Phytosterol supplementation in the treatment of dyslipidemia in children and adolescents: a systematic review / Suplementação de fitoesteróis no tratamento da dislipidemia em crianças e adolescentes: uma revisão sistemática

ABSTRACT Objective: To carry out a systematic review on the effects of phytosterol supplementation on the treatment of dyslipidemia in children and adolescents. Data sources: Review in the SciELO, Lilacs, Bireme, PubMed and Web of Science databases, with no time limit. Descriptors: phytosterols or plant sterols and dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, in English and Portuguese. The articles included were published in Portuguese, English or Spanish and evaluated the effect of phytosterol supplementation in pediatric patients with dyslipidemia. Documents that involved adults or animals, review papers, case studies and abstracts were excluded. Two authors performed independent extraction of articles. Of 113 abstracts, 19 were read in full and 12 were used in this manuscript. Data synthesis: Phytosterol supplementation to reduce cholesterol levels has been shown to be effective in reducing LDL-cholesterol levels by approximately 10%, with reductions above 10% in LDL-cholesterol levels observed after 8 to 12 weeks of intervention. Studies have not shown significant changes in HDL-cholesterol and triglyceride levels. Based on the absence of adverse effects, its use seems to be safe and of good tolerance in children and adolescents. Conclusions: Phytosterol supplementation seems to be of great therapeutic aid for the treatment of hypercholesterolemia in children and adolescents. Further studies assessing the long-term effect of phytosterol supplementation are necessary.

RESUMO Objetivo: Realizar uma revisão sistemática sobre os efeitos da suplementação de fitoesteróis no tratamento da dislipidemia em crianças e adolescentes. Fontes de dados: Revisão nos bancos SciELO, Lilacs, Bireme, Pubmed e Web of Science, sem limite de tempo. Descritores: phytosterols or plant sterols, dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, nas línguas inglesa e portuguesa. Os artigos incluídos foram publicados nos idiomas português, inglês ou espanhol e avaliaram o efeito da suplementação de fitoesteróis em pacientes pediátricos com dislipidemia. Estudos que envolviam adultos ou animais, trabalhos de revisão, estudos de caso e resumos foram excluídos. A extração independente de artigos foi realizada por dois autores. Do total de 113 resumos, 19 foram lidos na íntegra, e 12 utilizados neste manuscrito. Síntese de dados: A suplementação de fitoesteróis para a redução dos níveis de colesterol mostrou-se eficiente, de forma a promover a redução de aproximadamente 10% dos níveis de LDL-colesterol, sendo observadas reduções acima de 10% em 8 a 12 semanas de intervenção. Os estudos não mostraram alterações significantes nos níveis de HDL-colesterol e triglicérides. Com base na ausência de efeitos adversos, seu uso parece ser seguro e de boa tolerância em crianças e adolescentes. Conclusões: A suplementação com fitoesteróis parece ser de grande auxílio terapêutico para o tratamento da hipercolesterolemia em crianças e adolescentes. São necessários mais estudos que avaliem o efeito em longo prazo da suplementação de fitoesteróis.

CHILD syndrome: successful treatment of skin lesions with topical lovastatin and cholesterol lotion

Abstract: CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects) is a rare X-linked dominant disease. The authors report a 2-month-old patient presenting with typical features of CHILD syndrome that was treated with a topical solution containing cholesterol and lovastatin, with complete clearance of her CHILD nevus. The changes in skin lipid metabolism that explain the CHILD ichthyosiform nevus and their correction through topical application of cholesterol and lovastatin are discussed.

Statin Treatments And Dosages In Children With Familial Hypercholesterolemia: Meta-Analysis / Tratamentos e Dosagens de Estatinas em Crianças com Hipercolesterolemia Familiar: Uma Meta-Análise

Abstract Background: Children with familial hypercholesterolemia may develop early endothelial damage leading to a high risk for the development of cardiovascular disease (CVD). Statins have been shown to be effective in lowering LDL cholesterol levels and cardiovascular events in adults. The effect of statin treatment in the pediatric population is not clearly demonstrated. Objective: To systematically review the literature to evaluate the effects of different statins and dosages in total cholesterol levels in children and adolescents with familial hypercholesterolemia. We also aimed to evaluate statin safety in this group. Methods: PubMed, EMBASE, Bireme, Web of Science, Cochrane Library, SciELO and LILACS databases, were searched for articles published from inception until February 2016. Two independent reviewers performed the quality assessment of the included studies. We performed a meta-analysis with random effects and inverse variance, and subgroup analyses were performed. Results: Ten trials involving a total of 1543 patients met the inclusion criteria. Our study showed reductions in cholesterol levels according to the intensity of statin doses (high, intermediate and low): (-104.61 mg/dl, -67.60 mg/dl, -56.96 mg/dl) and in the low-density lipoprotein cholesterol level: [-105.03 mg/dl (95% CI -115.76, -94.30), I2 19.2%], [-67.85 mg/dl (95% CI -83.36, -52.35), I2 99.8%], [-58.97 mg/dl (95% CI -67.83, -50.11), I2 93.8%. The duration of statin therapy in the studies ranged from 8 to 104 weeks, precluding conclusions about long-term effects. Conclusion: Statin treatment is efficient in lowering lipids in children with FH. There is need of large, long-term and randomized controlled trials to establish the long-term safety of statins.

