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1.
PLoS One ; 15(11): e0242422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237943

RESUMO

Statins are used to lower cholesterol and prevent cardiovascular disease. Musculoskeletal side effects known as statin associated musculoskeletal symptoms (SAMS), are reported in up to 10% of statin users, necessitating statin therapy interruption and increasing cardiovascular disease risk. We tested the hypothesis that, when exposed to statins ex vivo, engineered human skeletal myobundles derived from individuals with (n = 10) or without (n = 14) SAMS and elevated creatine-kinase levels exhibit statin-dependent muscle defects. Myoblasts were derived from muscle biopsies of individuals (median age range of 62-64) with hyperlipidemia with (n = 10) or without (n = 14) SAMS. Myobundles formed from myoblasts were cultured with growth media for 4 days, low amino acid differentiation media for 4 days, then dosed with 0 and 5µM of statins for 5 days. Tetanus forces were subsequently measured. To model the change of tetanus forces among clinical covariates, a mixed effect model with fixed effects being donor type, statin concentration, statin type and their two way interactions (donor type*statin concentration and donor type* statin type) and the random effect being subject ID was applied. The results indicate that statin exposure significantly contributed to decrease in force (P<0.001) and the variability in data (R2C [R square conditional] = 0.62). We found no significant differences in force between myobundles from patients with/without SAMS, many of whom had chronic diseases. Immunofluorescence quantification revealed a positive correlation between the number of straited muscle fibers and tetanus force (R2 = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R2 = 0.482,P = 0.051) with no differences between donors with or without SAMS. There is also a correlation between statin exposure and presence of striated fibers (R2 = 0.833, P = 0.047). In patient-derived myobundles, statin exposure results in myotoxicity disrupting SAA organization and reducing force. We were unable to identify differences in ex vivo statin myotoxicity in this system. The results suggest that it is unlikely that there is inherent susceptibility to or persistent effects of statin myopathy using patient-derived myobundles.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Idoso , Aminoácidos/farmacologia , Células Cultivadas , Meios de Cultura/farmacologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Fadiga Muscular/fisiologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Mioblastos/efeitos dos fármacos , Músculo Quadríceps/citologia , Método Simples-Cego , Engenharia Tecidual
2.
Medicine (Baltimore) ; 99(40): e22572, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019469

RESUMO

RATIONALE: Atorvastatin is the most common drug used in therapy for cardiovascular diseases. The most common adverse side effects associated with statins are myopathy and hypertransaminasemia. Here, we report a rare case of gamma glutamyl transpeptidase (GGT) elevation induced by atorvastatin. PATIENT CONCERNS: A 47-year-old male was admitted to our hospital with dyslipidemia, he had been taking pitavastatin 2 mg/day for 2 months. The levels of total cholesterol (265.28 mg/dL) and low-density lipoprotein-cholesterol (LDL) (179.15 mg/dL) were also high. DIAGNOSIS: Blood lipid test showed mixed dyslipidemia. INTERVENTION: Atorvastatin 10 mg/day was given to the patient. OUTCOMES: The patient came back to our hospital for blood tests after 4 weeks. Although no symptoms were detectable, the patient's GGT level was markedly elevated (up to 6-fold over normal level) with less marked increases in alkaline phosphatase (ALP) and alanine aminotransferase (ALT). The serum GGT level returned to normal within 6 weeks of cessation of atorvastatin. LESSONS: This is a case of GGT elevation without hyperbilirubinemia, hypertransaminasemiam, or serum creatine phosphokinase (CPK) abnormalities despite an atorvastatin regimen. This case highlights GGT elevation caused by atorvastatin, a rare but serious condition. Clinicians should be aware of these possible adverse effects and monitor liver function tests in patients on statin therapy.


