Safety and Tolerability of 619C89 after Acute Stroke

• Published in: Cerebrovascular diseases (Basel, Switzerland) Vol. 8; no. 1; pp. 31 - 37
• Main Authors: Muir, Keith W., Hamilton, Steven J.C., Lunnon, Martin W., Hobbiger, Stephen, Lees, Kennedy R.
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.1998
• Subjects: Acute Disease; Aged; Cerebrovascular Disorders - drug therapy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuroprotective Agents - adverse effects; Neurotransmitter Uptake Inhibitors - adverse effects; Original Paper; Piperazines - adverse effects; Pyrimidines - adverse effects; Treatment Outcome; United Kingdom; Clinical trial; Excitatory amino acid; Sodium channel blocker
• ISSN: 1015-9770; 1421-9786
• DOI: 10.1159/000015812

Background: 619C89 is a use-dependent sodium channel blocker which reduces hemispheric infarction volume by up to 60% after permanent middle cerebral artery occlusion in rats. Intravenous doses of up to 1 mg/kg have been well tolerated by healthy young and elderly volunteers. This study sought to assess safety and tolerability of 619C89 in the treatment of acute stroke. Methods: Patients were randomised within 12 h of onset of stroke to receive 619C89 or placebo as an intravenous loading dose, followed by maintenance doses given 8 hourly for 64 h in a double-blind, ascending-dose tolerance study. Dosing commenced at 0.5 mg/kg loading plus 0.25 mg/kg/8 h maintenance for the first group and increased in increments of 0.5 mg/kg loading +0.25 mg/kg/8 h maintenance thereafter. Safety evaluation was continued for 3 months. Results: 48 patients were recruited. 12 received placebo and 36 received 619C89 in doses up to 2.5 mg/kg loading plus 1.25 mg/kg/8 h. Dose escalation was stopped after the occurrence of hallucinations in 5 of 18 patients who received 2 mg/kg +1 mg/kg/8 h or more. Gastro-intestinal upset and confusion were also possibly drug related. No drug-related effects on cardiovascular function were found. Conclusions: 619C89 was associated with significant central nervous system side-effects at doses of 2 mg/kg +1 mg/kg/8 h or greater as discrete intravenous infusions within 12 h of stroke onset. It may also cause gastro-intestinal side-effects. Doses below this are well tolerated in patients. No adverse cardiovascular effects were seen.