Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234

No description available.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234

Thesis (Ph.D.)--Flinders University, School of Medicine, Dept. of Clinical Pharmacology. / Typescript bound. Includes bibliographical references: (leaves 334-391) Also available electronically.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A consolidaÃÃo do mercado de medicamentos genÃricos no Brasil representa importante estratÃgia governamental, uma vez que significarà maior acesso da populaÃÃo aos medicamentos. A Lei n 9.787, de 10 de fevereiro de 1999, estabeleceu as bases legais para a instituiÃÃo do medicamento genÃrico no PaÃs. Os laboratÃrios de equivalÃncia farmacÃutica fazem a verificaÃÃo entre dois medicamentos que contÃm a mesma molÃcula terapeuticamente ativa, na mesma quantidade e forma farmacÃutica, podendo ou nÃo conter excipientes idÃnticos, se sÃo equivalentes in vitro. Os Centros de EquivalÃncia FarmacÃutica devem ser habilitados pela ANVISA, isto Ã, devem ser inspecionados pela GerÃncia-Geral de LaboratÃrio de SaÃde PÃblica (GGLAS), passando a fazer parte da Rede Brasileira de LaboratÃrios AnalÃticos em SaÃde (REBLAS) e apartir de entÃo, autorizados para a realizaÃÃo dos estudos de equivalÃncia farmacÃutica. Neste contexto foi implantado o LaboratÃrio de EquivalÃncia FarmacÃutica da Unidade de Farmacologia ClÃnica seguindo a seguinte metodologia: adequaÃÃo da infra-estrutura fÃsica do laboratÃrio; qualificaÃÃo e calibraÃÃo de aparelhos/equipamentos; validaÃÃo de MÃtodos AnalÃticos; preparaÃÃo dos Procedimentos Operacionais PadrÃo (POP) e implantaÃÃo do Sistema da Qualidade (SQ); realizaÃÃo de um ensaio piloto de EquivalÃncia FarmacÃutica. Um estudo piloto de equivalÃncia farmacÃutica foi realizado e utilizou-se para isso o medicamento Oxcarbazepina onde foram analisados os seguintes parÃmetros: Dureza, DesintegraÃÃo, IdentificaÃÃo, DissoluÃÃo e Perfil de dissoluÃÃo obtendo resultados favorÃveis em todos os testes. Conclui-se entÃo serem equivalentes farmacÃuticos os medicamentos teste e referÃncia analisados demonstrando que o laboratÃrio encontra-se apto para realizar as anÃlises a que se destina. No dia 22/06/2004 foi entÃo habilitado pela ANVISA recebendo o nÃmero EQFAR 047 / The consolidation of the generic medicine market in Brazil represents important governmental strategy, a time that will mean greater access of the population to medicines. The Law n 9,787, of 10 of February of 1999, it established the legal bases for the institution of the generic medicine in the Country. The laboratories equivalence pharmaceutical make the verification between two medicines that the same therapeutically active molecule contains, in the same amount and pharmaceutical form, being able or not to contain identical excipient, if vitro is equivalents in. The Centers of Equivalence Pharmaceutical must be qualified visor ANVISA, that is, they are evaluated by General Office of Laboratories of Public Health (GGLAS), second determined parameters, starting to be part of Brazilian Net of Analytical Laboratories in health (REBLAS) and being, from now on, authorized for the accomplishment of the studies equivalence pharmaceutical. (In this context it is that the following methodology was implemented the Pharmaceutical equivalence Laboratory of the UNIFAC having followed: Physical infrastructure and adequacy of the laboratory; Qualification and calibration of devices equipment; Validation of Analytical Methods; Preparation of Operational Procedures Standard (POP) and Implantation of the System of Quality (SQ); Accomplishment of a Pharmaceutical assay equivalence Pilot; Having been approved qualified for the ANVISA in day 22/06/2004. For the study pilot the Oxcarbazepine medicine was used for the pharmaceutical equivalence pilot and had been analyzed the following parameters: Hardness, Disintegration, Identification, Dissolution and Profile of dissolution getting resulted favorable in all the tests. It is concluded then to be pharmaceutical equivalents the analyzed medicines has tested and reference demonstrating that the laboratory meets apt to carry through the analyses the one that if destines

