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https://www.readbyqxmd.com/read/28884604/novel-treatment-options-for-the-management-of-heterozygous-familial-hypercholesterolemia
#1
Georgios Polychronopoulos, Konstantinos Tziomalos
Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe...
September 8, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28857822/impact-of-protease-inhibitors-on-circulating-pcsk9-levels-in-hiv-infected-antiretroviral-na%C3%A3-ve-patients-from-the-anrs-copana-cohort
#2
Franck Boccara, Mathilde Ghislain, Laurence Meyer, Cecile Goujard, Cedric Le May, Corinne Vigouroux, Jean Philippe Bastard, Soraya Fellahi, Jacqueline Capeau, Ariel Cohen, Bertrand Cariou
OBJECTIVE: The study aims to assess the association between proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of low-density lipoprotein cholesterol (LDL-C) homeostasis, and HIV-related dyslipidaemia in a cohort of HIV+ patients under protease inhibitors (PI). METHODS: Plasma PCSK9 levels were measured in 103 HIV-positive patients (HIV+) before and after initiating PI-based antiretroviral therapy (ART), and in 90 HIV-negative controls (HIV-) matched for age and sex...
August 28, 2017: AIDS
https://www.readbyqxmd.com/read/28529918/advances-in-dyslipidemia-management-for-prevention-of-atherosclerosis-pcsk9-monoclonal-antibody-therapy-and-beyond
#3
REVIEW
Nathan D Wong, Paul D Rosenblit, Robert S Greenfield
In 2003, select families with familial hypercholesterolemia were first identified to have gain-of-function mutations for proprotein convertase subtilisin kexin type 9 (PCSK9) followed, in 2006, by the identification of those with lifelong low levels of LDL-C and lowered atherosclerotic cardiovascular disease (ASCVD) risk who had loss-of-function PCSK9 mutations. These discoveries led to the rapid development of PSCK9-targeted monoclonal antibody (PCSK9 mAb) therapies and, in 2015, 2 'fully-humanized' PCSK9 mAbs (alirocumab and evolocumab) were marketed in the United States, Europe, and other countries...
April 2017: Cardiovascular Diagnosis and Therapy
https://www.readbyqxmd.com/read/28190386/high-density-lipoprotein-and-low-density-lipoprotein-therapeutic-approaches-in-acute-coronary-syndromes
#4
Emmanuel Androulakis, Effimia Zacharia, Nikolaos Papageorgiou, Eirini Lioudaki, Dimitris Bertsias, Marietta Charakida, Gerasimos Siasos, Dimitris Tousoulis
BACKGROUND: Low-density lipoprotein cholesterol (LDL), and especially its oxidized form, renders the atherosclerotic plaque vulnerable to rupture in acute coronary syndromes (ACS). On the other hand, high-density lipoprotein (HDL) is considered an anti-atherogenic molecule. The more recent HDL-targeted drugs may prove to be superior to those used before. Indeed, delipidated HDL and HDL mimetics are efficient in increasing HDL levels, while the apoA-I upregulation with RVX-208 appears to offer a clinical benefit which is beyond the HDL related effects...
2017: Current Cardiology Reviews
https://www.readbyqxmd.com/read/28179493/nutritional-and-lipid-modulation-of-pcsk9-effects-on-cardiometabolic-risk-factors
#5
REVIEW
Jacqueline A Krysa, Teik Chye Ooi, Spencer D Proctor, Donna F Vine
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease involved in the regulation of LDL receptor (LDLR) expression and apolipoprotein B lipoprotein cholesterol metabolism. Hepatic PCSK9 protein expression, activity, and secretion have been shown to affect cholesterol homeostasis. An upregulation of hepatic PSCK9 protein leads to increased LDLR degradation, resulting in decreased uptake of apoB lipoproteins and a consequent increase in the plasma concentration of these lipoproteins, including LDL and chylomicron remnants...
April 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/27784735/homozygous-familial-hypercholesterolemia-in-spain-prevalence-and-phenotype-genotype-relationship
#6
Rosa M Sánchez-Hernández, Fernando Civeira, Marianne Stef, Sofía Perez-Calahorra, Fátima Almagro, Nuria Plana, Francisco J Novoa, Pedro Sáenz-Aranzubía, Daniel Mosquera, Cristina Soler, Francisco J Fuentes, Yeray Brito-Casillas, Jose T Real, Francisco Blanco-Vaca, Juan F Ascaso, Miguel Pocovi
BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL protein receptor adaptor 1 (LDLRAP1). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition...
December 2016: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/27620638/novel-therapies-for-familial-hypercholesterolemia
#7
REVIEW
Justin Parizo, Ashish Sarraju, Joshua W Knowles
Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added...
