Introdução: A Doença do Refluxo Gastroesofágico (DRGE) possui elevada prevalência e morbidade. O tratamento clínico consiste em recomendações quanto ao estilo de vida e, essencialmente, no uso de inibidores da bomba protônica (IBP). A aderência (Ad) dos pacientes com DRGE à prescrição, embora fundamental para o sucesso terapêutico, tem sido pouco estudada. Objetivo: Avaliar a Ad ao tratamento com IBP e possíveis variáveis relacionadas em pacientes com DRGE. Métodos: Estudo transversal e prospectivo com 240 pacientes adultos consecutivos com DRGE erosiva e não-erosiva (ne-DRGE) que haviam recebido dose padrão ou dose dobrada de omeprazol em uso contínuo. Todos os pacientes foram classificados conforme o grau, segundo os achados da endoscopia digestiva alta (EDA) em ne-DRGE (162; 67,5%), classificação endoscópica de Los Angeles (LA) A (48; 20,0%), LA B (21; 8,6%), LA C (1; 0,4%), LA D (1; 0,4%) e Barrett (7; 2,9%). Foi aplicado o questionário de Morisky et al constituído de 4 questões com respostas dicotômicas para avaliar a Ad, classificando-a como baixa (0-2 pontos) e alta ad (3-4 pontos). Foi também aplicado o questionário QS-DRGE para a avaliação dos sintomas, com 10 questões com escores de 0 a 50, conforme a frequência menor ou maior dos sintomas. Os resultados de Ad foram relacionados com os dados sócio-demográficos, polifarmácia (PF) (uso de mais de cinco medicamentos diariamente), comorbidades (CM), tempo de tratamento (TT), escore QS-DRGE, presença de sintomas descrita em prontuário, achados da EDA e conhecimento do paciente sobre a doença. Resultados: (1) 126 pacientes (52,5%) apresentaram alta Ad e 114 (47,5%) baixa Ad; (2) Os pacientes mais jovens (p = 0,002) foram menos aderentes; (3) Pacientes sintomáticos de acordo com relato em prontuário apresentaram maior percentual de baixa Ad e 2 vezes maior probabilidade de ter baixa Ad em relação aos assintomáticos (p = 0,02); (4) Os pacientes casados apresentam probabilidade 2,41 vezes maior de ter baixa Ad do que os viúvos. (5) As demais variáveis estudadas não influenciaram a Ad ao tratamento. Conclusões: Pacientes em uso de IBP em tratamento ambulatorial em hospital terciário em São Paulo apresentaram grande percentual de baixa Ad ao tratamento, sendo esta uma possível causa da falha da terapia com IBP. Idade < 60 anos e estado civil casado podem ser fatores de risco para a baixa Ad / Introduction: The Gastroesophageal Reflux Disease (GERD) is a highly prevalent disease and a major cause of morbidity. Clinical treatment is based on lifestyle recommendations and, essentially, in the use of a proton pump inhibitor (PPI). Adherence (Ad) of GERD patients to the prescribed treatment, although critical for therapeutic success, has been little studied. Objective: Assess adherence to the PPI treatment and potential associated variables in patients with GERD. Case studies and Methods: Transversal and prospective study with 240 consecutive adult patients, diagnosed with erosive GERD (e-GERD) and non-erosive GERD (ne-GERD) for whom continuous use of the standard dose or the double dose of omeprazol had been prescribed. Patients were ranked according to the findings of high digestive endoscopy (HDE) in ne-GERD (162; 67.5%); e-GERD: Los Angeles (LA) endoscopic classification A (48; 20.0%), LA B (21; 8.6%), LA C (1; 0.5%), and LA D (1; 0.5%) and Barretts esophagus (7; 2.9%). The Morisky questionnaire, that includes four questions with dicotomic responses to assess Ad, was applied. Ad was classified as low (0-2 points) and high (3-4 points). In addition, the QS-GERD questionnaire was applied to assess symptoms, using 10 questions with score 0 to 50, according to the greater or lesser symptom frequency. Ad results were correlated with personal data (gender and age), demography, polypharmacy (PF), comorbidities (CM), treatment time (TT), QS-GERD scores, symptoms described in the patients record, HDE findings and patient awareness about the disease. Results: (1) 126 patients (52.5%) exhibited high Ad and 114 (47.5%) low Ad; (2) younger patients (p = 0,002) were less compliant; (3) married patients had a 2.41 greater probability to exhibit low Ad as compared to widowers (p = 0.03); (4) patients with symptoms indicated in the patients record exhibited a lower Ad rate and twice greater probability of exhibiting low Ad as compared to asymptomatic patients (p = 0.02); (5) the other variables studied had no influence on treatment adherence. Conclusion: Patients using PPI as out-patients in third care hospital in São Paulo exhibited high rate of reduced treatment adherence, and this may be a potential cause of PPI therapy failure. Age < 60 years and marital status may be risk factors for low adherence

Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2017-03-15T13:31:18Z No. of bitstreams: 1 Thamires Pandolfi Cappello.pdf: 1253483 bytes, checksum: e2b301173cd6f807ee509913ca02ecbf (MD5) / Made available in DSpace on 2017-03-15T13:31:18Z (GMT). No. of bitstreams: 1 Thamires Pandolfi Cappello.pdf: 1253483 bytes, checksum: e2b301173cd6f807ee509913ca02ecbf (MD5) Previous issue date: 2017-02-20 / Clinical research on medicines is a mandatory procedure for pharmaceutical development and registration of new drugs in Brazil. These tests are performed in healthy humans and/or with a certain pathology, in order to verify the possible effects of a substance with therapeutic potential in the human organism. Among its four phases, Phase I is performed with healthy individuals who provide researchers with their bodies, which are analyzed after the administration of substances not yet tested in a human body, through diagnostic tests and other procedures medical-scientific. Therefore, it is verified that the act of disposal of own body for submission to clinical trials of medicines, after free and informed consent, consists of an act based on individual freedom, on the bias of the autonomy of the will, which may, however, endanger the health and physical integrity of the participant. It is noted that several fundamental rights are involved in this area, implying, even, an evident collision to be solved by weighing. It is in this context that the present work is developed with the central objective of verifying that the disposal of own body for clinical research constitutes an individual fundamental right based on the free development of the personality and for the purpose of promoting collective health and national scientific development / A pesquisa clínica de medicamentos constitui procedimento obrigatório para o desenvolvimento farmacêutico e para registro de novos fármacos no Brasil. Trata-se de testes realizados em seres humanos saudáveis e/ou com determinada patologia, a fim de verificar os possíveis efeitos de determinada substância com potencial terapêutico no organismo humano. Dentre as suas quatro fases, a Fase I é realizada com indivíduos saudáveis que colocam à disposição dos pesquisadores seus corpos, os quais passam a ser analisados, após a administração de substâncias ainda não testadas em organismo humano, através de exames diagnósticos e demais procedimentos médico-científicos. Diante disso, verifica-se que o ato de dispor do próprio corpo para a submissão a estudos clínicos de medicamentos, após o consentimento livre e esclarecido, consiste em um ato baseado na liberdade individual, no viés da autonomia da vontade, que pode, entretanto, colocar em risco a saúde e a integridade física do participante. Nota-se que diversos direitos fundamentais são envolvidos nessa seara, implicando, inclusive, em evidente colisão a ser solucionada pela ponderação. É nesse contexto que o presente trabalho se desenvolve com o objetivo central de verificar se a disposição sobre o próprio corpo para pesquisas clínicas configura um direito fundamental individual com base no livre desenvolvimento da personalidade e com a finalidade de promoção da saúde coletiva e do desenvolvimento científico nacional

Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2017-03-24T11:46:17Z No. of bitstreams: 1 Antonio Carlos Cedenho.pdf: 8307782 bytes, checksum: 77b011484d6251debb81bd1e6d6df0f9 (MD5) / Made available in DSpace on 2017-03-24T11:46:17Z (GMT). No. of bitstreams: 1 Antonio Carlos Cedenho.pdf: 8307782 bytes, checksum: 77b011484d6251debb81bd1e6d6df0f9 (MD5) Previous issue date: 2017-03-15 / Healthcare, when seen as a subjective right, is a necessary condition for the realization of a fully developed human life, and once it is considered a social right, is a prerogative that coincides with the higher interests of the State. It has become expressly integrated into the roster of fundamental rights and guarantees alongside other social rights in the Constitution of 1988, demarcating the role of the Rule of Law. In this way, it is imposed as a positive right that requires provisions on the part of the State, demanding the realization of tasks – one of them being the concession of medications through public policy – whose very compliance is consubstantial to the right to healthcare. The current research, while inserted into this conjuncture, seeks