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[PMID]:28468788
[Au] Autor:Ruscica M; Ferri N; Fogacci F; Rosticci M; Botta M; Marchiano S; Magni P; D'Addato S; Giovannini M; Borghi C; Cicero AFG; Brisighella Heart Study Group
[Ad] Endereço:Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
[Ti] Título:Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study.
[So] Source:J Am Heart Assoc;6(5), 2017 May 03.
[Is] ISSN:2047-9980
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulating levels are significantly associated with an increased risk of cardiovascular events. This study aimed to evaluate the relationship between circulating levels of PCSK9 and arterial stiffness, an early instrumental biomarker of cardiovascular disease risk, in a large sample of overall healthy participants. METHODS AND RESULTS: From the historical cohort of the Brisighella Heart Study, after exclusion of active smokers, participants in secondary prevention for cardiovascular disease, and patients in treatment with statins or vasodilating agents, we selected 227 premenopausal women and 193 age-matched men and 460 postmenopausal women and 416 age-matched men. In these participants, we evaluated the correlation between PCSK9 plasma circulating levels and pulse wave velocity. Postmenopausal women showed higher PCSK9 levels (309.9±84.1 ng/mL) compared with the other groups ( <0.001). Older men had significant higher levels than younger men (283.2±75.6 versus 260.9±80.4 ng/mL; =0.008). In the whole sample, pulse wave velocity was predicted mainly by age (B=0.116, 95% CI 0.96-0.127, <0.001), PCSK9 (B=0.014, 95% CI 0.011-0.016, <0.001), and serum uric acid (B=0.313, 95% CI 0.024-0.391, =0.026). Physical activity, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and estimated glomerular filtration rate were not associated with pulse wave velocity ( >0.05).By considering the subgroups described, age and PCSK9 levels were mainly associated with pulse wave velocity, which also correlated with serum uric acid in postmenopausal women. CONCLUSIONS: In the Brisighella Heart Study cohort, circulating PCSK9 is significantly related to arterial stiffness, independent of sex and menopausal status in women.
[Mh] Termos MeSH primário: Doenças Cardiovasculares/enzimologia
Doenças Cardiovasculares/fisiopatologia
Pró-Proteína Convertase 9/sangue
Rigidez Vascular
[Mh] Termos MeSH secundário: Adulto
Fatores Etários
Idoso
Biomarcadores/sangue
Doenças Cardiovasculares/sangue
Doenças Cardiovasculares/diagnóstico
Feminino
Seres Humanos
Itália/epidemiologia
Estudos Longitudinais
Masculino
Meia-Idade
Pós-Menopausa/sangue
Análise de Onda de Pulso
Fatores de Risco
Fatores Sexuais
Regulação para Cima
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:29419393
[Au] Autor:Ford TJ; Rocchiccioli P
[Ad] Endereço:British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
[Ti] Título:A keen eye for risk.
[So] Source:BMJ;360:j5884, 2018 02 01.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Arco Senil/diagnóstico
Doenças da Córnea/diagnóstico
Doença da Artéria Coronariana/diagnóstico
Hiperlipoproteinemia Tipo II/diagnóstico
Receptores de LDL/genética
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/uso terapêutico
Anticolesterolemiantes/administração & dosagem
Anticolesterolemiantes/uso terapêutico
Arco Senil/etiologia
Colesterol/sangue
Doenças da Córnea/etiologia
Doença da Artéria Coronariana/complicações
Doença da Artéria Coronariana/etiologia
Feminino
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Hiperlipoproteinemia Tipo II/sangue
Hiperlipoproteinemia Tipo II/tratamento farmacológico
Hiperlipoproteinemia Tipo II/genética
Injeções Subcutâneas
Meia-Idade
Mutação
Pró-Proteína Convertase 9/antagonistas & inibidores
Xantomatose/diagnóstico
Xantomatose/etiologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Anticholesteremic Agents); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Receptors, LDL); 97C5T2UQ7J (Cholesterol); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); LKC0U3A8NJ (evolocumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180209
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.j5884


  3 / 1151 MEDLINE  
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[PMID]:27771416
[Au] Autor:Cronjé HT; Nienaber-Rousseau C; Zandberg L; Chikowore T; de Lange Z; van Zyl T; Pieters M
[Ad] Endereço:Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa.
