Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice.
To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland. jarogniew.luszczki@am.lublin.pl
Trojnar
Michal K
MK
Trojnar
Marcin P
MP
Kimber-Trojnar
Zaneta
Z
Szostakiewicz
Beata
B
Zadrozniak
Anna
A
Borowicz
Kinga K
KK
Czuczwar
Stanislaw J
SJ
D017311:Amlodipine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D004110:Diltiazem / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004597:Electroshock / Q000009:adverse effects; D016231:Fluorescence Polarization Immunoassay / Q000379:methods; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000077236:Topiramate; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D000077236:Topiramate; D017311:Amlodipine; D005632:Fructose; D014700:Verapamil; D004110:Diltiazem