November 2016: Current Treatment Options in Cardiovascular Medicine
https://www.readbyqxmd.com/read/27355907/value-of-improved-lipid-control-in-patients-at-high-risk-for-adverse-cardiac-events
#8
Anupam B Jena, Daniel M Blumenthal, Warren Stevens, Jacquelyn W Chou, Thanh G N Ton, Dana P Goldman
OBJECTIVES: Lipid-lowering therapy (LLT) is suboptimally used in patients with hyperlipidemia in the 2 highest statin benefit groups (SBGs), as categorized by the American College of Cardiology and the American Heart Association. This study estimated the social value of reducing low-density lipoprotein cholesterol (LDL-C) levels by 50% for patients in SBGs 1 and 2 who have been treated with standard LLT but have not reached LDL-C goal, as well as the potential value of PCSK9 inhibitors for patients in these groups...
June 1, 2016: American Journal of Managed Care
https://www.readbyqxmd.com/read/27352986/proprotein-convertase-subtilisin-kexin-type-9-pcsk9-inhibitors-present-perspectives-and-future-horizons
#9
REVIEW
K Yadav, M Sharma, K C Ferdinand
AIMS: Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition. BACKGROUND: Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality...
October 2016: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
https://www.readbyqxmd.com/read/27115873/alirocumab-a-therapeutic-human-antibody-to-pcsk9-does-not-affect-cd81-levels-or-hepatitis-c-virus-entry-and-replication-into-hepatocytes
#10
Aarti Ramanathan, Viktoria Gusarova, Neil Stahl, Anne Gurnett-Bander, Christos A Kyratsous
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PSCK9) is secreted mainly from the liver and binds to the low-density lipoprotein receptor (LDLR), reducing LDLR availability and thus resulting in an increase in LDL-cholesterol. While the LDLR has been implicated in the cell entry process of the hepatitis C virus (HCV), overexpression of an artificial non-secreted, cell membrane-bound form of PCSK9 has also been shown to reduce surface expression of CD81, a major component of the HCV entry complex, leading to concerns that pharmacological inhibition of PCSK9 may increase susceptibility to HCV infection by increasing either CD81 or LDLR availability...
2016: PloS One
https://www.readbyqxmd.com/read/27002618/familial-hypercholesterolaemia-in-the-era-of-genetic-testing
#11
REVIEW
D P Hughes, A Viljoen, A S Wierzbicki
Familial hypercholesterolaemia (FH) is a relatively common autosomal dominant genetic condition leading to premature ischaemic vascular disease and mortality if left untreated. Currently, a universal consensus on the diagnostic criteria of FH does not exist but the diagnosis of FH largely relies on the evaluation of low density lipoprotein-cholesterol (LDL-C) levels, a careful documentation of family history, and the identification of clinical features. Diagnosis based purely on lipid levels remains common but there are several limitations to this method of diagnosis both practically and in the proportion of false-negatives and false-positives detected, resulting in substantial under-diagnosis of FH...
May 2016: Current Cardiology Reports
https://www.readbyqxmd.com/read/26908111/lipids-lipoproteins-and-cardiovascular-disease-clinical-pharmacology-now-and-in-the-future
#12
REVIEW
Alan Chait, Robert H Eckel
CONTEXT: While substantial benefit has accrued with respect to prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) since the advent of statin therapy, much remains unknown and there is considerable need to address residual risk beyond statins. Moreover, many individuals are unable to tolerate statins. EVIDENCE ACQUISITION: As a result of several recent clinical trials and publications describing early Phase 1-3 clinical trials, the authors briefly discuss the current situation regarding pharmacological management for the prevention and treatment of individuals with disorders of lipid and lipoprotein metabolism, outline some of the unanswered questions, and speculate on where we might expect to be in 5-10 years...
March 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/25967607/effects-of-hedan-tablet-on-lipid-profile-proprotein-convertase-subtilisin-kexin-type-9-and-high-density-lipoprotein-subfractions-in-patients-with-hyperlipidemia-a-primary-study
#13
RANDOMIZED CONTROLLED TRIAL
Rui-Xia Xu, Na-Qiong Wu, Sha Li, Yan Zhang, Xiao-Lin Li, Yuan-Lin Guo, Cheng-Gang Zhu, Geng Liu, Qian Dong, Jian-Jun Li
OBJECTIVE: To investigate the effects of Hedan Tablet () on serum lipid profile, proprotein convertase subtilisin/kexin type 9 (PSCK9) and high-density lipoprotein (HDL) subfractions in patients with hyperlipidemia. METHODS: Thirty-seven patients with hyperlipidemia were randomized to treatment with Hedan Tablet 4.38 g/day as Hedan group (18 cases) or placebo (19 cases) as control group for 8 weeks. The lipid profile, PCSK9 and HDL subfractions were determined at day 0 and week 8 in both groups respectively...
September 2016: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/25172631/thyroid-hormone-reduces-pcsk9-and-stimulates-bile-acid-synthesis-in-humans
#14
Ylva Bonde, Olof Breuer, Dieter Lütjohann, Stefan Sjöberg, Bo Angelin, Mats Rudling
Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome...
