EFFECT OF TAMOXIFEN ON LOW DENSITY LIPOPROTEIN OXIDATION IN POSTMENOPAUSAL WOMEN

他莫昔芬对绝经后女性低密度脂蛋白氧化的影响

• 批准号: 5203590
• 负责人: R CANNON
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5203590
• 关键词: antiatherogenic agent; antioxidants; cardiovascular pharmacology; dosage; drug screening /evaluation; female; human subject; human therapy evaluation; low density lipoprotein; oxidation; postmenopause; tamoxifen

Tamoxifen, a nonsteroidal antiestrogen, is commonly used in the treatment of breast cancer in postmenopausal women and has been associated with a significant reduction of cardiovascular events in several breast cancer treatment trials. Although this effect may be due in part to favorable alteration of plasma lipoprotein concentrations to a less atherogenic profile, tamoxifen also inhibits lipid and human low density lipoprotein (LDL) oxidation in vitro, albeit at suprapharmacologic concentrations. We studied whether tamoxifen, orally administered to postmenopausal women, has antioxidant effects on their LDL, comparing its effect to that of conjugated equine estrogen in a randomized, double-blind, placebo-controlled crossover trial. The time to onset of LDL peroxidation was assessed by an in vitro assay. The time to onset of LDL peroxidation was measured in 24 postmenopausal women following 2 months treatment with daily tamoxifen 20 mg, conjugated equine estrogen 0.65 mg, and identical placebo taken in random order in 3 time periods. A one month washout period followed each treatment period. Tamoxifen and conjugated equine estrogen lowered LDL levels by 19% and by 13% respectively. Conjugated equine estrogen also increased high density lipoproteins by 13% compared to placebo. Time to onset of LDL oxidation differed from placebo only during the tamoxifen treatment: the onset of LDL oxidation was 20% longer on tamoxifen compared with placebo. Tamoxifen had significant carry-over effect on subsequent treatment periods: thus, although tamoxifen appeared to have no effect in the 11 subjects who received tamoxifen prior to placebo, in the 13 patients who received placebo prior to tamoxifen, compared to placebo tamoxifen increased the onset of LDL oxidation by 32% and reduced the maximum rate of oxidation by 28%. No correlation was found between the antioxidant effect of tamoxifen and the change in LDL concentrations on tamoxifen treatment. This study provides evidence of potent and prolonged antioxidant effects of tamoxifen on LDL when administered in conventional dosage to postmenopausal women. These effects are independent of changes in LDL concentration and may contribute to reduction of cardiovascular events on this drug.

他莫昔芬是一种非甾体类抗雌激素药， 治疗绝经后妇女的乳腺癌， 与心血管事件的显著减少相关， 几个乳腺癌治疗试验 虽然这种影响可能是由于 部分原因是血浆脂蛋白浓度的有利变化， 他莫昔芬是一种致动脉粥样硬化性较低的药物， 密度脂蛋白（LDL）氧化在体外，虽然在 超药理浓度。 我们研究了口服他莫昔芬 给绝经后妇女服用， 低密度脂蛋白，比较其效果的共轭马雌激素，在一个 随机、双盲、安慰剂对照交叉试验。 的时间 通过体外试验评估LDL过氧化反应的发生。 的 在24例绝经后妇女中测定了LDL过氧化反应发生的时间。 每天用他莫昔芬20毫克治疗2个月后的妇女， 结合马雌激素0.65 mg和相同的安慰剂， 3个时间段的随机顺序。 随后是一个月的洗脱期 每个治疗周期。 他莫昔芬和结合的马雌激素降低 LDL水平分别下降19%和13%。 马结合雌激素 与安慰剂相比，高密度脂蛋白也增加了13%。 至LDL氧化发生的时间仅在研究期间与安慰剂不同。 他莫昔芬治疗：LDL氧化的开始时间比对照组长20%。 他莫昔芬与安慰剂比较。 他莫昔芬有显著的残留 对后续治疗期的影响：因此，尽管他莫昔芬 在11名接受他莫昔芬的受试者中似乎没有效果 安慰剂给药前，在13例安慰剂给药前 他莫昔芬，与安慰剂相比，他莫昔芬增加了LDL的发生， 氧化减少了32%，最大氧化速率降低了28%。 没有 三苯氧胺的抗氧化作用与 他莫昔芬治疗后LDL浓度的变化。 本研究 提供了有效和长期的抗氧化作用的证据， 当以常规剂量给药时，他莫昔芬对LDL的影响 绝经后妇女。 这些影响与LDL的变化无关 浓度，并可能有助于减少心血管事件 在这种药物上。