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.

Atualmente os benzodiazepínicos constituem o grupo de fármacos de prescrição mais consumidas em todo o mundo. Além da utilização desta classe farmacológica como fármacos de abuso, mais recentemente seu uso está associado a uma nova cultura psicodélica emergente. O termo \"club drugs\" tem sido usado para descrever estes fármacos que levam a efeitos psicodélicos e euforizantes. Acresça-se a isto à preocupante utilização destas substâncias em situações de estupro e/ou assalto, as chamadas \"drug-facilitated sexual assault\", destacando-se o flunitrazepam. Devido às pequenas doses administradas e a extensiva metabolização, a identificação do flunitrazepam e seus metabólitos torna-se dificultada em relação a outros benzodiazepínicos. O presente trabalho constitui validação de metodologia analítica que permita a correta identificação e quantificação de flunitrazepam e seu principal produto de biotransformação, o 7-aminoflunitrazepam, em soro. O método desenvolvido mostrou boa linearidade, precisão, exatidão, rendimento e capacidade de detectar os analitos mesmo em baixas concentrações, permitindo desta forma a inferência sobre a realidade dos casos onde se utiliza este fármaco sem fins terapêuticos. / Currently the benzodiazepines are one of the most consumed groups among the prescripton drugs in the world. Beside this, they have been used as drugs of abuse and more recently their use is associated with the new emerging psychodelic culture. The term \"club drugs\" has been used to describe these drugs that cause psychodelic and euphoric effects. In addition to this, there is a growing concern with the use of these substances related to \"drug-facilitated sexual assault\", among of which Flunitrazepan is pointed out as one of the most important . Due to the small doses involved in the consumption for this purpose and also the extense biotransformation, the identification of this analyte and its metabolites become more difficult than that of other benzodiazeines. This study provides an analytical validation method that enables correct identification and quantification of Flunitrazepam and its main biotransformation product, the 7-aminoflunitrazepam, in serum. The method developed demonstrates good linearity, precision, accuracy, recovery and capacity of detect the analytes, even in low concentration. Thus making possible to makes inferences regarding the reality of cases where it is used as a drug without therapeutic use.

A importância de algumas abordagens psicoterápicas associadas à farmacoterapia no tratamento do Transtorno Depressivo Maior tem sido bastante destacada, no entanto, existem poucos dados sobre a Psicoterapia Psicodramática. O presente estudo comparou 20 pacientes com diagnóstico de TDM em uso de medicamentos antidepressivos e avaliados pela Escala de Depressão de HAM-D17 (escores entre 7 e 20), divididos em dois grupos: dez pacientes do Grupo Psicoterápico (GP) participaram de 4 sessões individuais de psicoterapia psicodramática e 24 de grupo. Dez pacientes do Grupo Controle (GC) não participaram de sessões psicoterápicas. Os dois grupos foram avaliados pela Escala de HAM-D17 e pela Escala de Adequação Social (EAS) no início e final do processo psicoterápico e o GP também foi avaliado pela Análise Sociométrica, fundamentada no método psicodramático. Em comparação ao GC, o GP apresentou uma melhora significativa quanto aos sintomas depressivos e ao funcionamento social, bem como uma expressiva mudança nos aspectos sociométricos investigados / The importance of several psychotherapic approaches associated to pharmacotherapy on the treatment of Major Depressive Disorder has been quite highlighted, although, there is little information as far as Psychodramatic Psychotherapy is concerned. The present study compared 20 patients diagnosed with MDD in use of antidepressant drugs and evaluated with the Hamilton Depression Scale (scores between 7 and 20), divided into two groups as follows: ten of the patients from the Psychotherapic Group (PG) took part in 4 individual psychodramatic psychotherapy sessions and 24 psychodramatic psychotherapy group sessions. Ten of the patients from the Control Group (CG) did not participate in the psychodramatic psychotherapy sessions. Both groups were evaluated with the HAM-D17 Scale and the Social Adjustment Scale - Self Report (SASSR) at the beginning and at the end of the psychotherapic process, and the PG was also evaluated through Sociometric Analysis, based on the psychodramatic method. In comparison to the CG, the PG presented a significant improvement regarding the symptoms of depression and social functioning, as well as an expressive change on the investigated sociometric aspects

O objetivo geral deste estudo foi investigar os fatores associados a Transtornos Mentais Comuns (TMC) e ao consumo de psicofármacos em Unidades Básicas de Saúde (UBSs) de Ribeirão Preto. É um estudo epidemiológico, transversal e correlacional com plano amostral estratificado e proporcional (n=430). Cada estrato foi formado pela maior UBS em número de usuários, na área de abrangência de cada um dos cinco distritos de saúde da cidade. Foram instrumentos de pesquisa: questionários sociodemográfico, econômico, farmacoterapêutico e de histórico de saúde; Self Reporting Questionnaire (SRQ-20), para estimar a prevalência de TMC e World Health Organization Quality of Life Assessment-Brief (WHOQOL-brief), para mensurar escores de qualidade de vida (QV) na amostra. TMC, uso de psicofármacos e QV foram considerados variáveis dependentes. Foram variáveis explicativas: sociodemográficas e econômicas, farmacoterapêuticas e histórico de saúde. Para a abordagem de TMC e uso de psicofármacos como variáveis dependentes, foram realizadas as análises: univariada (teste de Qui-quadrado) e regressão logística multivariada. Para a análise de QV, foram utilizados: t-teste de Student e regressão linear múltipla. Foram consideradas significativas as associações nas quais p<0,05. A prevalência de TMC foi de 41,4%, e a de consumo de psicofármacos foi de 25,8%. Os fatores preditores de TMC foram uso de psicofármacos (OR=3,88; IC95% 2,34-6,41) e sexo feminino (OR=1,96; IC95% 1,04- 3,69). Pelo teste Qui-quadrado, houve associação entre ser positivo para TMC e número de tipos de medicamentos e número de comprimidos por dia (p<0,05). Quanto ao uso de psicofármacos, os fatores preditores foram TMC (OR=3,9; IC95% 2,36-6,55), doenças clínicas (OR=5,4, IC95% 2,84-10,2) e baixa escolaridade (OR=1,7; IC95% 1,02-2,92). Segundo o t-teste de Student, pacientes com TMC apresentaram escores de QV menores que pacientes negativos para TMC, em todos os domínios (p<0,05). TMC foi o fator que mais contribuiu no modelo de regressão linear para piores escores de QV. O uso de psicofármacos influenciou negativamente os padrões de QV nos domínios físico e psicológico do WHOOQL- brief. Os resultados deste estudo apontam para a necessidade de estratégias em atenção básica à saúde (ABS) que busquem contemplar a integralidade dos indivíduos, visto a associação entre TMC, uso de psicofármacos e QV com variáveis sociodemográficas e econômicas. Os resultados com QV permitem a suposição de que quer estivessem em uso de psicofármacos ou não, os indivíduos apresentaram- se em sofrimento / The general aim of this study was to investigate the factors associated with Common Mental Disorders (CMD) and the use of psychotropic drugs in Basic Health Units (BHU), in Ribeirão Preto. This is an epidemiological cross-sectional and correlational study, with stratified proportional sampling plan. Each strata was formed by the largest BHU in the number of attendees in the coverage area of each of the five health districts in the entire city. The interview subjects included 430 individuals who had medical appointments scheduled in the BHUs. These elements were used as research instruments: economic, socio-demographic, and pharmacotherapeutic questionnaires; a self-reporting questionnaire (SRQ-20), to estimate the prevalence of CMDs; and a World Health Organization Quality of Life Assessment - Brief (WHOQOL-brief) to measure quality of life scores (QOL) in the sample. The dependent variables included CMD, the use of psychotropic drugs, and QOL. The explanatory variables involved socio-demographic, economic, and pharmacotherapeutic factors, as well as health history. While analyzing TMC and the use of psychotropics drugs as dependent variables, univariate (chi -square) analysis and a multivariate logistic regression were conducted. For the analysis of QOL, a Student t - test and a multiple linear regression were used. In associations in which p<0.05 were considered significant. The prevalence of CMDs was 41.4% and psychotropic drug was 25.8%. Predictors of CMD included the use of psychoactive drugs (OR = 3.88, 95% CI 2.34 to 6.41) and female gender (OR = 1.96, 95% CI 1.04 to 3.69). Information gathered by the Chi-square test indicated an association between being positive for TMC and the number of types of medications and the number of tablets per day (p<0.05.) Regarding the use of psychotropic drugs, the predictors were TMC (OR = 3.9; 95% CI 2.36 to 6.55), physical illness (OR = 5.4, 95% CI 2.84 to 10.2), and lower education (OR = 1, 95% CI 1.02 to 2.92). According to the Student t-test, patients with CMD had lower QOL scores than patients who were negative for TMC across all domains (p < 0.05). CMD was the major contributing factor in the linear regression model for lower QOL scores. The use of psychotropics negatively influenced the patterns of QOL, in the physical and psychological domains of WHOOQL-brief. The results of this study point to the need for strategies in primary health care (PHC) which seek to consider the individuals as a whole, since there was association between CMD, use of psychotropic drugs, and QOL with socio-demographic and economic variables. The results involving QOL allow for the assumption that, whether or not there was use of psychotropic drugs, individuals presented in distress

In this thesis I explore functions of the neuromodulator dopamine in the context of autonomous learning and behaviour. I first investigate dopaminergic influence within a simulated agent-based model, demonstrating how modulation of synaptic plasticity can enable reward-mediated learning that is both adaptive and self-limiting. I describe how this mechanism is driven by the dynamics of agentenvironment interaction and consequently suggest roles for both complex spontaneous neuronal activity and specific neuroanatomy in the expression of early, exploratory behaviour. I then show how the observed response of dopamine neurons in the mammalian basal ganglia may also be modelled by similar processes involving dopaminergic neuromodulation and cortical spike-pattern representation within an architecture of counteracting excitatory and inhibitory neural pathways, reflecting gross mammalian neuroanatomy. Significantly, I demonstrate how combined modulation of synaptic plasticity and neuronal excitability enables specific (timely) spike-patterns to be recognised and selectively responded to by efferent neural populations, therefore providing a novel spike-timing based implementation of the hypothetical ‘serial-compound' representation suggested by temporal difference learning. I subsequently discuss more recent work, focused upon modelling those complex spike-patterns observed in cortex. Here, I describe neural features likely to contribute to the expression of such activity and subsequently present novel simulation software allowing for interactive exploration of these factors, in a more comprehensive neural model that implements both dynamical synapses and dopaminergic neuromodulation. I conclude by describing how the work presented ultimately suggests an integrated theory of autonomous learning, in which direct coupling of agent and environment supports a predictive coding mechanism, bootstrapped in early development by a more fundamental process of trial-and-error learning.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-09-13T17:47:07Z No. of bitstreams: 1 MauricioFernandes.pdf: 1547228 bytes, checksum: 87d9e63be597d8eaf8f7a783479e1294 (MD5) / Made available in DSpace on 2017-09-13T17:47:07Z (GMT). No. of bitstreams: 1 MauricioFernandes.pdf: 1547228 bytes, checksum: 87d9e63be597d8eaf8f7a783479e1294 (MD5) Previous issue date: 2017-04-28 / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão / INTRODUCTION: In Brazil, it is reported that a great part of the patients who arrive for the primary care service have as main complaint: sadness (depression) and / or anxiety, also with more complex disorders such as problems