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Three-dimensional isobolographic analysis of interactions between lamotrigine and clonazepam in maximal electroshock-induced seizures in mice

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Abstract

The anticonvulsant effects of lamotrigine (LTG) and clonazepam (CZP) and combinations thereof against maximal electroshock (MES)-induced seizures in mice were investigated using three-dimensional (3D) isobolographic analysis. With this method, the doses of fixed-ratio combinations of the drugs (1:3, 1:1 and 3:1) that elicited 16, 50 and 84% of the maximum anticonvulsant effect were determined. Additionally, to evaluate the characteristics of interactions observed with 3D isobolography, the brain concentrations of both drugs were verified pharmacokinetically. The 3D isobolographic analysis showed that LTG and CZP combined at the fixed ratios of 3:1 and 1:1 interacted synergistically in the MES test for all anticonvulsant effects between 16% and 84% of maximum. In contrast, the combination of LTG and CZP at the fixed ratio of 1:3 showed only pure additivity for all estimated effects in 3D isobolography. Moreover, none of the examined antiepileptic drugs altered the brain concentrations of the coadministered drug, so the observed interactions in the MES test are of a pharmacodynamic nature. The 3D isobolographic findings suggest that in epilepsy therapy, increased efficacy of seizure control (synergistic interaction) might be achieved by using LTG and CZP in combination. In this study, some important problems and assumptions related to statistical analysis of data in 3D isobolography are discussed.

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Acknowledgments

This study was supported by a grant (PW 447/2002-2004) from the Skubiszewski Medical University of Lublin. The authors thank Mr W. Zgrajka (Institute of Agricultural Medicine, Lublin, Poland) for the skilful determination of the brain concentrations of LTG. Dr J.J. Luszczki is a recipient of the Fellowship for Young Researchers from the Foundation for Polish Science.

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Authors and Affiliations

  1. Department of Pathophysiology, Skubiszewski Medical University of Lublin, Jaczewskiego 8, 20-950, Lublin, Poland

    Jarogniew J. Luszczki & Stanislaw J. Czuczwar

  2. Isotope Laboratory, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950, Lublin, Poland

    Stanislaw J. Czuczwar

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  1. Jarogniew J. Luszczki
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  2. Stanislaw J. Czuczwar
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Correspondence to Jarogniew J. Luszczki.

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Luszczki, J.J., Czuczwar, S.J. Three-dimensional isobolographic analysis of interactions between lamotrigine and clonazepam in maximal electroshock-induced seizures in mice. Naunyn-Schmiedeberg's Arch Pharmacol 370, 369–380 (2004). https://doi.org/10.1007/s00210-004-0983-9

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