Resumo Fundamentos: Crianças com hipercolesterolemia familiar podem desenvolver dano endotelial precoce, aumentando o risco de desenvolver doenças cardiovasculares. As estatinas tiveram sua eficácia em diminuir níveis de colesterol LDL e eventos cardiovasculares em adultos comprovada. O efeito das estatinas na população pediátrica não está claramente demonstrado. Objetivo: Revisar sistematicamente a literatura para avaliar os efeitos e a segurança de diferentes estatinas e suas dosagens nos níveis de colesterol total em crianças e adolescentes com hipercolesterolêmica familiar. Métodos: Artigos publicados desde o início até fevereiro de 2016 foram pesquisados nas bases PubMed, EMBASE, Bireme, Web of Science, Cochrane Library, SciELO e LILACS. Dois revisores independentes avaliaram a qualidade dos estudos incluídos. Realizamos meta-análise com efeitos aleatórios e variância inversa. Análises de subgrupos foram realizadas. Resultados: Dez ensaios envolvendo 1.543 pacientes preencheram os critérios de inclusão. Em nosso estudo, as análises demostraram reduções nos níveis de colesterol, de acordo com a intensidade das doses de estatina (alta, intermediária e baixa): (-104,61 mg/dl, -67,60 mg/dl, -56,96 mg/dl) e no nível de lipoproteínas de baixa densidade: [-105,03 mg/dl (IC95% -115.76, -94.30), I2 19.2%], [-67.85 mg/dl (IC95% -83.36, -52.35), I2 99.8%], [-58.97 mg/dl (IC95% -67.83, -50.11), I2 93,8%. A duração da terapia com estatina variou de 8 a 104 semanas, impedindo conclusões sobre os efeitos a longo prazo. Conclusão: O tratamento com estatinas é eficiente na redução de lipídios em crianças com hipercolesterolemia familiar. É necessário realizar ensaios controlados randomizados de longo prazo para estabelecer a segurança do uso de estatinas a longo prazo.

Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases / Fitosteróis no Tratamento da Hipercolesterolemia e Prevenção de Doenças Cardiovasculares

Abstract Phytosterols are bioactive compounds found in foods of plant origin, which can be divided into plant sterols and plant stanols. Clinical studies consistently indicate that the intake of phytosterols (2 g/day) is associated with a significant reduction (8-10%) in levels of low-density lipoprotein cholesterol (LDL-cholesterol). Thus, several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels. As the typical western diet contains only about 300 mg/day of phytosterols, foods enriched with phytosterols are usually used to achieve the recommended intake. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. This review aims to address the evidence available in the literature on the relationship between phytosterols and risk of cardiovascular disease.

Resumo Os fitosteróis são compostos bioativos encontrados em alimentos de origem vegetal e que podem ser divididos em esteróis vegetais e estanóis vegetais. Estudos clínicos indicam de forma consistente que a ingestão de fitosteróis (2 g/dia) está associada a uma redução significativa (8-10%) de níveis de colesterol da lipoproteína de baixa densidade (LDL-C). Desta forma, diversas diretrizes recomendam a ingestão de 2 g/dia de esteróis e/ou estanóis vegetais com o objetivo de reduzir os níveis de LDL-C. Como uma dieta ocidental típica contém apenas cerca de 300 mg/dia de fitosteróis, normalmente são utilizados alimentos enriquecidos com fitosteróis para alcançar a ingestão recomendada. Apesar dos fitosteróis reduzirem os níveis de LDL-C, não há evidências de que reduzam o risco de doenças cardiovasculares. Pelo contrário, alguns estudos sugerem que a elevação na concentração sérica de fitosteróis possa estar associada com aumento no risco de aterosclerose. Esta revisão tem como objetivo abordar as evidências disponíveis na literatura sobre a relação entre fitosteróis e risco de doenças cardiovasculares.

Soy milk versus simvastatin for preventing atherosclerosis and left ventricle remodeling in LDL receptor knockout mice

Functional food intake has been highlighted as a strategy for the prevention of cardiovascular diseases by reducing risk factors. In this study, we compared the effects of oral treatment with soy milk and simvastatin on dyslipidemia, left ventricle remodeling and atherosclerotic lesion of LDL receptor knockout mice (LDLr-/-) fed a hyperlipidic diet. Forty 3-month old male LDLr-/- mice were distributed into four groups: control group (C), in which animals received standard diet; HL group, in which animals were fed a hyperlipidic diet; HL+SM or HL+S groups, in which animals were submitted to a hyperlipidic diet plus soy milk or simvastatin, respectively. After 60 days, both soy milk and simvastatin treatment prevented dyslipidemia, atherosclerotic lesion progression and left ventricle hypertrophy in LDLr-/- mice. These beneficial effects of soy milk and simvastatin were associated with reduced oxidative stress and inflammatory state in the heart and aorta caused by the hyperlipidic diet. Treatment with soy milk was more effective in preventing HDLc reduction and triacylglycerol and VLDLc increase. On the other hand, simvastatin was more effective in preventing an increase in total cholesterol, LDLc and superoxide production in aorta, as well as CD40L both in aorta and left ventricle of LDLr-/-. In conclusion, our results suggest a cardioprotective effect of soy milk in LDLr-/- mice comparable to the well-known effects of simvastatin.

Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe / Efeito Endotelial da Terapia com Estatina em Alta Dose versus Baixa Dose Associada à Ezetimiba

Abstract Background: The effect of statins on the endothelial function in humans remains under discussion. Particularly, it is still unclear if the improvement in endothelial function is due to a reduction in LDL-cholesterol or to an arterial pleiotropic effect. Objective: To test the hypothesis that modulation of the endothelial function promoted by statins is primarily mediated by the degree of reduction in LDL-cholesterol, independent of the dose of statin administered. Methods: Randomized clinical trial with two groups of lipid-lowering treatment (16 patients/each) and one placebo group (14 patients). The two active groups were designed to promote a similar degree of reduction in LDL-cholesterol: the first used statin at a high dose (80 mg, simvastatin 80 group) and the second used statin at a low dose (10 mg) associated with ezetimibe (10 mg, simvastatin 10/ezetimibe group) to optimize the hypolipidemic effect. The endothelial function was assessed by flow-mediated vasodilation (FMV) before and 8 weeks after treatment. Results: The decrease in LDL-cholesterol was similar between the groups simvastatin 80 and simvastatin 10/ezetimibe (27% ± 31% and 30% ± 29%, respectively, p = 0.75). The simvastatin 80 group presented an increase in FMV from 8.4% ± 4.3% at baseline to 11% ± 4.2% after 8 weeks (p = 0.02). Similarly, the group simvastatin 10/ezetimibe showed improvement in FMV from 7.3% ± 3.9% to 12% ± 4.4% (p = 0.001). The placebo group showed no variation in LDL-cholesterol level or endothelial function. Conclusion: The improvement in endothelial function with statin seems to depend more on a reduction in LDL-cholesterol levels, independent of the dose of statin administered, than on pleiotropic mechanisms.

Resumo Fundamento: O efeito das estatinas na função endotelial em seres humanos permanece em discussão. Particularmente, ainda carece resposta se a melhora na função endotelial deve-se à redução do LDL-colesterol ou a um efeito pleiotrópico arterial. Objetivo: Testar a hipótese de que a modulação da função endotelial promovida por estatinas é prioritariamente mediada pelo grau de redução do LDL-colesterol, independente da dose de estatina utilizada. Métodos: Ensaio clínico randomizado com dois grupos de tratamento hipolipemiante (16 pacientes/cada) e um grupo placebo (14 pacientes). Os dois grupos ativos foram desenhados para promover graus semelhantes de redução de LDL-colesterol: o primeiro utilizou estatina em alta dose (80 mg, grupo sinvastatina 80) e o segundo em baixa dose (10 mg) associada a ezetimiba (10 mg, grupo sinvastatina 10/ezetimiba) para otimizar o efeito hipolipemiante. A função endotelial foi analisada pela vasodilatação mediada por fluxo (VMF) antes e após 8 semanas de tratamento. Resultados: A redução no LDL-colesterol foi semelhante entre os grupos sinvastatina 80 e sinvastatina 10/ezetimiba (27% ± 31% e 30% ± 29%, respectivamente, p = 0,75). O grupo sinvastatina 80 apresentou incremento da VMF de 8,4% ± 4,3% no basal para 11% ± 4,2% após 8 semanas (p = 0,02). Da mesma forma, o grupo sinvastatina 10/ezetimiba apresentou melhora da VMF de 7,3% ± 3,9% para 12% ± 4,4% (p = 0,001). O grupo placebo não apresentou variação no nível de LDL-colesterol ou da função endotelial. Conclusão: A melhora da função endotelial com uso de estatina parece depender mais da redução do LDL-colesterol, independente da dose de estatina utilizada, do que de mecanismos pleiotrópicos.

Effects of single-dose atorvastatin on interleukin-6, interferon gamma, and myocardial no-reflow in a rabbit model of acute myocardial infarction and reperfusion

The mechanisms of statins relieving the no-reflow phenomenon and the effects of single-dose statins on it are not well known. This study sought to investigate the effects of inflammation on the no-reflow phenomenon in a rabbit model of acute myocardial infarction and reperfusion (AMI/R) and to evaluate the effects of single-dose atorvastatin on inflammation and myocardial no-reflow. Twenty-four New Zealand white male rabbits (5-6 months old) were randomized to three groups of eight: a sham-operated group, an AMI/R group, and an atorvastatin-treated group (10 mg/kg). Animals in the latter two groups were subjected to 4 h of coronary occlusion followed by 2 h of reperfusion. Serum levels of interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. The expression of interferon gamma (IFN-γ) in normal and infarcted (reflow and no-reflow) myocardial tissue was determined by immunohistochemical methods. The area of no-reflow and necrosis was evaluated pathologically. Levels of serum IL-6 were significantly lower in the atorvastatin group than in the AMI/R group (P<0.01). Expression of IFN-γ in infarcted reflow and no-reflow myocardial tissue was also significantly lower in the atorvastatin group than in the AMI/R group. The mean area of no-reflow [47.01% of ligation area (LA)] was significantly smaller in the atorvastatin group than in the AMI/R group (85.67% of LA; P<0.01). The necrosis area was also significantly smaller in the atorvastatin group (85.94% of LA) than in the AMI/R group (96.56% of LA; P<0.01). In a secondary analysis, rabbits in the atorvastatin and AMI/R groups were divided into two groups based on necrosis area (90% of LA): a small group (<90% of LA) and a large group (>90% of LA). There was no significant difference in the area of no-reflow between the small (61.40% of LA) and large groups (69.87% of LA; P>0.05). Single-dose atorvastatin protected against inflammation and myocardial no-reflow and reduced infarct size during AMI/R in rabbits. No-reflow was not dependent on the reduction of infarct size.

