Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice.
Retigabine (D-2319, 0.5-20 mg/kg i.p.) antagonised dose dependently audiogenic seizures in DBA/2 mice. Retigabine at 0.5 mg/kg i.p., a dose that per se did not affect the occurrence of audiogenic seizures significantly, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of additivity for the effect induced by retigabine was greatest for diazepam, phenobarbital, phenytoin and valproate, less for carbamazepine and lamotrigine and least for felbamate. The increase in anticonvulsant activity was usually associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment (drugs plus retigabine), was more favourable than the same drug plus vehicle. Since retigabine had no significant influence on the total and free plasma levels of the anticonvulsant drugs, pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that retigabine modifies the clearance of the anticonvulsant drugs from the brain cannot be excluded. Retigabine had no significant effect on the hypothermic effects of the anticonvulsants tested. In conclusion, retigabine showed an additive effect when administered in combination with classical anticonvulsants, most notably diazepam, phenobarbital, phenytoin and valproate.
De Sarro
G
G
Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University of Cantanzaro, Policlinico Mater Domini, Italy. desarro@unicz.it
Di Paola
E D
ED
Conte
G
G
Pasculli
M P
MP
De Sarro
A
A
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D001831:Body Temperature / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology* / Q000633:toxicity; D012640:Seizures / Q000097:blood / Q000188:drug therapy*
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine