Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients

Abstract

Background and Purpose-AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR. Methods-This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, nϭ36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (nϭ33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (nϭ59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (nϭ42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy. Results-Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524Ϯ536 ng/mL at the end of the 250-mg loading infusion and were 1847Ϯ478 ng/mL at steady state after the 9 maintenance doses of 120 mg. Conclusions-The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain. (Stroke. 2001;32:466-472.)

Blood Glutamate Scavenging as a Novel Neuroprotective Treatment for Paraoxon Intoxication

“…3,16 N-Methyl-D-aspartate receptor antagonists also failed to fill their optimistic prognosis, as none of the treatments that showed preclinical promise are available to date. 17,18 The maintenance of brain extracellular Glu at levels below its excitotoxic threshold is performed not only by Glu transporters located on glia and neurons but also by those present on the antiluminal side of the brain capillary endothelial cells. 19,20 These transporters remove the excess extracellular brain Glu into the blood stream.…”

Treatment of acute ischaemic stroke with the low-affinity, use-dependent NMDA antagonist AR-R15896AR

“…This might raise a concern taking into account the neurotoxic properties reported from a study in stroke with another NMDA antagonist [4]. However, in an earlier study in stroke patients a lower mortality rate was observed in the AR-R15896AR group [10]. As expected the primary cause of death was the neurological damage from the initial stroke.…”

“…Ascending loading and maintenance doses were tested in 175 patients with acute ischaemic stroke [10]. A loading dose of 250 mg AR-R15896AR and maintenance doses of 120 mg tid for three days were well tolerated.…”

“…The upper limit is based on the lowest concentration known to induce seizures in dogs [AstraZeneca, data on file]. In the study reported by Lees et al, the concentrations of AR-R15896AR reached during the maintenance phase of the treatment were in the neuroprotective range, but concentrations after the loading dose were not sufficiently high to produce neuroprotection [10]. Mean (SD) concentration at the end of the loading dose (C max ) was 1524 ± 536 ng/mL but after 8 hours, just before start of the maintenance dose regimen, the concentrations were down to 784 ± 101 ng/mL.…”

Clinical pharmacological issues in the development of acute stroke therapies

“…Mild-tomoderate hypothermia with cooling to 331C initiated within 2 h of cardiac arrest (Bernard et al, 2002) increased the likelihood of a good outcome (26-49%). The clinical development of AR-R15896AR was discontinued after phase II studies demonstrated adverse effects of dizziness, vomiting, nausea, stupor, agitation and hallucinations at plasma concentrations just after achieving the neuroprotective plasma concentrations (Lees et al, 2001;Diener et al, 2002). These adverse effects were seen with other NMDA antagonists taken through to clinical development and were a limiting factor in optimizing dosing (Muir and Lees, 1995).…”