3D printed scaffolds as delivery devices for nanocrystals: A proof of concept loading Atorvastatin with enhanced properties for sublingual route of administration.

Increasing the solubility of drugs is a recurrent objective of pharmaceutical research, and one of the most widespread strategies today is the formulation of nanocrystals (NCs). Beyond the many advantages of formulating NCs, their incorporation into solid dosage forms remains a challenge that limits their use. In this work, we set out to load Atorvastatin NCs (ATV-NCs) in a delivery device by combining 3D scaffolds with an "in situ" loading method such as freeze-drying. When comparing two infill patterns for the scaffolds at two different percentages, the one with the highest NCs load was chosen (Gyroid 20 % infill pattern, 13.8 ± 0.5 mg). Colloidal stability studies of NCs suggest instability in acidic media, and therefore, the system is postulated for use as a sublingual device, potentially bypassing stomach and hepatic first-pass effects. An ad hoc dissolution device was developed to mimic the release of actives. The nanometric size and properties acquired in the process were maintained, mainly in the dissolution rate and speed, achieving 100 % dissolution of the content in 180 s. Based on these results, the proof of concept represents an innovative approach to converting NCs suspensions into solid dosage forms.

Detecção de microalbuminúria em pacientes diabéticos tipo 2 como preditor de lesão endotelial / Detection of microalbuminuria in type 2 diabetic patients as a predictor of endothelial injury

Introdução: A detecção da microalbuminúria tem sido amplamente estudada como um indicador precoce de lesão endotelial em pacientes com diabetes tipo 2. A microalbuminúria é caracterizada pela presença de níveis aumentados de albumina na urina, refletindo disfunção endotelial e comprometimento da barreira glomerular. A lesão endotelial é um importante fator de risco para o desenvolvimento de complicações vasculares, como doença arterial coronariana, acidente vascular cerebral e insuficiência renal. Objetivos: Investigar a detecção da microalbuminúria através do teste rápido de urina de fita, como um preditor de lesão endotelial em pacientes diabéticos tipo 2. Métodos: Estudo observacional, analítico e transversal, realizado no Ambulatório de Geriatria do Hospital do Servidor Público Municipal de São Paulo. A amostra foi composta por 36 pacientes diabéticos tipo 2, avaliados entre dezembro de 2022 e abril de 2023. Todos os pacientes consentiram e assinaram o Termo de Consentimento Livre e Esclarecido. Resultados: Perfil composto principalmente por mulheres, com idade média de 76,9 anos e tempo médio de diagnóstico de 12,5 anos. A maioria dos pacientes não apresentava complicações macro ou microvasculares. Entre aqueles com complicações macrovasculares(19,4%), a doença arterial coronariana foi a mais comum. Apenas 8,3% dos pacientes possuíam clearence de creatinina abaixo de 30ml/min e os níveis de albuminuria avaliados pelo teste rápido estavam alterados em 52,8% dos participantes. Conclusão: Embora a microalbuminúria possa ser um indicador importante de lesão endotelial em pacientes diabéticos tipo 2 em trabalhos prévios, nossa pesquisa não conseguiu demonstrar associação com relevância estatística entre presença de complicação macro e microvascular e microalbuminúria, provavelmente devido ao número reduzido de pacientes analisados. Ainda assim, a detecção da microalbuminúria deve ser considerada na avaliação e monitoramento desses pacientes, visando uma intervenção precoce e o controle adequado das complicações vasculares. Palavras-chave: Diabetes Mellitus. Microalbuminúria. Angiopatias Diabéticas. Controle glicêmico. Testes de Função Renal.

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.

Prescription of statins and pharmacokinetic interactions in Colombian patients.

