mdl-100453 and Cerebral-Infarction

The competitive N-methyl-D-aspartate antagonist MDL-100,453 has been shown to attenuate ischemic cell damage when administered after permanent focal cerebral ischemia. The aim of the present study was to measure the dose-response of cerebral infarcted volume to the agent administered 30 min after permanent middle cerebral artery occlusion and to test whether short-term infusion of this drug reduces ischemic cell damage. Thirty-five Sprague-Dawley rats were randomly assigned to 4 groups: low dose group, a bolus of 12.4 mg/kg MDL-100,453 followed by infusion of 31.7 mg/kg/h MDL-100,453; middle and high dose groups, bolus and infusion doses increased to 24.8 mg/kg, 63.3 mg/kg/h and 49.6 mg/kg, 126.7 mg/kg/h, respectively; and control group, saline used for bolus and infusion. Middle cerebral artery occlusion (MCAO) was induced by insertion of intraluminal suture. The infusion was accomplished by a microprocessor controlled pump connected to a jugular vein, which delivered drug or saline over a period of 9 h. Infarct volume was calculated using 2,3,5-triphenyltetrazolium chloride staining 24 h after MCAO. The infarct volumes were significantly reduced in both middle (46%) and high (52%) dose groups compared with the saline group (p < 0.05). No reduction of infarct volume was found in the low dose group. A statistically significant (p < 0.05), but poor inverse correlation existed between the average blood level of MDL-100,453 and infarct volume. We demonstrated that a short-term (9 h) intravenous administration of an appropriate dose of MDL-100,453 beginning 30 min after MCAO significantly reduces ischemic lesion volume at 24 h after onset of permanent focal cerebral ischemia.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Cerebral Arteries; Cerebral Infarction; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Valine

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.

Topics: Animals; Blood Pressure; Body Temperature; Brain; Carbon Dioxide; Cerebral Arteries; Cerebral Infarction; Infusion Pumps; Injections, Intravenous; Ischemic Attack, Transient; Male; N-Methylaspartate; Pilot Projects; Placebos; Rats; Rats, Sprague-Dawley; Valine