RESUMEN
BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.
Asunto(s)
Complicaciones de la Diabetes/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Riñón/efectos de los fármacos , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Análisis de Varianza , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Atorvastatina , Creatinina/orina , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Europa (Continente) , Fluorobencenos/farmacología , Ácidos Heptanoicos/farmacología , Humanos , Lípidos/sangre , América del Norte , Proteinuria , Pirimidinas/farmacología , Pirroles/farmacología , Rosuvastatina Cálcica , América del Sur , Sulfonamidas/farmacologíaRESUMEN
OBJECTIVES: Prevention of the development of paraplegia during the repair of the damage caused by descending thoracic and thoracoabdominal aneurysms remains an important issue. Therefore, we investigated the protective effect of atorvastatin on ischemia-induced spinal cord injury in a rabbit model. METHOD: Thirty-two rabbits were divided into the following four equally sized groups: group I (control), group II (ischemia-reperfusion), group III (atorvastatin treatment) and group IV (atorvastatin withdrawal). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the iliac bifurcation. Seventy-two hours postoperatively, the motor function of the lower limbs of each animal was evaluated according to the Tarlov score. Spinal cord and blood samples were obtained for histopathological and biochemical analyses. RESULTS: All of the rabbits in group II exhibited severe neurological deficits. Atorvastatin treatment (groups III and IV) significantly reduced the level of motor dysfunction. No significant differences were observed between the motor function scores of groups III and IV at the evaluated time points. Light microscopic examination of spinal cord tissue samples obtained at the 72nd hour of reperfusion indicated greater tissue preservation in groups III and IV than in group II. CONCLUSION: This study demonstrates the considerable neuroprotective effect of atorvastatin on the neurological, biochemical and histopathological status of rabbits with ischemia-induced spinal cord injury. Moreover, the acute withdrawal of atorvastatin therapy following the induction of spinal cord ischemia did not increase the neuronal damage in this rabbit model.
Asunto(s)
Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Paraplejía/prevención & control , Pirroles/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Isquemia de la Médula Espinal/tratamiento farmacológico , Animales , Atorvastatina , Biopsia , Modelos Animales de Enfermedad , Malondialdehído/análisis , Óxido Nítrico/análisis , Paraplejía/patología , Conejos , Distribución Aleatoria , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , Reproducibilidad de los Resultados , Isquemia de la Médula Espinal/patología , Isquemia de la Médula Espinal/prevención & control , Superóxido Dismutasa/análisis , Factores de TiempoRESUMEN
Objective: To determine whether the use of a set of preoperative variables can predict the need for postoperative ICU admission. Methods: This was a prospective observational cohort study of 120 patients undergoing elective pulmonary resection between July of 2009 and April of 2012. Prediction of ICU admission was based on the presence of one or more of the following preoperative characteristics: predicted pneumonectomy; severe/very severe COPD; severe restrictive lung disease; FEV1 or DLCO predicted to be < 40% postoperatively; SpO2 on room air at rest < 90%; need for cardiac monitoring as a precautionary measure; or American Society of Anesthesiologists physical status ≥ 3. The gold standard for mandatory admission to the ICU was based on the presence of one or more of the following postoperative characteristics: maintenance of mechanical ventilation or reintubation; acute respiratory failure or need for noninvasive ventilation; hemodynamic instability or shock; intraoperative or immediate postoperative complications (clinical or surgical); or a recommendation by the anesthesiologist or surgeon to continue treatment in the ICU. Results: Among the 120 patients evaluated, 24 (20.0%) were predicted to require ICU admission, and ICU admission was considered mandatory in 16 (66.6%) of those 24. In contrast, among the 96 patients for whom ICU admission was not predicted, it was required in 14 (14.5%). The use of the criteria for predicting ICU admission showed good accuracy (81.6%), sensitivity of 53.3%, specificity of 91%, positive predictive value of 66.6%, and negative predictive value of 85.4%. Conclusions: The use of preoperative criteria for predicting the need for ICU admission after elective pulmonary resection is feasible and can reduce the number of patients staying in the ICU only for monitoring. .
