Preclinical profile of stereoisomers of the anticonvulsant remacemide in mice.
Stereoisomers of remacemide (racemate form) were compared for anticonvulsant efficacy and safety in mice. In the maximal electroshock seizure (MES) test for oral efficacy, the (-) stereoisomer, FPL 14145, was more potent than the racemate or the (+) stereoisomer, FPL 14144. Respective ED50 values (expressed as mg/kg) were: remacemide, 58; FPL 14145, 45; FPL 14144, 79. In 2 of 3 tests for neural impairment, FPL 14145 yielded significantly better therapeutic indices (toxic dose 50/ED50) than the racemate. The margin of safety (estimated median lethal dose ED50) was more favorable for FPL 14144: remacemide, 15.1; FPL 14144, 18.9; FPL 14145, 15.7. The duration of protection against MES indicated the stereoisomers were longer acting than the racemate. After intravenous administration the order of potency against MES was similar: FPL 14145 greater than remacemide greater than FPL 14144. Following daily administration of the oral ED98 for 4 days, with a dose response curve run on day 5, the MES ED50 values for all compounds were increased. The test indicates tolerance. In the pentylenetetrazol infusion test the racemate and FPL 14144 demonstrated more proconvulsant properties than FPL 14145. Intraperitoneal administration of 50 mg/kg or more produced changes in behavior with all compounds. At higher doses the racemate and FPL 14145 elicited more severe symptoms with death at 200 mg/kg.
Palmer
G C
GC
Fisons Pharmaceuticals, Divisional Research and Development, Rochester, NY 14623.
Stagnitto
M L
ML
Ordy
J M
JM
Griffith
R C
RC
Napier
J J
JJ
Gentile
R J
RJ
Woodhead
J H
JH
White
H S
HS
Swinyard
E A
EA
D000081:Acetamides / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004056:Differential Threshold; D004341:Drug Evaluation; D004597:Electroshock; D005650:Fumarates / Q000494:pharmacology; D000860:Hypoxia / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009420:Nervous System / Q000187:drug effects; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013237:Stereoisomerism; D013997:Time Factors
D000081:Acetamides; D000927:Anticonvulsants; D005650:Fumarates; C032005:fumaric acid; C067553:remacemide