity of the desease, therapeutic outcome and intolerable side effects have been evaluated of 233 patients in dependence of the CYP2D6- and CYP2C19-genotype. There were significant less clinical datas for the evaluation of long term therapy response be available, so that the results could be partially only analysed for the CYP2D6-genotype. The genetic analysis detected that the distribution of the CYP2D6-, CYP2C19- and CYP2C9-polymorphismen in the study population didn´t reached significant changes in comparison to the healthy population. While the influence of CYP2D6-genotypes on pharmacokinatic parameters is clear demonstrated, the results of this study mainly couldn´t establish a relation between the severity of depression, therapeutic response, frequency and severity of side effects and the CYP2D6 and CYP2C19-genotype.

Made available in DSpace on 2011-05-04T12:42:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 / A AIDS, desde o seu surgimento no início dos anos 80, apresentou-se como um relevante problema de saúde pública. Além da prevenção de doenças oportunistas e do tratamento da AIDS foi essencial estabelecer critérios para definir casos da doença. O objetivo do presente estudo foi ressaltar as diferenças observadas nas funções de sobrevida de casos definidos por diferentes critérios e conhecer o efeito da adesão à terapia anti-retroviral(TARV) no prognóstico dos pacientes HIV/AIDS. No primeiro artigo, 1.415 indivíduos HIV+ atendidos no IPEC foram avaliados pelos critérios de definição de caso do Ministério da Saúde (MS/2004) e dos Centers for Disease Control and Prevention (CDC/1993), e afunção de sobrevida foi estimada para cada critério, considerando o uso de TARV e cofatores sócio-demográficos e clínicos. Os resultados desta avaliação mostraram que a sobrevida estimada depende do critério adotado além de apresentar preditores distintos. No segundo artigo, em buscas no Medline e Lilacs, selecionou-se 38 artigos que avaliaram a ocorrência de desfechos relevantes na evolução da AIDS em função da adesão ao tratamento. Na avaliação desses artigos, foi evidenciado que a adesão dos pacientes ao tratamento antiretroviral nos diversos matizes considerados na literatura mostrou-se um preditor importante dos desfechos nas suas múltiplas representações no acompanhamento dos pacientes, independente do estadiamento clínico, uso prévio de tratamento, CD4 ecarga viral basais. No terceiro artigo, para 711 pacientes foram considerados os dados de fornecimento de anti-retrovirais (dispensas) disponíveis no Sistema de Controle Logístico de Medicamentos (SICLOM) para avaliar a adesão e estimar o risco de falha terapêutica pelo modelo de Cox. Com base neste estudo, pode-se concluir que o grau de não adesão à HAART está diretamente associado com o maior risco de ocorrência de desfechos desfavoráveis, e que a adesão <75 por cento teve impacto substancial na evolução da doença, independente de outros fatores. Em suma, pode-se concluir que apesar das dificuldades dese comparar estudos, devido à evolução do tratamento, dos inúmeros desfechos e formas de avaliações, é incontestável o melhor prognóstico nos anos recentes. Ainda que o sucesso do tratamento dependa da adesão, e esta, por sua vez, dependa de inúmeros fatores, é possível afirmar que melhorando a adesão do paciente ao tratamento, independente de praticamente todos demais fatores, é possível obter um bom prognóstico para a evolução da doença. / Since its emergence in the early 1980s, AIDS has appeared as a relevant public health problem. In addition to preventing opportunistic diseases and treating AIDS it was essential to establish disease-defining criteria. The aim of the present study was to highlight the differences in cases survival functions defined by different criteria and to know the effect of adherence to antiretroviral therapy on the prognosis of patients with HIV/AIDS. In the first article, 1,415 HIV+ subjects seen at IPEC were assessed by two case-defining criteria (MS/2004 and CDC/1993), their survival function was estimated for each standard, considering the use of ARV and socio-demographic and clinical cofactors. The results showed that estimated survival depends on the chosen standard, besides presenting distinct predictors. In the second article, through searches at MEDLINE and LILACS, there were selected 38 articles that evaluated the occurrence of relevant outcomes to the development of AIDS in function of adherence to treatment. The analysis of these articles emphasized that the adherence of patients to ARV or HAART in various aspects considered in the literature was an important predictor of outcomes in their multiple representations in the monitoring of patients, independent of their clinical staging, use of prior treatment and baseline CD4 and viral load. In the third article, to 711 patients, there were considered data from antiretroviral disposal available at SICLOM for adherence assessment and estimation of therapeutic failure risk by the Cox model. In this study, it can be concluded that the level of non-adherence to HAART is directly associated with the highest risk of adverse outcomes, and adherence <75% had a substantial impact on the evolution of the disease, independent of other factors. In short, it can be concluded that despite the difficulties of comparing studies, due to treatment development, innumerable outcomes and forms of evaluations, there is no doubt about the occurrence of better prognosis in recent years. Even though the success of treatment depends on adherence, and this, in turn, depends on numerous factors, it is possible to say that improving patient adherence to treatment, independent of practically all other factors, it is possible to obtain a good prognosis for the development of the disease.