related to abuse of alcohol and serious and persistent mental disorders, such as schizophrenia and affective psychoses (bipolar mood disorder). In the pharmacogenetic studies of antidepressants and antipsychotics, cytochrome P450 (CYPs) enzymes have been shown to be one of the most significant targets in the interindividual changes in drug response kinetic parameters. OBJECTIVE: To characterize the frequency of CYP2D6 polymorphisms (*4, *6 and *17) in users of psychotropic therapy, especially tricyclic antidepressants and antipsychotics. METHODS: Cross - sectional, descriptive study carried out in the city of São Luis – MA. RESULTS: From a total of 105 charts, a sample of 43 patients was collected. The mean age was 40.98 (± 11.04) years, of which 24 (55.81%) were male and 19 (44, 19%) of females. Regarding the pharmacotherapy, all participants (100%) were on daily use of the antipsychotic haloperidol, seventeen (39.53%) patients used risperidone and one (2.32%) patient used amitriptyline (tricyclic antidepressant), all three drugs are substrates of the enzyme CYP2D6. For the polymorphism of CYP2D6, we had a prevalence of 11 (25.48%) for allele 4, and all the patients presented with this polymorphism were heterozygous, that means they had one polymorphic allele and one normal allele. For allele 17, we had a prevalence of 4 (9.3%), also all patients being heterozygous for this allele. Allele 6 did not appear in any patient in our study. We also had two patients who presented the polymorphisms for alleles * 4 and * 17 at the same time. CONCLUSION: This study was able to characterize the frequency of CYP2D6 (* 4, * 6 and 17 *) polymorphisms in users of psychotropic therapy, including tricyclic antidepressants and antipsychotics, in addition to contributing to a higher dose / response do medication, ensuring greater safety and efficacy in the use of medicines, improving the quality of life of patients. / INTRODUÇÃO: No Brasil, tem-se o relato de que grande parte dos pacientes que chegam para o atendimento na atenção primária apresentam, como principal queixa, tristeza (depressão) e/ou ansiedade, aparecendo também transtornos mais complexos como os problemas relacionados ao abuso de álcool, assim como os transtornos mentais graves e persistentes, como a esquizofrenia e as psicoses afetivas (transtorno bipolar do humor). Nos estudos farmacogenéticos de antidepressivos e antipsicóticos, as enzimas do citrocromo P450 (CYPs) tem se mostrado um dos alvos mais significativos nas alterações interindividuais dos parâmetros cinéticos de resposta às drogas. OBJETIVO: caracterizar a frequência de polimorfismos do CYP2D6 (*4, *6 e 17*) em usuários da terapêutica com psicotrópicos, principalmente antidepressivos tricíclicos e antipsicóticos. MÉTODOS: Estudo transversal, descritivo realizado no Município de São Luís (MA). RESULTADO: De um total de 105 prontuários, coletou-se amostra de 43 pacientes, a média de idade foi de 40,98 (±11,04) anos, sendo 24 (55,81%) do sexo masculino e 19 (44,19%) do sexo feminino. Em relação à farmacoterapia, todos os participantes (100%) estavam em consumo diário do antipsicótico haloperidol, dezessete (39,53%) pacientes faziam uso de risperidona e um (2,32%) paciente utilizava amitriptilina (antidepressivo tricíclico), todos os três medicamentos são substratos da enzima CYP2D6. Para o polimorfismo da CYP2D6, tivemos para o alelo 4 uma prevalência de 11 (25,48%), sendo que todos os pacientes que apresentaram esse polimorfismo são heterozigotos, ou seja, apresentaram um alelo polimórfico e outro normal. Para o alelo 17, tivemos uma prevalência de 4 (9,3%), sendo também todos os pacientes heterozigotos para esse alelo. O alelo 6 não apareceu em nenhum paciente do nosso estudo. Tivemos também dois pacientes que apresentaram os polimorfismos para os alelos *4 e *17 ao mesmo tempo. CONCLUSÃO: Este estudo pôde caracterizar a frequência de polimorfismos do CYP2D6 (*4, *6 e 17*) em usuários da terapêutica com psicotrópicos, incluindo antidepressivos tricíclicos e antipsicóticos, além de contribuir para uma maior adequação da relação dose/resposta ao medicamento, garantindo maior segurança e eficácia quanto ao uso de medicamentos, melhorando a qualidade de vida dos pacientes.

