Safety and tolerability of 619C89 after acute stroke.
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.
Muir
K W
KW
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK.
Hamilton
S J
SJ
Lunnon
M W
MW
Hobbiger
S
S
Lees
K R
KR
D000208:Acute Disease; D000368:Aged; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000009:adverse effects*; D010879:Piperazines / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D016896:Treatment Outcome; D006113:United Kingdom
D018696:Neuroprotective Agents; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C081980:sipatrigine