CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys
| Autor: | Brian K Krause, Mark A. Spahr, Randy Ramharack, Helen T. Lee, R. F. Bousley, Catherine S. Sekerke, R. L. Stanfield |
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| Rok vydání: | 1998 |
| Předmět: |
Male
medicine.medical_specialty Apolipoprotein B Acetates Apoprotein(a) chemistry.chemical_compound In vivo Internal medicine Acetamides Blood plasma medicine Animals Enzyme Inhibitors Cells Cultured Apolipoproteins B Sulfonamides Apolipoprotein A-I biology Cholesterol Anticholesteremic Agents Lipoprotein(a) Animal Feed Macaca fascicularis Apolipoproteins medicine.anatomical_structure Endocrinology Liver chemistry Hepatocyte Low-density lipoprotein Apolipoprotein B-100 biology.protein lipids (amino acids peptides and proteins) Sulfonic Acids Cardiology and Cardiovascular Medicine Sterol O-Acyltransferase Lipoprotein |
| Zdroj: | Atherosclerosis. 136:79-87 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/s0021-9150(97)00189-5 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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