The high affinity noncompetitive
N-methyl-D-aspartate receptor antagonist
CNS 1102 (
aptiganel hydrochloride, Cambridge NeuroScience, Cambridge, MA.) is neuroprotective in preclinical models of
stroke when administered as pretreatment or up to 60 minutes postischemia, and has potential for treatment of
acute stroke or
traumatic brain injury in man. A total of 55 healthy male subjects have participated in three separate studies to determine the clinical pharmacology of
CNS 1102, 43 of whom have received
CNS 1102 in doses of up to 100 micrograms/kg. Administration of
CNS 1102 has been studied as a 15-minute
intravenous infusion, as a 15-minute loading
intravenous infusion followed by a 4-hour maintenance infusion, or as a fixed-dose intravenous bolus over 90 seconds.
CNS 1102 in normal volunteers is well tolerated in total doses up to 32 micrograms/kg whether as a bolus injection, 15-minute infusion or 4-hour infusion. Central nervous system affects are evident within minutes of administration, implying rapid
drug penetration.
CNS 1102 has a large and variable volume of distribution (mean +/- standard deviation, 6.2 +/- 1.9 l/kg), variable clearance (115 +/- 77 l/h), and plasma half-life of approximately 4.5 hours. Adjustment of doses by subject weight does not improve variability of these parameters, and fixed doses may thus be administered.
CNS 1102 causes dose-dependent elevation of blood pressure, accompanied by clinical evidence of vasoconstriction. Global cerebral blood flow is maintained, whilst middle cerebral artery flow velocity increases. Symptoms of
light-headedness, disorientation and
paresthesia progress through euphoria, disinhibition, and
hallucinations to psychomotor retardation,
paranoia and
catatonia as total administered dose increases.