Additive suppression of tonic-clonic seizures in mice receiving the combination of carbamazepine, phenobarbital and valproate

Załuska, Katarzyna; Marzęda, Paweł; Bojar, Hubert; Aleksandra, Walczak; Chmielewski, Jarosław; Wróblewska-Łuczka, Paula; Łuszczki, Jarogniew J.

doi:10.26444/jpccr/109381

Cited by 4 publications

(2 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, the ED 50 values for LCM, PB and VPA when used alone were determined in previous studies [10,30,35] that allowed for calculating the ED 50 add value for the three-drug mixture. This was the reason that in the current study only 32 animals were used in the mouse tonic-clonic seizure model for determining the ED 50 exp value.…”

Section: Discussionmentioning

confidence: 99%

“…LCM might be combined with PB and VPA for patients with refractory epilepsy uncontrolled with monotherapy. [33] OXC + PGB + TPM supra-additivity [11] PB + PHT + PGB supra-additivity [34] LCM + CBZ + LTG additivity [31] LCM + CBZ + PB additivity [30] LCM + LTG + PB additivity [32] CBZ + PB + VPA additivity [35] LCM + LTG + VPA sub-additivity [9] LCM + CBZ + VPA sub-additivity [10] CBZ -carbamazepine; LCM -lacosamide; LTG -lamotrigine; OXC -oxcarbazepine; PB -phenobarbital; PGB -pregabalin; PHT -phenytoin; TPM -topiramate; VPA -valproate.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Kondrat-Wróbel

Marzęda

Bojar

et al. 2020

J Pre Clin Clin Res.

Self Cite

View full text Add to dashboard Cite

Introduction. Triple-therapy with antiepileptic drugs (AEDs) is usually prescribed for epilepsy patients, whose seizures are not fully controlled with standard medications. Although 25 various AEDs are currently licensed for treating epilepsy, no algorithms allowing for the proper combination of AEDs are available. Objective. The aim of the study is to isobolographically assess the type of interaction among three AEDs (lacosamide [LCM], phenobarbital [PB] and valproate [VPA]), in the model of tonic-clonic seizures in mice. Materials and Method. The electrically-evoked (25 mA, 500 V, 50 Hz, 0.2 s of stimulus duration) tonic-clonic seizures in male albino Swiss mice allowed determination of the anticonvulsant action of the three-drug mixture of LCM, PB and VPA combined in a dose ratio of 1:1:1 by means of type I isobolographic analysis of interaction. Results. The experimentally-determined ED50 exp value for the three-drug mixture was 112.04 mg/kg and did not differ from the theoretically calculated ED50 add value, which was 112.36 mg/kg. Lack of statistical significance confirmed that the mixture of LCM, PB and VPA in a dose-ratio of 1:1:1 exerted additive interaction in the mouse tonic-clonic seizure model. Conclusions. Although the three-drug combination of LCM, PB and VPA produced additive interaction in the mouse tonic-clonic seizure model, the three-drug combination could be recommended for epilepsy patients whose seizures are refractory to the standard medication.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Kondrat-Wróbel

Marzęda

Bojar

et al. 2020

J Pre Clin Clin Res.

Self Cite

View full text Add to dashboard Cite

show abstract

Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: an isobolographic analysis

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Launching 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 methods The 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. 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; however, 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.

show abstract

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic–clonic seizure model in mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug–drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. Aim To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. Materials and method The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. Results The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. Conclusions The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

show abstract

Additive suppression of tonic-clonic seizures in mice receiving the combination of carbamazepine, phenobarbital and valproate

Cited by 4 publications

References 27 publications

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: an isobolographic analysis

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic–clonic seizure model in mice

Contact Info

Product

Resources

About