Antiepileptic and neuroprotective potential of remacemide hydrochloride

Palmer, Gene C.; Clark, Beverly G.; Hutchison, J.B.

doi:10.1358/dof.1993.018.11.233082

Cited by 38 publications

(18 citation statements)

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“…Improvements in pathological findings were matched by improvements in functional outcome (assessed by ability to complete a T maze). 2 Similar results have been obtained in canine models of global ischemia and in focal MCA occlusion models in rats (Astra, unpublished data, 1995).…”

supporting

confidence: 74%

“…Intravenous doses of 1 and 3 mg/kg were without cardiovascular effects in anesthetized and conscious dogs, whereas 10 and 30 mg/kg resulted in increased arterial pressure and heart rate in conscious dogs and increased arterial pressure and decreased heart rate, myocardial contractility, and cardiac output in anesthetized dogs. 2 The clinical pharmacology of remacemide hydrochloride, following oral administration, has been investigated in Ͼ400 healthy volunteers after single (up to 500 mg) and multiple doses (up to 800 mg/d). The most commonly reported adverse events were mild central nervous system (CNS) disorders such as dizziness, headache, mood changes, general fatigue, and somnolence or gastrointestinal symptoms such as abdominal pain, dyspepsia, nausea, and vomiting.…”

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confidence: 99%

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Remacemide Hydrochloride

Dyker

Lees

1999

Stroke

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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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confidence: 74%

mentioning

confidence: 99%

Remacemide Hydrochloride

Dyker

Lees

1999

Stroke

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“…From 200 mg up, their frequency was higher than in the placebo group, and their intensity was considered as limiting for the 600‐mg dose. Dizziness has been frequently reported for other NMDA‐antagonists such as ketamine, 27 dextromethorphan, 28 memantine, 29 remacemide, 30 aptiganel, 31 selfotel, 32 NPS1506, 33 AR‐R15896AR, 34 and CNS 5161 35 . Blurred vision has been described in healthy volunteers receiving aptiganel 31 and in patients under treatment with remacemide 30 …”

Section: Discussionmentioning

confidence: 99%

Safety, Pharmacokinetics, and Pharmacodynamics of CHF 3381, a Novel N‐Methyl‐D‐Aspartate Antagonist, after Single Oral Doses in Healthy Subjects

Tarral

Dostert

Guillevic

et al. 2003

The Journal of Clinical Pharma

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A double-blind, randomized, placebo-controlled study was performed to assess the safety, tolerability, and pharmacokinetics of single oral doses of CHF 3381 in 56 young healthy male volunteers. The central nervous system effects of CHF 3381 were also evaluated, as well as the effect of food on the rate and extent of CHF 3381 absorption. Seven doses of CHF 3381 (25, 50, 100, 200, 300, 450, and 600 mg) were evaluated in an escalating order. At each dose level, 6 subjects were given CHF 3381, and 2 subjects were given placebo. Safety and tolerability evaluation included adverse events, physical examination, vital functions, electrocardiogram, laboratory tests, and 24-hour Holter (100-mg and 450-mg dose panels). Plasma and urinary concentrations of CHF 3381 and its two main metabolites (CHF 3567 and 2-aminoindane) were measured with a validated high-performance liquid chromatography method. Central nervous system effects were evaluated with the simple reaction time (SRT); learning memory task (LMT); Bond & Lader Visual Analog Scale for alertness, contentedness, and calmness; Addiction Research Center Inventory (ARCI); and electroencephalogram. There were no serious adverse events; the most frequent adverse events were dizziness, abnormal thinking, and asthenia. The number of adverse events with moderate intensity increased sharply with the dose, with no or few events up to 450 mg and 17 events with 600 mg. Therefore, 600 mg was defined as the maximum tolerated dose. There were no significant treatment effects on cardiovascular function and electrocardiogram parameters at any CHF 3381 dose or on oral temperature or laboratory tests. There were no clinically significant changes in laboratory variables. CHF 3381 was absorbed rapidly (tmax = 0.5-2 h) and cleared from plasma with a half-life of 3 to 4 hours. Plasma levels of CHF 3381 and its two major metabolites were found to be proportional to the dose. 2-Aminoindane formed slowly and reached much lower concentrations compared to the parent compound and the other metabolite (CHF 3567). Within 48 hours after dosing, 2% to 6% of the administered dose was found in the urine as unchanged drug, about 50% to 55% as the acid derivative (CHF 3567), and 2% to 3% as 2-aminoindane. Ingestion of food did not affect the extent of absorption of the drug, while the rate of absorption was considerably reduced (tmax = 4 h). No significant effects of CHF 3381 were observed on attention (SRT) or memory (LMT). Visual analog scales revealed a decreasing effect of CHF 3381 on alertness at 1 hour that reached statistical significance at 300 and 600 mg. EEG spectral analysis revealed minor decreasing effects of the 200-mg dose on total electric power measured at 2 hours. A stimulant effect was detected by the ARCI scale 24 hours after the 300-mg dose and might be related to the slow formation of the 2-aminoindane metabolite. In conclusion, this study has shown that the maximum tolerated dose of CHF 3381 after single oral administration in young healthy male volunteers is 600 mg. CHF 3381 displ...

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“…Despite being shown to be effective in animal models of cerebral ischaemia, there remain some safety concerns regarding this group of drugs: PCP and other NMDA antagonists have been shown to induce a neurotoxic reaction within the cingulate and retrosplenial cortex of the adult rat (71), and both mitochondria and endoplasmic reticulum are acutely transformed into large intraplasmic vacuoles (72). Low doses of NMDA antagonists can lead to these reversible changes (73), but more prolonged administration may result in neuronal death (74). Reassuringly, no NMDA antagonist currently in development for stroke has been associated with permanent neuropsychiatric effects or pathological changes in humans.…”

Section: Mechanisms Of Neuroprotectionmentioning

confidence: 99%

The rationale for new therapies in acute ischaemic stroke

Dyker

Lees

1996

Journal of Clinical Pharmacy and Therapeutics

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Summary Although stroke is a major cause of morbidity and mortality, it is only relatively recently that a concerted effort has been made to develop acute treatments. Thrombolytics, such as recombinant tissue plasminogen activator (rt‐PA), may benefit selected patients within 3 h of cerebral infarction. Currently, rt‐PA is only licensed for use in the United States. Many potential strategies for neuroprotection exist and are currently under investigation. Because the mechanisms of neurotoxicity involve numerous interdependent processes, it may be that interruption of a single site in the cascade of events is insufficient to provide effective neuroprotection. Drugs acting at several sites in the neurotoxic cascade may be more effective, and the results of Phase III studies with the novel neuroprotectant lubeluzole are anticipated.

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Antiepileptic and neuroprotective potential of remacemide hydrochloride

Cited by 38 publications

References 0 publications

Remacemide Hydrochloride

Remacemide Hydrochloride

Safety, Pharmacokinetics, and Pharmacodynamics of CHF 3381, a Novel N‐Methyl‐D‐Aspartate Antagonist, after Single Oral Doses in Healthy Subjects

The rationale for new therapies in acute ischaemic stroke

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