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12:28 EST 18th December 2018 | BioPortfolio

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Showing "More Positives PCSK9 inhibitors Hypothesis" PubMed Articles 1–25 of 6,300+

Hyperlipidemia: What role do PCSK9 inhibitors play?

PCSK9 inhibitors are a new and safe option of lowering LDL cholesterol. This article summarizes current recommendations for the use of PCSK9 inhibitors. Statins and ezetimibe are still the basis of cholesterol-lowering therapy. Through their use, the largest proportion of patients can be adequately treated. PCSK9 inhibitors should be used in patients at very high cardiovascular risk if, despite the maximum tolerated statin/ezetimibe therapy, an LDL-C reduction of more than 50 % would be needed to achieve ...

Are PCSK9 Inhibitors Cost Effective?

The objective of this study was to review available health economic evaluations of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. These drugs reduce low-density lipid cholesterol levels and cardiovascular risk, but their cost effectiveness has been questioned. We searched Medline and Embase for economic evaluations in any language at any time. Studies were included if they analysed any PCSK9 inhibitor compared with either statin alone or in combination with ezetimibe or any other therapy ...

PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety.

Low-density lipoprotein (LDL) receptors on the surface of liver hepatocytes are the primary way that humans regulate serum LDL cholesterol levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol (LDL-C) by causing the destruction of LDL receptors. Less LDL receptors result in increased LDL-C in the bloodstream but inhibiting or binding the circulating PCSK9 results in increased LDL receptors with the resultant decrease in serum LD...

PCSK9 inhibitors for prevention of atherosclerotic cardiovascular disease.

The discovery of proprotein convertase subtilisin kexin-type 9 (PCSK9) and the development of inhibitors of PCSK9 function appear to mark an epochal advance in clinical lipidology. PCSK9 is a circulating protein that binds to low-density lipoprotein (LDL) receptors and facilitates their lysosomal degradation following internalization in cells. Blocking PCSK9 thus increases the recycling of LDL receptors and results in more receptors on the cell surface, particularly in the liver, thereby lowering LDL levels...

Key aspects of PCSK9 inhibition beyond LDL lowering.

Our primary objective is to review the most recent findings on the biology of PCSK9 and on two key aspects of PCSK9 inhibition beyond LDL control of great clinical relevance: the regulation of lipoprotein (a) circulating levels by PCSK9 inhibitors and the putative diabetogenic effects of these novel therapies.

Small molecules as inhibitors of PCSK9: Current status and future challenges.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were appro...

Economic Evaluation of the PCSK9 Inhibitors in Prevention of the Cardiovascular Diseases.

This review aims to explore and summarize the current literature on the cardiovascular disease (CVD) healthcare burden and determine the cost-effectiveness of the PCSK9 inhibitors.

PCSK9 inhibitors and LDL reduction: pharmacology, clinical implications and future perspectives.

PCSK9 inhibitors are monoclonal antibodies to proprotein convertase-subtilisin/kexin type 9 which significantly reduce LDL cholesterol concentration in vivo by inhibiting degradation of the LDL receptor in hepatocytes. The introduction of PCSK9 inhibitors heralded a new era of intensive LDL-C reduction with LDL-C concentrations lowered below levels ever thought possible with conventional treatments such as statins. With their introduction considerations regarding cost, clinical outcomes and long-term safety...

Adverse events associated with PCSK9 inhibitors: A real-world experience.

In randomized clinical trials (RCTs) pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitors showed a favorable safety profile, however "real-world" data on adverse events (AEs) is scarce. Three datasets, a hospital registry (n=164) and two Pharmacovigilance databases, Lareb (n=149) and VigiLyze (n=15,554), reporting AEs attributed to PCSK9 inhibitors (alirocumab or evolocumab) prescribed in clinical practice were analyzed. In the hospital registry 41.5% of the patients reported any AE, most often inje...

Proprotein convertase subtilisin/kexin type 9 inhibits interferon β expression through interacting with ATF-2.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism. A mutual interplay of lipid homeostasis and innate immune system has been increasingly recognized. We, therefore, studied the effect of PCSK9 on interferon (IFN) β expression. We show that PCSK9 decreases IFNβ promoter/enhancer activity, mRNA and protein levels, and its downstream 2',5'-oligoadenylate synthetase-1 mRNA level. ProPCSK9, but not the cleaved PCSK9, down-regulates IFNβ promoter/enhancer activity. Moreover, PCSK...

A single domain antibody against the Cys- and His-rich domain of PCSK9 and evolocumab exhibit different inhibition mechanisms in humanized PCSK9 mice.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that binds and escorts the low density lipoprotein receptor (LDLR) into the lysosomal degradation pathway. Prescribed monoclonal antibodies (mAbs) against PCSK9 prevent its binding to the LDLR, and result in ~60% lower LDL cholesterol (LDLc) levels. Although efficient, mAbs are expensive. Hence other PCSK9 inhibitors are needed. For screening purpose, we developed C57BL/6J mice expressing the human PCSK9 gene under the control of it...

Lipid-lowering Therapy with PCSK9-inhibitors in the Real World Setting: Two-year Experience of a Regional Lipid clinic.

PCSK9 inhibitors (PCSK9i) effectively lower cholesterol levels in randomized trials with reduction in cardiovascular outcomes and favorable safety profile. However, the access to PCSK9i is limited due to high cost and data regarding the use of PCSK9i in real-world practice is limited.

Role of PCSK9 in lipid metabolism and atherosclerosis.

Elevated plasma low-density lipoprotein cholesterol (LDL-C) is an important risk factor for cardiovascular diseases. Statins are the most widely used therapy for patients with hyperlipidemia. However, a significant residual cardiovascular risk remains in some patients even after maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new pharmacologically therapeutic target for decreasing LDL-C. PCSK9 reduces LDL intake from circulation by enhancing LDLR degradation a...

Potentiation of psoriasis-like inflammation by PCSK9.

Psoriasis is a systemic inflammatory disease, associated with metabolic disorders, including high level of low-density lipoprotein(LDL). Proprotein convertase subtilisin/kexin 9 (PCSK9), promoting the degradation of LDL receptors, and therefore the increased concentration of circulating LDL, is also involved in inflammation. This study aims to examine the role of PCSK9 in psoriasis and to investigate the potential of topically applying siRNA targeting Pcsk9 as a psoriasis treatment. We investigated the expr...

Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein receptor. PCSK9 has emerged as a target for lipid-lowering therapy, but the predictive value of the serum level of PCSK9 for the severity of coronary disease is largely unknown.

Access to PCSK9 Inhibitors.

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders.

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in car...

Small Molecule Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents.

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties and the off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n w...

PCSK9 inhibition: ready for prime time in CKD?

Lowering LDL cholesterol reduces the risk of atherosclerotic vascular disease in a wide range of patients with chronic kidney disease, with no evidence of a threshold below which further reductions no longer reduce risk. Statins safely lower LDL cholesterol, but novel inhibitors of proprotein convertase subtilisin kexin 9 (PCSK9) provide additional reductions which may reduce atherosclerotic vascular disease yet further in this high risk population.

The different relations of PCSK9 and Lp(a) to the presence and severity of atherosclerotic lesions in patients with familial hypercholesterolemia.

The relation of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) levels to coronary artery disease (CAD) has been well established in the general population, while little is known about the association between Lp(a) or PCSK9 and atherosclerotic lesions of different artery sites in patients with familial hypercholesterolemia (FH).

C679X loss-of-function PCSK9 variant lowers fasting glucose levels in a black South African population: A longitudinal study.

To determine the longitudinal association of the loss-of-function (LOF) PCSK9 variants (C679X and A443T), proxies of PCSK9 inhibitor drugs, with LDL-C, fasting glucose and glycated hemoglobin.

Indications of PCSK9 Inhibitors for Patients at High and Very High Cardiovascular Risk.

AAV8-mediated overexpression of mPCSK9 in liver differs between male and female mice.

The recombinant adeno-associated viral vector serotype 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (AAV8- PCSK9) is a new model for the induction of hypercholesterolemia. AAV8 preferentially infects hepatocytes and the incorporated liver-specific promoter should ensure expression of PCSK9 in the liver. Since tissue distribution of AAVs can differ between male and female mice, we investigated the differences in PCSK9 expression and hypercholesterolemia de...

Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population.

Some studies suggested that proprotein convertase subtilisin kexin type 9 (PCSK9) is linked to liver steatosis severity and non-alcoholic steatohepatitis (NASH). We aimed to assess whether circulating PCSK9 levels are associated with either liver fat content (LFC) or histological markers of NASH in high-risk patients.

Familial Hypercholesterolemia: Although Identification Advances, Appreciation and Treatment Lag.

Familial hypercholesterolemia is one of the most common autosomal dominant inherited genetic disorders, yet it is frequently undiagnosed, leading to a markedly increased risk for cardiovascular events. Understanding the pathophysiology of the disease as well as the importance of cascade screening is critical to appropriate treatment of patients. Though the mainstay of therapy for heterozygous familial hypercholesterolemia remains statins, many patients require additional therapy including ezetimibe and/or p...

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