Assuntos
Atorvastatina/efeitos adversos , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Quinolinas/efeitos adversos , gama-Glutamiltransferase/efeitos dos fármacos , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Atorvastatina/administração & dosagem , Atorvastatina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/diagnóstico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Suspensão de Tratamento , gama-Glutamiltransferase/sangue
3.
PLoS One ; 15(10): e0240166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33119602

RESUMO

BACKGROUND: The log linear association between on-treatment LDL-C levels and ASCVD events is amplified in higher risk patient subgroups of statin versus placebo trials. OBJECTIVES: Update previous systematic review to evaluate how the log linear association influences the magnitude of cardiovascular risk reduction from intensifying LDL-C lowering therapy. METHODS: MEDLINE/PubMED, Clinical trials.gov, and author files were searched from 1/1/2005 through 10/30/2019 for subgroup analyses of cardiovascular outcomes trials of moderate versus high intensity statin, ezetimibe, and PCSK9 mAbs with an ASCVD endpoint (nonfatal myocardial infarction or stroke, cardiovascular death). Annualized ASCVD event rates were used to extrapolate 5-year ASCVD risk for each treatment group reported in subgroup analyses, which were grouped into a priori risk groups according to annualized placebo/control rates of ≥4%, 3-3.9%, or <3% ASCVD risk. Data were pooled using a random-effects model. Weighted least-squares regression was used to fit linear and log-linear models. RESULTS: Systematic review identified 96 treatment subgroups from 2 trials of moderate versus high intensity statin, 2 trials of a PCSK9 mAb versus placebo, and 1 trial of ezetimibe versus placebo. A log linear association between on-treatment LDL-C and ASCVD risk represents the association between on-treatment LDL-C levels and ASCVD event rates, especially in higher risk subgroups. Greater relative and absolute cardiovascular risk reductions from LDL-C lowering were observed when baseline LDL-C was >100 mg/dl and in extremely high risk ASCVD patient groups. CONCLUSIONS: Greater cardiovascular and mortality risk reduction benefits from intensifying LDL-C lowering therapy may be expected in those with LDL-C ≥100 mg/dl, or in extremely high risk patient groups. When baseline LDL-C <100 mg/dl, the log linear association between LDL-C and event rates suggests that treatment options other than further LDL-C lowering should also be considered for optimal risk reduction.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Ensaios Clínicos como Assunto , Doença da Artéria Coronariana/epidemiologia , Uso de Medicamentos/estatística & dados numéricos , Ezetimiba/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem
4.
Vasc Health Risk Manag ; 16: 367-377, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061398

RESUMO

Background: High-intensity statin is recommended in high-risk type 2 diabetes (T2D); however, statin dose dependently increases the risk of developing new-onset diabetes, can potentially worsen glycemic control in T2D, and may cause cognitive impairment. This study aimed to investigate the effect of statin intensification on glucose homeostasis and cognitive function in T2D. Materials and Methods: T2D patients who were taking simvastatin ≤20 mg/day were randomized to continue taking the same dosage of simvastatin (low-dose simvastatin group; LS, n=63) for 12 weeks, or to change to atorvastatin 40 mg/day for 6 weeks, and if tolerated, atorvastatin was increased to 80 mg/day for 6 weeks (high-dose atorvastatin group; HS, n=62). Fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), plasma insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and of ß-cell function (HOMA-B), cognitive functions using Montreal Cognitive Assessment (MoCA), and Trail Making Test (TMT) were assessed at baseline, 6 weeks, and 12 weeks. Results: Mean age of patients was 58.8±8.9 years, and 72% were female. Mean baseline FPG and HbA1c were 124.0±27.5 mg/dl and 6.9±0.8%, respectively. No differences in baseline characteristics between groups were observed. Change in HbA1c from baseline in the LS and HS groups was -0.1% and +0.1% (p=0.03) at 6 weeks, and -0.1% and +0.1% (p=0.07) at 12 weeks. There were no significant differences in FPG, fasting plasma insulin, HOMA-B, HOMA-IR, MoCA score, or TMT between groups at 6 or 12 weeks. Conclusion: Switching from low-dose simvastatin to high-dose atorvastatin in T2D resulted in a slight increase in HbA1c (0.1%) without causing cognitive decline.


