Abstract
BackgroundLaunching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians’ experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug–drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice.Materials and methodsThe seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1.ResultsThe three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography.ConclusionThe antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.
Highlights
Polytherapy in epilepsy is usually prescribed for patients, whose seizure attacks are not adequately controlled with currently available antiseizure drugs (ASDs) [1, 2]
Some ASD combinations are frequently prescribed by doctors than other combinations because of accumulating experimental and clinical evidence confirming their efficacy in epilepsy patients [3, 4]
With type I isobolographic analysis, a sub-additive interaction was reported for the combination of LCM, LTG and VPA at the fixed ratio of 1:1:1 in the maximal electroshock-induced seizures (MES) test in mice
Summary
Polytherapy in epilepsy is usually prescribed for patients, whose seizure attacks are not adequately controlled with currently available antiseizure drugs (ASDs) [1, 2]. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. Results The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography. Conclusion The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy
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