Text in English / This research explores the meaning of the first and second-order therapeutic stances with reference to the therapist's professional and personal development. The dominant positivist paradigm was reflected in the therapist's initial position of expert observer, outside of the observed. The observed phenomena were a group of children suffering from thalassemia major, a terminal genetic disease, and their mothers. The initial idea of short-term intervention and focus on the observed evolved into six-year journey where the observer and the observed became an interconnected unit of observation, understanding and change. A first-order stance led to therapeutic stuckness, where the therapist's confrontation with her therapeutic failure and the limitations of the dominant paradigm provoked a deconstruction of the expert position and promoted a self-reflexive therapeutic stance. The author's self-searching process took her back to her personal self, her family of origin and the ''wounded healer". The researcher moved from an initial disconnection between her professional and personal selves to an awareness of the interface between the two and, ultimately, to a unification of her professional and personal selves. Such development involved an individuation process moving from a narcissistic belief in her objective stance towards a therapeutic stance where she sees herself less as a powerful agent of change and moves to an increasingly higher order of integration of the professional and personal selves (Skovholt & Ronnestad, 1992). The process with the children and mothers shifted from a focus on compliance and medical issues to more personal and emotional stories. The therapist's participation and collaborative stance created a context for change, where greatly improved medical compliance was just one of the many transformations experienced by all the participants. The researcher speculates that development of a second-order stance requires second-order change, which comes "at the end of long, often frustrating mental and emotional labor" (Watzlawick et al., 1974, p. 23), promoting integration between the professional and personal selves of the therapist. The researcher therefore contends that this process has important implications for psychotherapy training, supervision and continuing education. / Psychology / D. Litt. et Phil. (Psychology)

Text in English / This research explores the meaning of the first and second-order therapeutic stances with reference to the therapist's professional and personal development. The dominant positivist paradigm was reflected in the therapist's initial position of expert observer, outside of the observed. The observed phenomena were a group of children suffering from thalassemia major, a terminal genetic disease, and their mothers. The initial idea of short-term intervention and focus on the observed evolved into six-year journey where the observer and the observed became an interconnected unit of observation, understanding and change. A first-order stance led to therapeutic stuckness, where the therapist's confrontation with her therapeutic failure and the limitations of the dominant paradigm provoked a deconstruction of the expert position and promoted a self-reflexive therapeutic stance. The author's self-searching process took her back to her personal self, her family of origin and the ''wounded healer". The researcher moved from an initial disconnection between her professional and personal selves to an awareness of the interface between the two and, ultimately, to a unification of her professional and personal selves. Such development involved an individuation process moving from a narcissistic belief in her objective stance towards a therapeutic stance where she sees herself less as a powerful agent of change and moves to an increasingly higher order of integration of the professional and personal selves (Skovholt & Ronnestad, 1992). The process with the children and mothers shifted from a focus on compliance and medical issues to more personal and emotional stories. The therapist's participation and collaborative stance created a context for change, where greatly improved medical compliance was just one of the many transformations experienced by all the participants. The researcher speculates that development of a second-order stance requires second-order change, which comes "at the end of long, often frustrating mental and emotional labor" (Watzlawick et al., 1974, p. 23), promoting integration between the professional and personal selves of the therapist. The researcher therefore contends that this process has important implications for psychotherapy training, supervision and continuing education. / Psychology / D. Litt. et Phil. (Psychology)