Atualmente os benzodiazepínicos constituem o grupo de fármacos de prescrição mais consumidas em todo o mundo. Além da utilização desta classe farmacológica como fármacos de abuso, mais recentemente seu uso está associado a uma nova cultura psicodélica emergente. O termo \"club drugs\" tem sido usado para descrever estes fármacos que levam a efeitos psicodélicos e euforizantes. Acresça-se a isto à preocupante utilização destas substâncias em situações de estupro e/ou assalto, as chamadas \"drug-facilitated sexual assault\", destacando-se o flunitrazepam. Devido às pequenas doses administradas e a extensiva metabolização, a identificação do flunitrazepam e seus metabólitos torna-se dificultada em relação a outros benzodiazepínicos. O presente trabalho constitui validação de metodologia analítica que permita a correta identificação e quantificação de flunitrazepam e seu principal produto de biotransformação, o 7-aminoflunitrazepam, em soro. O método desenvolvido mostrou boa linearidade, precisão, exatidão, rendimento e capacidade de detectar os analitos mesmo em baixas concentrações, permitindo desta forma a inferência sobre a realidade dos casos onde se utiliza este fármaco sem fins terapêuticos. / Currently the benzodiazepines are one of the most consumed groups among the prescripton drugs in the world. Beside this, they have been used as drugs of abuse and more recently their use is associated with the new emerging psychodelic culture. The term \"club drugs\" has been used to describe these drugs that cause psychodelic and euphoric effects. In addition to this, there is a growing concern with the use of these substances related to \"drug-facilitated sexual assault\", among of which Flunitrazepan is pointed out as one of the most important . Due to the small doses involved in the consumption for this purpose and also the extense biotransformation, the identification of this analyte and its metabolites become more difficult than that of other benzodiazeines. This study provides an analytical validation method that enables correct identification and quantification of Flunitrazepam and its main biotransformation product, the 7-aminoflunitrazepam, in serum. The method developed demonstrates good linearity, precision, accuracy, recovery and capacity of detect the analytes, even in low concentration. Thus making possible to makes inferences regarding the reality of cases where it is used as a drug without therapeutic use.

A importância de algumas abordagens psicoterápicas associadas à farmacoterapia no tratamento do Transtorno Depressivo Maior tem sido bastante destacada, no entanto, existem poucos dados sobre a Psicoterapia Psicodramática. O presente estudo comparou 20 pacientes com diagnóstico de TDM em uso de medicamentos antidepressivos e avaliados pela Escala de Depressão de HAM-D17 (escores entre 7 e 20), divididos em dois grupos: dez pacientes do Grupo Psicoterápico (GP) participaram de 4 sessões individuais de psicoterapia psicodramática e 24 de grupo. Dez pacientes do Grupo Controle (GC) não participaram de sessões psicoterápicas. Os dois grupos foram avaliados pela Escala de HAM-D17 e pela Escala de Adequação Social (EAS) no início e final do processo psicoterápico e o GP também foi avaliado pela Análise Sociométrica, fundamentada no método psicodramático. Em comparação ao GC, o GP apresentou uma melhora significativa quanto aos sintomas depressivos e ao funcionamento social, bem como uma expressiva mudança nos aspectos sociométricos investigados / The importance of several psychotherapic approaches associated to pharmacotherapy on the treatment of Major Depressive Disorder has been quite highlighted, although, there is little information as far as Psychodramatic Psychotherapy is concerned. The present study compared 20 patients diagnosed with MDD in use of antidepressant drugs and evaluated with the Hamilton Depression Scale (scores between 7 and 20), divided into two groups as follows: ten of the patients from the Psychotherapic Group (PG) took part in 4 individual psychodramatic psychotherapy sessions and 24 psychodramatic psychotherapy group sessions. Ten of the patients from the Control Group (CG) did not participate in the psychodramatic psychotherapy sessions. Both groups were evaluated with the HAM-D17 Scale and the Social Adjustment Scale - Self Report (SASSR) at the beginning and at the end of the psychotherapic process, and the PG was also evaluated through Sociometric Analysis, based on the psychodramatic method. In comparison to the CG, the PG presented a significant improvement regarding the symptoms of depression and social functioning, as well as an expressive change on the investigated sociometric aspects

