O objetivo deste estudo foi determinar se a variação genética no gene do receptor P2X7 está associada com a diminuição da densidade mineral óssea e o risco de osteoporose em pacientes acima de 50 anos de idade com fratura de tornozelo. Foi realizado um estudo diagnóstico Nível I. Os pacientes acima de 50 anos com fratura de tornozelo submetidos ao tratamento cirúrgico foram divididos em dois grupos após o resultado da densitometria óssea: o grupo de estudo com osteopenia (T score entre -1 e -2,5) ou osteoporose (T score <= -2,5) e o grupo controle com valores de normalidade (com T score >= -1). Os critérios de exclusão foram alterações que levam à osteoporose secundária. Os pacientes foram genotipados para 15 polimorfismos de nucleotídeo único (SNPs) não sinônimos dentro do receptor P2X7 (numerados de 1 à 15) obtidos a partir da saliva. Avaliamos 121 pacientes com fratura de tornozelo, sendo 56 do grupo controle e 65 do grupo de estudo. Todos os pacientes eram sedentários, não utilizavam nenhum medicamento para tratamento de osteoporose, não eram tabagistas e sofreram trauma de baixa energia. A análise agrupada das alterações dos SNPs demonstrou que se o gene tem 3 ou mais variantes de SNPs (36,4% dos 121 pacientes), dos 15 possíveis, ele está alterado com repercussão clínica relacionada à perda ou ganho de função do gene. E ao analisar as alterações dos SNPs, individualmente, os resultados sugerem que: os SNPs 1,4,14 e 15 são variantes de perda de função; SNPs 5 e 10 são descritos como variantes de perda de função; entretanto, não têm influência na nossa população; SNPs 11 e 13 são variantes de perda de função e não ganho de função, como descrito na literatura; e SNP 12 foi associado à perda de função em nossa população. Podemos ressaltar como limitações do nosso estudo o fato de nos concentramos principalmente em polimorfismos não sinônimos que não cobrem toda a variação genética em P2X7 e no número pequeno de participantes quando comparados com a literatura mundial. Em contrapartida, um dos pontos fortes do nosso estudo é ser o primeiro a avaliar o P2X7 na população brasileira, que é bastante heterogênea do ponto de vista genético devido à nossa miscigenação, quando comparado com os outros estudos que avaliaram a população do norte da Europa, que é mais homogênea geneticamente. Em conclusão, o polimorfismo do SNP 12 em P2X7 está associado à densidade mineral óssea e risco de fraturas de tornozelo / The purpose of this study was to determine whether a genetic variation in the P2X7 receptor gene is associated with reduced bone mineral density and the risk of osteoporosis in patients over 50 years of age with ankle fractures. A Level-1 diagnostic study was conducted. Patients over 50 years of age with ankle fractures who had undergone surgical treatment were divided into two groups following the result of a bone densitometry: a study group with osteopenia (bone mineral density T score between -1 and -2.5) or osteoporosis (bone mineral density T score <= -2.5) and the control group with normal values (bone mineral density T score >= -1). Exclusion criteria were alterations that led to secondary osteoporosis. Patients were genotyped for 15 nonsynonymous single nucleotide polymorphisms (SNPs) within the P2X7 receptor (numbered from 1 to 15) obtained from saliva. We evaluated 121 patients with ankle fractures, 56 being from the control group, and 65 from the study group. All patients were sedentary, did not take any medication for the treatment of osteoporosis, did not smoke, and had suffered a low-impact trauma. The grouped assessment of the SNP alterations showed that if a gene has three or more SNP variants (36.4% of the 121 patients), out of the 15 possibilities, it is altered with clinical repercussions related to the loss or gain of the function of the gene. In evaluating the SNP alterations individually, the results suggest that: SNPs 1,4,14, and 15 are loss of function variants; SNPs 5 and 10 are described as loss of function variants; however, they have no influence on our study population; SNPs 11 and 13 are loss of function variants and not gain of function function as is described in the literature; and SNP 12 was associated with a loss of function in our population. In conclusion, we showed that the functional polymorphisms in P2X7 are associated with Bone Mineral Density and the risk of ankle fractures. As limitations to our study, we can point out the fact that we focused mainly on nonsynonymous polymorphisms, which do not cover all the genetic variations in P2X7, and the small number of participants when compared to the world literature. On the other hand, a strength of our study is that it was the first to assess P2X7 in the Brazilian population, which is quite heterogeneous from the genetic point of view due to our miscegenation, as compared to other studies that evaluated the population of northern Europe, which is genetically more homogeneous. In conclusion, the SNP12 polymorphism in P2X7 is associated with Bone Mineral Density and the risk of ankle fractures