to identify, analyze, and understand the judicial criteria for the construction of the right to healthcare elaborated within the scope of the Brazilian Supreme Court (STF), judiciary institution and constitutional court, especially in cases of the concession of medications which are not registered by the National Agency for Health Inspection (Anvisa). The significant judicialization of healthcare in recente decades, due to the negative response of the State regarding cases that extrapolate what has been foreseen by public policy and, furthermore, oppose what has been expressly determined by law (article 19-T of Law 8.080/90) indicates the complexity, relevance and urgency of the theme. Upon understanding healthcare as a fundamental right related to citizenship and human dignity, this research seeks to delineate the concept of healthcare and delimit current legal parameters. Starting from this outline, the deficits and challenges that present themselves in the form of metajudicial problems were pointed out and the orientations for the judicial standardization faced with considerable judicialization were presented. Through a selection of judgements issued by the Brazilian Supreme Court that deal with the concession of medication (especially medications not registered by Anvisa), the research aimed to identify and analyze arguments and counter-arguments in order to understand what judicial criteria are currently empolyed in the construction of access to healthcare / A saúde é circunstância necessária para a realização do pleno desenvolvimento da vida humana, na condição de direito subjetivo, e uma vez considerada direito social, é prerrogativa que coincide com os interesses superiores do Estado. Passou a integrar expressamente o rol de direitos e garantias fundamentais ao lado dos demais direitos sociais na Constituição de 1988, demarcando o perfil do Estado Democrático de Direito. Impõe-se, dessa forma, como direito positivo, que requer prestação por parte do Estado, exigindo a realização de tarefas – sendo a concessão de medicamentos por meio de políticas públicas uma delas – cujo próprio cumprimento se consubstancia no direito à saúde. A presente pesquisa, inserida nessa conjuntura, objetiva identificar, analisar e compreender os critérios jurídicos de construção do direito à saúde elaborados no âmbito do Supremo Tribunal Federal, instituição judiciária e corte constitucional, especialmente nos casos de concessão de medicamentos não registrados pela Agência Nacional de Vigilância Sanitária (Avisa). A significativa judicialização da saúde nas últimas décadas, em razão da negativa do Estado em atender os casos que ultrapassam o previsto nas políticas públicas, e mais, que se contrapõem à determinação legal expressa (artigo 19-T da Lei n. 8.080/90) sinalizam a complexidade, relevância e urgência do tema. Ao compreender a saúde como direito fundamental, relacionado com a cidadania e com a dignidade da pessoa humana, a presente pesquisa buscou delinear o conceito de saúde e delimitar os parâmetros legais atuais. A partir deste esboço, foram apontados os déficits e os desafios que se apresentam na forma de problemas metajurídicos, e foram apresentadas as orientações para uma padronização jurídica diante da considerável judicialização. Por meio da seleção de julgados que tratam da concessão de medicamentos (especialmente de medicamentos não registrados na Anvisa) proferidos pelo Supremo Tribunal Federal, objetivou-se identificar e analisar os argumentos e contraargumentos a fim de compreender quais são atualmente os critérios jurídicos na construção do acesso à saúde

Magister Public Health - MPH (Public Health) / The prevalence of diabetes in Africa has been on the increase. A prevalence of 1%- 10% has been reported by different authors in different regions in Nigeria. The International Diabetes Federation estimates that 1.9% of Nigerians are diabetic and most of them have complications at the time of diagnosis. Laboratory measurement of Glycosylated hemoglobin (HbA1c) is the method of choice for monitoring glycaemic control but due to its cost and limited availability, most developing countries use fasting plasma glucose (FPG) measurement (which is less reliable) to assess glycaemic control. Most diabetic patients in Nigeria have poor glycaemic control and several factors have been implicated especially socio-economic, behavioral and treatment-related factors. Understanding the reasons for poor glycaemic control is essential in order to reduce the rate of diabetes complications.

Background: Prescribing errors are the most frequent type of error in the medication use process. High risk medicines (HRMs) are a sub-class of medications that if used erroneously have potentially devastating consequences which defined by Institute for Safe Medication Practices (ISMP) as the drugs that bear a heightened risk of causing significant patient harm when they are used in error. Therefore, prescribing errors with HRMs are of concern to healthcare professionals that are responsible for ensuring mitigating patient safety. This thesis examines to what extent prescribing errors with HRMs in hospital occur, the causes of prescribing errors with HRMs and the differences to non-HRMs and the prescribing errors with HRMs during the on-call period. Method: The research adopted a mixed methods approach to explore prescribing errors with HRMs in hospitals and three studies were undertaken. The first study was a systematic review of the literature to explore the prevalence and incidence of prescribing errors with HRMs in hospitals. The second study was a secondary analysis of 59 existing interviews with foundation year doctors to explore the causes of prescribing errors with HRMs and compare them to those for non-HRMs reported in the same interviews. The third study was a qualitative study of the challenges of prescribing HRMs safely during the on-call period. This final study involved six focus groups with foundation year doctors (total participants number was 42). Results: Overall, findings demonstrated that there is paucity of studies that explored the prevalence of prescribing errors with HRMs and this literature showed inconsistency in definitions of prescribing errors, HRMs lists, severity scales and study methods (Study One). This resulted in a very wide range of prevalence of prescribing errors with HRMs. In terms of causes of prescribing errors with HRMs (Study Two), prescribing HRMs was considered a complex task for participants, especially those requiring dosage calculations, errors in the legal prescription requirements for controlled medications occurred with HRMs only and the on-call period was a particularly challenging period to prescribe safely especially with HRMs. In Study Three, the reasons found for this include the nature of the on-call period as a fast-paced environment, the methods of communication such as the bleep system, lack of accessibility to patient information and lack of plan from the primary team. Conclusions: HRMs form part of general medications, meaning they share similar traits, but the potentially devastating consequences of HRMs and the complicated task posed by prescribing them makes errors in their prescription profound. Therefore, HRMs need closer attention and more concern from healthcare professionals, researchers and policymakers. Such attention could result in a significant reduction in adverse outcomes and improved patient safety.

