Estatinas, una alternativa en el tratamiento de la COVID-19 / Statins, an Alternative in the Treatment of COVID-19

Resumen Las estatinas son ampliamente utilizadas para el control de los niveles de colesterol en pacientes con hipercolesterolemia, lo cual permite prevenir enfermedades cardiovasculares. Además de controlar la síntesis endógena de colesterol, las estatinas tienen efectos pleiotrópicos diversos, como son las propiedades antiinflamatoria, antioxidante y de inmunomodulación. La enfermedad causada por el virus SARS-CoV-2 (COVID-19) provoca una tormenta de citocinas que contribuye a la generación del síndrome respiratorio agudo, que puede llevar a cuadros graves de esta enfermedad e incluso a la muerte del paciente. Diversos estudios realizados en enfermos con COVID-19 que recibieron estatinas, antes o durante el curso de la enfermedad, registraron cuadros menos graves, estancias hospitalarias más cortas y menor mortalidad. El beneficio de las estatinas en la COVID-19 debe ser explorado más ampliamente, ya que potencialmente pueden contribuir al control de esta pandemia que ha postrado a la humanidad.

Abstract Statins are widely used to control cholesterol levels in patients with hypercholesterolemia, which helps prevent cardiovascular diseases. In addition to controlling endogenous cholesterol synthesis, statins have diverse pleiotropic effects, such as anti-inflammatory, antioxidant, and immunomodulatory properties. The disease caused by the SARS-CoV-2 virus (COVID-19) causes a cytokine storm that contributes to the generation of acute respiratory syndrome, which can lead to severe symptoms of this disease and even the death of the patient. Various studies carried out on patients with COVID-19 who received statins, before or during the disease, registered less severe symptoms, shorter hospital stays and lower mortality. The benefit of statins in COVID-19 should be explored more widely, as they can potentially contribute to the control of this pandemic that has devastated humanity.

[Efficacy and safety of atorvastatin in major cardiovascular events: Meta-analysis]. / Eficacia y seguridad de la atorvastatina en eventos cardiovasculares mayores: metaanálisis.

Introduction: Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary prevention of Major Cardiovascular Events (MACE). Objective: To evaluate the impact of high-dose atorvastatin on secondary prevention of MACE and adverse events. Material and methods: A systematic review and meta-analysis of Pubmed, Embase, Bireme and Cochrane Library Plus databases was performed, with a time scope from 1990 to July 2022. Six randomized clinical trials were included with a total of 29,333 patients who were treated with 80 mg, 10 mg or placebo doses of Atorvastatin where the main outcomes evaluated were Major Cardiovascular Events (MACE), mortality and treatment safety. Results: In the comparative study between the use of Atorvastatin 80 mg and other therapies, a relative risk (RR) of 0.8 (95%CI 0.69-0.92) was found, representing a 20% reduction in risk (RRR) and a number needed to treat (NNT) of 30-55. In the analysis of adverse effects, an RR of 2.37 (95% CI 0.86-6.53) and a number needed to harm (NNH) of 14-19 were observed. The use of 80 mg atorvastatin is associated with similar adverse events at lower doses. Conclusions: The use of atorvastatin 80 mg is effective in the secondary prevention of Major Cardiovascular Event (MACE). The drug has adverse events that should be taken into account in secondary prevention.

Introducción: la atorvastatina ha sido usada en el manejo de la dislipidemia y se conoce poco sobre la eficacia y seguridad de la administración de atorvastatina en altas dosis para la prevención secundaria de eventos cardiovasculares mayores (MACE). Objetivo: evaluar el impacto de altas dosis de atorvastatina en la prevención secundaria de MACE y eventos adversos. Material y métodos: se realizó una revisión sistemática y un metaanálisis de las bases de datos Pubmed, Embase, Bireme y Cochrane Library Plus, con un alcance temporal de 1990 a julio de 2022. Se incluyeron seis ensayos clínicos aleatorios con un total de 29,333 pacientes que fueron tratados con dosis de 80 mg, 10 mg o placebo de Atorvastatina donde los resultados principales evaluados fueron los eventos cardiovasculares mayores (MACE), la mortalidad y la seguridad del tratamiento. Resultados: en el estudio comparativo entre el uso de Atorvastatina de 80 mg y otras terapias, se encontró un riesgo relativo (RR) de 0.8 (IC95%: 0.69-0.92), lo que representa una reducción del 20% en el riesgo (RRR) y un número necesario a tratar (NNT) de 30 a 55. En el análisis de los efectos adversos, se observó un RR de 2.37 (IC95%: 0.86-6.53) y un número necesario a dañar (NNH) de 14 a 19. El uso de atorvastatina de 80 mg se asocia con eventos adversos similares a dosis menores. Conclusiones: el uso de atorvastatina de 80 mg es efectivo en la prevención secundaria de evento cardiovascular mayor (MACE). El medicamento tiene eventos adversos que deben de tomarse en cuenta en la prevención secundaria.

Alopecia Universal após Tratamento com Sinvastatina e Ezetimiba: Impactos na Família / Alopecia Universalis after Treatment with Simvastatin and Ezetimibe: Affects on Family

Resumo A alopecia areata (AA) é uma doença autoimune que se desenvolve no couro cabeludo ou em outras partes do corpo. A alopecia universal, que é uma forma rara de alopecia areata, é caracterizada pela perda de pelos que afeta todo o corpo. Nos dois pacientes apresentados, o tratamento com atorvastatina foi iniciado com o diagnóstico de hipercolesterolemia, mas, quando as metas de valores não foram alcançadas, foi iniciado o tratamento com uma combinação de sinvastatina e ezetimiba. Depois de um período de tratamento com sinvastatina e ezetimiba, o distúrbio de AA, o qual começou com a perda de cabelo no couro cabeludo, espalhou pelo corpo todo e se transformou em alopecia universal. Embora as estatinas possam causar alopecia com reações autoimunes, elas geralmente são utilizadas no tratamento da alopecia, por seus efeitos imunomoduladores.

Abstract Alopecia areata (AA) is an autoimmune disease that grows in the scalp or in other parts of the body. Alopecia universalis, which is a rare form of alopecia areata, is characterized by a loss of hair that affects the entire body. In the two patients presented in this study, atorvastatin treatment was implemented, with the diagnosis of hypercholesterolemia; however, when the target values were not reached, a combination of simvastatin and ezetimibe was implemented. After a period of simvastatin/ezetimibe treatment, the AA disorder, which began with hair loss on the scalp, spread to the entire body and turned into Alopecia Universalis. Although statins can cause alopecia with autoimmune reactions, they are generally used in the treatment of alopecia due to their immunomodulatory effects.

