Preoperative predictive factors for intensive care unit admission after pulmonary resection / Fatores preditivos pré-operatórios de internação em unidade de terapia intensiva após ressecção pulmonar

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. .

Evaluation of Nosocomial Infection Control Programs in health services / Avaliação dos Programas de Controle de Infecção Hospitalar em serviços de saúde / Evaluación de los Programas de Control de Infección Hospitalaria en servicios de salud

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. .

Neuroprotective effect of atorvastatin in spinal cord ischemia-reperfusion injury

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. .

La combinación de atorvastatina y meloxicam inhibe la neuroinflamación y atenúa el daño celular en la isquemia cerebral experimental por embolia arterial / Atorvastatin-meloxicam association inhibits neuroinflammation and attenuates the cellular damage in cerebral ischemia by arterial embolism.

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 .

Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia / La atorvastatina protege las neuronas gabérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

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.

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy / Influência de polimorfismos nos genes PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

OBJETIVO: O objetivo deste estudo foi investigar a associação de seis variantes genéticas nos genes de receptores nucleares PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas. SUJEITOS E MÉTODOS: O estudo foi realizado com 240 pacientes hipercolesterolêmicos em terapia com sinvastina e atorvastatina. Os polimorfismos foram analisados por meio de métodos baseados em PCR. RESULTADOS: A distribuição da frequência genotípica do polimorfismo NR1I3 rs2307424 foi diferente entre os pacientes com e sem efeito adverso à medicação; entre os sujeitos do grupo com efeitos adversos, nenhum homozigoto T/T foi observado, enquanto no grupo de indivíduos sem efeitos adversos a frequência desse genótipo foi 19,4% (P = 0,007, após correção para múltiplos testes P = 0,042). CONCLUSÃO: Os polimorfismos investigados nos genes PPARA (rs1800206), RXRA (rs11381416) e NR1I2 (rs1523130) não foram associados com eficácia hipolipemiante e segurança da terapia com estatinas. Nossos resultados mostram uma possível influência de variantes do gene NR1I3 (rs2307424) no desenvolvimento de efeitos adversos à terapia com estatinas.

El aumento de la expresión del ARNm de la enzima convertidora de angiotensina I homóloga (ECA-2) inducido por atorvastatina se asocia a menor fibrosis e hipertrofia ventricular izquierda en un modelo de cardiomiopatía diabética / Atorvastatin induced increase in homologous angiotensin i converting enzyme (ACE2) mRNA is associated to decreased fibrosis and decreased left ventricular hypertrophy in a rat model of diabetic cardiomyopathy

Objetivos. Evaluar el efecto de atorvastatina sobre la progresión del remodelado cardiaco y la expresión de ECA-2 en el miocardio de ratas diabéticas. Materiales y métodos. La diabetes fue inducida en ratas Holtzman con una inyección intraperitoneal de estreptozotocina. Los animales fueron divididos en tres grupos: (1) ratas control, (2) ratas diabéticas y (3) ratas diabéticas tratadas con atorvastatina (50 mg/kg/día). Después de ocho semanas de tratamiento, los corazones fueron extraídos para el análisis morfométrico, la cuantificación de colágeno y la determinación de los niveles de ARNm de ECA y ECA-2. Resultados. El índice de hipertrofia ventricular y el depósito de colágeno se incrementaron significativamente en las ratas diabéticas. La administración de atorvastatina previno estos cambios sin modificar los niveles de colesterol. La hiperglicemia produjo un incremento significativo en los niveles del ARNm de ECA y una marcada disminución en la expresión de ECA-2 en el miocardio de ratas diabéticas. La administración de atorvastatina indujo la expresión del ARNm de ECA-2 e inhibió la sobreexpresión del ARNm de ECA en el miocardio de las ratas diabéticas. Conclusiones. Nuestros resultados indican que la atorvastatina, independientemente de su capacidad para disminuir el colesterol, normaliza la relación de la expresión de ECA/ECA-2 y atenúa el desarrollo del remodelado adverso en el corazón diabético.

