The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters.
The hypocholesterolemic and anti-atherogenic properties of sulfamic acid ((2,4,6-tris (1-methylethyl) phenyl) acetyl) 2,6-bis(1-methylethyl) phenyl ester, the ACAT inhibitor, CI-1011, was tested in 120 male F1B hamsters fed a hypercholesterolemic chow-based diet containing 10%, coconut oil and 0.05% cholesterol plus: (i) no drug treatment (HCD); (ii) 3 mg/kg per day (HCD+3): (iii)10 mg/kg per day (HCD+10); (iv) 30 mg/kg per day (HCD+30) of CI-1011; or (v) 500 mg/kg per day of cholestyramine (CSTY). Plasma samples were collected at 8 and 10 weeks for measurement of total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). For the progression studies, animals were euthanized after 10 weeks for aortic fatty streak area and hepatic cholesterol analysis. For the regression study, a cohort of the HCD was treated with 30 mg/kg per day of CI-1011 (regression) for an additional 8 weeks. The HCD+3, HCD+10, HCD+30 and CSTY lowered plasma TC (25, 32, 34 and 32%, respectively), VLDL-C (62, 74, 71 and 75%, respectively), LDL-C (25, 38, 47 and 46%, respectively) and TG (48, 47, 42 and 45%, respectively). All treatments resulted in a significant lowering of aortic fatty streak area (68, 86, 93 and 94%, respectively) and reduction in hepatic cholesteryl esters (57, 65, 67 and 70%, respectively). Regression of aortic fatty streak area was 90% after 8 weeks of HCD+30 treatment. Also during the regression phase, plasma TC, LDL-C and TG were lowered 23, 33 and 47%, respectively, as well as, hepatic cholesteryl esters (76%). Significant correlations between plasma LDL-C concentration and aortic fatty streak area (r=0.62, P < 0.004) in the HCD+10 group, suggest that CI-1101 altered aortic lipid infiltration primarily by its effect on plasma lipids. However the 30 mg/kg per day dose of CI-1011 which additionally reduced aortic fatty streak area by 51% relative to the 10 mg/kg per day dose was only associated with a 14% further decrease in plasma LDL-C. Finally the 10-fold regression of aortic fatty streak area was associated with only a 35% reduction in plasma LDL-C. These exceptions to the lipid-lesion relationship raise the possibility of additional effects of CI-1011, which may occur independent of or in concert with lipoprotein cholesterol lowering. It is concluded that in hypercholesterolemic hamsters, CI-1011 is approximately 50 times more potent than cholestyramine in cholesterol-lowering, reduction and regression of aortic fatty streak area.
Nicolosi
R J
RJ
Department of Health and Clinical Science, Center for Chronic Disease Control, University of Massachusetts Lowell 01854, USA. NICOLOSIR@WOODS.UML.EDU
Wilson
T A
TA
Krause
B R
BR
D000081:Acetamides; D000085:Acetates; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D015243:Cholesterol, VLDL / Q000097:blood / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012016:Reference Values; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D000081:Acetamides; D000085:Acetates; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids; D014280:Triglycerides; C423185:avasimibe; D002784:Cholesterol; D002785:Sterol O-Acyltransferase