Simvastatin Blocks Reinstatement of Cocaine-induced Conditioned Place Preference in Male Mice with Brain Lipidome Remodeling / 神经科学通报·英文版

Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.

Lipid profile and response to statin therapy in patients with hypopituitarism

ABSTRACT Objective: Dyslipidemia is prevalent among patients with hypopituitarism, especially in those with growth hormone (GH) deficiency. This study aimed to evaluate the response to statin therapy among adult patients with dyslipidemia and hypopituitarism. Subjects and methods: A total of 113 patients with hypopituitarism following up at a neuroendocrinology unit were evaluated for serum lipid levels. Dyslipidemia was diagnosed in 72 (63.7%) of these patients. A control group included 57 patients with dyslipidemia and normal pituitary function. The distribution of gender, age, weight, and dyslipidemia type was well balanced across both groups, and all participants were treated with simvastatin at doses adjusted to obtain normal lipid levels. Results: Patients with hypopituitarism and dyslipidemia presented deficiency of TSH (69%), gonadotropins (69%), ACTH (64%), and GH (55%) and had a similar number of deficient pituitary axes compared with patients with hypopituitarism but without dyslipidemia. All patients with dyslipidemia (with and without hypopituitarism) had lipid levels well controlled with doses of simvastatin ranging from 20-40 mg/day. The mean daily dose of simvastatin was not significantly different between patients with and without hypopituitarism (26.7 versus 23.5 mg, p = 0.10). Similarly, no significant variation in simvastatin dose was observed between patients with different causes of hypopituitarism, presence or absence of GH deficiency, number of deficient pituitary axes, prior pituitary radiation therapy or not, and presence or absence of obesity. Conclusions: Patients with GH deficiency without GH replacement showed good response to simvastatin at a mean dose equivalent to that used in individuals with dyslipidemia and normal pituitary function.

Reporte de manejo exitoso con simvastatina y ezetimibe en alopecia areata / A report of successful management with simvastatin plus ezetimibe in alopecia areata

La alopecia areata es un tipo común de alopecia no cicatricial. Aunque la patogénesis exacta permanece sin dilucidar, se piensa que la alopecia areata tiene una etiología multifactorial en donde se interrelacionan predisposición genética y factores ambientales. En pacientes susceptibles, se han documentado que el estrés, infecciones y microtraumas disminuyen las citoquinas inmunosupresoras que normalmente mantienen el privilegio inmune del folículo piloso. Actualmente no hay terapia curativa para la alopecia areata, aunque ciertos tratamientos pueden inducir el crecimiento del cabello en un porcentaje de pacientes. Se postula que la simvastatina restablece el privilegio inmune y ezetimibe aportaría un efecto inmunomodulador y antiinflamatorio. Se presenta el caso de una mujer de 23 años con alopecia areata, exitosamente tratada con simvastatina y ezetimibe.

Alopecia areata is a common type of non-scarring alo¬pecia. Although the exact pathogenesis remains elusive, alopecia areata is thought to have a multifactorial etiology described as an interplay of genetic predisposition and environmental exposures. In patients with genetic susceptibility, stress, infection, and microtrauma have been documented to decrease immunosuppressive cytokines that generally maintain the hair follicle's immune privilege. There is currently no curative therapy for alopecia areata, although some treatments can induce hair growth in a percentage of patients. It has been postulated that simvastatin reestablishes the immune privilege, and ezetimibe would provide an immunomodulatory and anti-inflammatory effect. We report a case of a 23 years-old woman with alopecia areata successfully treated with simvastatin/ezetimibe.

Polifarmácia e cognição em pacientes com idade avançada / Polypharmacy and cognition in elderly patients

Objetivo: Avaliar a prevalência da polifarmácia e da prescrição de medicações inapropriadas, bem como suas associações com a capacidade cognitiva e funcional do idoso. Métodos: Estudo observacional transversal, no qual foram analisadas as medicações prescritas em 141 prontuários para pacientes acima de 50 anos, em associação com testes que quantificaram a capacidade funcional e cognitiva deles. Resultados: Observou-se média de 4,41 medicamentos por paciente, sendo que 0,41 deles foram considerados inapropriado, segundo o critério de Beers. Verificou-se também relação estatisticamente significativa quanto ao número de medicações e testes que mediam a capacidade funcional e cognitiva dos idosos. Conclusão: O aumento da polifarmácia e da prescrição de medicações potencialmente inadequadas acarretou significativa piora da capacidade cognitiva e funcional do idoso

