Respuesta de Aedes aegypti L. (Diptera: Culicidae) a transflutrina y linalol impregnados en diferentes tipos de tela / Response of Aedes aegypti L. (Diptera: Culicidae) to transfluthrin and linalool impregnated in different of fabric types

Resumen: Objetivo: Evaluar el efecto de repelencia espacial contra Ae. aegypti de dos compuestos químicos impregnados en diferentes tipos de telas. Material y métodos: El estudio se realizó en el periodo 2015-2016 en el Centro Regional de Investigación en Salud Pública, del Instituto Nacional de Salud Pública. Se utilizó el Sistema de Procesamiento de Alto-rendimiento para evaluar la respuesta de Ae. aegypti a transflutrina y linalol, impregnados individualmente a diferentes concentraciones en popelina, algodón y poliéster. También se determinó el efecto de sus mezclas, lavado sobre la residualidad y porcentaje de protección. Resultados: La mayor respuesta de repelencia espacial fue para el tratamiento linalol-algodón al 0.1% (RE= 70 ± 5.77%). La mezcla de linalol 0.1% y transflutrina 0.001% presentó un porcentaje de repelencia espacial similar para los tres tipos de tela. El tratamiento transflutrina-popelina 0.001% mantuvo una residualidad de cinco días. El linalol al 0.1% produjo 62.50% de protección en presencia de un estímulo de atracción. Conclusión: Se sugiere la impregnación de linalol al 0.1% en ropa como medida de protección de las picaduras de Ae. aegypti.

Abstract: Objective: Evaluate the effect of spatial repellency against Ae. aegypti of two chemical compounds impregnated in different types of fabrics. Materials and methods: The study was carried out in the year 2015-2016 in the Centro Regional de Investigación en Salud Pública, del Instituto Nacional de Salud Pública. The high-throughput screening system was used to evaluate the response of Ae. aegypti to transfluthrin and linalool, impregnated individually at different concentrations in poplin, cotton and polyester. The effect of their mixtures was also determined, washing on residuality and percentage of protection. Results: The highest spatial repellency response was for 0.1% linalool-cotton treatment (RE = 70 ± 5.77%). The mixture of 0.1% linalool and 0.001% transfluthrin presented a similar spatial repellence percentage for the three types of fabric. The transfluthrin-poplin treatment 0.001% maintained a residual of five days. 0.1% linalool produced a 62.50% protection in the presence of an attraction stimulus. Conclusion: It is suggested the impregnation of 0.1% linalool in clothing as a protection measure for Ae. aegypti.

Nebulización térmica intradomiciliar de la mezcla de flupyradifurona y transflutrina en mosquitos Aedes aegypti susceptibles y resistentes a piretroides en el Sur de México / Indoor thermal fogging of the mixture of flupyradifurone and transflutrin on Aedes aegypti mosquitoes susceptible and resistant to pyrethroids in southern Mexico

Resumen: Objetivo: Evaluar la efectividad de la mezcla de flupyradifurona 26.3 g/L y transflutrina 52.5 g/L aplicada como niebla térmica a mosquitos Aedes vectores de virus dengue, Zika y chikungunya. Material y métodos: Se colocaron grupos de 15 mosquitos de Ae. aegypti (susceptibles y resistentes a piretroides) dentro de jaulas, en sala, recámara y cocina. Posteriormente, se aplicó la mezcla de flupyradifurona y transflutrina dentro de las viviendas a una dosis de 2 y 4 mg/m3, respectivamente. Resultados: La mezcla de flupyradifurona y transflutrina causó mortalidades de 97 a 100% sobre las cepas de mosquitos Aedes y su efectividad fue la misma en los diferentes compartimentos de las viviendas. Conclusiones: La mezcla de flupyradifurona y transflutrina, aplicada en niebla térmica, es una herramienta prometedora para el control de poblaciones de mosquitos Aedes independientemente de su estado de resistencia a insecticidas.

Abstract: Objective: To evaluate the efficacy of thermal fogging of a mixture of flupyrafirudone (26.3 g/L) and transfluthrin (52.5 g/L) against dengue, Zika y chikungunya Aedes mosquito vectors. Materials and methods: Groups of 15 caged Ae. aegypti (susceptible and pyrethroid resistant) mosquitoes were placed in living room, kitchen and bedroom inside houses, after which a dose of 2 and 4 mg/m3 of flupyradifurone and transfluthrine, respectively, was applied as thermal fog. After one hour of exposure mosquitoes were transferred to the laboratory and mortality was recorded after 24 h. Results: The mixture killed 97 to 100% of mosquitoes from the strains and the efficacy was similar independently of their place within the premises. Conclusions: The mixture of flupyrafirudone and transfluthrin applied as thermal fog is a promising tool to control Aedes mosquito populations independently of the pyrethroid-insecticide resistance status.

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System / Efetividade de Estatinas em Dose Alta, Moderada e Baixa na Prevenção de Eventos Vasculares no SUS

Background: Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. Objective: To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective. Methods: We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied. Results: Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Conclusions: Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil. .

Fundamento: Estatinas tem eficácia comprovada na redução de eventos cardiovasculares, mas o impacto financeiro de seu uso disseminado pode ser substancial. Objetivo: Conduzir análise de custo-efetividade de três esquemas de doses de estatinas na perspectiva do SUS. Métodos: Foi desenvolvido modelo de Markov para avaliar a razão de custo-efetividade incremental (RCEI) de regimes de dose baixa, intermediária e alta, em prevenção secundária e quatro cenários de prevenção primária (risco em 10 anos de 5%, 10%, 15% e 20%). Regimes com redução de LDL abaixo de 30% (ex: sinvastatina 10mg) foram considerados dose baixa; entre 30-40% (atorvastatina 10mg, sinvastatina 40mg), dose intermediária; e acima de 40% (atorvastatina 20-80 mg, rosuvastatina 20 mg), dose alta. Dados de efetividade foram obtidos de revisão sistemática com aproximadamente 136.000 pacientes. Dados nacionais foram usados para estimar utilidades e custos (expressos em dólares internacionais - Int$). Um limiar de disposição a pagar (LDP) igual ao produto interno bruto per capita nacional (aproximadamente Int$11.770) foi utilizado. Resultados: A dose baixa foi dominada por extensão nos cenários de prevenção primária. Nos cinco cenários, a RCEI da dose intermediária ficou abaixo de Int$10.000 por QALY. A RCEI de dose alta ficou acima de Int$27.000 por QALY em todos os cenários. Nas curvas de aceitabilidade de custo-efetividade, dose intermediária teve probabilidade de ser custo-efetiva acima de 50% com RCEIs entre Int$9.000-20.000 por QALY em todos os cenários. Conclusões: Considerando um LDP razoável, uso de estatinas em doses intermediárias é economicamente atrativo, e deveria ser intervenção prioritária na redução de eventos cardiovasculares no Brasil. .

Toxicological effects of prolonged and intense use of mosquito coil emission in rats and its implications on malaria control / Efectos toxicológicos del uso prolongado e intenso de emisiones de espirales contra mosquitos en ratas y sus implicaciones sobre el control de la malaria

Efectos toxicológicos del uso prolongado e intenso de emisiones de espirales contra mosquitos en ratas y sus implicaciones sobre el control de la malaria. Mosquito coil is a vector control option used to prevent malaria in low income counties, while some studies have addressed this issue, additional reseach is required to increase knowledge on the adverse health effects caused by the prolonged use of coils. In this study we investigated the toxicological effects of fumes from two locally manufactured mosquito coil insecticides (with pyrethroids: transfluthrin and d-allethrin as active ingredients) on male albino rats. For this, we recorded the haematological and biochemical indices, and made histopathology and mutagenicity evaluations in rats exposed to mosquito fumes during 2, 4, 8, 12 and 16 week periods. Haematological determination was performed using automated hematology analyzer to determine White Blood Cell (WBC), Packed Cell Volume (PCV), Red Blood Cell (RBC) and Platelet (PLT) counts, while biochemical evaluations were determined using available commercial kits. Gross histopathological changes were studied for the kidney, liver and lungs in sacrificed rats. The rat sperm head abnormalities assessment was used to evaluate mutagenicity. Mosquito coil fumes produced significant increase (P<0.05) in the levels of total protein, total albumin and bilirubin, when animals were exposed from two weeks to 16 weeks with transfluthrin. Similarly, elevation in the activities of aspartate amino transferase, alanine amino transferase and alanine phosphatase, increased significantly in both insecticides. Increase in WBC, RBC and PCV were recorded for all the exposure periods, however PLT count showed no significant increase (P>0.05). Mutagenicity assessment revealed sperm abnormality was statistically significant (P<0.05) compared with the control at 8, 12 and 16 weeks post exposure to transfluthrin. Histological studies revealed severe lung damage evidenced by interstitial accumulations, pulmonary oedema and emphysema in exposed rats. Intracellular accumulations and severe sinusoidal congestion of liver cells were observed from 12 weeks exposure, indicating liver damage. Our studies indicate that mosquito coil fumes do initiate gradual damage to the host. These pathological effects must be taken into consideration by the malaria control program, particularly when regulating their long term and indoor usage.

