Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, and Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Int J Cardiol. 2022 Oct 15;365:34-40. doi: 10.1016/j.ijcard.2022.07.016. Epub 2022 Jul 14.
Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study.
Patients 7-28 days after myocardial infarction (±ST elevation), with <50% left anterior descending coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4- and 12-week cohorts. Change in urine leukotriene E (uLTE) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint.
Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE levels of >80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths.
In patients with recent myocardial infarction, AZD5718 was well tolerated, and leukotriene biosynthesis was dose-dependently inhibited. No significant changes in CFVR were detected.
gov identifier: NCT03317002.
白三烯是一种促炎的血管活性脂质介质，与动脉粥样硬化性心血管疾病的病理生理学有关。我们在一项单盲、2a 期研究中研究了 5-脂氧合酶激活蛋白抑制剂 AZD5718 对白细胞三烯生物合成和冠状动脉微血管功能的影响。
心肌梗死后 7-28 天（±ST 抬高）、经皮冠状动脉介入治疗后左前降支冠状动脉狭窄<50%且血栓溶解心肌梗死血流分级≥2 的患者，按 2:1:2 的比例随机分为 AZD5718 200mg 或 50mg 每日一次组或安慰剂组，共 4 周和 12 周两个队列。尿液白细胞三烯 E（uLTE）的变化为主要终点，冠状动脉血流速度储备（CFVR；通过超声心动图）为关键次要终点。
在 129 名随机患者中，128 名患者接受了治疗（200mg 组 n=52；50mg 组 n=25；安慰剂组 n=51）。在 4 周和 12 周时，与安慰剂组相比，AZD5718 组 uLTE 水平均显著降低>80%。与安慰剂相比，AZD5718 组 CFVR 无明显变化。在接受 200mg、50mg 和安慰剂的 4 周队列中，分别有 12/18、3/6 和 6/13 例患者和 27/34、14/19 和 24/38 例患者发生不良反应（AE），在接受 200mg、50mg 和安慰剂的 12 周队列中，分别有 27/34、14/19 和 24/38 例患者发生不良反应（AE）。7 例接受 AZD5718 治疗的患者和 4 例接受安慰剂的患者发生了 7 例严重不良事件，均与治疗无关，无死亡病例。
在近期心肌梗死患者中，AZD5718 耐受性良好，白细胞三烯生物合成呈剂量依赖性抑制。未检测到 CFVR 有显著变化。
gov 标识符：NCT03317002。
