Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial
Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial
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DOI：
10.1016/s0140-6736(14)60417-7
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发表时间：
2014-09-27
期刊：
影响因子：
168.9
通讯作者：
Granger, Christopher B.
中科院分区：
文献类型：
--
作者：
Newby, L. Kristin;Marber, Michael S.;Granger, Christopher B.
背景：抑制p38MAPK具有潜在的心肌保护作用。我们在一项双盲、随机、安慰剂对照试验中评估了口服有效的p38 MAPK抑制剂洛司帕莫特对非ST段抬高心肌梗死(NSTEMI)患者的疗效。5毫克或15毫克。负荷量为0 mg，后7 mg。每日两次，每次5毫克)或以3：3：2的比例配对安慰剂。安全性结果是超过12周的严重不良事件和丙氨酸氨基转移酶(ALT)浓度，以及90天的心脏事件(死亡、心肌梗死、复发性缺血、中风和心力衰竭)。观察治疗后72 h和12周的超敏C反应蛋白(HsCRP)和B型利钠肽(BNP)浓度，以及72 h以上肌钙蛋白I曲线下面积(AUC)。这项试验在ClinicalTrials.gov注册，编号为NCT00910962。研究发现，526名患者(98%)接受了至少一剂研究治疗(洛斯帕莫德n=388，安慰剂n=138)。不同组之间的安全结果没有差异。洛司帕莫组72小时的超敏C反应蛋白浓度低于安慰剂组(几何平均值)。1nmol/L，95%可信区间53。0比77。6比110。8nmol/L，83岁。1-147。7；p=0。0009)，但在12周时相似。早期几何平均BNP浓度在72 h时相似，但在12周时显著低于losmapimod组(37。2 ng/L，95%可信区间32。3-42。9比49。4 ng/L，38。7-63。0；p=0。04)。肌钙蛋白I的平均AUC值没有差异。口服洛莫帕米对p38MAPK的抑制在NSTEMI患者中耐受性良好，并可能改善急性冠状动脉综合征后的预后。
Background p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial.Methods From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7 . 5 mg or 15 . 0 mg loading dose followed by 7 . 5 mg twice daily) or matching placebo in a 3: 3: 2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962.Findings Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64 . 1 nmol/L, 95% CI 53 . 0-77 . 6 vs 110 . 8 nmol/L, 83 . 1-147 . 7; p=0 . 0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37 . 2 ng/L, 95% CI 32 . 3-42 . 9 vs 49 . 4 ng/L, 38 . 7-63 . 0; p=0 . 04). Mean troponin I AUC values did not differ.Interpretation p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes.