Interaction of tiagabine with valproate in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves.
OBJECTIVE
To characterize the interaction between tiagabine (TGB) and valproate (VPA)--two antiepileptic drugs in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model, type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs) was used.


METHODS
Clonic seizures were evoked in albino Swiss mice by subcutaneous injection of PTZ at its CD97 (100 mg/ kg). To ascertain the nature of interaction between TGB and VPA administered in combination, total brain concentrations of TGB and VPA were estimated by using high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA).


RESULTS
TGB and VPA produced clear-cut anticonvulsant effects against PTZ-induced clonic seizures in mice and their DRRCs were not parallel to one another. The type I isobolographic analysis for non-parallel DRRCs revealed that the combination of TGB with VPA at the fixed-ratio of 1:1 exerted additive interaction against PTZ-induced clonic seizures in mice. With FPIA, it was found that TGB did not affect total brain VPA concentrations in experimental animals. Moreover, VPA had no significant impact on total brain concentrations of TGB in mice, as measured with HPLC.


CONCLUSIONS
The additive interaction between TGB and VPA at the fixed-ratio of 1:1 in the mouse PTZ model was pharmacodynamic in nature.
Luszczki
J J
JJ
Department of Pathophysiology, Medical University of Lublin, Lublin, Poland. jarogniew.luszczki@am.lublin.pl
Krzyzanowski
M
M
Swiader
M J
MJ
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D001923:Brain Chemistry; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D011897:Random Allocation; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D000078308:Tiagabine; D014635:Valproic Acid / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*
D000927:Anticonvulsants; D003292:Convulsants; D009557:Nipecotic Acids; D014635:Valproic Acid; D010433:Pentylenetetrazole; D000078308:Tiagabine