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Background/Aim: To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice. Methods: Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1: 1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by highpressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs. Results: Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1: 1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction. Conclusion: LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims: To assess interactions between retigabine and levetiracetam in suppressing maximal electroshock-induced tonic seizures in Albino Swiss mice, type II isobolographic analysis was used. Total brain antiepileptic drug concentrations were measured with high pressure liquid chromatography. Results: The combinations of retigabine with levetiracetam at the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; p < 0.05) in terms of seizure suppression, while the combinations at the fixed-ratios of 1:1 and 1:2 were additive. No pharmacokinetic changes in total brain concentrations of levetiracetam and retigabine were documented, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse maximal electroshock-induced tonic seizure model. Conclusion: The combination of retigabine with levetiracetam at the fixed-ratios of 1:5 and 1:10 appears to be particularly beneficial combination exerting supra-additive interaction in suppressing maximal electroshock-induced tonic seizures. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Methods: Neuropathic pain results from nerve injury, and gabapentin, an antiepileptic drug, has been approved for the treatment of several types of neuropathic pain. On the other hand, nortriptyline, an antidepressant drug, has been suggested as an alternative treatment. In partial sciatic nerve ligation (PSNL) mice, the interaction of gabapentin with nortriptyline was evaluated by the hot plate assay using isobolographic analysis. Results: Gabapentin (3-100 mg/kg, i.p.) or nortriptyline (1-30 mg/kg, i.p.) induced dose-dependent antinociception, with an ED50 of 11.60 ± 0.54 mg/kg for gabapentin and of 5.16 ± 0.21 mg/kg for nortriptyline. The potency of gabapentin and nortriptyline in PSNL mice at 7 and 14 days after ligation was significantly increased (p < 0.05). Coadministration of gabapentin with nortriptyline, at a 1:1 ratio of their ED50, had a synergistic effect, with an interaction index of 0.311 and 0.348 for these mice at 7 and 14 days, respectively. Conclusion: The data showed a synergy in antinociception at a gabapentin-to-nortriptyline ratio of 1:1 in PSNL mice. This finding suggests that this combination could provide a therapeutic alternative that can be used for neuropathic pain management. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study focused on the evaluation of interactions between MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino(4,5-b)quinoline-5-oxide choline salt), an N-methyl-D-aspartate (NMDA) receptor antagonist acting at the NMDA receptor/glycineB site and four newer antiepileptic drugs (felbamate, lamotrigine, oxcarbazepine, and topiramate) in the mouse maximal electroshock seizure model. Results indicate that MRZ 2/576 administered intraperitoneally, 5 min before the test, exerted a clear-cut anticonvulsant effect in the maximal electroshock seizure test in mice and its ED50 value was 13.71 (11.95–15.73) mg/kg. In the subthreshold method, MRZ 2/576 (administered intraperitoneally, at a subthreshold dose of 5 mg/kg) significantly enhanced the anticonvulsant action of felbamate, oxcarbazepine and topiramate, by reducing their ED50 values from 73.0 to 53.8 mg/kg (p < 0.05) for felbamate, from 10.77 to 7.48 mg/kg (p < 0.05) for oxcarbazepine, and from 49.3 to 28.7 mg/kg (p < 0.01) for topiramate. In contrast, MRZ 2/576 (5 mg/kg, i.p.) did not significantly affect the antiseizure effects of lamotrigine in the maximal electroshock seizure test in mice. Isobolographic transformation of data revealed that MRZ 2/576 (5 mg/kg, i.p.) exerted barely additive interactions with all investigated antiepileptic drugs in the maximal electroshock seizure test. In conclusion, the isobolographic analysis revealed that MRZ 2/576 additively cooperates with newer antiepileptic drugs in terms of suppression of maximal electroshock-induced seizures in mice. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/aim: To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice., Methods: Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1:1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by high-pressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs., Results: Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1:1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction., Conclusion: LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy., (© 2017 S. Karger AG, Basel.)