Background: Statins have extensive hepatic metabolism and can have multiple pharmacological interactions. The aim was to identify the main pharmacokinetic interactions between statins and their comedications in a group of patients from Colombia.Research design and methods: A cross-sectional study of pharmacokinetic interactions in patients treated with statins who were identified from a population database. The interactions were documented using the Lexicomp® database.Results: A total of 123,026 patients with statin prescriptions were identified, with a mean age of 68.4 ± 11.5 years; 57.1% were women, and 81.6% received atorvastatin. A total of 19.4% (n = 23.831) of patients presented pharmacological interactions. Some 15,474 (12.6%) had interactions classified as category C, 7.4% (n = 9077) as category D, and 0.5% (n = 660) as category X. 36.8% of the patients with lovastatin prescriptions had some interaction. Age older than 65 years, male sex, residence in capital cities, comorbidities, endocrine pathologies and HIV were associated with an increase in the probability of having contraindicated or risky interactions.Conclusions: Important interactions between statins and other medications were more common in adults over 65 years of age and those with endocrine comorbidities or HIV infection. This knowledge should help when proposing solutions that reduce the risk of adverse reactions.

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial.

Atorvastatin (ATV) is a blood cholesterol-lowering drug used to prevent cardiovascular events, the leading cause of death worldwide. As pharmacokinetics, metabolism and response vary among individuals, we wanted to determine the most reliable metabolic ATV phenotypes and identify novel and preponderant genetic markers that affect ATV plasma levels. A controlled, randomized, crossover, single-blind, three-treatment, three-period, and six-sequence clinical study of ATV (single 80-mg oral dose) was conducted among 60 healthy Mexican men. ATV plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed by real-time PCR with TaqMan probes. Four ATV metabolizer phenotypes were found: slow, intermediate, normal and fast. Six gene polymorphisms, SLCO1B1-rs4149056, ABCB1-rs1045642, CYP2D6-rs1135840, CYP2B6-rs3745274, NAT2-rs1208, and COMT- rs4680, had a significant effect on ATV pharmacokinetics (P < 0.05). The polymorphisms in SLCO1B1 and ABCB1 seemed to have a greater effect and were especially important for the shift from an intermediate to a normal metabolizer. This is the first study that demonstrates how the interaction of genetic variants affect metabolic phenotyping and improves understanding of how SLCO1B1 and ABCB1 variants that affect statin metabolism may partially explain the variability in drug response. Notwithstanding, the influence of other genetic and non-genetic factors is not ruled out.

Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin.

The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0-4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP-1 and TNF-α, while the uncontrolled SLE group also showed higher plasma concentrations of IL-10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76-83.56) vs. 30.56 (22.69-41.15) ng⋅hour/mL) and its inactive metabolite ATV-lactone (98.74 (74.31-131.20) vs. 49.21 (34.89-69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30-457.00) vs. 654.5 (486.00-881.4) L/hour) and apparent volume of distribution (2,609 (1,607-4,234) vs. 7,159 (4,904-10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV-lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

Plasma mevalonic acid exposure as a pharmacodynamic biomarker of fluvastatin/atorvastatin in healthy volunteers.

Fluvastatin and atorvastatin are inhibitors of hydroxy-methylglutaryl-CoA (HMG-CoA) reductase, the enzyme that converts HMG-CoA to mevalonic acid (MVA). The present study reports for the first time the analysis of mevalonolactone (MVL) in plasma samples by UPLC-MS/MS as well as the use of MVA, analyzed as MVL, as a pharmacodynamics parameter of fluvastatin in multiple oral doses (20, 40 or 80 mg/day for 7 days) and atorvastatin in a single oral dose (20, 40 or 80 mg) in healthy female volunteers. this study presents the use of MVL exposure as a pharmacodynamics biomarker of fluvastatin in multiple oral doses (20, 40 or 80 mg/day for 7 days) or atorvastatin in a single oral dose (20, 40 or 80 mg) in healthy volunteers (n = 30). The administration of multiple doses of fluvastatin (n = 15) does not alter the values (geometric mean and 95 % CI) of AUC0-24 h of MVL [72.00 (57.49-90.18) vs 65.57 (51.73-83.12) ng∙h/mL], but reduces AUC0-6 h [15.33 (11.85-19.83) vs 8.15 (6.18-10.75) ng∙h/mL] by approximately 47 %, whereas single oral dose administration of atorvastatin (n = 15) reduces both AUC0-24 h [75.79 (65.10-88.24) vs 32.88 (27.05-39.96) ng∙h/mL] and AUC0-6 h [17.07 (13.87-21.01) vs 7.01 (5.99-8.22) ng∙h/mL] values by approximately 57 % and 59 %, respectively. In conclusion, the data show that the plasma exposure of MVL represents a reliable pharmacodynamic parameter for PK-PD (pharmacokinetic-pharmacodynamic) studies of fluvastatin in multiple doses and atorvastatin in a single dose.

Development of Poly (Methyl vinyl ether-alt-maleic acid) Microneedles for Transdermal Delivery of Atorvastatin Calcium.

AIMS: Biodegradable polymeric microneedles containing atorvastatin calcium were developed in order to improve the percutaneous absorption of the drug, useful for the treatment of hypercholesterolemia. BACKGROUND: The use of physical enhancers like microneedles have shown good results to increase the delivery of drugs through the skin, the use of microneedles has very important advantages for transdermal drug delivery, for example, they are painless, easy to use and safe, they increase time interval of drug activity, dose, and reductions in adverse reactions, they also offer, the facility to remove the system instantly of the skin. OBJECTIVE: Develop polymer microneedles loaded with a calcium atorvastatin and evaluate them by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, postwetting- bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies to demonstrate the use of microneedles atorvastatin is able to cross the skin. METHODS: The microneedles were made with poly (methyl vinyl ether-alt-maleic acid) as biodegradable polymer using the technique of casting in solution in a mold. After solidification these microneedles were characterized by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, post-wetting-bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies. RESULTS: In general, the performances were satisfactory for optimal formulation in terms of DSC with no interactions between drug and excipients, SEM shows microneedles with a conical shape, bioadhesion of 1570 g.f, post wetting-bioadhesion of 1503.4 g.f, breaking strength of 1566.7g.f that is sufficient to disrupt Stratum corneum, good drug release and a flux of 33.4 µg/cm2*h with a tLag of 15.14 h for the in vitro percutaneous absorption. CONCLUSION: The results indicate that it is possible to generate microneedles to increase the percutaneous absorption of calcium atorvastatin transdermally, with the potential to be used as an alternative to the oral route for the treatment of dyslipidemias.

Lipid-lowering drug prescriptions in a group of Colombian patients. / Patrones de prescripción de hipolipemiantes en pacientes de Colombia

INTRODUCTION: Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases. OBJECTIVE: To determine the prescription patterns of lipid-lowering drugs and the variables associated with their use in a Colombian population. MATERIALS AND METHODS: This is a cross-sectional descriptive study. From a drug dispensing database of approximately 4.5 million Colombian health system affiliates, patients of all ages and both sexes treated with lipid-lowering agents (statins, fibrates, ezetimibe) were identified between January and March, 2017. Demographic, pharmacological and co-medication variables were included. RESULTS: In total, 103,624 patients were identified as being treated with lipid-lowering agents. The average age was 67.5 years, and 49.8% were 65 years or older. Women comprised 58.0% of the patients. Statins were the most used (n=96,910; 93.5%), and atorvastatin (n=80,812; 78.0%) and lovastatin (n=12,621; 12.2%) were the most frequent. The mean atorvastatin dose was 30.3 mg/day, and 49.9% of its users received presentations of 40 mg or more. A total of 9,258 (8.9%) patients received fibrates, and only 780 (0.8%) were taking ezetimibe. Of this population, 94.9% were treated with lipid-lowering monotherapy, and 97.3% (n=100,813) had co-medication for their comorbidities, with the most frequent being antihypertensive (89.1%), antiplatelet (57.8%), antidiabetic (31.5%) and antiulcerative agents (34.2%). CONCLUSIONS: Atorvastatin is currently the most frequently used lipid-lowering drug in this group of Colombian patients, especially in monotherapy and at doses close to the defined daily dose. Only half received high-intensity doses. New studies are required to verify the efficacy of these therapies.

