Combination of phenobarbital with phenytoin and pregabalin produces synergy in the mouse tonic-clonic seizure model: An isobolographic analysis

Jarogniew J Luszczki; Lech P Mazurkiewicz; Paula Wroblewska-Luczka; Aleksandra Wlaz; Grazyna Ossowska; Monika Szpringer; Dorota Zolkowska; Magdalena Florek-Luszczki

doi:10.1016/j.eplepsyres.2018.06.003

Combination of phenobarbital with phenytoin and pregabalin produces synergy in the mouse tonic-clonic seizure model: An isobolographic analysis

Epilepsy Res. 2018 Sep:145:116-122. doi: 10.1016/j.eplepsyres.2018.06.003. Epub 2018 Jun 18.

Authors

Jarogniew J Luszczki¹, Lech P Mazurkiewicz², Paula Wroblewska-Luczka², Aleksandra Wlaz², Grazyna Ossowska³, Monika Szpringer⁴, Dorota Zolkowska⁵, Magdalena Florek-Luszczki⁶

Affiliations

¹ Department of Pathophysiology, Medical University, Lublin, Poland. Electronic address: jarogniew.luszczki@gmail.com.
² Department of Pathophysiology, Medical University, Lublin, Poland.
³ Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland.
⁴ Faculty of Medicine and Health Sciences, The Jan Kochanowski University, Kielce, Poland.
⁵ Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA, USA.
⁶ Department of Medical Anthropology, Institute of Rural Health, Lublin, Poland.

PMID: 29940514
DOI: 10.1016/j.eplepsyres.2018.06.003

Abstract

Aims: Despite many antiepileptic drugs (AEDs) are available to treat epilepsy, there is still about 30% of epilepsy patients inadequately treated with these AEDs. For these patients, polytherapy with two or three AEDs to fully control their seizure attacks is recommended. Unfortunately, polytherapy is always associated with drug interactions, whose nature may be beneficial, neutral or unfavorable. To determine a type of interaction for the combination of three AEDs (i.e., phenobarbital [PB], phenytoin [PHT] and pregabalin [PGB]) at the fixed-ratio of 1:1:1, we used a model of tonic-clonic seizures in male albino Swiss mice.

Materials and method: Tonic-clonic seizures in mice were evoked by a current (sine-wave, 25 mA, 500 V, 0.2 s stimulus duration) delivered via auricular electrodes. The anticonvulsant effects of the three-drug combination (PB, PHT and PGB) in terms of suppression of tonic-clonic seizures in mice were assessed with type I isobolographic analysis. Potential acute side effects for the mixture of PB, PHT and PGB along with total brain concentrations of the AEDs were determined to confirm pharmacodynamic nature of observed interaction.

Results: The three-drug combination of PB, PHT and PGB (at the fixed-ratio of 1:1:1) exerted synergistic interaction (at P < 0.01) in the mouse model of tonic-clonic seizures. The combination of PB, PHT and PGB did not produce any side effects in experimental animals, when measuring long-term memory, muscular strength and motor coordination. The measurement of total brain concentrations of PB, PHT and PGB was conducted to confirm that none of the three AEDs significantly influenced total brain concentrations (pharmacokinetic profiles) of the other co-administered AEDs in mice.

Conclusions: The synergistic pharmacodynamic interaction for the combination of PB, PHT and PGB observed in this preclinical study can be translated into clinical settings and this favorable AED combination is worthy of being recommended to some patients with refractory epilepsy.

Keywords: Drug interactions; Isobolographic analysis; Maximal electroshock.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticonvulsants / therapeutic use*
Avoidance Learning / drug effects
Brain / drug effects
Brain / metabolism
Disease Models, Animal
Drug Synergism
Drug Therapy, Combination / methods
Electric Stimulation / adverse effects
Male
Mice
Muscle Strength / drug effects
Phenobarbital / therapeutic use
Phenytoin / therapeutic use*
Pregabalin / therapeutic use
Seizures / drug therapy*
Seizures / etiology
Seizures / pathology

Substances

Anticonvulsants
Pregabalin
Phenytoin
Phenobarbital