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1.
N Engl J Med ; 383(14): 1317-1327, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865373

RESUMO

BACKGROUND: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Criança , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Masculino , Resultado do Tratamento
3.
N Engl J Med ; 383(8): 711-720, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32813947

RESUMO

BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/sangue , Criança , Método Duplo-Cego , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Infusões Intravenosas , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de LDL/metabolismo , Adulto Jovem
4.
Zhonghua Xin Xue Guan Bing Za Zhi ; 48(7): 593-599, 2020 Jul 24.
Artigo em Chinês | MEDLINE | ID: mdl-32842270

RESUMO

Objective: To compare the efficacy and safety profile of alirocumab (PCSK9 inhibitor) versus ezetimibe on top of maximally tolerated statin dose in high cardiovascular risk Chinese patients with hyperlipidemia. Methods: The ODYSSEY EAST study was a randomized, double-blinded, double dummy, active-control, parallel group, multi-centers clinical trial, the Chinese sub-population included 456 patients with hyperlipidemia and high cardiovascular risk on maximally tolerated statin dose. Patients were randomized (2∶1) to receive the subcutaneous injection of alirocumab (75 mg Q2W; with dose up titration to 150 mg Q2W at week 12 if low-density lipoprotein cholesterol (LDL-C) was ≥1.81 mmol/L at week 8) or the oral administration of ezetimibe (10 mg daily) for 24 weeks. The primary endpoint was percentage change in calculated LDL-C from baseline to week 24. Key secondary efficacy endpoints included percentage change from baseline to week 12 or 24 in LDL-C (week 12) and other lipid parameters, including apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (non-HDL-C), TC, lipoprotein(a) (Lp(a)), HDL-C, fasting triglycerides (TG), and Apo A1, and the proportion of patients reaching LDL-C<1.81 mmol/L at week 24. Safety profile of therapeutic drugs was also assessed during the treatment period. Results: The mean age of 456 Chinese patients was (59.5±10.9) years, 341(74.8%) patients were male, 303 patients (66.4%) in alirocumab group and 153 patients (33.5%) in ezetimibe group. Demographic characteristics, disease characteristics, and lipid parameters at baseline were similar between the two groups. LDL-C was reduced more from baseline to week 12 and 24 in alirocumab group versus ezetimibe group, the difference of their least-squares mean (standard error) percent change were(-35.2±2.2)% and (-36.9±2.5)% (both P<0.001). At 12 weeks, alirocumab had significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-40.3±2.8)%, (-27.7±1.8)%, (-19.6±1.5)% and (-27.7±1.9)%, respectively (all P<0.001). At 24 weeks, the percent of patients who reached LDL-C<1.81 mmol/L and LDL-C<1.42 mmol/L was significantly higher in alirocumab group (85.3% and 70.5%) than in ezetimibe group (42.2% and 17.0%, both P<0.001), and alirocumab use was also associated with significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-37.2±2.8)%, (-29.1±2.0)%, (-21.6±1.6)% and (-29.6±2.2)%, respectively (all P<0.001). The incidence of treatment related adverse events was similar between the two treatment groups (223/302 patients (73.8%) in alirocumab group and 109/153 patients (71.2%) in ezetimibe group). Respiratory infection, urinary infection, dizziness and local injection-site reactions were the most frequently reported adverse events. Conclusions: In high cardiovascular risk patients with hyperlipidemia from China on maximally tolerated statin dose, the reduction of LDL-C induced by alirocumab is more significant than that induced by ezetimibe. Both treatments were generally safe during the observation period of study.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Hipercolesterolemia , Hiperlipidemias , Idoso , Anticorpos Monoclonais Humanizados , China , Método Duplo-Cego , Ezetimiba/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Fatores de Risco , Resultado do Tratamento
5.
High Blood Press Cardiovasc Prev ; 27(4): 331-338, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32651891

