Remacemide Hydrochloride

Abstract

Background and Purpose-Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity noncompetitive N-methyl-D-aspartate (NMDA)-receptor channel blockers. Remacemide hydrochloride has demonstrated neuroprotection in animal models of hypoxia and ischemic stroke. This study assessed the safety, tolerability, and pharmacokinetics of ascending doses of remacemide hydrochloride in patients with recent onset (within 12 hours) ischemic stroke. Methods-This was a placebo-controlled, dose escalating, parallel group study. Groups of 8 patients (6 active, 2 placebo) were planned to receive twice-daily treatment, with l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg remacemide hydrochloride given as 2 intravenous infusions followed by 6 days' oral treatment. Patients who were unable to swallow discontinued study medication but continued to be monitored for safety; these patients were replaced. A CT or MRI scan was performed within 48 hours of admission to establish the cause of focal neurological deficit. Patients with ischemic stroke continued in the study. Patients with other causes of focal neurological deficit were withdrawn and replaced. Because the frequency of dysphagia after stroke in the first dose group (l00 mg BID) was higher than had been anticipated, the protocol was amended so that subsequent dose groups received 6 intravenous infusions (2 doses per day for 3 days). Neurological and functional outcome data were collected, but the study was not powered to demonstrate drug efficacy. Patient safety was assessed by clinical observation, laboratory tests, and ECGs, while tolerability was assessed by recording adverse events. Blood sampling was included to determine plasma concentrations of remacemide and the desglycinyl metabolite at fixed points during the dosing period. Results-The most common adverse events considered by the investigator to be possibly treatment related were related to the central nervous system (CNS), and these events appeared to increase with dose. Four patients were withdrawn from the study because of CNS-related events: 1 in the placebo group, 1 in the 500 mg BID group, and 2 in the 600 mg BID group. Infusion site reactions and gastrointestinal upset were also reported and considered to be treatment related. One patient in the placebo group and 4 patients in the 600 mg BID dose group experienced vomiting, whereas this event was not reported by patients in the other dose groups. Conclusions-On the evidence of this study, the maximum well-tolerated dose for remacemide hydrochloride in acute stroke is 400 mg BID. Doses of 200 mg BID or higher attained the putative neuroprotective plasma concentrations of remacemide predicted from animal models (250 to 600 ng/mL). The expected gradual accumulation of active metabolite might suggest that optimal neuroprotective concentrations are unlikely to be achieved within the early hours of treatment at this dose. However, plasma concentrations do not directly reflect brain concentrations, because studies in rats show that remace...

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“…519 Although remacemide may lower the frequency of ischemic neurological complications associated with cardiac surgery, its effectiveness in the setting of stroke is not established. 520, 521 The NMDA antagonist AR-R15896AR was tested in a clinical trial, but side effects, including psychiatric disturbances, meant that the agent could not be tolerated by the patient. 522 A preliminary study of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist ZK 200775 showed that the medication led to declines in consciousness and possible neurological worsening.…”

MRI-Based Neuroanatomical Predictors of Dysphagia after Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

“…1). Two articles were randomized controlled trials [38,39]. We eliminated them because MRI outcomes were not reported.…”

Therapeutic Effects of Coenzyme Q10and Remacemide in Transgenic Mouse Models of Huntington's Disease

“…Remacemide attenuates excitotoxicity in vitro and focal ischemic lesions in vivo (Bannan et al, 1994;Black et al, 1995) and is effective in blocking malonate lesions (Greene et al, 1996). Remacemide has been tolerated well in clinical trials for cerebral ischemia and in HD patients (Kieburtz et al, 1996;Dyker and Lees, 1999).…”