Ranolazine Interacts Antagonistically with Some Classical Antiepileptic Drugs-An Isobolographic Analysis.

Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.

Trimetazidine, an Anti-Ischemic Drug, Reduces the Antielectroshock Effects of Certain First-Generation Antiepileptic Drugs.

Trimetazidine (TMZ), an anti-ischemic drug for improving cellular metabolism, is mostly administered to patients with poorly controlled ischemic heart disease (IHD). Since IHD is considered the most frequent causative factor of cardiac arrhythmias, and these often coexist with seizure disorders, we decided to investigate the effect of TMZ in the electroconvulsive threshold test (ECT) and its influence on the action of four first-generation antiepileptic drugs in the maximal electroshock test (MES) in mice. The TMZ (up to 120 mg/kg) did not affect the ECT, but applied at doses of 20-120 mg/kg it decreased the antielectroshock action of phenobarbital. The TMZ (50-120 mg/kg) reduced the effect of phenytoin, and, when administered at a dose of 120 mg/kg, it diminished the action of carbamazepine. All of these revealed interactions seem to be pharmacodynamic, since the TMZ did not affect the brain levels of antiepileptic drugs. Furthermore, the combination of TMZ with valproate (but not with other antiepileptic drugs) significantly impaired motor coordination, evaluated using the chimney test. Long-term memory, assessed with a passive-avoidance task, was not affected by either the TMZ or its combinations with antiepileptic drugs. The obtained results suggest that TMZ may not be beneficial as an add-on therapy in patients with IHD and epilepsy.

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice.

BACKGROUND: Due to blocking ß-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. MATERIALS AND METHODS: As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography-mass spectrometry. RESULTS: Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80-100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. CONCLUSION: Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Amiodarone Enhances Anticonvulsive Effect of Oxcarbazepine and Pregabalin in the Mouse Maximal Electroshock Model.

Accumulating experimental studies show that antiarrhythmic and antiepileptic drugs share some molecular mechanisms of action and can interact with each other. In this study, the influence of amiodarone (a class III antiarrhythmic drug) on the antiseizure action of four second-generation antiepileptic drugs was evaluated in the maximal electroshock model in mice. Amiodarone, although ineffective in the electroconvulsive threshold test, significantly potentiated the antielectroshock activity of oxcarbazepine and pregabalin. Amiodarone, given alone or in combination with oxcarbazepine, lamotrigine, or topiramate, significantly disturbed long-term memory in the passive-avoidance task in mice. Brain concentrations of antiepileptic drugs were not affected by amiodarone. However, the brain concentration of amiodarone was significantly elevated by oxcarbazepine, topiramate, and pregabalin. Additionally, oxcarbazepine and pregabalin elevated the brain concentration of desethylamiodarone, the main metabolite of amiodarone. In conclusion, potentially beneficial action of amiodarone in epilepsy patients seems to be limited by neurotoxic effects of amiodarone. Although results of this study should still be confirmed in chronic protocols of treatment, special precautions are recommended in clinical conditions. Coadministration of amiodarone, even at low therapeutic doses, with antiepileptic drugs should be carefully monitored to exclude undesired effects related to accumulation of the antiarrhythmic drug and its main metabolite, desethylamiodarone.

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice.

BACKGROUND: Due to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. METHODS: The effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Given acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5-75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. CONCLUSIONS: Acute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.

Nebivolol attenuates the anticonvulsant action of carbamazepine and phenobarbital against the maximal electroshock-induced seizures in mice.