Two glucosinolates and their effects related to the prevention of cholesterol gallstones: a review / Dos glucosinolatos y sus efectos asociados con la prevención de cálculos biliares de colesterol: una revisión

Two glucosinolates (glucoraphasatin and glucoraphanin) and their degradation products (raphasatin and sulforaphane) are secondary metabolites which have shown antioxidant properties and inhibitory properties against the hepatic cholesterol; these effects are very important for the prevention of cholesterol gallstones because in their pathophysiology there is an imbalance in the transport and secretion of cholesterol. These effects produce oxygen reactive species formation, which damages the hepatic and biliary tissues. Cholesterol gallstones are a public health problem; their pharmacological treatment is very limited and the invasive surgical treatment for symptomatic gallstones is the cholecystectomy. Current research focuses on the search for preventive treatments, as there are many risk factors associated with the development of gallstones; therefore, a natural therapeutic alternative may be the use of these glucosinolates and their degradation products.

Dos glucosinolatos (glucorafasatina y glucorafanina) y sus productos de degradación (rafasatina y sulforafano) son metabolitos secundarios que han demostrado propiedades antioxidantes y propiedades inhibidoras contra el colesterol hepático; estos efectos son muy importantes para la prevención de cálculos biliares de colesterol porque en su fisiopatología existe un desajuste en el transporte y secreción del colesterol. Estos efectos producen la formación de especies reactivas de oxígeno, que dañan los tejidos hepático y biliar. Los cálculos biliares de colesterol son un problema de salud pública, su terapia farmacológica es muy limitada y el tratamiento quirúrgico invasivo para cálculos biliares sintomáticos es la colecistectomía. Las investigaciones actuales están orientadas a la búsqueda de tratamientos preventivos, porque hay muchos factores de riesgo asociados al desarrollo de cálculos biliares; por lo tanto, una alternativa terapéutica natural podría ser el uso de estos glucosinolatos, así como sus productos de degradación.

Estado de saúde percebido e adesão farmacológica em pacientes submetidos à intervenção coronária percutânea / Estado de salud percibido y la adhesión farmacológica en pacientes sometidos a intervención coronaria percutánea / Perceived health status and pharmacological adherence of patients who underwent percutaneous coronary intervention

Os objetivos foram avaliar o estado de saúde percebido e a adesão farmacológica, e verificar a correlação entre essas medidas em pacientes submetidos à intervenção coronária percutânea, após alta hospitalar. Trata-se de estudo transversal realizado no período de maio de 2011 a julho de 2012. Utilizaram-se os instrumentos SF-36 e Medida de Adesão aos Tratamentos, com 101 pacientes. Destes, 54 (53,5%) eram homens, a idade média era 59,5±10,3 e 32 (32,7%) haviam passado por tratamento cardíaco prévio. Todos utilizavam medicamentos anti-hipertensivos; 99 (98%) utilizavam antiagregantes plaquetários; 98 (97%), redutores de colesterol e 59 (58,4%), vasodilatadores coronarianos. A média do número de medicamentos utilizados foi 6,8±2,1. A adesão farmacológica foi verificada em 98 (97%) pacientes. Os participantes apresentaram melhor estado de saúde nos componentes "Aspectos sociais" e "Capacidade funcional". Constataram-se correlações positivas e de moderada magnitude entre as medidas de adesão e "Capacidade funcional", "Estado geral de saúde" e "Aspectos sociais". Houve correlação entre adesão farmacológica e estado de saúde percebido.

Las finalidades fueran evaluar el estado de salud percibido y la adhesión farmacológica y, verificar la correlación entre esas medidas en pacientes sometidos a intervención coronaria percutánea, tras el alta. Estudio transversal, realizado en el periodo de mayo/2011 a julio/2012. Los instrumentos utilizados fueron: SF-36 y Medida de Adhesión a los Tratamientos, con 101 pacientes, 54 (53,5%) hombres; promedio de edad 59,5±10,3; con tratamiento cardiaco previo 32 (32,7%). Todos estaban usando medicación antihipertensiva, la mayoría utilizaba antiplaquetario, 99 (98%); reductores de colesterol, 98 (97%); y vasodilatadores coronarios, 59 (58,4%). El número promedio de medicamentos utilizados fue 6,8±2,1. Se observó la adherencia farmacológica en 98 (97%) pacientes. Los participantes mostraron mejor estado de salud en los Aspectos Sociales y Capacidad Funcional. Fueron encontradas correlaciones positivas y moderadas entre la medida de adhesión farmacológica y Capacidad Funcional, Salud General y Aspectos Sociales. Hubo correlación entre adhesión farmacológica y estado de salud percibido.

The objectives of this study were to evaluate the perceived health status and pharmacological adherence, and to verify the correlation between these measures in patients who underwent percutaneous coronary intervention, after hospital discharge. It was a cross-sectional study carried out from May 2011 to July 2012. The instruments used were: SF-36 and Measurement of Adherence to Treatment, with 101 patients, 54 (53.5%) of which were men; average age of 59.5±10.3; and 32 (32.7%) with previous cardiac treatment. All study participants were using antihypertensive drugs; the majority 99 (98%) used antiplatelet drugs; 98 (97%) used cholesterol reducers, and 59 (58.4%) used coronary vasodilators. The average number of drugs used was 6.8±2.1. Pharmacological adherence was observed in 98 (97%) patients. The participants presented best perceived health status in Social Functioning and Physical Functioning. Positive correlations of moderate magnitude were found between measurements of pharmacological adherence and Physical Functioning, General Health and Social Functioning. There was correlation between pharmacological adherence and perceived health status.

Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies

Effective statin therapy is associated with a marked reduction of cardiovascular events. However, the explanation for full benefits obtained for LDL cholesterol targets by combined lipid-lowering therapy is controversial. Our study compared the effects of two equally effective lipid-lowering strategies on markers of cholesterol synthesis and absorption. A prospective, open label, randomized, parallel design study, with blinded endpoints, included 116 subjects. We compared the effects of a 12-week treatment with 40 mg rosuvastatin or the combination of 40 mg simvastatin/10 mg ezetimibe on markers of cholesterol absorption (campesterol and β-sitosterol), synthesis (desmosterol), and their ratios to cholesterol. Both therapies similarly decreased total and LDL cholesterol, triglycerides and apolipoprotein B, and increased apolipoprotein A1 (P < 0.05 vs baseline for all). Simvastatin/ezetimibe increased plasma desmosterol (P = 0.012 vs baseline), and decreased campesterol and β-sitosterol (P < 0.0001 vs baseline for both), with higher desmosterol (P = 0.007) and lower campesterol and β-sitosterol compared to rosuvastatin, (P < 0.0001, for both). In addition, rosuvastatin increased the ratios of these markers to cholesterol (P < 0.002 vs baseline for all), whereas simvastatin/ezetimibe significantly decreased the campesterol/cholesterol ratio (P = 0.008 vs baseline) and tripled the desmosterol/cholesterol ratio (P < 0.0001 vs baseline). The campesterol/cholesterol and β-sitosterol/cholesterol ratios were lower, whereas the desmosterol/cholesterol ratio was higher in patients receiving simvastatin/ezetimibe (P < 0.0001 vs rosuvastatin, for all). Pronounced differences in markers of cholesterol absorption and synthesis were observed between two equally effective lipid-lowering strategies.

La respuesta terapéutica a ezetimiba en ratones C57BL/6 es mediada por cambios en la expresión de NPC1L1, ABCG5 y ABCG8 en el enterocito / Therapeutic response to ezetimibe in C57BL/6 mice is mediated by changes in NPC1L1, ABCG5 and ABCG8 expression in the enterocyte

Las proteínas NPC1L1, ABCG5 y ABCG8 participan en la absorción intestinal de colesterol. Ezetimiba inhibe este proceso bloqueando a NPC1L1, sin embargo, su efecto sobre ABCG5 y ABCG8 aún no está claro. Así, el objetivo del presente trabajo fue evaluar en ratones C57BL/6 con hipercolesterolemia inducida por dieta y tratados con ezetimiba, la expresión de NPC1L1, ABCG5 y ABCG8 mediante PCR en tiempo real y Western blot, en 3 grupos de animales: 1, dieta hipercolesterolémica D12336; 2, dieta D12336 más 5 mg/kg/día de ezetimiba; 3, dieta control. El nivel sérico de colesterol total fue significativamente diferente entre los grupos estudiados (control: 1,85 +/- 0,49 mmol/L; dieta D12336: 3,11 +/- 0,73 mmol/L; ezetimiba: 2,11 +/- 0,50 mmol/L, P = 0,001). La expresión génica de NPC1L1 aumentó 5,4 veces en el grupo que recibió la dieta D12336 (P = 0,003). Por otro lado, la expresión génica de ABCG5 y ABCG8 no fue diferente en el grupo con hipercolesterolemia (P = 0,239 y P = 0,201, respectivamente). Después del tratamiento con ezetimiba, la expresión génica de ABCG5 se incrementó 15,6 veces (P = 0.038). No hubo diferencias significativas en la expresión génica de NPC1L1 (P = 0,134) y ABCG8 (P = 0,067). En relación a la expresión proteica, la dieta D12336 incrementó los niveles de expresión de NPC1L1 (P = 0,022) y ABCG5 (P = 0,008); el tratamiento con ezetimiba incrementó los niveles de NPC1L1 (P = 0,048) y redujo los niveles de ABCG5 (P = 0,036) y ABCG8 (P = 0,016). En conclusión, nuestros resultados sugieren que tanto la dieta hipercolesterolémica como el tratamiento con ezetimiba, en un modelo experimental, afectan los niveles de expresión de NPC1L1, ABCG5 y ABCG8, sugiriendo que ABCG5 y ABCG8 están involucrados en la respuesta hipolipemiante a este fármaco. No obstante, el mecanismo mediante el cual se explica esta interacción requiere de un futuro estudio.

Proteins NPC1L1, ABCG5 and ABCG8 are involved in the intestinal absorption of cholesterol. Ezetimibe inhibits this process by blocking NPC1L1, however, its effect on ABCG5 and ABCG8 is not yet clear. Thus, the objective of this study was to evaluate in C57BL / 6 mice with diet-induced hypercholesterolemia treated with ezetimibe, the expression of NPC1L1, ABCG5 and ABCG8 by real time PCR and Western blot, in 3 groups of animals: 1, diet hypercholesterolemic D12336, 2, D12336 diet plus 5 mg/kg/ day of ezetimibe, 3, diet control. The serum level of total cholesterol was significantly different between groups (control: 1.85 +/- 0.49 mmol / L; diet D12336: 3.11 +/- 0.73 mmol / L; ezetimibe: 2.11 +/- 0.50 mmol / L, P = 0.001). NPC1L1 gene expression increased 5.4-fold in the group receiving the diet D12336 (P = 0.003). Furthermore, the gene expression of ABCG5 and ABCG8 was not different in the group with hypercholesterolemia (P = 0.239 and P = 0.201, respectively). After treatment with ezetimibe, ABCG5 gene expression was increased 15.6 times (P = 0.038). No significant differences in gene expression of NPC1L1 (P = 0.134) and ABCG8 (P = 0.067). Regarding protein expression, the D12336 diet increased the levels of expression of NPC1L1 (P = 0.022) and ABCG5 (P = 0.008), treatment with ezetimibe increased the levels of NPC1L1 (P = 0.048) and reduced levels of ABCG5 (P = 0.036) and ABCG8 (P = 0.016). In conclusion, our results suggest that both hypercholesterolemic diet as treatment with ezetimibe, in an experimental model, affect the expression levels of NPC1L1, ABCG5 and ABCG8, suggesting that ABCG5 and ABCG8 are involved in lipid-lowering response to this drug. However, the mechanism by which this interaction is explained requires further study.

Medicamentos prescritos aos idosos em uma capital do Sul do Brasil e a Relação Municipal de Medicamentos / Medicines prescribed to the elderly in a city in southern Brazil and the Municipal Medicines List

O objetivo deste trabalho foi descrever os medicamentos prescritos aos idosos residentes na zona urbana do Município de Florianópolis, Santa Catarina, Brasil, nos 30 dias anteriores à entrevista e, a partir disto, comparar com a Relação Municipal de Medicamentos (REMUME). Foi realizado um estudo transversal populacional de base domiciliar, no qual os 1.705 idosos entrevistados relataram ter utilizado o total de 5.458 medicamentos prescritos e dentro dos critérios da pesquisa, que corresponderam a 374 princípios ativos diferentes. Os medicamentos mais utilizados foram os indicados para o sistema cardiovascular, sendo a classe farmacológica dos redutores de colesterol e triglicerídeos os mais prevalentes, apesar de não haver nenhum exemplar desta classe de medicamentos selecionado na REMUME. Embora haja algumas faltas, a REMUME coincide com a maior proporção dos medicamentos prescritos no Município de Florianópolis. A principal diferença entre as prescrições é que as oriundas do SUS estão em maior conformidade com a REMUME.

The aim of this study was to describe the medicines prescribed to elderly residents of Florianópolis, Santa Catarina State, Brazil, in the 30 days prior to the interview, and to compare them with the Municipal Medicines List (REMUME). A cross-sectional population-based household survey was conducted, in which 1,705 elderly respondents reported having used a total of 5,458 prescription drugs meeting the study criteria and corresponding to 374 different active ingredients. The most frequently used medicines were for the cardiovascular system, among which the most prevalent pharmacological class was lipid-lowering drugs (although there were no examples of this drug class in the REMUME list). Despite some gaps, the majority of the drugs prescribed in Florianópolis coincided with the REMUME list. Prescriptions filled through the Unified National Health System were in greater conformity with the REMUME list.

[ effects of different doses of atorvastatin on angiogenesis of chorioallantoic membrane of chick embryo]

Statins promote the proliferation, migration and survival of endothelial cells and bone marrow -derived endothelial progenitor cells [Angioblasts]. Angiogenesis, the formation of new blood vessels, is a dynamic and complex activity which is needed for embryogenesis and other physiological processes. However, in many pathological conditions such as solid tumor progression, the disease appears to be associated with persistent upregulated angiogenesis. In this research we used atorvastatin [0.1microm] and [10 microm] on angiogenesis of chick embryo. In this experimental study 42 Ross fertilized eggs were randomly divided into 3groups as follows: 1] control group, 2] group treated with atorvastatin [0.1microm], 3] group treated with atorvastatin [10microm]. In day 2 a window was opened on eggs in sterile condition and In day 8 gelatin sponge was placed on chorioallantic membrane [CAM] and was soaked with 10 microliters atorvastatin [0.1microm] and [10 microm] in group 2 and group 3. In day12 CAMs were examined and photographed by research photo-stereomicroscope in all cases. Data were analyzed statistically by ANOVA and Tukey tests. The average number and length of vessels in control and the group treated with atorvastatin [0.1microm] showed a significant increase [P<0.05] and the average number and length of vessels in the group treated with atorvastatin [10 microm] showed a significant decrease compare to control group [P<0.05]. The results of this study showed that atorvastatin has a stimulatory effect on angiogenesis in CAM and atorvastatin [10 microm] has an inhibitory effect on angiogenesis in CAM. It is suggested that astatine can be used as a new medicine for angiogenesis balancing in treat ment of diseases related to angiogenesis

Attenuation of hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats by chloroform extract of fruits ofFerocactus latispinus and Ferocactus histrix / Atenuación de la hiperglucemia y la hiperlipidemia en ratas diabéticas inducida por estreptozotocina por el extracto de cloroformo de los frutos de Ferocactus latispinus y Ferocactus histrix