Objective: To evaluate the prevalence of polypharmacy and of the prescription of inappropriate medications, as well as their associations with the cognitive and functional capacity of the elderly. Methods: Cross-sectional observational study which analyzed the drugs prescribed in 141 medical records for patients over 50 years of age, associated with tests that quantified their functional and cognitive capacity. Results: An average of 4.41 medications per patient was observed, and 0.41 were considered inappropriate according to the Beers criteria. There was also a statistically significant relation regarding the number of medications and tests that measure the functional and cognitive capacity of the elderly. Conclusion: The increase in polypharmacy and in the prescription of potentially inappropriate medications led to a significant impairment of the cognitive and functional capacity of the elderly

Drug interactions and adverse events in a cohort of Warfarin users attending Public Health Clinics / Interações medicamentosas e eventos adversos em uma coorte de usuários de varfarina que freqüentam clínicas de saúde pública

Background: Warfarin is an oral anticoagulant involved in important interactions with foods and other drugs. Objectives: To evaluate the occurrence of adverse events reported by warfarin users and their relationship with drug interactions. Methods: This was an open cohort, prospective study conducted in an 18-month period with warfarin users attending public health clinics of the city of Ijuí, Brazil. Data were collected by means of interviews administered at patients' home every month. Patients' responses were confirmed by review of medical records when patients sought medical care. Data were analyzed by descriptive statistics. Potential drug interactions were evaluated in a database and vitamin K consumption was quantified using a validated method. Results: A total of 68 patients were followed-up; 63 completed the study and 5 died in the study period. Mean number of medications taken by the patients was 9.6 ± 4.5, and mean number of interactions involving warfarin was 2.91 ± 1.52. Most potential interactions increased the risk of bleeding, 61 of them severe interactions and 116 moderate interactions. Eighty-seven episodes of bleeding and 4 episodes of thrombosis were reported by a total of 37 and 4 patients, respectively. At the occurrence of these events, 56.5% of warfarin users were also taking omeprazole, 35.9% were taking simvastatin and 25.0% paracetamol. Most patients had a low vitamin K intake. Conclusions: A high frequency of potential interactions between warfarin and other drugs was detected, but a low intake of foods that could possibly affect the effects of warfarin was observed. Based on our results, it seems prudent to follow patients on warfarin therapy for drug-drug interactions, aiming to control adverse effects and to promote a safe and effective therapy

Prevalence, treatment, and control of dyslipidemia in diabetic participants of two brazilian cohorts: a place far from heaven

SUMMARY OBJECTIVE Diabetes is one of the leading causes of cardiovascular mortality. Over the last years, mortality has decreased significantly, more in individuals with diabetes than in healthy ones. That is mostly due to the control of other cardiovascular risk factors. The objective of our study was to analyze the dyslipidemia control in two diabetes cohorts. METHODS Patients from two distinct cohorts were studied, 173 patients from the BHS (Brasília Heart Study) and 222 patients from the BDS (Brazilian Diabetes Study). The data on dyslipidemia control were studied in both different populations. All patients had diabetes. RESULTS There are significant differences concerning comorbidities between the LDL-C and BDS groups. The average glycated hemoglobin is of 8.2 in the LDL-C > 100 group in comparison with 7.7 and 7.5 in the 70-100 and < 70 groups, respectively (p = 0.024). There is a higher percentage of hypertensive patients with LDL between 70-100 (63.9%), when comparing the < 70 and > 100 groups (54.3% and 54.9%, respectively; p = 0.005). Diastolic pressure is higher in the group with LDL > 100, with an average of 87 mmHg, in comparison with 82.6 mmHg and 81.9 mmHg in the 70-100 and < 70 groups, respectively (p = 0.019). The group with LDL > 100 has the greatest percentage of smokers (8.7%) in comparison with the groups with LDL between 70-100 and < 70 (5.6% and 4.3%, respectively; p = 0.015). There is also a difference in the previous incidence of coronaropathy. In the group with LDL < 70, 28.3% of patients had already experienced a previous infarction, compared with 11.1% and 10.6% in the 70-100 and > 100 groups, respectively (p < 0.001). CONCLUSIONS The data in our study have shown that the dyslipidemia control in diabetic patients is inadequate and there is a tendency of direct association between lack of blood glucose control and lack of dyslipidemia control, in addition to the association with other cardiovascular risk factors, such as diastolic hypertension and smoking. This worsened control might be related to the plateau in the descending curve of mortality, and investments in this regard can improve the cardiovascular health in diabetic patients.

RESUMO OBJETIVO O diabetes é importante causa de mortalidade cardiovascular. Nos últimos anos, a mortalidade diminuiu substancialmente, mais em diabéticos do que em não diabéticos, em grande parte devido ao controle de outros fatores de risco cardiovasculares. Nosso estudo tem como objetivo analisar o controle de dislipidemia em duas coortes de diabéticos. MÉTODOS Foram estudados pacientes de duas coortes distintas, sendo 173 pacientes do BHS (Brasília Heart Study) e 222 pacientes do BDS (Brazilian Diabetes Study). Os dados sobre controle de dislipidemia foram estudados nas duas populações diferentes. Todos os pacientes eram diabéticos. RESULTADOS Há diferenças significativas em relação às comorbidades entre os grupos de LDL-C no BDS. A média de hemoglobina glicada é de 8,2 no grupo com LDL-C > 100, comparado com 7,7 e 7,5 nos grupos 70-100 e < 70, respectivamente (p = 0,024). Há maior porcentagem de pacientes hipertensos com LDL entre 70-100 (63,9%), quando comparado aos grupos < 70 e > 100 (54,3% e 54,9%, respectivamente; p = 0,005). A pressão diastólica é mais elevada no grupo com LDL > 100, com média de 87 mmHg, comparado com 82,6 mmHg e 81,9 mmHg nos grupos 70-100 e < 70, respectivamente (p = 0,019). O grupo com LDL > 100 tem maior porcentagem de tabagistas (8,7%) quando comparado aos grupos com LDL entre 70-100 e < 70 (5,6% e 4,3%, respectivamente; p = 0,015). Há, também, diferença na incidência prévia de coronariopatia. No grupo com LDL < 70, 28,3% dos pacientes já apresentaram infarto prévio, comparados com 11,1% e 10,6% nos grupos 70-100 e > 100, respectivamente (p < 0,001). CONCLUSÃO Os dados do nosso estudo mostram que o controle de dislipidemia em diabéticos é inadequado, e há uma tendência de associação direta entre descontrole glicêmico e descontrole de dislipidemia, além de associação com outros fatores de risco cardiovascular, como hipertensão diastólica e tabagismo. Esse pior controle pode estar relacionado ao platô no descenso da curva de mortalidade, e o investimento nesse quesito pode melhorar a saúde cardiovascular dos diabéticos.

Efeitos da sinvastatina na mucosite gastrointestinal induzida por 5-fluorouracil em ratos / Effects of simvastatin on 5-fluorouracil-induced gastrointestinal mucositis in rats

RESUMO Objetivo: examinar os efeitos da sinvastatina na mucosite gástrica e intestinal após o tratamento com 5-fluorouracil (5-FU), determinados pela expressão de citocinas e histologia em ratos. Métodos: ratos pesando 270±15g foram divididos em dois grupos. O grupo 5-FU+salina foi tratado com 5-FU (50mg/kg) mais solução salina a 0,9% por gavagem uma vez ao dia por cinco dias. O grupo 5-FU+sinvastatina foi tratado com 5-FU (50mg/kg), mais sinvastatina (10mg/kg), da mesma forma. Foi feita a eutanásia dos animais no sexto dia. O estômago e o intestino foram fotografados e removidos para exame. Dosagens séricas de TNF-a, IL-1ß, IL-6 e histopatologia (coloração HE) do estômago e intestino foram realizadas. Resultados: o peso corporal diminuiu em ratos no grupo 5-FU+salina. A sinvastatina não inibiu a perda de peso induzida pelo 5-FU. Danos significativos da mucosa no estômago e no jejuno foram observados em ratos que receberam apenas 5-FU. As dosagens séricas de citocinas foram significativamente menores no grupo 5-FU+sinvastatina do que no grupo 5-FU (p<0,05). A sinvastatina causou efeitos protetores significativos contra as lesões da mucosa gástrica e jejunal induzidas por 5-FU. Conclusão: a sinvastatina atenua a mucosite gástrica e intestinal relacionada à terapêutica com 5-FU. Nossos dados encorajam futuros estudos pré-clínicos e clínicos sobre a utilidade das estatinas na prevenção da mucosite gastrointestinal.

ABSTRACT Objective: simvastatin has pleiotropic anti-inflammatory and immunomodulatory effects potentially usefull to prevent chemotherapy-induced gastrointestinal mucositis. Studies on this are scarce. This study aimed to examine the effects of simvastatin on gastric and intestinal mucositis after 5-fluorouracil (5-FU) treatment in rats. Methods: rats weighing 270±18g were divided into two groups. The 5-FU+saline group (5-FU/SAL) rats were treated with 5-FU (50mg/kg) plus 0.9% saline orally (gavage) once daily for five days. The 5-FU+simvastatin (5-FU/SIMV) group was treated with 5-FU (50mg/kg), plus simvastatin (10mg/kg), in the same way. The rats were euthanased on the sixth day, then their stomach and intestine were photographed and removed for exams. Dosages of serum TNF-a, IL-1ß, IL-6 and histopathology were done for stomach and intestine. Results: body-weight was significantly lower in rats treated with 5-FU+saline than the weight loss of the 5-FU/SIMV group rats. TNF-a expression was lower in 5-FU/SIMV group (172.6±18pg/ml) than in 5-FU/SAL (347.5±63pg/ml). Serum IL-1b was lower in 5-FU/SAL group (134.5±23pg/ml) than in 5-FU/SIMV (48.3±9pg/ml). Serum IL-6 was 61.8±15pg/ml in 5-FU/SIMV and 129.4±17pg/ml in 5-FU/SAL groups. These differences were significant (p<0.05). Mucosal damage in stomach and jejunum were observed in rats receiving 5-FU alone. In the stomach and jejunum, simvastatin caused significant protective effects against 5-FU-induced mucosal injury. Conclusion: simvastatin attenuated gastric and intestinal mucositis related to 5-FU therapeutics in animal model. These data encourage forthcoming clinical studies addressing the usefulness of statins in the prevention and treatment of gastrointestinal mucositis.

Effect of metformin alone compared with metformin plus simvastatin on polycystic ovarian syndrome in Pakistani women

Objective: To determine the efficacy of metformin alone versus metformin plus simvastatin for treatment of polycystic ovarian syndrome [PCOS]

Study Design: Randomized controlled trial

Place and Duration of Study: Maternal and Child Health Centre, Unit II, Pakistan Institute of Medical Sciences [PIMS], from November 2014 to April 2015

Methodology: One hundred and eight patients [108] were randomly divided into metformin group [n=54] and metformin plus simvastatin group [n=54], detailed clinical history, including menstrual details, was taken with thorough examination performed. Baseline ultrasound was performed to evaluate ovarian size and these were considered enlarged with volume >10cc or with >12 follicles in any one ovary. Blood samples were taken at baseline and after three months of therapy to determine the LH/FSH ratio and lipid profile. Efficacy was defined as >15% decrease in the baseline values

Results: The mean age of patients was 28.82 +/- 7.18 years. Mean BMI of the patients was 22.41 +/- 1.55 Kg/m[2]. Efficacy was achieved in 66.7% patients with metformin alone, while in 92.6% with combination medication [p=0.001]

Conclusion: The combination of metformin plus simvastatin is more efficacious as compared to metformin alone for management of females with PCOS

Fosfatasa alcalina ósea sérica elevada no mediada por metástasis en un paciente con cáncer renal / Elevated bone alkaline phosphatase not mediated by metastasis in a patient with renal cancer

Presentamos un paciente de 63 años con cáncer renal y aumento de fosfatasa alcalina sérica de tipo óseo de acuerdo con su reactividad con anticuerpos monoclonales específicos. Se descartaron las causas conocidas de aumento de la isoenzima, incluyendo metástasis óseas. Los niveles enzimáticos cayeron abruptamente con la remoción del tumor, por lo que consideramos a este último como su origen. Diversas isoenzimas de fosfatasa alcalina pueden ser producidas y secretadas por tumores como manifestación paraneoplásica. El conocimiento de esto puede, en ocasiones, orientarnos hacia la presencia de una neoplasia oculta. Además, los cambios en los niveles séricos de esas isoenzimas pueden ser indicadores de respuesta al tratamiento o de recidiva tumoral. (AU)

A 63-year old man was seen in the outpatient clinic because of renal cancer and elevation in bone alkaline phosphatase measured by monoclonal antibodies assay. Known causes of bone isoenzyme augmentation, including bone metastases, were ruled out. The tumoral origin of the isoenzyme was diagnosed because after removal of the tumor the enzymatic levels fell sharply. Several alkaline phosphatase isoenzymes can be produced and secreted by tumors as a paraneoplasic manifestation and their elevation could be a manifestation of an occult neoplasia. Furthermore the monitoring of their blood levels can be useful means of treatment response and a tool to monitoring recurrence if a sharp decrease after removal of the tumor is observed. (AU)

Drogas promissoras na reparação óssea periodontal: sinvastatina, ranelato de estrôncio e alendronato de sódio / Promissing drugs for periodontal bone regeneration: simvastatin, strontium ranelate, and sodium alendronate