Objetivo: Avaliar se a utilização de um conjunto de variáveis pré-operatórias é capaz de antever a necessidade de internação em UTI no pós-operatório. Métodos: Estudo de coorte observacional prospectivo, com 120 pacientes submetidos à ressecção pulmonar eletiva entre julho de 2009 e abril de 2012. A previsão de indicação de internação em UTI indicação foi baseada na presença de uma ou mais das seguintes condições pré-operatórias: previsão de pneumonectomia; DPOC grave/muito grave; doença restritiva grave; VEF1 ou DLCO previstos para o pós-operatório < 40% do previsto; SpO2 em repouso e ar ambiente < 90%; necessidade de monitorização cardíaca profilática; classificação da American Society of Anesthesiologists ≥ 3. O padrão ouro para internação justificada em UTI foi baseado na presença de uma ou mais das seguintes condições pós-operatórias: manutenção de ventilação mecânica ou reintubação; insuficiência respiratória aguda ou necessidade de ventilação não invasiva; instabilidade hemodinâmica ou choque; intercorrências intraoperatórias ou no pós-operatório imediato (cirúrgicas ou clínicas); indicação do anestesiologista ou cirurgião para a manutenção de tratamento na UTI. Resultados: Dos 120 pacientes avaliados, houve previsão de necessidade de internação em UTI em 24 (20,0%), sendo essa considerada justificada em 16 deles (66,6%) desses 24, ao passo que dos 96 pacientes sem previsão de necessidade de internação em UTI, essa foi necessária em 14 (14,5%). A utilização dos critérios preditivos para a internação em UTI mostrou boa acurácia (81,6%), sensibilidade de 53,3%, especificidade de 91%, valor preditivo positivo de 66,6% e valor preditivo negativo de 85,4%. Conclusões: A utilização de critérios pré-operatórios para a indicação de internação em UTI após ressecção pulmonar eletiva é factível e é capaz de reduzir o número de pacientes que aí permanecem apenas para vigilância. .
Asunto(s)
Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/diagnóstico , /diagnóstico , Glutamato Descarboxilasa/inmunología , Edad de Inicio , Anticolesterolemiantes/uso terapéutico , Método Doble Ciego , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , /tratamiento farmacológico , /inmunología , Intolerancia a la Glucosa , Alemania/epidemiología , Ácidos Heptanoicos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/tratamiento farmacológico , Fenotipo , Prevalencia , Estudios Prospectivos , Pirroles/uso terapéutico , Factores de RiesgoRESUMEN
OBJECTIVES: to evaluate the Nosocomial Infection Control Programs in hospital institutions regarding structure and process indicators. METHOD: this is a descriptive, exploratory and quantitative study conducted in 2013. The study population comprised 13 Nosocomial Infection Control Programs of health services in a Brazilian city of the state of São Paulo. Public domain instruments available in the Manual of Evaluation Indicators of Nosocomial Infection Control Practices were used. RESULTS: The indicators with the highest average compliance were "Evaluation of the Structure of the Nosocomial Infection Control Programs" (75%) and "Evaluation of the Epidemiological Surveillance System of Nosocomial Infection" (82%) and those with the lowest mean compliance scores were "Evaluation of Operational Guidelines" (58.97%) and "Evaluation of Activities of Control and Prevention of Nosocomial Infection" (60.29%). CONCLUSION: The use of indicators identified that, despite having produced knowledge about prevention and control of nosocomial infections, there is still a large gap between the practice and the recommendations. .
OBJETIVOS: avaliar os Programas de Controle de Infecção Hospitalar nas instituições hospitalares, quanto aos indicadores de estrutura e processo. MÉTODO: trata-se de um estudo descritivo, exploratório e quantitativo, realizado em 2013. A população foi composta por 13 Programas de Controle de Infecção Hospitalar de serviços de saúde, de uma cidade brasileira do interior paulista. Foram utilizados instrumentos de domínio público, disponibilizados no Manual de Indicadores de Avaliação de Práticas de Controle de Infecção Hospitalar. RESULTADOS: os indicadores com maior média de conformidade foram "Avaliação da Estrutura dos Programas de Controle de Infecção Hospitalar" (75%) e "Avaliação do Sistema de Vigilância Epidemiológica de Infecção Hospitalar" (82%) e os com menores médias foram "Avaliação das Diretrizes Operacionais" (58,97%) e "Avaliação das Atividades de Controle e Prevenção de Infecção Hospitalar" (60,29%). CONCLUSÃO: o uso de indicadores identificou que, apesar do conhecimento produzido sobre ações de prevenção e controle de infecções hospitalares, ainda existe um grande hiato entre prática e recomendações. .
