Evinacumab in Patients with Refractory Hypercholesterolemia

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 383(24), P. 2307 - 2319

Published: Nov. 15, 2020

Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment lipid-lowering therapies at maximum tolerated doses, an increased risk of atherosclerosis. In such patients, the efficacy and safety subcutaneous intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known.In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients or without heterozygous familial hypercholesterolemia had screening LDL level 70 mg per deciliter higher atherosclerosis 100 were randomly assigned to receive evinacumab placebo. The primary end point was percent change from baseline in week 16 as compared placebo.In total, 272 following groups: dose 450 weekly (40 patients), 300 (43 every weeks (39 patients) placebo (41 patients); 15 kilogram body weight 4 5 (36 (34 patients). At 16, differences least-squares mean between groups weekly, group -56.0, -52.9, -38.5 percentage points, respectively (P<0.001 for all comparisons). -50.5 points (P<0.001) -24.2 respectively. incidence serious adverse events during period ranged 3 16% across trial groups.In use significantly reduced level, by more than 50% dose. (Funded Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Language: Английский

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RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2022, Volume and Issue: 384(1), P. 133 - 154

Published: June 9, 2022

RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes achieve posttranscriptional regulation. has proven be an adaptable powerful therapeutic strategy where advancements in chemistry pharmaceutics continue bring RNAi-based drugs the clinic. With four siRNA medications already approved by US Food Drug Administration (FDA), several therapeutics advance clinical trials functions that closely resemble their endogenous counterparts. Although intended enhance stability improve efficacy, chemical modifications may increase risk off-target effects altering structure, folding, biologic activity away from natural equivalents. Novel technologies development today seek use intact cells yield true agents better represent structures, stabilities, activities, safety profiles molecules. In this review, we provide examination mechanisms action miRNAs siRNAs, physiologic pharmacokinetic barriers delivery, summary delivery platforms use. We overview pharmacology FDA-approved (patisiran, givosiran, lumasiran, inclisiran) as well five siRNAs miRNA-based currently trials. Furthermore, discuss direct expression stable carrier-based, vivo production novel for research development. SIGNIFICANCE STATEMENT: our summarize concepts (RNAi), molecular mechanisms, current state challenges drug focus discussion on Administration-approved those entered investigations. approaches producing new biological molecules are highlighted.

Language: Английский

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Lipid Metabolism, Disorders and Therapeutic Drugs - Review

Biomolecules & Therapeutics, Journal Year: 2021, Volume and Issue: 29(6), P. 596 - 604

Published: Oct. 26, 2021

Different lifestyles have an impact on useful metabolic functions, causing disorders. lipids are involved in the functions that play various vital roles body, such as structural components, storage of energy, signaling, biomarkers, energy metabolism, and hormones. Inter-related disorders caused when these affected, like diabetes, cancer, infections, inflammatory neurodegenerative conditions humans. During Covid-19 period, there has been a lot focus effects all over world. Hence, this review collectively reports research concerning disorders, mainly cardiovascular diabetes mellitus. In addition, drug lipid metabolism also considered. This explores lipids, drugs used for

Language: Английский

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Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Heart Lung and Circulation, Journal Year: 2020, Volume and Issue: 30(3), P. 324 - 349

Published: Dec. 10, 2020

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected inadequately treated, consistent being leading challenge for public health genomics. To further address the unmet need, we provide updated guidance, presented as series systematically collated recommendations, on care patients families FH. These recommendations have been informed by exponential growth published works new evidence over last 5 years compatible contemporary global call action Recommendations given detection, diagnosis, assessment management adults children. also made genetic testing risk notification biological relatives who should undergo cascade Guidance based concepts re-stratification, adherence heart healthy lifestyles, treatment non-cholesterol factors, safe appropriate use LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors apheresis. Broad provided organisation development services. best practice need be underpinned good clinical judgment shared decision making families. Models adapted local regional needs available resources. A comprehensive realistic implementation strategy, research, assessments cost-benefit, will required ensure this guidance benefits all Australian or at

Language: Английский

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Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association

Journal of clinical lipidology, Journal Year: 2022, Volume and Issue: 17(1), P. 19 - 39

Published: Sept. 11, 2022

Statin-associated muscle symptoms (SAMS) are the most common form of statin intolerance and associated with increased risk cardiovascular events that manifest from underutilization discontinuation. The reported frequencies SAMS divergent in literature. writing group estimates prevalence SAMS, namely all temporally related to use but without regard causality, be about 10% (range 5% 25%), pharmacological specifically resulting properties statin, 1-2% 0.5% 4%). In clinical practice, likely result a combination nonpharmacological effects, however this does not make any less clinically relevant. Regardless etiology, need addressed accordance patients' preferences experiences. This perspective reviews epidemiology underlying pathophysiology consequences We present patient-centered communication strategies mitigate improve medication adherence outcomes among users. Treatment include 1) optimizing lifestyle interventions, 2) modulating factors may contribute symptoms, 3) tolerability by dose reduction, decreased dosing frequency, or an alternate more favorable pharmacokinetic properties, 4) non-statins, emphasizing those evidence for atherosclerotic either place therapy depending on patient's circumstances. focus is sustainable lipoprotein goal achievement, which important reduction.

Language: Английский

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Familial Hypercholesterolemia: Global Burden and Approaches

Current Cardiology Reports, Journal Year: 2021, Volume and Issue: 23(10)

Published: Sept. 4, 2021

Language: Английский

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Recent Advances on Familial Hypercholesterolemia in Children and Adolescents

Biomedicines, Journal Year: 2022, Volume and Issue: 10(5), P. 1043 - 1043

Published: April 30, 2022

Familial hypercholesterolemia is a common autosomal hereditary disorder characterized by elevated concentrations of low-density lipoprotein cholesterol and the development premature atherosclerosis cardiovascular disease. Early diagnosis, as well prompt aggressive treatment, are fundamental steps to prevent complications high rate mortality in children adolescents. Clinics genetics two main aspects on which diagnosis based. Widespread screening programs respectable option for early detection familial hypercholesterolemia. Different types have been proposed so far; however, optimal program has not yet found. The treatment approach both heterozygous homozygous pediatric population multidisciplinary, including lifestyle modifications, standard lipid-lowering medications, novel pharmacological agents. latter show promising results, especially patients who experience intolerance other or present with more severe conditions. Our purpose focus importance hypercholesterolemia, highlight best therapeutic strategies, recent approaches based current clinical evidence, that need be adopted from earliest stages life.

Language: Английский

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Hyperlipidemia and Cardiovascular Risk in Children and Adolescents

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 809 - 809

Published: March 7, 2023

Atherosclerotic cardiovascular disease (ASCVD) represents the major cause of morbidity and mortality worldwide. The onset atherosclerosis process occurs during childhood adolescence, subsequently leading to as young adults. Several risk factors can be identified in children adolescents; however, hyperlipidemia, conjunction with global obesity epidemic, has emerged most prevalent, playing a key role development ASCVD. Therefore, screening for hyperlipidemia is strongly recommended detect high-risk presenting these disorders, patients deserve more intensive investigation intervention. Treatment should initiated early possible order reduce future In this review, we will discuss lipid metabolism focusing on correlations therapeutic management or almost completely avoid

Language: Английский

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The Growing Class of Novel RNAi Therapeutics

Molecular Pharmacology, Journal Year: 2024, Volume and Issue: 106(1), P. 13 - 20

Published: May 6, 2024

The clinical use of RNA interference (RNAi) molecular mechanisms has introduced a novel, growing class therapeutics capable treating diseases by controlling target gene expression at the posttranscriptional level. With newly approved nedosiran (Rivfloza{trade mark, serif}), there are now six RNAi-based United States Food and Drug Administration (FDA). Interestingly, five FDA-approved small interfering (siRNA) [patisiran (Onpattro{trade lumasiran (Oxlumo{trade inclisiran (Leqvio{trade vutrisiran (Amvuttra{trade nedosiran] were revealed to act on 39-untranslated regions mRNAs, instead coding sequences, thereby following common mechanistic action genome-derived microRNAs (miRNA). Furthermore, three siRNA [patisiran, givosiran (Givlaari{trade induce mRNA degradation or cleavage via near-complete rather than complete base-pair complementarity. These features along with previous findings confound currently held characteristics distinguish siRNAs miRNAs biosimilars, which all converge in RNAi regulatory pathway action. Herein, we discuss mechanism current criteria for distinguishing between while summarizing unique chemistry pharmacology therapeutics. term "RNAi" therapeutics, as used previously, provides coherently unified nomenclature broader forms well number therapeutic biosimilars that best aligns pharmacological Significance Statement summarized, is approved. We point out surprisingly differences similarities supports using general align drug based embraces novel

Language: Английский

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Exploring the potential of cashew waste for food and health applications- A review

Future Foods, Journal Year: 2024, Volume and Issue: 9, P. 100319 - 100319

Published: Feb. 12, 2024

Nowadays, the effective utilization of food waste presents a significant challenge for industry. The transformation materials into useful products, and production healthy products by incorporation are focus many researchers these days. With increasing world population rising low-cost but high-quality food, development dietary choices is novel approach. Cashews become demanding nut due to their remarkable health advantages byproducts have vast applications. constituents cashew nutshell including proteins, fibers, vitamins, other phytonutrients essential human nutrition they also possess strong antioxidant anti-inflammatory potential. In this review, nutshell, testa or husk, apple, apple pomace bagasse that considered derived from nuts been focused on exploring nutritional composition, benefits, applications in industries. Cashew can be utilized confectionery, beverage, meat, baking industry produce eco-friendly packaging materials. nutshells shown evidence improving certain biomarkers ailments like diabetes mellitus, obesity, hypercholesterolemia, bone diseases.

Language: Английский

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