The hypoglycemic effects of hexane, chloroform and methanol extracts from fruits of Ferocactus latispinus and Ferocactus histrix were evaluated by oral administration to normoglucemic and streptozotocin-induced severe diabetic rats (SD). The anti-diabetic effect was examined by blood glucose, triglycerides, lipid peroxidation, total cholesterol levels in the serum, glycogen content of liver and skeletal muscles, superoxide dismutase (SOD) catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSHPx) levels. The most active extracts were obtained with chloroform. Chloroform extracts from F. latispinus and F. histrix increased activities of SOD, GR, GSHPx and CAT, hepatic glycogen content, glucose-6-phosphatase (G6Pase) and the plasma insulin levels. They also, decreased glucokinase (GK) and TBAR (thiobarbituric acid assay). Of the two plants studied F. latispinus showed better antihyperglycemic and antihyperlipidemic effects that F. histrix. In conclusion F. latispinus and F. histrix possesses significant antihyperglycemic properties after 4 h after a single oral dose. It can also improve hyperlipidemia and hypoinsulinemia in streptozotocin-induced diabetic. These results demonstrated that F. latispinus and F. histrix typically used as a health food, has strong antidiabetic effects in vivo, thus, it may have beneficial properties in the prevention of diabetes.

Los efectos hipoglucemiantes de extractos obtenidos con hexano, cloroformo y metanol a partir de frutos de Ferocactus latispinus y Ferocactus histrix fueron evaluados por la administración oral a ratas normales y con diabetes severa (SD) inducida por estreptozotocina. Los extractos más activos fueron obtenidos con cloroformo el cuál incrementa los niveles de SOD, GR, GSHPx y el CAT, el contenido de glucógeno hepático, la glucosa-6-fosfatasa (G6Pase) y los niveles de insulina plasmática. También producen disminución de la glucoquinasa (GK) y TBARS. De las dos plantas estudiadas la F. latispinus presento mayor actividad antihiperglicemiante y antihiperlipidémicos que la F. histrix. En conclusión F. latispinus y F. histrix pueden mejorar la hiperlipidemia y la hipoinsulinemia en animales diabéticos inducida por estreptozotocina. Estos resultados demostraron que F. latispinus y F. histrix utilizadas normalmente como un alimento saludable, tiene fuertes efectos antidiabéticos in vivo, por lo tanto, pueden tener propiedades beneficiosas en la prevención de la diabetes.

Effects of Combined Therapy with Ezetimibe Plus Simvastatin After Drug-Eluting Stent Implantation in a Porcine Coronary Restenosis Model

The aim of this study was to examine the anti-proliferative and anti-inflammatory effects of ezetimibe/simvastatin (E/S) after drug-eluting stent (DES) implantation in a porcine coronary restenosis model. Pigs were randomized into two groups in which the coronary arteries (23 pigs) had DES. Stents were deployed with oversizing (stent/artery ratio 1.3:1) in porcine coronary arteries. Fifteen pigs were taken 10/20 mg of E/S and eight pigs were not taken E/S. Histopathologic analysis was assessed at 28 days after stenting. In neointima, most inflammatory cells were lymphohistiocytes. Lymphohistiocyte count was not different between two groups (337+/-227 vs. 443+/-366 cells, P=0.292), but neointima area was significantly smaller (1.00+/-0.49 mm2 vs. 1.69+/-0.98 mm2, P=0.021) and percent area stenosis was significantly lower (23.3+/-10% vs. 39+/-19%, P=0.007) in E/S group compared with control group. There were no significant differences in fibrin score (1.99+/-0.79 vs. 1.81+/-0.88, P=0.49), endothelial score (1.75+/-0.66 vs. 1.80+/-0.59, P=0.79), and the percent of endothelium covered lumen (43+/-21% vs. 45+/-21%, P=0.84) between E/S group and control group. Combined therapy with ezetimibe and simvastatin inhibits neointimal hyperplasia, but does not inhibit inflammatory infiltration and arterial healing after DES implantation in a porcine coronary restenosis model.

Estudio observacional evaluando los efectos de Ezetimiba para disminuir el LDL-C como es prescrito en la práctica rutinaria diaria en la población peruana / Observational study evaluating the effects of ezetimibe to lower LDL-C as prescribed in daily routine practice in the Peruvian population

Evaluar la eficacia, seguridad y tolerabilidad terapéutica de ezetimiba coadministrada con una estatina en la reducción del colesterol LDL en la práctica clínica diaria. MATERIALES Y MÉTODOS: Estudio fase IV multicéntrico, prospectivo, randomizado, abierto llevado a cabo entre los meses de noviembre 2004 y marzo del 2005, en 204 pacientes ambulatorios, con diagnóstico de hipercolesterolemia primaria, de ambos sexos, entre 18 y 75 años. Los pacientes seleccionados fueron agrupados en INICIADORES (pacientes que iniciarían el tratamiento con ezetimiba más una estatina) y CONTINUADORES ( pacientes que estaban recibiendo una estatina y que no llegaron a sus valores meta, por lo que se le agrega ezetimiba a su tratamiento). Se les trató durante 6 semanas con ezetimiba (10mg/día) más una estatina y se realizaron mediciones de los parámetros lipídicos al inicio y al final del estudio. RESULTADOS: De los 204 pacientes del estudio, la terapia con ezetimiba coadministrada con una estatina produjo un cambio porcentual significativo en los niveles de LDL-c entre el grupo de Iniciadores y Continuadores: û26.6 por ciento y û26.04 por ciento (p menor que 0.001) respectivamente. Además, se observaron cambios en los otros parámetros lipídicos entre los grupos: Colesterol Total: -23.34 por ciento y -24.10 por ciento (p menor que 0.001), HDL-c: -16.36 por ciento (p menor que 0.20) y +8.43 (p menor que 0.20) y Triglicéridos: -23.83 por ciento y û15.77 por ciento (p menor que 0.001). Se observó que en el grupo de menor que de 65 años el 75, 51 por ciento logró el objetivo de LDL-c menor que 130mg/dl. Estos beneficios se asociaron a una baja incidencia de efectos adversos 31 casos (16.84 por ciento) fundamentalmente de tipo gastrointestinal (48.47 por ciento), seguido de los trastornos neurológicos (16,32 por ciento) y los músculo esqueléticos (14,28 por ciento).

