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document
Treatment of acute ischaemic stroke with the low-affinity , use-dependent NMDA antagonist AR-R15896AR . A safety and tolerability study . BACKGROUND AND PURPOSE A low-affinity , use-dependent N-Methyl-D-Aspartate ( NMDA ) antagonist AR-R15896AR has neuroprotective properties in animal models of ischaemic stroke . The aim of the present study was to examine the safety and tolerability of a new and higher dosage regimen that would enable acute stroke patients to achieve and maintain neuroprotective plasma concentrations . METHODS A randomised , multi-centre , double-blind , placebo-controlled , parallel group study was carried out at 19 centres in France , Germany and the Netherlands in patients with a clinical diagnosis of acute ischaemic stroke , and onset of symptoms within 12 hours before start of study drug administration . Two loading doses of 3.5 mg/kg of AR-R15896AR over 60 minutes , followed by a 2.5 mg/kg infusion over the next 120 minutes were given . Eight hours after the start of the loading dose infusion , the first maintenance dose ( 120 mg ) was administered over 60 minutes . Eight further maintenance infusions were administered at intervals of 8 hours over a total treatment period of 3 days . Main variables were safety , tolerability and pharmacokinetics . Follow-up assessments also included the Barthel Index ( BI ) and the NIH Stroke Scale ( NIHSS ) at 4-7 days after the end of the last infusion and at 30 days after the onset of stroke . RESULTS 103 patients with acute ischaemic stroke were randomised to either treatment with AR-R15896AR ( 70 patients ) or placebo ( 33 patients ) . Mortality was not significantly different in the AR-R15896AR group compared with the placebo group ( 10 % vs. 6 % ) . Serious adverse events during treatment due to psychiatric conditions were associated with AR-R15896AR ( 3 vs. 0 ) . Other side effects were more common in the group treated with AR-R15896AR : vomiting ( 29 % vs. 9 % ) , nausea ( 23 % vs. 12 % ) , fever ( 17 % vs. 12 % ) , agitation ( 7 % vs. 3 % ) , dizziness ( 7 % vs. 0 % ) , and hallucinations ( 6 % vs. 0 % ) . No significant difference between the two groups ( with respect to the proportions of patients with favourable outcome ) was detected in either the analysis of the BI or the NIHSS . Pharmacokinetic data showed that plasma concentrations of AR-R15896AR were in the expected neuroprotective range . CONCLUSION In most of the patients with acute stroke receiving AR-R15896AR the intended high plasma levels were reached within a short time period . However , active treatment produced more side effects than placebo , thus indicating safety concerns and tolerability issues for use in high doses in an acute stroke population .
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Intervention_Pharmacological
NMDA antagonist AR-R15896AR
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Intervention_Pharmacological
N-Methyl-D-Aspartate ( NMDA ) antagonist AR-R15896AR
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Intervention_Control
placebo-controlled
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Intervention_Pharmacological
Two loading doses of 3.5 mg/kg of AR-R15896AR
9110
Intervention_Pharmacological
AR-R15896AR
9111
Intervention_Control
placebo
9112
Intervention_Pharmacological
AR-R15896AR
9113
Intervention_Control
placebo
9114
Intervention_Pharmacological
AR-R15896AR
9115
Intervention_Pharmacological
AR-R15896AR
9116
Intervention_Pharmacological
AR-R15896AR
9117
Intervention_Pharmacological
AR-R15896AR
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Intervention_Control
placebo
9119
Outcome_Other
safety and tolerability
9120
Outcome_Other
safety , tolerability and pharmacokinetics .
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Outcome_Other
Barthel Index ( BI )
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Outcome_Other
NIH Stroke Scale ( NIHSS )
9123
Outcome_Mortality
Mortality
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Outcome_Adverse-effects
Serious adverse events
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Outcome_Adverse-effects
vomiting
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Outcome_Adverse-effects
nausea
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Outcome_Adverse-effects
fever
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Outcome_Adverse-effects
agitation
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Outcome_Adverse-effects
dizziness
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Outcome_Adverse-effects
hallucinations
9131
Outcome_Physical
plasma concentrations of AR-R15896AR
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Outcome_Physical
high plasma levels
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Outcome_Adverse-effects
side effects
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Participant_Condition
animal models of ischaemic stroke
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Participant_Condition
acute ischaemic stroke
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Participant_Sample-size
103 patients