[Ti] Título:Candidate gene analysis of the fibrinogen phenotype reveals the importance of polygenic co-regulation.
[So] Source:Matrix Biol;60-61:16-26, 2017 Jul.
[Is] ISSN:1569-1802
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Fibrinogen and its functional aspects have been linked to cardiovascular disease. There is vast discrepancy between the heritability of fibrinogen concentrations observed in twin studies and the heritability uncovered by genome wide association studies. We postulate that some of the missing heritability might be explained by the pleiotropic and polygenic co-regulation of fibrinogen through multiple targeted genes, apart from the fibrinogen genes themselves. To this end we investigated single nucleotide polymorphisms (SNPs) in genes coding for phenotypes associated with total and γ' fibrinogen concentrations and clot properties. Their individual and accumulative associations with the fibrinogen variables were explored together with possible co-regulatory processes as a result of the gain and loss of transcription factor binding sites (TFBS). Seventy-eight SNPs spanning the APOB, APOE, CBS, CRP, F13A1, FGA, FGB, FGG, LDL-R, MTHFR, MTR, PCSK-9 and SERPINE-1 genes were included in the final analysis. A novel PCSK-9 SNP (rs369066144) was identified in this population, which associated significantly (p=0.04) with clot lysis time (CLT). Apart from SNPs in the fibrinogen (FGA, FGB and FGG) and FXIII (F13A1) genes, the fibrinogen phenotypes were also associated with SNPs in genes playing a role in lipid homeostasis (LDL-R, PCSK-9) together with CBS and CRP polymorphisms (particularly, CRP-rs3093068). The genetic risk scores, presenting accumulative genetic risk, were significantly associated (p≤0.007) with total and γ' fibrinogen concentrations, lag time, slope and CLT, highlighting the importance of a polygenetic approach in determining complex phenotypes. SNPs significantly associated with the fibrinogen phenotypes, resulted in a total of 75 TFBS changes, of which 35 resulted in a loss and 40 in a gain of TFBS. In terms of co-regulation, V$IRF4.02, V$E2FF and V$HIFF were of particular importance. The investigation into TFBS provided valuable insight as to how sequence divergences in seemingly unrelated genes can result in transcriptional co-regulation of the fibrinogen phenotypes. The observed associations between the identified SNPs and the fibrinogen phenotypes therefore do not imply direct effects on cardiovascular disease outcomes, but may prove useful in explaining more of the genetic regulation of the investigated fibrinogen phenotypes.
[Mh] Termos MeSH primário: Coagulação Sanguínea/genética
Fibrinogênios Anormais/genética
Regulação da Expressão Gênica
Pleiotropia Genética
Polimorfismo de Nucleotídeo Único
Transcrição Genética
[Mh] Termos MeSH secundário: Adulto
Apolipoproteínas/genética
Apolipoproteínas/metabolismo
Sítios de Ligação
Proteína C-Reativa/genética
Proteína C-Reativa/metabolismo
Estudos Transversais
Cistationina beta-Sintase/genética
Cistationina beta-Sintase/metabolismo
Feminino
Tempo de Lise do Coágulo de Fibrina
Fibrinogênios Anormais/metabolismo
Perfilação da Expressão Gênica
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Meia-Idade
Pró-Proteína Convertase 9/genética
Pró-Proteína Convertase 9/metabolismo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins); 0 (Fibrinogens, Abnormal); 0 (fibrinogen gamma'); 9007-41-4 (C-Reactive Protein); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); EC 4.2.1.22 (Cystathionine beta-Synthase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  4 / 1151 MEDLINE  
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[PMID]:29241886
[Au] Autor:Cheng WH; Gaudette É; Goldman DP
[Ad] Endereço:Schaeffer Center for Health Policy and Economics, University of Southern California Price School and School of Pharmacy, Los Angeles, CA, USA. Electronic address: weihanch@usc.edu.
[Ti] Título:PCSK9 Inhibitors Show Value for Patients and the US Health Care System.
[So] Source:Value Health;20(10):1270-1278, 2017 12.
[Is] ISSN:1524-4733
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the US Food and Drug Administration (FDA) as cholesterol-lowering therapies for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease. OBJECTIVES: To estimate the long-term health and economic value of PCSK9 inhibitors for Americans (51 years and older). METHODS: We conducted simulations using the Future Elderly Model, an established dynamic microsimulation model to project the lifetime outcomes for the US population aged 51 years and older. Health effects estimates and confidence intervals from published meta-analysis studies were used to project changes in life expectancy, quality-adjusted life-years, and lifetime medical spending resulting from the use of PCSK9 inhibitors. We considered two treatment scenarios: 1) current FDA eligibility and 2) an extended eligibility scenario that includes patients with no pre-existing cardiovascular disease but at high risk. We assumed that the price of PCSK9 inhibitors was discounted by 35% in the first 12 years and by 57% thereafter, with gradual uptake of the drug in eligible populations. RESULTS: Use of PCSK9 inhibitors by individuals covered by current FDA approval would extend life expectancy at the age of 51 years by an estimated 1.1 years and would yield a lifetime net value of $5800 per person. If use was extended to those at high risk for cardiovascular disease, PCSK9 inhibitors would generate a lifetime net benefit of $14,100 per person. CONCLUSIONS: Expanded access to PCSK9 inhibitors would offer positive long-term net value for patients and the US health care system at the current discounted prices.
[Mh] Termos MeSH primário: Anticolesterolemiantes/uso terapêutico
Aterosclerose/tratamento farmacológico
Simulação por Computador
Hiperlipoproteinemia Tipo II/tratamento farmacológico
Pró-Proteína Convertase 9/antagonistas & inibidores
[Mh] Termos MeSH secundário: Idoso
Anticolesterolemiantes/economia
Anticolesterolemiantes/farmacologia
Aterosclerose/economia
Análise Custo-Benefício
Assistência à Saúde/economia
Aprovação de Drogas
Definição da Elegibilidade
Seres Humanos
Hiperlipoproteinemia Tipo II/economia
Expectativa de Vida
Meia-Idade
Anos de Vida Ajustados por Qualidade de Vida
Estados Unidos
United States Food and Drug Administration
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Anticholesteremic Agents); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


  5 / 1151 MEDLINE  
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[PMID]:29176657
[Au] Autor:Agrawal S; Zaritsky JJ; Fornoni A; Smoyer WE
[Ad] Endereço:Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, 700 Children's Drive, W303, Columbus, Ohio 43205, USA.
[Ti] Título:Dyslipidaemia in nephrotic syndrome: mechanisms and treatment.
[So] Source:Nat Rev Nephrol;14(1):57-70, 2018 Jan.
[Is] ISSN:1759-507X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently-developed anti-PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.