Las espirales contra los mosquitos se utilizan en los países de bajos ingresos como una opción para prevenir la malaria controlando el vector de esta enfermedad. A pesar de que algunos estudios han abordado este tema, se requiere más investigación para incrementar el conocimiento sobre los efectos adversos en la salud, causados por el uso prolongado de las espirales. En este estudio se investigaron los efectos toxicológicos de los gases de las espirales a partir de dos insecticidas fabricados en el país (con piretroides: transflutrina y d-aletrina como ingredientes activos) en machos de ratas albinas. Para esto, se registraron los índices hematológicos y bioquímicos, y se hicieron evaluaciones histopatológicas y de mutagenicidad en ratas expuestas a los gases de las espirales durante períodos de 2, 4, 8, 12 y 16 semanas. La determinación hematológica se realizó mediante un analizador de hematología automatizado para determinar el conteo de los Glóbulos Blancos (WBC), el Hematocrito (PCV), Glóbulos Rojos (RBC) y las Plaquetas (PLT), mientras que las evaluaciones bioquímicas se determinaron utilizando kits comerciales disponibles. Los cambios histopatológicos fuertes se estudiaron en el riñón, el hígado y los pulmones de ratas sacrificadas. Las anormalidades en la cabeza de los espermatozoides de las ratas se utilizaron para evaluar la mutagenicidad. El humo de las espirales contra los mosquitos producen un aumento significativo (p<0.05) en los niveles de proteína total, albúmina total y bilirrubina, cuando los animales fueron expuestos de dos semanas a 16 semanas con transflutrina. Del mismo modo, la elevación en las actividades de aspartato amino transferasa, alanina amino transferasa y alanina fosfatasa, aumentó significativamente con ambos insecticidas. Se registro un aumento en los leucocitos, eritrocitos y el hematocrito para todos los períodos de exposición, sin embargo el recuento de las plaquetas no mostró un aumento significativo (p>0.05). Las pruebas de mutagenicidad revelaron que las anormalidades en el esperma de las ratas fue estadísticamente significativa (p>0.05) al comparar el control a las 8, 12 y 16 semanas post exposición a la transflutrina. Los estudios histológicos revelaron una serie de daños pulmonares graves en las ratas expuestas al humo de la espiral, evidenciados por la acumulación intersticial, edema pulmonar y enfisema. Las acumulaciones intracelulares y la congestión sinusoidal severa de las células del hígado se observaron a partir de las 12 semanas de exposición, lo que indica daño hepático. Nuestros estudios indican que los vapores de las espirales contra mosquitos inician el daño gradual al huésped. Estos efectos patológicos deben ser tomados en cuenta por el programa de control de la malaria, particularmente a la hora de regular su uso a largo plazo y bajo techo.

Rosuvastatina e ciprofibrato no tratamento da dislipidemia em pacientes com HIV / Rosuvastatin and ciprofibrate in the treatment of dyslipidemia in patients with HIV

FUNDAMENTO: A dislipidemia secundária à terapia antirretroviral potente nos pacientes com HIV está associada à significativa elevação da morbimortalidade cardiovascular por doença aterosclerótica, sendo, portanto, necessário tratamento imediato e eficaz. OBJETIVO: Demonstrar a efetividade e a segurança da rosuvastatina e do ciprofibrato no tratamento da dislipidemia associada à terapia antirretroviral potente em pacientes com HIV. MÉTODOS: Trezentos e quarenta e seis pacientes com dislipidemia foram submetidos a tratamento farmacológico: 200 pacientes com hipertrigliceridemia receberam ciprofibrato (Grupo I); 79 pacientes com hipercolesterolemia receberam rosuvastatina (Grupo II); e 67 pacientes com dislipidemia mista receberam ciprofibrato associado a rosuvastatina (Grupo III). O perfil lipídico foi avaliado antes e após o tratamento hipolipemiante, sendo feita comparação estatística pelo teste de Wilcoxon. Transaminases hepáticas e creatinofosfoquinase foram dosadas para controle de toxicidade hepática e muscular. RESULTADOS: As concentrações séricas de triglicérides e de colesterol total foram significativamente menores do que as obtidas antes do tratamento, para os três grupos experimentais (p < 0,002). Observou-se aumento significativo do HDL colesterol nos grupos experimentais I e III (p < 0,002). Nos grupos I e II, o LDL-colesterol foi significativamente menor (p < 0,001). Nenhum dos pacientes apresentou elevações de transaminases ou de creatinofosfoquinase a níveis de toxicidade significativa. CONCLUSÃO: Os resultados deste estudo demonstram que ciprofibrato, rosuvastatina ou a combinação de ambos pode ser considerada tratamento hipolipemiante efetivo, seguro e com boa tolerância nos pacientes com Aids submetidos à terapia antirretroviral potente.