Eficacia de la atorvastatina en el infarto cerebral aterotrombótico agudo / Effectiveness of atorvastatin in acute atherothrombotic cerebral infartation

Introducción: Las enfermedades Cerebrovasculares constituyen un importante problema de salud a escala global y en Cuba ocupan la tercera causa de muerte y la primera causa de discapacidad. Objetivo: Evaluar el uso de atorvastatina en el infarto cerebral aterotrombótico agudo. Métodos: Se realizó un estudio prospectivo longitudinal en los pacientes que acudieron al cuerpo de guardia del Hospital Clínico Quirúrgico Julio Trigo López diagnosticados como infarto cerebral aterotrombótico agudo. De forma aleatoria y con previo consentimiento informado se les suministró una dosis de 0, 20 mg o 40 mg de atorvastatina. Se les realizó tomografía axial computarizada de cráneo, la cual fue repetida al tercer día y a los 30 días. Se determinó el valor de proteína C reactiva en el cuerpo de guardia, y a los 30 días fueron evaluados clínicamente de acuerdo a la escala de National Institute of Health Stroke Scale en cuerpo de guardia, diariamente durante su ingreso y 30 días después. Resultados: El tamaño del área infartada disminuyó un 19,4 por ciento con 40 mg de atorvastatina al igual que el valor de proteína C reactiva que se redujo en 16 mg/L. La evaluación clínica según la escala de National Institute of Health Stroke Scale mostró una reducción en más de 8 puntos de acuerdo a la dosis de atorvastatina empleada. Conclusiones: Se demostró la eficacia de la atorvastatina por la disminución del área infartada, la reducción de los valores de proteína C reactiva y la evolución clínica favorable. Todos estos factores fueron directamente proporcional a la dosis de atorvastatina empleada(AU)

Introduction: Cererovascular diseases represent an important health problem worldwide and in Cuba they rank the third cause of death and the first cause of disability. Objective: To evaluate the use of astorvastin in acute atherotrombotic cerebral infactation. Methods: A longitudinal prospective study was carried out in patients who attended the emergency room of Julio Trigo López Surgical Clinical Hospital diagnosed with acute atherothrombotic cerebral infarction. Randomly and with prior informed consent, they were given a dose of 0, 20 mg or 40 mg of atorvastatin. Computerized axial tomography of the skull was performed, which was repeated on day 3 and day 30. The value of C-reactive protein in the emergency room was determined, and at day 30, they were clinically evaluated daily during admission and 30 days later, according to the scale of the National Institute of Health Stroke Scale in emergency room. Results: The size of the infarcted area decreased by 19.4 percent with 40 mg of atorvastatin, as well as the value of C-reactive protein, which decreased by 16 mg/L. The clinical evaluation according to the National Institute of Health Stroke Scale showed reduction of more than 8 points according to the dose of atorvastatin used. Conclusions: The efficacy of atorvastatin was demonstrated by the reduction of the infarcted area, the reduction of C-reactive protein values and the favorable clinical evolution. All of these factors were directly proportional to the dose of atorvastatin used(AU)

Atorvastatina Atenua o Remodelamento Vascular em Camundongos com Síndrome Metabólica / Atorvastatin Attenuates Vascular Remodeling in Mice with Metabolic Syndrome

Resumo Fundamento A síndrome metabólica é caracterizada por um conjunto de comorbidades. Durante a síndrome, observam-se alterações estruturais no sistema cardiovascular, especialmente o remodelamento vascular. Uma das causas predisponentes para essas alterações é a inflamação crônica oriunda de mudanças na estrutura e composição do tecido adiposo perivascular. Atorvastatina é eficaz no tratamento das dislipidemias. No entanto, seus efeitos pleiotrópicos não são totalmente compreendidos. Supõe-se que, durante a síndrome metabólica, ocorre remodelamento vascular e que o tratamento com atorvastatina pode ser capaz de atenuar tal condição. Objetivos Avaliar os efeitos do tratamento com atorvastatina sobre o remodelamento vascular em modelo experimental de síndrome metabólica. Métodos Camundongos Swiss receberam dieta controle ou dieta hiperglicídica por 18 semanas. Após 14 semanas de dieta, os camundongos foram tratados com veículo ou atorvastatina (20mg/kg) durante 4 semanas. Foram avaliados o perfil nutricional e metabólico por testes bioquímicos; análise estrutural da artéria aorta por histologia e dosagem de citocinas por ensaio imunoenzimático. O nível de significância aceitável para os resultados foi p <0,05. Resultados A dieta hiperglicídica promoveu o desenvolvimento de síndrome metabólica. Tal fato culminou no remodelamento hipertrófico do músculo liso vascular e tecido adiposo perivascular. Além disso, houve aumentos das citocinas TNF-α e IL-6 circulantes e no tecido adiposo perivascular. O tratamento com atorvastatina reduziu significativamente os danos metabólicos, o remodelamento vascular e os níveis de citocinas. Conclusão Atorvastatina ameniza danos metabólicos associados à síndrome metabólica induzida por dieta hiperglicídica, além de atenuar o remodelamento vascular, sendo esses efeitos associados à redução de citocinas pró-inflamatórias.

Abstract Background Metabolic syndrome is characterized by an array of comorbidities. During this syndrome, structural changes are observed in the cardiovascular system, especially vascular remodeling. One of the predisposing causes for these changes is chronic inflammation resulting from changes in the structure and composition of perivascular adipose tissue. Atorvastatin is effective in the treatment of dyslipidemias. However, its pleiotropic effects have not been completely understood. We hypothesize that metabolic syndrome may lead to vascular remodeling and that atorvastatin therapy may be able to attenuate this condition. Objectives To assess the effects of atorvastatin therapy on vascular remodeling in an experimental model of metabolic syndrome. Methods Swiss mice received a control diet or a hyperglicemic diet for 18 weeks. After 14 weeks of diet, mice were treated with vehicle or atorvastatin (20mg/kg) during for 4 weeks. Nutritional and metabolic profiles were assessed by biochemical tests; moreover, a histological assessment of aorta structure was conducted, and cytokine levels were determined by the immunoenzyme assay. The acceptable level of significance for the results was set at p<0.05. Results Hyperglicemic diet promoted the development of metabolic syndrome. It indeed culminated in hypertrophic remodeling of vascular smooth muscle and perivascular adipose tissue. Furthermore, there were increases in the levels of circulating TNF-α and IL-6 and in the perivascular adipose tissue. Atorvastatin therapy significantly reduced metabolic damages, vascular remodeling, and cytokine levels. Conclusion Atorvastatin attenuate metabolic damages associated with metabolic syndrome induced by hyperglycemic diet, in addition to attenuating vascular remodeling; both effects are associated with reduced levels of pro-inflammatory cytokines.

