medicina48巻5号

2011年05月発行

今月の主題 脂質異常症―動脈硬化症を予防するためのStrategy 脂質異常症の治療

今後期待される新薬

著者： 塚本和久¹²

所属機関： ¹福島県立医科大学会津医療センター準備室（糖尿病・代謝・腎臓内科） ²福島県立会津総合病院内科

ページ範囲：P.855 - P.858

ポイント

★脂質異常症治療ガイドラインの目標値に到達しない症例の割合は，高リスク群や二次予防群で高い．

★PCSK9阻害薬，CETP阻害薬，MTP阻害薬などの脂質の値を良好な方向に導く薬剤の開発・臨床試験が進行している．

★脂質レベルには大きく影響しないものの，動脈硬化症を抑制すると考えられる薬剤の開発も進められている．

参考文献

1）Abifadel M, et al：Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34：154-156, 2003

2）Lambert G, et al：Molecular basis of PCSK9 function. Atherosclerosis 203：1-7, 2009

3）Kong W, et al：Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10：1344-1351, 2004

4）Li H, et al：Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem 284：28885-28895, 2009

5）Cameron J, et al：Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 201：266-273, 2008

6）Graham MJ, et al：Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res 48：763-767, 2007

7）Chan JC, et al：A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A 106：9820-9825, 2009

8）Ni YG, et al：A PCSK9-binding antibody that structurally mimics the EGF（A）domain of LDL-receptor reduces LDL cholesterol in vivo. J Lipid Res 52：78-86, 2011

9）Kastelein JJ, et al：Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 356：1620-1630, 2007

10）Nissen SE, et al：Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356：1304-1316, 2007

11）Barter PJ, et al：Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357：2109-2122, 2007

12）Cannon CP, et al：Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 363：2406-2415, 2010

13）Wren JA, et al：Biologic activity of dirlotapide, a novel microsomal triglyceride transfer protein inhibitor, for weight loss in obese dogs. J Vet Pharmacol Ther 30 Suppl 1：33-42, 2007

14）Spann NJ, et al：Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis. J Biol Chem 281：33066-33077, 2006

15）Bell DA, et al：Mipomersen, an antisense apolipoprotein B synthesis inhibitor. Expert Opin Investig Drugs, 2011

16）Burnett JR, Watts GF：MTP inhibition as a treatment for dyslipidaemias：time to deliver or empty promises? Expert Opin Ther Targets 11：181-189, 2007

17）Sakamoto S, et al：Glucuronidation converting methyl 1-（3,4-dimethoxyphenyl）-3-（3-ethylvaleryl）-4-hydroxy-6,7,8-trimethoxy-2-na phthoate（S-8921）to a potent apical sodium-dependent bile acid transporter inhibitor, resulting in a hypocholesterolemic action. J Pharmacol Exp Ther 322：610-618, 2007

18）Bloedon LT, et al：Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res 49：1344-1352, 2008

19）Serruys PW, et al：Effects of the direct lipoprotein-associated phospholipase A（2）inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118：1172-1182, 2008

20）Rosenson RS, et al：Effects of 1-H-indole-3-glyoxamide（A-002）on concentration of secretory phospholipase A2（PLASMA study）：a phase II double-blind, randomised, placebo-controlled trial. Lancet 373：649-658, 2009