RESUMO

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are proven to have profound lowering of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease or familial hypercholesterolemia. AIM: The primary purpose of this study was to evaluate PCSK9i utilization in older adults, with a focus on efficacy outcomes within 6 months of initiation. Secondary outcomes included tolerability, out-of-pocket expenses (OPE), and barriers to initiation of therapy. METHODS: We conducted a retrospective chart review of patients ≥ 65 years prescribed PCSK9i therapy by a pharmacist-run lipid clinic within a cardiology practice. RESULTS: A total of 136 older adults were prescribed PCSK9i therapy for a Food and Drug Administration-approved indication between September 2015 and March 2019 with 98 patients included in the analyses. In terms of efficacy, 51 patients who took ≥ 3 doses of PCSK9i with baseline and follow-up lipid panels were assessed. On average, LDL-C reduced by 60% (169-67 mg/dL, p < 0.001). For tolerability, 15 patients reported treatment-emergent side effects, resulting in 10 therapy discontinuations. For the cost analysis, 72 patients reported anticipated OPE for 1 month of therapy. Ultimately 17 patients were approved for manufacturer patient assistance with $0 OPE and 31 patients utilized insurance coverage to obtain therapy reporting a median OPE of $9 United States Dollars ($0-$450). The main barrier to initiation was high OPE. CONCLUSIONS: PCSK9i are effective at lowering LDL-C in older adults. Tolerability was high among patients without a history of statin intolerance. PCSK9i remain high-cost medications to both insurance companies and patients in terms of cost-sharing responsibilities.


Assuntos
Anticolesterolemiantes/economia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/economia , LDL-Colesterol/sangue , Custos de Medicamentos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/economia , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/economia , Inibidores de Serino Proteinase/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/diagnóstico , Biomarcadores/sangue , Regulação para Baixo , Feminino , Gastos em Saúde , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Seguro de Serviços Farmacêuticos/economia , Masculino , Pró-Proteína Convertase 9/metabolismo , Estudos Retrospectivos , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
6.
PLoS Med ; 17(7): e1003121, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673317

RESUMO

BACKGROUND: Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. METHODS AND FINDINGS: We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel-Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD -14.94%; 95% CI -17.31%, -12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD -18.17%; 95% CI -21.14%, -15.19%; p < 0.001), low-density lipoprotein cholesterol (MD -22.94%; 95% CI -26.63%, -19.25%; p < 0.001), low-density lipoprotein particle number (MD -20.67%; 95% CI -23.84%, -17.48%; p < 0.001), apolipoprotein B (MD -15.18%; 95% CI -17.41%, -12.95%; p < 0.001), high-density lipoprotein cholesterol (MD -5.83%; 95% CI -6.14%, -5.52%; p < 0.001), high-density lipoprotein particle number (MD -3.21%; 95% CI -6.40%, -0.02%; p = 0.049), and hsCRP (MD -27.03%; 95% CI -31.42%, -22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD -1.51%; 95% CI -3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI -9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD -1.83%; 95% CI -5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. CONCLUSIONS: Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/efeitos adversos , Apolipoproteínas B/sangue , Colesterol/sangue , LDL-Colesterol/sangue , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Ácidos Dicarboxílicos/efeitos adversos , Ácidos Graxos/efeitos adversos , Humanos , Hipercolesterolemia/sangue , Fragmentos de Peptídeos/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Am J Cardiol ; 128: 163-167, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650914

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide striking lowering of low-density lipoprotein cholesterol (LDL-C) when added to maximum tolerated therapy in patients with hypercholesterolemia. Ceramides, novel cardiac risk markers, have been associated with increased cardiovascular mortality, independent of traditional cardiovascular risk factors. The Ceramide Risk Score (CRS) predicts the likelihood of adverse cardiovascular events within 1 to 3 years in patients with coronary artery disease. The effect of PCSK9 inhibition on plasma ceramides is not well known. The study examines the effect of PCSK9 inhibitors on plasma ceramides and CRS in patients with clinical indication for this therapy. Retrospective chart review of consecutive patients with hypercholesterolemia on PCSK9 inhibitors was conducted (n = 24; Mayo Clinic 2015 to 2018). Plasma ceramides were measured before the initiation of PCSK9 inhibitors and 2 to 12 months after treatment. CRS was calculated before and after therapy based on individual plasma concentrations of 4 ceramides. Treatment with PCSK9 inhibitors was associated with significant reduction in mean CRS and individual ceramides levels (p <0.0001). CRS significantly improved with PCSK9 therapy. PCSK9 inhibitors significantly decreased LDL-C levels by 63% (p <0.0001). The absolute reduction in CRS did not correlate with the absolute reduction in LDL-C (r = 0.31; confidence interval -0.10 to 0.64), indicating that CRS may evaluate a different pathway for risk reduction beyond LDL-C lowering. In conclusion, treatment with PCSK9 inhibitors is associated with significant reduction in CRS and distinct ceramide levels.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Ceramidas/sangue , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Idoso , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
8.
Cardiovasc Ther ; 2020: 5936748, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636924

RESUMO

Background: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C). Because of underdiagnosis, acute coronary syndrome (ACS) is often the first clinical manifestation of FH. In Japan, there are few reports on the prevalence and diagnostic ratios of FH and the proportion of ACS among FH patients in clinical settings. Methods: This retrospective, observational study used anonymized data from electronic healthcare databases between April 2001 and March 2015 of patients who had ≥2 LDL-C measurements recorded after April 2009. The index date was defined as the date of the first LDL-C measurement after April 2009. The primary endpoint was the prevalence of definite or suspected FH; secondary endpoints included the proportion of FH patients hospitalized for ACS, the proportion of patients using lipid-lowering drugs (LLDs), and LDL-C levels. Results: Of the 187,781 patients screened, 1547 had definite or suspected FH (0.8%) based on data from the entire period; 832 patients with definite (n = 299, 0.16%) or suspected FH (n = 533, 0.28%) before the index date were identified in the main analysis cohort. LLDs were used in 214 definite FH patients (71.6%) and 137 suspected FH patients (25.7%). Among definite or suspected FH patients with ACS (n = 84) and without ACS (n = 748), 32.1% and 30.1% with definite FH and 3.2% and 2.4% with suspected FH had LDL-C levels < 2.6 mmol/L (<100 mg/dL), respectively. Sixty patients (7.2%) were hospitalized due to ACS at the index date. Conclusions: The prevalence of FH in this Japanese cohort of patients with ≥2 LDL-C measurements at hospitals was 0.8%, which is higher than that currently reported in epidemiological studies (0.2-0.5%). Patients with suspected FH, with or without ACS, had poorly controlled LDL-C levels and were undertreated. The proportion of FH patients who were hospitalized due to ACS was 7.2%.


Assuntos
Síndrome Coronariana Aguda/epidemiologia , Hiperlipoproteinemia Tipo II/epidemiologia , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , LDL-Colesterol/sangue , Bases de Dados Factuais , Regulação para Baixo , Registros Eletrônicos de Saúde , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Prevalência , Estudos Retrospectivos
9.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-595169

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/toxicidade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/toxicidade , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/toxicidade , Interações Medicamentosas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Agregação de Plaquetas/toxicidade , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Vasodilatadores/toxicidade
10.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 221-229, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: covidwho-603065

RESUMO

It can be misleading to think that the new severe acute respiratory syndrome coronavirus (SARS-CoV2) which has a very strong mutation and adaptation capabilities, uses only the angiotensin-converting enzyme II (ACE2) pathway to reach target cells. Despite all the precautions taken, the pandemic attack continues and the rapid increase in the number of deaths suggest that this virus has entered the cell through different pathways and caused damage through different mechanisms. The main reason why the ACE2 pathway comes to the fore in all scientific studies is that this receptor is located at the entry point of basic mechanisms that provide alveolo-capillary homeostasis. SARS-CoV-2 has to use nuclear factor-κB (NF-kB), caveloae, clathrin, lipoxin, serine protease and proteasome pathways in addition to ACE2 to enter the target cell and initiate damage. For this reason, while new drug development studies are continuing, in order to be beneficial to patients in their acute period, it is imperative that we are able to come up with drugs that activate or inhibit these pathways and are currently in clinical use. It is also critical that we adopt these new pathways to the treatment of pregnant women affected by SARS-CoV-2, based on the scientific data we use to treat the general population.