The majority of the population in South Africa use traditional health care to treat various mental conditions. This thesis has two main objectives; to bring together a comprehensive and detailed record of psychotropic plants used in southern Africa by indigenous peoples for medicinal or cultural purposes. Secondly, this research attempts to investigate the validity and rationale of the use of these plants by screening them in various biological assays for psychotropic activity. Plants were selected, based on their traditional use and availability, and were screened in four assays, which detect biological activity of a useful nature. A number of in vitro enzymatic and neuronal signal transduction assays were employed in this thesis, the inhibition of the serotonin reuptake transporter protein (SERT); inhibition of catabolic enzymes (e.g. acetylcholinesterase, monoamine oxidase); GABAA- benzodiazepine receptor binding. The influence of legislation, past and present, on the state of traditional medicine is highlighted. Aspects of the philosophies and practises of the various practitioners of South African traditional medicine will be discussed. An annotated list compiled from available ethnobotanical literature of plants traditionally used for central nervous system-related purposes is provided. It contains more than 330 species, from 94 families, which are currently used or have been used for cultural, medicinal and recreational purposes related to the central nervous system (CNS). Where available, information pertaining to plant part used, preparation method, dosage, route of administration, known and potentially active constituents are included. Seventy five extracts from 34 indigenous plant species used in South African traditional medicine or taxonomically related to these were investigated for their affinity to the serotonin reuptake transport protein, making use of an in vitro [3H]-citalopram serotonin reuptake transport protein binding assay. Aqueous and 70% ethanolic extracts of various plant parts were screened and 45 extracts derived from 15 plant species showed affinity. The affinity of 12 extracts from four plants was characterized as high (more than 50% inhibition at 5, 1, and 0.5 mg/ml). Plant species with high affinity to the serotonin reuptake transport protein included Agapanthus campanulatus, Boophone disticha, Datura ferox and Xysmalobium undulatum. Agapanthus campanulatus yielded high activity in aqueous extracts from leaves and flowers. B. disticha showed high activity both in aqueous and ethanolic extracts of leaves and bulbs. D. ferox showed high activity in aqueous extracts from the seeds and X. undulatum showed high activity in the ethanolic extract of the whole plant. Two compounds, buphanadrine and buphanamine, were isolated by bioassay-guided fractionation on vacuum-liquid-chromatography (VLC) and preparative thin-layer-chromatography (TLC) from B. disticha. The structures of the compounds were determined by 1H and 13C NMR. Fractions were tested for affinity to the serotonin transporter in a binding assay using [3H]-citalopram as a ligand. The IC50 values of buphanidrine and buphanamine were 274 ìM (Ki = 132 ìM) and 1799 ìM (Ki = 868 ìM), respectively. The two alkaloids were also tested for affinity to the 5HT1A receptor, but only showed slight affinity. Aqueous and ethanol extracts of 43 plants that are traditionally used to treat against epilepsy and convulsions were initially tested in the GABAA-benzodiazepine receptor binding assay, where the binding of 3H-Ro 15-1788 (flumazenil) to the benzodiazepine site is measured. The GABAA-benzodiazepine receptor complex is involved in epilepsy and convulsions. Out of the 118 extracts tested, one aqueous and 18 ethanol extracts showed activity. The most active extracts were the ethanolic leaf extracts of Searsia tridentata, Searsia rehmanniana and Hoslundia opposita and the ethanolic corm extract of Hypoxis colchicifolia, which all showed good dose-dependent activity. A further forty-six ethanol extracts from another 35 species, both indigenous and exotic that are traditionally used predominantly as sedatives or to treat various CNS-related ailments were tested in the GABAA-benzodiazepine