Isobolographic analysis of interaction between oxcarbazepine and valproate in pentylenetetrazole-induced seizures in mice

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Isobolographic analysis of interaction between oxcarbazepine and valproate in pentylenetetrazole-induced seizures in mice

Journal Title: Journal of Pre-Clinical and Clinical Research - Year 2008, Vol 2, Issue 1

Abstract

The objective of this study was to assess the characteristics of interaction between oxcarbazepine (OXC) and valproate (VPA) in pentylenetetrazole (PTZ)-induced clonic seizures in mice. The anticonvulsant effects produced by OXC and VPA in two-drug mixture at fi xed-ratios of 1:3, 1:1 and 3:1, were determined and statistically analyzed with type I isobolographic analysis for parallel dose-response relationship lines. Total brain concentrations of VPA were measured in order to ascertain any pharmacokinetic contribution to the pharmacodynamic interaction. Moreover, the acute adverse-effect profile for the combination of OXC with VPA was determined in the chimney test (motor coordination), step-through passive avoidance task (long-term memory), and grip-strength test (skeletal muscular strength) in mice. Results indicated that OXC combined with VPA at 3 fi xed-ratios of 1:3, 1:1 and 3:1 exerted additive interaction in PTZ-induced clonic seizures in mice, although the combination of OXC and VPA at the fi xed-ratio of 1:1 displayed a tendency towards supra-additivity (synergy) in the PTZ test in mice. Pharmacokinetic estimation of total brain antiepileptic (AED) concentrations revealed that OXC did not significantly affect total brain VPA concentrations; therefore, the observed interaction in the PTZ test was pharmacodynamic in nature. Evaluation of acute adverse effects for the combination of OXC with VPA revealed that neither drug had any impact on motor coordination, long-term memory, and skeletal muscular strength in mice. Based on this preclinical study, one can ascertain that the additive interaction between OXC and VPA against PTZ-induced seizures associated with lack of acute adverse effects and no pharmacokinetic interactions between drugs, deserve more attention from a clinical point of view.

Authors and Affiliations

Jarogniew Łuszczki

Keywords

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EP ID EP58594
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