Statin-related drug-induced liver injury / 中华肝脏病杂志

Statins are a kind of prescription drug that is widely used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic diseases. A common side effect of statin use is a mild rise in liver aminotransferases, which occurs in less than 3% of patients. Statin-related liver injury is most commonly caused by atorvastatin and simvastatin, but severe liver injury is uncommon. Therefore, understanding and evaluating hepatotoxicity and weighing the benefits and risks is of great significance to better realize the protective effect of statins.

Efeito da sinvastatina e do propranolol no desenvolvimento da lesão periapical de ratos submetidos ao estresse / Effect of Simvastatin and Propranolol on the development of periapical lesions in rats subjected to stress

Uma vez que o estresse crônico pode estimular o sistema nervoso simpático, diminuindo a resposta imune, favorecendo a perda óssea frente a um processo inflamatório, os objetivos deste estudo foram: 1) Avaliar os efeitos de modelos de indução de estresse no desenvolvimento da periodontite apical (P.a) e avaliar o nível de estresse gerado pelos mesmos; 2) A partir do melhor protocolo de estresse obtido foi avaliado o perfil inflamatório da PA induzida em animais sob condições de estresse, utilizando sistemicamente a Sinvastatina, Propranolol e a Sinvastatina associada ao propranolol. Na primeira parte foram utilizados 32 ratos Wistar (N=8) divididos aleatoriamente em: SE: sem estresse, sem periodontite apical (P.a); SE+P.a: sem estresse, com P.A; EP+P.a: Estresse previsível + P.a; EI+P.a: estresse imprevisível + P.a. Os animais foram submetidos ao estresse crônico por 42 dias sendo que no dia 21 foi induzida a P.a. Para comprovação do estresse foram utilizadas análises de peso e comportamentais de campo aberto (CA) e labirinto em y (Y). Foram realizadas análises micro tomográfica e histológica para avaliar o efeito de ambas as metodologias sobre a progressão da P.a. Os dados foram avaliados estatisticamente. Observou-se que não houve diferença no ganho de peso entre os animais SE e SE+P.a. Em relação aos grupos estressados o grupo estresse imprevisível apresentou menor ganho de peso quando comparado ao grupo sem estresse. Nos testes comportamentais, Y e CA observou-se um mesmo padrão de comportamento nos animais do grupo SE e SE+P.a (p>0.05). Verificou-se diferenças entre os grupos SE+P.a e EI +P.a no volume da lesão periapical, mas não houve diferença entre os protocolos de estresse. A Análise histológica mostrou maior área de P.a nos animais do grupo EI+P.a o que também foi observado pela análise microtomográfica. Na segunda etapa foram utilizados 48 animais divididos em 5 grupos (N=8): SE+P.a: sem estresse e com P.a; E+SS: Estresse + Periodontite Apical + soro; E+SN: Estresse + Periodontite Apical + Sinvastatina; E+P: Estresse + Periodontite Apical + Propranolol e S+SN+P: Estresse + Periodontite Apical + Sinvastatina + Propranolol. O protocolo de estresse utilizado foi o estresse crônico imprevisível por 42 dias. Realizou-se análises de peso e comportamentais de labirinto em y e campo aberto. Após a eutanásia foram realizadas as análises microtomográfica e a análise histológica e histomorfométrica. Os valores obtidos foram analisados estatisticamente.Observouse que todos os grupos medicados apresentaram ganho de peso maior do que o grupo solução salina. No grupo Sinvastatina e no grupo Propranolol, os animais apresentaram maior atividade locomotora do que no grupo Solução salina. O volume da P.a foi significativamente menor nos grupos Sinvastatina e Propranolol quando comparado ao grupo solução salina. Na análise histológica observou-se que a área da lesão foi significativamente menor nos animais do grupo Sinvastatina quando comparado ao da solução salina, bem como menor intensidade e extensão do infiltrado inflamatório. Concluindo-se que o estresse crônico imprevisível aumenta a perda óssea periapical em animais com PA induzida. Além disso, concluiu-se que tanto a Sinvastatina quanto o Propranolol reduze o estresse crônico, reduzindo a perda óssea nestes animias (AU)