BACKGROUND: Dyslipidemia secondary to highly active antiretroviral therapy in patients with HIV is associated with a significant increase in cardiovascular morbidity and mortality due to atherosclerotic disease, requiring, thus, immediate and effective treatment. OBJECTIVE: To demonstrate the effectiveness and safety of rosuvastatin and ciprofibrate in the treatment of dyslipidemia associated with highly active antiretroviral therapy in patients with HIV. METHODS: Three hundred and forty-six patients with dyslipidemia underwent pharmacological treatment as follows: 200 patients with hypertriglyceridemia received ciprofibrate (Group I); 79 patients with hypercholesterolemia received rosuvastatin (Group II); and 67 patients with mixed dyslipidemia received ciprofibrate associated with rosuvastatin (Group III). The lipid profile was assessed before and after the lipid-lowering treatment, and the Wilcoxon test was used for statistical comparison. Liver transaminases and creatine phosphokinase were measured to assess liver and muscle toxicity. RESULTS: The serum concentrations of triglycerides and total cholesterol were significantly lower than those obtained before the lipid-lowering treatment in the three experimental groups (p < 0.002). A significant increase in HDL-cholesterol was observed in Groups I and III (p < 0.002). In Groups I and II, LDL-cholesterol was significantly lower (p < 0.001). None of the patients experienced elevations in transaminases or creatine phosphokinase to significantly toxic levels. CONCLUSION: The results of this study show that ciprofibrate and rosuvastatin or a combination of both can be considered an effective, safe and well-tolerated lipid-lowering treatment for patients with AIDS on highly active antiretroviral therapy.

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.

The methyl ester of rosuvastatin elicited an endothelium-independent and 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent relaxant effect in rat aorta

The relaxant effect of the methyl ester of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g, 6 rats for each experimental group) with and without endothelium precontracted with 1.0 µM phenylephrine. The methyl ester presented a slightly greater potency than rosuvastatin in relaxing aortic rings, with log IC50 values of -6.88 and -6.07 M, respectively. Unlike rosuvastatin, the effect of its methyl ester was endothelium-independent. Pretreatment with 10 µM indomethacin did not inhibit, and pretreatment with 1 mM mevalonate only modestly inhibited the relaxant effect of the methyl ester. Nω-nitro-L-arginine methyl ester (L-NAME, 10 µM), the selective nitric oxide-2 (NO-2) inhibitor 1400 W (10 µM), tetraethylammonium (TEA, 10 mM), and cycloheximide (10 µM) partially inhibited the relaxant effect of the methyl ester on endothelium-denuded aortic rings. However, the combination of TEA plus either L-NAME or cycloheximide completely inhibited the relaxant effect. Inducible NO synthase (NOS-2) was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with methyl ester-treated rings. In conclusion, whereas rosuvastatin was associated with a relaxant effect dependent on endothelium and hydroxymethylglutaryl coenzyme A reductase in rat aorta, the methyl ester of rosuvastatin exhibited an endothelium-independent and only slightly hydroxymethylglutaryl coenzyme A reductase-dependent relaxant effect. Both NO produced by NOS-2 and K+ channels are involved in the relaxant effect of the methyl ester of rosuvastatin.

Rosuvastatin prevents myocardial necrosis in an experimental model of acute myocardial infarction

Dyslipidemia is related to the progression of atherosclerosis and is an important risk factor for acute coronary syndromes. Our objective was to determine the effect of rosuvastatin on myocardial necrosis in an experimental model of acute myocardial infarction (AMI). Male Wistar rats (8-10 weeks old, 250-350 g) were subjected to definitive occlusion of the left anterior descending coronary artery to cause AMI. Animals were divided into 6 groups of 8 to 11 rats per group: G1, normocholesterolemic diet; G2, normocholesterolemic diet and rosuvastatin (1 mg·kg-1·day-1) 30 days after AMI; G3, normocholesterolemic diet and rosuvastatin (1 mg·kg-1·day-1) 30 days before and after AMI; G4, hypercholesterolemic diet; G5, hypercholesterolemic diet and rosuvastatin (1 mg·kg-1·day-1) 30 days after AMI; G6, hypercholesterolemic diet and rosuvastatin (1 mg·kg-1·day-1) 30 days before and after AMI. Left ventricular function was determined by echocardiography and percent infarct area by histology. Fractional shortening of the left ventricle was normal at baseline and decreased significantly after AMI (P < 0.05 in all groups), being lower in G4 and G5 than in the other groups. No significant difference in fractional shortening was observed between G6 and the groups on the normocholesterolemic diet. Percent infarct area was significantly higher in G4 than in G3. No significant differences were observed in infarct area among the other groups. We conclude that a hypercholesterolemic diet resulted in reduced cardiac function after AMI, which was reversed with rosuvastatin when started 30 days before AMI. A normocholesterolemic diet associated with rosuvastatin before and after AMI prevented myocardial necrosis when compared with the hypercholesterolemic condition.

Rosuvastatin prevents proteinuria and renal inflammation in nitric oxide-deficient rats

OBJECTIVE: The aim of the present study was to assess the effects of rosuvastatin on renal injury and inflammation in a model of nitric oxide deficiency. METHODS: Male Wistar rats were randomly divided into four groups (n = 10/group) and treated for 28 days with saline (CTRL); 30 mg/kg/day L-NAME (L-name); L-NAME and 20 mg/kg/day rosuvastatin (L-name+ROS-20); or L-NAME and 2 mg/kg/day rosuvastatin (L-name+ROS-2). Systolic blood pressure was measured by plethysmography in the central artery of the tail. The serum total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, nitric oxide, interleukin-6, and tumor necrosis factor alpha levels were analyzed. Urine samples were taken to measure the albumin: urinary creatinine ratio. Kidneys were sectioned and stained with hematoxylin/eosin and Masson's trichrome. Immunohistochemical analysis of the renal tissue was performed to detect macrophage infiltration of the glomeruli. RESULTS: The systolic blood pressure was elevated in the L-name but not the L-name+rosuvastatin-20 and L-name+rosuvastatin-2 groups. The L-name group had a significantly reduced nitric oxide level and an increased interleukin-6 and tumor necrosis factor alpha level, albumin: urinary creatinine ratio and number of macrophages in the renal glomeruli. Rosuvastatin increased the nitric oxide level in the L-name+rosuvastatin-2 group and reduced the interleukin-6 and tumor necrosis factor alpha levels, glomerular macrophage number and albumin:urinary creatinine ratio in the L-name+rosuvastatin-20 and L-name+rosuvastatin-2 groups. CONCLUSION: Rosuvastatin treatment reduced glomerular damage due to improvement in the inflammatory pattern independent of the systolic blood pressure and serum lipid level. These effects may lead to improvements in the treatment of kidney disease.

Efeitos da rosuvastatina e da atividade física de baixa intensidade na morfologia renal de ratos normotensos e espontaneamente hipertensos (SHR) / Effects of rosuvastatin and low intensity physical activity on renal morphology in normotensive and spontaneously hypertensive rats (SHR)

Desordens do sistema renal podem ser as causas da hipertensão arterial, a qual pode, por sua vez, causar doenças renais. A pressão sanguínea elevada é muito comum também nas doenças crônicas dos rins, e é, além disso, um conhecido fator de risco para uma mais rápida progressão da falha renal. A incidência de doenças renais crônicas está aumentando no mundo, e há uma grande necessidade de identificar as terapias capazes de deter ou reduzir a progressão da doença. Há crescente evidência de que as estatinas poderiam desempenhar um papel terapêutico. Além disso, tem sido demonstrado que a atividade física melhora a função renal em pacientes. Estudos ultra-estruturais em humanos e em ratos demonstraram a presença de junções gap dentro de todas as células do glomérulo e os podócitos demonstraram conter principalmente conexina-43 (Cx-43). O presente estudo tem como objetivo observar os efeitos da rosuvastatina e da atividade física de baixa intensidade na estrutura e ultra-estrutura renal e na expressão glomerular de Cx-43 em ratos normotensos (WKY) e em ratos espontaneamente hipertensos (SHR). Os ratos foram divididos aleatoriamente em oito grupos: WKY-C: animais normotensos que não receberam rosuvastatina; WKY-ROS: animais normotensos que receberam rosuvastatina 20mg/kg/dia por gavagem orogástrica; SHR-C: animais hipertensos que não receberam rosuvastatina; SHR-ROS: animais hipertensos que receberam rosuvastatina, como descrito no grupo WKY-ROS; SED-WKY: animais normotensos sedentários; EX-WKY: animais normotensos exercitados; SED-SHR: animais hipertensos sedentários; e, EX-SHR: animais hipertensos exercitados. Os animais dos grupos SHR-C, SHR-ROS e SED-SHR apresentaram níveis de pressão arterial maiores que os animais dos grupos WKY-C, WKY-ROS, SED-WKY, EX-WKY e EX-SHR. A massa corporal dos grupos de animais não diferiram significativamente durante o experimento. Não houve diferença nos níveis sanguíneos de uréia, creatinina, ácido úrico e creatinafosfoquinase...

