分离胆固醇转移蛋白抑制剂的基于机制的和非向的作用与CETP基因多态性
Reecha Sofat1, Aroon D Hingorani, Liam Smeeth
1Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom.
Circulation
|December 23, 2009
概括
胆固醇转移蛋白 (CETP) 抑制剂会影响高密度胆固醇,但torcetrapib会导致高血压. 基因分析显示,TORCETRAPIBIB是一种抗生素.
科学领域:
- 药物基因组学 药物基因组学
- 心血管医学 心血管医学
- 脂质代谢 脂质代谢是什么
背景情况:
- 胆固醇转移蛋白 (CETP) 抑制剂增加了高密度胆固醇.
- 一种CETP抑制剂Torcetrapib意外增加了血压和心血管事件.
- 讨论了torcetrapib高血压作用的原因 (CETP抑制与非目标作用).
研究的目的:
- 确定CETP基因单核酸多态 (SNPs) 是否可以区分基于机制的CETP抑制剂与非目标效应.
- 通过分析基因与药物效应,验证CETP作为治疗点.
主要方法:
- 对CETP SNP和torcetrapib对脂质,血压和电解质的影响进行比较.
- 利用了遗传研究 (67,687人) 和随机试验 (17,911名参与者) 的数据.
- 分析了与CETP活性相关的脂质分数,血压和电解质变化.
主要成果:
- 无论是CETP SNP还是torcetrapib都降低了CETP活性,并且始终影响了8个脂质特征,包括HDL胆固醇.
- 托塞特拉皮 (60毫克) 显著提高了静缩 (4.47毫米升) 和静缩 (2.08毫米升) 血压.
- CETP SNPs对血压没有任何影响 (静缩:0.16 mm Hg,静缩: -0.04 mm Hg),与torcetrapib的影响有显著差异.
结论:
- 在CETP SNP和torcetrapib之间血压影响的不一致表明torcetrapib的高血压不是由于CETP抑制.
- 托塞特拉皮的高血压作用不太可能与其他CETP抑制剂共享.
- 遗传研究为药物开发提供了宝贵的工具,为人类的药物标验证提供随机证据.
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