Assuntos
Betacoronavirus/metabolismo , Caveolina 1/metabolismo , Infecções por Coronavirus/metabolismo , Lipoxinas/metabolismo , NF-kappa B/metabolismo , Pneumonia Viral/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , NF-kappa B/antagonistas & inibidores , Uso Off-Label , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Inibidores de Proteassoma/uso terapêutico , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/uso terapêutico , Internalização do Vírus
11.
Clín. investig. arterioscler. (Ed. impr.) ; 32(3): 111-116, mayo-jun. 2020. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-193355

RESUMO

BACKGROUND: Hyperlipidemia is a prevalent disorder and a main component of the metabolic syndrome resulting from various factors. The aerial parts and flowers of Lavandula officinalis possesses antioxidant activity, therefore, in this study; the effects of L. officinalis extract were investigated on serum lipid levels of mice. METHODS: Experimental mature female BALB/c mice were treated with 100, 300 or 500 mg/kg/day of lavender aqueous extract or distilled water for 15 days via intraperitoneally injections. At the end of 15th day, the serum biochemical parameters include cholesterol, triglyceride, HDL and LDL levels as well as the liver cell function test were determined. RESULTS: The aqueous extract of lavender significantly decreased serum cholesterol and LDL levels. Serum cholesterol level was lower in the 300 and 500 mg/kg/day experimental groups when compared with the control group. In liver histology evaluation, fat accumulation was not observed in the experimental group, which treated with high-fat foods and receiving high doses of extract. CONCLUSION: L. officinalis extract exerts a hypolipidemic effect in studied groups, however, further phytochemical and biological tests are suggested to determine the active chemical constituent responsible for these activities


ANTECEDENTES: La hiperlipidemia es un trastorno prevalente y un componente principal del síndrome metabólico originada por diversos factores. Las partes aéreas y flores de la Lavandula officinalis tienen una actividad antioxidante y, por tanto, investigamos en este estudio los efectos de su extracto en los niveles lipídicos séricos en ratones. MÉTODOS: Se trataron ratones BALB/c hembra maduras experimentales con 100, 300 o 500 mg/kg/día de extracto acuoso de lavanda o agua destilada durante 15 días, mediante inyecciones intraperitoneales. Al finalizar el 15.° día se investigaron los parámetros bioquímicos séricos incluyendo colesterol, triglicéridos, niveles de HDL y LDL, así como la prueba de la función hepática. RESULTADOS: El extracto acuoso de lavanda disminuyó significativamente los niveles séricos de colesterol y LDL. El nivel de colesterol sérico fue inferior en los grupos experimentales de 300 y 500 mg/kg/día, en comparación con el grupo control. En la evaluación de la histología hepática no se observó acumulación de grasa en el grupo experimental, que fue tratado con alimentos de alto contenido en grasa y recibió altas dosis de extracto. CONCLUSIÓN: El extracto de Lavandula officinalis ejerce un efecto hipolipidémico en el grupo estudiado, aunque son precisas más pruebas fitoquímicas y biológicas para determinar el constituyente químico activo responsable de estas actividades


Assuntos
Animais , Feminino , Camundongos , Lavandula , Extratos Vegetais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/veterinária , LDL-Colesterol/administração & dosagem , Camundongos Endogâmicos BALB C , LDL-Colesterol/efeitos dos fármacos , Modelos Animais
13.
Rev Med Liege ; 75(5-6): 386-391, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32496685

RESUMO

Over the past 10 years, meta-analyzes of statins, randomized clinical trials using ezetimibe and anti-PCSK9 antibodies, and Mendelian randomization studies have strengthened the central and causal role of LDL-c in the development of cardiovascular disease. The LDL-c target has been gradually lowered and to date there is no LDL-c threshold below which the benefit of the reduction disappears. The decrease in cardiovascular risk is proportional to the absolute reduction in the concentration of LDL-c regardless of the means by which this reduction is obtained. These data led to the formulation of new guidelines for the management of dyslipidemias relating in particular to a lowering of the LDL-c target and to the complementary use of ezetimibe and anti-PCSK9 antibodies after statins.


Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol , Dislipidemias/tratamento farmacológico , Ezetimiba , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/imunologia
14.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 221-229, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32538775

RESUMO

It can be misleading to think that the new severe acute respiratory syndrome coronavirus (SARS-CoV2) which has a very strong mutation and adaptation capabilities, uses only the angiotensin-converting enzyme II (ACE2) pathway to reach target cells. Despite all the precautions taken, the pandemic attack continues and the rapid increase in the number of deaths suggest that this virus has entered the cell through different pathways and caused damage through different mechanisms. The main reason why the ACE2 pathway comes to the fore in all scientific studies is that this receptor is located at the entry point of basic mechanisms that provide alveolo-capillary homeostasis. SARS-CoV-2 has to use nuclear factor-κB (NF-kB), caveloae, clathrin, lipoxin, serine protease and proteasome pathways in addition to ACE2 to enter the target cell and initiate damage. For this reason, while new drug development studies are continuing, in order to be beneficial to patients in their acute period, it is imperative that we are able to come up with drugs that activate or inhibit these pathways and are currently in clinical use. It is also critical that we adopt these new pathways to the treatment of pregnant women affected by SARS-CoV-2, based on the scientific data we use to treat the general population.


