A terapia renal substitutiva contínua (TRSC) é amplamente utilizada em pacientes criticamente enfermos com insuficiência renal aguda (IRA). O meropenem é um carbapenêmico usado em pacientes críticos que tem uma atividade antibacteriana dependente do tempo. O objetivo do estudo foi avaliar a farmacocinética do meropenem infundido em três horas em pacientes submetidos à TRSC. Estudamos as concentrações plasmáticas e de efluente em cinco pacientes submetidos à TRSC. As amostras foram coletadas em momentos 0, 30 min, e 1, 2, 4, 6 e 8 horas após o início de uma infusão de 3 horas. As determinações de meropenem foram feitas por cromatografia líquida de alta eficiência. Quatro pacientes do sexo masculino e um feminino, idade de 53,0 ± 19,7 (23 a 80 anos), 62,1 ± 10,6 kg, foram estudados. Parâmetros farmacocinéticos apresentados em mediana (amplitude): concentrações plasmáticas, 34.86mg / L (10,08-139,27); tempo de meia vida (t ½), 1,8 h (1,4-3,0); volume de distribuição (Vd), 8,29 L (5,8-15,3); depuração total (Dept ) 3,98 L / h (2,51-4,35); concentração máxima (Cmax) 48,5 mg/L (37,0-105,8); concentração mínima (Cmin) 20,1 mg / L (14,0-16,6); constante de eliminação (Kel), 0,38 (0,34-0,43); área sob a curva de concentração versus tempo (AUC 0 a 8 h), 251,1 mg / Lh (229,7-398,4); (AUC de 0a∞), 275,1 mg /Lh (263,8-453,6).A depuração total pela TRSC variou de 8,46 a 18,33 ml/min. No efluente as concentrações máximas foram 24,35 e 74,81 mg /L. A eliminação de meropenem por TRSC é semelhante ao que é relatado pelo rim normal, quando é infundido por 3 horas a cada 8 h. Os níveis plasmáticos foram sempre acima do MIC necessário. Podemos concluir que não houve necessidade de ajuste de dose do meropenem com a dose de TRSC prescrita. / Continuous renal replacement therapy (CRRT) is widely used in critically ill patients with acute kidney injury (AKI). Meropenem is a carbapenem used in critically ill patients, which has a time dependent antibacterial activity. The aim of the study was to assess the pharmacokinetics of meropenem on a 3-hour infusion in patients undergoing CRRT due to AKI. We studied the plasmatic and effluent concentrations in five patients undergoing CRRT. The samples were collected at moments 0, 30 minutes, and 1, 2, 4, 6 and 8 hours after the beginning of the 3-hour infusion. The meropenem determinations were made through high performace efficiency liquid chromatography (HPLC). Four male patients and one female patient, with a mean age of 53,0 ± 19,7 (23 to 80 years), weighing 62,1 ± 10,6 kgs were studied. Pharmacokinetic parameters presented in medians (range): plasmatic concentrations, 34.86mg / L (10,08-139,27); half-life (t ½), 1,8 h (1,4-3,0); volume of distribution (Vd), 8,29 L (5,8-15,3); total clearance (CLT) 3,98 L / h (2,51-4,35); (Cmax) (maximum plasma concentration), 48,5 mg / L (37,0-105,8); Cmin (minimum plasma concentration)20,1 mg / L (14,0-16,6); elimination constant (Kel), 0,38 (0,34-0,43); area under the concentration versus time curve (AUC 0 a 8 h), 251,1 mg / Lh (229,7-398,4); (AUC 0 a ∞) 275,1 mg / Lh (263,8-453,6). In the effluent, the maximum concentrations varied from 24,35 to 74,81 mg/L, and the clearance from the therapy varied from 8,46 to 18,33 ml/min. The elimination of meropenem through CRRT is similar to that of a normal kidney, given a 3-hour infusion every 8 hours. Plasmatic levels were always above the necessary MICs. We can conclude there was no need for dose adjustment of meropenem with the prescribed CRRT dose.