Objectives. This study has investigated the effect of atorvastatin on the progression of cardiac remodelling and ACE- 2 expression in diabetic myocardium in rats. Materials and Methods. Diabetes was induced in Holtzman rats with an intraperitoneal injection of streptozotocin. The animals were divided into 3 groups: (1) normal control rats, (2) diabetic rats and (3) diabetic rats treated orally with atorvastatin (50 mg/kg/day). After eight weeks of treatment, the hearts were removed for morphometric studies, collagen content assay and genetic expressions of ACE and ACE2 mRNA. Results. Myocardial hypertrophy index and collagen deposition were increased in diabetic rats, but not in the treated-diabetic rats, without producing changes in cholesterol levels. Myocardial ACE mRNA levels were increased while ACE2 mRNA levels were decreased in diabetic rats. Atorvastatin administration attenuated overexpression of ACE mRNA and overexpression of ACE-2 mRNA in diabetic rats. Conclusions. Our results indicate that atorvastatin, independently of its cholesterol-lowering capacity, lowers the ACE/ACE2 ratio to normal values and attenuates the development of adverse remodeling in the diabetic heart.

Efecto de variantes de los genes ABCB1 y CYP3A4 sobre la respuesta terapéutica a atorvastatina en individuos chilenos hipercolesterolémicos / The effect of a variant of gene ABCB1 and CYP3A4A on Atorvastatin therapeutic answer in chilean hypercholesterolemic individuals

Introducción: El tratamiento farmacológico con estatinas es eficaz en el control de la hipercolesterolemia Sin embargo, su respuesta terapéutica presenta gran variabilidad interindividual. Factores como edad, género y etnia han sido relacionados a esta variabilidad. Además, estudios recientes demuestran que polimorfismos genéticos también pueden influir sobre la respuesta terapéutica a estos hipolipemiantes. Así, el objetivo del presente trabajo fue investigar el efecto de tres polimorfismos de los genes ABCB1 (3435C>T y 2677G>A>T) y CYP3A4 (-290A>G) sobre la respuesta al tratamiento con atorvastatina en individuos chilenos hipercolesterolémicos. Métodos: Fueron evaluados 94 individuos hipercolesterolémicos adultos, 35 hombres y 59 mujeres, tratados con atorvastatina (10mg/día) durante 4 semanas. Se realizó medición de los niveles séricos de colesterol total, triglicéridos, HDL-c y LDL-c, antes y después del tratamiento. La genotipificación de los polimorfismos se realizó mediante PCR-RFLP Resultados: Después de 4 semanas de tratamiento, se observaron reducciones significativas en los niveles de colesterol total (275 +/- 18 vs. 235 +/- 22 mg/dL, p<0.001), LDL-c (183 +/- 16 vs. 146 +/- 24 mg/dL, p<0.001) y triglicéridos (225 +/- 48 vs. 172 +/- 51 mg/dL, p<0.001). Además, se observó un aumento en las concentraciones de HDL-c (47 +/- 10 vs. 55 ± 7, p<0.001). La distribución de genotipos para el polimorfismo 3435C>T (ABCB1) fue: CC=47.9 por ciento, CT= 41.5 por ciento y TT=10.6 por ciento; para el polimorfismo trialélico 2677G>A>T (ABCB1): AA=1.1 por ciento, GA=14.9 por ciento, GT=28.7 por ciento, TA=9.6 por ciento, TT=8.5 por ciento y GG=37.2 por ciento y para -290A>G (CYP3A4) fue: AA= 77.7 por ciento, AG= 22.3 por ciento y GG=0.0 por ciento. Los portadores del alelo G de la variante -290A>G (CYP3A4) presentaron mayor reducción de colesterol total (p=0.001) y LDL-C (p<0.001), y un mayor aumento de HDL-c (p<0.001). No se observaron diferencias significativas para...

Background: : statins are effective in the control of hypercholesterolemia. However, the therapeutic response to these drugs presents a great inter-individual variability. Factors such as age, gender and ethnicity have been associated to this variability. Recent studies show that polymorphisms can influence the lipid-lowe-ring response to statins. The aim of the present study was to investigate the effect of three polymorphisms 3435C>T (ABCB1), 2677G>A/T (ABCB1) and -290 A>G (CYP3A4) gene on the response to atorvastatin treatment in Chilean hypercholesterolemic individuals. Methods: 94 hypercholesterolemic individuals, were treated with atorvastatin, 10mg/day for 4 weeks. We determined serum levels of total cholesterol, HDL-c, LDL-c and triglycerides, before and after treatment. The polymorphisms were analyzed by PCR-RFLP. Results: Significant reductions were observed in total cholesterol (275 +/- 18 vs. 235 +/- 22 mg/dL, p<0.001), LDL-c (183 +/- 16 vs. 146 +/- 24 mg/dL, p<0.001) and triglycerides levels (225 +/- 48 vs. 172 +/- 51 mg/dL, polymorphisms on the therapeutic hypercholesterolemic individuals p<0.001). In addition, an increase in the HDL-C levels was observed (47 +/- 10 vs. 55 ± 7, p<0.001). The genotype distribution for 3535C>T variant of ABCB1 gene was: CC=47.9 percent, CT=41.5 percent and TT=10.6 percent. The genotype distribution for 2677G>A/T polymorphism (ABCB1) was AA=1.1 percent, GA=14.9 percent, GT=28.7 percent, TA=9.6 percent, TT=8.5 percent and GG=37.2 percent. The genotype distribution for -290A>G variant of CYP3A4 gene was: AA=77.7 percent. AG=22.3 percent and GG=0.0 percent. Subjects carrying the G allele for the -290 A>G variant of the CYP3A4 gene, exhibited a greater reduction in total cholesterol (p=0.001) and LDL-C levels (p<0.001). No differences were observed for the other polymorphisms studied. Conclusion: This study suggests that the therapeutic response to atorvastatin (10mg/day during 4 weeks) is influenced by the -290 A>G...

Asociación de niveles de lípidos y haplogrupos Amerindios de DNA mitocondrial en individuos chilenos hipercolesterolémicos tratados con atorvastatina / Association of serum lipid levels and mitochondrial DNA Amerindian haplogroups in hypercholesterolemic subjects receiving atorvastatin

Resumen: Introducción: La respuesta terapéutica a estatuías se ve influenciada por factores como la edad, género y etnicidad. Con respecto a esto, el background genético de la población chilena es predominantemente Amerindio, definido por la presencia de haplogrupos Amerindios A, B, C y D de DNA mitocondrial (mtDNA). Así, el objetivo del estudio fue evaluar la potencial asociación entre la presencia de haplogrupos Amerindios de mtDNA y niveles de lípidos en individuos chilenos hipercolesterolémicos tratados con Atorvastatina. Métodos: Un total de 42 individuos en dos centros de salud del sur de Chile fueron incluidos en el estudio. En el grupo de pacientes se evaluó la presencia de haplogrupos Amerindios de mtDNA por PCR-RFLP, además de la cuantificación de Colesterol Total, Triglicéridos, Colesterol-HDL y Colesterol-LDL, antes y después del tratamiento con Atorvastatina (10 mg/día). Resultados: El 88.1 por ciento de los sujetos presentó algún haplogrupo Amerindio, no observándose diferencias en los niveles de lípidos pre- tratamiento de acuerdo al haplogrupo. Interesantemente, individuos de haplogrupo B presentaron niveles mayores de Colesterol Total (B: 254 +/- 30 mg/dl v/s C: 213 +/- 48 mg/dl, D: 230 +/- 50 mg/dl; p= 0.0319) y Colesterol-LDL (B: 157 +/- 34 mg/dl v/s C: 118 +/- 45 mg/dl, D: 135 +/- 42 mg/dl; p=0.0344) post-tratamiento. Conclusiones: El haplogrupo B se asocia a niveles mayores de lípidos post-tratamiento en pacientes tratados con Atorvastatina. Estos hallazgos sugieren por primera vez, que la presencia de haplogrupo B de mtDNA determinaría una menor respuesta al tratamiento con Atorvastatina en individuos chilenos con background genético amerindio.

