Jarogniew J. Luszczki

Interactions between oxcarbazepine and conventional antiepileptic drugs in the maximal electroshock test in mice: An isobolographic analysis

Summary:  Purpose: The aim of this study was to determine the types of interactions between oxcarbazepine (OCBZ) and conventional antiepileptic drugs (AEDs) against maximal electroshock‐induced seizures (MES test) in mice, by using a method of isobolographic analysis.

Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: A comparative study

The aim of this study was to determine and compare the anticonvulsant and acute adverse (neurotoxic) effects of imperatorin and osthole (two natural coumarin derivatives) with valproate (a classical antiepileptic drug) in the maximal electroshock seizure and chimney tests in mice. The anticonvulsant and acute adverse effects of imperatorin, osthole and valproate were determined at 15, 30, 60 and 120 min after their systemic (i.p.) administration. The evaluation of time-course and dose-response relationships for imperatorin, osthole and valproate in the maximal electroshock seizure test revealed that the compounds produced a clear-cut antielectroshock action in mice and the experimentally derived ED(50) values for imperatorin ranged between 167 and 290 mg/kg, those for osthole ranged from 253 to 639 mg/kg, whereas the ED(50) values for valproate ranged from 189 to 255 mg/kg. The evaluation of acute neurotoxic effects in the chimney test revealed that the TD(50) values for imperatorin ranged between 329 and 443 mg/kg, the TD(50) values for osthole ranged from 531 to 648 mg/kg, while the TD(50) values for valproate ranged from 363 to 512 mg/kg. The protective index (as a ratio of TD(50) and ED(50) values) for imperatorin ranged between 1.13 and 2.60, for osthole ranged from 0.83 to 2.44, and for valproate ranged between 1.72 and 2.00. In conclusion, both natural coumarin derivatives deserve more attention from a preclinical point of view as compounds possessing some potentially favorable activities in terms of suppression of seizures, quite similar to those reported for valproate.

Pharmacological and Behavioral Characteristics of Interactions between Vigabatrin and Conventional Antiepileptic Drugs in Pentylenetetrazole-Induced Seizures in Mice: An Isobolographic Analysis

To characterize the anticonvulsant effects and types of interactions exerted by mixtures of vigabatrin (VGB) and conventional antiepileptic drugs (valproate (VPA), ethosuximide (ESM), phenobarbital (PB), and clonazepam (CZP)) in pentylenetetrazole (PTZ)-induced seizures in mice, the isobolographic analysis for three fixed-ratio combinations of 1 : 3, 1 : 1, and 3 : 1 was used. The adverse-effect profile of the combinations tested, at the doses corresponding to their median effective doses (ED50) at the fixed-ratio of 1 : 1 against PTZ-induced seizures, was determined by the chimney (motor performance), step-through passive avoidance (long-term memory), pain threshold (pain sensitivity), and Y-maze (general explorative locomotor activity) tests in mice. Additionally, the observed isobolographic interactions were verified in terms of a pharmacokinetic interaction existence. VGB combined with PB or ESM exerted supra-additive (synergistic) interactions against the clonic phase of PTZ-induced seizures, which was associated with the increment of PB or ESM concentrations in the brains of examined animals. The remaining combinations tested (ie VGB+VPA and VGB+CZP) occurred additive in the PTZ test, which was associated with no significant changes in the brain concentrations of VPA and CZP. None of the examined combinations exerted motor impairment in the chimney test in mice. In the standard variant of passive avoidance task (current of 0.6 mA; 2 s of stimulus duration), the combinations of VGB+CZP and VGB+VPA significantly affected long-term memory in mice. Moreover, VGB in a dose-dependent manner lengthened the latency to the first pain reaction in the pain threshold test in mice. The modified variant of step-through passive avoidance task (current of 0.6 mA; stimulus duration based on the latency from the pain threshold test) revealed no significant changes in the long-term memory of animals for the combinations of VGB+VPA and VGB+CZP; so the observed effects in the standard variant of passive avoidance task were a result of the antinociceptive effects produced by VGB. In the Y-maze test, VGB also, in a dose-dependent manner, increased the general explorative locomotor activity of the animals tested. Similarly, the total number of arm entries in the Y-maze was significantly increased for the combinations of VGB+CZP and VGB+ESM, but not for VGB+PB and VGB+VPA. The application of VGB in combination with PB, ESM, CZP, and VPA suppressed the clonic phase of PTZ-induced seizures, having no harmful or deleterious effects on behavioral functioning of the animals tested, which might be advantageous in further clinical practice.

Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin - PHT, carbamazepine - CBZ, valproate - VPA and phenobarbital - PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.

Preclinical profile of combinations of some second-generation antiepileptic drugs: An isobolographic analysis

Summary:  Purpose: The need for an efficacious treatment of patients with intractable seizures is urgent and pressing, because ∼30% of epilepsy patients worldwide are still inadequately medicated with current frontline antiepileptic drugs (AEDs). This study sought to determine the interactions among some newer AEDs [topiramate (TPM), felbamate (FBM), oxcarbazepine (OXC), and lamotrigine (LTG)] in the maximal electroshock‐induced seizures (MES) and chimney test (motor performance) in mice, by using the isobolographic analysis.

Interactions of Lamotrigine with Topiramate and First‐generation Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis

Summary:  Purpose: The study investigated the types of interactions between lamotrigine (LTG) and first‐generation antiepileptic drugs (AEDs) or topiramate (TPM) with isobolographic analysis.

Isobolographic and subthreshold methods in the detection of interactions between oxcarbazepine and conventional antiepileptics—a comparative study

Until now, a character of interactions among the antiepileptic drugs (AEDs), in some experimental models of epilepsy, has been determined alternatively with subthreshold and isobolographic methods. In order to elicit the precise and adequate method for evaluating two drug interactions, the comparative study was performed in the maximal electroshock-induced seizure test in mice. In this experimental model, the exact types of interactions among oxcarbazepine (OXC) and conventional AEDs (diphenylhydantoin, phenobarbital, valproate, carbamazepine, and clonazepam) were determined with both methods. Results from the subthreshold method showed a considerable reduction of ED(50) values of clonazepam, diphenylhydantoin and valproate (after administration of OXC at the highest subthreshold dose of 2.5 mg/kg), whilst ED(50)s of carbamazepine or phenobarbital were almost unchanged when OXC (2.5 mg/kg) was co-administered with these AEDs. Results from the 2-dimensional (2-D) isobolographic analysis of interactions for a 50% anticonvulsant effect, for three fixed drug dose ratio combinations of 1:2, 1:1, and 2:1, indicate antagonism between OXC and diphenylhydantoin as regards their anticonvulsant (protective) activity. Furthermore, the interactions between OXC and clonazepam occurred either antagonistic (for the fixed-ratios of 1:4 and 1:3) or synergistic (for the fixed-ratio combinations of 1:1 and 2:1) depending on the proportions of used drugs. Remaining interactions between OXC and carbamazepine, OXC and valproate, or OXC and phenobarbital (for the fixed-ratios of 1:3, 1:1, and 3:1) were isobolographically additive for a 50% anticonvulsant effect tested. The 3-dimensional (3-D) isobolographic analysis of interactions between OXC and CZP revealed that the dual character of interactions (antagonistic and synergistic) observed for a 50% anticonvulsant effect (ED(50)) was also present for additional drug-dose effects tested, i.e. ED(16) and ED(84). The 3-D isobologram for the combination of OXC with CZP clearly visualized either synergy or antagonism between the drugs in combinations.Distinct differences resulting from two experimental methods prove evidently the superiority of isobolographic analysis over the subthreshold method. The former clearly and adequately detects the exact types of interactions between two AEDs, becoming a potent and powerful paradigm for further studies evaluating the character of interactions among AEDs.

Effect of Gabapentin on the Anticonvulsant Activity of Antiepileptic Drugs against Electroconvulsions in Mice : An Isobolographic Analysis

Summary:  Purpose: The objective of this study was the isobolographic evaluation of the interactions between the novel antiepileptic drug (AED) gabapentin (GBP) and a number of other AEDs against electroconvulsion‐induced convulsions in mice.

Osthole suppresses seizures in the mouse maximal electroshock seizure model.

The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one]--a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED(50) values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies.

Pharmacodynamic and pharmacokinetic characterization of interactions between levetiracetam and numerous antiepileptic drugs in the mouse maximal electroshock seizure model: an isobolographic analysis.

Summary:  Purpose: Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV)