Interactions of 1-methyl-1,2,3,4-tetrahydroisoquinoline with lamotrigine, oxcarbazepine, pregabalin, and topiramate in the mouse maximal electroshock-induced seizure model: A type I isobolographic analysis

Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.

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INTERACTION OF THREE-DRUG COMBINATION OF LACOSAMIDE, CARBAMAZEPINE AND PHENOBARBITAL IN THE MOUSE MAXIMAL ELECTROSHOCK-INDUCED SEIZURE MODEL – AN ISOBOLOGRAPHIC ANALYSIS

Health Problems of Civilization ◽

10.5114/hpc.2016.58209 ◽

2016 ◽

Vol 1 ◽

pp. 55-61 ◽

Cited By ~ 11

Author(s):

Maria W. Kondrat-Wróbel ◽

Jarogniew J. Łuszczki

Keyword(s):

Drug Combination ◽

Maximal Electroshock ◽

Isobolographic Analysis ◽

Seizure Model

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

Pharmacological Reports ◽

10.1007/s43440-020-00117-y ◽

2020 ◽

Vol 72 (5) ◽

pp. 1288-1296 ◽

Cited By ~ 1

Author(s):

Jarogniew J. Łuszczki ◽

Maria Kondrat-Wróbel ◽

Mirosław Zagaja ◽

Sławomir Karwan ◽

Hubert Bojar ◽

...

Keyword(s):

Seizure Activity ◽

Fixed Ratio ◽

Mechanisms Of Action ◽

Clinical Settings ◽

Maximal Electroshock ◽

Type I ◽

Pharmacodynamic Interaction ◽

Isobolographic Analysis ◽

Mes Test ◽

Patients With Epilepsy

Abstract 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.

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Additive interaction for three-drug combination of carbamazepine, lacosamide and lamotrigine against maximal electroshock-induced seizures – a type I isobolographic analysis

European Journal of Clinical and Experimental Medicine ◽

10.15584/ejcem.2017.4.1 ◽

2018 ◽

Vol 15 (4) ◽

pp. 303-309 ◽

Cited By ~ 2

Author(s):

Maria Kondrat-Wróbel ◽

◽

Jarogniew J. Łuszczki ◽

Keyword(s):

Drug Combination ◽

Maximal Electroshock ◽

Type I ◽

Additive Interaction ◽

Isobolographic Analysis

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Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis

Pharmacology ◽

10.1159/000480019 ◽

2017 ◽

Vol 101 (1-2) ◽

pp. 22-28 ◽

Cited By ~ 5

Author(s):

Jarogniew J. Luszczki ◽

Mirosław Zagaja ◽

Barbara Miziak ◽

Maria W. Kondrat-Wrobel ◽

Katarzyna Zaluska ◽

...

Keyword(s):

Dose Response ◽

Treatment Plan ◽

Linear Regression Analysis ◽

Fixed Ratio ◽

Maximal Electroshock ◽

Type I ◽

Additive Interaction ◽

Pharmacoresistant Epilepsy ◽

Isobolographic Analysis ◽

Chimney Test

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.

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