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Statin therapy alone and in combination with an acyl-CoA:cholesterol O-acyltransferase inhibitor on experimental atherosclerosis.

Abstract
The ability to modify the enzymatic processes involved in promoting atherosclerotic plaque disruption and to serially monitor atherosclerotic evolution could provide novel information in the management of patients with atherosclerosis. We studied the effects of a statin (atorvastatin) and its combination with an acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor (avasimibe) on atherosclerotic regression and plaque stability as measured by matrix metalloproteinase 1 and 3 (MMP-1 and MMP-3) levels. Watanabe Heritable Hyperlipidemic (WHHL) rabbits treated with atorvastatin alone experienced an attenuated increase in atherosclerotic burden versus controls as determined by MR imaging. The mean vessel wall area (VWA) prior to drug therapy was 5.57 +/- 0.01 mm2. The VWA increased to 6.71 +/- 0.03 and 7.16 +/- 0.03 mm2, respectively, in atorvastatin-treated and control groups (p < 0.0001 for both). The combination of atorvastatin and avasimibe induced a significant regression of the previously established atherosclerotic lesions, with the VWA decreasing to 4.54 +/- 0.04 mm2 (p = 0.009). Atorvastatin alone induced a nonsignificant reduction in the percent staining of MMP-1 in atherosclerotic lesions, but the combination treatment with avasimibe led to a significant reduction versus controls (p = 0.005). However, a reduction in MMP-3 staining was significant for rabbits treated with both atorvastatin alone (p = 0.007) and in combination with avasimibe (p = 0.04) versus controls. In this animal model, the addition of avasimibe to atorvastatin has beneficial effects on both atherosclerotic plaque regression and stabilization.
AuthorsStephen G Worthley, Gérard Helft, Roberto Corti, Matthew I Worthley, Derek P Chew, Zahi A Fayad, Azfar G Zaman, John T Fallon, Valentin Fuster, Juan J Badimon
JournalPathophysiology of haemostasis and thrombosis (Pathophysiol Haemost Thromb) Vol. 36 Issue 1 Pg. 9-17 ( 2007) ISSN: 1424-8840 [Electronic] Switzerland
PMID18332609 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2008 S. Karger AG, Basel.
Chemical References
  • Acetamides
  • Acetates
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Sulfonamides
  • Sulfonic Acids
  • avasimibe
  • Cholesterol
  • Atorvastatin
  • Sterol O-Acyltransferase
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1
Topics
  • Acetamides
  • Acetates (administration & dosage, therapeutic use)
  • Animals
  • Aorta, Abdominal (enzymology, injuries, pathology)
  • Aortic Diseases (drug therapy, enzymology, etiology, pathology)
  • Atherosclerosis (drug therapy, enzymology, etiology, pathology, prevention & control)
  • Atorvastatin
  • Catheterization (adverse effects)
  • Cholesterol (blood)
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Drug Therapy, Combination
  • Heptanoic Acids (administration & dosage, therapeutic use)
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage, therapeutic use)
  • Hyperlipidemias (blood, complications, drug therapy, genetics)
  • Magnetic Resonance Imaging
  • Matrix Metalloproteinase 1 (analysis)
  • Matrix Metalloproteinase 3 (analysis)
  • Pyrroles (administration & dosage, therapeutic use)
  • Rabbits
  • Random Allocation
  • Sterol O-Acyltransferase (antagonists & inhibitors)
  • Sulfonamides
  • Sulfonic Acids (administration & dosage, therapeutic use)

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