OBJETIVOS: evaluar los Programas de Control de Infección Hospitalaria en las instituciones hospitalarias respecto a los indicadores de estructura y proceso. MÉTODO: se trata de un estudio descriptivo, exploratorio y cuantitativo, desarrollado en 2013. La población fue compuesta por 13 Programas de Control de Infección Hospitalaria de servicios de salud de una ciudad brasileña del interior paulista. Fueron utilizados instrumentos de dominio público, disponibles en el Manual de Indicadores de Evaluación de Prácticas de Control de Infección Hospitalaria. RESULTADOS: los indicadores con mayor promedio de conformidad fueron "Evaluación de la Estructura de los Programas de Control de Infección Hospitalaria" (75%) y "Evaluación del Sistema de Vigilancia Epidemiológica de Infección Hospitalaria" (82%) y aquellos con menores promedios "Evaluación de las Directivas Operacionales" (58,97%) y "Evaluación de las Actividades de Control y Prevención de Infección Hospitalaria" (60,29%). CONCLUSIÓN: el uso de indicadores posibilitó identificar que, a pesar del conocimiento producido sobre acciones de prevención y control de infecciones hospitalarias, todavía existe un gran hiato entre la práctica y las recomendaciones. .
Asunto(s)
Humanos , Masculino , Femenino , Anciano , Amlodipino/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea , Ácidos Heptanoicos/uso terapéutico , Hipertensión/tratamiento farmacológico , Riñón/fisiopatología , Pirroles/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Amlodipino/farmacología , Antihipertensivos/farmacología , Biomarcadores/metabolismo , Presión Sanguínea/efectos de los fármacos , Cápsulas , Quimioterapia Combinada , Glucosa/metabolismo , Ácidos Heptanoicos/farmacología , Hipertensión/complicaciones , Hipertensión/fisiopatología , Inflamación/patología , Pruebas de Función Renal , Riñón/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Análisis Multivariante , Estrés Oxidativo/efectos de los fármacos , Pirroles/farmacología , Análisis de Regresión , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
OBJECTIVES: Prevention of the development of paraplegia during the repair of the damage caused by descending thoracic and thoracoabdominal aneurysms remains an important issue. Therefore, we investigated the protective effect of atorvastatin on ischemia-induced spinal cord injury in a rabbit model. METHOD: Thirty-two rabbits were divided into the following four equally sized groups: group I (control), group II (ischemia-reperfusion), group III (atorvastatin treatment) and group IV (atorvastatin withdrawal). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the iliac bifurcation. Seventy-two hours postoperatively, the motor function of the lower limbs of each animal was evaluated according to the Tarlov score. Spinal cord and blood samples were obtained for histopathological and biochemical analyses. RESULTS: All of the rabbits in group II exhibited severe neurological deficits. Atorvastatin treatment (groups III and IV) significantly reduced the level of motor dysfunction. No significant differences were observed between the motor function scores of groups III and IV at the evaluated time points. Light microscopic examination of spinal cord tissue samples obtained at the 72nd hour of reperfusion indicated greater tissue preservation in groups III and IV than in group II. CONCLUSION: This study demonstrates the considerable neuroprotective effect of atorvastatin on the neurological, biochemical and histopathological status of rabbits with ischemia-induced spinal cord injury. Moreover, the acute withdrawal of atorvastatin therapy following the induction of spinal cord ischemia did not increase the neuronal damage in this rabbit model. .
