Did clinical trials in which erythropoietin failed to reduce acute myocardial infarct size miss a narrow therapeutic window?
Did clinical trials in which erythropoietin failed to reduce acute myocardial infarct size miss a narrow therapeutic window?
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DOI：
10.1371/journal.pone.0034819
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lakatta EG
中科院分区：
文献类型：
--
作者：
Talan MI;Ahmet I;Lakatta EG
为了验证在急性心肌梗死（MI）患者红细胞生成素阴性临床试验中，红细胞生成素（rhEPO）可以在狭窄的治疗窗口外给予的假设。尽管在动物研究中有大量证据表明rhEPO具有心脏保护作用，但最近结束的II期临床试验的结果未能证明rhEPO对急性心肌梗死患者的疗效。然而，在阴性临床试验中，rhEPO出现症状和给药之间的时间要比成功的动物实验长得多。在大鼠中，永久性结扎冠状动脉降支或阻断2小时后再灌注诱导心肌梗死。rhEPO, 3000 IU/kg，于再灌注时、再灌注开始后4小时、永久闭塞后6小时腹腔注射。冠状动脉闭塞后24小时组织学测量心肌梗死大小。各组心肌危险面积相似。未治疗大鼠心肌梗死面积平均为危险面积的42%，或左心室面积的24%，再灌注时接受rhEPO治疗的大鼠心肌梗死面积减少了50%以上（p<0.001）。心肌梗死大小不受再灌注后4小时或永久性冠状动脉闭塞后6小时治疗的影响。因此，我们对心肌梗死大鼠实验模型的研究表明，冠状动脉闭塞后2小时内给予rhEPO可有效减少心肌梗死大小，但如果延迟给予rhEPO，与临床试验中遇到的情况相似，则对心肌梗死大小没有影响。未能证明rhEPO对心肌梗死患者有效的临床试验可能错过了动物实验中定义的狭窄治疗窗口。
To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phase II clinical trials have failed to demonstrate the efficacy of rhEPO in patients with acute MI. However, the time between symptoms onset and rhEPO administration in negative clinical trials was much longer that in successful animal experiments. MI was induced in rats either by a permanent ligation of a descending coronary artery or by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000 IU/kg, was administered intraperitoneally at the time of reperfusion, 4 hrs after beginning of reperfusion, or 6 hrs after permanent occlusion. MI size was measured histologically 24 hrs after coronary occlusion. The area of myocardium at risk was similar among groups. The MI size in untreated rats averaged ∼42% of area at risk, or ∼24% of left ventricle, and was reduced by more than 50% (p<0.001) in rats treated with rhEPO at the time of reperfusion. The MI size was not affected by treatment administered 4 hrs after reperfusion or 6 hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administered within 2 hrs of a coronary occlusion effectively reduces MI size, but when rhEPO was administered following a delay similar to that encountered in clinical trials, it had no effect on MI size. The clinical trials that failed to demonstrate rhEPO efficacy in patients with MI may have missed a narrow therapeutic window defined in animal experiments.
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作者：
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DOI：
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