(Stroke. 1995;26:602-605.)
© 1995 American Heart Association, Inc.
Articles |
Safety and Tolerability of the Glutamate Antagonist CGS 19755 (Selfotel) in Patients With Acute Ischemic Stroke
Results of a Phase IIa Randomized Trial
Presented at the 19th International Joint Conference on Stroke and Cerebral Circulation, San Diego, Calif, February 17-19, 1994.
From the Department of Neurology, University of Texas Health Science Center, Houston, Tex (J.G.); the Oregon Health Science University, Portland, Ore (W.C., B.C.); the Department of Neurology, University of Kentucky (Lexington) (L.C.P.); the Atlanta Neurologic Institute, Riverdale, Ga (B.M.); Duke University Medical Center, Durham, NC (L.B.G.); the Department of Neurology, Mayo Clinic, Rochester, Minn (I.M.); and the Pharmaceutical Division, CIBA-GEIGY Corporation, Summit, NJ (L.L., D.M.).
Correspondence to James Grotta, MD, University of Texas Health Science Center, Department of Neurology, 6431 Fannin, Room 7044, Houston, TX 77030.
Background and Purpose CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist that limits neuronal damage in animal stroke models. The objectives of this multicenter (7 centers), randomized, double-blind, placebo-controlled, ascending-dose phase IIa study were to evaluate the safety and tolerability of CGS 19755 and obtain pharmacokinetic and preliminary data on its efficacious dose range in patients treated within 12 hours of hemispheric ischemic stroke.
Methods At each dose level, 6 patients were randomized to one or two intravenous bolus doses of CGS 19755, and 2 patients were randomized to placebo. An unblinded safety and monitoring committee evaluated results at each dose before ascending to the next level. All patients at the first level (1 mg/kg) received two doses separated by 12 hours. The first 2 patients at 2 mg/kg received two doses, but adverse experiences occurred in both; subsequent patient groups received single doses of 2.0, 1.75, or 1.5 mg/kg.
Results Adverse experiences (agitation, hallucinations,
confusion, paranoia, and delirium) occurred in all 6 patients treated
with 2 mg/kg, and in 3 of 5 at 1.75 mg/kg. Similar but milder adverse
experiences were noted in 4 of 7 patients at 1.5 mg/kg and 1 of 6
patients at 1.0 mg/kg. Adverse experiences began between 20 minutes and
22 hours (mean, 8 hours) after treatment and lasted 2 to 60 hours
(mean, 24 hours). Mortality was 1 of 8 in patients receiving placebo
and 3 of 24 in treated patients. In treated survivors, median and mean
percent improvement in National Institutes of Health Stroke Scale
scores from baseline to terminal visit (mean, 86 days) was comparable
at all doses, and 95% of treated patients had Barthel Index scores of
70 at the terminal visit.
Conclusions We conclude that a single intravenous dose of 1.5 mg/kg CGS 19755 is safe and tolerable in patients with acute ischemic stroke. An efficacy trial is indicated.
Key Words: cerebral ischemia • glutamate antagonists • glutamates • neuroprotection
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