Asunto(s)
Animales , Conejos , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Paraplejía/prevención & control , Pirroles/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Isquemia de la Médula Espinal/tratamiento farmacológico , Atorvastatina , Biopsia , Modelos Animales de Enfermedad , Malondialdehído/análisis , Óxido Nítrico/análisis , Paraplejía/patología , Distribución Aleatoria , Reproducibilidad de los Resultados , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , Isquemia de la Médula Espinal/patología , Isquemia de la Médula Espinal/prevención & control , Superóxido Dismutasa/análisis , Factores de TiempoRESUMEN
High levels of low-density lipoprotein cholesterol (LDL-C) enhance platelet activation, whereas high levels of high-density lipoprotein cholesterol (HDL-C) exert a cardioprotective effect. However, the effects on platelet activation of high levels of LDL-C combined with low levels of HDL-C (HLC) have not yet been reported. We aimed to evaluate the platelet activation marker of HLC patients and investigate the antiplatelet effect of atorvastatin on this population. Forty-eight patients with high levels of LDL-C were enrolled. Among these, 23 had HLC and the other 25 had high levels of LDL-C combined with normal levels of HDL-C (HNC). A total of 35 normocholesterolemic (NOMC) volunteers were included as controls. Whole blood flow cytometry and platelet aggregation measurements were performed on all participants to detect the following platelet activation markers: CD62p (P-selectin), PAC-1 (GPIIb/IIIa), and maximal platelet aggregation (MPAG). A daily dose of 20 mg atorvastatin was administered to patients with high levels of LDL-C, and the above assessments were obtained at baseline and after 1 and 2 months of treatment. The expression of platelets CD62p and PAC-1 was increased in HNC patients compared to NOMC volunteers (P<0.01 and P<0.05). Furthermore, the surface expression of platelets CD62p and PAC-1 was greater among HLC patients than among HNC patients (P<0.01 and P<0.05). Although the expression of CD62p and PAC-1 decreased significantly after atorvastatin treatment, it remained higher in the HLC group than in the HNC group (P<0.05 and P=0.116). The reduction of HDL-C further increased platelet activation in patients with high levels of LDL-C. Platelet activation remained higher among HLC patients regardless of atorvastatin treatment.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Ácidos Heptanoicos/uso terapéutico , Hipercolesterolemia/sangre , Activación Plaquetaria , Pirroles/uso terapéutico , Anciano , Análisis de Varianza , Atorvastatina , Biomarcadores/análisis , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Femenino , Citometría de Flujo , Humanos , Hipercolesterolemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Selectina-P/sangre , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/análisis , Estadísticas no ParamétricasRESUMEN
INTRODUCTION: Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. OBJECTIVE: To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. MATERIALS AND METHODS: Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. RESULTS: Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. CONCLUSION: These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue .
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Embolia Intracraneal/complicaciones , Degeneración Nerviosa/prevención & control , Pirroles/uso terapéutico , Tiazinas/uso terapéutico , Tiazoles/uso terapéutico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Atorvastatina , Biomarcadores , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Antígeno CD11b/análisis , Estenosis Carotídea/complicaciones , Estenosis Carotídea/patología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Proteína Ácida Fibrilar de la Glía/análisis , Ácidos Heptanoicos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inflamación , Embolia Intracraneal/patología , Meloxicam , Microglía/efectos de los fármacos , Microglía/patología , Proteínas del Tejido Nervioso/análisis , Pirroles/administración & dosificación , Distribución Aleatoria , Ratas , Ratas Wistar , Tiazinas/administración & dosificación , Tiazoles/administración & dosificaciónRESUMEN
Introducción. El accidente cerebrovascular es la segunda causa de muerte y la primera de discapacidad en el mundo, y más de 85 % es de origen isquémico. Objetivo. Evaluar en un modelo de infarto cerebral por embolia arterial el efecto de la atorvastatina y el meloxicam, administrados por separado y de forma conjunta, sobre la respuesta neuronal, los astrocitos y la microglia. Materiales y métodos. Se sometieron ratas Wistar a embolia de la arteria carótida y a tratamiento con meloxicam y atorvastatina, administrados por separado y conjuntamente, a las 6, 24, 48 y 72 horas. Se evaluó la reacción de las proteínas COX-2, GFAP y OX-42 en las neuronas, los astrocitos y la microglia mediante inmunohistoquímica y estudios morfológicos y de densitometría. Los datos obtenidos se evaluaron por medio de un análisis de varianza y de pruebas no paramétricas de comparación múltiple. Resultados. La isquemia cerebral por embolia arterial incrementó significativamente (p<0,001) la reacción de los astrocitos y la microglia, en tanto que la atorvastatina y el meloxicam, administrados por separado y de forma conjunta, la redujeron. La isquemia produjo acortamiento de las proyecciones de los astrocitos, engrosamiento celular, ruptura de las expansiones protoplásmicas (clasmatodendrosis) y cambios morfológicos en la microglia propios de diversas etapas de actividad. En las zonas circundantes del foco se incrementó la reacción inmunológica de la COX-2 y se redujo en el foco isquémico, en tanto que el meloxicam y la atorvastatina redujeron significativamente (p<0,001) la reacción inmunológica en la zona circundante del foco, restableciendo la marcación de la ciclooxigenasa en el foco isquémico. Conclusión. La combinación de meloxicam y atorvastatina atenúa la respuesta de los astrocitos y la microglia en el proceso inflamatorio posterior a la isquemia cerebral por embolia arterial, reduciendo la degeneración neuronal y restableciendo el equilibrio morfológico y funcional del tejido nervioso.
Introduction: Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. Objective: To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. Materials and methods: Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. Results: Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. Conclusion: These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue .
Asunto(s)
Animales , Femenino , Ratas , Isquemia Encefálica/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Embolia Intracraneal/complicaciones , Degeneración Nerviosa/prevención & control , Pirroles/uso terapéutico , Tiazinas/uso terapéutico , Tiazoles/uso terapéutico , Atorvastatina , /análisis , Astrocitos/efectos de los fármacos , Astrocitos/patología , Biomarcadores , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Estenosis Carotídea/complicaciones , Estenosis Carotídea/patología , Inhibidores de la Ciclooxigenasa/administración & dosificación , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Proteína Ácida Fibrilar de la Glía/análisis , Ácidos Heptanoicos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inflamación , Embolia Intracraneal/patología , Microglía/efectos de los fármacos , Microglía/patología , Proteínas del Tejido Nervioso/análisis , Pirroles/administración & dosificación , Distribución Aleatoria , Ratas Wistar , Tiazinas/administración & dosificación , Tiazoles/administración & dosificaciónRESUMEN
BACKGROUND: A previous study reported that the myosin regulatory light chain interacting protein (MYLIP) might serve as a novel therapeutic class for treating dyslipidemia. It contributes to variations in the levels of circulating low-density lipoprotein cholesterol (LDL-C), promoting the degradation of LDL-LDLR, thus limiting absorption. The effect of genetic variation in the MYLIP gene in a disease scenario characterized by mutations in the LDLR gene has not been previously evaluated. OBJECTIVE: The aim of this study was to assess the effect of the p.N342S variant on the response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia (FH). PATIENTS AND METHODS: A total of 156 patients with heterozygous FH were followed up for 12 months and received lipid-lowering therapy (different doses of atorvastatin with the addition of ezetimibe in over half the patients of each genotype group). Cholesterol data were assessed, and analysis of the MYLIP rs9370867 (p.N342S) genotypes was carried out by melting curve analysis. RESULTS: Baseline total cholesterol and baseline LDL-C levels were not different between genotypes. After 1 year of treatment, LDL-C responses (expressed as mg/dl and as %) were significantly different among genotypes (AA: -79±68 and -39±27, GA: -60±79 and -27±32, and GG: -30±83 and -15±38; P=0.02 and 0.005, respectively). In addition, FH patients carrying the AA genotype were more likely to achieve LDL-C levels of less than 130 mg/dl after 1 year of treatment (75.0%) compared with patients with the GG and GA genotypes (34.5 and 34.8%, respectively; P=0.001). CONCLUSION: Our study indicates that MYLIP p.N342S might be a pharmacogenetic marker for lipid-lowering therapy in patients with FH.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Polimorfismo Genético , Pirroles/uso terapéutico , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Atorvastatina , Secuencia de Bases , Brasil , Colesterol/sangre , Cartilla de ADN , Femenino , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana EdadRESUMEN
Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.
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Antituberculosos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/patogenicidad , Rifampin/uso terapéutico , Animales , Atorvastatina , Línea Celular , Sinergismo Farmacológico , Ácidos Heptanoicos/uso terapéutico , Humanos , Lepra/tratamiento farmacológico , Macrófagos/microbiología , Ratones , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Pirroles/uso terapéutico , Simvastatina/uso terapéuticoRESUMEN
Statins are potent cholesterol biosynthesis inhibitors that exert protective effects in humans and in experimental models of stroke. The mechanisms involved in these protective actions are not completely understood. This study evaluates whether atorvastatin (ATV) treatment affects the GluN1 and GluN2B subunits of the N-methyl-D-aspartic acid receptor in the somatosensory cerebral cortex at short and long periods following ischemia. Sham and ischemic male Wistar rats received 10 mg/kg of ATV or placebo by gavage every 24 hr for 3 consecutive days. The first dose was administered 6 hr after ischemia-reperfusion or the sham operation. ATV treatment resulted in faster recovery of neurological scores than placebo, prevented the appearance of pyknotic neurons, and restored microtubule-associated protein 2 and neuronal nuclei staining to control values in the somatosensory cerebral cortex and the hippocampus at 72 hr and 15 days postischemia. Furthermore, ATV prevented spatial learning and memory deficits caused by cerebral ischemia. Cerebral ischemia reduced the number of GluN1/PSD-95 and GluN2B/PSD-95 colocalization clusters in cortical pyramidal neurons and reduced the levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. These effects of the ischemic insult were prevented by ATV, which also induced GluN2B/PSD-95 colocalization in neuronal processes and an association of GluN2B with TrkB. The GluN2B pharmacological inhibitor ifenprodil prevented the increase in BDNF levels and the motor and cognitive function recovery caused by ATV in ischemic rats. These findings indicate that GluN2B is involved in the neuroprotective mechanism elicited by ATV to promote motor and cognitive recovery after focal cerebral ischemia.
