| RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. | |
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MedLine Citation:
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PMID: 20513599 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVES: The aim of this study was to determine whether a novel small molecule RVX-208 affects apolipoprotein (apo)A-I and high-density lipoprotein cholesterol (HDL-C) levels in vitro and in vivo. BACKGROUND: Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease. METHODS: HepG2 cells were treated with 0 to 60 mumol/l RVX-208 followed by assays for apoA-I and HDL-C production. For in vivo studies, African green monkeys (AGMs) received 15 to 60 mg/kg/day RVX-208, and the serum was analyzed for lipoprotein levels, HDL-subparticle distribution, cholesterol efflux, and activity of lipid-modifying enzymes. A phase I clinical trial was conducted in healthy volunteers (given 1 to 20 mg/kg/day of RVX-208) to assess safety, tolerability, and pharmacokinetics. RESULTS: The RVX-208 induced apoA-I messenger ribonucleic acid and protein synthesis in HepG2 cells, leading to increased levels of pre-beta-migrating and alpha-lipoprotein particles containing apoA-I (LpA-I) in spent media. Similarly, in AGMs, RVX-208 treatment for 63 days increased serum apoA-I and HDL-C levels (60% and 97%, respectively). In addition, the levels of pre-beta(1)-LpA-I and alpha1-LpA-I HDL-subparticles were increased as well as adenosine triphosphate binding cassette AI, adenosine triphosphate binding cassette G1, and scavenger receptor class B type I-dependent cholesterol efflux. These changes were not mediated by cholesteryl-ester-transfer protein. Treatment of humans for 1 week with oral RVX-208 increased apoA-I, pre-beta-HDL, and HDL functionality. CONCLUSIONS: RVX-208 increases apoA-I and HDL-C in vitro and in vivo. In AGMs, RVX-208 raises serum pre-beta(1)-LpA-I and alpha-LpA-I levels and enhances cholesterol efflux. Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis. |
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Authors:
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Dana Bailey; Ravi Jahagirdar; Allan Gordon; Anouar Hafiane; Steven Campbell; Safia Chatur; Gregory S Wagner; Henrik C Hansen; Fabrizio S Chiacchia; Jan Johansson; Larbi Krimbou; Norman C W Wong; Jacques Genest |
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Publication Detail:
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Type: Clinical Trial; Clinical Trial, Phase I; In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of the American College of Cardiology Volume: 55 ISSN: 1558-3597 ISO Abbreviation: J. Am. Coll. Cardiol. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-01 Completed Date: 2010-07-01 Revised Date: 2010-09-03 |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: United States |
Other Details:
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Languages: eng Pagination: 2580-9 Citation Subset: AIM; IM |
Copyright Information:
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Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, Montréal, Québec, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apolipoprotein A-I / biosynthesis, blood*, drug effects*, metabolism Cells, Cultured Cercopithecus aethiops Cholesterol, HDL / blood*, drug effects*, metabolism Cricetinae Disease Models, Animal Dose-Response Relationship, Drug Drug Administration Schedule Female Follow-Up Studies Hep G2 Cells / drug effects, metabolism Humans Macaca fascicularis Male Molecular Weight Probability Quinazolines / chemistry, pharmacology* Random Allocation Risk Assessment |
| Grant Support | |
ID/Acronym/Agency:
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MOP-15042//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Apolipoprotein A-I; 0/Cholesterol, HDL; 0/Quinazolines; 0/RVX 208 |
| Comments/Corrections | |
Erratum In:
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J Am Coll Cardiol. 2010 Aug 31;56(10):825 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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