Safety study of tirilazad mesylate in patients with acute ischemic stroke (STIPAS).
OBJECTIVE
Tirilazad mesylate, a 21-amino-steroid, is a potent membrane lipid peroxidation inhibitor and free radical scavenger that has shown promise in animal models of focal cerebral ischemia. Safety in patients with acute ischemic stroke has not yet been established.


METHODS
The study comprised a randomized (three drugs to one vehicle), vehicle-controlled, double-blind, sequential dose-escalation trial at five centers. Treatment was begun within 12 hours of stroke onset and was continued intravenously for 3 days.


RESULTS
One hundred eleven patients (mean +/- SD age, 66 +/- 13 years; 56% male) were enrolled in three successive dosage tiers: 36 at 0.6 mg/kg per day, 35 at 2.0 mg/kg per day, and 40 at 6.0 mg/kg per day. Median time from stroke onset to treatment was 8.5 (range, 3 to 12) hours and was not significantly different among the groups. Tirilazad was well tolerated at all three doses, except for mild-to-moderate injection site irritation that occurred in both the tirilazad- and vehicle-treated groups. No significant differences in measures of either cardiac or hepatic toxicity were observed in this small sample. Imbalances in baseline medical and neurological condition made comparisons of outcome difficult. Although no evidence suggestive of tirilazad efficacy was apparent in this study, the trial was not designed to test for differences in outcome.


CONCLUSIONS
These observations suggest that intravenous tirilazad at doses of up to 6.0 mg/kg per day for 3 days is well tolerated in this population of predominantly elderly stroke patients. Larger studies with earlier treatment will be needed to demonstrate efficacy.
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville 22908.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy*; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers; D006801:Humans; D007262:Infusions, Intravenous; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D011281:Pregnatrienes / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D011281:Pregnatrienes; C053355:tirilazad