Background: Therapeutic response to statins is influenced by age, gender and ethnicity. The genetic background of the Chilean population is predominantly Amerindian, defined by the presence of mitochondrial DNA (mtDNA) Amerindian haplogroups A, B, C and D Amerindian haplogroups and serum lipid levéis in hypercholesterolemic Chilean subjects receiving atorvastatin Methods: 42 subjects from southern Chile were included. The presence of mtDNA Amerindian haplogroups was evaluated by PCR-RFLP; in addition, total cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol were measured before and after treatment with atorvastatin 10 mg/day. Aim: to evaluate a possible association of mtDNA. Ameridian haplogroups and serum lipid levels in hypercholesterolemic Chilean subjects receiving atorvastatin. Result: 88.1 percent of subjects exhibited some Amerindian haplogroup. No relation of lipid levels with haplogroups was observed before treatment. Interestingly, haplogroup B individuals had higher levels of total cholesterol compared to other haplogroups after treatment (haplogroup B : 254 +/- 30 mg/dl; C : 213 +/- 48 mg/dl; D : 230 +/- 50 mg/dl, p=0.0319). Corresponding levels for LDL-cholesterol after treatment in the three groups were 157 +/- 34,118 +/-45 and 135 +/-42 mg/ di, respectively, p=0.0344. Conclusion: Compared to other haplogroups, haplogroup B is associated to higher levels of lipids after treatment with atorvastatin. For the first time, these findings suggest that the presence of mtDNA haplogroup B determines a dimished response to atorvastatin in Chilean subjets with an Amerindian genetic background.

Effect of Atorvastatin in radiographic density on alveolar bone loss in wistar rats

The purpose of this study was to evaluate the effect of Atorvastatin (ATV) on alveolar bone loss induced in rats. Periodontitis was induced by ligature placement around the upper second left molar in a total of 24 male Wistar rats (± 200 g). Groups of 6 animals received via oral gavage either saline or ATV (1, 3 and 9 mg/kg) during 11 days. After this time, the animals were sacrificed and their maxillae were removed, defleshed, radiographed by Digora System®, and latter stained to be photographed using a digital camera. Data were analyzed statistically by ANOVA and Bonferroni test at 5 percent significance level and presented as mean ± SEM. ATV (9 mg/kg) caused a significant increase on gray tone variation of over 48 percent (118.3 ± 12.0 gray tones) when compared to saline (79.8 ± 6.2 gray tones), indicating greater radiographic density. These data were corroborated by macroscopic findings, where ATV (9 mg/kg) reduced alveolar bone loss by over 47 percent (p<0.05), when compared to the group of untreated animals (saline). In summary, ATV was able to prevent alveolar bone loss seen on a ligature-induced periodontitis model.

O objetivo deste estudo foi avaliar o efeito da Atorvastatina (ATV) na perda óssea alveolar induzida em ratos. A periodontite foi induzida através da colocação de ligadura ao redor do segundo molar superior esquerdo de um total de 24 ratos Wistar machos (± 200 g). Grupos de 6 animais receberam por via oral solução Salina a 0,9 por cento ou Atorvastatina (1, 3 e 9 mg/kg), por 11 dias, quando então foram sacrificados e suas maxilas foram removidas, dissecadas, radiografadas através do Sistema Digora System®, e fotografados usando câmara digital. Os dados foram expressos como média ± EPM (ANOVA e teste de Bonferroni). Atorvastatina (9 mg/kg) causou aumento significante de aproximadamente 48 por cento na variação de tons de cinza (ATV 9=118,3 ± 12,0 tons de cinza), indicando maior densidade radiográfica, quando comparada ao controle (solução salina =79,8 ± 6,2 tons de cinza). Estes dados foram corroborados pelos achados macroscópicos, onde Atorvastatina (9 mg/kg) reduziu a perda óssea alveolar em 47 por cento (p<0,05), quando comparado aos animais não tratados (solução salina). Em suma, a Atorvastatina preveniu a perda óssea alveolar vista no modelo de periodontite induzida por ligadura.

Effect of atorvastatin on LDL & hs-CRP in a selected Thai population.

BACKGROUND: LDL and hs-CRP are risk factors for vascular events and can be modified by Statin. OBJECTIVE: To evaluate the baseline hs-CRP of a certain Thai population who would need Atorvastatin, to evaluate the dose response of Atorvastatin toward LDL and hs-CRP level, and to evaluate the efficacy and safety of different types of Atorvastatin. MATERIAL AND METHOD: Subjects, who needed Statin therapy, were randomized to receive either 20 mg of Berlin(B)-Atorvastatin(R) or Pfizer(P)-Atorvastatin(R). The cross over took place after 8 weeks of therapy and continued for 16 weeks. Baseline blood tests were compared to 8 and 16 weeks. The effect of two brands of 20 mg Atorvastatin toward serum lipid, LFT, muscle enzyme and hs-CRP were compared. RESULTS: One hundred and ten subjects aged between 20-75 years enrolled in the present study. Fifty-four and 56 patients were randomized to group A and B. Baseline total cholesterol, LDL, HDL, and TG were 251, 174, 55, and 160 mg/dl respectively. There was a wide variation of baseline hs-CRP level. One hundred and seven patients completed this 16 weeks study. Atorvastatin 20 mg lowered TC by 32%, LDL 44% and hs-CRP 10% at 16 weeks for the entire study (p < 0.003). The effect of either Atorvastatin the lipid profiles and hs-CRP were different. There was no significant change in LFT or muscle enzyme. CONCLUSION: Atorvastatin 20 mg has a dramatic effect on the lipid but moderate effect on CRP. The two different types of Atorvastatin (group A and B) have similar effect on both safety and efficacy.

Effects of atorvastatin on warfarin-induced aortic medial calcification and systolic blood pressure in rats / 华中科技大学学报（医学）（英德文版）

The effect of atorvastatin on warfarin-induced aortic medial calcification and systolic blood pressure (SBP) of rats induced by warfarin was studied. Thirty healthy and adult rats were randomly divided into Warfarin group (n=10), Atorvastatin group (n=10) and normal control group (n=10). Caudal arterial pressure of rats was measured once a week, and 4 weeks later, aorta was obtained. Elastic fiber, collagen fiber and calcium accumulation in tunica media of cells were measured by Von Kossa staining. The results showed that warfarin treatment led to elevation of systolic blood pressure and aortic medial calcification. The chronic treatment also increased collagen, but decreased elastin in the aorta. However, the atorvastatin treatment had adverse effects. It was concluded that treatment with atorvastatin presented evidence of blood pressure lowing and calcification reducing. These data demonstrate that atorvastatin protected aortic media from warfarin-induced calcification and elevation of systolic blood pressure.

Vascular and metabolic response to statin in the mildly hypertensive hypercholesterolemic elderly

