title: Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers.
abstract: Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
authors.affiliation: University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland.
authors.forename: K W
authors.initials: KW
authors.lastname: Muir
authors.forename: D G
authors.initials: DG
authors.lastname: Grosset
authors.forename: K R
authors.initials: KR
authors.lastname: Lees
mesh_terms: D000293:Adolescent; D000328:Adult; D000804:Angiotensin II / Q000097:blood; D002395:Catecholamines / Q000097:blood; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006146:Guanidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012083:Renin / Q000097:blood
chemical_list: D002395:Catecholamines; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D016194:Receptors, N-Methyl-D-Aspartate; D000804:Angiotensin II; C079779:aptiganel; D012083:Renin