O tratamento de defeitos ósseos intrabucais tem sido um desafi o na área odontológica, e a pesquisa de novas drogas para otimizar os resultados cirúrgicos regenerativos é de extrema importância. Existem evidências de que algumas drogas, como o ranelato de estrôncio (RSr), a sinvastatina (SNV) e o alendronato de sódio (ALE), têm propriedades anabólicas no metabolismo ósseo. A proposta desta revisão foi apresentar o estado atual da arte sobre o emprego da SNV, do RSr e do ALE em terapias odontológicas. Foi realizada uma busca bibliográfica na base PubMed e incluídos estudos relevantes relacionados ao tema para síntese deste trabalho. Concluiu-se que a aplicação do ALE e da SIN são efetivos como coadjuvantes no tratamento mêcanico da doença periodontal e como indutores de neoformação óssea, entretanto, o RSr merece ser mais bem estudado para tal afirmação.

The treatment of intraoral bone defects has been a challenge in dentistry, in this way the development of new drugs in order to optimize surgical regenerative results are extreme important. There are evidences that drugs such as strontium ranelate (RSr), simvastatin (SNV) and sodium alendronate (ALE) have anabolic properties in bone metabolism and several studies have been performed aiming to improve therapeutic strategies in bone regeneration. Therefore, the purpose of this review is to present the current state of art about the usage of SNV, RSr and ALE in dental therapies, targeting better clinical outcomes in bone manipulation techniques. A literature research was performed in PubMed database and relevant studies between were included. Our study concluded that application of ALE and SNV are effective as adjuncts with mechanical therapy of periodontal disease and also induces bone formation. In the other hand, the application of RSr as a promising bone formation drug needs to be better elucidated.

O efeito da sinvastatina na osseointegração / The effect of simvastatin on osseointegration ­ a literature review

O crescente aumento de instalações de implantes dentais com carga imediata e de suas fixações em tecido ósseo de baixa densidade tem gerado a necessidade real de aceleração e aprimoramento do processo de osseointegração, e muitos métodos e técnicas têm sido propostos para solucionar este problema. Neste contexto, a presente revisão teve por objetivo discutir os principais aspectos do papel da sinvastatina como intervenção para a melhoria no processo de osseointegração. Os resultados indicaram que a sinvastatina apresentou efeitos positivos em estudos experimentais, sendo necessários ensaios clínicos randomizados.

With increasing applications of dental implants with immediate loading and their installation in low quality bone, there is a real need to speed up and improve the osseointegration process. This review aimed to discuss the use of simvastatin in improving the osseointegration. The results indicate that simvastatin showed positive results in experimental studies, although randomized clinical trials are necessary.

Participação do setor público no fornecimento de medicamentos para dislipidemias em estudo de base populacional / Public sector participation in the supply of dyslipidemia medication in a population-based study

Resumo A utilização de medicamentos para tratamento das dislipidemias é relevante no controle das doenças cardiovasculares. O objetivo deste artigo é analisar a prevalência, a utilização e a participação do setor público no fornecimento de medicamentos para as pessoas a partir de 40 anos em farmacoterapia de controle das dislipidemias, residentes em um município da região Sul do Brasil. Estudo transversal de base populacional. Foram entrevistados no domicilio 1180 indivíduos a partir de 40 anos residentes em Cambé/PR, dos quais 967 realizaram exames laboratoriais. A prevalência de dislipidemias foi de 69,2%, dos quais 16,1% utilizavam medicamentos. Entre os indivíduos em tratamento para as dislipidemias, 22,2% apresentaram resultados de exames adequados. Os fármacos hipolipemiantes mais utilizados foram sinvastatina (81,5%) e bezafibrato (6,5%), obtidos principalmente por pagamento direto em farmácias e drogarias privadas (52,2%) e serviços próprios do SUS (33,6%). Em nível populacional a prevalência das dislipidemias foi elevada, o seu controle baixo, com menor participação do setor público no fornecimento dos medicamentos do que a aquisição mediante pagamento direto em farmácias e drogarias privadas, sugerindo alcance limitado das políticas públicas de controle das dislipidemias.

Abstract The use of medications for the treatment of dyslipidemia is relevant in the control of cardiovascular disease. This article aims to analyze the prevalence, the use and the participation of the public sector in the supply of medication for adults aged 40 years and above using pharmacotherapy for dyslipidemia control living in a city in the southern region of Brazil. A cross-sectional, population-based study was conducted. Household interviews were staged with 1180 individuals aged over 40 living in Cambé, State of Paraná, of which 967 took laboratory examinations. The prevalence of dyslipidemia was 69.2%, of which 16.1% were taking medication. Among individuals undergoing treatment for dyslipidemia, 22.2% had adequate test results. Lipid-lowering medication used were simvastatin (81.5%) and bezafibrate (6.5%), mainly obtained by direct payment to private pharmacies and drug stores (52.2%) and NHS services (33.6%). A high prevalence of dyslipidemias was observed in population terms, together with a low level of dyslipidemia control and low participation of the public sector regarding the supply of medication compared to acquisition through direct payment for medication in private pharmacies. These results suggest a limited range of public policy for control of dyslipidemia.