INTRODUCTION: Much evidence indicates the importance of the endothelium and hypercholesterolemia in atherosclerosis, as well as the decline in endothelial function with aging. However, it is unclear if treating dyslipidemia in elderly patients improves endothelial function and reduces C-reactive protein levels. OBJECTIVES: To evaluate vasomotor function, lipids and C-reactive protein in mildly hypertensive and hypercholesterolemic elderly patients treated with atorvastatin. METHODS: Forty-seven elderly Brazilian subjects (> 65 years old) with LDL cholesterol (LDL-c) > 130 mg/dL were randomly assigned, in a double-blinded manner, to receive either placebo (n = 23) or 20 mg/day of atorvastatin (n = 24) for 4 weeks. Exclusion criteria included diabetes, serious hypertension, obesity, steroid use, hormone replacement, and statin use within the previous six months. All patients underwent clinical examinations, laboratory tests (glucose, lipids, liver enzymes, creatine phosphokinase and high sensitivity C-reactive protein) and assessment of vasomotor function by high-resolution ultrasound examination of the brachial artery (flow-mediated dilation and sublingual nitrate), both before and after treatment. RESULTS: The patients were 65 to 91 years old; there was no significant difference between basal flow-mediated dilation of placebo (7.3 ± 6.1 percent) and atorvastatin (4.5 ± 5.1 percent; p = 0.20). The same was observed after treatment (6.6 ± 6.2 vs. 5.0 ± 5.6; p = 0.55). The initial nitrate dilatation (8.1 ± 5.4 percent vs. 10.8 ± 7.5 percent; p = 0.24) and that after 4 week treatment (7.1 ± 4.7 percent vs. 8.6 ± 5.0 percent; p = 0.37) were similar. Atorvastatin produced a reduction of 20 percent of the C-reactive protein and 42 percent in the LDL-c; however, there were no changes in the flow-mediated dilation. CONCLUSIONS: Atorvastatin produced a significant change of lipids and C-reactive protein; however, there were no changes in vasomotor ...

¿Puede la atorvastatina mejorar la respuesta a sildenafil en hombres con disfunción eréctil que no respondieron inicialmente a sildenafil? / Can atorvastatine increase sildenafil response in patients resistant to initial sildenafil therapy?

La disfunción eréctil puede ser una de las manifestaciones de enfermedad vascular generalizada, caracterizada por disfunción endotelial. Las estatinas pueden mejorar la función endotelial, incluso antes de alterar el perfil lipídico. Objetivo: Evaluar la mejoría de disfunción eréctil con atorvastatina en pacientes que no respondieron inicialmente a sildenafil. Material y métodos: Estudio controlado, placebo, randomizado, doble ciego, en el cuál se incluyeron hombres con disfunción eréctil moderada a severa, apesar de un esquema adecuado de Sildenafil. Se definió disfunción eréctil con un cuestionario auto administrado, score < o = a 16, según el Indice Internacional de Función Eréctil. La mejoría en el score de disfunción eréctil con Sildenafil fue reevaluada a los 6 y 12 semanas de tratamiento con Atorvastatina (80mg/día) v/s placebo. Resultado: Se incluyeron 18 hombres (edad media de 62 +/-12 años), con un score medio de 7.9 +/-5.8 y una duración media de la disfunción eréctil de 5.2 años. El tratamiento con Atorvastatina disminuyó el colesterol LDL en un 39 por ciento y resultó en una mejoría en el score de 7.6 (p < 0.05) con Sildenafil; este efecto se mantuvo por 6 semanas. El grupo placebo si bien logró mejoría en el score, esta no tuvo significación estadística. Conclusión: El tratamiento con Atorvastatina mejora la función sexual y la respuesta a sidenafil oral en hombres que no respondieron inicialmente al tratamiento con Sildenafil. Los resultados de este estudio avalan la hipótesis de que la disfunción vascular endotelial contribuye a la disfunción eréctil en pacientes no respondedores a Sildenafil.

Introduction: Erectile dysfunction (ED) may be one manifestation of a generalized vascular disordercharacterized by endothelial dysfunction. Statins may improve endothelial function, even before modifying the lipid profile. Objective: We sought to determine whether the addition of a statin would improve ED in men who initially responded poorly to sildenafil. Methods: Men with moderate to severe ED despite an adequate sildenafil trial were enrolled in this randomized, double-blind, placebo-controlled pilot study. ED was defined using a validated self-administered questionnaire as a score of <16 on the International Index of Erectile Function (erectile function domain score range of 6-30). Improvement in ED score withsildenafil and atorvastatin (80 mg daily) versus sildenafil and placebo was reassessed at 6 and 12 weeks of treatment. Results: Eigthteen men (mean age 62 +/- 12 years) with a mean domain score of 7.9 +/- 5.8 anda mean duration of ED of 5.2 years were enrolled in the study. Treatment with sildenafil and atorvastatin decreased mean low-density lipoprotein cholesterol by 39 percent and resulted in an improvement in erectile function domain score of 7.6 (P < 0.036). This effect was observed at 6 weeks of treatment. The increase in domain score in the sildenafil and placebo group was not statistically significant. Conclusions: Addition of atorvastatin to oral sildenafil significantly improves ED in men who initially responded poorly to sildenafilalone. The results of this pilot study supports the hypothesis that vascular endothelial dysfunction contributesto ED in sildenafil nonresponders and deserves further testing in a large clinical trial.

Terapia hipolepemiante intensiva en el manejo del riesgo cardiovascular ateroesclerótico / Intensive cholesterol lowering therapy to reduce cardiovascular risk

Primary and secondary prevention trials have clearly demonstrated that lowering serum cholesterol levels with statins reduces the incidence of cardiovascular events. Recent studies plus post hoc analysis of previous clinical trials show that risk reduction is proportional to the magnitude of LDL cholesterol lowering. Therefore, new recommendations of the National Cholesterol Education Program (USA) have defined a category of patients with very high cardiovascular risk, who should achieve serum LDL cholesterol levels below 70 mg/dl. This proposal will require new and more efficient pharmacologic strategies to attain the increasingly strict therapeutic goals for LDL cholesterol. This article reviews the clinical studies that support the use of intensive lipid lowering therapy to reduce cardiovascular risk. An effective reduction of serum cholesterol can be obtained using statins in high doses or a combination of hypolipidemic drugs with different mechanisms of action.

Prevention of atherosclerosis progression using atorvastatin in normolipidemic coronary artery disease patients--a controlled randomized trial.

BACKGROUND: Statins have been known to reduce progression of atherosclerosis when used in high dosage in patients with elevated cholesterol. A large majority of Indian patients, however, develop coronary artery disease with average or below average cholesterol level. There is insufficient data on effect of low-dose statins on progression of atherosclerosis in such patients with normal/average lipid levels. METHODS AND RESULTS: In this prospective study, 150 patients with angiographically proven coronary artery disease and baseline total cholesterol <200 mg/dl and low-density lipoprotein cholesterol <130 mg/dl were randomized to treatment with low-dose atorvastatin (10 mg) or placebo. Both groups were comparable in demographic characteristics. Progression of atherosclerosis was assessed using carotid intima media thickness as surrogate marker using standard protocol on B-mode ultrasound including common carotid artery, common carotid bifurcation and internal carotid artery measurements. Follow-up study for carotid intima media thickness was done at end of one year. A decrease in mean maximum carotid intima media thickness was recorded for all the three carotid segments individually from basal to end of one year in atorvastatin group [common carotid artery -0.008 mm (p = 0.01), common carotid bifurcation-0.022 mm (p = 0.001), internal carotid artery -0.009 mm (p = 0.01)] while the same showed an increase in placebo group [common carotid artery +0.011 mm (p = NS), common carotid bifurcation +0.013 mm (p=NS), internal carotid artery +0.007 mm (p=NS)]. The average mean carotid intima media thickness (all three segments included) decreased from 0.739 +/- 0.114 mm to 0.726 +/- 0.115 mm (difference -0.013 mm) in statin group and increased from 0.733 +/- 0.124 mm to 0.742 +/- 0.117 mm (difference + 0.009 mm) in placebo group (p < 0.001). Along side, there was a reduction in the total cholesterol from 144 +/- 26 mg/dl to 130 +/- 18 mg/dl (decreased arrow 9.7%, p = 0.05) and in low-density lipoprotein cholesterol from 86 +/- 24 mg/dl to 74 +/- 19 mg (decreased arrow 13.9%, p = 0.05) in study group and an increase in total cholesterol from 148 +/- 32 mg/dl to 154 +/- 8 mg/dl (increased arrow 4.05%, p=NS) and in low-density lipoprotein cholesterol from 84 +/- 19 mg/dl to 87 +/- 16 mg/dl (increased arrow 3.57%, p=NS) in placebo group at end of one year (p=NS). No adverse effects of statins were reported in the treatment arm. CONCLUSIONS: We conclude that low-dose statins reduce progression of atherosclerosis as observed by carotid intima media thickness in Indian patients with known coronary heart disease and normal lipid values independent of lipid lowering. The study favors use of this therapy in patients with normal/below average cholesterol levels.

