Hasegawa Y, Fisher M, Baron B M, Metcalf G
Dept. of Neurology, Medical Center of Central Massachusetts-Memorial, Worcester 01605.
Stroke. 1994 Jun;25(6):1241-4; discussion 1245-6. doi: 10.1161/01.str.25.6.1241.
The competitive N-methyl-D-aspartate antagonist MDL-100,453 was used to determine whether a neuroprotective effect is demonstrable when the drug is administered beginning 30 minutes after the initiation of focal ischemia and whether the effect is related to blood levels of the drug.
Forty-eight Sprague-Dawley rats were randomly assigned to one of four intravenous treatment categories: a bolus of 100 mg/kg MDL-100,453 followed by a saline infusion for 24 hours, isotonic saline as a bolus and 100 mg/kg per 24 hours of MDL-100,453 as an infusion over 24 hours, active drug in the bolus and 24-hour infusion, and control treatment of an isotonic saline bolus and infusion. Focal cerebral ischemia was induced by the intraluminal suture, middle cerebral artery occlusion method. The drug infusion was accomplished by an osmotic minipump implanted under the skin and attached to the jugular vein, which delivered drug or vehicle over a period of 24 hours. Infarct volume was calculated using 2,3,5-triphenyltetrazolium chloride staining after 24 hours of middle cerebral artery occlusion.
Infarct volume of animals that received the MDL-100,453 bolus injection followed by MDL-100,453 infusion was significantly smaller than that of controls (P < .01). A significant effect of infusion on the reduction of extent of infarct size was also demonstrated (P = .015). Moreover, a statistically significant inverse correlation was demonstrated between the infarct volume and blood levels of MDL-100,453 at 60 minutes and 120 minutes after injection (r = -.33 and r = -.49, respectively).
We demonstrated a significant neuroprotective effect of MDL-100,453 when treatment was initiated 30 minutes after ischemia began and was maintained for 24 hours.
使用竞争性N-甲基-D-天冬氨酸拮抗剂MDL-100,453来确定在局灶性缺血开始30分钟后给药时是否能证明其具有神经保护作用，以及该作用是否与药物的血药浓度有关。
48只Sprague-Dawley大鼠被随机分为四个静脉治疗组之一：静脉推注100mg/kg MDL-100,453，随后输注生理盐水24小时；静脉推注等渗盐水，每24小时静脉输注100mg/kg MDL-100,453共24小时；静脉推注活性药物并静脉输注24小时；静脉推注和输注等渗盐水作为对照治疗。采用管腔内缝合、大脑中动脉闭塞法诱导局灶性脑缺血。通过植入皮下并连接到颈静脉的渗透微型泵进行药物输注，该微型泵在24小时内输送药物或赋形剂。大脑中动脉闭塞24小时后，使用2,3,5-三苯基氯化四氮唑染色计算梗死体积。
接受MDL-100,453静脉推注后再进行MDL-100,453输注的动物梗死体积显著小于对照组（P<.01）。输注对梗死面积缩小也有显著作用（P=.015）。此外，注射后60分钟和120分钟时，梗死体积与MDL-100,453血药浓度之间存在统计学显著的负相关（分别为r=-.33和r=-.49）。
我们证明了MDL-100,453在缺血开始30分钟后开始治疗并持续24小时时具有显著的神经保护作用。