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No. of bitstreams: 1 juliocesarmoraeslovisi.pdf: 3660990 bytes, checksum: 9bfd65df440e1a934d906a3918e427d5 (MD5) Previous issue date: 2013-09-09 / INTRODUÇÃO: A epidemia de obesidade e de síndrome metabólica (SM) observada nos últimos anos se associa a uma série de agravos clínicos como neoplasias, diabetes mellitus e doenças cardiovasculares, notadamente a hipertensão arterial (HA). Diversos mecanismos etiopatogênicos têm sido descritos na HA associada à SM entre os quais citam-se a participação da aldosterona (ALDO) e da disfunção endotelial. OBJETIVOS: avaliar os efeitos do bloqueio do receptor mineralocorticoide (RMC) na função endotelial, na pressão arterial (PA) e em parâmetros inflamatórios e renais de indivíduos com SM. PACIENTES E MÉTODOS: Foram selecionados 42 pacientes elegíveis para o protocolo. Todos os voluntários foram submetidos a exame clínico, avaliação laboratorial com dosagens de mediadores inflamatórios e de excreção urinária de albumina, além de avaliação cardiológica, com monitorização ambulatorial da pressão arterial (MAPA), ecocardiograma e estudo da vasodilatação fluxo-mediada (VDFM), antes e após o tratamento. Destes, 28 indivíduos foram tratados com espironolactona (ESPIRO) na dose de 25-50 mg/dia e 14 com amlodipina (AMLO) na dose 5-10 mg/dia por 16 semanas (Resultados 1). Após essa avaliação, com objetivo de homogeneizar os grupos para melhor comparação dos parâmetros de VDFM, inflamatórios e renais, foram selecionados 27 indivíduos alocados em dois grupos por meio da aplicação da técnica do Propensity Score (PS). Deste modo foram constituídos dois grupos homogêneos, a saber: 16 pacientes em um grupo tratado com ESPIRO e 11 no grupo controle, tratados com AMLO, por um período de 16 semanas (Resultados 2). Resultados 1: Os dados iniciais mostraram que o tratamento da HA com ESPIRO e com AMLO resultou em redução significante da PA em ambos os grupos. No grupo ESPIRO foi observado aumento da VDFM, enquanto no grupo AMLO houve redução significativa desse parâmetro. Observamos ainda redução significativa da microalbuminúria e de mediadores inflamatórios no grupo ESPIRO, o que não ocorreu no grupo AMLO. Finalmente, observou- se aumento significativo do colesterol HDL no grupo ESPIRO o que não foi observado no grupo AMLO. Resultados 2: com a aplicação do PS e consequente maior homogeneidade entre os grupos houve a confirmação desses achados nos 2 grupos (ESPIRO e AMLO) e, adicionalmente, permitiu a subdivisão destes em inflamados (PCR>3,0 mg/dL) e não inflamados (PCR < 3,0 mg/dL). Quando se avaliaram a VDFM, o comportamento pressórico e de parâmetros metabólicos e renais observou-se aumento da VDFM, maior redução da PA, aumento do colesterol HDL e redução da albuminúria que foram significativas no grupo ESPIRO, notadamente no subgrupo não inflamado em comparação ao grupo inflamado. CONCLUSÃO: O bloqueio dos RMC em hipertensos com SM melhorou a função endotelial e reduziu a pressão arterial, com impacto favorável sobre marcadores metabólicos, inflamatórios e na excreção urinária de albumina. Estes achados apontam para efeitos benéficos adicionais à redução pressórica em pacientes portadores de SM tratados com bloqueadores dos RMC. / INTRODUCTION: The epidemic of obesity and metabolic syndrome (MS) described in recent years is associated with a series of clinical conditions such as malignancy, diabetes mellitus, and cardiovascular diseases, chiefly systemic arterial hypertension (AH). There are several mechanisms proposed to explain the development of MS-associated AH, among which the role of aldosterone and endothelial dysfunction are noteworthy. OBJECTIVES: assess the effects of mineralocorticoid receptor blockade (MRB) on endothelial function, blood pressure (BP) and inflammatory and renal parameters of individuals with the MS. PATIENTS AND METHODS: Forty-two eligible patients were selected. All volunteers underwent clinical examination, laboratory determination of inflammatory mediators and urinary albumin excretion, and cardiologic examination with 24-hour ambulatory blood pressure (24-h ABPM), echocardiography and assessment of the flow-mediated vasodilation (FMD) at baseline and after treatment. Twenty-eight individuals received spironolactone (SPIRO), 25-50mg/day, and 14 individuals received amlodipine (AMLO), 5-10mg/day, for 16 weeks (Results 1). In order to homogenize the groups and better compare the FMD and the inflammatory and renal parameters, 27 individuals were selected and allocated to two groups according to the propensity score (PS) technique: 16 individuals treated with SPIRO and 11 controls, treated with AMLO, for 16 weeks (Results 2). Results 1: Both SPIRO-treated and AMLO-treated groups had significant BP reductions. While the SPIRO-treated group had increased FMD, the AMLO-treated group had a significant reduction of this parameter. There was also a significant reduction of microalbuminuria and inflammatory mediators in the SPIRO-treated group, but not in the AMLO one. There was a significant increase of HDL-cholesterol in the SPIRO group, but not in the AMLO one. Results 2: With the PS technique, and consequent better homogenization of the groups, we confirmed these findings in the two groups (SPIRO and AMLO) and further subdivided them into those with inflammation (CRP>3.0mg/dl) and those without inflammation (CRP<3.0mg/dl). There were significantly increased FMV, greater BP reduction, increased HDL-cholesterol, and significant reduction of albuminuria in the SPIRO group, notably in the subgroup without inflammation, as compared with that with inflammation. CONCLUSION: MRB in hypertensive subjects with the MS improved endothelial function and reduced blood pressure, with a favorable impact on metabolic and inflammatory markers and on the urinary albumin excretion. These findings point to MRB as a new option for treatment of AH in individuals with the MS.

Le système rénine-angiotensine-aldostérone est impliqué dans la physiopathologie de l’insuffisance cardiaque (IC). L’inhibition de l’aldostérone par les antagonistes du récepteur aux minéralocorticoïdes (ARM), la spironolactone et l’éplérénone, est associée à une réduction de morbidité et mortalité. Or, la spironolactone est un antagoniste non sélectif, avec des effets hors-cibles sur d’autres récepteurs stéroïdiens. Des données suggèrent qu’elle pourrait avoir un effet défavorable sur l’homéostasie du glucose, avec une augmentation en hémoglobine glyquée (HbA1c), un marqueur de contrôle du glucose à long terme. Au contraire, l’éplérénone semble exercer un effet neutre. Les objectifs de cette thèse de doctorat sont les suivants : 1) Assembler toutes les connaissances dans la littérature au sujet de l’effet glycémique des ARM; 2) Évaluer le risque de développement de diabète avec la spironolactone chez les patients IC; 3) Analyser si la spironolactone peut moduler l’effet glycémique d’autres médicaments utilisés en IC; 4) Comparer la spironolactone à l’éplérénone sur des marqueurs de glucose chez les patients IC avec dérèglements glycémiques. Quatre projets ont été effectués afin de répondre à ces questions. Premièrement, une revue systématique a permis d’identifier toutes les études publiées contenant de l’information sur l’effet glycémique des ARM. Les résultats étaient hétérogènes, mais ont suggéré que l’effet est dépendant de la pathologie et serait potentiellement néfaste dans les maladies à haut risque d’évènements cardiovasculaires. Une méta-analyse d’études en diabète indique que l’effet à long terme serait non significatif. Le deuxième projet utilise une cohorte de patients IC de bases de données administratives entre 1995 et 2009 (suivi jusqu’en 2010). Nous n’avons pas détecté d’association significative entre l’utilisation de la spironolactone et le risque de diabète. Par contre, l’étude a démontré qu’un âge plus jeune, la digoxine, et les corticostéroïdes augmentent le risque de diabète. Le troisième projet est une sous-étude d’une étude clinique CANDIID-II (Effect of ACE inhibitor alone versus ACE inhibitor plus high dose candesartan on BNP, immune markers, inflammatory status, and urinary kinins in patients with symptomatic