Assuntos
Betacoronavirus/metabolismo , Caveolina 1/metabolismo , Infecções por Coronavirus/metabolismo , Lipoxinas/metabolismo , NF-kappa B/metabolismo , Pneumonia Viral/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , NF-kappa B/antagonistas & inibidores , Uso Off-Label , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Inibidores de Proteassoma/uso terapêutico , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/uso terapêutico , Internalização do Vírus
15.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32519978

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/toxicidade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/toxicidade , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/toxicidade , Interações Medicamentosas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Agregação de Plaquetas/toxicidade , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Vasodilatadores/toxicidade
16.
Arch Biochem Biophys ; 689: 108470, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32592802

RESUMO

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy.


Assuntos
Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Obesidade/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Feminino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Ratos
18.
J Lipid Res ; 61(7): 972-982, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32457038

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.


Assuntos
Anticolesterolemiantes/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Androstenos/uso terapêutico , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Colesterol/metabolismo , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Reposicionamento de Medicamentos/métodos , Humanos , Hidroxicloroquina/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Lisossomos/virologia , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/metabolismo , Doença de Niemann-Pick Tipo C/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Ligação Proteica , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
19.
Lancet Gastroenterol Hepatol ; 5(7): 649-657, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389183

RESUMO

BACKGROUND: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. METHODS: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. INTERPRETATION: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. FUNDING: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ezetimiba/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Canadá/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Vírus de RNA/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Doadores de Tecidos/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Transplantes/virologia , Carga Viral/estatística & dados numéricos
20.
Life Sci ; 254: 117756, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389832

RESUMO

Polydatin (PD) is a monocrystalline metabolite from the underground parts of Polygonum cuspidatum Sieb. et Zucc., a member of the Polygonaceae family, which has been traditionally used in Asian countries as both foodstuffs and medicine. PD, also reckoned as pieceid, 3,4',5-trihydroxystilbene-3-ß-D-glucoside, (E)-piceid, (E)-polydatin, and trans-polydatin. It possesses potent biological activities i.e. analgesic, anti-inflammatory, antidiabetic, anticancer, and anti-atherosclerotic properties. The initial part of this report specifically explains distinct sequential mechanisms underlying the initiation and development of atherosclerotic plaques and later part deals with the pharmacological efficacy of PD in the management of major cardiac event i.e. atherosclerotic cardiovascular diseases (ASCVD) via modulation of a set of molecular mechanisms i.e. antioxidant potential, lipid and lipoprotein metabolism including total cholesterol (TC) and low density lipoprotein (LDL) levels, ß-hydroxy-ß-methyl-glutaryl-CoA reductase (HMG-R) expression and functionality, SIRT signalling, LDL-receptor (LDL-R), LDL oxidation status (Ox-LDL), effects on endothelial cells (ECs), smooth muscle cells (SMCs), macrophage, foam cell formation and plaque stabilization, inflammatory signalling pathways and hypertension. In contrast, one of the major insight into the potential cardioprotective molecular mechanism is the PD-mediated targeting of proprotein convertase subtilisin/kexin type-9 (PCSK-9) and LDL-R pathway, both at transcriptional and protein functional level, which makes it a better alternative therapeutic medicinal candidate to treat hypercholesterolemia, especially for the patients facing inadequate lipid lowering with classical HMG-R inhibitors (statins) and statin intolerance. Finally, to sum up the whole, we concluded that PD may be promoted from alternative to mainstream medicine in targeting risk factors mediated ASCVD.


Assuntos
Aterosclerose/tratamento farmacológico , Glucosídeos/farmacologia , Estilbenos/farmacologia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/metabolismo , Células Endoteliais/metabolismo , Fallopia japonica/metabolismo , Glucosídeos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Lipoproteínas LDL , Placa Aterosclerótica/tratamento farmacológico , Receptores de LDL/metabolismo , Fatores de Risco , Estilbenos/uso terapêutico
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