Navab Mohamad, Anantharamaiah G M, Hama Susan, Hough Greg, Reddy Srinivasa T, Frank Joy S, Garber David W, Handattu Shaila, Fogelman Alan M
Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, Calif 90095-1679, USA.
Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1426-32. doi: 10.1161/01.ATV.0000167412.98221.1a. Epub 2005 Apr 21.
We tested for synergy between pravastatin and D-4F by administering oral doses of each in combination that were predetermined to be ineffective when given as single agents.
The combination significantly increased high-density lipoprotein (HDL)-cholesterol levels, apolipoprotein (apo)A-I levels, paraoxonase activity, rendered HDL antiinflammatory, prevented lesion formation in young (79% reduction in en face lesion area; P<0.0001) and caused regression of established lesions in old apoE null mice (ie, mice receiving the combination for 6 months had lesion areas that were smaller than those before the start of treatment (P=0.019 for en face lesion area; P=0.004 for aortic root sinus lesion area). After 6 months of treatment with the combination, en face lesion area was 38% of that in mice maintained on chow alone; P<0.00004) with a 22% reduction in macrophage content in the remaining lesions (P=0.001), indicating an overall reduction in macrophages of 79%. The combination increased intestinal apoA-I synthesis by 60% (P=0.011). In monkeys, the combination also rendered HDL antiinflammatory.
These results suggest that the combination of a statin and an HDL-based therapy may be a particularly potent treatment strategy.
我们通过口服预先确定单用时无效的普伐他汀和D-4F联合剂量，来测试二者之间的协同作用。
联合用药显著提高了高密度脂蛋白（HDL）胆固醇水平、载脂蛋白（apo）A-I水平、对氧磷酶活性，使HDL具有抗炎作用，预防了年轻小鼠病变形成（正面病变面积减少79%；P<0.0001），并使老年载脂蛋白E基因敲除小鼠已形成的病变消退（即接受联合治疗6个月的小鼠病变面积小于治疗开始前的病变面积（正面病变面积P=0.019；主动脉根窦病变面积P=0.004）。联合治疗6个月后，正面病变面积为仅喂食普通饲料小鼠的38%；P<0.00004），剩余病变中的巨噬细胞含量减少22%（P=0.001），表明巨噬细胞总体减少79%。联合用药使肠道apoA-I合成增加60%（P=0.011）。在猴子中，联合用药也使HDL具有抗炎作用。
这些结果表明，他汀类药物与基于HDL的治疗方法联合使用可能是一种特别有效的治疗策略。