Assuntos
Atorvastatina/administração & dosagem , Glicemia/efeitos dos fármacos , Cognição/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Substituição de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Sinvastatina/administração & dosagem , Idoso , Atorvastatina/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/psicologia , Feminino , Hemoglobina A Glicada/metabolismo , Homeostase , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Sinvastatina/efeitos adversos , Tailândia , Fatores de Tempo , Teste de Sequência Alfanumérica , Resultado do Tratamento
5.
SEMERGEN, Soc. Esp. Med. Rural Gen. (Ed. Impr.) ; 46(7): 497-502, oct. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-192622

RESUMO

ANTECEDENTES Y OBJETIVOS: La pandemia por COVID-19 ha puesto de manifiesto que las enfermedades cardiovasculares conllevan mayor riesgo de mortalidad. Han surgido dudas en cuanto a la terapia lipídica en estos pacientes. Nuestro objetivo en esta revisión es analizar la eficacia y la seguridad de la terapia hipolipemiante en los pacientes con COVID-19. MATERIAL Y MÉTODOS: Se realizó una revisión de la literatura científica en PubMed, informes CDC, NIH y NCBI SARS-CoV-2 utilizando las palabras clave: COVID-19, statins, ezetimibe, PCSK9 inhibitors, hypercholesterolemia and hypolipidemic drugs. RESULTADOS: Las estatinas se deben seguir utilizando en los pacientes con COVID-19 en base a su eficacia, seguridad, efectos inmunosupresores, antiinflamatorios, disponibilidad y accesibilidad. En función de los niveles de riesgo cardiovascular de estos pacientes puede ser necesario el empleo de estatinas de alta potencia y/o ezetimiba y/o inhibidores de la proproteína convertasa subtilisina (iPCSK9) en pacientes de alto y muy alto riesgo cardiovascular. Los pacientes tratados con iPCSK9 deben seguir con el tratamiento por sus efectos beneficiosos sobre la prevención de la enfermedad cardiovascular. Los pacientes con hipercolesterolemia familiar y COVID-19 son especialmente vulnerables a la enfermedad cardiovascular precoz y deben seguir recibiendo el tratamiento hipolipemiante intensivo. CONCLUSIONES: En los pacientes con COVID-19 la mayoría de las enfermedades cardiovasculares basales son de origen aterosclerótico, con peor pronóstico para los pacientes con alto riesgo y muy alto riesgo de enfermedad cardiovascular. En estos pacientes el tratamiento intensivo con estatinas y/o combinación fija con ezetimiba y/o iPCSK9 juega un papel fundamental


BACKGROUND AND OBJECTIVES: The COVID-19 pandemic has shown that cardiovascular diseases carry a higher risk of mortality. Doubts have been raised regarding lipid therapy in these patients. The objectives are to analyze the efficacy and safety of lipid lowering therapy in patients with COVID-19. MATERIAL AND METHODS: A review of the scientific literature was conducted in PubMed, CDC Reports, NIH, and NCBI SARS-CoV-2 using the keywords: COVID-2, statins, ezetimibe, PCSK9 inhibitors, hypercholesterolemia, and hypolipidemic drugs. RESULTS: The statins should continue to use patients with COVID-19 based on their efficacy, safety, immunosuppressive effects, anti-inflammatory availability and accessibility. Depending on the cardiovascular risk levels of these patients, the use of high potency statins and/or ezetimibe and/or iPCSK9 may be necessary in patients with high and very high cardiovascular risk. Patients treated with iPCSK9 should continue treatment for its beneficial effects in preventing cardiovascular disease. Patients with familial hypercholesterolemia and COVID-19 are especially vulnerable to cardiovascular disease and should continue to receive severe lipid lowering therapy. CONCLUSIONS: In patients with COVID-19, the majority of baseline CVDs are of atherosclerotic origin, with the worst prediction for patients with high risk and very high risk of CVD. In these patients, intensive treatment with statins and/or fixed combination with ezetimibe and/or iPCSK9 plays a fundamental role


