First Observations of the Safety and Tolerability of a Competitive Antagonist to the Glutamate NMDA Receptor (CGS 19755) in Patients with Severe Head Injury

Abstract

A dose escalation, safety, and tolerability study of a competitive antagonist to the N-methyl-D-aspartate (NMDA) glutamate receptor (CGS 19755, Selfotel) in patients with severe head injury is reported. The drug was administered i.v. on two separate occasions, 24 h apart, to 31 patients. The dosage was escalated during the study from 1 mg/kg to 6 mg/kg. Continuous monitoring of mean arterial pressure (MABP), intracranial pressure (ICP), cerebral pressure (CPP), arterial oxygen saturation (SaO2), jugular bulb oxygen saturation (SjO2), and temperature was performed. Intermittent measurements of middle cerebral artery (MCA) velocity via transcranial Doppler ultrasound were also made 2 h before drug administration and continued for 24 h after dosing. The patients were ventilated and sedated with morphine and either midazolam or propofol. There were no behavioral changes during or after administration of the drug, and disorders of perception were reported by only three subjects, several days after relatively low doses; these were transient and were not recalled at later follow-up. We did not detect consistent changes in any of the hemodynamic parameters monitored, up to dosages of 3 mg/kg. After higher doses, some patients showed changes in MABP, ICP, and temperature during the 4 to 8-h period following the first bolus of the drug, with a return toward baseline afterwards. No consistent, serious, adverse events were considered to be due to drug effects, and death, in the one patient who died, was due to the effects of the injury. Our results indicate that CGS 19755 may be given at dosages < or = 3-5 mg/kg with acceptable safety and tolerability in stable, ventilated, and carefully monitored severe head-injured patients.

Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

“…Second, NMDA receptor antagonists provide a degree of neuroprotection even after SE [ 16 , 18 ]. This neuroprotective effect has even been studied within the traumatic brain injury literature [ 19 , 20 ]. Third, in regard to ketamine, this drug is readily available and cheap, allowing for application in a variety of settings.…”

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015

“…Activation of these receptors is known to result in neuronal cell death by excessive calcium influx, and that antagonistic action at iGluRs may promote the survival of neurons 13 . The competitive NMDA antagonist selfotel 14 , 15 , 16 and the noncompetitive NMDA antagonist aptiganel 17 , 18 were effective in preclinical studies but ineffective in clinical use 16 , 19 . Of the AMPA antagonists ZK 200775 20 , 21 and YM872, the first was discontinued in a phase II clinical trial for stroke in Europe in 1999 and the second even never reached clinical trial evaluation because of its severe side effects 22 .…”

Glutamate and post-traumatic cerebral excitoxicity as possible therapeutic targets – A literature review

“…However, as with every clinical trials with neuroprotective agents in trauma, tests with Selfotel (CGS-19755) or Traxoprodil (CP-101606), NMDA-receptors antagonists, failed to show any improvement in morbidity and/or mortality. [68][69][70] Other therapeutic targets were tested in animal models, including neuropeptide Substance P, a modulator for Glutamate levels and NMDA receptors, using Neurokinin antagonists and cannabinoid receptors type 2 antagonists, with promising results regarding functional outcome. [71][72][73][74][75] The transition from animal experimental models to large prospective clinical trials has failed showing significant efficacy for these therapeutic agents, and none is included in the diverse daily-practice clinical protocols.…”