达拉匹林治疗对动脉内膜切除术患者颈动脉斑块脂蛋白相关磷脂酶A2活性的影响：一项随机对照试验。
Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial.
作者信息
Johnson Joel L, Shi Yi, Snipes Rose, Janmohamed Salim, Rolfe Timothy E, Davis Bill, Postle Anthony, Macphee Colin H
机构信息
GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
出版信息
PLoS One. 2014 Feb 20;9(2):e89034. doi: 10.1371/journal.pone.0089034. eCollection 2014.
BACKGROUND
The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.
METHODS
Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.
RESULTS
Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.
CONCLUSIONS
Short-term treatment (14 ± 4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.
背景
本研究旨在评估选择性口服研究性脂蛋白相关磷脂酶A2抑制剂达拉匹林对血浆和斑块脂蛋白相关磷脂酶A2活性的影响。
方法
接受择期颈动脉内膜切除术的患者被随机分为达拉匹林40毫克组（n = 34）、80毫克组（n = 34）或安慰剂组（n = 34），为期14天，在最后一剂研究药物服用24小时后进行颈动脉内膜切除术。
结果
与安慰剂相比，达拉匹林40毫克组和80毫克组分别使血浆脂蛋白相关磷脂酶A2活性降低了52%和81%（均P<0.001）。与安慰剂相比，斑块脂蛋白相关磷脂酶A2活性也显著降低（P<0.0001），与安慰剂相比分别降低了52%和80%。尽管在80毫克达拉匹林组观察到斑块基质金属蛋白酶-9 mRNA表达呈剂量依赖性降低（与安慰剂相比P = 0.053），但各组间斑块溶血磷脂酰胆碱含量或其他生物标志物未观察到显著差异。在事后分析中，发现80毫克达拉匹林组的斑块半胱天冬酶-3（P<0.001）和半胱天冬酶-8（P<0.05）活性显著低于安慰剂组。本研究未发现重大安全问题。
结论
达拉匹林短期治疗（14±4天）可使血浆脂蛋白相关磷脂酶A2活性产生显著的剂量依赖性降低。更重要的是，达拉匹林显示出经安慰剂校正后，颈动脉斑块脂蛋白相关磷脂酶A2活性有类似幅度的降低。达拉匹林总体耐受性良好，未发现安全问题。需要进行更长时间的额外研究，以探讨这些药效学效应是否如假设的那样与临床结局改善相关。
Zotero 插件