Hyperuricemia is the hallmark of gout. Pathogenic mechanisms of hyperuricemia include uric acid overproduction in the liver or underexcretion in the kidney. Current antihyperuricemic agents include xanthine oxidase inhibitors in which allopurinol is the most often prescribed. Inhibitors of renal urate reabsorption such as probenecid and benzbromarone are also employed. However, these existing antihyperuricemic agents possess some undesirable effects such as hypersensitivity towards allopurinol and hepatotoxicity associated with benzbromarone. Therefore, search for alternative antihyperuricemic agents with a more favorable toxicological profile or via mechanisms other than the above two mentioned is highly warranted. / The present project represents such an effort. Four in vitro experimental models were developed for the screening of new antihyperuricemic agents. The effects of the potential compounds from natural sources on the activities of phosphoribosyl pyrophosphate synthetase, hypoxanthine-guanine phosphoribosyl transferase and xanthine oxidase, as well as the uptake of urate through rat renal brush border membrane vesicles were investigated. Several compounds emerged with strong urate uptake inhibitory activities in which morin (3, 5, 7, 2', 4'-pentahydroxyflavone) was the most potent. Interestingly some of these compounds including morin were also demonstrated to be xanthine oxidase inhibitors. The subsequent in vivo experiment showed that morin indeed exhibited hypouricemic and uricosuric actions in an acute oxonate-induced hyperuricemic rat model. The uricosuric action of morin was hirther studied in transfected HEK293 cells expressing the human urate anion transporter 1 (hURATI) which is believed to regulate blood urate level by mediating urate reabsorption. In hURAT1-expressing HEK293 cells, urate uptake was significantly increased as compared to the non-transfected parental cells. Incorporation of morin into the uptake buffer could dose-dependently inhibit urate uptake in the transfected cells. Taken together our data indicated that morin is a potentially useful antihyperuricemic agent which acts by inhibiting xanthine oxidase and inhibiting urate reabsorption. In addition, the favorable safety profile of this natural compound makes it a potential candidate worthy of further investigations. / Yu Zhifeng. / "June 2006." / Advisers: Christopher H. K. Cheng; Wing Ping Fong. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1584. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 155-169). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Background: Chronic Kidney Disease (CKD) is a worldwide public health problem. There are few studies in Latin America, especially in primary care settings. Our objective was to determine the prevalence, stages, and associated factors of CKD in primary care setting. Methods: We did a retrospective secondary analysis of a database from the Diabetes and Hypertension Primary Care Center of the Peruvian Social Security System (EsSalud) in Lima, Peru. We defined CKD as the presence of eGFR <60 mL/min and/or albuminuria >30 mg/day in 24 h, according to Kidney Disease: Improving Global Outcomes (KDIGO). Factors associated with CKD were evaluated with Poisson Regression models; these factors included age, gender, type 2 diabetes mellitus (DM2), hypertension (HTN), body mass index (BMI), and uric acid. Associations were described as crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI). Results: We evaluated 1211 patients (women [59%], mean age 65.8 years [SD: 12.7]). Prevalence of CKD was 18%. Using the estimated glomerular filtration rate (eGFR), the prevalence was 9.3% (95% CI 5.3 – 13.3) in patients without HTN or DM2; 20.2% (95% CI 17.6 – 22.8) in patients with HTN, and 23.9% (95% CI 19.4 – 28.4) in patients with DM2. The most common stages were 1 and 2 with 41.5% and 48%, respectively. Factors associated with CKD in the adjusted analysis were: age in years (PR = 1.03, 95% CI 1.01 – 1.04), DM2 (PR = 3.37, 95% CI 1.09 – 10.39), HTN plus DM2 (PR = 3.90, 95% CI 1.54 – 9.88), and uric acid from 5 to <7 mg/dL (PR = 2.04, 95% CI 1.31 – 3.19) and ≥7 mg/dL (PR = 5.19, 95% CI 3.32 – 8.11). Conclusions: Prevalence of CKD in the primary care setting population was high. CKD is more frequent in the early stages of the disease, and individuals with hypertension, DM2, older age and hyperuricemia have higher prevalence of CKD.