O efeito da atorvastatina + aspirina na função endotelial difere com a idade em pacientes com HIV: Um estudo de caso-controle / The effect of atorvastatin + aspirin on the endothelial function differs with age in patients with HIV: A case-control study

Resumo Fundamento Pacientes com HIV têm maior probabilidade de apresentar doenças cardiovasculares quando comparados à população em geral. Objetivo Este foi um estudo de caso-controle que teve como objetivo avaliar quais fatores estavam associados a uma redução na espessura médio-intimal da carótida (IMT) da carótida e ao aumento na dilatação mediada por fluxo (DMF) da artéria braquial em pacientes com HIV que receberam atorvastatina + aspirina por um período de 6 meses. Métodos Foi realizada uma análise secundária de um ensaio clínico, que incluiu pessoas vivendo com HIV e baixo risco cardiovascular. Um total de 38 pacientes alocados para o braço de intervenção e tratados por 6 meses com uma combinação de atorvastatina + aspirina foram incluídos. Todos os participantes foram submetidos a ultrassonografia da carótida e da artéria braquial, tanto no início quanto no final do estudo. Os casos que responderam com aumento >10% da dilatação braquial (DMF) e redução da espessura médio-intimal da carótida (IMT) foram considerados casos, e aqueles que não responderam foram considerados controles. Avaliamos os fatores associados às respostas positivas obtidas através da IMT e DMF. Resultados A redução do IMT não se associou significativamente a nenhum dos fatores de risco avaliados: idade (p = 0,211), sexo (p = 0,260), tabagismo (p = 0,131) ou tempo de diagnóstico do HIV (p = 0,836). Um aumento na DMF foi significativamente associado com a idade entre aqueles na faixa etária de 40-59 anos, p = 0,015 (OR = 4,37; IC 95%: 1,07-17,79). Conclusões Os indivíduos mais velhos foram mais propensos a apresentar um aumento na DMF após 6 meses de tratamento com atorvastatina + aspirina.

Abstract Background Patients with HIV are more likely to present with cardiovascular disease when compared to the general population. Objective This was a case-control study that aimed to assess which factors were associated with a reduction in the carotid intima-media thickness (IMT) and an increase in the brachial artery flow-mediated dilation (FMD) in HIV patients who received atorvastatin + aspirin during a period of 6 months. Methods A secondary analysis of a clinical trial was conducted, which included people living with HIV infection and low cardiovascular risk. A total of 38 patients allocated to the intervention arm and treated for 6 months with a combination of atorvastatin + aspirin were included. All participants underwent a carotid and brachial artery ultrasound, both at the beginning and the end of the study. Cases that responded with an increase of >10% of the brachial dilatation (FMD) and reduction of the carotid intima-media thickness (IMT) were considered cases, and those who did not respond were considered controls. We assessed the factors associated with the positive responses obtained through IMT and FMD. Results A reduction in the IMT was not significantly associated with any of the evaluated risk factors: age (p=0.211), gender (p=0.260), smoking (p=0.131) or time since HIV diagnosis (p=0.836). An increase in the FMD was significantly associated with age amongst those in the 40-59 age group, p = 0.015 (OR = 4.37; 95% CI: 1.07-17.79). Conclusions Older individuals were more likely to present with an increased FMD after 6 months of treatment with atorvastatin + aspirin.

Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents?

INTRODUCTION AND OBJECTIVES: To compare the pharmacodynamics of the CNIC polypill (atorvastatin 40mg/ramipril 10mg/aspirin 100mg) in terms of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP), with the corresponding reference products (atorvastatin and ramipril). METHODS: This was a multicenter, randomized, open-label, and parallel 3-arm study comparing the effect of the CNIC polypill vs ramipril 10mg and atorvastatin 40mg on SBP and LDL-C. The coprimary endpoints were differences in the adjusted mean 24-hour SBP (using ambulatory BP measurement) and LDL-C during the study period estimated using an ANCOVA model. RESULTS: Of the 241 patients included in the per protocol population, 84 received the CNIC polypill (group A), 84 atorvastatin (group B), and 73 ramipril (group C). SBP decreased from 139.3±12.5 to 133.2±12.9mmHg in group A and from 138.1±11.9 to 134.0±12.8mmHg in group C (baseline adjusted mean difference for the decrease in SBP was 1.77mmHg (90%CI, -0.5 to 4.0) in favor of group A, without reaching statistical significance. LDL-C was reduced by 33.9±21.6 and 29.2±25.8mg/dL in groups A and B, respectively (baseline adjusted mean difference for the decrease in LDL-C was 7.0% (90%CI, 1.5-12.4), a significantly greater decrease with the polypill). The 3 treatments were well tolerated. CONCLUSIONS: The results of this study rule out a negative effect on blood pressure of the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, suggesting a synergistic effect of the components.

Atorvastatina Reduz o Acúmulo de Células Musculares Lisas Vasculares para Inibir a Hiperplasia Intimal pela Inibição de Via p38 MAPK em um Modelo de Enxerto de Veia em Ratos / Atorvastatin Reduces Accumulation of Vascular Smooth Muscle Cells to Inhibit Intimal Hyperplasia via p38 MAPK Pathway Inhibition in a Rat Model of Vein Graft