Combinação de fármacos na abordagem das dislipidemias: associação entre estatinas e niacina / Combination of drugs: statins and niacin

A combinação de estatinas com niacina se apresenta como uma atraente associação, na presença de dislipidemia mista com níveis de HDL baixo, quando monoterapia é insuficiente para o alcance das metas lipídicas. Benefícios clínicos foram observados com a combinação de estatinas com niacina nos estudos FATS, HATS e ARBITER 2, mostrando atenuação no desenvolvimento da aterosclerose e/ou redução de eventos coronários, acompanhados de alterações lipídicas favoráveis. Em geral, esta combinação é bem tolerada. Recomenda-se monitoração adequada das enzimas hepáticas e muscular e, ainda, titulação cuidadosa de cada uma das drogas combinadas.

High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent

The MDR1 gene encodes the P-glycoprotein, an efflux transporter with broad substrate specificity. P-glycoprotein has raised great interest in pharmacogenetics because it transports a variety of structurally divergent drugs, including lipid-lowering drugs. The synonymous single-nucleotide polymorphism C3435T and the nonsynonymous single-nucleotide polymorphism G2677T/A in MDR1 have been indicated as potential determinants of variability in drug disposition and efficacy. In order to evaluate the effect of G2677T/A and C3435T MDR1 polymorphisms on serum levels of lipids before and after atorvastatin administration, 69 unrelated hypercholesterolemic individuals from São Paulo city, Brazil, were selected and treated with 10 mg atorvastatin orally once daily for four weeks. MDR1 polymorphisms were analyzed by PCR-RFLP. C3435T and G2677T polymorphisms were found to be linked. The allelic frequencies for C3435T polymorphism were 0.536 and 0.464 for the 3435C and 3435T alleles, respectively, while for G2677T/A polymorphism allele frequencies were 0.580 for the 2677G allele, 0.384 for the 2677T allele and 0.036 for the 2677A allele. There was no significant relation between atorvastatin response and MDR1 polymorphisms (repeated measures ANOVA; P > 0.05). However, haplotype analysis revealed an association between T/T carriers and higher basal serum total (TC) and LDL cholesterol levels (TC: 303 ± 56, LDL-C: 216 ± 57 mg/dl, respectively) compared with non-T/T carriers (TC: 278 ± 28, LDL-C: 189 ± 24 mg/dl; repeated measures ANOVA/Tukey test; P < 0.05). These data indicate that MDR1 polymorphism may have an important contribution to the control of basal serum cholesterol levels in Brazilian hypercholesterolemic individuals of European descent.

Effect of chitosan on lipid levels when administered concurrently with atorvastatin--a placebo controlled study.

In a placebo controlled trialthe lipid lowering effects of chitosan, a unique dietary fibre, was assessed when given along with atorvastatin 10 mg in patients with chronic coronary heart disease. Altogether 100 patients were studied. They were randomly allocated in two groups of 50 patients each. Patients of group A received atorvastatin 10 mg before dinner plus 2 g/day chitosan in two divided doses. The groupB patients received atorvastatin 10 mg plus placebo. Patients were followed up for a period of 6 weeks. There was significant reduction in mean body weight in group A patients (3.14% versus 1,29% of body weight, p<0.05). There was also a significant rise in HDL cholesterol value (3.8% versus 1.07%, p=0.02) in group A patients. However, there was no significant reduction in the mean values of total cholesterol, LDL cholesterol and triglyceride in the two groups, although group A patients showed marginally lower values.