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Anticolesterolemiantes/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Pirroles/uso terapéutico , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Anticolesterolemiantes/farmacología , Atorvastatina , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Células Cultivadas , Corteza Cerebral/citología , Modelos Animales de Enfermedad , Embrión de Mamíferos , Ácidos Heptanoicos/farmacología , Masculino , Aprendizaje por Laberinto , Proteínas del Tejido Nervioso/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiología , Piperidinas/farmacología , Piperidinas/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pirroles/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/genética , Recuperación de la Función/efectos de los fármacos , Corteza Somatosensorial/efectos de los fármacos , Factores de TiempoRESUMEN
INTRODUCTION: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. OBJECTIVE: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. MATERIALS AND METHODS: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. RESULTS: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. CONCLUSION: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.
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Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Ácidos Heptanoicos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Ataque Isquémico Transitorio/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Pirroles/uso terapéutico , Sustancia Negra/efectos de los fármacos , Animales , Atorvastatina , Conducta Animal , Cuerpo Estriado/irrigación sanguínea , Cuerpo Estriado/patología , Neuronas Dopaminérgicas/enzimología , Neuronas Dopaminérgicas/patología , Evaluación Preclínica de Medicamentos , Inducción Enzimática/efectos de los fármacos , Neuronas GABAérgicas/enzimología , Neuronas GABAérgicas/patología , Glutamato Descarboxilasa/biosíntesis , Glutamato Descarboxilasa/genética , Ácidos Heptanoicos/farmacología , Infarto de la Arteria Cerebral Media/patología , Ataque Isquémico Transitorio/patología , Masculino , Trastornos del Movimiento/etiología , Trastornos del Movimiento/prevención & control , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/farmacología , Pirroles/farmacología , Ratas , Ratas Wistar , Recuperación de la Función , Trastornos de la Sensación/etiología , Trastornos de la Sensación/prevención & control , Organismos Libres de Patógenos Específicos , Sustancia Negra/irrigación sanguínea , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/biosíntesis , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Materials and methods: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. Results: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Conclusion: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.
Introducción. La isquemia cerebral es la tercera causa de muerte y la primera de discapacidad permanente en el mundo. La atorvastatina es un fármaco neuroprotector prometedor para el tratamiento de la apoplejía; sin embargo, su acción sobre las poblaciones neuronales del sistema nigroestriatal después de la isquemia aún se desconoce. Objetivo. Evaluar el efecto de la atorvastatina sobre poblaciones gabérgicas y dopaminérgicas en regiones exofocales en un modelo de oclusión transitoria de la arteria cerebral media. Materiales y métodos. Se utilizaron 28 ratas Wistar macho de ocho semanas de edad. Los ejemplares con isquemia simulada y los ejemplares sometidos a isquemia fueron tratados con atorvastatina (10 mg/kg) y carboximetilcelulosa (placebo) administrados por medio de sonda a las 6, 24, 48 y 72 horas después de la reperfusión. Se analizó la inmunorreacción de la descarboxilasa del ácido glutámico y de la tirosina hidroxilasa en el globo pálido, el putamen caudado y la sustancia negra. Resultados. Los datos confirmaron el daño neurológico y la pérdida celular en el putamen caudado. Se incrementó la inmunorreacción de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata , disminuyendo la inmunorreacción de la descarboxilasa del ácido glutámico en el globo pálido lateral de los animales isquémicos tratados con placebo; sin embargo, el tratamiento con atorvastatina pudo revertirla, lo que logró una disminución significativa de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata y aumentando los niveles de descarboxilasa del ácido glutámico en el globo pálido lateral. Conclusión. Nuestros datos sugieren que la atorvastatina en el tratamiento posterior a la isquemia ejerce neuroprotección en las zonas exofocales, modulando las poblaciones neuronales gabérgicas y dopaminérgicas del sistema nigroestriatal, lo que podría prevenir trastornos neurológicos.
