Kinga K. Borowicz

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.

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.

Melatonin in experimental seizures and epilepsy

Although melatonin is approved only for the treatment of jet-lag syndrome and some types of insomnia, clinical data suggest that it is effective in the adjunctive therapy of osteoporosis, cataract, sepsis, neurodegenerative diseases, hypertension, and even cancer. Melatonin also modulates the electrical activity of neurons by reducing glutamatergic and enhancing GABA-ergic neurotransmission. The indoleamine may also be metabolized to kynurenic acid, an endogenous anticonvulsant. Finally, the hormone and its metabolites act as free radical scavengers and antioxidants. The vast majority of experimental data indicates anticonvulsant properties of the hormone. Melatonin inhibited audiogenic and electrical seizures, as well as reduced convulsions induced by pentetrazole, pilocarpine, L-cysteine and kainate. Only a few studies have shown direct or indirect proconvulsant effects of melatonin. For instance, melatonin enhanced low Mg2+-induced epileptiform activity in the hippocampus, whereas melatonin antagonists delayed the onset of pilocarpine-induced seizures. However, the relatively high doses of melatonin required to inhibit experimental seizures can induce some undesired effects (e.g., cognitive and motor impairment and decreased body temperature). In humans, melatonin may attenuate seizures, and it is most effective in the treatment of juvenile intractable epilepsy. Its additional benefits include improved physical, emotional, cognitive, and social functions. On the other hand, melatonin has been shown to induce electroencephalographic abnormalities in patients with temporal lobe epilepsy and increase seizure activity in neurologically disabled children. The hormone showed very low toxicity in clinical practice. The reported adverse effects (nightmares, hypotension, and sleep disorders) were rare and mild. However, more placebo-controlled, double-blind randomized clinical trials are needed to establish the usefulness of melatonin in the adjunctive treatment of epilepsy.

Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice

Melatonin (50 mg/kg; 60 min before the test) significantly raised the electroconvulsive threshold in mice. The protective action of melatonin (50 mg/kg) in the electroconvulsive threshold test was reversed by aminophylline, picrotoxin and bicuculline. Melatonin at the subconvulsive dose of 25 mg/kg potentiated the anticonvulsive activity of carbamazepine and phenobarbital (ED50 values were significantly decreased from 12.1 to 8.3 and from 18.9 to 11.8 mg/kg, respectively). No potentiation was observed in the case of valproate and diphenylhydantoin (their ED50s were changed from 253 to 249 and from 10.3 to 9.7 mg/kg, respectively). Melatonin did not influence the plasma or brain levels of anti-epileptics studied, so a pharmacokinetic interaction is not probable. Melatonin (25 mg/kg) alone and its combinations with carbamazepine or phenobarbital, providing a 50% protection against maximal electroshock, were devoid of significant motor adverse effects, but caused strong long-term memory deficit. Consequently, it does not seem to be a good candidate for the treatment of epilepsy.

Polytherapy in epilepsy: the experimental evidence

Monotherapy is recommended preferentially among newly diagnosed epileptic patients. In monotherapy-resistant patients polytherapy may be necessary. Two antiepileptic drugs may produce antagonistic, additive, and supra-additive (synergistic) anticonvulsant effects. The drug combination providing the supra-additive effect seems of clinical significance. However, when the supra-additive anticonvulsant efficacy is also associated by a distinct increase in toxicity, the protective index may be not affected or even lowered. Synergistic interactions have been shown for the combinations of valproate-phenytoin/ethosuximide, topiramate-carbamazepine/phenobarbital and felbamate-all major conventional antiepileptics. In contrast, the protective action of conventional antiepileptics has not been affected by felbamate at subprotective doses against maximal electroshock in mice. This is indicative that synergism is evident at only some drug ratios. Potential antiepileptic drugs, excitatory amino acid antagonists and calcium channel inhibitors, generally enhanced the protection offered by antiepileptic drugs. The experimental data may be helpful for predicting which drug combinations may prove effective in epileptic patients.

