First observations of the safety and tolerability of a competitive antagonist to the glutamate NMDA receptor (CGS 19755) in patients with severe head injury

Linda B. Stewart, R. Bullock, G. M. Teasdale, A. Wagstaff

Research output: Contribution to journalArticle

9 Scopus citations

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 (S(J)O2), 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 ≤3-5 mg/kg with acceptable safety and tolerability in stable, ventilated, and carefully monitored severe head-injured patients.

Original languageEnglish (US)
Pages (from-to)843-850
Number of pages8
JournalJournal of neurotrauma
Volume16
Issue number9
DOIs
StatePublished - Sep 1999

Keywords

  • Blood pressure
  • Cerebral perfusion pressure
  • Head injury
  • Intracranial pressure
  • N-methyl-D-aspartate
  • Neuroprotection
  • Temperature

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

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