Ramharack R, Spahr M A, Sekerke C S, Stanfield R L, Bousley R F, Lee H T, Krause B K
Department of Vascular Diseases, Parke-Davis, Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Atherosclerosis. 1998 Jan;136(1):79-87. doi: 10.1016/s0021-9150(97)00189-5.
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.
脂蛋白(a)（Lp(a)）是通过载脂蛋白(a)（apo(a)）与载脂蛋白B-100-低密度脂蛋白（apo B-100-LDL）的共价结合产生的，是多种血管疾病的独立危险因素。因此，人们对开发降低Lp(a)的疗法很感兴趣。本研究旨在确定CI-1011（一种在啮齿动物中有效的脂质调节剂）对食蟹猴（猕猴）的Lp(a)和其他脂质参数的影响。9只正常饮食的健康雄性猴子每天口服30 mg/kg的CI-1011，持续3周。1周后Lp(a)和总胆固醇水平显著降低，治疗3周后分别最大程度降至对照水平的68%和73%。总胆固醇的降低主要归因于低密度脂蛋白（LDL）的变化。LDL与高密度脂蛋白（HDL）的比率下降了30%。甘油三酯不受治疗影响。停止治疗后，Lp(a)和总胆固醇水平恢复到治疗前的值，表明该化合物对它们有直接抑制作用。进一步研究表明，给药1周后，每天3 mg/kg的低剂量CI-1011也有效。CI-1011还将apo B-100降低至对照水平的80%，但这种变化不足以解释Lp(a)的降低。Lp(a)的变化与apo B-100水平之间也没有相关性。用CI-1011处理食蟹猴原代肝细胞培养物导致Lp(a)水平呈剂量依赖性抑制，表明该化合物对肝脏有直接作用。对样本的蛋白质印迹分析表明，Lp(a)的变化主要与apo(a)减少（47%）有关，而与apo B-100减少（17%）无关。这些结果表明，CI-1011在体内和体外均能有效降低Lp(a)水平。
