The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia

Al-Shaer, Moutasim H.; Choueiri, Nabil E; Suleiman, Ehab S

doi:10.1186/1476-511x-3-22

Cited by 21 publications

(3 citation statements)

References 42 publications

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“…Ezetimibe is the first example of a new class of lipidlowering compounds that selectively inhibits the intestinal absorption of cholesterol. Although ezetimibe significantly lowered total cholesterol, low-density lipoprotein cholesterol (LDL-c) and triglycerides, and increased high-density lipoprotein cholesterol (HDL-c) (Van Heek et al, 1997;Sudhop et al, 2002;Al-Shaer et al, 2004), its greatest effectiveness results from its use in combination with statins. Thus, the addition of ezetimibe to statins produced further lowering of LDL-c of around 20% and had a more favourable effect on HDL-c and triglycerides when compared with statin therapy alone, even after doubling the dose of the statins (Al-Shaer et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid‐lowering effect

Gómez‐Garre¹,

Muñoz-Pacheco²,

Gonzalez-Rubio³

et al. 2009

British J Pharmacology

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Background and purpose: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis. Experimental approach: Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg·kg), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet. Key results: Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor kB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone. Conclusions and implications: Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids.

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Section: Introductionmentioning

confidence: 99%

Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid‐lowering effect

Gómez‐Garre¹,

Muñoz-Pacheco²,

Gonzalez-Rubio³

et al. 2009

British J Pharmacology

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“…The present study aimed at evaluating all the existing drugs molecules and compounds as ligands against the APOE4, a potential predictor for CAD. Among the drugs, Ezetimibe has been earlier studied and found to be used in the treatment of hypercholesterolemia (Burnett & Huff, 2006) and is effective for lowering LDL-C and non HDL-C as monotherapy or in combination with statins (Al-Shaer et al, 2004). In the present study, the drug had a binding affinity of -7.4 kcal/mol to APOE4, presenting its candidature.…”

Section: Resultsmentioning

confidence: 53%

Identification of APOE4 modulators, targeted therapeutic candidates in Coronary Artery Disease, using Molecular Docking studies

Hazarika

Sen

Zawar³

et al. 2021

Preprint

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A significant genetic suspect for coronary artery disease is the pathological adaptation of apolipoprotein E4 (APOE4) through intramolecular interaction. With the prevailing evidence on APOE4 genotype and its prevalence in coronary artery disease, the present study has investigated the protein-ligand binding affinity and unveil the receptor binding abilities of different classes of ligands for APOE4 through molecular docking studies. Structural basis of APOE4 involvement in CAD suggests that the intramolecular domain interactions to be a suitable target for therapeutic intervention. Various classes of ligands including known drugs used in the treatment of CAD, fragment-based stabilizers and their similar structures and molecules with known bioactivity against APOE4 were screened for their binding affinity and further investigated for their interactions with APOE4. Computational studies show the benzyl amide derived structures to be useful candidates in modulation of APOE4. The dynamics of the binding analysis can be further achieved with an in-depth understanding of drug-receptor interactions performing molecular dynamic simulation studies.

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“…The present study aimed at evaluating all the existing drugs molecules and compounds as ligands against the APOE4, a potential predictor for CAD. Among the drugs, Ezetimibe has been earlier studied and found to be used in the treatment of hypercholesterolemia [40] and is effective for lowering LDL-C and non-HDL-C as monotherapy or in combination with statins [41]. In the present study, the drug had a binding affinity of -7.4 kcal/mol to APOE4, presenting its candidature.…”

Section: Discussionmentioning

confidence: 53%

Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies

Hazarika¹,

Sen²,

Zawar³

et al. 2021

JDDMC

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Investigate the protein-ligand binding affinity and evaluate the receptor binding abilities of different classes of ligands for APOE4 through molecular docking studies. The polymorphic nature of human Apo E gene encodes one of 3 common epsilon (ε) alleles (ε2, ε3, and ε4), reported to influence the risk of cardiovascular diseases. Structural basis of APOE4 involvement in CAD suggests that the intramolecular domain interactions to be a suitable target for therapeutic intervention. Identification of APOE4 modulators, targeted towards therapeutic candidates in CAD using Molecular Docking studies. Various classes of ligands including known drugs used in the treatment of CAD, fragment-based stabilizers and their similar structures and molecules with known bioactivity against APOE4 were screened for their binding affinity and further investigated for their interactions with APOE4. Computational studies show the benzyl amide derived structures to be useful candidates in modulation of APOE4. The protein-ligand binding affinities predicted in the study indicated receptor binding abilities of APOE4 that can lead to have interesting insights on structural conformity of APOE4 and its correlated functional aspects. Understanding modulation of APOE4 can pave ways to use it as biomarker for CAD as well as for its therapeutics. Further analysis of the variation of the docked protein structure, molecular dynamic simulation can be performed to generate a dynamic structure for binding analysis.

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The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia

Cited by 21 publications

References 42 publications

Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid‐lowering effect

Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid‐lowering effect

Identification of APOE4 modulators, targeted therapeutic candidates in Coronary Artery Disease, using Molecular Docking studies

Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies

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