Interakcja trójlekowej kombinacji lakozamidu, karbamazepiny i fenobarbitalu w teście maksymalnego wstrząsu elektrycznego u myszy – analiza izobolograficzna

Background. Epilepsy is one of the serious neurological diseases characterized by seizures that affect about 1% of people worldwide (65 million), and therefore, epilepsy can be considered as a disease of civilization. Although seizures are controllable with antiepileptic drugs (AEDs) in about 70% of cases, it remains still about 30% of epilepsy patients inadequately medicated with these AEDs, who need a full control of their seizure attacks. One of the treatment options in these patients is application of two or three AEDs in combination. The aim of this study was to characterize the anticonvulsant effects of a combination of three AEDs (i.e., carbamazepine [CBZ], lacosamide [LCM] and phenobarbital [PB]) at the fixed-ratio of 1:1:1 in the mouse maximal electroshock (MES)-induced seizure model. Materials and 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 was used to analyze the three-drug combination. Results. Type I isobolographic analysis revealed that the combination of CBZ, LCM and PB (at the fixed-ratio of 1:1:1) exerted additive interaction with a slight tendency towards antagonism in the mouse MES-induced seizure model. Conclusions. A special caution is advised to patients taking LCM in combination with CBZ and PB because this three-drug combination offered additive interaction with a slight tendency towards antagonism in the mouse MES model.Wprowadzenie. Padaczka jest jedną z poważnych chorób neurologicznych charakteryzującą się występowaniem drgawek, które dotykają około 1% ludzi na świecie (65 milionów) i dlatego też padaczka może być uważana za chorobę cywilizacyjną. Chociaż drgawki padaczkowe kontrolowane są lekami przeciwpadaczkowymi w około 70% przypadków, wciąż pozostaje około 30% pacjentów z padaczką niewłaściwie leczonych tymi lekami, którzy wymagają pełnej kontroli napadów. Jedną z opcji leczniczych u tych pacjentów jest zastosowanie dwóch lub trzech leków przeciwpadaczkowych w kombinacji. Celem badania była ocena działania przeciwdrgawkowego kombinacji trzech leków przeciwpadaczkowych (tj.: karbamazepiny [CBZ], lakozamidu [LCM] i fenobarbitalu [PB]) w stałej proporcji dawek 1:1:1 w teście maksymalnego wstrząsu elektrycznego u myszy. Materiały i metody. Toniczny wyprost kończyn tylnych (aktywność drgawkową) wywoływano u dorosłych myszy szczepu albino Swiss prądem (25 mA, 500 V, 50 Hz, 0,2 s czas stymulacji) dostarczanym przez elektrody uszne. Zastosowano typ I analizy izobolograficznej do oceny trójlekowej kombinacji. Wyniki. Typ I analizy izobolograficznej wykazał, że kombinacja CBZ, LCM i PB (w stałej proporcji dawek 1:1:1) wykazuje interakcje addytywną z niewielką tendencją do antagonizmu w teście maksymalnego wstrząsu elektrycznego u myszy. Wnioski. Zaleca się szczególną ostrożność pacjentom przyjmującym LCM do kombinacji CBZ i PB ponieważ ta trójlekowa kombinacja oferuje addycję z niewielką tendencją do antagonizmu w teście maksymalnego wstrząsu elektrycznego u myszy

SYM 2206 (a potent non-competitive AMPA receptor antagonist) elevates the threshold for maximal electroshock-induced seizures in mice

The aim of this study was to determine the effect of SYM 2206 (a potent non-competitive AMPA receptor antagonist) on the threshold for maximal electroshock (MEST)-induced seizures in mice. Electroconvulsions were produced in mice by means of a current (sinewave, 50 Hz, maximum 500 V, strength from 4 to 14 mA, 0.2-s stimulus duration, tonic hind limb extension taken as the endpoint) delivered via ear-clip electrodes. SYM 2206 administered systemically (i.p.), 30 min before the MEST test, at doses of 2.5 and 5 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, SYM 2206 at doses of 10 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (P<0.01 and P<0.001). Linear regression analysis of SYM 2206 doses and their corresponding threshold increases allowed for the determination of threshold increasing doses by 20% and 50% (TID20 and TID50 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 and TID50 values for SYM 2206 were 4.25 and 10.56 mg/kg, respectively. SYM 2206 dose-dependently increased the threshold for MEST-induced seizures, suggesting the anticonvulsant action of the compound in this seizure model in mice

Interactions of levetiracetam with ethosuximide in the mouse 6 Hz psychomotor seizure model - a type II isobolographic analysis

The aim of the present study was to characterize the anticonvulsant effects of levetiracetam in combination with ethosuximide in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes; type II isobolographic analysis was used to characterize the consequent anticonvulsant interactions between the drug combinations for fixed-ratios of 1:1, 1:2, 1:5 and 1:10. With type II isobolographic analysis, the combinations of levetiracetam with ethosuximide for the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; P<0.05 and P<0.01, respectively) in terms of seizure suppression, while the combinations for the fixed-ratios of 1:1 and 1:2 were additive in the mouse 6 Hz psychomotor seizure model. The combinations of levetiracetam with ethosuximide for the fixed-ratios of 1:5 and 1:10 appear to be particularly favorable combinations exerting supra-additive interaction in the mouse 6 Hz psychomotor seizure model. Finally, it may be concluded that because of the synergistic interactions between levetiracetam and ethosuximide, the combination might be useful in clinical practice

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

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

Effects of arachidonyl-2’-chloroethylamide (ACEA) on the protective action of various antiepileptic drugs in the 6-Hz corneal stimulation model in mice

<div><p>Accumulating evidence indicates that cannabinoid CB₁ receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2′-chloroethylamide (ACEA–a selective cannabinoid CB₁ receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (<i>P</i><0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB₁ receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future.</p></div