Effect of Tirilazad Mesylate on Middle Cerebral Artery Occlusion/Reperfusion in Nonhuman Primates

Abstract

Agents with lipid membrane protective properties may theoretically reduce the zone of ischemic damage during cerebral arterial recanalization in the early hours of focal cerebral ischemia. The effect of the putative lipid peroxidation inhibitor tirilazad mesylate (U74006F) on infarction volume and neurological outcome following 3-hour middle cerebral artery occlusion and subsequent reperfusion in an awake baboon model was examined in a blinded, randomized placebo-controlled study. Awake subjects (8 each) were assigned randomly to receive either tirilazad mesylate (3 mg/kg) or matched vehicle given 15 min prior to reperfusion, and again at 2, 4, 12, and 24 h after reperfusion. Neurological status was serially assessed according to a quantitative scale and infarction volumes were computed on perfusion-fixed specimens at 14 days. A 40% reduction in mean total infarction volume index, normalized for basal ganglia volume, was seen in the tirilazad group. Persistent and increased improvement in mean neurological score with tirilazad infusion paralleled that of the placebo. Parallel studies on polymorphonuclear leukocyte responses indicated no significant changes in polymorphonuclear leukocyte reactivity. A reduction in infarction volume, predominantly in the cortex/subcortical white matter, and an improvement in neurological outcome were observed when tirilazad mesylate was given prior to reperfusion, but after the onset of focal cerebral ischemia.