Made available in DSpace on 2016-04-26T18:16:55Z (GMT). No. of bitstreams: 1 Paula Renata Camargo de Jesus.pdf: 3112968 bytes, checksum: 599a83f95db4218467d98ec851808c6f (MD5) Previous issue date: 2008-03-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Studying slogans as advertising messages is a rather complex task, particularly medication slogans, which, in addition to seeking to be objective, concise, and persuasive characteristics that are peculiar to slogans , must also be concerned with the regulations that govern this type of advertisement in Brazil. This thesis proposes a transdisciplinary study of communications, health, and semiotics (with emphasis placed on Charles Sanders Peirce s semiotics). The research is based on the theoretical perspective built based on a set of conceptions found among authors who transit in these apparently distinct areas. Slogans were analyzed based on bibliographic research, in books and documents, in search of fundamental historical elements to understand how they are configured, their function, and trends in advertisements designed for medications marketed freely over means of mass communication, particularly billboards and external media, where they are propagated, even with legal restrictions. Additionally, they were also studied through professional opinion interviews, the purpose of which was hear several voices on the matter. The empirical research contributed to the Peircean semiotics analysis, via records of advertisement images presented in open air, in order to undertake the verbal and visual analyses as exhibited in the exterior media and in billboards. Finally, it is concluded that medication slogans inherit a language that appeals to salvation which was used by poets of past centuries and which, when currently inserted in certain contexts, such as in external media, is persuasive, although the slogans often disrespect the laws that govern medication-related advertisement in Brazil. Through verbal and visual complementarity, it is noticed that the slogans persuasive language is made legitimate when inserted in the means of mass communication / Estudar o slogan como mensagem publicitária constitui tarefa bastante complexa, sobretudo o slogan de medicamentos, que além de procurar ser objetivo, conciso e persuasivo, características peculiares do slogan, deve se preocupar com regulações existentes nesse tipo de propaganda no Brasil. Esta tese propõe um estudo transdisciplinar de comunicação, saúde e semiótica (com ênfase na semiótica de Charles Sanders Peirce). A pesquisa é embasada na perspectiva teórica construída com base num conjunto de concepções encontradas em autores que transitam nessas áreas aparentemente distintas. Estudou-se o slogan a partir da pesquisa bibliográfica, em livros e documentos, em busca de elementos históricos fundamentais para compreender sua configuração, função e tendências nas propagandas de medicamentos de venda livre na mídia de massa, em especial nos outdoors e na mídia exterior, onde ele é propagado, mesmo com restrições legais, e nas entrevistas de opinião profissional, a fim de ouvir várias vozes a respeito do assunto. A pesquisa empírica contribuiu para a análise semiótica peirceana, por meio de registros de imagens de propagandas ao ar livre, a fim de se fazer as análises verbal e visual expostas na mídia exterior e no outdoor. Por fim, conclui-se que os slogans de medicamentos têm como herança a linguagem de apelo à salvação utilizada por poetas em séculos passados, e que, ao serem inseridos atualmente em determinado contexto, como na mídia de exterior, são persuasivos, embora, muitas vezes, deixem de respeitar leis que regulam a propaganda de medicamentos no país. Por meio da complementaridade entre verbal e visual, percebe-se que a linguagem persuasiva dos slogans é legitimada quando inserida na mídia de massa

The overall aim of this thesis was to evaluate clinical pharmacist interventions with the focus on methods aiming to improve the quality of drug therapy and increase patient safety. Adverse drug events caused by medication errors, suboptimal dosages and inappropriate prescribing are common causes of drug-related morbidity and mortality. Clinical pharmacists integrated in multi-professional health-care teams are increasingly addressing these issues. A randomised controlled trial (RCT) was conducted to investigate the effectiveness of clinical pharmacists’ interventions in reducing morbidity and use of hospital care for patients 80 years or older. The results showed that the intervention group had fewer visits to hospital and that the intervention was cost-effective. In a subsequent study based on the population in the RCT, the appropriateness of prescribing was assessed using three validated tools. The results indicated improved appropriateness of prescribing for the intervention group as a result of the intervention. The tools and the number of drugs at discharge were then tested for validity in terms of causal links between the scores at discharge and hospitalisation. No clear correlations between high scores for the tools or a high number of drugs and increased risk of hospitalisation could be detected. During the inclusion period of the RCT a survey based study was conducted where the perceived value of ward-based clinical pharmacists, from the perspective of hospital-based physicians and nurses as well as from general practitioners (GPs) was evaluated. The respondents were positive to the new collaboration to a high degree and stated increased patient safety and improvements in patients’ drug therapy as the main advantages. In the last study the frequency and severity of prescription and transcription errors, when patients enrolled in the multidose-dispensed medications (MDD) system are discharged from hospital, was investigated. The results showed that errors frequently occur when MDD patients are hospitalised.

