Marais A D, Naoumova R P, Firth J C, Penny C, Neuwirth C K, Thompson G R
Department of Internal Medicine, University of Cape Town Medical School, Cape Town, South Africa.
J Lipid Res. 1997 Oct;38(10):2071-8.
Apheresis only partially controls raised low density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually respond poorly to lipid-lowering drugs. The efficacy and mechanism of action of a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin, was therefore investigated in seven homozygotes undergoing apheresis. One receptor-negative and six receptor-defective homozygotes undergoing plasma exchange or LDL apheresis every 2 weeks were studied during 2 months each on placebo and on atorvastatin 80 mg daily. Changes in plasma lipids and mevalonic acid, an index of cholesterol synthesis, were measured and the kinetics of the rebound of low density lipoprotein cholesterol and apolipoprotein B after apheresis were analyzed. All subjects had significant improvements on atorvastatin. Mean decreases in low density lipoprotein cholesterol were 31% greater both pre- and post-apheresis on atorvastatin compared with placebo, accompanied by a 63% decrease in mevalonic acid. Percentage changes in low density lipoprotein cholesterol and mevalonic acid were closely correlated (r = 0.89, P = 0.007). The mean production rates of low density lipoprotein cholesterol and apolipoprotein B were 21% and 25% lower, respectively, on atorvastatin than on placebo (P < 0.005 and <0.02) but changes in mean fractional clearance rates were not statistically significant. We conclude that atorvastatin enhances the efficacy of plasma exchange and low density lipoprotein apheresis in patients who lack low density lipoprotein receptors. This effect appears to be due to marked inhibition of cholesterol synthesis which results in a decreased rate of production of low density lipoprotein.
对于纯合子家族性高胆固醇血症患者，单采术只能部分控制升高的低密度脂蛋白胆固醇水平，这类患者通常对降脂药物反应不佳。因此，研究了一种新型3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂阿托伐他汀在7例接受单采术的纯合子患者中的疗效及作用机制。在2个月的时间里，对1例受体阴性和6例受体缺陷的纯合子患者进行研究，他们每2周接受一次血浆置换或低密度脂蛋白单采术，分别服用安慰剂和每日80 mg阿托伐他汀。测量血浆脂质和胆固醇合成指标甲羟戊酸的变化，并分析单采术后低密度脂蛋白胆固醇和载脂蛋白B的反弹动力学。所有受试者服用阿托伐他汀后均有显著改善。与安慰剂相比，服用阿托伐他汀的患者在单采术前和术后低密度脂蛋白胆固醇的平均降幅均高出31%，同时甲羟戊酸下降了63%。低密度脂蛋白胆固醇和甲羟戊酸的百分比变化密切相关（r = 0.89，P = 0.007）。与安慰剂相比，服用阿托伐他汀时低密度脂蛋白胆固醇和载脂蛋白B的平均生成率分别降低了21%和25%（P < 0.005和<0.02），但平均清除率分数的变化无统计学意义。我们得出结论，阿托伐他汀可增强血浆置换和低密度脂蛋白单采术对缺乏低密度脂蛋白受体患者的疗效。这种作用似乎是由于显著抑制胆固醇合成，从而导致低密度脂蛋白生成率降低。