receptor-binding assay. Out of the 46 extracts tested, seven showed good activity and 10 showed moderate activity. The most active extracts were the ethanolic leaf extracts of Arctopus echinatus, Artemisa afra, four Helichrysum species and Mentha aquatica which all showed good dose-dependent activity. Two biflavonoids with activity in the 3H-Ro 15-1788 (flumazenil) binding assay were isolated by high pressure liquid chromatography (HPLC) fractionation of the ethanol extract of the leaves from Searsia pyroides. The structures of the two biflavonoids were elucidated by nuclear magnetic resonance spectroscopy (NMR) to be agathisflavone and amentoflavone. Agathisflavone and amentoflavone competitively inhibited the binding of 3H-Ro 15-1788 with a Ki of 28 and 37 nM, respectively. Extracts of Searsia dentata and Searsia pentheri were not as active as the extract from Searsia pyroides; both were found to contain apigenin and agathisflavone. The monomer apigenin, agathisflavone and amentoflavone were fitted into a pharmacophore model for ligands binding to the GABAA receptor benzodiazepine site. This reflected the affinities of the compounds in the [3H]-flumazenil binding assay. Mentha aquatica, a mint that is found in Europe and Africa, is used in Zulu traditional medicine for spiritual purposes. The ethanolic leaf extract showed a strong affinity to the GABA-benzodiazepine receptor. Viridiflorol from the essential oil and (S)-naringenin from an ethanolic extract was isolated by bioassay-guided fractionation using binding to the GABA-benzodiazepine site. Viridiflorol had an IC50 of 0.19 M and (S)-naringenin of 0.0026 M. Twenty plants used in Zulu traditional medicine for several CNS-related ailments were screened for MAO inhibition and specific MAO-B inhibition activity. MAO-B inhibitors are currently employed in the treatment of neurodegenerative related illnesses such as Parkinson's and Alzheimer's diseases. A photometric peroxidase linked assay was used to determine the inhibition of the oxidative deamination of tyramine by MAO isolated from rat liver. Ruta graveolens exhibited the best MAO inhibitory activity (ethyl acetate leaf extract = IC50 5 ± 1 ìg/ml, petroleum ether extract = 3 ± 1 ìg/ml) and specific MAO-B inhibition (ethyl acetate leaf extract = IC50 7 ± 6 ìg/ml petroleum ether extract = 3 ± 1 ìg/ml). Schotia brachypetala, Mentha aquatica and Gasteria croucheri also exhibited good MAO-B inhibition activity. Six extracts of varying polarity of Mentha aquatica were tested in a photometric peroxidase linked MAO bioassay. The 70% ethanol extract had highest inhibitory activity. (S)-Naringenin was isolated from the extract by bioassay guided fractionation on VLC and preparative TLC. The structure of the compound was determined by 1H, 13C and 13C-DEPT NMR and optical rotation. The IC50 values for MAO inhibition by naringenin were 342 ± 33 ìM for the rat liver mitochondrial fraction, 955 ± 129 ìM for MAO-A and 288 ± 18 ìM for MAO-B respectively. South African traditional medicine clearly utilizes many botanical species with CNS-related activity. Only a small number of the more than 330 southern African plant species reported to treat or alter the CNS have been scientifically evaluated. To date very few of the active compounds have been isolated and identified. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2009.

Background: Drug utilisation among the elderly is complex due to multiplemorbidities, extensive drug utilisation and an increased sensitivity to drugs. One of the most common drug groups utilised in this population is psychotropic drugs, which include antipsychotics, anxiolytics, hypnotics, and antidepressants. In appropriat eutilisation of drugs among the elderly is an issue of great public health importance. Aims: The overall aim of this thesis is to assess and analyse potentially in appropriat eutilisation of psychotropic drugs among the elderly in Sweden. The specific aims are to assess to what extent the indicator “concurrent use of three or more psychotropic drugs”captures the utilisation of Potentially Inappropriate Psychotropics (PIP) among theelderly, and to analyse potentially inappropriate utilisation of psychotropic drugs inrelation to time, mental disorders, institutionalisation, and socioeconomic determinants among the elderly in Sweden. Methods: Data from individual-based registers on dispensed drugs and socioeconomic determinants in 2006, the Gothenburg 95+ Study (1996-1998), and aggregated drug sales statistics from 2000-2008 were used. The agreement between the two indicators“concurrent use of three or more psychotropic drugs” and PIP was assessed. Utilisationof psychotropic drugs and PIP was assessed in relation to mental disorders and institutionalisation among the 95-year olds, and in relation to socioeconomic determinants among individuals aged 75 years and older. Further, trends over time inutilisation of PIP and recommended drugs were analysed. Results: During 2006, about half of the elderly aged 75 years and older utilised psychotropic drugs and one fifth of all elderly utilised PIP. One fourth of individualsutilising PIP were captured by the indicator “concurrent use of three or morepsychotropic drugs”. In 1996-1998, less than one tenth of the 95-year olds with depression utilised antidepressants, while hypnotics and anxiolytics were more common. Individuals with low income and the non-married were more likely to utilise PIP compared to those with high income and the married, respectively. During 2000-2008, utilisation of PIP decreased and utilisation of recommended psychotropic drugs increased. Conclusions: There are substantial problems in the utilisation of psychotropic drugsamong the elderly. This thesis found that the agreement between two indicators of inappropriate psychotropic drug utilisation was poor, which emphasises the importance of choosing relevant indicators. The findings also show socioeconomic inequities inpsychotropic drug utilisation among the elderly, a low utilisation of antidepressants among 95-year olds diagnosed with depression, and a trend towards the utilisation of recommended rather than inappropriate psychotropic drugs among the elderly / Bakgrund: Användning av läkemedel bland äldre är komplicerat på grund avmultisjuklighet, användning av flera läkemedel och en ökad känslighet för läkemedel.En av de vanligaste läkemedelsgrupperna hos äldre är psykofarmaka, som inkluderarantipsykotika, ångestdämpande, sömnmedel och antidepressiva läkemedel. Olämpliganvändning av läkemedel bland äldre är ett betydande folkhälsoproblem. Syfte: Det övergripande syftet med avhandlingen är att beskriva och analyserapotentiellt olämplig användning av psykofarmaka bland äldre i Sverige. De specifikasyftena är att undersöka i vilken utsträckning indikatorn ”samtidig användning av treeller fler psykofarmaka” fångar användningen av potentiellt olämpliga psykofarmaka(PIP) bland äldre och att analysera potentiellt olämplig användning av psykofarmaka irelation till förändring över tid, psykiatriska diagnoser, boendeform och socioekonomiska determinanter bland äldre i Sverige. Metod: Avhandlingen baseras på data från individbaserade register över läkemedelsköp och socioekonomiska determinanter under 2006, Göteborg 95+ studien (1996-1998)samt aggregerade data över läkemedelsförsäljning under 2000-2008. Överensstämmelsen mellan de två indikatorerna ”samtidig användning av tre eller flerpsykofarmaka” och PIP undersöktes. Användning av psykofarmaka och PIP studerades i relation till psykiatriska diagnoser och boendeform hos 95-åringar och i relation till socioekonomiska determinanter hos de som var 75 år och äldre. Vidare analyseradesförändring över tid i användning av PIP och rekommenderade psykofarmaka. Resultat: Hälften av alla äldre som var 75 år och äldre använde psykofarmaka under2006 och en femtedel av alla äldre använde PIP. En fjärdedel av individerna somanvände PIP fångades av indikatorn ”samtidig användning av tre eller flerpsykofarmaka”. Bland 95-åringarna med depression år 1996-1998 använde färre än enav tio antidepressiva läkemedel, medan sömnmedel och ångestdämpande läkemedel varvanligare. PIP var vanligare hos de äldre med låg inkomst och bland de som inte vargifta, jämfört med individer med hög inkomst och de gifta. Under 2000-2008 minskade användningen av PIP medan användningen av rekommenderade psykofarmaka ökade. Slutsatser: Det finns fortfarande stora problem i äldres användning av psykofarmaka.Avhandlingen visar en låg överensstämmelse mellan två indikatorer för olämpliganvändning av psykofarmaka, vilket pekar på betydelsen av att välja relevantaindikatorer. Avhandlingen visar också på socioekonomiska ojämlikheter i användningenav psykofarmaka hos äldre, en låg användning av antidepressiva läkemedel bland 95-åringar med depression och en ökning i användningen av rekommenderade istället förolämpliga psykofarmaka bland äldre