Heart and systemic effects of statin pretreatment in a rat model of abdominal sepsis. Assessment by Tc99m-sestamibi biodistribition

PURPOSE: To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis. METHODS: Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis. RESULTS: Myocardial histologic alterations were not detected 24 hours post-sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9±0.3%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0±0.2%ID/g), control sham group+ simvastatin (1.2±0.3%ID/g) and control sham group (1.3±0.2%ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups. CONCLUSIONS: Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins. .

The effect of simvastatin on relapse of tooth movement and bone mineral density in rats measured by a new method using microtomography

PURPOSE: To evaluate the effect of simvastatin on relapse of tooth movement in rats using microtomography (micro CT), as well as the correlation of bone density with the orthodontic relapse. METHODS: Twenty-five adult male Wistar rats, divided into two groups, had stainless steel springs installed on left maxillary first molar. The molars were moved for 18 days, and after removing the springs, were applied by oral gavage, 5mg/kg of simvastatin in the experimental group for 20 days. Tooth relapse was assessed with a micro CT scanner, and the images chosen through the Data Viewer software 1.5.0.0 had their measurement guides made and checked by the software Image ProR plus 5.1, and compared by Mann-Whitney test. After rats were sacrificed, bone mineral density was evaluated by micro CT through the software CT Analyzer 1.13 and compared by independent T-test, as well as by Spearman correlation test. RESULTS: Relapse and bone mineral density (BMD) was lower in the experimental group than in the control group, however without a statistically significant difference. CONCLUSION: Simvastatin did not inhibit the relapse of tooth movement in rats, and there was no correlation between bone density and orthodontic relapse. .

Antioxidant protection of statins in acute kidney injury induced by sepsis / Protección antioxidante de la estatina en la insuficiencia renal aguda inducida por la sepsis / Proteção antioxidante da estatina na lesão renal aguda induzida pela sepse

Objective Evaluating the effect of preconditioning with simvastatin in acute kidney injury induced by sepsis. Method Male adult Wistar rats were divided into the following groups: SHAM (control); SHAM+Statin (0.5 mg/kg simvastatin, orally); Sepsis (cecal puncture ligation – CPL); Sepsis+Statin. Physiological parameters, peritoneal fluid culture, renal function, oxidative metabolites, severity of acute kidney injury and animal survival were evaluated. Results The treatment with simvastatin in induced sepsis showed elevation of creatinine clearance with attenuation of generation of oxidative metabolites, lower severity of acute kidney injury and reduced mortality. Conclusion This investigation confirmed the renoprotection with antioxidant principle of the simvastatin in acute kidney injury induced by sepsis in an experimental model. .

Objetivo Evaluar el efecto del pre condicionamiento con sinvastatina en la insuficiencia renal aguda inducida por sepsis. Método Ratas Wistar, adultas, machos, fueron distribuidos en los grupos: SHAM (control); SHAM+Estatina (0,5 mg/kg sinvastatina, vía oral); Sepsis (ligadura y punción cecal – LPC); Sepsis+Estatina. Fueron evaluados los parámetros fisiológicos, la cultura de líquido peritoneal, la función renal, los metabolitos oxidativos, la severidad de la insuficiencia renal aguda y la supervivencia de los animales. Resultados El tratamiento con sinvastatina en la sepsis inducida demostró elevación del aclaramiento de creatinina con atenuación de la generación de los metabolitos oxidativos, menor severidad del fallo renal agudo y reducción del índice de mortalidad. Conclusión Esta investigación confirmó la renoprotección con principio antioxidante de la sinvastatina en el fallo renal agudo inducido por la sepsis en modelo experimental. .

Objetivo Avaliar o efeito do pré-condicionamento com sinvastatina na lesão renal aguda induzida por sepse. Método Ratos Wistar, adultos, machos foram distribuídos nos grupos: SHAM (controle); SHAM+Estatina (0,5 mg/kg sinvastatina, via oral); Sepse (ligadura punção de cécum – LPC); Sepse+Estatina. Foram avaliados parâmetros fisiológicos, cultura líquido peritoneal, função renal, metabólitos oxidativos, gravidade da lesão renal aguda e sobrevida dos animais. Resultados O tratamento com sinvastatina na sepse induzida demonstrou elevação do clearance de creatinina com atenuação da geração dos metabólitos oxidativos, menor gravidade da lesão renal aguda e redução da taxa de mortalidade. Conclusão Esta investigação confirmou a renoproteção com princípio antioxidante da sinvastatina na lesão renal aguda induzida pela sepse em modelo experimental. .

