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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
3.
Med. infant ; 26(3): 287-295, Septiembre 2019. Tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-1025029

RESUMO

La Hipercolesterolemia Familiar (HF) es una enfermedad hereditaria frecuente que se caracteriza por niveles elevados de colesterol ligado a las lipoproteínas de baja densidad (C-LDL). El exceso de LDL se acumula en las arterias produciendo aterosclerosis prematura. El diagnóstico y tratamiento desde la infancia mejoran el pronóstico de la enfermedad. Existe subdiagnóstico de la HF lo que provoca muertes prematuras por enfermedad cardiovascular (ECV). Para mejorar el subdiagnóstico la Sociedad Argentina de Pediatría propuso en el año 2015 realizar tamizaje universal al ingreso escolar. Es relevante entonces que el pediatra pueda diagnosticar la hipercolesterolemia y diferenciar las hipercolesterolemias monogénicas o familiares, de las secundarias (AU)


Familial hypercholesterolemia (FH) is a common hereditary disease that is characterized by high cholesterol levels, linked to low-density lipoproteins (LDL). Excess LDL accumulates in the arteries leading to premature atherosclerosis. Early diagnosis and treatment since childhood improve the prognosis of the disease. FH is underdiagnosed resulting in premature death due to cardiovascular disease (CVD). To improve diagnosis, in 2015 the Argentine Society of Pediatrics proposed a universal screening program at school age. It is relevant, therefore, for the pediatrician to be able to diagnose hypercholesterolemia and differentiate monogenic or familial from secondary hypercholesterolemia (AU)


Assuntos
Humanos , Pré-Escolar , Criança , Adolescente , Doenças Cardiovasculares/prevenção & controle , Colesterol/metabolismo , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/fisiopatologia , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Programas de Rastreamento , Diagnóstico Diferencial , Anticolesterolemiantes/uso terapêutico
5.
Adv Clin Exp Med ; 28(9): 1243-1248, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430072

RESUMO

BACKGROUND: FoxP3 is a marker of human T regulatory cells (Tregs), which are supposed to play an important role in the pathophysiology of atherosclerosis. Interleukin 10 (IL-10) is a cytokine with pleiotropic, immunoregulatory properties, produced mostly by Tregs and B regulatory cells. Due to their anti-inflammatory action, both Tregs and IL-10 are believed to inhibit plaque development and decrease atherosclerosis progression. The effect of hypolipidemic drugs - statins or ezetimibe - on FoxP3-positive Tregs and anti-inflammatory cytokines, such as IL-10, is still unclear. OBJECTIVES: The objective of the study was to investigate the effects of 3 different therapies of equivalent hypolipidemic activity: atorvastatin, rosuvastatin, and combination therapy of atorvastatin and ezetimibe on FoxP3-Tregs transcription factor and IL-10 mRNA expression in peripheral blood mononuclear cells (PBMCs) from patients with stable coronary artery disease (CAD). MATERIAL AND METHODS: Sixty-five patients with diagnosed CAD participated in the study. They were randomly assigned to 3 therapeutic groups: atorvastatin at a dose of 40 mg/day (A40 group); rosuvastatin 20 mg/day (R20 group); and atorvastatin 10 mg/day combined with ezetimibe 10 mg/day (A10+E10 group). After 1 month and 6 months of therapy, the mRNA expression for FoxP3 and IL-10 in PBMCs was evaluated using real-time polymerase chain reaction (RT-PCR) and lipid parameters. RESULTS: An improvement in lipid parameters was observed in each of the groups studied; however, hypolipidemic treatment did not induce any change in FoxP3 and IL-10 mRNA expression. After 6 months, an increase in FoxP3 mRNA expression was noted in A40 group as compared to R20 group. CONCLUSIONS: None of the therapies of equal hypolipidemic efficacy affected FoxP3 and IL-10 mRNA expression in patients with stable CAD.


Assuntos
Anticolesterolemiantes , Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Ezetimiba/uso terapêutico , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares , RNA Mensageiro
6.
High Blood Press Cardiovasc Prev ; 26(3): 199-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236902

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-related discoveries of the turn of the century have translated into substantial novelty in dyslipidemia treatment in the last 5 years. With chronic preventable atherosclerotic cardiovascular diseases (ASCVD) representing an epidemic of morbidity and mortality worldwide, low-density lipoprotein cholesterol (LDL-c) reduction represents a public health priority. By overcoming two major statin-related issues, namely intolerance and ineffectiveness, PCSK9 inhibitors have offered a safe and effective option in selected clinical settings where LDL-c reduction is required. Herein, we recapitulate recent findings, clinical applications, and ASCVD prevention potential of PCSK9 inhibition, with focus on anti-PCSK9 monoclonal antibodies, evolocumab and alirocumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/epidemiologia , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
7.
Drugs Today (Barc) ; 55(5): 329-344, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131843

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of death all over the world. Its etiopathogenesis involves many correlated processes, with hypercholesterolemia being one of the main risk factors. Several large clinical trials have established the association between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. With the aim to take control over high LDL-C levels, several drugs with different targets in the cholesterol pathway have been developed. Statins are the cornerstone of pharmacological lipid-lowering treatment, although they are not always successful in attaining the recommended LDL-C levels. Therefore, newer and more potent therapies have been developed, being prominent among them ezetimibe and especially the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recent trials with these new therapies have reaffirmed the theory of 'the lower, the better' when it comes to LDL-C levels, and 'the earlier, the better' when it comes to atherosclerotic physiopathology.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/antagonistas & inibidores , Pró-Proteína Convertase 9/antagonistas & inibidores , Subtilisinas/antagonistas & inibidores , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Humanos
8.
Medicina (B Aires) ; 79(2): 104-110, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31048275

RESUMO

LDL-cholesterol (LDL-C) lowering is a primary objective in cardiovascular prevention. Recent studies demonstrated clinical benefit when proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) were added to the treatment in patients who had not achieved the LDL-C goal despite being treated with high intensity statins and ezetimibe, however the use of these drugs is limited by their cost. The American College of Cardiology, the Argentine Society of Cardiology and the European Society of Cardiology recommend an LDL-C goal less than 70 mg/dl in secondary prevention, determining thresholds of LDL-C to start treatment with PCSK9i of 70, 100 or 140 mg/dl respectively. In order to evaluate the lipid-lowering regimen prescribed in patients hospitalized for acute coronary syndrome or coronary revascularization and analyze the proportion of eligible to be treated with PCSK9i in a real and simulated scenario, we conducted a study that included 351 patients with coronary disease collected from an electronic database of a university hospital. The 48.4% received high intensity statins, 11.4% ezetimibe and 54.7% did not achieve the LDL-C goal of less than 70 mg/dL. Using a simulation model in which all would be treated with high intensity statins and ezetimibe, the eligibility to prescribe PCSK9i was 31.1%, 12.8% and 9.1% according to the C- LDL thresholds determined by the three scientific societies. Our study demonstrated a gap between the consensus recommendations for LDL-C lowering and the current practice that should be minimized to optimize the cost/effectiveness ratio in secondary prevention.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Argentina , Estudos Transversais , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Fatores Sexuais , Sociedades Científicas , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-31049144

RESUMO

Given its role in many biochemical processes essential to life, cholesterol remains a topic of intense research. Of all the plasma lipids, cholesterol is distinctive because it is a precursor to steroidogenic molecules, some of which regulate metabolism, and its blood concentration in the form of low- and high-density lipoprotein cholesterol (HDL-C) are positive and negative risk factors for atherosclerotic cardiovascular disease (ASCVD). New research, however, has challenged the widely held belief that high HDL-C levels are atheroprotective and is showing that both low and high plasma HDL-C levels confer an increased risk of ASCVD. Furthermore, it is disputing the widely cited mechanism involved in reverse cholesterol transport. This review explores the evolution of cholesterol research starting with the Gofman and Framingham studies, the development of traditional and emerging lipid-lowering therapies, and the role of reverse cholesterol transport in HDL cardioprotection.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/etiologia , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/sangue , HDL-Colesterol/efeitos adversos , HDL-Colesterol/sangue , LDL-Colesterol/efeitos adversos , LDL-Colesterol/sangue , Animais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/genética , Aterosclerose/prevenção & controle , Transporte Biológico , Humanos , Placa Aterosclerótica , Prognóstico , Fatores de Proteção , Fatores de Risco
10.
Methodist Debakey Cardiovasc J ; 15(1): 39-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049148

RESUMO

High-density lipoprotein (HDL) is a protein-lipid nanoparticle that has predominately been characterized by its cholesterol concentration (HDL-C). Recent studies have challenged the presumed inverse association between HDL-C and cardiovascular events, suggesting a more U-shaped association. This has opened new opportunities to evaluate more novel measures of HDL metabolism, such as HDL particle number (HDL-P) and one of HDL's key functions, cholesterol efflux. Both HDL-P and cholesterol efflux are inversely associated with incident cardiovascular events and may perhaps be better targets for intervention. This review includes recent research on the emerging U-shaped association between HDL-C and cardiovascular events, recent observational studies related to HDL-P, and the effects of established and novel interventions on cholesterol efflux.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Animais , Anticolesterolemiantes/efeitos adversos , Transporte Biológico , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Proteínas de Transferência de Ésteres de Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Exercício , Dieta Saudável , Humanos , Comportamento de Redução do Risco , Resultado do Tratamento
11.
Methodist Debakey Cardiovasc J ; 15(1): 47-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049149

RESUMO

Dysregulated free cholesterol (FC) metabolism has been implicated in nearly all stages of atherosclerosis, the underlying cause of most cardiovascular disease. According to a widely cited model, the burden of macrophage FC in the arterial wall is relieved by transhepatic reverse cholesterol transport (RCT), which comprises three successive steps: (1) macrophage FC efflux to high-density lipoprotein (HDL) and/or its major protein, apolipoprotein AI; (2) FC esterification by lecithin:cholesterol acyltransferase (LCAT); and (3) HDL-cholesteryl ester (CE) uptake via the hepatic HDL-receptor, scavenger receptor class B type 1 (SR-B1). Recent studies have challenged the validity of this model, most notably the role of LCAT, which appears to be of minor importance. In mice, most macrophage-derived FC is rapidly cleared from plasma (t1/2 < 5 min) without esterification by hepatic uptake; the remainder is taken up by multiple tissue and cell types, especially erythrocytes. Further, some FC is cleared by the nonhepatic transintestinal pathway. Lastly, FC movement among lipid surfaces is reversible, so that a higher-than-normal level of HDL-FC bioavailability-defined by high plasma HDL levels concurrent with a high mol% HDL-FC-leads to the transfer of excess FC to cells in vivo. SR-B1-/- mice provide an animal model to study the mechanistic consequences of high HDL-FC bioavailability that provokes atherosclerosis and other metabolic abnormalities. Future efforts should aim to reduce HDL-FC bioavailability, thereby reducing FC accretion by tissues and the attendant atherosclerosis.


Assuntos
Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , Dislipidemias/sangue , Macrófagos/metabolismo , Animais , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/sangue , Disponibilidade Biológica , Transporte Biológico , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Humanos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Receptores Depuradores Classe B/metabolismo
12.
Methodist Debakey Cardiovasc J ; 15(1): 70-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049152

RESUMO

Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through which cholesterol is disposed from the body. In the process of TICE, cholesterol is taken up from lipoprotein particles at the basolateral side of the enterocyte and translocates towards the apical side of the enterocyte. At the apical side, the ATP-binding cassette transporters G5 and G8 form a heterodimer that transports cholesterol into the intestinal lumen. A substantial amount of the secreted cholesterol is likely reabsorbed by the cholesterol influx transporter Niemann-Pick C1-Like 1 (NPC1L1) since recent data indicate that inhibition of NPC1L1 increases the efficacy of TICE for disposal of cholesterol via the feces. The pathways and proteins involved in intracellular cholesterol trafficking in the enterocyte have not yet been identified. Therefore, in addition to discussing known mediators of TICE, this review will also examine potential candidates involved in cholesterol translocation in the enterocyte. Both the cholesterol reuptake and efflux pathways can be influenced by pharmaceutical means; thus, the TICE pathway is a very attractive target to increase cholesterol excretion from the body and prevent or mitigate atherosclerotic cardiovascular disease.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Enterócitos/efeitos dos fármacos , Eliminação Intestinal/efeitos dos fármacos , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Animais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Enterócitos/metabolismo , Fezes/química , Humanos , Proteínas de Membrana Transportadoras/metabolismo
13.
Chem Pharm Bull (Tokyo) ; 67(5): 419-425, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061366

RESUMO

Patients with type 2 diabetes (T2DM) and hyperlipidemia are with high risk of myocardial infarction (MI) or coronary death events. The combined use of ezetimibe and atorvastatin could improve treatment efficacy and safety. To explore the efficacy and safety of ezetimibe in combination with atorvastatin for the treatment of patients with T2DM and acute coronary syndrome (ACS). This was a non-randomized cohort study of 95 consecutive, treatment-naïve patients with T2DM and ACS treated at the Quanzhou First Hospital of Fujian Province between February 2014 and March 2016. According to the treatment strategy they selected, the patients were categorized into the atorvastatin (n = 46) and atorvastatin + ezetimibe (n = 49) groups. The patients were followed up at 2 weeks and 12 months. The primary endpoints included the incidence of adverse cardiovascular events and changed in blood lipids and high-sensitivity C-reactive protein (hs-CRP). At 12 months, serum total cholesterol (TC), triglycerides, and low-density lipoprotein cholesterol (LDL-C) levels were significantly lower, and high-density lipoprotein cholesterol (HDL-C) levels were significantly higher in the atorvastatin + ezetimibe (EZ) group than in the atorvastatin group (all p < 0.05). The LDL-C control rate at 12 months was significantly higher in the atorvastatin + EZ group compared with the atorvastatin group (p = 0.006). Seven patients in the atorvastatin group were re-hospitalized for angina pectoris, while only one patient in the atorvastatin + EZ group was re-hospitalized for angina pectoris (p = 0.02). The efficacy of atorvastatin + EZ in treating T2DM patients accompanied with ACS was significantly higher than using atorvastatin alone. This combined strategy has good safety profile, and could be recommended for clinical application.


Assuntos
Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Ezetimiba/uso terapêutico , Síndrome Coronariana Aguda/sangue , Anticolesterolemiantes/efeitos adversos , Atorvastatina/efeitos adversos , Proteína C-Reativa/análise , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Ezetimiba/efeitos adversos , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Miocárdio/enzimologia
14.
Bioanalysis ; 11(8): 679-687, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30997829

RESUMO

Aim: Evolocumab is a human monoclonal antibody used in the treatment of cardiovascular diseases, which targeted proprotein convertase subtilisin kexin type 9. To accurately quantify free (including partially bound) and total evolocumab concentrations in serum, indirect and generic ELISA methods were developed and validated in rat serum. Results: Indirect ELISA was accurate and precise over the concentration range of 23.4-1500 ng/ml, and the method was validated for selectivity, specificity, accuracy and precision, dilution linearity, parallelism and stability. Similarly, generic antihuman IgG ELISA method was validated for selectivity, accuracy and precision, and dilution linearity. Moreover, incurred sample reanalysis were carried out for the above two methods, and the percent difference met the acceptable criteria. Conclusion: The validated methods can be effectively used to evaluate pharmacokinetics of free and total evolocumab after subcutaneous administration of evolocumab to rats.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Ensaio de Imunoadsorção Enzimática/métodos , Imunoensaio/métodos , Animais , Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , Humanos , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
15.
Neurología (Barc., Ed. impr.) ; 34(3): 198-203, abr. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-180783

RESUMO

Introducción: La proproteína convertasa subtilisina kexina tipo 9 (PCSK9) desempeña un papel importante en la modulación de los niveles plasmáticos de colesterol unido a las lipoproteínas de baja densidad (LDLC). La PCSK9 se une al receptor del LDLC (LDL[R]) perturba su reciclado endocítico y lo dirige a la degradación lisosomal. Por tanto, la activación de PCSK9 disminuye la expresión de los LDL(R) a nivel hepático e inhibe la captación de LDLC, lo que provoca hipercolesterolemia. Desarrollo: Hoy se sabe que diferentes polimorfismos de la PCSK9 se asocian a la aparición de ictus isquémico. Por otra parte, los fármacos inhibidores de PCSK9 inhiben la unión de PCSK9 con el LDL(R) y evitan la degradación del LDL(R) por lo que aumentan la captación hepática de LDLC, disminuyendo sus niveles en sangre. Diferentes estudios con anticuerpos monoclonales en fase 2 y 3 como el OSLER y el ODYSSEY LONG TERM han demostrado la eficacia y seguridad de los nuevos anticuerpos monoclonales contra PCSK9 como el evolucumab y alirocumab, y los primeros análisis exploratorios ya evidencian su eficacia en la disminución de eventos vasculares, incluidos los ictus. Conclusiones: Aunque el número de ictus recogidos en estos estudios ha sido bajo, en la actualidad existen varios ensayos centrados en resultados cardiovasculares en curso con evolocumab (estudio FOURIER), con alirocumab (estudio ODYSSEY OUTCOMES) y con bococizumab (estudios SPIRE-1 y SPIRE-2) que nos desvelarán el auténtico potencial de estos fármacos en la enfermedad cardiovascular y, en particular, en la prevención del ictus


Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of plasma levels of low density lipoprotein cholesterol (LDLC). PCSK9 binds to the LDL receptor (LDLR), disrupts its endocytic recycling itinerary and directs it to lysosomal degradation. Activation of PCSK9 can thus decrease the expression of LDLR in the liver and inhibit LDL uptake, which leads to hypercholesterolaemia. Development: Currently we now know that different polymorphisms of PCSK9 are associated with the occurrence of ischaemic stroke. On the other hand, PCSK9 inhibitors prevent binding of PCSK9 to LDLR and inhibit degradation of LDLR, which results in increased hepatic uptake of LDL and lower LDL levels in blood. Different phase 2 and 3 studies, including OSLER and ODYSSEY LONG-TERM, have demonstrated the efficacy and safety of the new monoclonal antibodies against PCSK9 such as evolucumab and alirocumab, and the first exploratory analyses have shown evidence of their efficacy in decreasing vascular events, including stroke. Conclusions: Although few strokes have been reported by these studies, new ongoing trials examining the cardiovascular effects of evolucumab (FOURIER study), alirocumab (ODYSSEY OUTCOMES study), and bococizumab (SPIRE-1 and SPIRE-2 studies) will reveal the true potential of these drugs, particularly for the prevention of stroke


Assuntos
Humanos , Pró-Proteína Convertase 9/metabolismo , Hipercolesterolemia/fisiopatologia , Anticorpos Monoclonais/uso terapêutico , Acidente Vascular Cerebral/fisiopatologia , Hipercolesterolemia/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Anticolesterolemiantes/uso terapêutico
16.
Nutrients ; 11(4)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013851

RESUMO

We evaluated the effects of Cynanchum wilfordii (CW) ethanolic extract on blood cholesterol levels in adults with high low-density lipoprotein cholesterol (LDL-C) levels. In a double-blind, randomized, placebo-controlled, parallel trial, 84 subjects were recruited. Participants were randomly divided into two groups with a low-dose (300 mg/d) or high-dose (600 mg/d) of CW. Levels of very low-density lipoprotein (p = 0.022) and triglycerides (p = 0.022) were significantly lower in the low-dose CW group than in the placebo group after 8 weeks. In a subgroup of participants with LDL-C≥ 150 mg/dL (n = 33), there was a significant decrease in total cholesterol (low-dose, p = 0.012; high-dose, p = 0.021), apolipoprotein B (low-dose, p = 0.022; high-dose, p = 0.016), and cholesteryl ester transfer protein (low-dose, p = 0.037; high-dose, p = 0.016) after 8 weeks of CW. The correlation between changes in total cholesterol and baseline LDL-C levels was significant in the groups that received both doses of CW (low-dose, p = 0.010; high-dose, p = 0.015). These results show that the CW ethanolic extract can regulate blood cholesterol in subjects with LDL-C≥ 150 mg/dL.


Assuntos
Anticolesterolemiantes/uso terapêutico , Colesterol/sangue , Cynanchum , Hipercolesterolemia/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Anticolesterolemiantes/farmacologia , Apolipoproteínas B/sangue , Proteínas de Transferência de Ésteres de Colesterol/sangue , LDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/farmacologia , Triglicerídeos/sangue
17.
Vascul Pharmacol ; 116: 8-15, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30910670

RESUMO

BACKGROUND: Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9-I) reduce low-density lipoprotein (LDL) cholesterol in human studies. Previous studies suggest that PCSK9-I may also affect very-low-density lipoproteins (VLDL). We therefore studied VLDL size and composition in a "real-world" study population with the use of ß-quantification. SUBJECTS AND METHODS: 350 patients (62 ±â€¯11 years old, 58% men, 22% with diabetes mellitus) with different concomitant lipid lowering therapies, and in whom PCSK9-I treatment was indicated, received either evolocumab (140 mg) or alirocumab (75 or 150 mg). The major lipoprotein fractions were separated by ß-quantification and lipid and apolipoprotein compositions were determined before and 4 weeks after initiation of PCSK9-I treatment. RESULTS: After 4 weeks of PCSK9-I treatment, the ratio of triglycerides to apolipoprotein B in VLDL particles (VLDL-TG/apoB ratio) increased by 40% (p < .0001). VLDL-associated apolipoproteins E, CII, and CIII were reduced by 29.4%, 16.4%, and 12.4%, respectively (all p < .0001). CONCLUSION: PCSK9-I treatment increased VLDL size (estimated by an increased VLDL-TG/apoB ratio) and reduced VLDL-associated apolipoproteins in a heterogeneous "real-world" study-population, reflecting a higher clearance of small atherogenic VLDL remnant particles by PCSK9-I. This may potentially lower cardiovascular risk in clinical routine patients beyond low-density cholesterol (LDL-C) reduction.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Apolipoproteína B-100/sangue , Dislipidemias/tratamento farmacológico , Lipoproteínas VLDL/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Triglicerídeos/sangue , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Regulação para Baixo , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/enzimologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Pró-Proteína Convertase 9/metabolismo , Estudos Prospectivos , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
18.
Expert Opin Pharmacother ; 20(8): 917-928, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908086