Since chronic stress can stimulate the sympathetic nervous system, decreasing the immune response, favoring bone loss in the face of an inflammatory process, the objectives of this study were: 1) To evaluate the effects of stress induction models on the development of apical periodontitis (P.a) and assess the level of stress generated by them; 2) Based on the best stress protocol obtained, the inflammatory profile of BP induced in animals under stress conditions was evaluated, systemically using Simvastatin, Propranolol and Simvastatin associated with propranolol. In the first part, 32 Wistar rats (N=8) were randomly divided into: SE: without stress, without apical periodontitis (P.a); SE+P.a: without stress, with P.A; EP+P.a: Predictable stress + P.a; EI+P.a: unpredictable stress + P.a. The animals were subjected to chronic stress for 42 days, and on the 21st, P.a. To prove the stress, weight and behavioral analyzes of open field (CA) and maze in y (Y) were used. Micro tomographic and histological analyzes were performed to evaluate the effect of both methodologies on the progression of P.a. Data were statistically evaluated. It was observed that there was no difference in weight gain between SE and SE+P.a animals. In relation to the stressed groups, the unpredictable stress group showed less weight gain when compared to the non-stress group. In the behavioral tests, Y and CA, the same pattern of behavior was observed in animals from the SE and SE+P.a groups (p>0.05). There were differences between groups SE+P.a and EI +P.a in the volume of the periapical lesion, but there was no difference between the stress protocols. The histological analysis showed a greater area of P.a in the animals from the EI+P.a group, which was also observed by the microtomographic analysis. In the second stage, 48 animals were divided into 5 groups (N=8): SE+P.a: without stress and with P.a; E+SS: Stress + Apical Periodontitis + serum; E+SN: Stress + Apical Periodontitis + Simvastatin; E+P: Stress + Apical Periodontitis + Propranolol and S+SN+P: Stress + Apical Periodontitis + Simvastatin + Propranolol. The stress protocol used was unpredictable chronic stress for 42 days. Weight and behavioral analyzes of y-maze and open field were performed. After euthanasia, microtomographic analysis and histological and histomorphometric analysis were performed. The values obtained were statistically analyzed. It was observed that all medicated groups had greater weight gain than the saline group. In the Simvastatin group and in the Propranolol group, the animals showed greater locomotor activity than in the Saline group. The BP volume was significantly lower in the Simvastatin and Propranolol groups when compared to the saline group. In the histological analysis, it was observed that the area of the lesion was significantly smaller in the animals of the Simvastatin group when compared to the saline solution, as well as lower intensity and extension of the inflammatory infiltrate. Concluding that unpredictable chronic stress increases periapical bone loss in animals with induced AP. In addition, it was concluded that both Simvastatin and Propranolol reduce chronic stress, reducing bone loss in these animals. (AU)

Prescription of statins according to the ASCVD estimator at Pablo Arturo Suarez Hospital, March 2021 to February 2022 / Prescripción de estatinas según el estimador ASCVD en el Hospital Pablo Arturo Suárez, marzo 2021 a febrero 2022

Worldwide, the leading cause of death is cardiovascular disease. The study details the prescription of statins at the Pablo Arturo Suarez Hospital in Ecuador between March 2021 and February 2022 following the ASCVD risk scale of the American College of Cardiology and the American Heart Association. There are 563 people in this cross-sectional and retrospective study: 70% women, 30% men, 93.30% mestizos, 48.10% diabetics, 62.30% hypertensives, and 18.70% smokers. 26.10% of all patients received statins, with simvastatin being the most common (96.60%). The mean cardiovascular risk in the general population was 15.52 ± 14.51%, 44.99% of subjects had a risk lower than 7.50%, and 29% had a risk higher than 20%, with a statistically significant difference (p<0.001) according to sex. The study determined that 58.60% of the population received a statin or an inadequate dosage.

A nivel mundial, la principal causa de muerte es la enfermedad cardiovascular. El estudio detalla la prescripción de estatinas en el Hospital Pablo Arturo Suárez de Ecuador entre marzo de 2021 y febrero de 2022, siguiendo la escala de riesgo ASCVD del Colegio Americano de Cardiología y la Asociación Americana del Corazón. Son 563 personas en este estudio transversal y retrospectivo: 70% mujeres, 30% hombres, 93.30% mestizos, 48.10% diabéticos, 62.30% hipertensos y 18.70% fumadores. El 26.10% de los pacientes recibía estatinas, siendo la simvastatina la más frecuente (96.60%). El riesgo cardiovascular medio en la población general fue de 15.52 ± 14.51%, el 44.99% de los sujetos tenía un riesgo inferior al 7.50%, y el 29% tenía un riesgo superior al 20%, con una diferencia estadísticamente significativa (p<0.001) según el sexo. El estudio determinó que el 58.60% de la población recibía una estatina o una dosis inadecuada.

