Dujovne C A, Harris W S, Gerrond L L, Fan J, Muzio F
Department of Medicine, University of Kansas Medical Center, Kansas City.
Am J Cardiol. 1994 Jul 1;74(1):38-42. doi: 10.1016/0002-9149(94)90488-x.
Oxidative modification of low-density lipoprotein (LDL) cholesterol appears to contribute to atherogenesis. Probucol reduces LDL cholesterol oxidation susceptibility, but the consistency, dose, and time course are not well described. Twelve hyperlipidemic patients were given probucol for 4 weeks at the usual dose for cholesterol reduction (1,000 mg/day), or one half (500 mg/day) or one quarter (250 mg/day) the usual dose. Lipoprotein oxidation susceptibility of apolipoprotein B-containing lipoproteins was assessed using a rapid test in which LDL cholesterol and very-low-density lipoprotein are precipitated with dextran sulfate and magnesium ions, redissolved, incubated with copper ions for 3 hours, and tested for thiobarbituric acid-reactive substances. Results are expressed as nmoles of malonyldialdehyde (MDA) generated per mg (nmol MDA/mg) non-high-density lipoprotein cholesterol. Lipoproteins from probucol-treated patients become resistant to oxidation with a predrug value of 85 +/- 19, and decreasing to 3 +/- 1 nmol MDA/mg after drug administration (p < 0.001). Both "half" and "full" doses were effective in lowering lipoprotein oxidation susceptibility by 95%. The "quarter" dose was less effective. Oxidation inhibition was maximized within 2 weeks, returning to baseline 4 to 6 weeks after discontinuing probucol. Four patients were subsequently crossed over to vitamin E (1,200 IU/day). Vitamin E had a milder, less predictable antioxidant effect, lowering lipoprotein oxidation susceptibility by a mean of 24%. In conclusion, probucol treatment effectively and predictably reduces plasma lipoprotein susceptibility to ex vivo, copper-induced oxidation. This clinically applicable test may provide quantitation of antioxidant effects of probucol or other antioxidants and thus facilitate dose adjustments and correlation with antiatherosclerotic effects.
低密度脂蛋白（LDL）胆固醇的氧化修饰似乎在动脉粥样硬化形成过程中起作用。普罗布考可降低LDL胆固醇的氧化易感性，但相关的一致性、剂量和时间进程尚无充分描述。12名高脂血症患者接受普罗布考治疗4周，剂量分别为降胆固醇常用剂量（1000毫克/天）、常用剂量的一半（500毫克/天）或四分之一（250毫克/天）。使用一种快速检测方法评估含载脂蛋白B的脂蛋白的氧化易感性，该方法是先用硫酸葡聚糖和镁离子沉淀LDL胆固醇和极低密度脂蛋白，再重新溶解，与铜离子孵育3小时，然后检测硫代巴比妥酸反应性物质。结果以每毫克非高密度脂蛋白胆固醇产生的丙二醛（MDA）纳米摩尔数表示（nmol MDA/mg）。接受普罗布考治疗患者的脂蛋白对氧化产生抗性，给药前的值为85±19，给药后降至3±1 nmol MDA/mg（p<0.001）。“半量”和“全量”剂量均能有效降低脂蛋白氧化易感性达95%。“四分之一量”剂量效果较差。氧化抑制在2周内达到最大值，停用普罗布考后4至6周恢复至基线水平。随后4名患者换用维生素E（1200国际单位/天）。维生素E的抗氧化作用较温和且较难预测，平均降低脂蛋白氧化易感性24%。总之，普罗布考治疗可有效且可预测地降低血浆脂蛋白对体外铜诱导氧化的易感性。这种临床适用的检测方法可对普罗布考或其他抗氧化剂的抗氧化作用进行定量，从而有助于调整剂量以及与抗动脉粥样硬化作用进行关联分析。
