EFFECTS OF PROLONGED INFUSIONS OF THE NMDA ANTAGONIST APTIGANEL HYDROCHLORIDE (CNS-1102) IN NORMAL VOLUNTEERS

Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channe l-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neurop rotective in focal cerebral ischemia. Short intravenous infusions of u p to 30 mu g/kg have been well tolerated by healthy male volunteers. W e undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascul ar and psychomotor effects of a dosing paradigm similar to that envisa ged for therapeutic use. Aptiganel HCl was infused over 4 h in total d oses of 15, 32, 50, or 73 mu g/kg. Mean arterial pressure increased si gnificantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r(2) = 0.21 , p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 mu g/kg . Higher doses were associated with motor retardation, perceptual dist urbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 mu g/kg of aptiganel HCl infused over 4 h are well tolerated by healt hy males. Aptiganel HCl causes elevation of blood pressure and is asso ciated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.