Department of Medicine, Radiology, Montreal Heart Institute and Université de Montréal, Montreal, Canada.
Circ Cardiovasc Imaging. 2010 May;3(3):298-307. doi: 10.1161/CIRCIMAGING.110.937169. Epub 2010 Feb 27.
Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor.
In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291-treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291-treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01).
VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.
5-脂氧合酶（5-LO）产生的白三烯与不稳定的动脉粥样硬化斑块和心血管事件有关。VIA-2291 是一种有效的 5-LO 抑制剂。
在一项双盲研究中，191 例急性冠状动脉综合征患者在发病后 3 周被随机分配，每天接受 25、50 或 100mg VIA-2291 或安慰剂治疗 12 周。所有 VIA-2291 组的主要研究终点，即全血刺激的白三烯 LTB4 在谷药物水平时，呈剂量依赖性降低（P<0.0001），100mg 组中约 90%的患者抑制率>80%。所有剂量组的尿白三烯 LTE4 均显著降低。没有严重的不良事件被认为与研究药物有关。在基线时进行了 64 层冠状动脉 CT 检查的 93 例患者亚组继续接受研究药物治疗，总共 24 周，并进行了重复扫描。其中 5 例患者退出或不遵守规定，28 例扫描结果不可评估。在其余 60 例患者中，18 例安慰剂治疗患者中有 5 例（27.8%）和 42 例 VIA-2291 治疗患者中有 2 例（4.8%）出现新的冠状动脉斑块（P=0.01）。在这些 60 例患者中有 34 例可分析的终点中，与安慰剂相比，VIA-2291 治疗组在 24 周时观察到非钙化斑块体积减少（P<0.01）。
VIA-2291 在急性冠状动脉综合征后 12 周时减少白三烯的产生。CT 亚研究的初步数据表明，这种白三烯产生的减少可能会影响动脉粥样硬化；然而，这需要在更大的研究中得到证实。临床试验注册-网址：http://www.clinicaltrials.gov。独特标识符：NCT00358826。
