Safety and tolerability of 619C89 after acute stroke.

Abstract

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/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.

• Authors: K W Muir, S J Hamilton, M W Lunnon, S Hobbiger, K R Lees
• Journal: Cerebrovascular diseases (Basel, Switzerland) (Cerebrovasc Dis) 1998 Jan-Feb Vol. 8 Issue 1 Pg. 31-7 ISSN: 1015-9770 [Print] Switzerland
• PMID: 9645979 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• Neurotransmitter Uptake Inhibitors
• Piperazines
• Pyrimidines
• sipatrigine

Topics

• 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)
• Piperazines (adverse effects)
• Pyrimidines (adverse effects)
• Treatment Outcome
• United Kingdom