Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke.
OBJECTIVE
GV150526 is a novel glycine site antagonist at the N-methyl-D-aspartate receptor complex. It is a potent neuroprotective agent in animal models of stroke, including permanent middle cerebral artery occlusion in the rat. Unlike antagonists at the glutamate ligand binding site, GV150526 appears to be free of hemodynamic and central nervous system adverse effects. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of loading and maintenance infusions of GV150526 in patients with acute stroke.


METHODS
This was a randomized, placebo-controlled, parallel-group, ascending-dose study conducted in 2 phases. In part A of the study, loading doses of 50, 100, 200, 400, or 800 mg were administered. In part B, the maximum loading dose from part A was followed by maintenance infusions (5 infusions at 12-hour intervals), aiming to maintain neuroprotective levels. Safety data were collected throughout. The study was not designed to test efficacy, but outcome data (Barthel Index and National Institutes of Health Stroke Scale) were collected.


RESULTS
Sixty-six patients were recruited to the study over 11 months; 18 patients received placebo. GV150526 was well tolerated by the 48 patients who received it. There was no excess of central nervous system or hemodynamic adverse events compared with placebo. Minor abnormalities in liver function tests were observed in association with the higher maintenance doses tested. Four of 7 patients receiving the 800-mg loading dose followed by 400 mg BID and 1 of 6 patients who received the 200-mg BID maintenance dose showed a small rise in bilirubin, and 3 patients had increases in transaminases; the mean values at 72 hours remained under twice the upper limit of normal. These changes were asymptomatic and resolved within 10 days.


CONCLUSIONS
GV150526 is an emerging neuroprotective agent, with no apparent significant central nervous system or hemodynamic effects. Dose-limiting effects appear to be restricted to mild transient and asymptomatic rises in bilirubin and/or transaminases, primarily observed at high maintenance doses, and there were no findings that should preclude further clinical development.
Dyker
A G
AG
Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland. ad47q@clinmed.gla.ac.uk
Lees
K R
KR
D000208:Acute Disease; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D004562:Electrocardiography; D005260:Female; D018684:Glycine Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D010349:Patient Compliance; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D005723:gamma-Glutamyltransferase / Q000097:blood
C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D018684:Glycine Agents; D007211:Indoles; D016194:Receptors, N-Methyl-D-Aspartate; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin