Preclinical profile of remacemide: a novel anticonvulsant effective against maximal electroshock seizures in mice.
Anticonvulsant tests in mice revealed specific, potent actions of remacemide for protection of mice against maximal electroshock seizures (MES). Comparisons of oral efficacy to reference compounds yielded the following ED50 values (expressed as mg/kg): remacemide = 33, phenytoin = 11, phenobarbital = 20, carbamazepine = 13 and valproate = 631. The duration for protection by remacemide was longer than carbamazepine or valproate, but shorter than phenytoin or phenobarbital. In neural impairment tests (inverted screen or rotorod) to determine the oral toxic dose 50 (TD50) the following therapeutic indices (TD50/ED50) were obtained: (1) inverted screen--remacemide = 17.6, phenytoin = 57.4, phenobarbital = 5.1, carbamazepine = 10.2, and valproate = greater than 3; and (2) rotorod--remacemide = 5.6, phenytoin = 9.6, phenobarbital 4.8, and valproate = 1.9. Remacemide was devoid of sedative actions and possessed a favorable 28.1 margin of safety value (median estimated lethal dose/ED50 for MES). An intermediate potency against either audiogenic- or N-methyl-D-aspartate-induced seizures was exhibited by remacemide. Tolerance to MES was not apparent after 5 days of oral daily dosing of remacemide. Remacemide was inactive in vitro against gamma-aminobutyrate or benzodiazepine receptors and adenosine uptake mechanisms. Therapeutic utility for generalized tonic/clonic seizures is predicted for remacemide.
Stagnitto
M L
ML
Fisons Pharmaceuticals, Divisional Research and Development, Rochester, NY 14603.
Palmer
G C
GC
Ordy
J M
JM
Griffith
R C
RC
Napier
J J
JJ
Becker
C N
CN
Gentile
R J
RJ
Garske
G E
GE
Frankenheim
J M
JM
Woodhead
J H
JH
D000081:Acetamides / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006993:Hypnotics and Sedatives; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000502:physiology; D009420:Nervous System / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D011092:Polyethylene Glycols; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology* / Q000517:prevention & control; D012996:Solutions; D014867:Water
D000081:Acetamides; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D012996:Solutions; D014867:Water; D011092:Polyethylene Glycols; C067553:remacemide; D010634:Phenobarbital