Disorders of the renal system may be the cause of hypertension, which can in turn cause kidney disease. The high blood pressure is also very common in chronic kidney diseases, and is also a known risk factor for faster progression of renal failure. The incidence of chronic kidney disease is increasing woldwide, and there is a great need to identify therapies to stop or slow the progression of the disease. There is growing evidence that statins could play a therapeutic role. Moreover, it has been shown that physical activity improves renal function in patients. Ultrastructural studies in humans and rats have shown the presence of gap junctions in all cells of the glomerular podocytes and also to contain mainly connexin-43 (Cx-43). This study aims to observe the effects of rosuvastatin and low-intensity physical activity on the structure and ultrastructure of kidney and glomerular expression of Cx-43 in normotensive rats (WKY) and spontaneously hypertensive rats (SHR). The rats were randomly divided into eight groups: WKY-C: normotensive animals not receiving rosuvastatin, WKY-ROS: normotensive animals that received rosuvastatin 20mg/kg/day by orogastric gavage, C-SHR: hypertensive animals not receiving rosuvastatin; SHR-ROS: hypertensive rats that received rosuvastatin, as described in ROS-WKY group, WKY-SED: sedentary normotensive, WKY-EX: normotensive rats exercised, SHR-SED: sedentary hypertensive rats, and EX-SHR: hypertensive rats exercised. The animals in groups C-SHR, SHR-SED and SHR-ROS had blood pressure levels higher than the animals in groups WKY-C, ROS-WKY, WKY-SED, EX-SHR and EX-WKY. The body mass of groups of animals did not differ significantly during the experiment. There was no difference in urea, creatinine, uric acid and creatine phosphokinase blood levels among animals of the studied groups. However, there was an increased excretion of 24 hours protein in SHR-C group. There was an increase in the capsule in group SHR-C...

WT-1 mRNA expression is modulated by nitric oxide availability and Hsp70 interaction after neonatal unilateral ureteral obstruction

Wilms tumor gene 1 (wt-1), a key regulator of mesenchymal-epithelial transformation, is downregulated during congenital obstructive nephropathy, leading to apoptosis. There is a functional interaction between WT-1 and inducible nitric oxide synthase (iNOS). In this regard, we reported that after neonatal unilateral ureteral obstruction, rosuvastatin prevents apoptosis through an increase in nitric oxide bioavailability, which in turn is linked to higher Hsp70 expression. Hence, the goal of this study was to determine whether a nitric oxide/Hsp70 interaction is involved in changes in WT-1 mRNA expression after ureteral obstruction. Neonatal rats submitted to experimental ureteral obstruction were treated with either vehicle or rosuvastatin for 14 days. Decreased nitric oxide and iNOS/Hsp70 expression associated wit h WT-1 low expression was shown in obstructed kidneys. Apoptosis was induced and it was associated with an increased Bax/BcL2 ratio. Conversely, iNOS/Hsp70 upregulation and an increased WT-1 mRNA expression, without an apoptotic response, were observed in the cortex of obstructed kidneys of rosuvastatin-treated rats. Nitric oxide also modulated Hsp70 and WT-1 mRNA expression in MDCK cells. Finally, in vivo experiments with nitric oxide modulators support our hypothesis that WT-1 mRNA expression is associated with nitric oxide level. Results suggest that rosuvastatin may modulate WT-1 mRNA expression through renal nitric oxide bioavailability, preventing neonatal obstruction-induced apoptosis associated with Hsp70 interaction.

Implications of dibenzyl trisulphide for disease treatment based on its mode of action / Implicaciones del trisulfuro de dibencilo para el tratamiento de enfermedades a partir de su modo de acción

Studies conducted on the secondary metabolite (natural product), dibenzyl trisulphide (DTS), which was isolated from the sub-tropical shrub Petiveria alliacea (guinea hen weed, anamu) [Phytolaccaceae] have shown tremendous pharmaceutical promise as a drug prototype. This is now reflected in the development of the broad spectrum anti-cancer molecule, fluorapacin (bis(4-fluorobenzyl) trisulphide) which has an excellent safety profile. The mode of action elucidated for DTS is the mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases ERK 1 and ERK 2). The MAPKinase signal transduction biochemical pathways are important in the regulation of a wide range of cellular processes which are important in disease establishment. These processes include: cancer cell proliferation, nerve repair, memory enhancement, autoimmune diseases, which are linked to thymic cell involution and bone marrow functions, cerebrovascular and cardiovascular diseases. In addition to the MAPkinase signal transduction mode of action, DTS also prevents the denaturation of serum albumin which is a feature of nonsteroidal anti-inflammatory drugs, thus supporting the molecule's possible role in the treatment of inflammatory ageing diseases.

Los estudios realizados sobre el metabolito secundario (producto natural), trisulfuro de dibencilo (TSD), que fue aislado del arbusto subtropical Petiveria alliacea (hierba de guinea, anamú) [Phytolaccaceae] muestran que se trata de una tremenda promesa farmacéutica como prototipo de droga. Esto se refleja actualmente en el desarrollo de la molécula anticancerígena de amplio espectro, la fluorapacina (bis (4-fluorobencilo) trisulfuro) que posee un excelente perfil de seguridad. El modo de acción para el TSD se explica partiendo de las proteínas quinasas 1 y 2 activadas por mitógenos y reguladas por señales extracelulares (Quinasas MAP ERK 1 y ERK 2). Las vías bioquímicas de transducción de la señal de la quinasa MAP, son importantes en la regulación de una amplia variedad de procesos celulares, importantes a la hora de determinar una enfermedad. Dichos procesos comprenden: la proliferación de la célula cancerosa, la reparación de nervios, el mejoramiento de la memoria, y las enfermedades autoinmunes, vinculadas con la involución tímica y las funciones de la médula, las enfermedades cerebrovasculares y cardiovasculares. Además del modo de acción de las transducción de señales de la quinasa MAP, el TSD previene también la desnaturalización de la albúmina sérica, lo cual constituye una característica de las drogas anti-inflamatorias no esferoidales, apoyando así el posible papel de las moléculas en el tratamiento de las enfermedades inflamatorias en el proceso de envejecimiento.

Impacto del uso de rosuvastatina en los primeros días de un síndrome coronario agudo en la fiunción endotelial y el poder oxidativo / Influence of rosuvastatin in endothelial function and oxidative stress, in patients with acute coronary syndrome

PURPOSE: The endothelial function is the cornerstone of several cardiovascular disease. In this trial we compared how the Nitric Oxide (NO) and Oxidative Stress (OS) serum levels, as surrogate markers of endothelial function, change in patients who received (or not) rosuvastatin during the first seven days of an acute coronary syndrome (ACS). METHODS: Twenty-two patients with ACS (age:66 +/- 9 years, gender: ten female and 12 male) were randomized in two groups. Patients in the first group (G1) received the conventional treatment for an ACS, plus placebo. The other group (G2) additionally received a daily oral dose of 40 mg of rosuvastatin. We measured the blood levels of nitrates and OS in both groups twice: at baseline (admission to Intensive care unit) and seven days after. The statistical analysis was performed using the paired t-test or the Chi2 test depending of the variables. Statistical significance was considered with a p < 0.05. RESULTS: Groups (G1 and G2) differed statistically on age (G1=71 years +/- 10 vs. G2 63 +/- 9 years, p=0.04). After 7 days of the ACS onset, ON levels diminished on 21% (p=0.17) in G1, but raised on 24% in the group who re- ceived rosuvastatin (p=0.005), with statistically difference between groups (p=0.005). On the other hand, the OS, augmented statistically on both groups: G1 (17%, p<0.001) and G2 (13%, p<0.001), without any difference between groups (p=0.77). Conclusion: The endothelial dysfunction in the first days of an ACS is accentuated, but with the use of rosuvastatina, the endothelial function improves. In contrast, the OS increase in both groups, without differences between groups.

Rosuvastatin and vascular dysfunction markers in pulmonary arterial hypertension: a placebo-controlled study

