Lu Aigang, Kurosawa Yuko, Luskey Kenneth, Pyne-Geithman Gail, Caudell Danielle, Clark Joseph
Department of Neurology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH, USA.
Neurol Res. 2009 Mar;31(2):209-14. doi: 10.1179/174313209X393933.
Recanalization therapies for ischemic stroke have been slow to change clinical practice because of perceived and published risks of hemorrhage associated with lytic administration. We quantified alfimeprase in an acute ischemia-reperfusion model, as compared with recombinant tissue plasminogen activator, with hemorrhagic transformation as the primary endpoint and infarction volume and blood-brain barrier permeability as secondary endpoints.
Five groups were studied in a blinded fashion: alfimeprase at doses of 0.03 (n=8), 0.1 (n=11) and 0.3 mg/kg (n=8); recombinant tissue plasminogen activator at 1 mg/kg (n=9); carrier infused controls (n=9). The middle cerebral artery was occluded for 5 hours followed by removal of the suture for reperfusion. Drugs were infused immediately following reperfusion over a 10-minute period. Approximately 24 hours later, the animals were anesthetized and decapitated, and the brains were rapidly harvested and frozen. Serial brain sections were obtained and inspected for hemorrhages. Infarction and blood-brain barrier permeability were also evaluated in additional experiments in control, 0.1 mg/kg alfimeprase and 1 mg/kg recombinant tissue plasminogen activator-treated rats.
The hemorrhagic transformation frequency, neurological deficit and the mortality rate of alfimeprase were significantly lower than for recombinant tissue plasminogen activator at the 0.03 mg/kg dose and not statistically different at the higher doses. Infarction and blood-brain barrier permeability were not significantly different among control, 0.1 mg/kg alfimeprase and recombinant tissue plasminogen activator.
In this model, alfimeprase, a new fibrinolytic agent, exhibits a profile comparable to recombinant tissue plasminogen activator.
由于与溶栓给药相关的出血风险已被认识到并发表，缺血性中风的再通疗法在改变临床实践方面进展缓慢。我们在急性缺血再灌注模型中对阿夫米普酶进行了定量分析，将重组组织型纤溶酶原激活剂作为对照，以出血性转化为主要终点，梗死体积和血脑屏障通透性为次要终点。
对五组进行盲法研究：剂量为0.03mg/kg（n = 8）、0.1mg/kg（n = 11）和0.3mg/kg（n = 8）的阿夫米普酶组；1mg/kg的重组组织型纤溶酶原激活剂组（n = 9）；载体输注对照组（n = 9）。大脑中动脉闭塞5小时，然后移除缝线进行再灌注。再灌注后立即在10分钟内输注药物。约24小时后，将动物麻醉并断头，迅速取出大脑并冷冻。获取连续的脑切片并检查出血情况。在对照、0.1mg/kg阿夫米普酶和1mg/kg重组组织型纤溶酶原激活剂治疗的大鼠的额外实验中，还评估了梗死和血脑屏障通透性。
在0.03mg/kg剂量下，阿夫米普酶的出血性转化频率、神经功能缺损和死亡率显著低于重组组织型纤溶酶原激活剂，在较高剂量下无统计学差异。对照、0.1mg/kg阿夫米普酶和重组组织型纤溶酶原激活剂之间的梗死和血脑屏障通透性无显著差异。
在该模型中，新型纤溶药物阿夫米普酶表现出与重组组织型纤溶酶原激活剂相当的特性。
