The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models.
OBJECTIVE
To evaluate the anticonvulsant profile and behavioral toxicity of rufinamide in animal seizure models compared to the established antiepileptic drugs (AEDs): phenytoin, phenobarbital, valproate, and ethosuximide, or vehicle.


METHODS
In acute studies of anticonvulsant efficacy, the AEDs were administered via oral (CF1 mice and Sprague-Dawley rats) and intraperitoneal (CF1 mice) routes. The AEDs were assessed for their ability to inhibit seizures induced by maximal electroshock (MES) or subcutaneous pentylenetetrazol, and ability to block seizures induced by subcutaneous strychnine, bicuculline, or picrotoxin. Tolerance of oral rufinamide was assessed in rats following 5-day (versus single-dose) treatment with oral rufinamide using the dose equivalent necessary to achieve a 50% decrease in seizure frequency (ED(50)). Metabolic tolerance was also evaluated using an in vitro liver microsomal assay.


RESULTS
Oral rufinamide suppressed pentylenetetrazol-induced seizures in mice (ED(50) 45.8 mg/kg) but not rats, and was active against MES-induced tonic seizures in mice (ED(50) 23.9 mg/kg) and rats (ED(50) 6.1 mg/kg). Intraperitoneal rufinamide suppressed pentylenetetrazol-, bicuculline-, and picrotoxin-induced clonus in mice (ED(50) 54.0, 50.5, and 76.3 mg/kg, respectively). Rufinamide was partially effective in the mouse strychnine test. The behavioral toxicity of rufinamide was similar to or better than established AEDs tested in this study. In general, the protective index of rufinamide was greater than that of the other AEDs.


CONCLUSIONS
The efficacy and behavioral toxicity profiles in these animal models suggest that rufinamide may be effective in the treatment of generalized and partial seizures.
White
H Steve
HS
Anticonvulsant Drug Development Program, Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, Utah 84108, USA. swhite@hsc.utah.edu
Franklin
Michael R
MR
Kupferberg
Harvey J
HJ
Schmutz
Markus
M
Stables
James P
JP
Wolf
Harold H
HH
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use* / Q000633:toxicity*; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology / Q000627:therapeutic use; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000517:prevention & control*; D012720:Severity of Illness Index; D014230:Triazoles / Q000627:therapeutic use* / Q000633:toxicity*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D014230:Triazoles; D014635:Valproic Acid; D010672:Phenytoin; C079703:rufinamide; D010634:Phenobarbital