[Mh] Termos MeSH primário: Anticolesterolemiantes/uso terapêutico
Dislipidemias/tratamento farmacológico
Ácidos Fíbricos/uso terapêutico
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Síndrome Nefrótica/metabolismo
[Mh] Termos MeSH secundário: Colesterol/metabolismo
HDL-Colesterol/metabolismo
VLDL-Colesterol/metabolismo
Dislipidemias/complicações
Dislipidemias/metabolismo
Ezetimiba/uso terapêutico
Seres Humanos
Hipolipemiantes/uso terapêutico
Lipase/metabolismo
Lipase Lipoproteica/metabolismo
Lipoproteínas/metabolismo
Síndrome Nefrótica/complicações
Niacina/uso terapêutico
Pró-Proteína Convertase 9/metabolismo
Triglicerídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, VLDL); 0 (Fibric Acids); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Hypolipidemic Agents); 0 (Lipoproteins); 0 (Triglycerides); 0 (lipoprotein cholesterol); 2679MF687A (Niacin); 97C5T2UQ7J (Cholesterol); EC 3.1.1.3 (Lipase); EC 3.1.1.3 (hepatic lipase, human); EC 3.1.1.34 (Lipoprotein Lipase); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); EOR26LQQ24 (Ezetimibe)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180117
[Lr] Data última revisão:
180117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1038/nrneph.2017.155


  6 / 1151 MEDLINE  
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[PMID]:29310364
[Au] Autor:Qiu C; Zhou Q; Li X; Zhang Z; Zeng P; Cao Z; Pan B; Li X; Chen AF
[Ad] Endereço:Xiangya school of Pharmaceutical Sciences, Central South University, Changsha.
[Ti] Título:High circulating proprotein convertase subtilisin/Kexin type 9 concentration associates with cardiovascular risk: A meta-analysis of cohort studies.
[So] Source:Medicine (Baltimore);96(48):e8848, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Whether the baseline circulating proprotein convertase subtilisin/Kexin type 9 (PCSK9) concentration associates with cardiovascular risk remains uncertain. This study aimed to investigate the predictive value of circulating PCSK9 in cardiovascular risk prediction.Relevant studies were searched through the MEDLINE, EMBASE, and Cochrane Library databases. The relative risk (RR) and 95% confidence interval (CI) were pooled to evaluate the association between the circulating PCSK9 concentration and cardiovascular risk. Dose-response meta-analysis was also performed in this study.A total of 11 cohort studies with 13,761 participants were included. The RR for cardiovascular risk was 1.25 (95% CI: 1.14-1.38, P < .001, I = 25%) while compared highest to lowest PCSK9 concentration. Subgroup meta-analysis, which sorted by ethnicity, base risk characteristic, and follow-up time, presented consistent results that there was a pronounced association between highest PCSK9 concentration and cardiovascular risk, such relationship was not significant in the statin-taking subjects. Seven studies were included in dose-response meta-analysis, and a nonlinear association between PCSK9 concentration and cardiovascular risk was observed [(χ test for nonlinearity = 6.7, (df = 2), P = .036].This study suggests that high circulating PCSK9 concentration associates with significantly increased cardiovascular risk, and demonstrates for the first time that it is a nonlinear dose-response association between circulating PCSK9 concentration and cardiovascular risk. These results provide the evidence that PCSK9 is an independent risk factor beyond the traditional cardiovascular risk factors and indicates a potential role of PCSK9 measurement for medical decisions. The clinical value of PCSK9 measurement and the identification of risk threshold should be confirmed in appropriately designed clinical trials.
[Mh] Termos MeSH primário: Doenças Cardiovasculares/sangue
Pró-Proteína Convertase 9/sangue
[Mh] Termos MeSH secundário: Seres Humanos
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180115
[Lr] Data última revisão:
180115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008848


  7 / 1151 MEDLINE  
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[PMID]:28461454
[Au] Autor:Eisenga MF; Zelle DM; Sloan JH; Gaillard CAJM; Bakker SJL; Dullaart RPF
[Ad] Endereço:Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands m.f.eisenga@umcg.nl.
[Ti] Título:High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients.
[So] Source:Diabetes Care;40(7):894-901, 2017 07.