Orientador: Gilberto de Nucci / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-04T02:37:59Z (GMT). No. of bitstreams: 1 Petrellis_MariaCarla_M.pdf: 11345531 bytes, checksum: ffdc235c08929ac07ceecf4c90887171 (MD5) Previous issue date: 2004 / Resumo: A tese de doutoramento intitulada "A questão da passividade na melancolia: paradigma de Hamlef' trata de alguns o questionamentos clínicos sobre a ação da passividade e, conseqüente impacto sobre a relação analítica, num caso de melancolia. Sua descrição teórica é feita a partir das noções de paixão encontradas na literatura filosófica até chegar a psicanálise e sua problemática metapsicológica. As diferentes modalidades de passividade são descritas sob a ótica do sadismo e do masoquismo na teoria fteudiana para permitir uma articulação com a hipótese argumentativa de que é a passividade que faz certa A tese de doutoramento intitulada "A questão da passividade na melancolia: paradigma de Hamlef' trata de alguns o questionamentos clínicos sobre a ação da passividade e, conseqüente impacto sobre a relação analítica, num caso de melancolia. Sua descrição teórica é feita a partir das noções de paixão encontradas na literatura filosófica até chegar a psicanálise e sua problemática metapsicológica. As diferentes modalidades de passividade são descritas sob a ótica do sadismo e do masoquismo na teoria fteudiana para permitir uma articulação com a hipótese argumentativa de que é a passividade que faz certas coisas acontecerem na melancolia. A peça shakesperiana de Hamlet fornece uma perspectiva heurística, ficcional na qual o personagem principal atrai sobre si uma sorte de fatalidade que isola-o do contato com o outro e torna-o cada vez mais passivo. Trata-se de uma passividade curiosa, atípica, intrigante. Uma passividade que transporta rapidamente o leitor à clínica psicanalítica e interpela diretamente o papel do analista na relação transferencial / Abstract: The doctorate thesis entitled "The issue of passivity in melancholy: the paradigm of Hamlef' deals with some clinical questionings about the action of passivity and its consequent impact on the analytical relationship in a case of melancholy. Its theoretical description begins ITomthe notions of passion found in the philosophicalliterature to arrive to psychoanalysis and its metapsychological problematic. The different modalities of passivity are described ITom the standpoint of sadism and masochism in the Freudian theory to better link them to the argumentative hypothesis tOOtpassivity makes certain things OOppen.The Shakespearean play Harnlet offers a heuristic, fictional perspective in which the main character attracts a kind of fatality that isolates him ITomthe contact to the others and makes him increasingly passive. This is a weird, atypical and amazing passivity, which quickly refers the reader to the psychoanalytical clinic and directly questions the role ofthe analyst in the transferential situation / Mestrado / Farmacologia / Mestre em Farmacologia

La maladie rénale chronique (MRC) est caractérisée par une fréquence élevée de complications cardiovasculaires (CV). La rigidité artérielle est un marqueur de la maladie CV, corrélé avec la morbi-mortalité des patients en dialyse chronique. Notre équipe a déjà observé que des modifications structurelles et fonctionnelles des gros troncs artériels apparaissent néanmoins dès les stades précoces de la MRC.Le suivi prospectif d’une large cohorte de patients insuffisants rénaux non dialysés, nous a permis de démontrer que le remodelage artériel s’accentue avec la progression de la MRC, avec notamment une augmentation de la rigidité carotidienne, une diminution de l’épaisseur intima-média, une augmentation du diamètre interne de la carotide et du stress circomférentiel. Notre étude prospective a permis de montrer que le stress circonférentiel est prédictif de la vitesse de dégradation de la fonction rénale, même après ajustement sur les autres facteurs de risque CV et de progression de la MRC. Nous avons également étudié la morbi-mortalité globale et CV en fonction des paramètres artériels mesurés lors de l’inclusion. Après analyse multivariée, il apparaît que la rigidité aortique est corrélée au risque de décès ou de survenue d’un événement CV, alors que le diamètre interne de la carotide est associé à la mortalité globale, même après ajustement sur les facteurs CV classiques. La transplantation rénale permet une amélioration du pronostic CV des patients insuffisants rénaux. Nos études, réalisées sur 2 cohortes prospectives de patients transplantés rénaux ont permis d’objectiver une nette amélioration de la rigidité aortique dans les mois qui suivent la greffe. Nous démontrons par ailleurs que le remodelage artériel est également réversible, avec diminution du diamètre interne, augmentation de l’épaisseur intima-média et correction partielle du stress circonférentiel au niveau de la carotide interne. Cette réversibilité de la rigidité est particulièrement importante chez les receveurs bénéficiant d’une transplantation avec un donneur jeune, et ceci indépendamment du degré d’amélioration la fonction rénale observée dans la période post-greffe.Elle est aussi beaucoup plus marquée chez les patients recevant un greffon rénal provenant d’un donneur vivant.La qualité du greffon, déterminée par l’âge du donneur ou son origine (donneur vivant vs donneur décédé) est donc capitale pour prédire l’amélioration des paramètres artériels chez le receveur et indirectement son pronostic CV à moyen terme. / Chronic Kidney Disease (CKD) is associated with frequent cardiovascular complications. Arterialstiffness is a marker of cardiovascular (CV) disease and is associated with mortality in patients with end-stagerenal disease (ESRD). Our group has previously suggested that a maladaptative arterial remodeling occurs earlyduring CKD, even in patients with mild kidney dysfunction. Our first prospective study was based on a large CKD cohort. Our data confirm that the large arteries modifications, which include increase of carotid stiffness, decrease of intima-media thickness, carotid arterydilatation with enhancement of circumferential wall stress (CWS), worsen during CKD progression. We also showthat initial CWS is associated with the rate of kidney function deterioration, even after adjustment for other CV andCKD risk factors. In addition, we found that aortic stiffness was associated with both the overall survival and therisk of cardiovascular events. The internal carotid diameter is predictive of the overall mortality, after multivariateanalysis. Kidney transplantation reduces the CV risk of ESRD patients. Our 2 prospective studies demonstratethat aortic stiffness can improve during the first year after transplantation. The maladaptative arterial remodelingcan also reverse after transplantation, with a significant reduction of the carotide diameter, an increase of theintima-media thickness and a partial correction of the CWS. The improvement of the aortic stiffness and thereversal of this maladaptative arterial remodeling is particularily important in patients receiving a kidney allograftform a young allograft donor, independently of the post-transplant renal function. The kidney recipients with aliving donor experience a major improvement of their arterial parameters when compared with recipients withdeceased donors, and this difference remains significant after adjustment for other confounding factors. Inconclusion, the quality of the kidney allograft (age and source) may play an important role in the cardiovascularoutcome of the recipient. This advantage could be mediated a beneficial effect of transplantation on centralarteries structure and function.

Magister Pharmaceuticae - MPharm / Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials. / South Africa

<div><b>Background:</b> Bupropion, an atypical antidepressant and smoking cessation aid, is associated with wide inter-subject variability in its efficacy and safety. Variability in response to bupropion therapy is thought to be driven by variability in metabolism. Bupropion undergoes complex phase 1 and 2 stereoselective metabolism. Though bupropion`s pharmacology is not fully understood, much of it is thought to be due to its metabolites, specially, S, S-hydroxybupropion. In vitro studies (functional assays measuring IC50 at dopamine transporter-DAT, norepinephrine transporter-NET, various subtypes of nicotinic receptors-nAChR) and mouse models (forced swim test to assess antidepressant effect, antinociceptive models to assess antagonism of nicotine effects) indicate S, S-hydroxybupropion to contribute more towards efficacy as an antidepressant and smoking cessation aid than racemic bupropion and R, R-hydroxybupropion, respectively. Both pharmacokinetics (PK) and pharmacodynamics (PD) of bupropion and its metabolites are complex and reported to be stereoselective. As bupropion is known to act on multiple central nervous system (CNS) targets (DAT, NET nAChR), understanding CNS disposition (target site) is critical to explain variability in bupropion`s therapeutic and toxic effects. </div><div><b>Objective: </b>The objective of our study was to characterize the exposure of bupropion enantiomers and corresponding phase 1 metabolite diastereomers in plasma and brain in a surrogate non-clinical species, and to subsequently develop animal-to-human-translational population-PK and Physiologically Based PK (PBPK) models to predict human brain concentrations of bupropion and its active metabolite S, S-hydroxybupropion. Application of these PK modeling approaches to map the time course of unbound brain concentration can then be compared to in vitro potency measures at DAT, NET and nAChRs to predict target engagement over time (PD). Establishing relationships between plasma PK, target site PK along with PD would elucidate possible cause(s) of inter-patient variability to bupropion therapy. </div><div><b>Methods: </b>The first step towards development of a CNS model was to identify a nonclinical species with phase 1 metabolism closest to humans. To accomplish this, hepatic microsomal incubations