Assuntos
Humanos , Infecções por Coronavirus/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vírus da SARS/patogenicidade , Hipolipemiantes/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Pandemias , Atenção Primária à Saúde/organização & administração , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Ezetimiba/administração & dosagem
6.
Thromb Res ; 196: 382-394, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32992075

RESUMO

BACKGROUND: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.


Assuntos
Anticoagulantes/administração & dosagem , Atorvastatina/administração & dosagem , Enoxaparina/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Trombose/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Anticoagulantes/efeitos adversos , Atorvastatina/efeitos adversos , /diagnóstico , Estado Terminal , Método Duplo-Cego , Enoxaparina/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Irã (Geográfico) , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombose/diagnóstico , Trombose/etiologia , Fatores de Tempo , Resultado do Tratamento , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiologia
7.
Ann Intern Med ; 173(10): 822-829, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-32956597

RESUMO

DESCRIPTION: In June 2020, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) released a joint update of their clinical practice guideline for managing dyslipidemia to reduce cardiovascular disease risk in adults. This synopsis describes the major recommendations. METHODS: On 6 August to 9 August 2019, the VA/DoD Evidence-Based Practice Work Group (EBPWG) convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched and evaluated the literature (English-language publications from 1 December 2013 to 16 May 2019), and developed 27 recommendations and a simple 1-page algorithm. The recommendations were graded by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. RECOMMENDATIONS: This synopsis summarizes key features of the guideline in 7 crucial areas: targeting of statin dose (not low-density lipoprotein cholesterol goals), additional tests for risk prediction, primary and secondary prevention, laboratory testing, physical activity, and nutrition.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Adesão à Medicação , Doenças Cardiovasculares/prevenção & controle , Dieta Mediterrânea , Exercício Físico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/terapia , Guias de Prática Clínica como Assunto , Medição de Risco , Prevenção Secundária
8.
Sci Rep ; 10(1): 14965, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917914

RESUMO

The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41-0.71) and erlotinib (HR 0.62, 95% CI 0.46-0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08-2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas de Neoplasias/genética , Afatinib/administração & dosagem , Afatinib/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antiácidos/administração & dosagem , Antiácidos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/efeitos adversos , Feminino , Gefitinibe/administração & dosagem , Gefitinibe/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Esteroides/administração & dosagem , Esteroides/efeitos adversos , Falha de Tratamento
9.
AAPS PharmSciTech ; 21(7): 263, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978691

RESUMO

In the current research, the main focus was to overcome dermal delivery problems of atorvastatin. To this end, atorvastatin solid lipid nanoparticles (ATR-SLNs) were prepared by ultra-sonication technique. The prepared SLNs had a PDI value of ≤ 0.5, and the particle size of nanoparticles was in the range 71.07 ± 1.72 to 202.07 ± 8.40 nm. It was noticed that, when the concentration of lipid in ATR-SLNs increased, the size of nanoparticles and drug entrapment efficiency were also increased. Results showed that a reduction in the HLB of surfactants used in the preparation of SLN caused an increase in the particle size, zeta potential (better stability), and drug entrapment efficiency. Despite Tween and Span are non-ionic surfactants, SLNs containing these surfactants showed a negative zeta potential, and the absolute zeta potential increased when the concentration of Span 80 was at maximum. DSC thermograms, FTIR spectra, and x-ray diffraction (PXRD) pattern showed good incorporation of ATR in the nanoparticles without any chemical interaction. In vitro skin permeation results showed that SLN containing atorvastatin was capable of enhancing the dermal delivery of atorvastatin where a higher concentration of atorvastatin can be detected in skin layers. This is a hopeful promise which could be developed for clinical studies of the dermal delivery of atorvastatin nanoparticles as an anti-inflammatory agent.


Assuntos
Anti-Inflamatórios/administração & dosagem , Atorvastatina/administração & dosagem , Portadores de Fármacos/química , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipídeos/química , Nanopartículas/química , Animais , Anti-Inflamatórios/química , Atorvastatina/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Tamanho da Partícula , Polissorbatos , Pele/metabolismo , Absorção Cutânea , Tensoativos/metabolismo , Difração de Raios X
10.
Expert Opin Drug Metab Toxicol ; 16(12): 1133-1145, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32909838

RESUMO

INTRODUCTION: Persons aged more than 65 years may be more prone to suffer from chronic diseases and comorbidities (as demonstrated by the recent COVID-19 pandemics) and are treated with multiple concomitant medications. This may result in drug-drug interactions (DDIs) that are often overlooked in clinical practice. Elderly patients are more affected by comorbidities increasing the risk of DDIs and adverse drug reactions (ADRs). Statins are effective in elderly patients with or at risk for cardiovascular disease (CVD) and are prescribed on a long-term basis and may undergo DDIs, particularly on pharmacokinetic bases. The risk of DDIs varies among statins, and safety and ADRs of statins are of special concern in patients affected by multiple chronic conditions requiring concomitant therapies at risk of DDIs, such as the elderly. AREAS COVERED: The purpose of this manuscript is to give an update on the potential statin DDIs and related ADRs with an exclusive focus on the data available in elderly patients. EXPERT OPINION: A better and more close attention to the potential DDIs among statins and other therapeutic options will help physicians in selecting the more effective and less harmful treatment for their patients. This is of importance, especially in older patients.


Assuntos
Infecções por Coronavirus , Interações Medicamentosas , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pandemias , Pneumonia Viral , Idoso , Doença Crônica , Comorbidade , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Fatores de Risco
11.
Ned Tijdschr Geneeskd ; 1642020 05 20.
Artigo em Holandês | MEDLINE | ID: mdl-32749800

RESUMO

A recent Dutch study in patients with familial hypercholesterolaemia (FH), suggests that long-term statin treatment initiated at childhood reduces the risk for cardiovascular events in adulthood. None of the patients developed rhabdomyolysis or other serious adverse effects. Early detection of FH is crucial for early treatment initiation. However, the Dutch cascade screening program ended at the end of 2013, at which point approximately 40,000 FH patients had not yet been identified. In order to trace this cohort, in 2014 the 'LEEFH' foundation (National Expertise Centre for Genetic Testing for Familial Cardiovascular Diseases) was set up. Family members of index patients are no longer actively approached to be tested, and as a result the number of detected family members has decreased significantly. These study findings underline the importance of actively screening the family members of index patients, including children and adolescents.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Doenças Cardiovasculares/genética , Criança , Esquema de Medicação , Diagnóstico Precoce , Feminino , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Masculino , Países Baixos , Fatores de Tempo , Adulto Jovem
12.
Toxicol Appl Pharmacol ; 404: 115185, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32771489

RESUMO

The development of resistance to endocrine therapy of estrogen receptor alpha (ERα)-positive breast cancer is inevitable, necessitating the introduction of alternative treatment strategies. Therefore, the current study was carried out to investigate the in vivo efficacy and tolerability of nilotinib/rosuvastatin novel combination against ERα-positive breast carcinoma. Results showed that treatment of tumor-bearing mice with nilotinib/rosuvastatin exerted a significant antitumor activity. Mechanistically, the combination treatment efficiently inhibited the in vivo ERα protein expression, whereas ERα mRNA levels were unaffected suggesting a posttranslational regulation. In addition, the combination treatment markedly downregulated the expression of two ERα downstream target genes: C3 and pS2 confirming the inhibition of ERα signaling in vivo. Further, nilotinib/rosuvastatin combination strongly induced apoptosis evidenced by a marked caspase-3 cleavage and downregulation of tumor nitric oxide levels. Moreover, histopathology showed significant declines in mitotic figures and tumor giant cells implying the in vivo capability of the combination treatment to interfere with cancer cell proliferation and persistence. Of note, the combination treatment abrogated nilotinib-induced hypercholesterolemia and did not adversely affect the liver function or body weight. Overall, the present study provided evidences that warrant further assessment of nilotinib/rosuvastatin combination as an alternative therapeutic modality for ERα-positive breast cancer.


Assuntos
Adenocarcinoma/veterinária , Receptor alfa de Estrogênio/antagonistas & inibidores , Neoplasias Mamárias Animais/tratamento farmacológico , Pirimidinas/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Pirimidinas/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
13.
Expert Opin Pharmacother ; 21(16): 1971-1974, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32749892

RESUMO

INTRODUCTION: If statins are unsuccessful at achieving the LDL cholesterol level goal in subjects with hypercholesterolemia, non-statin therapy should be added to reduce cardiovascular morbidity and mortality. The first inhibitors of proprotein convertase substilisin-kexin type 9 (PCSK9) were human monoclonal antibodies and these reduced LDL cholesterol and cardiovascular events. Inclisiran is a small interfering RNA molecule (siRNAs) directed against PCSK9. AREAS COVERED: This key paper evaluation focuses on Phase 3 trials that assess inclisiran in the treatment of hypercholesterolemia and heterozygous familial hypercholesterolemia. EXPERT OPINION: To date, the findings with inclisiran have been very promising as it causes large decreases in LDL cholesterol with few adverse effects. However, there are some limitations to its widespread use. Firstly, cardiovascular outcomes trials have not been completed, so we do not know how inclisiran compares to the PCSK9 monoclonal antibodies, which, seem to me, to only have a modest effect on cardiovascular outcomes. Secondly, a major problem with the PCSK9 monoclonal antibodies is that they are expensive, and their use is often discontinued or not pursued, which can leave the subjects intended for treatment at high cardiovascular risk. At present, it is not clear whether similar problems around cost will apply to inclisiran.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/economia , LDL-Colesterol/sangue , Ensaios Clínicos como Assunto , Esquema de Medicação , Custos de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/enzimologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/enzimologia , Adesão à Medicação , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/economia
14.
Expert Opin Pharmacother ; 21(17): 2137-2151, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32772741

RESUMO

INTRODUCTION: Statins are the first-line treatment to reduce cardiovascular (CV) events, mainly by reducing low-density-lipoprotein cholesterol (LDL-C), but many patients need additional treatments to reach the current lipid goals. AREAS COVERED: Herein, the authors review the published literature on the efficacy and safety of the therapies that are most often added to statins to achieve lipid targets. EXPERT OPINION: Ezetimibe is usually the first additional treatment to achieve LDL-C targets. It reduces LDL-C by about a further 20% and has an excellent safety and tolerability profile. The monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab, and alirocumab, can reduce LDL-C by ≥50% when added to statins and they also have a well-established safety and tolerability record. The recently approved bempedoic acid is well tolerated and appears to be free of skeletal muscle-related problems, but the CV outcome study with this drug has not been completed. Inclisiran, a small-interfering RNA targeting PCSK9 is at an advanced stage of development and the available data indicate a satisfactory safety profile and LDL-C lowering efficacy similar to the PCSK9 monoclonal antibodies with the advantage of less frequent administration.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , LDL-Colesterol/sangue , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Resultado do Tratamento
15.
Clin Drug Investig ; 40(9): 809-826, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32671595

RESUMO

BACKGROUND: Several clinical trials have investigated the effect of statin/ezetimibe combination therapy on secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in the Asian population. OBJECTIVE: This study aimed to summarize study results regarding the effect of statin/ezetimibe combination therapy on lipid parameters and highly sensitive C-reactive protein (HsCRP) biomarkers in ASCVD patients from Asian countries. METHODS: We searched the PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar databases for relevant papers published from 2008 to June 2020. We included randomized controlled trials (RCTs) that (1) were conducted in ASCVD patients in Asian countries; (2) examined the effects of statin/ezetimibe combination therapies compared with a control group; and (3) reported sufficient data on lipid parameters and HsCRP biomarkers. The results were reported as weighted mean differences (WMDs) with 95% confidence intervals (CI) using random-effects models. Funnel plots and Egger's regression test were used to assess publication bias. RESULTS: Twenty-four RCTs were reviewed and 20 were included in the meta-analysis. A total of 4344 participants were included (n = 2197 in the intervention group and n = 2147 in the control group), and the intervention durations ranged from 6 weeks to 3.6 years. Ezetimibe coadministered with statin therapy, compared with control treatment, significantly reduced low-density lipoprotein cholesterol (LDL-C; n = 20 studies) [WMD - 0.39 mmol/L, 95% CI - 0.73 to - 0.05; p < 0.001], triglycerides (TG; n = 18 studies) [WMD - 0.23 mmol/L, 95% CI - 0.33 to - 0.13; p < 0.001], and total cholesterol (TC; n = 17 studies) [WMD - 0.31 mmol/L, 95% CI - 0.45 to - 0.17; p < 0.001). Although the effect of statin/ezetimibe combinations on high-density lipoprotein cholesterol (HDL-C; n = 17 studies) [WMD 0.02 mmol/L, 95% CI - 0.05 to 0.09; p < 0.001) was very minimal and no effect was observed on HsCRP levels (n = 11 studies). CONCLUSIONS: Our study found that statin/ezetimibe combinations reduced LDL-C, TC, and TG levels but had minimal effects on HDL-C and no effect HsCRP biomarkers in ASCVD patients. The statin/ezetimibe therapy enabled a more effective reduction in LDL-C levels; however, the duration of the treatment was suboptimal.


Assuntos
Anticolesterolemiantes/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Aterosclerose/prevenção & controle , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária , Anticolesterolemiantes/administração & dosagem , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem
16.
J Postgrad Med ; 66(3): 162-164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32675453

RESUMO

Plus-minus lid syndrome is a rare manifestation of midbrain infarct, characterized by ptosis of one eye and lid retraction in the other eye. It has also been described in ocular myasthenia gravis, orbital myositis, or after lesions of the oculomotor nerve. Our patient was a 55-year-old man with hypertension and atrial fibrillation, who presented to us with acute onset left-sided ptosis and right-sided eyelid retraction. He was apathic and had right-sided ataxia. His MRI of the brain showed acute infarct involving the paramedian midbrain. To our knowledge, severe apathy and resultant executive function disorder have not been described previously in a patient having plus-minus lid syndrome with ataxia.


Assuntos
Fibrilação Atrial/complicações , Blefaroptose/etiologia , Hipertensão/complicações , Doenças do Nervo Oculomotor/complicações , Anticoagulantes/administração & dosagem , Apatia , Ataxia , Fibrilação Atrial/tratamento farmacológico , Blefaroptose/fisiopatologia , Infarto Cerebral/complicações , Infarto Cerebral/fisiopatologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipertensão/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Mesencéfalo/irrigação sanguínea , Pessoa de Meia-Idade , Nervo Oculomotor/fisiopatologia , Doenças do Nervo Oculomotor/fisiopatologia , Inibidores da Agregação de Plaquetas/administração & dosagem , Síndrome , Resultado do Tratamento
17.
Sci Rep ; 10(1): 12016, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694638

