Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Abstract

Background/Aims: To characterize the anticonvulsant effects of a combination of 3 antiepileptic drugs (AEDs; i.e. carbamazepine (CBZ), phenobarbital (PB) and topiramate (TPM)) at the fixed-ratio of 1:1:1 in the mouse maximal electroshock (MES)-induced seizure model. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to analyze the 3-drug combination. Results: In the mouse MES model, all the studied AEDs (i.e. CBZ, PB and TPM) administered singly had their DRRCs parallel to each other. With type I isobolography for parallel DRRCs, a combination of CBZ, PB and TPM at the fixed-ratio of 1:1:1 exerted supra-additive (synergistic) interaction in the mouse MES model. Conclusions: Synergistic interaction among CBZ, PB and TPM at the fixed-ratio of 1:1:1 against MES-induced seizures is worthy of consideration in further clinical settings. All detailed calculations required to perform type I isobolographic analysis for the 3-drug combination were presented.

Isobolographic additivity among lacosamide, lamotrigine and phenobarbital in a mouse tonic-clonic seizure model

“…28 The interaction among the 3 AEDs (LCM, LTG and PB) from this study can also be compared to the interactions observed previously for the combinations of LCM, carbamazepine (CBZ) and PB, 16 or topiramate (TPM), CBZ and PB, against maximal electroconvulsions in mice. 17 More specifically, a supra-additivity (synergy) for the combination of TPM, CBZ and PB was found in the MES test in mice. 17 In contrast, the replacement of TPM with LCM in the mixture of LCM, CBZ and PB resulted in additivity with a trend to sub-additivity in the MES test in mice.…”

“…17 More specifically, a supra-additivity (synergy) for the combination of TPM, CBZ and PB was found in the MES test in mice. 17 In contrast, the replacement of TPM with LCM in the mixture of LCM, CBZ and PB resulted in additivity with a trend to sub-additivity in the MES test in mice. 16 On the other hand, the replacement of CBZ with LTG produced additivity without any trend to sub-additivity (antagonism) in the MES test, as documented in this study for LCM, LTG and PB.…”

“…24 After verifying the parallelism of dose-effect functions of LCM, LTG and PB, the median additive dose of the mixture of these 3 AEDs (ED 50 add ) at a fixed-ratio combination of 1:1:1 was calculated according to the methods described earlier. 16,17 Admittedly, LCM displayed parallelism to PB and LTG. However, these latter 2 AEDs, when compared to each other, had their doseeffect functions nonparallel.…”

“…16,17 The animals, after receiving different drug doses, were subjected to the MES test and protection from maximal electroconvulsions was noted so as to construct dose-effect functions for the investigated AEDs (LCM, LTG and PB) when injected separately, as described earlier. 16,18 The anticonvulsant properties of LCM, LTG and PB, when injected alone and combined at a fixed-ratio of 1:1:1, were presented in the form of median effective doses (i.e., ED 50 and ED 50 exp values).…”

“…15,[24][25][26] The anticonvulsant protection offered by the 3 AEDs in mixture 1:1:1 was presented in the form of ED 50 exp value, reflecting a dose of 3 drugs in mixture that protected 50% of the mice from MES-induced seizures. 16,17 The unpaired Student's t-test was used to statistically compare the ED 50 exp and ED 50 add values.…”