京都大学 / 新制・課程博士 / 博士(社会健康医学) / 甲第24537号 / 社医博第129号 / 新制||社医||12(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 中山 健夫, 教授 近藤 尚己, 教授 山本 洋介 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25165号 / 医博第5051号 / 新制||医||1071(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 尾野 亘, 教授 西浦 博, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Orientador: Luis Cuadrado Martin / Resumo: Fundamentação: É crescente o número de trabalhos revelando a associação de hiperuricemia assintomática com hipertensão, síndrome metabólica, doenças cardiovasculares e doença renal crônica. Alguns estudos revelam que o tratamento da hiperuricemia assintomática reduz o número de desfechos renais e cardiovasculares. Tal premissa, no entanto, ainda não foi avaliada em uma subpopulação brasileira. Objetivos: Avaliar a associação entre tratamento com alopurinol e ocorrência de desfechos definitivos em portadores de doença renal crônica com hiperuricemia assintomática. Materiais e métodos: Foram avaliados, de forma retrospectiva, pacientes hiperuricêmicos e portadores de doença renal crônica não dialítica, em tratamento no HC-FMB – UNESP, os quais iniciaram acompanhamento no ambulatório de Insuficiência Renal Crônica ou de Nefrologia Geral do HC-UNESP desde janeiro 2002 a dezembro 2017. Com o intuito de avaliar a associação do uso do alopurinol sobre desfechos definitivos (entrada em terapia renal substitutiva, duplicação da creatinina ou morte). Resultados: Foram avaliados 109 pacientes sendo 53 do sexo feminino, cuja média de idade foi de 68 ± 11 anos. Destes, 95 eram brancos, 13 afrodescendentes e um asiático. Vinte e seis pacientes apresentaram o desfecho estudado no período; entre todos os 36 pacientes que iniciaram o uso de alopurinol no primeiro ano seguimento, ocorreram oito desfechos (22%). A proteinúria em 24 h associou-se aos desfechos avaliados Hazzard Ratio de 1,301 (I... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Rationale: There is increasing number of studies revealing an association of hyperuricemia with hypertension, metabolic syndrome, cardiovascular diseases and chronic kidney disease. Some studies have shown that treatment of asymptomatic hyperuricemia reduces the number of renal and cardiovascular outcomes. This premise, however, has not yet been evaluated in a Brazilian subpopulation. Objectives: To evaluate the association between treatment with allopurinol and the occurrence of definitive outcomes in patients with chronic kidney disease with asymptomatic hyperuricemia. Materials and methods: Hyperuricemic patients with chronic non-dialytic kidney disease under treatment at HC-FMB - UNESP who began follow-up at the Chronic Kidney Insufficiency or General Nephrology outpatient clinic at HC-UNESP, were retrospectively evaluated, from January 2002 to December 2017. In order to evaluate the association of the use of allopurinol on definitive outcomes (renal replacement therapy, creatinine doubling or death). Results: A total of 109 patients were evaluated, of which 53 were females, whose mean age was 68 ± 11 years. Of these, 95 were white, 13 Afro-descendants and one Asian. Twenty-six patients presented the outcome studied in the period; among all 36 patients who started using allopurinol in the first year of follow-up, eight outcomes (22%) occurred. Proteinuria at 24 h was associated with the Hazzard Ratio of 1.301 (95% CI: 1.122 -1.508), p: 0.011. In univariate analysis, phosp... (Complete abstract click electronic access below) / Mestre