Primum non nocere: lecciones del estudio SEAS

Reducción intensiva de lìpidos con simvastatina y ezetimibe en estenosis aórtica (Intensive lipids lowering with simvastatin and ezetimibe in aortic stenosis). Publicado en: N Engl J Med 2008; 359:1343-1356. Existe evidencia de que el colesterol juega un rol en el desarrollo y evolución de la estenosis aòrtica. En este estudio se quiso evaluar si la disminución intensa de los valores de colesterol tienen efecto en la progresion de esta enfermedad. Este fue en estudio aleatorizado, doble ciego controlado con placebo, donde los pacientes fueron distribuidos a recibir simvastatina 40 mg más ezetimibe 10 mg/día o placebo. La variable de desenlace primario fue el compuesto de eventos cardiovasculares mayores, reemplazo de válvula aórtica, infarto del miocardio no fatal, hospitalizaciones por angina inestable, insuficiencia cardíaca, cirugía cardíaca intervenciones percutáneas e ictus cerebral. Las variables de desenlaces secundarios fueron los eventos relacionados con la estenosis aòrtica y los eventos isquémicos cardiovasculares. La muestra estuvo constituida por 1.873 pacientes que fueron seguidos por 52 meses. El punto final primario ocurrió en 35% (333 pacientes) en el grupo simvastatina/ezetimibe versus 38,2% (355 pacientes) en el grupo placebo (HR: 0,96 IC 95% 0,83-1,2; P=0,59). El reemplazo de válvula aórtica tampoco presento diferencias entre los grupos, 28,3% en el grupo simvastatina/ezetimide versus 29,9% en el grupo placebo (P=0,97). Menos pacientes en el grupo de tratamiento activo presentaron eventos isquémicos cardiovasculares que en el grupo placebo (148 versus 187; HR 0,78 IC 95%: 0,63-097; P=0,02). La incidencia de cáncer fue mayor en el grupo simvastatina/ezetimibe 105 versus 70, P=0,01. La combinación de simvastatina/ezetimibe no reduce la variable de desenlace primaria compuesto en pacientes con estenosis aórtica ni los eventos relacionados a la válvula aórtica. Esta combinación tiene efecto positivo sobre la incidencia de ventos cardiovasculares.

Atorvastatin improves arterial stiffness in normotensive normolipidaemic persons with type 2 diabetes.

Increased arterial stiffness is an independent predictor of cardiovascular disease and mortality in middle-aged and olderadults. We measured arterial stiffness by pulse wave velocity (PWV)in brachial-ankle segments by automated oscillometry in 71 normotensive and normolipidaemic subjects with type 2 diabetes (40 males and 31 females). 57 patients (whose baPWV was more than 1400 cm/second) were randomised into two groups, group A (n=29) were given 10 mg atorvastatin daily for 6 months and group B (n=28) were given placebo. After 6 months, atorvastatin group had significant improvement in brachial-ankle pulse wave velocity (baPWV) (1712.03 +/- 349.9 cm/second versus 1558.81 +/- 303.26 cm/ second, p< 0.05). Though the placebo group showed some improvement (1692.03 +/- 425.15 cm/second versus 1636.78 +/- 425.1 cm/second) it was not statistically significant. Despite correlation was noted between baPWV and systolic blood pressure (SBP), there was no significant correlation between the mean baPWV and duration of diabetes, body mass index (BMI), waist circumference, waist-hip ratio (WHR), waist to height ratio (WHtR), glycated haemoglobin (HbA1c), LDL, HDL cholesterol and spot urine albumin creatinine ratio (ACR) at the baseline. The decrement of LDL-cholesterol is correlated with the decrement of the baPWV in the atorvastatin group only (p<0.01).

The effects of lovastatin on conventional medical treatment of lower urinary tract symptoms with finasteride

OBJECTIVE: To explore whether or not statins have any impact on the progression of components of benign prostatic hyperplasia (lower urinary tract symptoms severity, prostate volume and serum prostate specific antigen (PSA) when combined with other agents inhibiting growth of prostate cells. MATERIALS AND METHODS: This was a preliminary, clinical study. Eligible patients were aged > 50 yrs, with International Prostate Symptom Score (IPSS) between 9 and 19, total prostate volume (TPV) > 40 mL, and serum PSA > 1.5 ng/mL. Patients were divided in two groups: those with and those without lipidemia. After selection, eligible BPH patients with lipidemia (n = 18) were prescribed lovastatin 80 mg daily and finasteride 5 mg daily, while eligible patients without lipidemia (n = 15) were prescribed only finasteride 5 mg daily. IPSS, TPV and serum PSA were evaluated at end point (4 months). RESULTS: There was no difference between the two groups on the primary end point of mean change from baseline in IPSS (p = 0.69), TPV (p = 0.90) and PSA (p = 0.16) after 4 months of treatment. CONCLUSIONS: Short-term lovastatin treatment does not seem to have any effect on IPSS, TPV and PSA in men with prostatic enlargement due to presumed BPH.