The non-competitive AMPA/kainate receptor antagonist, GYKI 52466, potentiates the anticonvulsant activity of conventional antiepileptics

1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466), up to 5 mg/kg, did not influence the electroconvulsive threshold but potentiated the anticonvulsant activity of valproate, carbamazepine and diphenylhydantoin against maximal electroshock-induced convulsions in mice. No potentiation was observed in the case of phenobarbital. Moreover, this non-NMDA receptor antagonist did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction, in terms of total and free plasma levels, is not probable. The combined treatment of GYKI 52466 with either carbamazepine or diphenylhydantoin (providing a 50% protection against maximal electroshock) was devoid of significant side effects (motor and long-term memory impairment). Valproate applied at a dose equal to its ED50 caused serious worsening of motor coordination and long-term memory. It is noteworthy that the combined treatment of GYKI 52466 with valproate was superior to valproate alone, as regards adverse effects. The results suggest that concomitant administration of GYKI 52466 with some conventional antiepileptic drugs may offer a novel approach in the treatment of epilepsy.

7-Nitroindazole, a nitric oxide synthase inhibitor, enhances the anticonvulsive action of ethosuximide and clonazepam against pentylenetetrazol-induced convulsions

Summary. The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.

Effect of topiramate on the anticonvulsant activity of conventional antiepileptic drugs in two models of experimental epilepsy.

Summary:  Purpose: The objective of this study was to evaluate the interaction of the novel antiepileptic drug (AED), topiramate (TPM), with conventional AEDs against amygdala‐kindled seizures in rats and pentylenetetrazol‐induced convulsions in mice.

Influence of combined treatment with NMDA and non-NMDA receptor antagonists on electroconvulsions in mice

alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate (AMPA/kainate) receptor antagonists (at subthreshold doses against electroconvulsions), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466 at maximally 5 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX at maximally 20 mg/kg) enhanced the protective effects of NMDA receptor antagonists, MK-801 (dizocilpine) or 2-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene), against electroconvulsions. Similarly, MK-801 or D-CPP-ene reduced the ED50 values of both NBQX and GYKI 52466 against maximal electroshock. The adverse effects of D-CPP-ene, evaluated in the chimney and rotorod tests, were potentiated by both GYKI 52466 (2.5 mg/kg) and NBQX (10 mg/kg). Also, D-CPP-ene (0.1 mg/kg) worsened the motor performance of mice pretreated with GYKI 52466 in the rotorod test. Neither MK-801 (0.025 mg/kg) nor D-CPP-ene (0.1 mg/kg) affected the NBQX-induced impairment of motor coordination. Similarly, GYKI 52466 (2.5 mg/kg) or NBQX (10 mg/kg) did not influence the performance of mice treated with MK-801 (0.2 mg/kg). It may be concluded that the blockade of more than one subtype of glutamate receptors leads to a more pronounced anticonvulsive effect when compared with the effect of blockade of an individual receptor subtype. In some cases more efficient seizure protection was not associated with increased adverse effects.

NG-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice

SummaryNitric oxide may be involved in seizure phenomena even though data often seem to be contradictory. This prompted us to study the influence of nitric oxide upon electrically and chemically induced seizures. The effects of nitric oxide synthase inhibitor, NG-nitro-L-arginine (NNA), on pentylenetetrazol-, aminooxyacetic acid-, aminophylline-induced seizures or electroconvulsive shock were evaluated. NNA was applied at 1, 10 and 40 mg/kg 0.5 and 2.0 h before chemical seizures and at 1 and 40 mg/kg 0.5 and 2.0 h prior to electroconvulsions. The nitric oxide synthase inhibitor (up to 40 mg/kg) did not affect the susceptibility of mice to pentylenetetrazol, aminooxyacetic acid or electroconvulsions. However, NNA significantly enhanced the convulsive properties of aminophylline when applied at 40 mg/kg, 0.5 h before the test. The CD50 value for aminophylline-induced clonus and tonus/mortality was decreased from 233 to 191 and from 242 to 212 mg/kg, respectively. However, this pretreatment also led to a significant increase in the plasma levels of theophylline. Our results suggest that differential effects of NNA on chemically-induced convulsions might in some cases be associated with a pharmacokinetic interaction.