Avaliação do efeito hipolipemiante do extrato seco de Solanum Melongena L. (berinjela) versus placebo e sinvastatina: ensaio clínico randomizado / Evaluation of lipid-lowering effect of dry extract of Solanum melongena L. (eggplant) versus placebo and simvastatin: a randomized clinical trial

JUSTIFICATIVA E OBJETIVO: As dislipidemias são uma das principais causas de morbidade e mortalidade por doenças car- diovasculares. O objetivo deste estudo foi avaliar o efeito hipo- lipemiante do extrato seco de Solanum melongena L. (berinjela) versus placebo e sinvastatina, em pacientes com hipercolesterole- mia. MÉTODOS: Foi realizado um ensaio clínico randomiza- do com 36 indivíduos adultos, hipercolesterolêmicos, alocados em quatro grupos: Grupo 1, ao qual foi administrado placebo (n=10); Grupo 2, que recebeu extrato seco de berinjela (n=10; colesterol total=200 a 239mg/dL); Grupo 3 que também recebeu extrato seco de berinjela (n=9; colesterol total ?240mg/dL); e Grupo 4, que foi tratado com sinvastatina (n=7; colesterol total ?240mg/dL). Foram realizados exames laboratoriais na linha de base, após 30, 60 e 90 dias de tratamento. RESULTADOS: Houve redução significativa de colesterol total e LDL no Grupo 4 (p<0,001 e p=0,001, respectivamente). Os demais valores e grupos não apresentaram diferença no tratamento. CONCLU- SÃO: O extrato seco de Solanum melongena L. não apresentou diferença estatisticamente significativa na redução dos níveis do colesterol total, frações e triglicerídeos quando comparado ao uso de sinvastatina ou placebo.(AU)

BACKGROUND AND OBJETIVE: Dyslipidemia is the leading cause of morbidity and mortality from cardiovascular disease. The aim of this study was to evaluate the lipid-lowering effect of dry extracts of Solanum melongena L. (eggplant) versus placebo and simvastatin in patients with hypercholesterolemia. METHODS: A randomized clinical trial was performed on 36 adult subjects with hypercholesterolemia. They were divided into four groups: Group 1, which was treated with placebo (n=10); Group 2, that received dry extract of eggplant (n=10; total cholesterol=200 to 239mg/dL); Group 3, that also received dry extract of eggplant (n=9; total cholesterol ?240mg/dL) and Group 4, treated with simvastatin (n=7; total cholesterol ?240mg/dL). Laboratory tests were carried out at baseline and 30, 60 and 90 days after the start of treatment. RESULTS: There was a significant reduction in total cholesterol and LDL in Group 4 (p<0.001 and 0.001, respectively). There was no significant difference in cholesterol levels in the other groups because of treatment. CONCLUSION: The dry extract of Solanum melongena L. showed no statistically significant difference in reducing the levels of total cholesterol, fractions, and triglycerides, when compared with the use of simvastatin or placebo.(AU)

Attenuation of airway inflammation by simvastatin and the implications for asthma treatment: is the jury still out?

Although some studies have explained the immunomodulatory effects of statins, the exact mechanisms and the therapeutic significance of these molecules remain to be elucidated. This study not only evaluated the therapeutic potential and inhibitory mechanism of simvastatin in an ovalbumin (OVA)-specific asthma model in mice but also sought to clarify the future directions indicated by previous studies through a thorough review of the literature. BALB/c mice were sensitized to OVA and then administered three OVA challenges. On each challenge day, 40 mg kg-1 simvastatin was injected before the challenge. The airway responsiveness, inflammatory cell composition, and cytokine levels in bronchoalveolar lavage (BAL) fluid were assessed after the final challenge, and the T cell composition and adhesion molecule expression in lung homogenates were determined. The administration of simvastatin decreased the airway responsiveness, the number of airway inflammatory cells, and the interleukin (IL)-4, IL-5 and IL-13 concentrations in BAL fluid compared with vehicle-treated mice (P<0.05). Histologically, the number of inflammatory cells and mucus-containing goblet cells in lung tissues also decreased in the simvastatin-treated mice. Flow cytometry showed that simvastatin treatment significantly reduced the percentage of pulmonary CD4+ cells and the CD4+/CD8+ T-cell ratio (P<0.05). Simvastatin treatment also decreased the expression of the vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 proteins, as measured in homogenized lung tissues (P<0.05) and human epithelial cells. The reduction in the T cell influx as a result of the decreased expression of cell adhesion molecules is one of the mechanisms by which simvastatin attenuates airway responsiveness and allergic inflammation. Rigorous review of the literature together with our findings suggested that simvastatin should be further developed as a potential therapeutic strategy for allergic asthma.