Analysis of potential drug interactions in medical clinic sector in a Hospital of João Pessoa - PB

Abstract The objective of this study was to evaluate drug interactions based on medical records of patients hospitalized in University Hospital Lauro Wanderley (UHLW) in João Pessoa-PB, Brazil. This was a quantitative, descriptive study with a cross-sectional design. This research was conducted in the medical clinic of the above hospital by analyzing pharmaceutical intervention in medical records. The investigated samples consisted of all medical profiles with drug interaction information of patients hospitalized from June 2016 to June 2017. Most of these drug interactions were determined and classified by Micromedex® Solutions database. This research was approved by the Ethics Committee in Institutional Human Research, protocol number 2.460.206. In total, 331 drug interactions were found in 131 medical profiles. Dipyrone, enoxaparin, sertraline, ondansetron, quetiapine, tramadol, bromopride, amitriptyline, and simvastatin were medications that showed highest interactions. According to Anatomical Therapy Classification (ATC), drugs that act on the central nervous system result in more interactions. The most prevalent interaction was between dipyrone and enoxaparin. Some limitations of this study are the lack of notifications and data on drug interactions.

Estudo do efeito de estatinas e antiplaquetários na evolução do infarto agudo do miocárdio: uma abordagem metabolômica multiplataform / Effect of statins and antiplatelets in the evolution of acute myocardium infarction: a multiplatform metabolomics approach

O infarto agudo do miocárdio (IAM) é a maior causa de mortalidade no mundo. A oclusão coronária determina a necrose completa de cardiomiócitos (células musculares cardíacas) durante as primeiras horas do IAM. Porém, mesmo após a perda de massa de miocárdio viável cessar, a região infartada pode se expandir ou contrair no decorrer das primeiras semanas, afetando o prognóstico dos pacientes. Alguns tratamentos podem auxiliar na recuperação e melhoria do prognóstico desses pacientes, como o uso de estatinas e antiplaquetários, que quando utilizados em conjunto, proporcionam efeitos sinérgicos. O presente estudo investigou e comparou, através da óptica da metabolômica global multiplataforma, tratamentos concomitantes de estatinas (sinvastatina ou rosuvastatina) e antiplaquetários bloqueadores do receptor de ADP (clopidogrel ou ticagrelor), em pacientes que sofreram IAM. Foram coletadas amostras de plasma e urina de cerca 40 pacientes tratados com clopidrogrel e sinvastatina ou ticagrelor e rosuvastatina no Hospital São Paulo em diferentes períodos (basal, 1 mês e 6 meses após IAM). Amostras de plasma (basal e 1 mês) foram analisadas por RPLC-MS nos modos de ionização positivo e negativo, GC-MS e CEMS. Amostras de urina (basal, 1 mês e 6 meses) foram analisadas por RPLC-MS no modo de ionização positivo e HILIC-MS nos modos de ionização positivo e negativo. A abordagem metabolomica global multiplataforma evidenciou alterações no metabolismo de diferentes vias pelos dois tratamentos. Os dois tratamentos proporcionaram um efeito pronunciado no metabolismo de diferentes lipídios, como glicerolipídios, esfingolipídios, glicerofosfolipídios e ácidos graxos, sendo que a combinação rosuvastatina e ticagrelor resultou num efeito mais acentuado. Já o tratamento com clopidogrel e sinvastatina alterou de maneira mais pronunciada o metabolismo de aminoácidos ramificados e de acilcarnitinas de cadeia curta. Observou-se ainda a alteração de possíveis biomarcadores relatados na literatura como associados a problemas cardiovasculares, como hipoxantina, ácido 2-hidroxibutírico, algumas espécies de ceramidas, fosfatidilcolinas e acilcarnitinas de cadeia curta

cute myocardium infarction (AMI) is the main mortality cause in the world. The coronary occlusion determines the complete necrosis of cardiomyocytes (cardiac muscle cells) during the first hours of AMI. However, even after the loss of viable myocardial mass ceases, the infarcted area may still expand or contract during the first weeks after AMI, affecting the patient prognosis. Some treatments may assist patient recovery and improve prognostic, such as statins and antiplatelets which, when combined, provide synergic effects. This study investigated and compared, by untargeted multiplatform metabolomics, simultaneous treatments of statins (simvastatin or rosuvastatin) and ADP receptor antagonist antiplatelets (clopidogrel or ticagrelor) in patients that suffered AMI. Plasma and urine samples from around 40 patients treated with clopidogrel and simvastatin or ticagrelor and rosuvastatin were collected in Hospital Sao Paulo at different time points (basal, 1 month, 6 months after AMI). Plasma samples (basal and 1 month) were analyzed by RPLC-MS in positive and negative ionization modes, GC-MS and CE-MS. Urine samples (basal, 1 month, 6 months) were analyzed by RPLC-MS in positive ionization mode and by HILIC-MS in positive and negative ionization modes. The untargeted multiplatform metabolomics approach has shown that different metabolic pathways have been altered by the two treatments. Both treatments had a profound impact on the metabolism of different lipids, such as glycerolipids, sphingolipids, glycerophospholipids, and fatty acids. However, the combined treatment using rosuvastatin and ticagrelor impacted the most the lipid pathways. On the other hand, clopidogrel and simvastatin treatment affected more intensily the branched chain amino acids and short chain acylcarnitines metabolisms. Reported biomarkers in the literature related to cardiovascular diseases were also observed in this study, such as hypoxanthine, 2-hydroxybutyric acid, some species of ceramides, phosphatidylcholines and short chain acylcarnitines

Effects of multiple doses of simvastatin and artesunate monotherapy on SCHISTOSOMA MANSONI adult worms during infection in hyperlidemic mice / Efectos de múltiples dosis de simvastatina y artesunato en monoterapia en gusanos adultos de SCHISTOSOMA MANSONI durante la infección en ratones hiperlidémicos / Efeitos de doses múltiplas de monoterapia com sinvastatina e artesunato em vermes adultos SCHISTOSOMA MANSONI durante a infecção em camundongos hiperlidêmicos

A single dose of simvastatin and of artesunate monotherapy cause damage to the reproductive system of schistosomes as well as severe tegumental damage in male worms recovered from mice fed high-fat chow. This study aims to investigate whether treatment with multipledose regimes may offer more antischistosomal activity advantages than single daily dosing in mice fed high-fat chow. For this purpose, nine weeks post-infection, Swiss Webster mice were gavaged with simvastatin (200 mg/kg) or artesunate (300 mg/kg) for five consecutive days and euthanized two weeks post-treatment. Adult worms were analyzed using brightfield microscopy, confocal microscopy and scanning electron microscopy, presenting damages caused by simvastatin and artesunate to the reproductive system of males and females as well as tegument alterations, including peeling, sloughing areas, loss of tubercles, tegumental bubbles and tegument rupture exposing subtegumental tissue. The overall findings in this study revealed the potential antischistosomal activity of simvastatin and artesunate against Schistosoma mansoni adult worms, in addition to showing that multiple doses of either monotherapy caused severe damage to the tegument.

Una sola dosis de simvastatina y de artesunato en monoterapia causa daño al sistema reproductivo de los esquistosomas, así como daño tegumental severo en gusanos machos recuperados de ratones alimentados con comida rica en grasas. Este estudio tiene como objetivo investigar si el tratamiento con regímenes de dosis múltiples puede ofrecer más ventajas de actividad antiesquistosomal que la dosis única diaria en ratones alimentados con comida rica en grasas. Para este propósito, nueve semanas después de la infección, los ratones Swiss Webster se alimentaron por sonda con simvastatina (200 mg / kg) o artesunato (300 mg / kg) durante cinco días consecutivos y se sacrificaron dos semanas después del tratamiento. Los gusanos adultos se analizaron utilizando campo claro microscopía, microscopía confocal y microscopía electrónica de barrido, presentando daños causados ​​por simvastatina y artesunato en el sistema reproductivo de machos y hembras, así como alteraciones del tegumento, incluyendo descamación, desprendimiento, pérdida de tubérculos, burbujas tegumentales y rotura del tegumento exponiendo tejido subtegumental. Los hallazgos generales de este estudio revelaron la posible actividad antiesquistosomal de la simvastatina y el artesunato contra los gusanos adultos de Schistosoma mansoni, además de mostrar que dosis múltiples de cualquiera de las dos monoterapia causaron daños graves al tegumento.

Uma única dose de sinvastatina e de monoterapia com artesunato causa danos ao sistema reprodutivo dos esquistossomos, bem como danos graves ao tegumento em vermes machos recuperados de camundongos alimentados com ração rica em gordura. Este estudo tem como objetivo investigar se o tratamento com regimes de múltiplas doses pode oferecer mais vantagens da atividade anti-esquistossomótica do que uma única dose diária em ratos alimentados com ração rica em gordura. Para tanto, nove semanas após a infecção, camundongos Swiss Webster foram inoculados com sinvastatina (200 mg / kg) ou artesunato (300 mg / kg) por cinco dias consecutivos e sacrificados duas semanas após o tratamento. Vermes adultos foram analisados ​​usando campo claro microscopia, microscopia confocal e microscopia eletrônica de varredura, apresentando danos causados ​​pela sinvastatina e artesunato ao sistema reprodutivo de homens e mulheres, bem como alterações do tegumento, incluindo descamação, áreas de descamação, perda de tubérculos, bolhas tegumentais e ruptura do tegumento com exposição de tecido subtegumentar. Os achados gerais deste estudo revelaram a potencial atividade anti-esquistossomótica da sinvastatina e do artesunato contra vermes adultos do Schistosoma mansoni, além de mostrar que doses múltiplas de ambas as monoterapias causaram danos graves ao tegumento.

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.

Potenciais interações entre medicamentos alopáticos e fitoterápicos/ plantas medicinais no Município de Rondonópolis ­ MT / Potential interactions between allopathic and phytotherapy mediciation/medicinal plants in the Municipality of Rondonópolis

Introdução: no Brasil, a utilização de fitoterápicos e plantas medicinais é uma prática amplamente difundida, todavia, o consumo destes compostos em associação com medicamentos alopáticos caracteriza um risco à saúde devido às potenciais interações medicamentosas e seus efeitos. Objetivo: analisar as potenciais interações envolvendo fitoterápicos e plantas medicinais com medicamentos alopáticos na população de Rondonópolis, MT. Metodologia: trata-se de um estudo transversal de base populacional com 370 participantes. Os dados foram coletados em visitas domiciliares com um instrumento estruturado e padronizado. Para identificar as potenciais interações foi utilizada a base de dados Medscape® e a literatura nacional e internacional. Resultados: 131 (35,40%) indivíduos informaram consumir plantas medicinais e ou fitoterápicos concomitante a medicamentos alopáticos. A interação entre fitoterápicos e medicamentos alopáticos mais frequente foi entre Passiflora incarnata e cinarizina, para plantas medicinais foi entre hortelã e sinvastatina. As consequências mais prevalentes decorrentes das interações foram a intensificação da depressão do Sistema Nervoso Central, o aumento da anticoagulação e o risco de hipoglicemia. Conclusão: os dados analisados no presente estudo possibilitaram identificar potenciais interações existentes entre medicamentos alopáticos e plantas medicinais/fitoterápicos na população de Rondonópolis-MT e apontam para a necessidade de se estimular o uso racional da fitoterapia no âmbito da saúde pública.

Introduction: in Brazil, the use of phytotherapy medication and medicinal plants is a widespread practice. However, the consumption of these compounds in association with allopathic medicinal products is a health risk due to potential drug interactions and their effects. Objective: to analyze the potential interactions involving phythotherapy medication and medicinal plants with allopathic drugs in the population of Rondonópolis, state of MT. Methodology: this is a cross-sectional population-based study with 370 participants. Data were collected in home visits with a structured and standardized instrument. Medscape® database and national and international literature were used to identify potential interactions. Results: 131 (35, 40%) individuals reported consuming medicinal plants and/or phytotherapy medication concomitantly with allopathic drugs. The most frequent interaction between phytotherapeutic and allopathic drugs was between Passiflora incarnata and cinnarizine, and in medicinal plants, it was between peppermint and simvastatin. The most prevalent consequences of the interactions were intensification of central nervous system depression, increased anticoagulation and risk of hypoglycemia. Conclusion: data analyzed in the present study enabled the identification of potential interactions between allopathic medicines and herbal plants/phytotherapeutic medication in the population of Rondonópolis (MT), and demonstrated the need to stimulate the rational use of phytotherapy in public health.

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.

Simvastatin-enriched macro-porous chitosan-calcium-aluminate scaffold for mineralized tissue regeneration

Abstract The present study evaluated the odontogenic potential of human dental pulp cells (HDPCs) exposed to chitosan scaffolds containing calcium aluminate (CHAlCa) associated or not with low doses of simvastatin (SV). Chitosan scaffolds received a suspension of calcium aluminate (AlCa) and were then immersed into solutions containing SV. The following groups were established: chitosan-calcium-aluminate scaffolds (CHAlCa - Control), chitosan calcium-aluminate with 0.5 µM SV (CHAlCa-SV0.5), and chitosan calcium-aluminate with 1.0 µM SV (CHAlCa-SV1.0). The morphology and composition of the scaffolds were evaluated by SEM and EDS, respectively. After 14 days of HDPCs culture on scaffolds, cell viability, adhesion and spread, mineralized matrix deposition as well as gene expression of odontogenic markers were assessed. Calcium aluminate particles were incorporated into the chitosan matrix, which exhibited regular pores homogeneously distributed throughout its structure. The selected SV dosages were biocompatible with HDPCs. Chitosan-calcium-aluminate scaffolds with 1 µM SV induced the odontoblastic phenotype in the HDPCs, which showed enhanced mineralized matrix deposition and up-regulated ALP, Col1A1, and DMP-1 expression. Therefore, one can conclude that the incorporation of calcium aluminate and simvastatin in chitosan scaffolds had a synergistic effect on HDPCs, favoring odontogenic cell differentiation and mineralized matrix deposition.

Resumo O presente estudo avaliou o potencial odontogênico de células da polpa dental humana (HDPCs) em contato com scaffolds de quitosana contendo aluminato de cálcio (CHAlCa) associado ou não à baixas dosagens de sinvastatina (SV). Scaffolds de quitosana receberam uma suspensão de aluminato de cálcio e foram imersos em soluções contendo a droga. Foram estabelecidos três grupos experimentais: scaffolds de quitosana e aluminato de cálcio (CHAlCa - controle), scaffolds de quitosana-aluminato de cálcio com 0.5 µM SV (CHAlCa-SV0.5), e quitosana-aluminato de cálcio com 1.0 µM SV (CHAlCa-SV1.0). A morfologia e composição foram avaliados por MEV e EDS, respectivamente. Após 14 dias do cultivo das HDPCs sobre os scaffolds, foram avaliados a viabilidade celular, adesão e espalhamento, deposição de matriz mineralizada e expressão gênica de marcadores odontogênicos. Observou-se que as partículas de aluminato de cálcio foram incorporadas à matriz de quitosana, a qual exibiu poros regulares distribuídos por toda sua estrutura. As dosagens selecionadas de sinvastatina foram biocompatíveis com as HDPCs. A concentração de 1 µM de SV induziu intensa expressão de fenótipo odontoblástico pelas HDPCs, demonstrando aumento da deposição de matriz mineralizada e maior expressão de ALP, Col1A1 e DMP-1. Portanto, podemos concluir que a incorporação de aluminato de cálcio e sinvastatina em scaffolds de quitosana apresentou um efeito sinérgico nas HDPCs, favorecendo a diferenciação celular e deposição de matriz mineralizada.

Calcium phosphate carrying simvastatin enhances bone regeneration: a systematic review

Abstract Several studies have aimed to develop alternative therapeutic biomaterials for bone repair. The purpose of this systematic review was to evaluate how statins carried by calcium phosphate affect the formation and regeneration of bone tissue in animal models when compared to other biomaterials or spontaneous healing. This systematic review followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, the PRISMA guidelines, and the Preclinical Systematic Review & Meta-analysis Facility (SyRF). The protocol of this systematic review was registered in PROSPERO (CRD42018091112) and in CAMARADES. In addition, ARRIVE checklists were followed in order to increase the quality and transparency of the search. An electronic search was performed using the MEDLINE/PubMed, Scopus, SciELO, and PROSPERO library databases. The authors used a specific search strategy for each database, and they also conducted a search in the grey literature and cross-references. The eligibility criteria were animal studies, which evaluated bone repair treated with calcium phosphate as a simvastatin carrier. The selection process yielded 8 studies from the 657 retrieved. All manuscripts concluded that locally applied simvastatin carried by calcium phosphate is biocompatible, enhanced bone repair and induced statistically greater bone formation than cloth or calcium phosphate alone. In conclusion, the pertinent pre-clinical studies evidenced the calcium phosphate biocompatibility and its effectiveness in delivering SIM to improve the repair of bone defects. So, clinical trials are encouraged to investigate the impact of SIM associated with calcium phosphate bone graft in repairing bone defect in humans.

Resumo Muitos estudos objetivaram desenvolver biomateriais terapêuticos alternativos para o reparo ósseo. O objetivo desta revisão sistemática foi avaliar o efeito da estatina carreada por fosfato de cálcio na formação e regeneração de tecido ósseo em modelos animais quando comparado com outros biomateriais ou coágulo. Esta revisão sistemática seguiu as recomendações do Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines, e o Preclinical Systematic Review & Meta-analysis Facility (SyRF). O protocolo desta revisão sistemática foi registrado no PROSPERO (CRD42018091112) e no CAMARADES. Além disso, o guia ARRIVE foi utilizado com o objetivo de aumentar a qualidade e transparência do estudo. Uma pesquisa eletrônica foi realizada através do MEDLINE/PubMed, Scopus, SciELO, e biblioteca do PROSPERO. Os autores utilizaram uma estratégia de busca específica para cada base de dados, e uma busca foi conduzida na literatura cinza e nas referências dos artigos selecionados. Os critérios de elegibilidade foram estudos em animais, os quais avaliaram o repara do ósseo tratado com fosfato de cálcio como carreador de estatina. O processo de seleção obteve 8 estudos dos 657 encontrados. Todos os estudos concluíram que a aplicação local da sinvastatina carreada pelo fosfato de cálcio é biocompatível, melhora o reparo ósseo e induz uma formação óssea significantemente maior que coágulo ou fosfato de cálcio sozinho. Em conclusão, os estudos pré-clínicos pertinentes evidenciaram a biocompatibilidade do fosfato de cálcio e sua eficácia na entrega do SIM para melhorar o reparo de defeitos ósseos. Assim, estudos clínicos são encorajados a investigar o impacto do SIM associado ao enxerto ósseo de fosfato de cálcio na reparação de defeito ósseo em humanos.

Synergic effect of simvastatin in combination with amphotericin B against environmental strains of Cryptococcus neoformans from northeastern Brazil: a prospective experimental study

BACKGROUND: Statins are used as cholesterol-lowering drugs and may also have direct antimicrobial effects. OBJECTIVE: To evaluate synergic interactions between simvastatin and both amphotericin B and fluconazole, against environmental strains of Cryptococcus neoformans isolated from captive birds' droppings. DESIGNAND SETTING: Experimental study conducted at Federal University of Piauí, Parnaíba, in collaboration with Federal University of Triângulo Mineiro, Uberaba, Brazil. METHODS: Statin susceptibility tests of Cryptococcus neoformans samples were performed as prescribed in standards. Interactions of simvastatin with amphotericin and fluconazole were evaluated using the checkerboard microdilution method. Presence of these interactions was quantitatively detected through determining the fractional inhibitory concentration index (FICI). RESULTS: Isolates of Cryptococcus neoformans were obtained from 30 of the 206 samples of dry bird excreta (14.5%) that were collected from pet shops and houses. Ten isolates were selected for susceptibility tests. All of them were susceptible to amphotericin and fluconazole. All presented minimum inhibitory concentration (MIC) > 128 µg/ml and, thus, were resistant in vitro to simvastatin. An in vitro synergic effect was shown through combined testing of amphotericin B and simvastatin, such that six isolates (60%) presented FICI < 0.500. Two isolates showed considerable reductions in MIC, from 1 µg/ml to 0.250 µg/ml. No synergic effect was observed through combining fluconazole and simvastatin. CONCLUSION: These results demonstrate that simvastatin should be considered to be a therapeutic alternative, capable of potentiating the action of amphotericin B. However, further studies are necessary to clarify the real effect of simvastatin as an antifungal agent.

Novel Eudragit® -based polymeric nanoparticles for sustained release of simvastatin

This paper reports on the development of nanoparticles aiming at the in vitro controlled release of simvastatin (SVT). The nanoparticles were prepared by the nanoprecipitation method with polymers Eudragit® FS30D (EDGFS) or Eudragit® NE30D (EDGNE). EDGFS+SVT nanoparticles showed mean size of 148.8 nm and entrapment efficiency of 76.4%, whereas EDGNE+SVT nanoparticles showed mean size of 105.0 nm and entrapment efficiency of 103.2%. Infrared absorption spectra demonstrated that SVT incorporated into the polymer matrix, especially EDGNE. Similarly, the differential scanning calorimeter (DSC) curve presented no endothermic peak of fusion, indicating that the system is amorphous and the drug is not in the crystalline state. The maintenance of SVT in the amorphous state may favors its solubilization in the target release sites. In the in vitro dissolution assay, the SVT incorporated into the EDGFS+SVT nanoparticles showed a rapid initial release, which may be related to the pH of the dissolution medium used. Regarding the EDGNE+SVT nanoparticles, the in vitro release occurred in a bimodal behavior, i.e., an initial "burst" followed by a sustained delivery, with the kinetics of drug release following Baker-Lonsdale's mathematical model. All these features suggest the nanoparticulate system's potential to modulate SVT delivery and enhance its bioavailability.

