CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys.
Lipoprotein(a) (Lp(a)), which is generated through the covalent association of apolipoprotein(a) (apo(a)) and apo B-100-LDL, is an independent risk factor for several vascular diseases. Therefore, there is interest in developing therapies for lowering Lp(a). This investigation was carried out to determine the effect of CI-1011, a potent lipid regulator in rodents, on Lp(a) and other lipid parameters in cynomolgus monkeys (Macaca fascicularis). Nine healthy male monkeys on a normal chow diet were orally treated with CI-1011 at 30 mg/kg per day for 3 weeks. Lp(a) and total cholesterol levels were significantly decreased after 1 week and maximally reduced to 68 and 73% of control levels, respectively, after 3 treatment weeks. The decreases in total cholesterol were mainly due to changes in low density lipoprotein (LDL). The LDL:HDL ratio decreased by 30%. Triglycerides were unaffected by treatment. Lp(a) and total cholesterol levels returned to pretreatment values after stopping treatment suggesting a direct effect of the compound on their inhibition. Further studies demonstrated that CI-1011 was effective at a low dose of 3 mg/kg per day after 1 week of administration. CI-1011 also decreased apo B-100 to 80% of control levels, but this change was not sufficient to account for the Lp(a) lowering. There was also no correlation between the changes in Lp(a) and apo B-100 levels. Treatment of cynomolgus monkey primary hepatocyte cultures with CI-1011 resulted in a dose-dependent inhibition of Lp(a) levels suggesting a direct hepatic effect of the compound. Western blot analysis of the samples showed that changes in Lp(a) were associated mainly with decreased apo(a) (47%), but not apo B-100 (17%). These results demonstrate that CI-1011 effectively decreases Lp(a) levels both in vivo and in vitro.
Ramharack
R
R
Department of Vascular Diseases, Parke-Davis, Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI 48105, USA. ramharr@aa.wl.com
Spahr
M A
MA
Sekerke
C S
CS
Stanfield
R L
RL
Bousley
R F
RF
Lee
H T
HT
Krause
B K
BK
D000081:Acetamides; D000085:Acetates; D000821:Animal Feed; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000378:metabolism; D053299:Apolipoprotein B-100; D001053:Apolipoproteins / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D053241:Apoprotein(a); D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017270:Lipoprotein(a) / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology*
D000081:Acetamides; D000085:Acetates; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D001053:Apolipoproteins; D001055:Apolipoproteins B; D004791:Enzyme Inhibitors; D017270:Lipoprotein(a); D013449:Sulfonamides; D013451:Sulfonic Acids; C423185:avasimibe; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D053241:Apoprotein(a)