Resumo Fundamento: A taxa de falha de enxerto de veia safena um ano após a cirurgia de revascularização do miocárdio varia de 10% a 25%. O objetivo deste estudo foi de investigar se a atorvastatina pode reduzir o acúmulo de células musculares lisas vasculares para inibir a hiperplasia intimal por meio da inibição da via p38 MAPK. Métodos: Quarenta e cinco ratos Sprague-Dawley foram randomizados em três grupos. Trinta ratos foram submetidos à cirurgia de enxerto de veia e randomizados para tratamento com veículo ou atorvastatina; quinze ratos foram submetidos à cirurgia sham. Detectamos a hiperplasia intimal por meio de coloração com hematoxilina-eosina e a expressão de proteínas relacionadas por meio de análise imuno-histoquímica e Western blot. Foram realizadas as comparações por análise de variância de fator único e pelo teste da diferença mínima significativa de Fisher, com p < 0,05 considerado significativo. Resultados: A íntima analisada pela coloração com hematoxilina-eosina era dramaticamente mais espessa no grupo controle que no grupo atorvastatina e no grupo sham (p < 0,01). Os resultados da coloração imuno-histoquímica de α-SMA demonstraram que a porcentagem de células positivas para α-SMA no grupo controle era mais alta que no grupo atorvastatina (p < 0,01). Nós também avaliamos α-SMA, PCNA, p38 MAPK e fosforilação de p38 MAPK após o tratamento com estatina por meio de análise de Western blot e os resultados indicaram que a atorvastatina não levou à redução de p38 MAPK (p < 0,05); no entanto, resultou na inibição da fosforilação de p38 MAPK (p < 0,01) e reduziu significativamente os níveis de α-SMA e PCNA, em comparação com o grupo controle (p < 0,01). Conclusão: Nós demonstramos que a atorvastatina pode inibir o acúmulo de células musculares lisas vasculares por meio da inibição da via p38 MAPK e é capaz de inibir a hiperplasia intimal em modelos de enxerto de veia em ratos.

Abstract Background: The rate of saphenous vein graft failure one year after coronary artery bypass grafting ranges from 10% to 25%. The aim of this study was to explore whether atorvastatin can reduce accumulation of vascular smooth muscle cells to inhibit intimal hyperplasia via p38 MAPK pathway inhibition. Methods: Forty-five Sprague-Dawley rats were randomized to three groups. Thirty rats received a vein graft operation, and they were randomized to be treated with vehicle or atorvastatin; fifteen rats received a sham operation. We detected intimal hyperplasia by hematoxylin-eosin staining and related protein expression by immunohistochemical and Western blot analysis. Comparisons were analyzed by single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant. Results: The intima analyzed by hematoxylin-eosin staining was dramatically thicker in the control group than in the atorvastatin group and sham group (p < 0.01). The outcomes of immunohistochemical staining of α-SMA demonstrated that the percentage of α-SMA-positive cells in the control group was higher than in the atorvastatin group (p < 0.01). We also evaluated α-SMA, PCNA, p38 MAPK, and phosphorylation of p38 MAPK after statin treatment by Western blot analysis, and the results indicated that atorvastatin did not lead to p38 MAPK reduction (p < 0.05); it did, however, result in inhibition of p38 MAPK phosphorylation (p < 0.01), and it significantly reduced α-SMA and PCNA levels, in comparison with the control group (p < 0.01). Conclusion: We have demonstrated that atorvastatin can inhibit accumulation of vascular smooth muscle cells by inhibiting the p38 MAPK pathway, and it is capable of inhibiting intimal hyperplasia in a rat vein graft model.

Efeito da administração local e sistêmica da atorvastatina no reparo ósseo de defeitos críticos em calvária de ratos / Effect of local or systemic administration of atorvastatin on bone repair of critical defects in rats' calvaria

Objetivo: O presente estudo teve como objetivo comparar o efeito da Atorvastatina, aplicada de forma local e sistêmica, em defeitos críticos de calotas de ratos. Material e médodos: 36 (trinta e seis) ratos (Rattus norvegicus, albinus, Wistar), adultos foram divididos aleatoriamente em 3 grupos, o grupo aplicação de membrana de colágeno com água destilada (GAD) com defeitos de tamanho crítico contendo água destilada; o grupo aplicação Sistêmica de Atorvastatina (GAS) foram realizado defeitos de tamanho crítico e os animais foram tratados com atorvastatina (3,6mg/kg/dia) por gavagem; e o grupo de aplicação local de Atorvastatina (GAL) com defeitos de tamanho crítico contendo Atorvastatina. Cada grupo foi avaliado através da histometria, mensuração do defeito residual, área de osso néo formado (AON), área de membrana e tecido mole, contagem de células (osteócitos, osteoblastos, células inflamatórias) e imunoistoquímica (OSTEOCALCINA e CD31), nos períodos de 14 e 28 dias. Resultados: Os dados mostraram diminuição do defeito residual para GAS quando comparada ao GAL (p=0,024) e ao GAD (p=0,033), o GAS revelou diminuição de número de osteócitos em comparação ao GAD (p=0,026), e em comparação com GAL (p=0,020). Os osteoblastos não apresentaram diferença entre os grupos (p>0,05), a quantidade de fibroblastos mostrou maiores somente para o GAL de 14 para 28 dias (p=0,019). Aos 28 dias, tanto para GAL quanto GAS, a quantidade de células inflamatórias foram maiores comparadas ao GAD (p< 0,05). A marcação de imunoistoquimica para CD31 não apresentou alteração, e OCN nos osteoblastos mostrou maior imunomarcação aos 14 dias em comparação aos 28 dias somente para o GAS (p=0,026; Holm-Sidak), OCN na marcação da matriz extra celular (MEC) mostrou aumento da imunomarcação aos 14 quando comparado aos 28 dias no GAL e GAS (p=0,041; Holm-Sidak). Conclusão: A Atorvastatina promoveu efeito positivo na osteogênese e sugere-se que ela não exerça função anti-inflamatória(AU)

Objective: This study aimed to compare the effect of Atorvastatin, applied locally and systemically, on critical defects of rat caps. Material and medicaments: 36 (thirty-six) rats (Rattus norvegicus, albinus, Wistar), adults were randomly divided into 3 groups, the collagen membrane application group with distilled water (GAD) with critical size defects containing distilled water; the systemic application group of Atorvastatin (GAS) was performed with critical size defects and the animals were treated with atorvastatin (3.6mg/kg/day) per gavage; and the local application group of Atorvastatin (GAL) with critical size defects containing Atorvastatin. Each group was evaluated by histometry, measurement of the residual defect, area of neo formed bone (AON), area of membrane and soft tissue, cell count (osteocytes, osteoblasts, inflammatory cells) and immunohistochemistry (OSTEOCALCINE and CD31), in periods of 14 and 28 days. Results: The data showed a decrease of residual defect for GAS when compared to GAL (p=0.024) and GAD (p=0.033), GAS showed a decrease of osteocytes in comparison to GAD (p=0.026), and in comparison to GAL (p=0.020). The osteoblasts did not present difference between the groups (p>0.05), the amount of fibroblasts showed higher only for the GAL from 14 to 28 days (p=0.019). At 28 days, both for GAL and GAS, the amount of inflammatory cells were higher compared to GAD (p<0.05). The immunohistochemistry marking for CD31 showed no change, and CSF in osteoblasts showed higher immunomarkings at 14 days compared to 28 days only for GAS (p=0.026; Holm-Sidak), CSF in extra cellular matrix marking (SCM) showed increased immunomarkings at 14 days compared to 28 days in GAL and GAS (p=0.041; Holm-Sidak). Conclusion: Atorvastatin promoted a positive effect on osteogenesis and it is suggested that it does not have an anti-inflammatory function(AU)