Local effect of simvastatin combined with different osteoconductive biomaterials and collagen sponge on new bone formation in critical defects in rat calvaria

Abstract Purpose To evaluate the local effect of simvastatin (SVT) combined with deproteinized bovine bone (DBB) with hydroxyapatite/β-tricalcium phosphate biphasic ceramics (HA/TCP) and with collagen sponge (CS) on bone repair in critical size defects (CSDs) in rat calvaria. Methods Forty-two 5-mm diameter CSDs were made bilaterally in the calvaria of 18 rats. The animals were allocated according to the type of biomaterial and associations used to fill the CSD. After 8 weeks, the animals were euthanized, and their calvaria were evaluated for repaired tissue composition using histologic and histometric analyses. Results In the histometric analysis, the use of SVT showed to increase bone formation in the CSDs when combined with all the bone substitutes tested in this study (p<0.05). Greater bone formation was observed in the groups with SVT compared to the groups without SVT. Conclusions The use of SVT without the need for a vehicle and combined with a commercially available biomaterial may be a cheaper way to potentiate the formation of bone tissue without the need to produce new biomaterials. Therefore, SVT combined with DBB induced significantly greater new bone formation than did the other treatments.

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.

The effect of graft application and simvastatin treatment on tibial bone defect in rats. A histological and immunohistochemical study

Abstract Purpose: To evaluate histologically and immunohistochemically the bone regeneration after application of simvastatin on tibial bone defects in rats. Methods: Sixty Wistar albino rats were divided into 3 groups as control (6 mm tibial bone defect), defect + graft (allograft treatment), and defect + graft + simvastatin (10 mg/kg/day) for 28 days. Results: Histopathological examination revealed inflammation in control group (defect group), congestion in blood vessels, and an increase in osteoclast cells. In defect + graft group, osteoclastic activity was observed and osteocyte cells were continued to develop. In defect + graft + simvastatin group, osteocytes and matrix formation were increased in the new bone trabeculae. Osteopontin and osteonectin expression were positive in the osteclast cells in the control group. Osteoblasts and some osteocytes showed a positive reaction of osteopontin and osteopontin. In defect + graft + simvastatin group, osteonectin and osteopontin expression were positive in osteoblast and osteocyte cells, and a positive expression in osteon formation was also seen in new bone trabeculae. Conclusion: The simvastatin application was thought to increase bone turnover by increasing the osteoinductive effect with graft and significantly affect the formation of new bone.

Simvastatin promotes murine osteoclasts apoptosis through NFATc1 pathway / 南方医科大学学报

OBJECTIVE@#To explore the mechanism by which simvastatin (SIM) regulates osteoclast apoptosis.@*METHODS@#Murine macrophage RAW264.7 cells were divided into 5 groups, namely group A (control group), group B (sRANKL+ M-CSF), group C (SIM+sRANKL+M-CSF), group D (VIVIT peptide+sRANKL+ M-CSF), and group E (SIM+VIVIT peptide+sRANKL+M-CSF). WST-1 assay was used to assess the effects of simvastatin on the proliferation activity of the osteoclasts, and flow cytometry was performed to analyze the effects of SIM and VIVIVIT peptide (a NFATc1 pathway inhibitor) on apoptosis of the osteoclasts. The translocation of NFATc1 into the nucleus was investigated using immunofluorescence assay, and Western blotting was employed to assess the effect of SIM on the phosphorylation of NFATc1 in the nucleus.@*RESULTS@#WST-1 assay showed that SIM (1×10 mol/L) treatment for 24 and 48 h significantly inhibited the proliferation of the osteoclasts (=0.039 and 0.022, respectively). Compared with the control group, the SIM-treated osteoclasts exhibited significantly reduced cell percentage in G0/G1 phase (=0.041) and increased cells in sub-G1 phase (=0.028) with obvious cell apoptosis. DAPI staining and flow cytometry showed that both SIM and VIVIVIT peptide alone significantly promoted osteoclast apoptosis (=0.002 and 0.015, respectively), and their combination produced a similar pro-apoptosis effect (=0.08). Immunofluorescence and Western blotting showed that SIM significantly inhibited the intranuclear translocation of NFATc1 and the phosphorylation of NFATc1 pathway protein (=0.013).@*CONCLUSIONS@#SIM promotes osteoclast apoptosis through NFATc1 signaling pathway.