Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
King's College London BHF Centre, Cardiovascular Division, Rayne Institute, St Thomas' Hospital, London, UK.
Lancet. 2014 Sep 27;384(9949):1187-95. doi: 10.1016/S0140-6736(14)60417-7. Epub 2014 Jun 12.
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.
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.
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.
p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes.
GlaxoSmithKline.
p38 MAPK 抑制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洛马普肽（一种有效的口服 p38 MAPK 抑制剂）在非 ST 段抬高型心肌梗死（NSTEMI）患者中的作用。
从 2009 年 10 月到 2011 年 11 月，NSTEMI 患者以 3:3:2 的比例随机分配接受口服洛马普肽（7.5mg 或 15.0mg 负荷剂量，随后每日两次 7.5mg）或匹配安慰剂。安全性结局为 12 周时的严重不良事件和丙氨酸氨基转移酶（ALT）浓度，以及 90 天时的心脏事件（死亡、心肌梗死、再发缺血、卒中和心力衰竭）。疗效结局为 72 小时和 12 周时的高敏 C 反应蛋白（hsCRP）和 B 型利钠肽（BNP）浓度，以及 72 小时时肌钙蛋白 I 曲线下面积（AUC）。将洛马普肽组合并进行分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT00910962。
在纳入的 535 例患者中，526 例（98%）至少接受了一次研究治疗（洛马普肽组 388 例，安慰剂组 138 例）。两组的安全性结局无差异。洛马普肽组的 hsCRP 浓度在 72 小时时低于安慰剂组（几何均数 64.1nmol/L，95%CI 53.0-77.6 与 110.8nmol/L，83.1-147.7；p=0.0009），但在 12 周时相似。72 小时时，早期的 BNP 浓度的几何均数相似，但在 12 周时洛马普肽组显著更低（37.2ng/L，95%CI 32.3-42.9 与 49.4ng/L，38.7-63.0；p=0.04）。肌钙蛋白 I AUC 的均值无差异。
NSTEMI 患者口服洛马普肽耐受性良好，可能改善急性冠脉综合征后的结局。
葛兰素史克公司。