Introdução: Em torno de 30 a 50% dos pacientes críticos desenvolvem insuficiência renal aguda (IRA), sendo que sua progressão leva à necessidade de terapia renal substitutiva (TRS). Dentre os sobreviventes, em torno de 15 a 23% possuem a necessidade de diálise após alta. A ocorrência da insuficiência renal aguda tem sido associada à futura progressão para doença renal crônica. É possível que marcadores tubulares estejam alterados após a recuperação da IRA, antecipando o desenvolvimento de doença renal crônica. Objetivos: Comparar a β2 Microglobulina, as enzimas urinárias N-acetil- β-D-glucosaminidase, lactato desidrogenase e fosfatase alcalina, as frações de excreção de magnésio, fósforo, potássio e ácido úrico e o gradiente transtubular de potássio, bem como a presença de microalbuminúria e proteinúria entre pacientes normais sem qualquer história prévia de dano ou qualquer tipo de disfunção renal, com pacientes sobreviventes de IRA severa com necessidade de hemodiálise que recuperaram função renal de forma a avaliar se existem diferenças entre os 2 grupos. Métodos: Foram incluídos pacientes que apresentaram insuficiência renal aguda com necessidade de hemodiálise internados no centro de terapia intensiva (CTI) do Hospital de Clínicas de Porto Alegre e que receberam alta nos períodos de 2007 a 2010, sem apresentar as seguintes co-morbidades: insuficiência renal crônica, hepatopatia crônica, pacientes HIV positivo, transplantados, doença vascular severa, diabetes com complicações crônicas e rim único funcionante e que apresentavam função renal normal definida por taxa de filtração glomerular > 60 mL/min/1.73m2 calculada pela equação CKD-EPI. Os mesmos foram comparados com voluntários sadios pareados por sexo e idade (+/- 4 anos). Para avaliação das frações de excreção e do gradiente transtubular de potássio foram feitas análises excluindo o uso de medicamentos diuréticos, inibidores da ECA e bloqueadores dos receptores de angiotensina. Resultados: A fração de excreção de magnésio encontrou-se aumentada no grupo com IRA prévia seguida por um menor gradiente transtubular de potássio bem como lactato desidrogenase elevada. O grupo com IRA prévia apresentou proteinúria e microalbuminúria e embora sem significância estatística (P=0,052) uma maior fração de excreção de fósforo. Conclusão: Mesmo com taxa de filtração glomerular normal comparável, os sujeitos do grupo com ira prévia apresentaram sugestivas alterações em nível tubular refletidas por maior fração de excreção de magnésio, elevada lactato desidrogenase e um menor gradiente transtubular de potássio, microalbuminúria e proteinúria que refletem um possível dano renal. Estes achados levam à hipótese de que sujeitos com prévia IRA severa com necessidade de terapia de renal substitutiva, apresentam uma possível sequela relativa à IRA prévia ou uma predisposição para insuficiência renal crônica. / Background: About 30 to 50% of the critically ill patients develop acute renal failure (ARF) and the progression leads to the need of renal replacement therapy. Between the survivors 15 to 23% has the need of dialysis after discharge. The severity of the ARF is a robust predictor for the development of a future chronic kidney disease. The occurrence of acute renal failure has been associated with future progression of chronic kidney disease. Objective: Compare β2-microglobulin, the urinary enzymes N-acetyl-β- D-glucosaminidase, lactate dehydrogenase, alkaline phosphatase fractional excretion of magnesium, phosphorous, potassium and uric acid transtubular potassium gradient, including the presence of microalbuminuria and proteinuria between subjects with normal renal function without any previous history of acute renal injury or any kind of renal dysfunction with survivors of severe ARF with the needed of hemodialysis that recovered renal function in order to evaluate if there are differences between the 2 groups. Methods: It was enrolled patients that presented acute renal failure with the need of hemodialysis hospitalized on intensive care unit (ICU) and discharged on the period of 2007 to 2010 at Hospital de Clínicas de Porto Alegre, without the following co-morbidities chronic renal failure, chronic hepatopathy, positive HIV, transplants, severe vascular disease, diabetes with chronic complications and single functioning kidney that presented normal renal function defined as glomerular filtration rate (GFR) > 60 mL/min/1.73m2 calculated by CKD EPI formula The subjects were compared with healthy volunteers and paired by sex and age (+/- 4 years). To evaluate fractional excretions and transtubular potassium gradient, analyses were made excluding subjects that were taken diuretic medication, ACE inhibitors and angiotensin block receptors. Results: The fractional excretion of magnesium was finding increased on the previous ARF group followed by a lower transtubular potassium gradient and elevated lactate dehydrogenase. The previous ARF group showed proteinuria and microalbuminuria and although without statistical significance (p=0.052) an elevated phosphorous excretion. Conclusion: Although normal glomerular filtration rate, the subjects with previous ARF, showed suggested tubular alterations reflected by a higher fractional excretion of magnesium, elevated lactate dehydrogenase and a lower transtubular potassium gradient, microalbuminuria and proteinuria that reflects a possible renal damage. Those findings lead to the hypothesis that subjects with previous severe ARF with the need of renal replacement therapy present a possible sequel related to previous ARF or a predisposition to chronic kidney disease.