Asunto(s)
Animales , Masculino , Ratas , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Ácidos Heptanoicos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Ataque Isquémico Transitorio/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Pirroles/uso terapéutico , Sustancia Negra/efectos de los fármacos , Conducta Animal , Cuerpo Estriado/irrigación sanguínea , Cuerpo Estriado/patología , Evaluación Preclínica de Medicamentos , Neuronas Dopaminérgicas/enzimología , Neuronas Dopaminérgicas/patología , Inducción Enzimática/efectos de los fármacos , Neuronas GABAérgicas/enzimología , Neuronas GABAérgicas/patología , Glutamato Descarboxilasa/biosíntesis , Glutamato Descarboxilasa/genética , Ácidos Heptanoicos/farmacología , Infarto de la Arteria Cerebral Media/patología , Ataque Isquémico Transitorio/patología , Trastornos del Movimiento/etiología , Trastornos del Movimiento/prevención & control , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/farmacología , Pirroles/farmacología , Ratas Wistar , Recuperación de la Función , Organismos Libres de Patógenos Específicos , Trastornos de la Sensación/etiología , Trastornos de la Sensación/prevención & control , Sustancia Negra/irrigación sanguínea , Sustancia Negra/patología , /biosíntesis , /genéticaRESUMEN
The objective of this study was to evaluate whether levels of high mobility group box 1 (HMGB1) in granulomatosis with polyangiitis (GPA) patients are associated with carotid atherosclerosis, related to levels of soluble receptor for advanced glycation end-products (sRAGE) and influenced by immunosuppressive or lipid-lowering therapy. Twenty-three GPA patients and 20 controls were evaluated for HMGB1- and sRAGE levels and for carotid atherosclerosis using ultrasound to determine intima-media thickness (IMT). In vitro the effect of atorvastatin on the production of HMGB1 by lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVEC) was assessed. Serum HMGB1 and sRAGE levels did not differ between patients and controls. A negative correlation was found between sRAGE and maximum IMT but HMGB1 and carotid IMT were not related. HMGB1 levels were reduced in GPA patients on statins and prednisolone. In vitro, atorvastatin reduced HMGB1 levels in supernatants of activated HUVEC. In conclusion, carotid IMT is inversely correlated with sRAGE levels but not with HMGB1 levels. Statins and prednisolone are associated with reduced serum HMGB1 levels and atorvastatin decreases HMGB1 release by activated HUVEC in vitro, indicating an additional anti-inflammatory effect of statins.
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Aterosclerosis/sangre , Aterosclerosis/complicaciones , Granulomatosis con Poliangitis/complicaciones , Proteína HMGB1/sangre , Receptores Inmunológicos/sangre , Receptores Inmunológicos/química , Aterosclerosis/tratamiento farmacológico , Atorvastatina , Femenino , Ácidos Heptanoicos/farmacología , Ácidos Heptanoicos/uso terapéutico , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Prednisolona/farmacología , Prednisolona/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Receptor para Productos Finales de Glicación Avanzada , SolubilidadRESUMEN
Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice. Data demonstrate that the serotonin (5-HT) depleting agent p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p.) completely abolished atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. Besides atorvastatin, fluoxetine (10 mg/kg, p.o.), a serotonin selective reuptake inhibitor (SSRI) was able to exert an antidepressant-like effect, but any of them changed 5-HT content in the hippocampus or frontal cortex. The 5H-T1A (WAY100635, 0.1 mg/kg, s.c) or the 5-HT2A/2C (ketanserin, 5 mg/kg, s.c.) receptor antagonists prevented atorvastatin antidepressant-like effect. In addition, a combinatory antidepressant-like effect was observed when mice received the co-administration of sub-effective doses of atorvastatin (0.01 mg/kg, p.o.) and the SSRI fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.). Taken together, these results indicate that the antidepressant-like effect of atorvastatin depends on the serotonergic system modulation.
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Antidepresivos/uso terapéutico , Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Ácidos Heptanoicos/uso terapéutico , Pirroles/uso terapéutico , Serotonina/metabolismo , Animales , Antidepresivos/farmacología , Atorvastatina , Encéfalo/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Masculino , Ratones , Pirroles/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Resultado del TratamientoRESUMEN
This study aimed to investigate the relationship between the cholesterol ester transfer protein (CETP) gene TaqIB polymorphism and the lipid-lowering effect of atorvastatin in patients with coronary atherosclerotic heart disease. Two hundred eighty-eight patients were divided into a control group, an acute coronary syndrome (ACS) group, and a stable coronary heart disease (CHD) group. Blood biochemical indices were determined using the enzyme method, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to study the TaqIB polymorphism of the CETP gene. The ACS and stable CHD groups were treated with atorvastatin, and blood lipid levels were reexamined after three months. Plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a) were all significantly higher in the ACS and stable CHD groups compared to the control group (P < 0.05 or P < 0.01). After three months of treatment with atorvastatin, plasma levels of TC, LDL-C, triglycerides (TG) (only in patients with genotype B2B2), and lipoprotein(a) (only in patients with genotype B1B2) were all significantly decreased (P < 0.05 or P < 0.01). After treatment, the plasma level of TG was lower in patients with genotype B2B2 compared to patients with genotypes B1B1 or B1B2 (B1 carriers) (P < 0.01). Therefore, the CETP TaqIB polymorphism is associated with the lipid-lowering effect of atorvastatin in patients with CHD.
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Proteínas de Transferencia de Ésteres de Colesterol/genética , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/genética , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Polimorfismo de Longitud del Fragmento de Restricción , Pirroles/uso terapéutico , Adulto , Anciano , Alelos , Atorvastatina , Enfermedad de la Arteria Coronaria/sangre , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: This study evaluated the influence of the polymorphisms G1784C (rs4822063) and A2386G (rs12487736) of SREBP-2 and SCAP genes, respectively, on the response to atorvastatin treatment in a cohort of Chilean subjects with Amerindian background. METHODS: A total of 142 hypercholesterolemic individuals underwent atorvastatin therapy (10 mg/day/1 month). Serum lipids levels before and after treatment were measured. Genotyping of the studied polymorphisms and ethnic characterization through Amerindian haplogroups (A, B, C, and D) of mitochondrial DNA was achieved by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP), respectively. RESULTS: Of all individuals, 85 % turned out to be Amerindian. C allele carriers for polymorphism G1784C, had a lower total cholesterol reduction (p = 0.015) and low-density lipoprotein cholesterol (LDL-C) (p = 0.013). No differences were found for the A2386G variant. However, those who carried both polymorphisms had a lower LDL-C reduction than carriers of just one of the variants (p = 0.030). CONCLUSION: The G1784C polymorphism of SREBP-2 gene affects atorvastatin response in Chilean subjects with Amerindian background, and may be an important marker for predicting efficacy of lipid-lowering therapy.
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Ácidos Heptanoicos/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Polimorfismo Genético/genética , Pirroles/uso terapéutico , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Atorvastatina , LDL-Colesterol , Femenino , Haplotipos/genética , Humanos , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/genética , Masculino , Polimorfismo de Longitud del Fragmento de Restricción/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Our aim was to investigate the effects of four different statins on acute lung inflammation induced by cigarette smoke (CS). C57BL/6 male mice were divided into a control group (sham-smoked) and mice exposed to CS from 12 cigarettes/day for 5 days. Mice exposed to CS were grouped and treated with vehicle (i.p.), atorvastatin (10 mg/kg), pravastatin (10 mg/kg), rosuvastatin (5 mg/kg), or simvastatin (20 mg/kg). Treatment with statins differentially improved the pulmonary response when compared to the CS group. Atorvastatin and pravastatin demonstrated slightly effects on inflammation and oxidative stress. Rosuvastatin demonstrated the best anti-inflammatory effect, whereas simvastatin demonstrated the best antioxidant response.
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Fluorobencenos/farmacología , Ácidos Heptanoicos/farmacología , Pulmón/metabolismo , Estrés Oxidativo/fisiología , Pravastatina/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Simvastatina/farmacología , Fumar/metabolismo , Sulfonamidas/farmacología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Atorvastatina , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Pravastatina/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Rosuvastatina Cálcica , Simvastatina/uso terapéutico , Fumar/tratamiento farmacológico , Fumar/patología , Sulfonamidas/uso terapéuticoRESUMEN
OBJECTIVES: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. METHODS: For 14 ± 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. RESULTS: The frequencies of the types of LDLR mutations were: null-mutation (n = 40, 25.6%), defective-mutation (n = 59, 37.8%), and without an identified mutation (n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 ± 1.9 mmol/L, 7.9 ± 1.7 mmol/L), compared to those with a defective (8.9 ± 2.2 mmol/L, 7.0 ± 2.0 mmol/L), or no mutation (7.9 ± 1.9 mmol/L, 5.8 ± 1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) (p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41-58.16, p = 0.02). CONCLUSIONS: Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation.
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Ácidos Heptanoicos/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Lípidos/sangre , Pirroles/uso terapéutico , Receptores de LDL/genética , Adulto , Anciano , Atorvastatina , Azetidinas/uso terapéutico , Brasil , LDL-Colesterol/sangre , Ezetimiba , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.