Safety and pharmacokinetics of the neuroprotective drug lubeluzole in patients with ischemic stroke.
A total of 22 patients with acute ischemic stroke participated in two randomized, single-masked, placebo-controlled studies that evaluated the safety and pharmacokinetics of single escalating intravenous doses of lubeluzole. The first dose of study medication in all patients was given within 6 hours of the first sign of stroke onset. In the first study, 6 patients received a single 1-hour intravenous infusion of 5 mg of lubeluzole; 4 of these patients received an additional 10-mg dose 3 to 4 days later. Two additional patients received placebo. In the second study, 4 patients received a single 1-hour infusion of 10 mg of lubeluzole, and 2 patients received placebo. After a safety evaluation of the second study, 6 additional patients received 15 mg of lubeluzole, and 2 other patients received placebo. Lubeluzole had no clinically relevant effects on any cardiovascular variable compared with placebo. The majority of adverse experiences were mild to moderate and resolved during treatment. No unexpected electroencephalogram abnormalities were observed, and no evidence of epileptiform discharges was found in any of the patients. At the end of the infusion, plasma lubeluzole concentrations decayed biphasically, with mean distribution half-lives of 46.3 to 101.0 minutes and mean terminal half-lives of 20.8 to 27.7 hours. Comparisons of the dose-normalized value of the individual plasma concentrations at the end of the infusion and the total area under the curve from time 0 to infinity suggested that lubeluzole exhibited linear kinetics over the dose range evaluated in patients with ischemic stroke. In the small number of patients studied, lubeluzole's favorable safety profile was demonstrated by the lack of clinically relevant effects on cardiovascular variables and by neurologic examination and clinical laboratory findings.
De Keyser
J
J
Department of Neurology, Academisch Ziekenhuis, Groningen, The Netherlands.
Van de Velde
V
V
Schellens
R L
RL
Hantson
L
L
Tritsmans
L
L
Gheuens
J
J
Van Peer
A
A
Woestenborghs
R
R
Franke
C L
CL
van Gorp
J
J
D000368:Aged; D002561:Cerebrovascular Disorders / Q000378:metabolism*; D004562:Electrocardiography / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D010880:Piperidines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D013844:Thiazoles / Q000009:adverse effects* / Q000493:pharmacokinetics*
D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; C097722:lubeluzole