[Is] ISSN:1935-5548
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: New-onset diabetes after transplantation (NODAT) is a major complication in renal transplant recipients (RTRs). Cholesterol metabolism has been linked to diabetes development. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucial in LDL receptor regulation. Its association with NODAT is unknown. We prospectively determined the association between serum PCSK9 levels and NODAT development and then with all-cause mortality, cardiovascular mortality, and renal graft failure. RESEARCH DESIGN AND METHODS: In a university setting, nondiabetic RTRs recruited between 2001 and 2003 with a functional graft for ≥1 year were eligible. Serum PCSK9 was measured by ELISA. Cox proportional hazards analysis was used to assess the association of PCSK9 with the development of NODAT, all-cause mortality, cardiovascular mortality, and graft failure. RESULTS: In 453 RTRs (age 51 ± 12 years, 56% male; 6.1 [2.7-11.7] years after transplantation), serum PCSK9 was 107.1 ± 43.4 µg/L. During a median follow-up of 10 years, 70 RTRs developed NODAT, 123 died, and 59 developed graft failure. NODAT occurred more frequently in the upper PCSK9 tertile (23%) versus the lowest two PCSK9 tertiles (12%; < 0.001). In crude Cox regression analyses, PCSK9 was significantly associated with development of NODAT (hazard ratio 1.34 [95% CI 1.10-1.63]) per SD change ( = 0.004). This association remained independent of adjustment for potential confounders, including statin use. PCSK9 was not associated with all-cause mortality, cardiovascular mortality, or graft failure. CONCLUSIONS: Circulating PCSK9 is associated with NODAT in RTRs. The PCSK9 pathway may contribute to the pathogenesis of NODAT.
[Mh] Termos MeSH primário: Diabetes Mellitus/sangue
Transplante de Rim/efeitos adversos
Pró-Proteína Convertase 9/sangue
[Mh] Termos MeSH secundário: Adulto
LDL-Colesterol/sangue
Diabetes Mellitus/etiologia
Feminino
Seguimentos
Seres Humanos
Masculino
Meia-Idade
Modelos de Riscos Proporcionais
Estudos Prospectivos
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholesterol, LDL); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.2337/dc16-2258


  8 / 1151 MEDLINE  
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[PMID]:29231064
[Au] Autor:Cicero AFG; Bove M; Borghi C
[Ad] Endereço:a Medical and Surgical Sciences Department , University of Bologna , Bologna Italy.
[Ti] Título:Pharmacokinetics, pharmacodynamics and clinical efficacy of non-statin treatments for hypercholesterolemia.
[So] Source:Expert Opin Drug Metab Toxicol;14(1):9-15, 2018 Jan.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Hypercholesterolemia is the main modifiable risk factor for atherosclerosis progression and cardiovascular disease (CVD) development. Its pharmacological management is usually based on the prescription of statins, that in some cases are not however fully effective to reach the desired Low-Density-Lipoproteins cholesterol (LDL-C) target, or are not tolerated by patients due to side effects. Areas covered: This manuscript summarizes the basic properties of the emerging new classes of lipid-lowering drugs such as ezetimibe, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, and Microsomal Triglyceride Transfer Protein (MTP) inhibitors, also citing new drugs in development. Our aim is to describe the main pharmacodynamic and pharmacokinetic characteristics, the available efficacy, tolerability and safety data obtained in randomized clinical trials where these drugs were tested. Expert opinion: Non-statin lipid-lowering drugs can be considered an excellent strategy to reduce the residual CV risk, also represented by non-target LDL-C values and high lipoprotein(a) serum levels. In particular, the approved PCSK9 inhibitors (Evolocumab and Alirocumab) have been very effective in optimizing plasma LDL-C values and reducing CV event risk.
[Mh] Termos MeSH primário: Anticolesterolemiantes/administração & dosagem
Desenho de Drogas
Hipercolesterolemia/tratamento farmacológico
[Mh] Termos MeSH secundário: Anticolesterolemiantes/efeitos adversos
Anticolesterolemiantes/farmacologia
Doenças Cardiovasculares/etiologia
Doenças Cardiovasculares/prevenção & controle
LDL-Colesterol/sangue
Seres Humanos
Hipercolesterolemia/fisiopatologia
Pró-Proteína Convertase 9/antagonistas & inibidores
Ensaios Clínicos Controlados Aleatórios como Assunto
Fatores de Risco
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Cholesterol, LDL); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1416094


  9 / 1151 MEDLINE  
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[PMID]:29235977
[Au] Autor:Li Z; Liu Q
[Ad] Endereço:1​VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
[Ti] Título:Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A.