Introducción. Los fármacos hipolipemiantes, especialmente las estatinas, han demostrado gran relevancia para la prevención y el tratamiento de las enfermedades cardiovasculares. Objetivo. Determinar los patrones de prescripción de los fármacos hipolipemiantes y las variables asociadas con su uso en una población de Colombia. Materiales y métodos. Se trata de un estudio descriptivo y transversal. A partir de una base de datos de dispensación de medicamentos de 4,5 millones de afiliados al sistema de salud de Colombia, se identificaron los pacientes de cualquier edad y sexo en tratamiento con hipolipemiantes (estatinas, fibratos, ezetimibe), entre enero y marzo de 2017. Se incluyeron variables demográficas, farmacológicas y de comedicaciones. Resultados. Se identificaron 103.624 pacientes en tratamiento con hipolipemiantes. La edad promedio fue de 67,5 años y el 49,8 % tenía 65 o más años. El 58,0 % eran mujeres. Las estatinas fueron los más utilizados (n=96.910; 93,5 %), siendo la atorvastatina (n=80.812; 78,0 %) y la lovastatina (n=12.621; 12,2 %) las más frecuentes. La dosis promedio de atorvastatina fue de 30,3 mg/día y el 49,9 % de sus usuarios recibía presentaciones de 40 mg o más. Un total de 9.258 (8,9 %) pacientes recibían fibratos y solo 780 (0,8 %) tomaban ezetimibe. El 94,9 % de casos recibió tratamiento en monoterapia hipolipemiante y el 97,3 % (n=100.813) tenía comedicaciones para comorbilidades, siendo las más frecuentes antihipertensivos (89,1 %), antiagregantes plaquetarios (57,8 %), antidiabéticos (31,5 %) y antiulcerosos (34,2 %). Conclusiones. La atorvastatina es actualmente el medicamento hipolipemiante más utilizado en este grupo de pacientes de Colombia, especialmente en monoterapia y a dosis cercanas a las definidas, aunque solo la mitad recibían dosis recibían dosis de alta intensidad. Se requieren nuevos estudios que verifiquen la efectividad de estos tratamientos.

Phase I/IIa Trial of Atorvastatin in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysm.

OBJECTIVES: To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA). STUDY DESIGN: This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment. RESULTS: A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls. CONCLUSIONS: Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.

Simultaneous analysis of the total plasma concentration of atorvastatin and its five metabolites and the unbound plasma concentration of atorvastatin: Application in a clinical pharmacokinetic study of single oral dose.

Atorvastatin (ATV) and its two active metabolites, o-hydroxy atorvastatin acid (o-OH-ATV) and p-hydroxy atorvastatin acid (p-OH-ATV) are responsible for its HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme-A) reductase inhibitory activity, while its corresponding inactive lactone forms (LAC) are related to the manifestation of myopathy. The present study reports the development and validation of a method for the simultaneous analysis of ATV and its five metabolites (o-OH-ATV, p-OH-ATV, ATV-LAC, o-OH-ATV-LAC, p-OH-ATV-LAC) as total plasma concentration and ATV as unbound plasma concentration using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of a single oral 20, 40 or 80 mg ATV dose in healthy volunteers (n = 15). ATV and its five metabolites were separated on a C18 column using as mobile phase a mixture of 0.2% formic acid and acetonitrile (55:45, v/v) at a flow of 0.4 mL/min. The method showed linearity from 25 pg/mL to 200 ng/mL plasma as total concentration and from 6.25 pg to 25 ng/mL plasma ultrafiltrate as ATV unbound concentration. The coefficients of variation and the relative standard errors of the accuracy and precision analyses were <15%. The method allowed quantification of plasma concentrations of ATV and its five metabolites up to 36 h after 20, 40 or 80 mg ATV administration. The pharmacokinetic parameters dose normalized to 20 mg are presented as follow (n = 15, mean): unbound fraction 9.38%, maximum plasma concentration 9.52 ng/mL, time to reach maximum plasma concentration 0.98 h, apparent total clearance 742.90 L/h, apparent distribution volume 9005 L, and AUC metabolite/ATV ratios 0.06 for p-OH-ATV, 0.94 for o-OH-ATV, 1.43 for ATV-LAC, 0.25 for p-OH-ATV-LAC and 1.75 for o-OH-ATV-LAC. In conclusion, the methods for simultaneous analysis of ATV and its five metabolites as total plasma concentration and ATV as the unbound plasma concentration showed sensitivity, linearity, precision and accuracy compatible with application in pharmacokinetic studies of single oral dose of 20, 40 or 80 mg ATV.