November 2014: Journal of Lipid Research
https://www.readbyqxmd.com/read/24857672/investigational-therapies-for-the-treatment-of-atherosclerosis
#15
REVIEW
Gerald H Tomkin, Daphne Owens
INTRODUCTION: There is great need for new drugs to reduce cholesterol in those patients who have not achieved target levels on statins as well as those who are statin intolerant. AREAS COVERED: In this review, the authors discuss the new antisense oligotide inhibitor of apo B synthesis, mipomersen; pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and cholesterol ester transport protein (CETP) inhibitors. Furthermore, the authors discuss cholesterol absorption and chylomicron synthesis with an emphasis on microsomal triglyceride transfer protein (MTP) inhibitors, which inhibit very-low-density lipoprotein production in the liver and chylomicron inhibition in the intestine...
October 2014: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/24701672/-pcsk9-inhibitors-emerging-treatment-to-lower-cholesterol
#16
B Gencer, N Rodondi, F Mach
The achievement rate of recommended low-density lipoprotein cholesterol (LDL-C) targets of < 1.8 mmol/l for secondary prevention in very high risk patients is difficult. Observational studies reported that loss of function mutation of the PCS9 was associated with LDL-C decrease level and reduction of cardiovascular events. Monoclonal antibodies to PCSK9 (REGN727 and AMG 145, PSCK9 inhibitors) have been tested in clinical studies of phase I and II and showed LDL-C level reduction of 60-70% compared to placebo...
March 5, 2014: Revue Médicale Suisse
https://www.readbyqxmd.com/read/23889692/current-phase-ii-proprotein-convertase-subtilisin-kexin-9-inhibitor-therapies-for-dyslipidemia
#17
REVIEW
Paul Lee, Robert A Hegele
INTRODUCTION: Reduction of plasma low-density lipoprotein (LDL) cholesterol concentration with statins reduces adverse cardiovascular outcomes. However, lack of efficacy and intolerance of statins in many patients requires alternative treatments. Currently available non-statin alternatives include bile acid sequestrants, the cholesterol absorption inhibitor ezetimibe, niacin-based preparations and fibrates; however, each of these has limitations. Newer agents for LDL cholesterol reduction include the cholesterol ester transfer protein inhibitors, the microsomal triglyceride transfer protein inhibitor lomitapide, the apolipoprotein B antisense oligonucleotide mipomersen and several molecules that inhibit or interfere with proprotein convertase subtilisin/kexin 9 (PCSK9)...
November 2013: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/23652470/pcsk9-inhibitors
#18
REVIEW
Michel Farnier
PURPOSE OF REVIEW: To summarize the therapeutic strategies to inhibit PCSK9 and to describe the main results obtained in phase I and II trials with monoclonal antibodies targeting PCSK9. RECENT FINDINGS: Among the various approaches for PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDL receptor by monoclonal antibodies. Promising preclinical studies have also been reported with other strategies, including inhibition of PCSK9 synthesis by gene silencing agents...
June 2013: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/23433768/comparison-of-effects-of-pitavastatin-versus-pravastatin-on-serum-proprotein-convertase-subtilisin-kexin-type-9-levels-in-statin-naive-patients-with-coronary-artery-disease
#19
RANDOMIZED CONTROLLED TRIAL
Tsuyoshi Nozue, Hiroaki Hattori, Mitsuaki Ishihara, Tadao Iwasaki, Tsutomu Hirano, Masa-aki Kawashiri, Masakazu Yamagishi, Ichiro Michishita
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein cholesterol levels. Although statins increase serum PCSK9 levels, the effects of different types of statins on the serum PCSK9 levels have not been examined in detail. The purpose of the present study was to compare the effects of pitavastatin versus pravastatin on the serum PCSK9 levels. A total of 164 patients with coronary artery disease who were not receiving lipid-lowering therapy were randomly assigned to receive either 4 mg/day of pitavastatin (intensive lipid-lowering therapy) or 20 mg/day of pravastatin (moderate lipid-lowering therapy)...
May 15, 2013: American Journal of Cardiology
https://www.readbyqxmd.com/read/23371064/potential-of-proprotein-convertase-subtilisin-kexin-type-9-based-therapeutics
#20
REVIEW
Evan A Stein, Gary D Swergold
The link between proprotein convertase subtilisin/kexin type 9 (PCSK9) and cholesterol metabolism was established only in 2003 when genetic mapping and positional cloning in patients with autosomal dominant hypercholesterolemia in which linkage to the loci coding for the LDL receptor and apolipoprotein B had been excluded identified the genetic defect missense as mutations in PCSK9, a protein/enzyme previously unknown to be related to lipid metabolism. Laboratory-based investigations confirmed that these were gain-of-function mutations...
March 2013: Current Atherosclerosis Reports
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