Asthma is a chronic disease of the airways and affects many people regardless of their age, gender, race and socioeconomic status. Since asthma is recognised as one of the major causes of morbidity and mortality in people and especially in South Africa, the prescribing patterns, prevalence and medication cost of asthma in South Africa are saliently important and need to be investigated. A non-experimental, quantitative retrospective drug utilisation review was conducted on medicine claims data of a pharmaceutical benefit management company in a section of the private health care sector of South Africa. The study period was divided into four annual time periods (1 January 2008 to 31 December 2008, 1 January 2009 to 31 December 2009, 1 January 2010 to 31 December 2010 and 1 January 2011 to 31 December 2011). The prescribing patterns and cost of asthma medication were investigated and stratified according to province, age and gender. Patients were included if the prescriptions which were provided by the health care practitioners matched the Chronic Disease List (CDL) of South Africa and the International Classification of Disease (ICD-10) coding for asthma and chronic obstructive pulmonary disease (COPD). Data analysis was conducted by means of the SAS 9.3® computer package. Asthma patients were divided according to different age groups (there were five different age groups for this study), gender and geographical areas of South Africa. The study indicated a steady increase in the prevalence of asthma patients from 0.82% (n = 7949) in 2008 to 1.18% (n = 15 423) in 2009 and reached a minimum of 0.79% (n = 8554) in 2011. Analysis of the prevalence regarding geographical areas in South Africa suggested that Gauteng had the highest number [n = 17 696, (0.85%)] of asthma patients throughout the study period, followed by KwaZulu Natal [n = 8 628, 1.16%)] and the Western Cape [(n = 8513, 0.97%) (p < 0.05)]. The prevalence of asthma in female patients [0.89% (n = 26 588)] was higher than in their male counterparts [0.79% (n = 19 244)] (p > 0.05). The results showed that asthma was not as common chronic disease in children. The total number of asthma patients younger than 7 years represented 0.64% (n = 2 909). It was found that patients over 65 years of age showed the highest prevalence of the five age groups [1.94% (n = 13 403) (p < 0.05)]. The average number of asthma prescriptions per patient per year was 8.28 (95% CI, 8.16- 8.40) and 5.15 (95% CI, 5.06-5.23) in 2008 and 2011, respectively. The number of asthma items per prescription varied from 1.55 (95% CI, 1.55-1.56) in 2008 to 1.40 (95% CI, 1.39- 1.40) in 2011. Medication from the MIMS® pharmacological group (anti-asthmatics and bronchodilators) was used to identify asthma medication. The top three asthma medication with the highest prevalence in the study period were the anti-inflammatory inhaler of fluticasone (n = 39 721) followed by the single item combination product of budesonide/ formoterol (n = 25 121) and salbutamol (n = 24 296). The influence of COPD on asthma treatment and the costimplication thereof were investigated. Medication from the MIMS® pharmacological group (anti-asthmatics and bronchodilators) was used to identify COPD medication. This study also showed that COPD had an influence in the economic burden of the South African asthma population. The cost of medication is responsible for the single largest direct cost involved in the economic burden of asthma. This study showed that asthma represented 0.88% of the direct medication cost in the study (excluding hospitalisation and indirect cost). The average cost per prescription and average cost per asthma item both increased throughout the study period. The prescribing patterns for the different medication used in the treatment of asthma were investigated and recommendations for further research in this field of study were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

The brain of Alzheimer???s disease (AD) is characterized by accumulations of ??-amyloid peptide aggregates which promote neurodegentartive dysfunction. Comprehensive understanding of the interaction between ??-amyloid aggregates and acetylcholine (ACh) neurocycle is required to uncover the physiological processes related to AD and might result in improving therapeutic approaches for AD. Pharmacokinetics (PK) and pharmacodynamics (PD) techniques were applied to allow predicting the extent of the interaction of certain doses of AD drugs and ??-amyloid inhibitors and levels of ACh as well. Although many researchers focused on the ??-amyloid interactions, the mechanisms by which ??-amyloid affects cholinergic neurons and reduction of ACh are still unclear. The prediction of ACh and drug concentrations in the tissues and body needs an understanding of the physiology and mechanisms of ??