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NPS 1506, A Novel NMDA Receptor Antagonist and Neuroprotectant: Review of Preclinical and Clinical Studies
Author(s) -
MUELLER ALAN L.,
ARTMAN LINDA D.,
BALANDRIN MANUEL F.,
BRADY ELLEN,
CHIEN YONGWEI ERIC,
DELMAR ERIC G.,
GEORGE KAREN,
KIERSTEAD ALLISON,
MARRIOTT THOMAS B.,
MOE SCOTT T.,
NEWMAN MICHAEL K.,
RASZKIEWICZ JOANNA L.,
SANGUINETTI ELIZABETH L.,
VAN WAGENEN BRADFORD C.,
WELLS DAVID
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb08023.x
Subject(s) - neuroprotection , lightheadedness , nmda receptor , pharmacology , phencyclidine , psychotomimetic , antagonist , medicine , toxicity , antidote , excitotoxicity , anesthesia , chemistry , receptor
NPS 1506 is a moderate affinity, uncompetitive N ‐methyl‐d‐aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2‐hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1–1.0 mg/kg, with peak plasma concentrations ranging from 8–80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK‐801‐like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5–100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100‐mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP‐like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half‐life of NPS 1506 (∼60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.