Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke.
BACKGROUND
The sodium channel blocker sipatrigine (619C89) prevents ischemia-induced glutamate release and is neuroprotective in animal models of stroke. Previous clinical experience found neuropsychiatric effects attributed to sipatrigine that may have been related to peak plasma concentrations of the drug.


METHODS
Patients within 12 h of clinically diagnosed stroke were randomized to placebo or sipatrigine at total doses of 10, 18, 27, or 36 mg/kg by continuous intravenous infusion over 65 h. Pharmacokinetic and routine laboratory analyses were undertaken. The outcome at 30 days or 3 months was assessed by Barthel and Rankin scores.


RESULTS
Twenty-seven patients were recruited: 7 of 21 patients stopped the sipatrigine infusion early due to adverse events as compared with none of 6 placebo patients. Neuropsychiatric effects (reduced consciousness, agitation, confusion, visual perceptual disturbance, or frank hallucinations) occurred in 16 of 21 patients receiving sipatrigine and in no placebo patients. Nausea, vomiting, infusion site reactions, and hyponatremia were also commoner in sipatrigine patients. Pharmacokinetic parameters were similar to those observed previously. No effects on outcome measures were demonstrated.


CONCLUSIONS
Continuous infusion of sipatrigine is associated with neuropsychiatric effects. No difference in the nature of these events was evident between this regimen and repeated short infusions, but it was possible to administer higher doses.
Muir
K W
KW
Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK. k.muir@clinmed.gla.ac.uk
Holzapfel
L
L
Lees
K R
KR
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D015222:Sodium Channels / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D010879:Piperazines; D011743:Pyrimidines; D015222:Sodium Channels; D005973:Glutamine; C081980:sipatrigine