-amyloid aggregates processes and their compilation into a mechanistic model In this work, two hypotheses are proposed to investigate the dynamic behavior of the interaction between ??-amyloid peptide aggregates and cholinergic neurocycle and the possible therapeutic approaches through proposing pharmacokinetic/pharmacodynamics (PK/PD) models to represent the impact of ??-amyloid aggregates in AD. The effect of ??-amyloid peptide aggregates is formulated through incorporating ??- amyloid aggregates into non-linear model for the neurocycle of ACh where the presynaptic neuron is considered as compartment 1 and both synaptic cleft and postsynaptic neurons are considered as compartment 2. In the first hypothesis which is choline leakage hypothesis, ??-amyloid peptide aggregates are considered to be located in the membrane of the presynaptic neuron and create pathways inside the membrane to allow for the intracellular choline to leak outside the cholinergic system. It is observed that ??-amyloid aggregates via the choline leakage hypothesis could cause significant reductions of ACh and choline levels in both compartments. Furthermore, the process rates of ACh synthesis and hydrolysis have been affected negatively by a wide range of ??-amyloid aggregate concentrations. It is found that as the input rate of ??-amyloid aggregates to compartment 1 increases, the loss of choline from compartment 1 increases leading to an increase in the intracellular concentration of ??-amyloid. In the second hypothesis, ??-amyloid peptide aggregates are proposed to interact with the enzyme ChAT which is responsible for the synthesis of ACh in compartment 1; three different kinetic mechanisms are suggested to account for the interaction between ??-amyloid aggregates and ChAT activity. In the first and second kinetic mechanisms, ??-amyloid aggregate is supposed to attack different species in the enzyme. It is found that there is a significant decrease in the rate of ACh synthesis in compartment 1 and ACh concentrations in both compartments. However, it is observed that there is no effect on choline levels in both compartments, the rate of ACh hydrolysis in compartment 2, pH, and ACh levels in compartment 2. In the third kinetic mechanism, all species in ChAT are attacked by ??-amyloid aggregates; it is observed that at very high input rates of ??-amyloid aggregates, the oscillatory behavior dominates all components of the neurocycle of ACh. The disturbance observed in ACh levels in both compartments explains the harmful effect of the full attack of ??-amyloid aggregates to all species of ChAT. It is found that to contribute significantly in ACh neurocycle, choline leakage hypothesis needs concentration of ??-amyloid aggregates lower than that needed in ChAT activity hypothesis which is in agreement with experimental observations. The significant decrease in ACh levels observed in both choline leakage and loss of ChAT activity hypotheses leads to cognitive loss and memory impairment which were observed in individuals with AD. A one-compartment drug PK/PD model is proposed to investigate a therapeutic approach for inhibiting ??-amyloid aggregation via choline leakage hypothesis where the maximum feed rate of ??-amyloid (KL2 = 1) is considered. The drug is assumed to interact with the tissues of the presynaptic neurons where ??-amyloid aggregates are located. The PK/PD model is built based on the effect of ??-amyloid aggregates via choline leakage hypothesis where the maximum feed rate of ??-amyloid aggregates is considered. The dynamic behavior of all concentrations of ??-amyloid aggregates, choline, ACh, acetate, and pH in both compartments in addition to the rate of ACh synthesis in compartment 1 and ACh hydrolysis are investigated by monitoring the impacts of the drug on ??-amyloid aggregates and cholinergic neurocycle over a wide range of the input drug dosage. The PK/PD model is able to predict the reduction in levels of ??-amyloid aggregates and the increase in choline and ACh, in both compartments as well as both rates of ACh synthesis and hydrolysis catalyzed. The parameters of the PK/PD model such as maximum concentration (Cmax), maximum time (Tmax), area under the curve (AUC), and maximum effect (Emax) were investigated. It was found that it takes a longer time (Tmax) (3-5 h) to reach Emax as the drug dose increases. Furthermore, AUC was found to increase with increasing drug dosage. The results of the current work show that drugs / therapeutic agents inhibiting ??- amyloid aggregation in the brain represent a likely successful therapeutic approach to give systematic highlights to develop future trials, new diagnostic techniques, and medications for AD. This study is helpful in designing PK and PD and developing experimental animal models to support AD drug development and therapy in the future.

Submitted by Ana Valéria de Jesus Moura (anavaleria_131@hotmail.com) on 2018-05-30T17:03:54Z No. of bitstreams: 1 Luciana Mirella Lacerda de Jesus.pdf: 1213904 bytes, checksum: 05376e2d44d2d1faaa84f90715f8aaf7 (MD5) / Approved for entry into archive by Ana Valéria de Jesus Moura (anavaleria_131@hotmail.com) on 2018-05-30T17:12:28Z (GMT) No. of bitstreams: 1 Luciana Mirella Lacerda de Jesus.pdf: 1213904 bytes, checksum: 05376e2d44d2d1faaa84f90715f8aaf7 (MD5) / Made available in DSpace on 2018-05-30T17:12:28Z (GMT). No. of bitstreams: 1 Luciana Mirella Lacerda de Jesus.pdf: 1213904 bytes, checksum: 05376e2d44d2d1faaa84f90715f8aaf7 (MD5) / O presente trabalho versa acerca da concretização do direito fundamental à saúde pelo Estado brasileiro, através do fornecimento de medicamentos excepcionais, que são caracterizados pelo seu alto custo. Objetiva-se realizar uma investigação sobre os critérios que legitimam a concessão judicial de medicamentos não previstos na Política de Dispensação em Caráter Excepcional, elaborada pelo Ministério da Saúde. Assim, a partir da contextualização da assistência farmacêutica como medida relevante das ações de saúde, bem como a partir da análise da força normativa dos preceitos constitucionais e da dimensão do direito ao acesso à justiça, pretende-se demonstrar que o Poder Judiciário está autorizado a apreciar as demandas individuais e, a depender das peculiaridades de cada caso, imputar aos Entes Federativos à obrigação de fornecer medicamento excepcional, se for comprovada a sua imprescindibilidade para assegurar a dignidade da pessoa humana. Para tal, será destacada a inadequação da utilização da teoria da reserva do possível no Brasil, bem como enaltecida a necessidade de serem ultrapassados diversos argumentos teóricos que, na prática, acabam por inviabilizar a concretude dos direitos fundamentais e dificultar o atendimento das necessidades sociais. / The present work circumscribes on the realization of the fundamental right to health by the Brazilian State, through the provision of exceptional medicines, which is characterized by their high costs. The objective is to carry out an investigation into the criteria that legitimize the legal concession of medicines not provided by the Exceptional Dispensation Policy, elaborated by the Ministry of Health. Thus, from the contextualization of pharmaceutical assistance as a relevant measure of health action, as well, based on an analysis of the normative force of the constitutional precepts and the right of access to justice, attempts to demonstrate that the Judiciary is authorized to assess the individual demands and, depending on the peculiarities of each case, to impute to the entities of the Federation the obligation to provide an exceptional remedy if it is proven that it is essential to guarantee the dignity of the human being. For this purpose, it will be highlighted the inadequacy of the use of reserve theory of what is possible in Brazil, as well the need to overcome various theoretical arguments that, in practice, end up making the concreteness of fundamental rights impractical and making it difficult to meet social needs.