Abstract
Although monotherapy in epilepsy treatment is frequently advocated, this is not based on studies with equal drug loads. This study was performed to investigate the experimental background of polytherapy with standardized drug loads. Dose-dependent effects on grip strength, accelerod performance, and spontaneous behavior of rats was used to study the effect of combining valproate and ethosuximide. The potency of the drugs (combination) was obtained by fitting the sigmoid Emax equation to the data. Drug interaction was assessed using the isobologram method and quantified by comparing equivalent drug loads with their 95% confidence intervals. We found that the effects of valproate and ethosuximide combine in a simple additive way in the grip strength experiment as well as in the accelerod experiment. In the behavioral studies, however, a higher drug load of the combination was needed to obtain the same amount of sedation, signifying infra-additivity. Infra-additivity of sedative effects is an important finding because this is by far the most frequent side effect mentioned in human studies. However, assessment of the therapeutic effect of the combination will have to be completed before a preference for mono- or polytherapy, based on the balance of adverse effects and efficacy, can be expressed.
Footnotes
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Send reprint requests to: C.M. van Rijn, MD, Ph.D., NICI/Department of Psychology, University of Nijmegen, PO Box 9104, 6500 HE Nijmegen, the Netherlands. Email:rijn{at}nici.kun.nl
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↵1 Grants 95-02 and 96-02 from the Dutch National Epilepsy Fund supported this work.
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↵2 Present address of G.R.: Dept. of Epidemiology and Biostatistics, Erasmus University, Rotterdam, the Netherlands. An abstract of this work appeared in the proceedings of the International Epilepsy Congress in Dublin, Ireland, July 1997.Epilepsia, 3 (Suppl 3):186.
- Abbreviations:
- CI
- confidence intervals
- FEC
- fractional effective concentration
- TD50
- amount of drug causing 50% of maximum effect
- Received March 31, 1998.
- Accepted September 7, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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