CI-1011 LOWERS LIPOPROTEIN(A) AND PLASMA-CHOLESTEROL CONCENTRATIONS IN CHOW-FED CYNOMOLGUS MONKEYS

Lipoprotein(a) (Lp(a)), which is generated through the covalent associ ation of apolipoprotein(a) (apo(a)) and apo B-100-LDL, is an independe nt risk factor for several vascular diseases. Therefore, there is inte rest in developing therapies for lowering Lp(a). This investigation wa s carried out to determine the effect of CI-1011, a potent lipid regul ator in rodents, on Lp(a) and other lipid parameters in cynomolgus mon keys (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 afte r 1 week and maximally reduced to 68 and 73% of control levels, respec tively, after 3 treatment weeks. The decreases in total cholesterol we re mainly due to changes in low density lipoprotein (LDL). The LDL:HDL ratio decreased by 30%. Triglycerides were unaffected by treatment. L p(a) and total cholesterol levels returned to pretreatment values afte r stopping treatment suggesting a direct effect of the compound on the ir 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-1 011 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. Trea tment of cynomolgus monkey primary hepatocyte cultures with CI-1011 re sulted in a dose-dependent inhibition of Lp(a) levels suggesting a dir ect hepatic effect of the compound. Western blot analysis of the sampl es 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. (C) 1998 Elsevier Science Ireland Ltd.