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.

Simvastatin attenuates neutrophil recruitment in one-lung ventilation model in rats

PURPOSE: To investigate the anti-inflammatory effects of simvastatin in rats undergoing one-lung ventilation (OLV) followed by lung re-expansion. METHODS: Male Wistar rats (n=30) were submitted to 1-h OLV followed by 1-h lung re-expansion. Treated group received simvastatin (40 mg/kg for 21 days) previous to OLV protocol. Control group received no treatment or surgical/ventilation interventions. Measurements of pulmonary myeloperoxidase (MPO) activity, pulmonary protein extravasation, and serum levels of cytokines and C-reactive protein (CRP) were performed. RESULTS: OLV significantly increased the MPO activity in the collapsed and continuously ventilated lungs (31% and 52% increase, respectively) compared with control (p<0.05). Treatment with simvastatin significantly reduced the MPO activity in the continuously ventilated lung but had no effect on lung edema after OLV. The serum IL-6 and CRP levels were markedly higher in OLV group, but simvastatin treatment failed to affect the production of these inflammatory markers. Serum levels of IL-1β, TNF-α and IL-10 remained below the detection limit in all groups. CONCLUSIONS: In an experimental one-lung ventilation model pre-operative treatment with simvastatin reduces remote neutrophil infiltration in the continuously ventilated lung. Our findings suggest that simvastatin may be of therapeutic value in OLV-induced pulmonary inflammation deserving clinical investigations.

The influence of simvastatin in induced peritoneal fibrosis in rats by peritoneal dialysis solution with glucosis 4.25% / Influência da sinvastatina na fibrose peritoneal induzida em ratos pelo uso de solução de diálise peritoneal com glicose a 4,25%

PURPOSE: To investigate the influence of using simvastatin on the peritoneal fibrosis induced in rats using peritoneal dialysis solution with glucoses 4.25%. METHODS: Prospective controlled study in 20 non-uremic Wistar rats. The animals received a peritoneal infusion of 10 ml/100 g of peritoneal dialysis solution glucose 4.25% on a daily basis. The animals were divided in two groups: experimental and control. The experimental group received simvastatin 4 mg/kg/d, by a gastric tube. The control group did not receive any drug. The follow-up was 21 and 49 days. At the end, one surgical procedure was performed to get histological samples of visceral and parietal peritoneum. The samples were analyzed using Hematoxylin Eosin and Sirius Red, to evaluate the severity of the fibrosis. RESULTS: The analysis showed that the intensity of the fibrosis, the peritoneal thickness and the cell number in experimental and control groups were not statistically significant different in experimental and control groups. CONCLUSION: The simvastatin do not decrease the intensity of fibrosis on the peritoneal membrane that happens on rats on peritoneal dialysis.

OBJETIVO: Investigar a influência do uso da sinvastatina na fibrose peritoneal induzida em ratos pelo uso de solução de diálise peritoneal rica em glicose. MÉTODOS: Estudo prospectivo controlado, em ratos Wistar não urêmicos. Foram estudados 20 animais. Os animais foram submetidos diariamente à punção abdominal, sendo infundida solução de diálise peritoneal com glicose a 4,25% na dose de 10 ml/100 g de peso. Os animais foram divididos em dois grupos: experimental e controle. O grupo experimental recebeu sinvastatina na dose de 4 mg/kg/dia por gavagem. O grupo controle não recebeu nenhuma droga. Foram acompanhados por 21 e 49 dias. Ao final do período foram submetidos à procedimento cirúrgico para retirada de peritônio parietal e visceral. As amostras obtidas foram analisadas histologicamente, usando-se coloração Hematoxilina - Eosina e Sirius Red, para avaliação do grau de fibrose. RESULTADOS: A análise mostrou que a intensidade da fibrose, a espessura do peritônio e o número de células não atingiram diferença estatisticamente significante entre os grupos experimental e controle. CONCLUSÃO: A sinvastatina não foi capaz de alterar a intensidade da fibrose peritoneal induzida pelo uso de solução de diálise em ratos.