Assessing the potential toxicity of MK-801 and remacemide: chronic exposure in juvenile rhesus monkeys.
The present experiment examined the effects of chronic exposure to either 0.1 or 1.0 mg/kg MK-801 [a selective N-methyl-D-aspartate (NMDA) receptor antagonist] or 20.0 or 50.0 mg/kg remacemide (an NMDA receptor antagonist which also blocks fast sodium channels) in juvenile rhesus monkeys. Endpoints were monitored to provide a general index of subjects' health and included measures of clinical chemistry, hematology, ophthalmology, spontaneous home-cage behavior, and peak drug plasma levels. In general, both drugs were well tolerated and produced no treatment-related effects during 2 years of dosing and assessment. Periodic plasma drug level determinations provided limited evidence that both compounds may induce their own metabolism. The present results contrast sharply with previously reported effects of long-lasting impairments in the acquisition of incremental learning and in the development of color and position discrimination in these same subjects. These observations highlight the importance of collecting a broad range of toxicology data, including tests of cognitive function, to make comprehensive assessments of new drug safety. In the present case, the less obvious effects of these drugs on cognition defined the toxicologic response.
Popke
E J
EJ
Division of Neurotoxicology, HFT-132, National Center for Toxicological Research, U.S. FDA, 3900 NCTR Road, Jefferson, AR 72079-950, USA.
Patton
R
R
Newport
G D
GD
Rushing
L G
LG
Fogle
C M
CM
Allen
R R
RR
Pearson
E C
EC
Hammond
T G
TG
Paule
M G
MG
D000081:Acetamides / Q000097:blood / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D016291:Dizocilpine Maleate / Q000097:blood / Q000633:toxicity*; D005260:Female; D008253:Macaca mulatta; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000081:Acetamides; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C067553:remacemide