BACKGROUND: Due to co-occurrence of seizures and cardiovascular disorders, nebivolol, a widely used selective ß1-blocker with vasodilatory properties, may be co-administered with antiepileptic drugs. Therefore, we wanted to assess interactions between nebivolol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital in the screening model of tonic-clonic convulsions. METHODS: Seizure experiments were conducted in the electroconvulsive threshold and maximal electroshock tests in mice. The chimney test served as a method of assessing motor coordination, whereas long-term memory was evaluated in the computerized step-through passive-avoidance task. To exclude or confirm pharmacokinetic interactions, we measured brain concentrations of antiepileptic drugs using the fluorescence polarization immunoassay. RESULTS: It was shown that nebivolol applied at doses 0.5-15 mg/kg did not raise the threshold for electroconvulsions. However, nebivolol at the dose of 15 mg/kg reduced the anti-electroshock properties of carbamazepine. The effect of valproate, phenytoin, and phenobarbital remained unchanged by combination with the ß-blocker. Nebivolol significantly decreased the brain concentration of valproate, but did not affect concentrations of remaining antiepileptic drugs. Therefore, contribution of pharmacokinetic interactions to the final effect of the nebivolol/carbamazepine combination seems not probable. Nebivolol alone and in combinations with antiepileptic drugs did not impair motor performance in mice. Nebivolol alone did not affect long-term memory of animals, and did not potentiate memory impairment induced by valproate and carbamazepine. CONCLUSIONS: This study indicates that nebivolol attenuated effectiveness of some antiepileptic drugs. In case the results are confirmed in clinical settings, this ß-blocker should be used with caution in epileptic patients.

Advances with extended and controlled release formulations of antiepileptics in the elderly.

INTRODUCTION: As a matter of course, elderly people are more sensitive to both the pharmacological and toxicological effects of pharmacotherapy. A senior's treatment, therefore, requires more attention compared to younger adults. Extended release (ER) formulations of anti-epileptic drugs (AEDs) have been developed to improve safety, efficacy and long-term adherence. In senior patients, ER AEDs are used to treat epilepsy, psychiatric conditions, and neuropathic pain. However, very limited clinical evidence is available on the use of these ER AEDs in these populations. AREAS COVERED: The authors of this paper have identified clinical studies of ER AED formulations used in elderly populations through literature searches looking, both, at their use in epileptic and non-epileptic indications. Additionally, immediate release (IR) and ER formulations of AEDs were compared whenever possible. EXPERT OPINION: The broad use of ER AED formulations in elderly patients with swallowing problems is limited by the fact that ER AED tablets (or capsules) must not be cut, crushed or chewed. The only exception is the ER formulation of valproate or topiramate which can be mixed with soft food. Although, the ER formulations of AEDs seem better tolerated than the IR equivalents, a possibility of numerous interactions with drugs prescribed for other reasons must be carefully considered.

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis.

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.

Influence of propafenone on the anticonvulsant activity of various novel antiepileptic drugs in the mouse maximal electroshock model.

BACKGROUND: The main mechanism of action of propafenone (antiarrhythmic drug) involves the inhibition of the fast inward sodium current during phase 0 of the action potential. Sodium channel-blocking activity is also characteristic for some antiepileptic drugs. Therefore, it could be assumed that propafenone may also affect seizures. In the present study, we evaluated the effect of propafenone on the protective effect of oxcarbazepine, lamotrigine, topiramate and pregabalin against the maximal electroshock-induced seizures in mice. METHODS: Anticonvulsant activity of propafenone was assessed with the maximal electroshock seizure threshold (MEST) test. Influence of propafenone on the anticonvulsant activity of antiepileptic drugs was estimated in the mouse maximal electroshock model (MES). Drug-related adverse effects were determined in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Brain concentrations of antiepileptics were assessed by fluorescence polarization immunoassay. RESULTS: Propafenone at doses 60-90mg/kg significantly increased the threshold of seizures, in turn at doses 5-50mg/kg did not affect this parameter. Administration of propafenone at the subthreshold dose of 50mg/kg increased antielectroshock activity of oxcarbazepine, topiramate and pregabalin, but not that of lamotrigine. As regards adverse effects, propafenone alone and in combination with antiepileptic drugs did not significantly impair motor coordination or long-term memory in mice. Propafenone (50mg/kg) significantly increased the brain level of pregabalin. Brain concentrations of topiramate and oxcarbazepine were not affected. CONCLUSION: Our findings show that propafenone has own anticonvulsant action and enhances efficacy of oxcarbazepine, topiramate and pregabalin, but not that of lamotrigine, at least in experimental condition.

Amiodarone, a multi-channel blocker, enhances anticonvulsive effect of carbamazepine in the mouse maximal electroshock model.

Cardiac arrhythmia may occur in the course of epilepsy. Simultaneous therapy of the two diseases might be complicated by drug interactions since antiarrhythmic and antiepileptic agents share some molecular targets. The aim of this study was to evaluate the influence of amiodarone, an antiarrhythmic drug working as a multi-channel blocker, on the protective activity of four classical antiepileptic drugs in the maximal electroshock test in mice. Amiodarone at doses up to 75 mg/kg did not affect the electroconvulsive threshold in mice. Acute amiodarone at the dose of 75 mg/kg significantly potentiated the anticonvulsive effect of carbamazepine, but not that of valproate, phenytoin or phenobarbital in the maximal electroshock-induced seizures in mice. The antiarrhythmic agent and its combinations with antiepileptic drugs did not impair motor performance or long-term memory in mice, except for the combination of amiodarone and phenobarbital. Brain concentrations of antiepileptic drugs were not changed. Despite favourable impact of amiodarone on the anticonvulsive action of carbamazepine in the maximal electroshock, co-administration of the two drugs should be carefully monitored in clinical conditions. Further studies are necessary to evaluate effects of chronic treatment with amiodarone on seizure activity and the action of antiepileptic drugs.

Sotalol enhances the anticonvulsant action of valproate and diphenylhydantoin in the mouse maximal electroshock model.

BACKGROUND: Sotalol as a drug blocking ß-receptors and potassium KCNH2 channels may interact with different substances that affect seizures. Herein, we present interactions between sotalol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. METHODS: Effects of sotalol and antiepileptics alone on seizures were determined in the electroconvulsive threshold test, while interactions between sotalol and antiepileptic drugs were estimated in the maximal electroshock test in mice. Motor coordination and long-term memory were evaluated, respectively, in the chimney test and passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Sotalol at doses up to 100mg/kg did not affect the electroconvulsive threshold. Applied at doses 60-100mg/kg, sotalol potentiated the antielectroshock action of valproate, while at doses 80-100mg/kg that of phenytoin. Sotalol (up to 100mg/kg) did not affect the action of carbamazepine or phenobarbital in the maximal electroshock. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Finally, sotalol did not change brain concentration of valproate and phenytoin, so pharmacokinetic interactions between the drugs are not probable. CONCLUSIONS: As far as obtained data may be extrapolated into clinical conditions, sotalol may be considered as an arrhythmic drug that does not reduce the action of classical antiepileptic drugs and thereby can be used in epileptic patients with cardiac arrhythmias.

Pharmacokinetic/pharmacodynamic considerations for epilepsy - depression comorbidities.

INTRODUCTION: Epilepsy may be frequently associated with psychiatric disorders and its co-existence with depression usually results in the reduced quality of life of patients with epilepsy. Also, the efficacy of antiepileptic treatment in depressed patients with epilepsy may be significantly reduced. AREAS COVERED: Results of experimental studies indicate that antidepressants co-administered with antiepileptic drugs may either increase their anticonvulsant activity, remain neutral or decrease the protective action of antiepileptic drugs in models of seizures. Apart from purely pharmacodynamic interactions, pharmacokinetic mechanisms have been proven to contribute to the final outcome. We report on clinical data regarding the pharmacokinetic interactions of enzyme-inducing antiepileptic drugs with various antidepressants, whose plasma concentration may be significantly reduced. On the other hand, antidepressants (especially selective serotonin reuptake inhibitors) may influence the metabolism of antiepileptics, in many cases resulting in the elevation of plasma concentration of antiepileptic drugs. EXPERT OPINION: The preclinical data may provide valuable clues on how to combine these two groups of drugs - antidepressant drugs neutral or potentiating the anticonvulsant action of antiepileptics are recommended in this regard. Avoidance of antidepressants clearly decreasing the convulsive threshold or decreasing the anticonvulsant efficacy of antiepileptic drugs (f.e. bupropion or mianserin) in patients with epilepsy is recommended.

Propafenone enhances the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model.

BACKGROUND: Antiarrhythmic and antiepileptic drugs share some mechanisms of actions. Therefore, possibility of interactions between these in epileptic patients with cardiac arrhythmias is quite considerable. Herein, we attempted to assess interactions between propafenone and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. METHODS: Effects of propafenone on seizures were determined in the electroconvulsive threshold test in mice. Interactions between propafenone and antiepileptic drugs were estimated in the model of maximal electroshock. Motor coordination was evaluated in the chimney test, while long-term memory in the passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Propafenone up to 50mg/kg did not affect the electroconvulsive threshold, significantly enhancing this parameter at doses of 60-90mg/kg. Applied at its subthreshold doses, propafenone potentiated the antielectroshock action of all four tested classical antiepileptics: carbamazepine, valproate, phenytoin, and phenobarbital. Propafenone alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Propafenone did not change brain concentration of phenytoin and phenobarbital; however, it significantly decreased brain levels of carbamazepine and increased those of valproate. CONCLUSIONS: Propafenone exhibits its own anticonvulsant effect and enhances the action of classical antiepileptic drugs against electrically induced convulsions in mice. Further investigations are required to determine the effect of propafenone on antiepileptic therapy in humans.

Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis.

Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.

Pharmacokinetic/pharmacodynamic evaluation of eslicarbazepine for the treatment of epilepsy.

INTRODUCTION: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug registered as the adjunctive treatment of partial-onset seizures in adults. As a third-generation medication, ESL is believed to have favorable efficacy/safety profile and pharmacokinetic properties in comparison with related drugs (carbamazepine and oxcarbazepine). AREAS COVERED: The aim of the paper was to evaluate pharmacodynamic and pharmacokinetic properties of ESL with aspect to epilepsy treatment. The review of the scientific literature was based on the PubMed database, Clinical Trials, FDA and European Medicines Agency websites to elicit current information on drug metabolism, mechanism of action and efficacy/safety profile. EXPERT OPINION: Results of clinical trials indicate that ESL possessed a favorable profile of anticonvulsant efficacy and tolerability as an add-on therapy in adult patients at daily doses of 800 and 1200 mg. Pediatric trials are in progress and their results will allow to characterize a role of ESL in the treatment of epilepsy in children.

Effects of Chronic Lamotrigine Administration on Maximal Electroshock- Induced Seizures in Mice.

The aim of the study was to determine anticonvulsant activity of lamotrigine (LTG) after acute and chronic treatment in four different protocols against maximal electroshock-induced seizures in mice. Such a knowledge seems to be valuable in view of the fact that all interactions between LTG and other drugs are evaluated in acute, not chronic, experiments. Electroconvulsions were produced by means of alternating current (50 Hz, 25 mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were assessed in the chimney test and in passive avoidance task, respectively. Brain and plasma concentrations of LTG were measured by HPLC. Chronic treatment with LTG (2 injections for 14 days) significantly potentiated the anticonvulsant effects of this antiepileptic in the maximal electroshock test in mice, significantly decreasing ED50 value for this antiepileptic. No impairment in motor coordination or long-term memory after acute or chronic treatment with LTG was noted. Nevertheless, prolonged treatment aggravated toxicity of LTG assessed in the chimney test as TD50 value. Repeated administration of LTG significantly increased plasma and brain concentrations of the antiepileptic drug when compared to the control group (single drug application). In conclusion, anticonvulsant action of LTG in the maximal electroshock test in mice may change, depending on the length of therapy. Both acute and chronic protocols are necessary in preclinical assessment of the anticonvulsant effects of drugs and possible interactions between them.