Combined Effect of Diosgenin Along with Ezetimibe or Atorvastatin on the Fate of Labelled Bile Acid and Cholesterol in Hypercholesterolemic Rats.

We analyzed the effect of diosgenin, administered with atorvastatin or ezetimibe, on the fate of ³H(G)-taurocholic acid or 26-14C-cholesterol in hypercholesterolemic rats. Male Wistar rats received a hypercholesterolemic diet (HD), HD + atorvastatin (HD+ATV), HD + ezetimibe (HD+EZT), HD + diosgenin (HD+DG), HD+ATV+EZT, or HD+ATV+DG for 40 days. We also included a control normal group (ND). The labelled compounds were administered on day 30. The animals were placed in metabolic cages for daily feces collection. At day 40 the rats were sacrificed. Lipid extracts from blood, liver, spinal cord, testicles, kidneys, epididymis, intestine, and feces were analyzed for radioactivity. Cholesterol activity was the highest in the liver in HD rats. DG diminished one half of this activity in HD+DG and HD+ATV+DG groups in comparison with the HD group. HD+ATV rats showed four to almost ten-fold cholesterol activity in the spinal cord compared with the ND or HD rats. Fecal elimination of neutral steroids was approximately two-fold higher in the HD+DG and HD+ATV+DG groups. Taurocholic acid activity was four to ten-fold higher in HD+DG intestine as compared to the other experimental groups. Taurocholic activity in the liver of HD and HD+DG groups was two and a half higher than in ND. Our results show that the combination of DG and ATV induced the highest cholesterol reduction in the liver and other tissues.

Atorvastatin: A Review of Analytical Methods for Pharmaceutical Quality Control and Monitoring.

Background: Atorvastatin, a lipid-regulating drug, was the best-selling drug in the world in the early 2000s. Thus, monitoring of this drug is important because it is accessible to a large portion of the population. In addition, its quality control is fundamental to provide quality medicines. Method of analysis can be the first step in the rational use of pharmaceuticals. Objective/Methods: In this context, a critical review of analytical methods present in the literature and official compendia for the pharmaceutical quality control of atorvastatin was made. Results: Among the analytical methods most used in the evaluation of atorvastatin, HPLC is highlighted, followed by HPLC coupled to MS, and spectrophotometry in UV. Tablets are the most studied pharmaceutical samples, and plasma is the most studied biological matrix. In the literature, studies with atorvastatin-based pharmaceutical products are more common than biological materials. Acetonitrile is the organic solvent most commonly used in the methods surveyed to evaluate atorvastatin. Conclusions: Currently, awareness of the impact that the analytical choice has on the health of the operator and the environment is growing. Therefore, the suitability of existing methods for the determination of atorvastatin can be made to adhere to the current analytical chemistry. In this way, the analytical, environmental, and human consciousness will remain united. Highlights: Although the literature shows interesting methods from an economic and environmental point of view, such as UV, Vis miniaturized, and TLC, they can still be improved to meet the requirements of the current sustainable analytical chemistry.

Timing of Loading Dose of Atorvastatin in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes: Insights From the SECURE-PCI Randomized Clinical Trial.

Importance: Loading doses of atorvastatin did not show reduction on clinical outcomes in the overall population of patients with acute coronary syndrome (ACS) enrolled in the Statins Evaluation in Coronary Procedures and Revascularization (SECURE-PCI) trial, but a potential benefit was identified in patients who subsequently underwent percutaneous coronary intervention (PCI). Objectives: To determine whether periprocedural loading doses of atorvastatin are associated with decreased 30-day major adverse cardiovascular events (MACE) in patients with ACS undergoing PCI according to type of ACS and timing of atorvastatin administration before PCI. Design, Setting, and Participants: Secondary analysis of a multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites that enrolled 4191 patients with ACS intended to be treated with PCI between April 18, 2012, and October 06, 2017. Interventions: Patients were randomized to 2 loading doses of 80 mg of atorvastatin or matching placebo before and 24 hours after a planned PCI. By protocol, all patients (regardless of treatment group) received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures: The primary outcome was MACE through 30 days, composed by all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization. Cox regression models adjusting for key baseline characteristics were used to assess the association between atorvastatin and MACE in patients undergoing PCI. Results: From the overall trial population, 2710 (64.7%) underwent PCI (650 women [24.0%]; mean [SD] age, 62 [11.3] years). Loading atorvastatin was associated with reduced MACE at 30 days by 28% in the PCI group (adjusted hazard ratio [HR], 0.72; 95% CI 0.54-0.97; P = .03). Loading dose of atorvastatin was administered less than 12 hours before PCI in 2548 patients (95.3%) (45.1% < 2 hours and 54.3% between 2 and 12 hours). There was no significant interaction between treatment effect and timing of study drug administration. The treatment effect of loading atorvastatin was more pronounced in patients with ST-segment elevation myocardial infarction than in patients with non-ST-segment elevation ACS (adjusted HR, 0.59; 95% CI, 0.38-0.92; P = .02; HR, 0.85; 95% CI, 0.58-1.27; P = .43, respectively). Conclusions and Relevance: In patients with ACS undergoing PCI, periprocedural loading doses of atorvastatin appeared to reduce the rate of MACE at 30 days, most clearly in patients with ST-segment elevation myocardial infarction. This beneficial effect seemed to be preserved and consistent, irrespective of the timing of atorvastatin administration, including within 2 hours before PCI. Trial Registration: clinicaltrials.gov Identifier: NCT01448642.

Characterization of hybrid microparticles/Montmorillonite composite with raspberry-like morphology for Atorvastatin controlled release.

In this work, we prepared a novel composite based on hybrid gelatin carriers and montmorillonite clay (MMT) to analyze its viability as controlled drug delivery system. The objective of this research involves the characterization of composites formed by structured lipid-gelatin micro-particles (MP) and MMT clay. This analysis included the evaluation of the composite according to its rheological properties, morphology (SEM), particle size, XRD, FT-IR, and in vitro drug release. The effect of pH in the properties of the composite is evaluated. A novel raspberry-like or armor MP/MMT clay composite is reported, in which the pH has an important effect on the final structure of the composite for ad-hoc drug delivery systems. For pH values below the isoelectric point, we obtained defined morphologies with entrapment efficiencies up to 67%. The pH level controls the MP/MMT composite release mechanism, restringing drug release in the stomach-like environment. Intended for oral administration, these results evidence that the MP/MMT composite represents an attractive alternative for intestinal-colonic controlled drug delivery systems.

Statins and bonehealth: a mini review / Estatinas y salud ósea: una minirevisión

Statins are a widely prescribed class of medications that inhibit similar pathways as the anti-resorptive bisphosphonate drugs. Statins target the mevalonate pathway by blocking HMG-CoA reductase. Several recent meta-analyses concluded statins are osteoprotective in the general population. Here we present current literature exploring the mechanisms underlying the putative osteoprotective effects of statins. We also review recent clinical studies, ranging from observational cohort studies to randomized clinical trials, testing the effect of statins on bone health in various populations. (AU)

Las estatinas son un grupo de drogas prescriptas en forma habitual, con la capacidad de bloquear vías de señalización similares a las inhibidas por los amino-bisfosfonatos. Las estatinas inhiben la vía del mevalonato, a través del bloqueo de diferentes enzimas. Varios metaanálisis recientes llevaron a la conclusión de que las estatinas tienen capacidad osteoprotectora en la población general. En esta revisión presentamos la literatura actual describiendo los mecanismos que subyacen en el potencial efecto osteoprotector de las estatinas, como así también estudios observacionales y clínicos aleatorizados sobre el efecto de estatinas en la salud ósea en diversas poblaciones. (AU)

Atorvastatin dose-dependently promotes mouse lung repair after emphysema induced by elastase.

Emphysema results in a proteinase - antiproteinase imbalance, inflammation and oxidative stress. Our objective was to investigate whether atorvastatin could repair mouse lungs after elastase-induced emphysema. Vehicle (50 µL) or porcine pancreatic elastase (PPE) was administered on day 1, 3, 5 and 7 at 0.6 U intranasally. Male mice were divided into a control group (sham), PPE 32d (sacrificed 24 h after 32 days), PPE 64d (sacrificed 24 h after 64 days), and atorvastatin 1, 5 and 20 mg treated from day 33 until day 64 and sacrificed 24 h later (A1 mg, A5 mg and A20 mg, respectively). Treatment with atorvastatin was performed via inhalation for 10 min once a day. We observed that emphysema at day 32 was similar to emphysema at day 64. The mean airspace chord length (Lm) indicated a recovery of pulmonary morphology in groups A5 mg and A20 mg, as well as recovery of collagen and elastic fibers in comparison to the PPE group. Bronchoalveolar lavage fluid (BALF) leukocytes were reduced in all atorvastatin-treated groups. However, tissue macrophages were reduced only in the A20 mg group compared with the PPE group, while tissue neutrophils were reduced in the A5 mg and A20 mg groups. The redox balance was restored mainly in the A20 mg group compared with the PPE group. Finally, atorvastatin at doses of 5 and 20 mg reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and matrix metalloproteinase-12 (MMP-12) compared with the PPE group. In conclusion, atorvastatin was able to induce lung tissue repair in emphysematous mice.

Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial.

Importance: The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective: To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions: Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures: The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results: Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, -0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance: Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration: clinicaltrials.gov Identifier: NCT01448642.

Atorvastatin Prevents Early Oxidative Events and Modulates Inflammatory Mediators in the Striatum Following Intranasal 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Administration in Rats.

Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor with cholesterol-lowering, anti-inflammatory, and antioxidant properties. Increasing evidence show atorvastatin acts as a protective agent against insults in the central nervous system (CNS). The regular use of statins has been associated with a reduced risk of Parkinson's disease (PD) development. Here, we evaluated early events involved in the neurotoxicity induced by intranasal (i.n.) infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats and the potential of atorvastatin to prevent these early toxic events. Male Wistar rats were pretreated orally with atorvastatin (10 mg/kg/day) or vehicle once a day during seven consecutive days. Twenty-four hours after atorvastatin administration, animals received a single bilateral i.n. infusion of MPTP (1 mg/nostril), and 6 h later, the striatum and the hippocampus were collected to evaluate early oxidative stress parameters and inflammatory cytokines. Atorvastatin prevented MPTP-induced increase in reactive species (RS) generation and in glutathione levels in the striatum. Atorvastatin also prevented the reduction in mitochondrial respiratory chain complex I and II activities evoked by MPTP in the striatum. Atorvastatin per se reduced the levels of the cytokines TNF-α and IL-1ß, and surprisingly, it reduced IL-10 and nerve growth factor levels in the striatum. However, the anti-inflammatory IL-10 levels increased in the striatum following atorvastatin plus MPTP treatment. These effects were not observed in the hippocampus. Our findings reinforce and extend the notion of the neuroprotective effects of atorvastatin in a PD model and indicate the modulation of oxidative and inflammatory responses as the mechanisms associated with therapeutic action of atorvastatin in PD.