SYSTEMIC AND CEREBRAL HEMODYNAMIC-RESPONSES TO THE NONCOMPETITIVE N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST CNS-1102

The excitatory amino acid antagonists are being developed as neuroprot ective drugs aimed at limiting ischemic neuronal damage. Their hemodyn amic and neurologic side effects are important in assessing safety and tolerability. We studied CNS 1102, a high-affinity noncompetitive N-m ethyl-D-aspartate (NMDA) receptor-channel antagonist, in normal volunt eers. The effects of 2 mg CNS 1102 were assessed in a single-blind, pl acebo-controlled, fixed-dose, cross-over trial comparing administratio n by intravenous infusion for 15 min or bolus for 2 min in 8 healthy m ale subjects. Cerebral hemodynamics were studied with carotid and vert ebral duplex ultrasound imaging, common carotid artery walltracking, a nd middle cerebral artery velocity readings, CNS 1102 administration w as associated with light-headedness, mild disorientation, perioral and peripheral paresthesias, and flushing. Mean arterial blood pressure ( MAP) increased significantly from baseline 1 h after CNS 1102 administ ration, with a maximal increase of 17 mm Hg over placebo. Pulse rate w as unchanged. Common carotid artery pulsatility decreased by 38.4% [8. 3-64.5, 95% confidence interval (CI)] and vertebral pulsatility by 43. 8% [11.5-74.1], both p < 0.02. No significant differences were detecte d for other velocity and flow parameters. Middle cerebral artery mean velocity increased by 4.6 cm/s (1.6-7.8 cm/s) and diastolic velocity b y 4.6 cm/s (2.4-7.3 cm/s) (both p < 0.01), but systolic velocity was u nchanged. The middle cerebral pulsatility index decreased by 11% (3.8- 16.1), p < 0.001. CNS 1102 is well tolerated at a fixed dose of 2 mg i n normal volunteers. Cerebral arteriolar constriction is inferred from the ultrasound results. In the presence of systemic hypertension, adv erse cerebral hemodynamic changes were not observed.