[So] Source:J Gen Virol;99(1):44-61, 2018 Jan.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease actively involved in regulating lipid homeostasis. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, the underlying mechanisms have not been thoroughly characterized. Moreover, whether PCSK9 regulates HCV translation and assembly/secretion has not been determined. We therefore further studied the effects of PCSK9 on the HCV life cycle. We showed that PCSK9 did not affect HCV translation or assembly/secretion. Overexpression of PCSK9 inhibited HCV replication in HCV genomic replicon cells in a dose-dependent manner and after cell culture-derived HCV (HCVcc) infection. Knocking down PCSK9 increased HCV replication. The gain-of-function (D374Y) or loss-of-function (Δaa. 31-52) PCSK9 mutants for low-density lipoprotein receptor (LDLR) degradation had no effect on HCV replication, suggesting that HCV replication inhibition by PCSK9 was not due to LDLR degradation. The uncleaved ProPCSK9, but not cleaved PCSK9, down-regulated HCV replication, suggesting that the auto-cleavage of PCSK9 affected HCV replication. We also found that PCSK9 interacted with NS5A through NS5A aa. 95-215, and this region played an important role in NS5A dimerization, NS5A-RNA binding and was essential for HCV replication. More importantly, NS5A dimerization and NS5A-RNA binding were suppressed by PCSK9 upon interaction. These results suggested that PCSK9 inhibited HCV replication through interaction with NS5A. Our study should help optimize anti-HCV treatment regimen in patients with abnormal lipid profiles.
[Mh] Termos MeSH primário: Hepacivirus/metabolismo
Hepatócitos/metabolismo
Interações Hospedeiro-Patógeno
Pró-Proteína Convertase 9/metabolismo
Proteínas não Estruturais Virais/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Sítios de Ligação
Linhagem Celular Tumoral
Regulação da Expressão Gênica
Células HEK293
Hepacivirus/genética
Hepacivirus/crescimento & desenvolvimento
Hepatócitos/virologia
Seres Humanos
Mutação
Plasmídeos/química
Plasmídeos/metabolismo
Pró-Proteína Convertase 9/antagonistas & inibidores
Pró-Proteína Convertase 9/genética
Ligação Proteica
Proteólise
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Receptores de LDL/genética
Receptores de LDL/metabolismo
Transdução de Sinais
Transfecção
Proteínas não Estruturais Virais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LDLR protein, human); 0 (NS-5 protein, hepatitis C virus); 0 (RNA, Small Interfering); 0 (Receptors, LDL); 0 (Viral Nonstructural Proteins); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1099/jgv.0.000987


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[PMID]:28459663
[Au] Autor:Eslami SM; Nikfar S; Ghasemi M; Abdollahi M
[Ad] Endereço:Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials.
[So] Source:J Pharm Pharm Sci;20:81-96, 2017.
[Is] ISSN:1482-1826
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C  by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
HDL-Colesterol/antagonistas & inibidores
LDL-Colesterol/antagonistas & inibidores
Hiperlipoproteinemia Tipo II/tratamento farmacológico
Pró-Proteína Convertase 9/antagonistas & inibidores
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/química
HDL-Colesterol/química
HDL-Colesterol/metabolismo
LDL-Colesterol/química
LDL-Colesterol/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Hiperlipoproteinemia Tipo II/metabolismo
Modelos Moleculares
Pró-Proteína Convertase 9/metabolismo
Ensaios Clínicos Controlados Aleatórios como Assunto
Inibidores de Serino Proteinase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 0 (Serine Proteinase Inhibitors); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); LKC0U3A8NJ (evolocumab)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171222
[Lr] Data última revisão:
171222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.18433/J36C8N



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