Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke

Background: The sodium channel blocker sipatrigine (619C89) prevents ischem ia-induced glutamate release and is neuroprotective in animal models of str oke. 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 wer e 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 rou tine laboratory analyses were undertaken, The outcome at 30 days or 3 month s was assessed by Barthel and Rankin scores. Results: Twenty-seven patients were recruited: 7 of 21 patients stopped the sipatrigine infusion early du e to adverse events as compared with none of 6 placebo patients. Neuropsych iatric effects (reduced consciousness, agitation, confusion, visual percept ual disturbance, or frank hallucinations) occurred in 16 of 21 patients rec eiving sipatrigine and in no placebo patients. Nausea, vomiting, infusion s ite reactions, and hyponatremia were also commoner in sipatrigine patients. Pharmacokinetic parameters were similar to those observed previously. No e ffects on outcome measures were demonstrated. Conclusions: Continuous infus ion of sipatrigine is associated with neuropsychiatric effects. No differen ce in the nature of these events was evident between this regimen and repea ted short infusions, but it was possible to administer higher doses. Copyri ght (C) 2000 S. Karger AG, Basel.