Objetivos: Descrever o perfil epidemiológico dos pacientes em Terapia Renal Substitutiva (TRS) no período de 2000 a 2006 a partir do subsistema de Autorização de Procedimentos de Alta Complexidade em Terapia Renal Substitutiva – APAC/TRS e avaliar o potencial desse sistema para a vigilância e o monitoramento da Doença Renal Crônica Terminal no Brasil. Metodologia: Este estudo constituiu-se na descrição da Doença Renal Crônica e APAC/TRS por meio da análise dos instrumentos normativos e outros documentos técnico– administrativos e análise do perfil epidemiológico dos pacientes no período de 2000 a 2006. Resultados: No período, 148.284 pacientes iniciaram procedimentos de diálise e hemodiálise, destes 57% eram do gênero masculino. A incidência relativa foi maior em homens que em mulheres e aumentou com a idade, mas nas mulheres o pico ocorreu na faixa etária de 65 a 74 anos. A incidência global anual foi de 119,8/1.000.000 habitantes para todo Brasil, variando de 143,6/1.000.000 na região sul a 66,3/1.000.000 na região norte e se mantendo estável no período. Hipertensão foi causa da insuficiência renal em 32.571 (22,0%), diabetes mellitus em 20.412 (13,8%) e glomerulonefrites em 10.654 (7,2%) casos, sendo 66.439 (44,8%) casos de causa incerta. Conclusão: A APAC/TRS apresenta limitações inerentes a bancos de dados administrativos, com lacunas a serem preenchidas. Mesmo assim, recomenda-se sua utilização para subsidiar ações de promoção, prevenção, assistência da doença renal crônica terminal , elaboração de indicadores e fomento de estudos epidemiológicos e econômicos. / Objectives: Describe the subsystem Authorization of Procedures of High Complexity in Therapy Renal Substitutiva - APAC TRS, the epidemiological profile of the patients in the period 2000 to 2006 and evaluate its potential as one of the tools to support the monitoring and tracking of Chronic Renal Disease. Methodology: This study’s objective is to describe the Authorization of High Complexity Procedures for Renal Replacement Therapy database, and evaluate its potential for surveillance of chronic renal disease through analysis of the epidemiologic profile of incident cases of dialysis. APAC datafiles were aggregated and verified for inconsistencies and duplicities. Incident cases were described according to age, gender, region of the country, and underlying cause of renal disease. Results: From 2000 to 2006, 148.284 patients initiated dialysis, 57% being men. The relative incidence is higher in men than in women and increases monotonically with age, although the peak in women occurs in the age bracket of 65 to 74 years. The overall annual incidence was 119,8/1,000,000 habitants, varying from 143,6/1,000,000 in southern Brazil to 66,3/1,000,000 in the northern region, and maintaining stability over the period. Hypertension was listed as cause of renal disease in 32.571 (22,0%), diabetes mellitus in 20.412 (13.4%) and glomerulonephritis in 10.654 (7,2%), with 66.439 (44,8%) cases having no determined cause. Conclusion: The APAC/TRS system presents limitations inherent to administrative databases, with gaps requiring attention. Nevertheless, these data demonstrate its potential to support public health measures for chronic renal disease, including the elaboration of health indicators and to stimulate epidemiologic and economic studies.

Objetivos: Investigar o dano a lipídios, proteínas e ao DNA, níveis de glicosaminoglicanos (GAGs) e as concentrações de interleucina 1-β (IL1-β) em sangue de pacientes com Mucopolissacaridose (MPS) tipo II no diagnóstico e durante a terapia de reposição enzimática (TRE) e correlacioná-los com parâmetros de estresse oxidativo, bem como analisar o efeito in vitro da genisteína sob o dano ao DNA em leucócitos de pacientes com MPS tipo IVA. Métodos: Amostras de sangue e urina de doze pacientes com MPS II no diagnóstico e sob tratamento com TRE, além de controles saudáveis foram utilizados para avaliar: índice de lipoperoxidação e oxidação de proteínas (medida a partir do conteúdo de grupamentos carbonila e SH) em plasma, GAGs urinários, níveis de IL1-β plasmáticos, bem como índice de dano ao DNA em leucócitos através do ensaio cometa, também utilizada para avaliar o dano ao DNA em leucócitos de pacientes com MPS IVA, previamente incubados em diferentes concentrações de genisteína ou em tampão fosfato salino e dimetilsulfóxido. Resultados e Discussão: Foi observada a presença de dano oxidativo a biomoléculas em sangue de pacientes com MPS II, com altos níveis de lipoperoxidação, conteúdo de grupamentos carbonila, dano ao DNA e redução de grupos sulfidrila. Houve redução no dano ao DNA e na lipoperoxidação após TRE, além de aumento de grupamentos sulfidrila, embora a terapia não tenha sido capaz de reverter o dano a carbonila. Nossos resultados sugerem que o aumento dos GAGs induz o dano aos lipídios e ao DNA. A adição in vitro de genisteína (10, 30 e 50 μM) em amostras de sangue de pacientes MPS IVA acarretou em um aumento estatisticamente significativo no índice de dano ao DNA. Conclusões: Estresse oxidativo e inflamação estão envolvidos na fisiopatologia da MPS II. Além disso, a TRE mostrou ter papel protetor contra o dano ao DNA e a lipídios. A genisteína nas doses 10, 30 e 50 μM aumentou in vitro o índice de dano ao DNA em leucócitos de pacientes MPS IVA, demonstrando citotoxicidade. / Objectives: Investigate lipid, protein and DNA damage, glycosaminoglycans (GAGs) levels and the inflammatory marker interleukin 1-β (IL1-β) concentration of mucopolysaccharidosis (MPS) II patients at the moment of diagnosis and during enzyme replacement therapy (ERT), correlate these findings with oxidative stress parameters, as well as investigate the in vitro effect of genistein on DNA injury in leukocytes from MPS IVA patients. Material and Methods: Blood and urine samples from twelve MPS II patients at diagnosis and under ERT and healthy controls were evaluated regarding the parameters: lipid peroxidation index and protein oxidation (carbonyl and SH group contents) in plasma, urinary GAGs, as well as IL-1β in plasma and DNA damage index in leukocytes. Besides, blood samples from MPS IVA patients were incubated with different concentrations of genistein or phosphate buffered saline (PBS) and dimethylsulfoxide (DMSO), and the DNA damage index in leukocytes was evaluated by the comet assay. Results and Discussion: MPS II patients presented oxidative damage to biomolecules with high levels of lipid peroxidation, carbonyl content and DNA damage, as well as a reduction on SH groups. There was a decrease in DNA damage and lipid oxidative injury after ERT, and an increase in SH levels, although this therapy was not able to reverse carbonyl content. The high levels of urinary GAGs in MPS II patients were reduced after ERT and positively correlated with DNA and lipid oxidative injury, suggesting that GAGs accumulation induce lipid peroxidation and DNA damage. MPS IVA patients blood treated in vitro with genistein (10, 30 e 50 μM) had higher DNA damage index when compared to samples treated with PBS buffer and DMSO. Conclusions: Oxidative stress and inflammation process are involved in MPS II pathophysiology, and ERT protects against DNA and lipid injury, probably by reducing GAGs accumulation. Genistein increased in vitro DNA damage in leukocytes from MPS IVA patients, demonstrating cytotoxicity.

Dissertação(mestrado) - Universidade Federal do Rio Grande, Programa de Pós-Graduação em Enfermagem, Escola de Enfermagem, 2006. / Submitted by eloisa silva (eloisa1_silva@yahoo.com.br) on 2012-11-19T17:15:08Z No. of bitstreams: 1 rosaurapinto.pdf: 928121 bytes, checksum: 7c54a392f96fa8daa07d4f0d24204fa9 (MD5) / Approved for entry into archive by Bruna Vieira(bruninha_vieira@ibest.com.br) on 2012-11-30T15:10:19Z (GMT) No. of bitstreams: 1 rosaurapinto.pdf: 928121 bytes, checksum: 7c54a392f96fa8daa07d4f0d24204fa9 (MD5) / Made available in DSpace on 2012-11-30T15:10:19Z (GMT). No. of bitstreams: 1 rosaurapinto.pdf: 928121 bytes, checksum: 7c54a392f96fa8daa07d4f0d24204fa9 (MD5) Previous issue date: 2006 / O objetivo desta pesquisa foi avaliar a influência da terapia hormonal (TH) na qualidade de vida das mulheres no climatério. Realizou-se um estudo de corte transversal com mulheres entre 40 e 65 anos atendidas no Ambulatório de Climatério do Hospital Universitário da Fundação Universidade Federal do Rio Grande (HU-FURG) e em clínica privada, nos meses de junho, julho e agosto de 2005. Foram consideradas como usuárias aquelas que usavam TH há pelo menos 6 meses no momento da coleta de dados. Foram excluídas usuárias de anticoncepcional hormonal e usuárias de qualquer tipo de medicação, não hormonal, para alívio dos sintomas climatéricos nos últimos 6 meses. Participaram do estudo 229 mulheres, 61 usuárias de TH e 168 não usuárias. Avaliaram-se características sócio demográficas e biológicas. O instrumento utilizado para a avaliação da qualidade de vida no climatério foi o Questionário de Saúde da Mulher (QSM). A análise dos dados foi realizada através dos testes do Qui-quadrado (exato de Fisher), teste “t” de student, teste de tendência linear, teste de análise de variância fatorial 2 x 2 e teste post-hoc de Tukey. A idade média (49,2 ± 5,2 anos) e idade média da menopausa (44,5 ± 5,2 anos) das usuárias de TH foram menores do que as das não usuárias (50,9 ± 6,8 anos e 47,11± 4,8 anos respectivamente) (p=0,04 e p=0,02). Ocorreu aumento do uso de TH com o aumento da renda (p<0,05). Não ocorreu interação entre renda e TH, quando se procurou identificar se as maiores rendas e não a TH melhoravam a qualidade de vida. Dos 9 domínios de qualidade de vida avaliados pelo QSM, em 6 os escores foram melhores para as usuárias de TH (sintomas vasomotores, ansiedade e temores, memória e concentração,comportamento sexual, sintomas somáticos e sintomas depressivos). Independente do uso ou não de TH as mulheres com renda familiar maior do que 5 salários apresentaram melhores escores para qualidade de vida nos domínios sintomas vasomotores (p<0,05), ansiedade e temores (p<0,01), memória e concentração (p<0,05), comportamento sexual (p<0,05), sintomas depressivos (p<0,01) e problemas do sono (p<0,05) do que as mulheres com menor renda familiar. Os sintomas vasomotores foram os referidos como sendo os mais difíceis de conviver (p<0,01). A usuárias de TH apresentaram melhor qualidade de vida. / This research aims at assessing the influence of hormonal therapy (HT) on climacteric women’s quality of life. A cross-sectional study was carried out with women between 40 and 65 years old who sought for assistance at the Ambulatório de Climatério, a health center that focus on climacterics, in the university hospital that belongs to the Fundação Universidade do Rio Grande (HU-FURG), and at a private office, in June, July, and August 2005. Women who had already used HT for at least 6 months when the data was collected were considered users of the therapy. Women who had used hormonal birth control or any kind of non-hormonal treatment to relieve climacteric symptoms in the previous 6 months were excluded. The study was carried out with 229 women; 61 were users of HT, whereas 168 were non-users. Sociodemographic and biological features were assessed. The instrument chosen to assess climacteric women’s quality of life was the Women’s Health Questionnaire (WHQ). Data analysis used Chi-square tests (Fisher), student’s “t” test, linear tendency test, analysis of factorial variance 2x2, and Tukey’s post-hoc test. The average age of the users of HT (49.2 ± 5.2 years old) and the average age in which their menopause started (44.5 ± 5.2 years old) are under those of the non-users (50.9 ± 6.8 and 47.11 ± 4.8 years old, respectively)(p = 0.04 and p = 0.02). Higher income (p < 0,05) increased use of HT. No interaction was found between income and HT when I tried to identify if higher income, rather than HT, had improved their quality of life. Taking into consideration the nine dimensions of quality of life assessed by the WHQ, six of them presented better scores for users of HT (vasomotor symptoms, anxiety and fears, memory and concentration, sexual behavior, somatic symptoms, and depressive symptoms). Regardless of the use of HT, women with a family income above five minimum salaries (when compared to women with lower family income) presented better scores for quality of life in the following dimensions: vasomotor symptoms (p < 0.05), anxiety and fears (p < 0.01), memory and concentration (p < 0.05), sexual behavior (p < 0.05), depressive symptoms (p < 0.01), and sleep problems (p < 0.05). The vasomotor symptoms were considered the hardest to live with (p < 0.01). HT users had better quality of life. / El objetivo de esta pesquisa fue evaluar la influencia de la terapia hormonal (TH) en la calidad de vida de las mujeres en el climaterio. Se realizó un estudio de corte transversal con mujeres entre 40 y 65 años atendidas en el Ambulatorio de Climaterio del Hospital Universitario de la Fundação Universidade Federal do Rio Grande (HU-FURG) y en clínica privada, en los meses de junio, julio y agosto de 2005. Fueron consideradas como usuarias aquellas que utilizaban TH hace 6 meses en el momento de la colecta de datos. Fueron excluidas usuarias de anticonceptivo hormonal y usuarias de cualquier tipo de medicación, no hormonal, para el alivio de los síntomas climatéricos en los últimos 6 meses. Participaron del estudio 229 mujeres, 61 usuarias de TH y 168 no usuarias. Fueron evaluadas características sócio demográficas y biológicas. El instrumento utilizado para la evaluación de la calidad de vida en el climaterio fue el Cuestionario de Salud de la Mujer (QSM). El análisis de los datos fue realizado a través de los testes del Qui-quadrado (exacto de Fisher), test “t” de student, test de tendencia linear, test de análisis de la variancia factorial 2 x 2 y el test post-hoc de Tukey. La edad media (49,2 ± 5,2 años) y la edad media de la menopausia (44,5 ± 5,2 años) de las usuarias de TH fueron menores de lo que de las no usuarias (50,9 ± 6,8 anos e 47,11± 4,8 años respectivamente)(p=0,04 y p=0,02). Ocurrió aumento del uso de TH con el aumento de la renta (p<0,05). No ocurrió interacción entre la renta y TH, cuando se buscó identificar si las mayores rentas y no la TH mejoraban la calidad de vida. De los 9 dominios de calidad de vida evaluados por QSM, en 6 los escores fueron mejores para las usuarias de TH (síntomas vasomotores, ansiedad y temores, memoria y concentración, comportamiento sexual, síntomas somáticos y síntomas depresivos). Independiente del uso o no de TH las mujeres con renta familiar mayor de 5 salarios presentaron mejores escores para calidad de vida en los dominios síntomas vasomotores (p<0,05), ansiedad y temores (p<0,01), memoria y concentración (p<0,05), comportamiento sexual (p<0,05), síntomas depresivos (p<0,01) y problemas del sueño (p<0,05) de lo que las mujeres con menor renta familiar. Los síntomas vasomotores fueron los referidos como siendo los más difíciles de convivir (p<0,01). Las usuarias de TH presentaron mejor calidad de vida.

End stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Despite the advances in both Cardiovascular disease (CVD) management and renal replacement therapy (RRT), there still is a major burden of cardiovascular mortality and morbidity in the chronic kidney disease (CKD) population. Declining renal function itself represents a continuum of cardiovascular risk and in those individuals who survive to reach ESRD, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Pro-thrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) the time taken to form an occlusive platelet rich thrombus and thrombolytic status (time taken to lyse such thrombus) as assessed by measuring Lysis Time (LT), may identify vulnerable patients. The aim of this study was to assess overall thrombotic status in ESRD and relate this to cardiovascular and peripheral thrombotic risk. Small sub studies were also planned to establish the effect of RRT modality on the thrombotic status.

Les maladies lysosomales forment un groupe hétérogène d’une cinquantaine d’affections qualifiées de « rares ». Actuellement, seulement 9 maladies lysosomales disposent d’un traitement spécifique, principalement par enzymothérapie substitutive, mais les effets bénéfiques sont souvent limités. Le manque de ciblage pour le Récepteur du Mannose 6-Phosphate (RM6P), responsable de l’internalisation dans les lysosomes, expliquerait en partie cette efficacité modérée des enzymes thérapeutiques. Dans ce contexte, nous avons développé une approche de ciblage innovante basée sur des Analogues synthétiques du Mannose 6-Phosphate fonctionnalisés sur l’Aglycone (appelés AMFA) afin de répondre aux besoins non satisfaits par les traitements actuels.Les travaux de cette thèse portent principalement sur la maladie de Pompe, myopathie causée par la déficience d’une enzyme lysosomale, l’Alpha Glucosidase Acide (GAA), responsable de la conversion du glycogène en glucose. Afin d’améliorer l’adressage de l’enzyme thérapeutique aux lysosomes via le RM6P, nous avons fonctionnalisé la GAA recombinante humaine (rhGAA) avec les AMFA. Nos études sur la forme adulte de la maladie ont démontré une augmentation significative de l’internalisation et pour la première fois, chez des souris âgées modèles de la maladie, une restauration de la santé musculaire et une amélioration significative de la fonction motrice ont été observées (article 1). Nous nous sommes ensuite intéressés aux propriétés de la rhGAA-AMFA. Nous avons démontré que l’efficacité de la rhGAA-AMFA n’était pas uniquement due à une meilleure internalisation mais également à une meilleure maturation intracellulaire de l’enzyme (article 2). En effet, nos résultats ont démontré que chez les patients atteints de la maladie de Pompe, il existe une surexpression des phosphatases acides ACP2 et ACP5. Ces phosphatases peuvent détruire le signal mannose 6-phosphate (M6P) naturellement présent sur l’enzyme, ce qui interrompt sa maturation en forme active. L’AMFA, contrairement au M6P, est insensible à cette dégradation et assure donc la stabilité de l’adressage de l’enzyme in vitro, mais également in vivo.L’ensemble de ces résultats suggèrent que le greffage des AMFA sur des enzymes recombinantes représente une nouvelle solution thérapeutique pour le traitement de la maladie de Pompe et potentiellement pour le traitement d’autres maladies lysosomales. / Lysosomal diseases form a heterogeneous group of about fifty rare diseases. At present, only 9 lysosomal diseases have a specific treatment, mainly by enzyme replacement therapy but the beneficial effects appear often limited. The lack of targeting for the Mannose 6-Phosphate Receptor (M6PR), responsible for internalization into the lysosomes, would partly explain this moderate efficiency of the therapeutic enzymes. In this context, we have developed an innovative targeting approach based on Mannose 6-Phosphate Synthetic Analogues Functionalized at the Aglycone position (called AMFAs) to address the unmet needs of current treatments.The work of this thesis focuses mainly on Pompe disease which is a myopathy caused by the deficiency of a lysosomal enzyme, Acid Alpha Glucosidase (GAA), responsible for the conversion of glycogen into glucose. In order to improve the targeting of the therapeutic enzyme to lysosomes via the M6PR, we have functionalized the human recombinant GAA (rhGAA) with the AMFAs. Our studies on aged mice model of the adult form of the disease have demonstrated a significant increase of the enzyme internalization and for the first time, the restoration of muscle health and the significant improvement in motor function (article 1). We then investigated the properties of rhGAA-AMFA. We have proved that the effectiveness of rhGAA-AMFA is not only due to a better cell uptake but also to a more complete intracellular processing of the enzyme (article 2). Indeed, our results demonstrated that in myoblasts of patients affected by Pompe disease there is an overexpression of ACP2 and ACP5 acid phosphatases. These phosphatases can destroy the mannose 6-phosphate signal (M6P) naturally present on the enzyme, therefore possibly interrupting its processing into the active form. AMFA, unlike M6P, is insensitive to this degradation and thus ensures the stability of enzyme addressing in vitro, but also in vivo.All together, these results suggest that the grafting of the AMFAs on recombinant enzymes represents a new therapeutic solution for the treatment of Pompe disease and potentially for other lysosomal diseases.

Analysis of spontaneous adverse drug reactions reporting hormonal contraception and hormone replacement therapy Author: Vendula Ryndová Supervisor: PharmDr. Kateřina Malá, Ph.D. Consultant: PharmDr. Eva Zimčíková, Ph.D. Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction: Hormonal contraception (HC) is the most widely used method to prevent pregnancy worldwide. In addition to pregnancy planning and other non-contraceptional benefits, it also has certain risks. Hormone replacement therapy (HRT) is used primarily for treatment of estrogen deficiency in postmenopausal women. HRT is associated with a number of risks, in particularly for women 60+ of age. Analysis of spontaneous adverse drug reactions (ADRs) reporting contribute to detection of potential risks associated with pharmacotherapy, thereby increases the safety of the drugs. Aim: The aim of this thesis was to analyse spontaneous ADRs reports of HC and HRT registered in the Czech Central Database of ADRs of the State Institute for Drug Control (SÚKL). Methods: Retrospective analysis of the spontaneous ADRs reports of HC and HRT registered in the database of SÚKL from 10/2004 to 6/2017. Mainly, method of receiving the report, reporting person, patient information, seriousness, and...

Rökning är en av de vanligaste riskfaktorerna för hjärtkärlsjukdom i Sverige. Det finns ett flertal vetenskapligt underbyggda metoder för att sluta röka. Rådgivning och motiverande samtal kring rökavvänjning, samt nikotinersättningsmedel är väl utarbetade metoder. Syftet är att undersöka vilket stöd till rökfrihet som rökande patienter får på avdelning 10 på UMAS. Metoden är en enkätstudie och resultatet presenteras genom kvantitativ data. Urvalet består av de patienter som befann sig på avdelningen (n = 75) de två veckor som studien genomfördes. Urvalet är ett icke slumpmässigt, ett konsekutivt, urval. Resultatet av studien visar att ett stort antal patienter inte tillfrågas i fall de är rökare. Det är också vanligare att män tillfrågas i fall de röker än kvinnor. Bland rökande patienter var nikotinersättningsmedel den vanligaste metoden som erbjudits för att vara rökfri. Vidare visar resultatet att flera av de patienter som svarat att de inte är rökare, tidigare har rökt. Då materialet som ligger till underlag för studiens resultat är litet bör slutsatserna av studien betraktas med försiktighet. Av samma anledning kan inte heller resultatet av studien anses vara generaliserbart för populationen och bör därför inte överföras på annan verksamhet. / Smoking is one of the most common risk factors for heart and vascular diseases in Sweden. There are many scientifically proven methods to quit smoking. Among the well established ones are counselling and Motivational Interviewing together with different nicotine replacement therapies. The aim of this study was to investigate the support smoking patients are given not to smoke at ward 10 at UMAS. The chosen method is a survey study and the result is presented as quantitative data. The respondents are patients who were present at the ward (n = 75) during the two weeks when data was collected. It is a non-probability sample, a consecutive selection. The result shows that a large number of patients are not asked if they smoke. It is also more common to ask men than women if they smoke. Among the smoking patients nicotine replacement therapy is the most frequent method offered to stay off smoking. Further on the result shows that several of the patients who answered that they did not smoke were previous smokers. Considering the size of data collected the conclusions made in the study should be looked upon tentatively. For the same reason there is no possibility to generalize the result and convert it on to other areas.

No description available.