Desenvolvimento de metodologia para avaliação do perfil de dissolução de comprimidos de atorvastatina cálcica 20 mg comercializados no Peru, Brasil e Bolívia / Development of a methodology to evaluate the dissolution profile of atorvastatin calcium tablets 20 mg marketed in Peru, Brazil and Bolivia

O presente estudo teve por finalidade desenvolver uma metodologia de dissolução discriminativa para avaliar comprimidos contendo diferentes polimorfos de atorvastatina cálcica (ATR). Este trabalho é conformado por quatro capítulos, no qual o primeiro apresenta uma breve revisão de literatura sobre as características dos polimorfos da ATR, abordando-se informações mais relevantes sobre o ATR em relação ao polimorfismo e sua influência na biodisponibilidade. No segundo capítulo, apresenta-se a importância da caracterização dos polimorfismos e suas implicações para a ATR. As amostras de ATR foram identificadas por difração raio X e análise térmica e, posteriormente, demonstrou-se as diferenças entre quatro amostras comercializadas no mercado brasileiro relacionadas ao hábito cristalino, tamanho de partícula e solubilidade. No terceiro capítulo, demonstra-se o desenvolvimento do método de dissolução discriminativo para comprimidos contendo duas formas polimórficas da ATR. Para tanto, avaliou-se a solubilidade destas pelo método do equilíbrio e determinou-se as condições experimentais mais adequadas para o ensaio de dissolução por intermédio de planejamento fatorial completo do tipo 23, sendo as variáveis independentes o meio de dissolução, a velocidade de agitação e as formas polimórficas (I e VIII). Os resultados obtidos foram tratados estatisticamente através da análise de variância, dos gráficos de Pareto e de superfície de resposta. Concluiu-se que a velocidade de agitação e o meio de dissolução impactam os resultados, afetando a dissolução das formulações com os polimorfos avaliados. Assim, as condições selecionadas foram: 750 mL de meio água a 65 rpm. Após o desenvolvimento do método, este foi comparado com o da Food and Drug Administration (FDA) para comprimidos de atorvastatina cálcica. Ao final dos ensaios, o método desenvolvido mostrou-se adequado para apontar diferenças entre os polimorfos da ATR. No quarto capítulo, o método desenvolvido foi utilizado para avaliar o perfil de dissolução de comprimidos comercializados em três países sul-americanos: Brasil, Peru e Bolívia. As porcentagens de fármaco dissolvidas e a Eficiência de Dissolução foram as variáveis estudadas e, posteriormente, tratadas estatisticamente através da análise de componentes principais, sendo possível comparar o perfil de dissolução de dessete formulações. Dessa forma, foi possível concluir que cinco formulações avaliadas (BR1, BR2 PE6, BR7 e BO3) possuíam a forma polimórfica VIII, enquanto duas formulações (BR5 e PE2) continham a forma polimórfica I. As demais, possivelmente, apresentam misturas ou outras formas polimórficas

This present study was aimed at developing a discriminative dissolution methodology to evaluate tablets containing different calcium atorvastatin (ATR) polymorphs. This paper consists of four chapters. The first chapter presents a brief literature review of the characteristics of ATR polymorphs, and addresses more relevant information about ATR in relation to polymorphism and its influence on bioavailability. The second chapter presents the importance of the characterization of polymorphs and their implications for ATR. The ATR samples were identified by X-ray diffraction and thermal analysis. Subsequently, the differences among the four samples marketed in the Brazilian market with relation to crystalline habit, particle size and solubility were demonstrated. The third chapter demonstrates the development of the discriminative dissolution method for tablets containing two polymorphic forms of ATR. For this, their solubilities were evaluated by the equilibrium method and the most suitable experimental conditions for the dissolution test were determined by means of complete factorial design of type 23, and the independent variables were the dissolution medium, the stirring speed and polymorphic forms (I and VIII). The results obtained were statistically treated through analysis of variance, Pareto and response surface graphs. It was concluded that the stirring speed and the dissolution medium influenced the results, affecting the dissolution of the formulations with the evaluated polymorphs. Thus, the selected condition was 750 mL of water at 65 rpm. Following the development of the method, it was compared with that of the Food and Drug Administration (FDA) for atorvastatin calcium tablets. At the end of the tests, the developed method was adequate to point out differences between the ATR polymorphs. In the fourth chapter, the developed method was used to evaluate the dissolution profile of tablets marketed in three South American countries: Brazil, Peru and Bolivia. Dissolved drug percentages and Dissolution Efficiency were the studied variables and statistically treated by principal component analysis. Through this method, it was possible to compare the dissolution profile of seventeen formulations. Thus, it was possible to conclude that five formulations evaluated (BR1, BR2, PE6, PE7 e BO3) had the polymorphic form VIII, while two formulations (BR5 e PE2) contained the polymorphic form I. The others possibly have mixtures or other forms polymorphic

Use of the cardiovascular polypill 40mg in secondary cardiovascular prevention. / Uso de la polipíldora cardiovascular 40mg en prevención cardiovascular secundaria.

Controlling cardiovascular risk factors (CV) is essential for patients with cardiovascular disease. The CV polypill contains aspirin 100mg, atorvastatin 20mg or 40mg, and ramipril 2.5mg, 5mg or 10mg in a fixed combination pill. The objective was to review the evidence on the secondary prevention of cardiovascular disease, to establish the eventual patient profiles suitables to consider the use of CV polypill with atorvastatin 40mg in secondary CV prevention (P40PS), and to define the priority situations most adequate for the use of P40PS. A bibliographic review was carried out, which was complemented with the clinical opinion of 19 specialists. During hospitalization and discharge, P40PS is an option for patients admitted because of an atherothrombotic event, peripheral arterial disease, or other causes, and with the indication of the monocomponents. Its priority use is proposed in: prior intolerance to the highest dose of atorvastatin (80mg), age>75 years, low weight, stage 3 of chronic renal failure, hypothyroidism, drug interactions and Asian origin. Outside the hospital setting, the P40PS is a therapeutic alternative in patients with a need for secondary CV prevention and with indication to receive the monocomponents. The priority situations to receive the P40PS are: to be taking the three components separately, to require polypharmacy, lack of adherence or understanding of the treatment, and lack of control of CV risk factors. This work is the first with proposals for the use of P40PS and can facilitate the treatment of patients with cardiovascular disease in secondary prevention.