of four species-rat, mouse, non-human primates (NHPs) and humans were conducted separately for the R- and S-bupropion enantiomers, and the formation of enantiomer-specific metabolites was determined using LC-MS/MS. Intrinsic formation clearance (CLint) of metabolites across the four species (rats, mice, NHPs, humans) was determined from the formation rate versus substrate concentration relationship. </div><div>Racemic bupropion (10 mg/kg) and preformed S, S-hydroxybupropion (2 mg/kg) were administered subcutaneously to adult male Sprague Dawley rats (n = 24/compound). Brain and plasma were collected from rats (n = 3) at eight time points for 6 hours and analyzed using a chiral LC-MS/MS method. Rat plasma protein and brain homogenate binding studies were conducted for all analytes to correct for unbound fraction using equilibrium dialysis method.</div><div>A plasma-brain compartmental pharmacokinetic approach was used to describe the blood–brain-barrier transport of both bupropion and S, S-hydroxybupropion. Also, a 2-compartment permeability-limited brain model consisting of brain blood, brain mass compartments was developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) parent-metabolite model for bupropion and S, S-hydroxybupropion. Both population PK and PBPK modeling approaches were subsequently translated to humans to predict human plasma and brain site exposure and its relationship to DAT and NET IC50 potencies.</div><div><b>Results: </b>The total clearance of S-bupropion was higher than that of R-bupropion in monkey and human liver microsomes. The contribution of hydroxybupropion to the total racemic bupropion clearance was 38%, 62%, 17%, and 96% in human, monkey, rat, and mouse, respectively. In the same species order, threohydrobupropion contributed 53%, 23%, 17%, and 3%, and erythrohydrobupropion contributed 9%, 14%, 66%, and 1.3%, respectively, to racemic bupropion clearance. Hepatic microsomal incubation studies indicated non-human primates to be the appropriate species to model CNS disposition. However, the cost and limited pharmacokinetic and pharmacodynamic data in NHPs were insurmountable barriers to conducting in vivo studies in NHPs. After considering multiple factors, such as the formation of reductive metabolites (higher in rats than mice), which are also thought to contribute to bupropion`s therapeutic efficacy, availability of microdialysis data measuring bupropion and dopamine, norepinephrine levels in brain extracellular fluid (ECF) and other in vitro potency evaluations in rats, rat was chosen as the surrogate species to model bupropion`s disposition.</div><div>In rats, unbound plasma and brain exposures and plasma clearances of both R and S-bupropion were similar. The exposure to parent was higher (50 to 100-fold) than to metabolites. The exposure of oxidative metabolites (R, R- and S, S-hydroxybupropion) was 2 to 3-fold higher in brain and plasma than reductive metabolites (R, R- and S, S-threohydrobupropion, S, R- and R, S-erythrohydrobupropion). Hepatic clearances of R- and S-bupropion scaled from in vitro rat hepatic microsomal incubation studies were 3-fold and 25-fold lower than their respective in vivo unbound apparent clearances. This could possibly be due to substantial contribution of metabolic pathways not characterized in this in vivo study and/or possible extrahepatic disposition in the rat. The unbound brain to unbound plasma AUC0-6h ratio (Kp,uu) of R- and S-bupropion were 0.43 and 0.38 respectively. Kp,uu of oxidative metabolites (R, R- and S, S-hydroxybupropion) and reductive metabolites (R, R- and S, S-threohydrobupropion) were close to 1. Kp,uu of S, R-erythrohydrobupropion was 0.43 and that of pre-formed S, S-hydroxybupropion was 5.</div><div>With respect to population PK modeling of both bupropion and S, S-hydroxybupropion, a plasma-brain compartmental model structure with time dependent change in brain influx clearance was required to adequately characterize the BBB transport of parent and this active metabolite. Using a physiologically-based pharmacokinetic model (PBPK) approach too, incorporation of active efflux and carrier mediated uptake terms in addition to passive permeability was necessary to adequately characterize brain disposition of bupropion and S, S-hydroxybupropion. Both modeling approaches (population-PK and PBPK) when translated to humans indicated that the predicted human brain exposures fall below the reported DAT and NET IC50 measures of bupropion and S, S-hydroxybupropion. </div><div><b>Conclusion: </b>Specific to our work in the rat, the discrepancy between in vitro scaled hepatic clearance and in vivo plasma clearance of R and S-bupropion suggests alternative non-CYP mediated clearance pathways and/or extra hepatic disposition of bupropion. Both translational PK models indicate active process such as efflux transporter or carrier mediated uptake could be involved in bupropion`s disposition in the brain. Variability in expression of these speculated active/carrier mediated transporters could possibly cause variability in response. Also, other CNS targets could contribute to bupropion`s therapeutic efficacy, elucidation of which would require further investigation.</div><div><br></div>