We investigated whether chronic rosuvastatin administration could improve the abnormalities of the circulating levels of vascular dysfunction markers in pulmonary arterial hypertension (PAH). Sixty patients, aged 13 to 60 years, with idiopathic (N = 14) or congenital heart disease-associated PAH (N = 46) were equally but randomly assigned to rosuvastatin treatment (10 mg a day, orally) or placebo for 6 months in a blind fashion. Plasma levels of P-selectin, tissue-plasminogen activator and its inhibitor as well as von Willebrand factor antigen were measured by enzyme-linked immunoassay before and after 1, 3, and 6 months of treatment. Baseline levels of biomarkers were elevated (68, 16, 45 and 46 percent increase relative to controls, for P-selectin, von Willebrand factor antigen, tissue-plasminogen activator and its inhibitor, respectively; P < 0.001). P-selectin values at baseline, 1, 3, and 6 months were 39.9 ± 18.5, 37.6 ± 14.6, 34.8 ± 14.6, and 35.4 ± 13.9 ng/mL, respectively, for the rosuvastatin group and 45.7 ± 26.8, 48.0 ± 26.9, 48.1 ± 25.7, and 45.7 ± 25.6 ng/mL for the placebo group. The P-selectin level was lower in the rosuvastatin group compared with placebo throughout treatment (P = 0.037, general linear model). A trend was observed towards a decrease in tissue-plasminogen activator in the statin group (16 percent reduction, P = 0.094), with no significant changes in the other markers. Since P-selectin is crucial in inflammation and thrombosis, its reduction by rosuvastatin is potentially relevant in the pathophysiological scenario of PAH.

Efectos pleiotrópicos de las estatinas: [revisión] / Pleiotropic effects of statins: [review]

Results of numerous epidemiologic studies indicate that elevated serum cholesterol, especially the LDL fraction, is a major cause of coronary heart disease (CHD). Epidemiologic and angiographic evidence from primary and secondary prevention studies involving several HMG-CoA reducíase inhibitors (statins) indicate that decreasing elevated serum cholesterol concentration (specifically LDL-cholesterol) can reduce the incidence of CHD and/or progression of atherosclerosis and results in a decrease in associated morbidity and mortality. It has been estimated that each 1 percent reduction in LDL-cholesterol concentration may result in a 1 percent decrease in the incidence of CHD. Furthermore, an analysis of pooled data from primary and secondary prevention studies found that treatment with a statin for a median duration of 5.4 years was associated with a 31 percent and 21 percent reduction in the risk of major coronary events and total mortality, respectively. This paper deals with the pharmacology of statins, specially with the pleiotropic effects ofthese drugs.

McArdle disease with rhabdomyolysis induced by rosuvastatin: case report

The rosuvastatin inducing rhabdomyolysis in McArdle disease (MD) has not been reported to date. A 35-years-old man had exercise intolerance, muscular fatigue and cramps during physical activity since infancy. He presented severe rhabdomyolysis episode with seizure and coma after use of rosuvastatin. The investigation showed increased serum creatinekinase levels and the forearm ischemic exercise did not increased venous lactate. The muscle biopsy showed subsarcolemmal and central acummulation of glycogen and absence of the myophosphorylase enzyme. The statin induced myopathy is discussed and the danger of its use in MD is emphasized.

Rosuvastatina induzindo rabdomiólise na doença de McArdle (MD) não foi relatada até o momento. Descrevemos o caso de um homem de 35 anos que desde a infância apresentava sintomas de intolerância aos exercícios, fadiga muscular e cãibras durante o esforço físico, porém após o uso de rosuvastatina apresentou episódio de rabdomiólise com crises convulsivas e coma. A investigação mostrou creatinoquinase sérica elevada e teste do esforço isquêmico sem aumento no lactato venoso. A biópsia muscular revelou acúmulo central e subsarcolemal de glicogênio nas fibras e ausência da enzima miofosforilase. Discutimos as estatinas induzindo miopatia, enfatizando o risco do seu uso na MD.

Tratamento hipolipemiante em situações especiais: pós-transplante e/ou terapia imunossupressora / Hypolipidemic treatment under special conditions: posttransplant and/or immunosupressive therapy

Existem dados limitados sobre o uso concomitante de agentes hipolipemiantes e drogas imunosupressoras. As melhores evidências provêm do uso de estatinas e ciclosporina. Em termos farmacodinâmicos, estas duas drogas têm substratos diferentes. No tocante a farmacocinética, as estatinas não modificam as concentrações plasmáticas de ciclosporina. Entretanto, quando combinada a qualquer estatina, um controle rigoroso dos níveis de ciclosporina é recomendado, levando-se em conta o seu estreito intervalo terapêutico. Ciclosporina afeta a área sob a curva de muitas estatinas, pela inibição do CYP450 3A4, aumentando a exposição sistêmica dessas drogas. Pravastatina se apresenta como o composto de maior segurança, uma vez que é glucuronidado. A área sob a curva para as outras estatinas (sinvastatina, lovastatina, atorvastatina, cerivastatina e rosuvastatina) pode aumentar em graus variáveis de acordo com o seu sítio de metabolização, extração hepática pelo OATP-transportador, secreção biliar, excreção renal, e extrusão da droga pelo sistema MDR.