El legado científico y el papel actual de la atorvastatina en el manejo del riesgo de enfermedad cardiovascular aterosclerótica / The scientific legacy and the current role of atorvastatin in the management of risk of atherosclerotic cardiovascular disease

Resumen Durante mucho tiempo, los esfuerzos para disminuir el riesgo cardiovascular en los adultos se centraron en el intento de reducir tanto como fuese posible las concentraciones plasmáticas de colesterol 6, LDL (c-LDL). Hasta muy recientemente se concluyó que en los estudios clínicos de medicamentos con acción en los lípidos circulantes no existía evidencia directa que permitiera determinar cuál es la mejor meta de c-LDL para la disminución del riesgo cardiovascular y tampoco se concedió importancia suficiente a los eventos adversos de las diferentes combinaciones farmacológicas recomendadas para el logro de las concentraciones de c-LDL más bajas posibles. El análisis exhaustivo realizado para la actualización del Programa para el Control del Colesterol en el Adulto de Estados Unidos (NCEP-ATP-III), que comprendió una gran cantidad de estudios controlados con distribución al azar, permitió en 2013 la postulación de un nuevo paradigma de tratamiento que abandona el concepto de metas determinadas de c-LDL y que insiste en la importancia de las modificaciones favorables en el estilo de vida, además de que recomienda la administración preferencial de estatinas, en tipos y dosis fijas, debido a que un importante volumen de evidencia ha demostrado que estos agentes atenúan la progresión de la aterosclerosis coronaria y promueven la regresión de ésta, con lo que disminuyen significativamente la morbilidad y mortalidad cardiovasculares en la prevención primaria y en la secundaria. En este nuevo paradigma terapéutico fue posible también la identificación de los grupos de pacientes que pueden beneficiarse con la administración de estatinas. En consensos y guías más recientes, algunas asociaciones sostienen la necesidad de lograr ciertas metas de cLDL de acuerdo con el riesgo, pero mantienen a las estatinas como el pilar del tratamiento, solas o en combinación con ezetimiba o con antagonistas de la convertasa de proproteínas subtilisina/kexina de tipo 9 (PCSK9: proprotein convertase subtilisin/kexin type 9). En este artículo se revisa la evidencia clínica relativa a la administración de atorvastatina, que en gran medida permitió el desarrollo del nuevo paradigma de manejo del riesgo cardiovascular.

Abstract For a long time, efforts to reduce cardiovascular risk in adults focused on the attempt to reduce plasmatic LDL cholesterol (LDLc) levels as much as possible. Until very recently, it was concluded that in clinical studies of drugs with action on circulating lipids, there was no direct evidence to determine the best LDLc target for cardiovascular risk reduction, and that adverse events, or the almost absent demonstration of impact on hard outcomes of the different pharmacological combinations recommended for the achievement of the lowest possible LDLc concentrations, were not considered. The comprehensive analysis for the update of NCEP-ATP-III (National Cholesterol Education Program, Adult Treatment Panel III), which included a large number of controlled and randomized trials, allowed in 2013 the postulation of a new treatment paradigm, which leaves the concept of specific goals of LDLc and postulates the importance of favorable lifestyle modifications and which commends the pre-ferential use of statins, fixed doses and type, because a large volume of evidence has shown that these agents attenuate the progression of coronary atherosclerosis and promote the regression of this, which significantly decrease cardiovascular morbidity and mortality in both primary and secondary prevention. In this new therapeutic paradigm, it was also possible to identify the groups of patients that can benefit from the use of statins. In more recent consensuses and guidelines, some associations support the need to achieve risk-adjusted LDLc, but keep statins as the mainstay of treatment, alone or in combination with ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCKS-9) antagonists. This article reviews the clinical evidence regarding the use of atorvastatin, which allowed the development of the new cardiovascular risk management paradigm.

Avaliação do papel da fibrina rica em plaquetas em defeito crítico cirurgicamente criado em calota de ratos induzidos à hipercolesterolemia tratados ou não com atorvastatina / Evaluation of the role of Platelet Rich Fibrin in surgical critical-size calvarial defect in rats with diet-induced hypercholesterolemia treated or not with atorvastatin

Objetivos: avaliar a ação da membrana de fibrina rica em plaquetas, na reparação óssea, em defeito crítico de calota de ratos induzidos à hipercolesterolemia, bem como a atuação do tratamento de atorvastatina nesse processo Materiais e método: 40 defeitos críticos de 6 mm de diâmetro foram criados em calotas cranianas de ratos. Cada defeito foi aleatoriamente dividido em 8 grupos experimentais (GC, GCPRF, GCA, GCH, GHA, GPRFA, GPRFH, GPRFHA), avaliados aos 28 dias pós-operatórios com análises histológica e microtomográfica. Resultados: Os resultados mostraram que houve formação óssea em todos os grupos analisados. O grupo GPRFH apresentou formação óssea mais acentuada com relação aos demais grupos. Dos grupos em que foi administrado atorvastatina, o GPRFHA apresentou maior taxa de formação óssea (p<0,05). Conclusão: Com a metodologia utilizada, a fibrina rica em plaquetas, quando associada à condição de hipercolesterolemia, induziu ao aumento da formação óssea(AU)

Objectives: The aim of this study was to evaluate the efficacy of Platelet Rich Fibrin (PRF) in the healing process of surgically created critical-size defects in rat calvarial induced to hypercholesterolemia treated or not with atorvastatin. Materials and method: 40 critical defects were created with 6 mm diameter calvaria of rats. Each defect was randomly divided into eight experimental groups (GC, GCPRF, GCA, GCH, GHA, GPRFA, GPRFH, GPRFHA), evaluated at 28 postoperative days for histomorphometry and microtomography. Results: The results showed new bone formation in all groups. The GPRFH group just did differ from all groups in the new bone formation (p<0.05). Among the groups treated with atorvastatin, the GPRFHA group showed the highest bone formation rate. Conclusion: With the methodology used, the platelet-rich fibrin associated with the hypercholesterolemia induced to new bone formation(AU)