left ventricular systolic dysfunction) chez des patients IC traités avec un inhibiteur de l’enzyme de conversion à l’angiotensine et le candésartan, antagoniste du récepteur à l’angiotensine II. Ces classes pharmacologiques ont des effets bénéfiques sur la glycémie. En comparant les patients traités aussi avec la spironolactone versus les patients sans ARM, nous n’avons pas trouvé que la spironolactone module l’effet bénéfique du candésartan sur le métabolisme du glucose. Le dernier projet consiste d’une étude prospective, multicentrique, randomisée, contrôlée à double-insu : SNOW (A comparison of the effects of selective and non selective mineralocorticoid antagonism on glucose homeostasis and lipid profile of heart failure patients with glucose intolerance or type 2 diabetes). Elle compare, pendant 16 semaines, la spironolactone à l’éplérénone sur des marqueurs glycémiques, notamment, l’HbA1c, chez 62 patients IC avec diabète de type II ou intolérance au glucose. Aucune différence significative n’a été observée entre les groupes. En résumé, les résultats de cette thèse indiquent que les ARM ne présentent pas de risque de détérioration du contrôle du glucose sur une durée modérée à longue en IC. / The renin-angiotensin-aldosterone system is involved in the pathophysiology of heart failure (HF). The inhibition of aldosterone by mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, is associated with a reduction in morbidity and mortality. However, spironolactone is a non selective antagonist, with off-target effects on other steroid receptors. There is some evidence suggesting that it may have an unfavorable effect on glucose homeostasis, with an increase in glycated hemoglobin (HbA1c), a marker of long-term glucose control. On the contrary, eplerenone seems to exert a neutral effect. The objectives of this doctoral thesis were the following: 1) Compile all current knowledge in the literature on the subject of MRAs’ glycemic effects; 2) Evaluate the risk of developing diabetes with spironolactone in HF patients; 3) Analyze if spironolactone may modulate the glycemic effects of other medications used in HF; 4) Compare spironolactone to eplerenone on markers of glucose control in HF patients with glycemic disorders. Four projects were conducted in order to meet these objectives. Firstly, a systematic review allowed us to identify all published studies containing information on MRAs’ glycemic effects. The literature search yielded heterogenous results; however, it suggested that the effect was disease-specific and would be potentially harmful in diseases with a high risk of cardiovascular events. A meta-analysis of studies in diabetes insinuated that the effect is non significant on a long-term basis. The second project uses a cohort of HF patients from administrative databases between 1995 and 2009 (follow-up till 2010). We did not detect a significant association between the use of spironolactone and the risk of diabetes. On the other hand, the study demonstrated that younger age, digoxin, and corticosteroids increase the risk of diabetes. The third project is a substudy of a clinical trial CANDIID-II (Effect of ACE inhibitor alone versus ACE inhibitor plus high dose candesartan on BNP, immune markers, inflammatory status, and urinary kinins in patients with symptomatic left ventricular systolic dysfunction) among HF patients treated with an angiotensin converting enzyme inhibitor and candesartan, an angiotensin II receptor blocker. These pharmacological classes have beneficial effects on glycemia. By comparing patients also treated with spironolactone versus patients without an MRA, we did not find that spironolactone alters the effect of candesartan on glucose metabolism. The last project consisted of a prospective, multicenter, randomized, controlled, double-blind trial: SNOW (A comparison of the effects of selective and non selective mineralocorticoid antagonism on glucose homeostasis and lipid profile of heart failure patients with glucose intolerance or type 2 diabetes). It compares, for 16 weeks, spironolactone to eplerenone on glycemic markers, notably, HbA1c, among 62 HF patients with type II diabetes or glucose intolerance. There was no significant difference between groups. In summary, the research results from this thesis reveal that, in HF, MRAs do not present additional risks of deterioration in glucose control over a moderate to long period.

Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2008.

Acid-related disorders are common, chronic conditions that have considerable impact on a patient's quality of life. In a study conducted by Majumdar et al. (2003:2411) the prevalence of chronic acid-related disorders was 2.3%. Acid-related disorders represent a major financial consideration with respect to the costs of drug prescribing (Whitaker, 1998:6). Health care cost increases each year. This leads to an increased interest in economic evaluation of health care and medical technologies (Anell & Svarvar, 2000:175). Health care providers no longer make treatment decisions independent of the consideration of the resultant cost. The treatment provided must not only provide value but the value must be documented to justify spending money. Economic evaluation research has emerged to offer guidance to policy makers, practitioners, health plans and institutions facing difficult treatment and coverage decisions (Ellis era/., 2002:271). The main objectives of this study were to investigate the prescribing patterns and cost of acid reducing medicine with special reference to proton pump inhibitors and histamine-2 receptor antagonists in a section of the private health care sector of South Africa from 2001 to 2006. A longitudinal retrospective drug utilisation study was done on acid reducing medicine items claimed through a national medicine claims database. The five study years were 2001, 2002, 2004, 2005 and 2006. All the study years stretched from 1 January to 31 December. It was determined that acid reducing medicine items prescribed decreased from 2.74% during 2001 to 2.50% during 2006 of all medicine items claimed. The same decreasing trend was observed regarding the cost of acid reducing medicine items. The cost percentage decreased from 4.89% (2001) to 3.72% (2006). However, the average cost per medicine item for the acid reducers increased by 5.35% from 2001 (R230.04 ± 176.29) to 2002 (R243.72 ± 184.18) and then decreased by 15.23% from 2002 to 2004. It again decreased with 15.05% from 2004 (R206.19 ± 179.42) to 2006 (R175.70 ± 172.55). The changes in the average cost of acid reducers were of no practical significance. Proton pump inhibitors represented about half of the acid reducing medicine items prescribed and more than 70% of the total cost of acid reducing medicine items during the study years. The average cost of PPIs revealed a practical significant decrease (d > 0.8) from 2002 (R372.42 ± 156.62) to 2006 (R241.56 ± 177.21). H2RAs contributed between 15.00% and 18.26% of all acid reducing medicine items while contributing to between 9.68% and 16.85% of the total cost of all acid reducers. The active ingredient most often prescribed was lansoprazole during 2001 and 2002, esomeprazole during 2004 and omeprazole during 2005 and 2006. Lanzor® 30mg was the acid reducer with the highest cost from 2001 to 2005, while Pariet® 20mg took the lead in 2006. Zantac® 150mg effervescent tablets were the H2RA, with the highest cost, during the five study years. The percentage innovator items decreased by 4.50% from 2001 to 2002, increased by 1.01% from 2002 to 2004 and decreased again by 31.06% from 2004 to 2006. The slight increase in the percentage innovator medicine items claimed from 2002 to 2004 may be explained by the introduction of Nexiam® (esomeprazole) into the market in 2002. The total number of generic medicine items claimed contributed between 9.62% (n = R1 788 242.25) in 2001 and 30.75% (n = R3 196 163.34) in 2006 of the total cost of acid reducing medicine items. The average cost per day of innovator medicine items was higher than the average cost per day of generic medicine items. This might be explained by a lower average cost for generic medicine items. It was also determined that the prevalence of the two-drug regimens was the highest during the five study years. The Helicobacter pylori (H.pylori) eradication treatments, which included different antibiotics, increased from 2.72% in 2001 to 5.05% in 2006. The PDD for most of the active ingredients of H2RAs and PPIs remained stable during the study years. However, it appears that the PDDs, of the PPIs, active ingredients were more constant than the PDDs, or the H2RAs, active ingredients. The median of the different PPI active ingredients was reasonably more constant than the median of the different H2RA active ingredients. Thus the changes between the PPIs' and H2RAs' active ingredients might be explained by the variation in the median (the number of days the relevant medicine item was claimed for). It is then also recommended that the aspects of generic substitution as well as the usage of H2RAs as prescribed vs. self medication should be further investigated to increase possible cost savings. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2008.

Acid-related disorders are common, chronic conditions that have considerable impact on a patient's quality of life. In a study conducted by Majumdar et al. (2003:2411) the prevalence of chronic acid-related disorders was 2.3%. Acid-related disorders represent a major financial consideration with respect to the costs of drug prescribing (Whitaker, 1998:6). Health care cost increases each year. This leads to an increased interest in economic evaluation of health care and medical technologies (Anell & Svarvar, 2000:175). Health care providers no longer make treatment decisions independent of the consideration of the resultant cost. The treatment provided must not only provide value but the value must be documented to justify spending money. Economic evaluation research has emerged to offer guidance to policy makers, practitioners, health plans and institutions facing difficult treatment and coverage decisions (Ellis era/., 2002:271). The main objectives of this study were to investigate the prescribing patterns and cost of acid reducing medicine with special reference to proton pump inhibitors and histamine-2 receptor antagonists in a section of the private health care sector of South Africa from 2001 to 2006. A longitudinal retrospective drug utilisation study was done on acid reducing medicine items claimed through a national medicine claims database. The five study years were 2001, 2002, 2004, 2005 and 2006. All the study years stretched from 1 January to 31 December. It was determined that acid reducing medicine items prescribed decreased from 2.74% during 2001 to 2.50% during 2006 of all medicine items claimed. The same decreasing trend was observed regarding the cost of acid reducing medicine items. The cost percentage decreased from 4.89% (2001) to 3.72% (2006). However, the average cost per medicine item for the acid reducers increased by 5.35% from 2001 (R230.04 ± 176.29) to 2002 (R243.72 ± 184.18) and then decreased by 15.23% from 2002 to 2004. It again decreased with 15.05% from 2004 (R206.19 ± 179.42) to 2006 (R175.70 ± 172.55). The changes in the average cost of acid reducers were of no practical significance. Proton pump inhibitors represented about half of the acid reducing medicine items prescribed and more than 70% of the total cost of acid reducing medicine items during the study years. The average cost of PPIs revealed a practical significant decrease (d > 0.8) from 2002 (R372.42 ± 156.62) to 2006 (R241.56 ± 177.21). H2RAs contributed between 15.00% and 18.26% of all acid reducing medicine items while contributing to between 9.68% and 16.85% of the total cost of all acid reducers. The active ingredient most often prescribed was lansoprazole during 2001 and 2002, esomeprazole during 2004 and omeprazole during 2005 and 2006. Lanzor® 30mg was the acid reducer with the highest cost from 2001 to 2005, while Pariet® 20mg took the lead in 2006. Zantac® 150mg effervescent tablets were the H2RA, with the highest cost, during the five study years. The percentage innovator items decreased by 4.50% from 2001 to 2002, increased by 1.01% from 2002 to 2004 and decreased again by 31.06% from 2004 to 2006. The slight increase in the percentage innovator medicine items claimed from 2002 to 2004 may be explained by the introduction of Nexiam® (esomeprazole) into the market in 2002. The total number of generic medicine items claimed contributed between 9.62% (n = R1 788 242.25) in 2001 and 30.75% (n = R3 196 163.34) in 2006 of the total cost of acid reducing medicine items. The average cost per day of innovator medicine items was higher than the average cost per day of generic medicine items. This might be explained by a lower average cost for generic medicine items. It was also determined that the prevalence of the two-drug regimens was the highest during the five study years. The Helicobacter pylori (H.pylori) eradication treatments, which included different antibiotics, increased from 2.72% in 2001 to 5.05% in 2006. The PDD for most of the active ingredients of H2RAs and PPIs remained stable during the study years. However, it appears that the PDDs, of the PPIs, active ingredients were more constant than the PDDs, or the H2RAs, active ingredients. The median of the different PPI active ingredients was reasonably more constant than the median of the different H2RA active ingredients. Thus the changes between the PPIs' and H2RAs' active ingredients might be explained by the variation in the median (the number of days the relevant medicine item was claimed for). It is then also recommended that the aspects of generic substitution as well as the usage of H2RAs as prescribed vs. self medication should be further investigated to increase possible cost savings. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2008.