Vague effects of chronic topiramate administration on maximal electroshock-induced seizures in mice.

BACKGROUND: Almost all experimental studies evaluating interactions between antiepileptic and non-antiepileptic drugs are based on their single administration, whereas epileptic patients require chronic pharmacotherapy. Herein, we attempted to figure out whether single and repeated administration of topiramate leads to the same anticonvulsant and undesired effects. METHODS: Experiments were conducted in the model of maximal electroshock in mice. Motor coordination was evaluated in the chimney test. Brain concentrations of topiramate were determined by high-performance liquid chromatography and triple quadrupole mass spectrometry. RESULTS: The anticonvulsant activity of topiramate administered once or twice a day for 7 days did not significantly differ from the respective effect of topiramate given acutely in a single injection. However, calculating of 50% effective doses for topiramate applied in 14-days protocol (once or two times a day) was impossible. The antiepileptic administered at the dose range of 80-150 mg/kg did not offer protection in more than 50% of mice. This phenomenon cannot be attributed to pharmacokinetic events, because there were no significant differences between plasma and brain concentrations of topiramate after its acute and chronic administration. Topiramate (150 mg/kg) did not affect motor performance in mice. CONCLUSIONS: Maximal electroshock in mice does not seem to be an appropriate seizure model to test anticonvulsant effects of chronic topiramate.

Statins - are they anticonvulsant?

Statins are the most popular and effective lipid-lowering medications beneficial in hypercholesterolemias and prevention of cardiovascular diseases. Growing evidence supports theory that statins exhibit neuroprotective action in acute stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis or epilepsy. Hereby, we present available experimental data regarding action of this group of drugs on seizure activity and neuronal cell death. The most commonly examined statins, such as atorvastatin and simvastatin, display anticonvulsant action with only inconsiderable exceptions. However, the mechanism of this effect remains unexplained. Simvastatin, as a lipophilic statin, which can pass blood-brain barrier easily, was recommended as the best candidate for an anticonvulsant agent. Nevertheless, it is still indistinct, whether the protective activity of statins depends on cholesterol lowering properties or its pleiotropic characteristics. One of the most interesting of 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor's actions involves influence on nitric oxide metabolism.

Antiarrhythmic drugs and epilepsy.

For a long time it has been suspected that epilepsy and cardiac arrhythmia may have common molecular background. Furthermore, seizures can affect function of the central autonomic control centers leading to short- and long-term alterations of cardiac rhythm. Sudden unexpected death in epilepsy (SUDEP) has most likely a cardiac mechanism. Common elements of pathogenesis create a basis for the assumption that antiarrhythmic drugs (AADs) may affect seizure phenomena and interact with antiepileptic drugs (AEDs). Numerous studies have demonstrated anticonvulsant effects of AADs. Among class I AADs (sodium channel blockers), phenytoin is an established antiepileptic drug. Propafenone exerted low anti-electroshock activity in rats. Lidocaine and mexiletine showed the anticonvulsant activity not only in animal models, but also in patients with partial seizures. Among beta-blockers (class II AADs), propranolol was anticonvulsant in models for generalized tonic-clonic and complex partial seizures, but not for myoclonic convulsions. Metoprolol and pindolol antagonized tonic-clonic seizures in DBA/2 mice. Timolol reversed the epileptiform activity of pentylenetetrazol (PTZ) in the brain. Furthermore, amiodarone, the representative of class III AADs, inhibited PTZ- and caffeine-induced convulsions in mice. In the group of class IV AADs, verapamil protected mice against PTZ-induced seizures and inhibited epileptogenesis in amygdala-kindled rats. Verapamil and diltiazem showed moderate anticonvulsant activity in genetically epilepsy prone rats. Additionally, numerous AADs potentiated the anticonvulsant action of AEDs in both experimental and clinical conditions. It should be mentioned, however, that many AADs showed proconvulsant effects in overdose. Moreover, intravenous esmolol and intra-arterial verapamil induced seizures even at therapeutic dose ranges.