Atorvastatin-medicated dentifrice significantly inhibits CD4+ T cell proliferation: in vitro pilot study / Pasta dental medicada con atorvastatina inhibe de forma significativa la proliferación de células T CD4+: un estudio piloto in vitro

Reports indicate that statins (cholesterol-lowering drugs), in addition to lowering cholesterol, have an immunomodulatory effect. This effect may be beneficial for the treatment of several diseases, including periodontal disease. The aim of the present study was to evaluate the immunomodulatory effect of an atorvastatin-medicated dentifrice on CD4+ T cell proliferation. CD4+ T cell proliferation assays and peripheral blood mononuclear cell (PBMC) viability assays were conducted on PBMCs from healthy donors cultured under the following conditions: control, atorvastatin solution, atorvastatin-medicated dentifrice, and dentifrice without atorvastatin at concentrations of 1, 5, 10, 50 and 100 µM. A Generalized Equation Estimation (GEE) model was used to analyze concentration versus proliferation and concentration versus percentage of dead cells within each group evaluated. Atorvastatin-medicated dentifrice (p-value <0.0001) and atorvastatin solution (p-value <0.0001) significantly inhibited CD4+ T cell proliferation in a dose-dependent manner compared with the dentifrice without atorvastatin and control conditions. Only the relationship between atorvastatin solution and percentage of dead cells was significant compared to the other conditions (p-value 0.019). The results revealed that atorvastatin-medicated dentifrice at concentrations of 1 to 100 µM had immunomodulatory effects, inhibiting CD4+ T cell proliferation without affecting PBMC viability. The other components of the dentifrice did not affect CD4+ T cell proliferation or cell viability, indicating its utility as a vehicle to achieve the desired effects of atorvastatin in periodontal tissue. Controlled clinical trials are still needed to evaluate the clinical effects of an atorvastatin-medicated dentifrice on the periodontium.

La literatura indica que las estatinas (medicamentos para bajar el colesterol), además de reducir el colesterol, tienen un efecto inmunomodulador. Este efecto puede ser beneficioso para el tratamiento de varias enfermedades, incluyendo la enfermedad periodontal. El objetivo de este estudio es evaluar el efecto inmunomodulador de una pasta dental medicada con atorvastatina sobre la proliferación celular de linfocitos T CD4+. A partir de células mononucleares de sangre periférica de donantes sanos (PBMC), se realizaron ensayos de proliferación y viabilidad de linfocitos T CD4+ bajo las siguientes condiciones: control, solución de atorvastatina, dentífrico medicado con atorvastatina y dentífrico sin atorvastatina, en concentraciones 1, 5, 10, 50 and 100 µM. Se realizó el análisis estadístico utilizando el modelo Generalized Equation Estimation (GEE) a fin de analizar la concentración versus la proliferación y la concentración versus el porcentaje de muerte celular para cada uno de los grupos. El dentífrico medicado con atorvastatina (valor p <0,0001) y solución de atorvastatina (valor p <0,0001) inhibieron significativamente la proliferación de células T CD4 + de una manera dependiente de la dosis en comparación con el dentífrico sin atorvastatina y condiciones de control. Sólo la relación entre la atorvastatina solución y el porcentaje de células muertas fue significativa en comparación con las otras condiciones (vale-p 0,019). Los resultados revelaron que el dentífrico medicado con atorvastatina en concentraciones de 1 a 100 mM tenía efectos inmunomoduladores, inhibiendo la proliferación de células T CD4 + sin afectar la viabilidad de PBMC. Los otros componentes del dentífrico no afectaron la proliferación de células T CD4 + o la viabilidad celular, indicando su utilidad como vehículo para conseguir los efectos deseados de atorvastatina en el tejido periodontal. Todavía se necesitan ensayos clínicos controlados para evaluar los efectos clínicos de un dentífrico medicado con atorvastatina sobre el periodonto.

Atorvastatin calcium loaded chitosan nanoparticles: in vitro evaluation and in vivo pharmacokinetic studies in rabbits / Atorvastatina de cálcio carregadas nanopartículas de quitosana: avaliação farmacocinética in vitro e in vivo em estudos de coelhos

In this study, we prepared atorvastatin calcium (AVST) loaded chitosan nanoparticles to improve the oral bioavailability of the drug. Nanoparticles were prepared by solvent evaporation technique and evaluated for its particle size, entrapment efficiency, zeta potential, in vitro release and surface morphology by scanning electron microscopy (SEM). In addition, the pharmacokinetics of AVST from the optimized formulation (FT5) was compared with marketed immediate release formulation (Atorva^(r)) in rabbits. Particle size of prepared nanoparticles was ranged between 179.3 ± 7.12 to 256.8 ± 8.24 nm with a low polydispersity index (PI) value. Zeta potential study showed that the particles are stable with positive values between 13.03 ± 0.32 to 46.90 ± 0.49 mV. FT-IR studies confirmed the absence of incompatibility of AVST with excipient used in the formulations. In vitro release study showed that the drug release was sustained for 48 h. Results of pharmacokinetics study showed significant changes in the pharmacokinetic parameter (2.2 fold increase in AUC) of the optimized formulation as compared to marketed formulation (Atorva^(r)). Thus, the developed nanoparticles evidenced the improvement of oral bioavailability of AVST in rabbit model...

No presente estudo, preparamos nanopartículas de quitosana com atorvastatina cálcica (AVST) para melhorar a biodisponibilidade oral do fármaco. As nanopartículas foram preparadas pela técnica de evaporação de solvente, avaliando-se a granulometria, a eficiência de encapsulamento, o potencial zeta, a liberação in vitroe a morfologia da superfície, por meio da microscopia eletrônica de varredura (MEV). Além disso, a farmacocinética da formulação otimizada de AVST (FT5) foi comparada com a formulação comercial, de liberação imediata, comercializada (Atorva(r)), em coelhos. O tamanho das das nanopartículas variou na faixa de 179,3 a 256,8 ± 7,12 ± 8,24 nm, com baixo índice polidispersibilidade (PI). O estudo do potencial Zeta mostrou que as partículas são estáveis, com valores positivos entre 13,03 ± 0,32 a 46,90 ± 0,49 mV. Os estudos de FT-IR confirmaram a ausência de incompatibilidade de AVST com o excipiente utilizado nas formulações. O estudo de liberação in vitro mostrou que liberação sustentada do fármaco por 48 horas. Os resultados do estudo farmacocinético mostraram alterações significativas nos parâmetros (aumento de 2,2 vezes na ASC) da formulação otimizada em relação à comercializada (Atorva(r) ). Assim, o desenvolvimento de nanopartículas evidenciou a melhora da biodisponibilidade oral de AVST em coelhos...

Atorvastatin reduces T-cell activation and exhaustion among HIV-infected cART-treated suboptimal immune responders in Uganda: a randomised crossover placebo-controlled trial.

OBJECTIVE: T-cell activation independently predicts mortality, poor immune recovery and non-AIDS illnesses during combination antiretroviral therapy (cART). Atorvastatin showed anti-immune activation effects among HIV-infected cART-naïve individuals. We investigated whether adjunct atorvastatin therapy reduces T-cell activation among cART-treated adults with suboptimal immune recovery. METHODS: A randomised double-blind placebo-controlled crossover trial, of atorvastatin 80 mg daily vs. placebo for 12 weeks, was conducted among individuals with CD4 increase <295 cells/µl after seven years of suppressive cART. Change in T-cell activation (CD3 + CD4 + /CD8 + CD38 + HLADR+) and in T-cell exhaustion (CD3 + CD4 + /CD8 + PD1 + ) was measured using flow cytometry. RESULTS: Thirty patients were randomised, 15 to each arm. Atorvastatin resulted in a 28% greater reduction in CD4 T-cell activation (60% reduction) than placebo (32% reduction); P = 0.001. Atorvastatin also resulted in a 35% greater reduction in CD8-T-cell activation than placebo (49% vs. 14%, P = 0.0009), CD4 T-cell exhaustion (27% vs. 17% in placebo), P = 0.001 and CD8 T-cell exhaustion (27% vs. 16%), P = 0.004. There was no carry-over/period effect. Expected adverse events were comparable in both groups, and no serious adverse events were reported. CONCLUSION: Atorvastatin reduced T-cell immune activation and exhaustion among cART-treated adults in a Ugandan cohort. Atorvastatin adjunct therapy should be explored as a strategy to improve HIV treatment outcomes among people living with HIV in sub-Saharan Africa.

[Atorvastatin inhibits the atherosclerotic lesion induced by tumor necrosis factor-like weak inducer of apoptosis in apolipoprotein E deficient mice]. / La atorvastatina inhibe la progresión de la lesión aterosclerótica inducida por el factor inductor débil de apoptosis similar al factor de necrosis tumoral en ratones deficientes en apolipoproteína E.

AIM: Interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) with its receptor Fn14 accelerates atherosclerotic plaque development in ApoE deficient mice (ApoE KO). In this work, an analysis has been made on the effect of an HMG-CoA reductase inhibitor, atorvastatin, on atherosclerotic plaque development accelerated by TWEAK in ApoE KO mice. MATERIALS AND METHODS: Eight week-old ApoE KO mice were fed with a high cholesterol diet for 4 weeks. The animals were then randomized into 3 groups: mice injected i.p. with saline, recombinant TWEAK (10 µg/kg/twice a week), or recombinant TWEAK plus atorvastatin (1 mg/kg/day) for 4 weeks. The lesion size, cellular composition, lipid and collagen content were analyzed, as well as inflammatory response in atherosclerotic plaques present in aortic root of mice. RESULTS: TWEAK treated mice showed an increase in atherosclerotic plaque size, as well as in collagen/lipid ratio compared with control mice. In addition, macrophage content, MCP-1 and RANTES expression, and NF-κB activation were augmented in atherosclerotic plaques present in aortic root of TWEAK treated mice compared with control mice. Treatment with atorvastatin prevented all these changes induced by TWEAK in atherosclerotic lesions. Atorvastatin treatment also decreased Fn14 expression in the atherosclerotic plaques of ApoE KO mice. CONCLUSIONS: Atorvastatin prevents the pro-atherogenic effects induced by TWEAK in ApoE KO mice, which could be related to the inhibition of Fn14 expression. The results of this study provide new information on the beneficial effects of statin treatment in cardiovascular diseases.

Stability indicating method development and validation for simultaneous estimation of atorvastatin calcium and celecoxib in bulk and niosomal formulation by RP-HPLC

The present work describes development and validation of a specific, sensitive, precise and stability-indicating high-performance liquid chromatographic method of analysis of atorvastatin calcium and celecoxib, both as a bulk drug and in niosomal formulation. The analysis has been performed by using Cosmosil-C18 column (4.6 mm´250 mm, 5 m) at 25 °C using acetonitrile: ammonium acetate buffer pH 5.0: methanol (50:25:25 v/v/v) as mobile phase. The detection was carried out at 277nm with a flow rate of 1.0mL/min. The retention times of Atorvastatin calcium and Celecoxib were 6.195 and 3.989min, respectively. The method was validated according to ICH guidelines, for specificity, precision, linearity, accuracy and robustness. Atorvastatin calcium and Celecoxib were subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. The degradation was observed in oxidation and acid hydrolysis. The linearity for atorvastatin calcium and celecoxib were in the range of 100-500 µg/mL. The recovery study of atorvastatin and celecoxib were found to be in the range of 98.96 - 99.92% and 98.90-100%, respectively. The proposed method was validated and successfully applied to the estimation of Atorvastatin calcium and Celecoxib in combined in-house niosomal formulation.

O presente trabalho descreve o desenvolvimento e a validação de método de análise por cromatografia de alta eficiência específico, sensível, preciso e indicador de estabilidade de atorvastatina cálcica e celecoxibe, ambos como fármaco e como formulação niosômica. A análise foi realizada utilizando coluna Cosmosil-C18 (4,6 mm´250 mm, 5 m) a 25 °C, e acetonitrila: tampão acetato de amônio pH 5,0: metanol (50:25:25 v/v/v) como fase móvel. A detecção foi realizada a 277 nm, com fluxo de 1,0 mL/min. Os tempos de retenção de atorvastatina cálcica e de celecoxibe foram 6,195 e 3,989 min, respectivamente. O método foi validado de acordo com as regras da ICH para especificidade, precisão, exatidão e robustez. A atorvastatina cálcica e o celecoxibe foram submetidos a condições de estresse por hidrólise, oxidação, fotólise e degradação térmica. A degradação foi observada por oxidação e hidrólise ácida. Observou-se a linearidade da atorvastatina cálcica e do celecoxibe na faixa de 100-500 µg/mL. A recuperação da atorvastatina e do celecoxibe foi observada na faixa de 98,96-99,92% e 98,90-100%, respectivamente. O método proposto foi validado e aplicado com sucesso para a determinação de atorvastatina cálcica e celecoxibe em formulação niosômica caseira combinada.