The Rational Drug Use Training Project is a district-oriented programme designed to improve rational drug use among primary health care prescribers in the South African public sector. This thesis describes the development of the project and details the initial implementation study in 3 facilities in Region B of KwaZulu-Natal. This was a small before-after study, with no control. There were three components: 1. A series of easily collectable drug use indicators, adapted from those developed by WHO/INRUD. These allow primary health care staff to monitor their prescribing patterns in a district or facility. Ninety sets of prescribing indicators were collected as a baseline at 3 facilities in KwaZulu-Natal in December 1996, by the district trainers and the Rational Drug Use Training Project staff. The process was repeated in March 1997, after the training intervention, by the district trainers alone. 2. The intervention was a 2-day training workshop in rational drug use. This is problem-based and trained on-site in primary health facilities. Training was done by 8 district trainers from Region B who were taught to present the workshop by the Rational Drug Use Training Project staff. The workshop covers principles of prescribing, use of standard treatment guidelines, principles of clinic stock management and principles of good dispensing. Staff are encouraged to develop their self-learning skills through questioning, and seeking answers to clinical and drug related queries. 3. A set of resources, including texts, treatment guidelines and information centres, to provide quality, safe and unbiased drug information, are made accessible to staff at primary care level. These are available by post, telephone or e-mail. The Primary Care Medicines Resource Centre at the University of Durban-Westville was developed as a result of this study. Significant improvements in prescribing habits were noticed after the study. There was an increase in the percentage of drugs prescribed by their generic names (p=0.000); an increase in the number of medications adequately labelled (p=0.0132); a decrease in the cost of prescriptions (p=0.0134); and a decrease in the number of prescriptions that did not follow standard treatment guidelines at all for that diagnosis (p=0.0109). The Mann-Whitney U- test was used for statistical analysis. There were no significant changes in the average number of drugs per prescription; the percentage of drugs from the Essential Drugs List; and the number of prescriptions that completely followed standard treatment guidelines. Qualitative feedback was favourable too. This was a difficult study to undertake. The staff and funding organisation, Health Systems Trust, fell outside of the provincial health structure and met resistance at that level. Regional politics shaped the programme's design. District trainers needed for the cascade approach were not available. District staff remained entrenched in a traditional health hierarchy and found it difficult to function as a team. The will of district prescribing staff to learn was low. Rational drug use training is only one of a number of essential elements of in-service training urgently needed by these staff. Despite these problems, quantitative and qualitative success was shown. The Training Manual, developed in support of the training, has been in demand. The Primary Care Medicines Resource Centre is growing. Primary care prescribers have been motivated to monitor their own practices and manage their own clinic stock. The project is a successful example of multi-disciplinary and institutional collaboration. The Rational Drug Use Training Project has expanded to eight other health districts in 1997. A list of criteria, such as the need for a district trainer, have been set. These must be met by the district before training will commence. The project is a resource for Initiative for Sub-District Support, a joint district development programme of Health System Trust and the Department of Health. Most expansion in 1998 will be through this initiative. The difficulties encountered and achievements made during this small study will be used to support, and hopefully strengthen, the development of the primary health care oriented district health system, so urgently needed by the South African population.