Safety and tolerability study of aptiganel hydrochloride in patients with an acute ischemic stroke

Background and Purpose-Aptiganel (CNS 1102) is a selective, noncompetitive antagonist that acts on the ion channel associated with the N-methyl-D-aspa rtate (NMDA) receptor and is neuroprotective in experimental focal cerebral . ischemia models at a plasma concentration of 10 ng/mL. In human volunteer s, dose-limiting effects of aptiganel are blood pressure increases and cent ral nervous system (CNS) excitation or depression. This study assessed the safety and tolerability of non-weight-adjusted doses of aptiganel in patien ts with acute ischemic stroke. Methods-This was a double-blind, randomized, placebo-controlled multicenter study in patients presenting within 24 hours of acute ischemic stroke. Asc ending single intravenous bolus doses of aptiganel (3, 4.5, 6, and 7.5 mg) were assessed in 21 patients with a 3:1 active drug:placebo randomization s chedule. In 15 subsequent patients, selected bolus doses were followed by c onstant intravenous infusion for 6 to 12 hours (6 mg plus 1 mg/h, n=10; the n 4.5 mg plus 0.75 mg/h, n=15) in a 4: 1 randomization schedule. Prospectiv ely collected pharmacokinetic data guided selection of infusion rates. Neur ological and functional status were recorded at entry and after I week, alt hough the study was not designed to test efficacy. Results-Forty-six patients were randomized from 4 centers (3 in the United States and 1 in the United Kingdom): 36 received aptiganel HCl, and 10 were given placebo. Hypertension and CNS events were commonly reported after a bolus dose of 7.5 mg and after a 6-mg bolus followed by an infusion of 1 mg /h. The lower regimen of 4.5-mg bolus followed by infusion of 0.75 mg/h ach ieved plasma aptiganel concentrations of >10 ng/mL and was well tolerated b y patients but still raised systolic blood pressure by approximate to 30 mm Hg over baseline. Conclusions-A 4.5-mg intravenous bolus of aptiganel HCl followed by infusio n of 0.75 mg/h for 12 hours is a tolerable dose that can produce plasma dru g concentrations shown to be neuroprotective in animal models. However, inc reases in systolic blood pressure and an excess of CNS effects were both ob served at this dose.