Serum S-100B protein levels in left- and right-hemisphere strokes.

S-100B is a calcium-binding protein that is expressed in astrocytes. We compared the kinetics of serum S-100B in left- and right-hemisphere strokes. Data from 38 acute ischaemic stroke patients who had serial serum S-100B measurements during the first 8 days were analyzed. Stroke severity at baseline, as assessed by the National Institutes of Health Stroke Scale (NIHSS), was similar in the two groups. Mean S-100B values were greater in the right-hemisphere stroke group at all time points. Maximum S-100B levels were low in all patients with lower baseline NIHSS scores, and began to rise at a baseline NIHSS score of 16 for right-hemisphere stroke and 20 for left-hemisphere stroke. S-100B levels were significantly correlated with language in left-hemisphere stroke and with neglect in right-hemisphere stroke. These results are consistent with previous clinical/radiological findings, suggesting that serum S-100B is brain-specific and reflects the extent of brain injury in acute ischaemic stroke.

Pharmacokinetics of arundic acid, an astrocyte modulating agent, in acute ischemic stroke.

Arundic acid is an astrocyte modulating agent that improves neurological outcome in experimental acute stroke models. The pharmacokinetics of arundic acid in patients with acute ischemic stroke was investigated in a randomized, double-blind study. Six groups of 8 to 9 patients each received 2, 4, 6, 8, 10, or 12 mg/kg/h of arundic acid for a daily 1-hour infusion until completion of 7 doses. Maximum plasma concentrations of arundic acid increased with increasing dose; however, the systemic exposure was less than dose proportional at higher doses. The mean terminal half-life was approximately 2 to 3 hours. There was no excessive accumulation in plasma. Although systemic exposure in elderly patients was 30% greater than that in younger patients, the plasma concentration returned to nearly or below the limit of quantification prior to next administration. The pharmacokinetics of arundic acid in acute stroke patients assessed in this study were similar to that in healthy adults.

Safety and tolerability of arundic acid in acute ischemic stroke.

Arundic acid (AA; ONO-2506), a novel modulator of astrocyte activation, may improve neuronal survival after stroke. We conducted a multicenter, dose-escalating, randomized, double-blind Phase I trial of AA in acute ischemic stroke. Subjects were randomized to treatment with AA or placebo in sequential dose tiers of 2-12 mg/kg/h (10-16 patients/group) within 24 h of stroke onset. Study drug was infused for 1 h daily over 7 days, and follow-up terminated at 40 days. Neurological and functional outcomes were evaluated through Day 40 as exploratory endpoints. A total of 92 subjects were enrolled with no dose-related pattern of serious adverse events (AEs). Premature terminations caused by AEs occurred in four (8.2%) patients treated with AA and five (11.6%) treated with placebo. Two subjects treated with AA (4.1%) and four given placebo (9.3%) died. Exploratory efficacy analysis showed a trend toward improvement in the change from baseline National Institutes of Health Stroke Scale (NIHSS) in the 8 mg/kg/h AA group on Days 3 (p=0.023 vs. placebo), 7 (p=0.002), 10 (p=0.003), and 40 (p=0.018). A dose of 8 mg/kg/h AA produced a favorable trend in reduction of NIHSS that should be confirmed in a future clinical trial.

Effect of arundic acid on serum S-100beta in ischemic stroke.

We prospectively examined the effect of arundic acid (AA; ONO-2506) on S-100beta, an astrocyte-derived protein, in a phase I acute stroke study. Subjects with acute ischemic stroke were randomized to daily infusion of AA or placebo for 7 days. Serum S-100beta levels were assayed pre-infusion on Days 1-7 and post-infusion on Days 1, 3, and 7, and correlated with National Institutes of Health Stroke Scale (NIHSS). Samples were obtained from 86 subjects (46 AA, 40 placebo). Increase in S-100beta protein level from baseline was less in the AA cohort than in the placebo cohort at 7 (p=0.0471; t-test) and 12 (p=0.0095)-hours post-infusion on Day 3. Baseline NIHSS correlated with maximal S-100beta levels between Days 1 and 3 in the AA (r=0.51; p=0.0003) and placebo (r=0.41; p=0.0084) cohorts and in the pooled aggregate (n=86; r=0.46; p<0.0001). The same correlations were observed between Day 10 NIHSS and Day 1-3 maximum serum S-100beta levels. Treatment with AA was associated with lower serum levels of S-100beta after acute ischemic stroke. Our results showing correlation between S-100beta and NIHSS indicate that this protein is a clinically relevant marker of neurological deficit in acute stroke.