Although uric acid has a character antioxidant, when in increased serum levels, has been associated in several studies with various pathological conditions, particularly with obesity, cardiovascular disease, diabetes mellitus, dyslipidemia, hyperinsulinemia and insulin resistance, this being identified as the primary change of the metabolic syndrome. However, these studies were not performed on samples formed specifically for morbid obeses, where hyperuricemia is a common finding in obesity. This study was undertaken to answer the question: serum uric acid in morbid obeses is associated with insulin resistance and other components of metabolic syndrome? Hundred and sixty-seven subjects with morbid obesity (49 men and 119 women, 20 to 71 years) were allocated into 4 groups according to their quartile distribution of serum uric acid. All data were obtained from their respectives records in a private clinic in Maceió (Alagoas). Patients in quartile 4 had values of BMI, triglycerides, insulin, creatinine, HOMA% and HOMA-s (p <0.05) higher than those observed among patients in the 1st quartile. The variables that correlated positively and significantly with the levels of uric acid (the Spearman correlation) were waist circumference, creatinine, BMI, insulin, HOMA%, HOMA-s and triglycerides. The multiple linear regression analysis adjusted for age indicated that the variables that associated independently and significantly to the plasma level of uric acid were the HOMA-s, waist circumference, creatinine and be male. It was concluded that the plasma uric acid in morbid obeses is independently associated with, among other factors, insulin resistance and waist circumference, and it is therefore a possible risk factor for metabolic syndrome. / Apesar do ácido úrico ter caráter antioxidante, em níveis séricos aumentados, tem sido associado em diversos estudos a diversas condições patológicas, particularmente, à obesidade, doenças cardiovasculares, diabetes mellitus, dislipidemias, hiperinsulinemia e à resistência insulina, esta apontada como sendo a alteração primária da síndrome metabólica. Todavia, esses estudos não foram realizados em amostras constituidas especificamente por grandes obesos, sendo que a hiperuricemia é um achado comum na obesidade. O objetivo deste trabalho foi responder à seguinte pergunta: o ácido úrico plasmático em obesos mórbidos correlaciona-se à resistência à insulina e aos demais componentes da síndrome metabólica? Foram estudados 167 homens e mulheres (20 a 71 anos) portadores de obesidade mórbida a partir da análise de seus respectivos prontuários numa clínica particular de Maceió (Alagoas). Os indivíduos foram categorizados em quatro grupos segundo os quartis de ácido úrico plasmático. Os pacientes do 4º quartil tinham valores de IMC, triglicerídeos, insulina, creatinina, HOMA% e HOMA-s maiores (p<0,05) que os observados entre os pacientes do 1º quartil. As variáveis que se correlacionaram positivamente e de forma significativa com os níveis de ácido úrico (correlação de Spearman) foram a circunferência da cintura, creatinina, IMC, insulina, HOMA%, HOMA-s e os triglicerídeos. A análise de regressão linear múltipla indicou que as variáveis que se correlacionaram de forma independente e significativa ao nível plasmático de ácido úrico foram o HOMA-s, a circunferência da cintura, a creatinina e ser do sexo masculino. Concluiu-se que a o ácido úrico plasmático em obesos mórbidos associa-se de forma positiva e independente, dentre outros fatores, à resistência à insulina e à circunferência da cintura, podendo constituir-se , portanto, num possível fator de risco para a síndrome metabólica.

Submitted by Lúcia Brandão (lucia.elaine@live.com) on 2015-12-09T18:35:17Z No. of bitstreams: 1 Dissertação - Neila Hiraishi Mallmann.pdf: 1069042 bytes, checksum: 634f83ffec4d5bd0d8f350f9a675caad (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2016-01-19T19:44:22Z (GMT) No. of bitstreams: 1 Dissertação - Neila Hiraishi Mallmann.pdf: 1069042 bytes, checksum: 634f83ffec4d5bd0d8f350f9a675caad (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2016-01-19T19:45:25Z (GMT) No. of bitstreams: 1 Dissertação - Neila Hiraishi Mallmann.pdf: 1069042 bytes, checksum: 634f83ffec4d5bd0d8f350f9a675caad (MD5) / Made available in DSpace on 2016-01-19T19:45:25Z (GMT). No. of bitstreams: 1 Dissertação - Neila Hiraishi Mallmann.pdf: 1069042 bytes, checksum: 634f83ffec4d5bd0d8f350f9a675caad (MD5) Previous issue date: 2014-04-25 / Não Informada / The cardiovascular diseases become up main causes of mortality and obesity in the world. Despite of several preventive measures, these are still insufficiently and deathly index due cardiovascular diseases recurrences continue increasing as such in developed countries as development countries. Studies demonstrated significant the association both uric acid levels and inviduals components of metabolic diseases, but the prevalence ambit of metabolic syndrome using recently definitions among hypeuricemic peoples is unknown and many intrinsic factors in both situations remain unclear. The present study evaluated relations among metabolic syndrome and antiinflamatory markers in hyperuricemic individuals. It have been 499 peoples attended in the Clincal Analyses laboratory of Getulio Vargas University Hospital in Manaus – Amazonas – Brazil, with range age 15-45, above sexs, were grouped into four groups : 1 Control (n=75) 2 Pre - Metabolic Syndrome (n=226) 3.Metabolic Síndrome (129) 4.Hyperuricemic (n=68). For the evaluation of oxidative stress levels of total thiols , total antioxidant capacity , total capacity oxidant , glutathione peroxidase and malondialdehyde were measured. For the evaluation of the inflammatory process parameters C-reative protein, alpha 1- glycoprotein , ferritin , tryptophan and kynurenine were evaluated . In this study, metabolic syndrome was estimated at 34 % and the obesity range was 28 % . Biochemical markers showed statistical differences between the groups, being higher in hyperuricemic subjects with metabolic syndrome than in the control group and metabolic síndorme isolated . The hyperuricemic participants with metabolic syndrome had the following changes compared to the control group: increased inflammatory marker ( kynurenine ) and antioxidant ( glutathione peroxidase ) decreased. Regarding the group with metabolic syndrome only, these parameters were less pronounced . No statistical difference between groups of malondialdehyde was observed. Correlation analysis showed that high levels of kynurenine was positively related to waist, glucose and ferritin in patients with metabolic syndrome who were not found in the control group Thus, hyperuricemic subjects with metabolic syndrome may have a higher inflammation status and a higher level of oxidative stress. A higher inflammation status was correlated with decrease in the levels of antioxidant enzymes and increase in risk metabolic syndrome .Therefore, these results suggest that kynurenine and glutathione peroxidase can be used as a biomarker for cardiovascular disease in patients hyperuricemic with metabolic syndrome . / A doença cardiovascular se tornou a principal causa de mortalidade e morbidade no mundo. Apesar de várias medidas preventivas estas ainda são insuficientes e índices de mortes em decorrência de doenças cardiovasculares continuam aumentando tanto em países desenvolvidos como em desenvolvimento. Estudos mostram significante associação entre níveis de ácido úrico e componentes individuais da síndrome metabólica, mas o âmbito da prevalência da síndrome metabólica usando recentes definições entre individuos com hiperuricemia é desconhecida e vários fatores intrínsecos a ambas as situações permanecem obscuras. O presente estudo avaliou marcadores bioquímicos da síndrome metabólica em indivíduos hiperuricêmicos. Foram avaliados 499 indivíduos atendidos no Laboratório de Análises Clinicas do Hospital Universitário Getúlio Vargas em Manaus-Amazonas, com idade de 18 a 45 anos, de ambos os sexos, agrupados em quatro grupos: 1. Controle (n=75 ) 2. Pré-síndrome (n=226 ) 3.Síndrome Metabólica (n=129 ) 4.Hiperuricêmicos (n=68 ). Para a avaliação do estresse oxidativo foram dosados os níveis de tióis totais, capacidade antioxidante total, capacidade oxidante total, glutationa peroxidase e dosagem de malondialdeído. Para a avaliação do processo inflamatório foram avaliados os parâmetros da proteína C reativa ultra-sensível, alfa 1-glicoproteina, ferritina, triptofano e quinurenina. A síndrome metabólica foi observada em 34% da população estudada e a obesidade em 28% destes. Os marcadores bioquímicos apresentaram diferenças estatísticas entre os grupos, sendo maior nos indivíduos hiperuricêmicos com síndrome metabólica do que no grupo controle ou com síndrome metabólica isoladamente. Os participantes hiperuricêmicos com síndrome metabólica apresentaram as seguintes alterações em relação ao grupo controle: níveis de quinurenina aumentada e atividade de glutationa peroxidase diminuída. Com relação ao grupo com apenas síndrome metabólica, esses parâmetros foram menos acentuados. Não foi observada diferença estatística no malondialdeído entre os grupos. A análise de correlação mostrou que níveis elevados de quinurenina foi positivamente relacionados com a cintura, glicemia e ferritina nos pacientes com síndrome metabólica e que não foram encontrados no grupo controle. Desta maneira, indivíduos hiperuricêmicos com síndrome metabólica apresentaram níveis mais elevados marcadores da inflamação e de estresse oxidativo. O processo inflamatório foi correlacionado com a diminuição nos níveis de enzimas antioxidantes e um aumento no risco de síndrome metabólica. Assim, esses resultados sugerem que a quinurenina e a glutationa peroxidase podem ser utilizados como um biomarcador para doenças cardiovasculares em pacientes hiperuricêmicos com síndrome metabólica.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-14T12:00:52Z No. of bitstreams: 1 ritamariarodriguesbastos.pdf: 8856213 bytes, checksum: 6dee07487561f1bf58dac658cd89ca60 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-06-26T20:27:15Z (GMT) No. of bitstreams: 1 ritamariarodriguesbastos.pdf: 8856213 bytes, checksum: 6dee07487561f1bf58dac658cd89ca60 (MD5) / Made available in DSpace on 2017-06-26T20:27:15Z (GMT). No. of bitstreams: 1 ritamariarodriguesbastos.pdf: 8856213 bytes, checksum: 6dee07487561f1bf58dac658cd89ca60 (MD5) Previous issue date: 2007-09-03 / A Doença Renal Crônica (DRC) é considerada hoje um problema mundial de saúde pública. Estudos que estimem a prevalência da epidemia, além de fornecerem um importante indicador epidemiológico, respaldam a elaboração de estratégias para a detecção de casos novos. No Brasil, a literatura é escassa e os métodos utilizados não contemplam os critérios diagnósticos sugeridos nas Diretrizes Brasileiras para a DRC. O presente trabalho teve como objetivos estimar a prevalência da DRC, utilizando registros de indivíduos submetidos a exames laboratoriais por causas diversas em laboratório da rede particular do município de Juiz de Fora, MG, durante os anos de 2004 e 2005, analisar a freqüência de detecção da doença entre as especialidades médicas e investigar o papel do ácido úrico como marcador de risco da doença renal. Realizou-se um estudo transversal para o reconhecimento da prevalência da DRC e, posteriormente, um desenho longitudinal não concorrente visando estimar a associação entre a presença de hiperuricemia prévia e a DRC. A detecção da doença foi consubstanciada pelo cálculo estimado da filtração glomerular utilizando-se a equação do estudo MDRD (Modification of Diet in Renal Disease) e seguiu os critérios propostos pelo K/D0Q1 (Kidney Disease Outcomes Quality Initiatíve) para o diagnóstico e classificação. Encontramos uma prevalência de 9,6% da DRC, sendo 12,2% no sexo feminino, 5,8% no masculino, 25,2% entre os indivíduos com idade acima de 60 anos e 3,7% abaixo de 60 anos. Indivíduos com hiperuricemia apresentaram o dobro do risco de desenvolvimento da DRC quando comparados aos não portadores de hiperuricemia. Quanto às especialidades, observamos na Cardiologia uma maior potencialidade de detecção dos casos. Os resultados do presente estudo demonstram um aspecto operacional alternativo para otimizar a capacidade de detecção dos casos e fornece subsídios para estudos dos fatores relacionados à doença renal. / Chronic kidney disease (CKD) is considered a problem of public health worldwide. Studies of prevalence of the disease are important to measure the disease burden on a population and are extremely valuable to determine public health policies. In Brazil, the date on the epidemiology of CKD are scarce, and those available are not in accordance with the guidelines of the Brazilian Society of Nephrology. In the present study we aimed to establish the prevalence of CKD in the adult population of Juiz de Fora, Minas Gerais, in the years of 2004 and 2005, using a laboratory database available in a private laboratory, analyze the frequency of detection of the disease among the medical specialties, and determine whether uric acid is risk factor for the development of the disease. A transversal study was done to recognize the prevalence of CKD, which was followed by a non concurrent longitudinal design to determine the association between hyperuricemia and CKD. Glomerular filtration rate was determined from the serum creatinine by the MDRD formula, and the disease was diagnosed and staged as recommended by the KDOQI of National Kidney Foundation and the Brazilian Society of Nephrology. The prevalence of CKD stage 3, 4 and 5 as a whole was 9.6%, being 12.2%, 5.8%, 25.2% and 3.7% among women, men, people >60 and 60 years, respectively. Compared to people with normouricemia, those with hyperuricemia had a two fold risk for developing CKD. Regarding to the medical specialties, we found that the majority of patients with CKD the creatinine was ordered by cardiologists. In conclusion: Our results present an alternative operational strategy to identify cases of CKD, confirms that cardiologists have the highest potenciality to identify the disease, and offer subsidies for studies of related factors.

1 ABSTRACT Lorencová Š.: Nutraceuticals: possibilities in decreasing of hyperuricemia and alleviating gout. Diploma thesis, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmaceutical Botany and Ecology, Hradec Kralove 2020, 82 p. This research work was conducted on the basis of literature analysis, reviewing papers mainly from international but also domestic journals. The review describes pathophysiology of gout and discusses options to mitigate the disease with the aid of dietary supplements. This work presents symptoms and a clinical picture of the disease as well as its origin and risk factors, pathological processes leading to the development of the disease, and a short overview of current pharmacotherapy. Furthermore this work summarises natural substances including plant extracts that may be utilised in the prevention and support of gout treatment. In particular, these include vitamins, unsaturated fatty acids, polyphenols and peptides. This work also describes plants used in the traditional treatment of gout and gives a brief overview of natural substances including plant extracts contained in food supplements that are available on the market in Czech Republic. This work also describes the role of purines, fructose, alcoholic drinks and tomatoes in triggering...

There are localised proteins (so-called urate transporters) in the renal proximal tubules and in the intestine, which excrete and reabsorb uric acid. Polymorphisms in the genes coding these proteins can result in the disruption of the transport function and development of hyperuricemia and gout. However the serum level of uric acid is also determined by other factors which include the intake of exogenous purines in food, synthesis of endogenous purines and degradation of nucleic acids, but also certain conditions. In 250 patients with primary hyperuricemia and gout we used Sanger sequencing to analyse the exons and adjacent intron regions in ten genes coding urate transporters: ABCG2, ABCC4, SLC2A9, SLC22A12, SLC22A11, SLC22A13, SLC17A1, SLC17A3, SLC22A6 and SLC22A8. We examined a possible connection between the identified genetic variants and primary hyperuricemia and gout based on a comparison of allele frequencies with the European population, according to topological models, according to programs predicting the functional impacts of variants and searches in specialised literature. We also took into account the conclusions of functional studies analysing the impact of nonsynonymous variants in the ABCG2 and SLC2A9 genes. We also focused on the effect of the concomitant occurrence of several...