Lapchak Paul A, Zivin Justin A
University of California San Diego, Department of Neuroscience, 9500 Gilman Drive MTF316, La Jolla, CA 92093-0624, USA.
Exp Neurol. 2009 Jan;215(1):95-100. doi: 10.1016/j.expneurol.2008.09.004. Epub 2008 Sep 26.
Edaravone is a lipophilic drug with multiple mechanisms of action. Because edaravone is a promising drug candidate for the treatment of stroke, we tested the hypothesis that edaravone would be neuroprotective following cerebral ischemia using a rabbit embolic stroke model with a well-defined behavioral endpoint. Using the rabbit small clot embolic stroke model (RSCEM), a drug or drug combination is considered beneficial if it significantly increases the amount of microclots (mg) measured in brain that produce neurologic dysfunction in 50% of a group of animals (P(50)) compared to the control group. Edaravone (100 mg/kg, s.c.), increased the P(50) value to 1.80+/-0.24 mg (p<0.05) when administered 5 min following embolization and increased P(50) values by 195% and 161% (compared to control) when administered 1 and 3 h following embolization, respectively, but was inactive when applied 6 h following embolization, compared to the cumulative control group (P(50)=0.93+/-0.16 mg). To simulate the design of current clinical trials, edaravone was also given following a standard tPA regimen, which by itself increased the P(50) value to 2.72+/-0.28 mg. When tPA was infused 1 h following embolization and edaravone was given 3 h following embolization, the P(50) was 2.68+/-0.56 mg. This study indicates that edaravone may have substantial therapeutic benefit for the treatment of AIS since it had a therapeutic widow of at least 3 h in rabbits. Edaravone can also be administered with a thrombolytic to improve behavior.
依达拉奉是一种具有多种作用机制的亲脂性药物。由于依达拉奉是治疗中风的一种有前景的候选药物，我们使用具有明确行为终点的兔栓塞性中风模型，检验了依达拉奉在脑缺血后具有神经保护作用的假设。使用兔小血栓栓塞性中风模型（RSCEM），如果一种药物或药物组合与对照组相比能显著增加在一组动物中50%（P(50)）产生神经功能障碍的脑内微血栓量（mg），则认为其有益。栓塞后5分钟给予依达拉奉（100mg/kg，皮下注射），P(50)值增加到1.80±0.24mg（p<0.05）；栓塞后1小时和3小时给予依达拉奉，P(50)值分别比对照组增加195%和161%，但与累积对照组（P(50)=0.93±0.16mg）相比，栓塞后6小时给予依达拉奉则无活性。为模拟当前临床试验的设计，依达拉奉也按照标准tPA方案给药，该方案本身可使P(50)值增加到2.72±0.28mg。当栓塞后1小时输注tPA且栓塞后3小时给予依达拉奉时，P(50)为2.68±0.56mg。这项研究表明，依达拉奉对急性缺血性中风的治疗可能具有显著的治疗益处，因为它在兔体内有至少3小时的治疗窗。依达拉奉也可与溶栓药物联合使用以改善行为。