RESUMO

Prostate cancer patients using cholesterol-lowering statins have 30% lower risk of prostate cancer death compared to non-users. The effect is attributed to the inhibition of the mevalonate pathway in prostate cancer cells. Moreover, statin use causes lipoprotein metabolism changes in the serum. Statin effect on serum or intraprostatic lipidome profiles in prostate cancer patients has not been explored. We studied changes in the serum metabolomic and prostatic tissue lipidome after high-dose 80 mg atorvastatin intervention to expose biological mechanisms causing the observed survival benefit. Our randomized, double-blind, placebo-controlled clinical trial consisted of 103 Finnish men with prostate cancer. We observed clear difference in post-intervention serum lipoprotein lipid profiles between the study arms (median classification error 11.7%). The atorvastatin effect on intraprostatic lipid profile was not as clear (median classification error 44.7%), although slightly differing lipid profiles by treatment arm was observed, which became more pronounced in men who used atorvastatin above the median of 27 days (statin group median classification error 27.2%). Atorvastatin lowers lipids important for adaptation for hypoxic microenvironment in the prostate suggesting that prostate cancer cell survival benefit associated with statin use might be mediated by both, local and systemic, lipidomic/metabolomic profile changes.


Assuntos
Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Ácidos Graxos/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipoproteínas/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Idoso , Estudos de Coortes , Método Duplo-Cego , Finlândia , Humanos , Lipidômica/métodos , Masculino , Metaboloma , Pessoa de Meia-Idade , Gradação de Tumores , Próstata/metabolismo , Neoplasias da Próstata/patologia , Resultado do Tratamento
19.
J Am Med Dir Assoc ; 21(7): 909-914.e2, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32674818

RESUMO

OBJECTIVES: Angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors ("statins") have been hypothesized to affect COVID-19 severity. However, up to now, no studies investigating this association have been conducted in the most vulnerable and affected population groups (ie, older adults residing in nursing homes). The objective of this study was to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19-infected older adults residing in nursing homes. DESIGN: We undertook a retrospective multicenter cohort study to analyze the association between ACEi/ARB and/or statin use with clinical outcome of COVID-19. The outcomes were (1) serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset, and (2) asymptomatic (ie, no disease symptoms in the whole study period while still being diagnosed by polymerase chain reaction). SETTING AND PARTICIPANTS: A total of 154 COVID-19-positive subjects were identified, residing in 1 of 2 Belgian nursing homes that experienced similar COVID-19 outbreaks. MEASURES: Logistic regression models were applied with age, sex, functional status, diabetes, and hypertension as covariates. RESULTS: We found a statistically significant association between statin intake and the absence of symptoms during COVID-19 (odds ratio [OR] 2.91; confidence interval [CI] 1.27-6.71), which remained statistically significant after adjusting for covariates (OR 2.65; CI 1.13-6.68). Although the effects of statin intake on serious clinical outcome were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.24-1.87). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 2.72; CI 0.59-25.1) or serious clinical outcome (OR 0.48; CI 0.10-1.97). CONCLUSIONS AND IMPLICATIONS: Our data indicate that statin intake in older, frail adults could be associated with a considerable beneficial effect on COVID-19 clinical symptoms. The role of statins and renin-angiotensin system drugs needs to be further explored in larger observational studies as well as randomized clinical trials.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Bélgica/epidemiologia , Causas de Morte , Estudos de Coortes , Feminino , Avaliação Geriátrica , Instituição de Longa Permanência para Idosos/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Casas de Saúde/estatística & dados numéricos , Razão de Chances , Pandemias/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
20.
Br J Pharmacol ; 177(21): 4873-4886, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32562276

RESUMO

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed healthcare systems requiring the rapid development of treatments, at least, to reduce COVID-19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID-19 patients based on evidence that they may target virus receptors, replication, degradation, and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could modulate virus entry, acting on the SARS-CoV-2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well-known anti-inflammatory properties of statins, by blocking several molecular mechanisms, including NF-κB and NLRP3 inflammasomes, could limit the "cytokine storm" in severe COVID-19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improving COVID-19 outcomes. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/imunologia , Reposicionamento de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Internalização do Vírus/efeitos dos fármacos
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