RESUMO

INTRODUCTION: Cardiovascular disease is a major cause of morbidity and mortality throughout the world and hypercholesterolemia is one of the key risk factors. Statins are the first line treatment to reduce atherogenic lipids and there is substantial and robust evidence with atorvastatin for reduction of cardiovascular events and mortality. Ezetimibe can be combined with any dose of atorvastatin for incremental lipid-lowering effects. Areas covered: In this review, the authors summarize the pharmacokinetics, pharmacodynamics and clinical efficacy of the components and the combination of ezetimibe and atorvastatin. Clinical benefits have been seen with ezetimibe combined with simvastatin but studies of its combination with atorvastatin are generally limited to the effects on lipid parameters where the addition of ezetimibe to atorvastatin is generally more effective than titrating the atorvastatin dose. Expert opinion: Although there are no cardiovascular outcomes studies with the combination of ezetimibe and atorvastatin, the greater reduction in atherogenic lipids can be assumed to have greater benefits in reducing cardiovascular events. The ezetimibe-atorvastatin combination is very effective in this respect and well tolerated. Fixed-dose combinations improve medication adherence and this combination should be useful for patients who cannot reach their lipid targets with maximally tolerated statin doses.


Assuntos
Atorvastatina/administração & dosagem , Ezetimiba/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Combinação de Medicamentos , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Fatores de Risco , Sinvastatina/administração & dosagem , Sinvastatina/uso terapêutico
19.
High Blood Press Cardiovasc Prev ; 26(2): 85-100, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30877603

RESUMO

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Despite the clinical long-term and near-term benefits of lowering cholesterol in, respectively, primary and secondary prevention of ASCVD, cholesterol levels remain under-treated, with many patients not achieving their recommended targets. The present article will review the latest updates on lipid management with emphases on the different classes of cholesterol-lowering agents and their clinical uses.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Triglicerídeos/sangue , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/mortalidade , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/mortalidade , Exercício , Dieta Saudável , Humanos , Fatores de Proteção , Fatores de Risco , Comportamento de Redução do Risco , Resultado do Tratamento
20.
J Steroid Biochem Mol Biol ; 190: 104-114, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30878503

RESUMO

Alzheimer's disease (AD) is the most common form of dementia and it is characterized by the deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain. However, the complete pathogenesis of the disease is still unknown. High level of serum cholesterol has been found to positively correlate with an increased risk of dementia and some studies have reported a decreased prevalence of AD in patients taking cholesterol-lowering drugs. Years of research have shown a strong correlation between blood hypercholesterolemia and AD, however cholesterol is not able to cross the Blood Brain Barrier (BBB) into the brain. Cholesterol lowering therapies have shown mixed results in cognitive performance in AD patients, raising questions of whether brain cholesterol metabolism in the brain should be studied separately from peripheral cholesterol metabolism and what their relationship is. Unlike cholesterol, oxidized cholesterol metabolites known as oxysterols are able to cross the BBB from the circulation into the brain and vice-versa. The main oxysterols present in the circulation are 24S-hydroxycholesterol and 27-hydroxycholesterol. These oxysterols and their catalysing enzymes have been found to be altered in AD brains and there is evidence indicating their influence in the progression of the disease. This review gives a broad perspective on the relationship between hypercholesterolemia and AD, cholesterol lowering therapies for AD patients and the role of oxysterols in pathological and non-pathological conditions. Also, we propose cholesterol metabolites as valuable targets for prevention and alternative AD treatments.


Assuntos
Doença de Alzheimer/metabolismo , Colesterol/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Animais , Anticolesterolemiantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colestanotriol 26-Mono-Oxigenase/metabolismo , Colesterol 24-Hidroxilase/metabolismo , Humanos , Hidroxicolesteróis/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de Risco
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