CBD in the Treatment of Epilepsy.

It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.

Ketogenic Diet in the Treatment of Epilepsy.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Genetic Background of Epilepsy and Antiepileptic Treatments.

Advanced identification of the gene mutations causing epilepsy syndromes is expected to translate into faster diagnosis and more effective treatment of these conditions. Over the last 5 years, approximately 40 clinical trials on the treatment of genetic epilepsies have been conducted. As a result, some medications that are not regular antiseizure drugs (e.g., soticlestat, fenfluramine, or ganaxolone) have been introduced to the treatment of drug-resistant seizures in Dravet, Lennox-Gastaut, maternally inherited chromosome 15q11.2-q13.1 duplication (Dup 15q) syndromes, and protocadherin 19 (PCDH 19)-clusterig epilepsy. And although the effects of soticlestat, fenfluramine, and ganaxolone are described as promising, they do not significantly affect the course of the mentioned epilepsy syndromes. Importantly, each of these syndromes is related to mutations in several genes. On the other hand, several mutations can occur within one gene, and different gene variants may be manifested in different disease phenotypes. This complex pattern of inheritance contributes to rather poor genotype-phenotype correlations. Hence, the detection of a specific mutation is not synonymous with a precise diagnosis of a specific syndrome. Bearing in mind that seizures develop as a consequence of the predominance of excitatory over inhibitory processes, it seems reasonable that mutations in genes encoding sodium and potassium channels, as well as glutamatergic and gamma-aminobutyric (GABA) receptors, play a role in the pathogenesis of epilepsy. In some cases, different pathogenic variants of the same gene can result in opposite functional effects, determining the effectiveness of therapy with certain medications. For instance, seizures related to gain-of-function (GoF) mutations in genes encoding sodium channels can be successfully treated with sodium channel blockers. On the contrary, the same drugs may aggravate seizures related to loss-of-function (LoF) variants of the same genes. Hence, knowledge of gene mutation-treatment response relationships facilitates more favorable selection of drugs for anticonvulsant therapy.

The Role of Probiotics and Their Metabolites in the Treatment of Depression.

Depression is a common and complex mental and emotional disorder that causes disability, morbidity, and quite often mortality around the world. Depression is closely related to several physical and metabolic conditions causing metabolic depression. Studies have indicated that there is a relationship between the intestinal microbiota and the brain, known as the gut-brain axis. While this microbiota-gut-brain connection is disturbed, dysfunctions of the brain, immune system, endocrine system, and gastrointestinal tract occur. Numerous studies show that intestinal dysbiosis characterized by abnormal microbiota and dysfunction of the microbiota-gut-brain axis could be a direct cause of mental and emotional disorders. Traditional treatment of depression includes psychotherapy and pharmacotherapy, and it mainly targets the brain. However, restoration of the intestinal microbiota and functions of the gut-brain axis via using probiotics, their metabolites, prebiotics, and healthy diet may alleviate depressive symptoms. Administration of probiotics labeled as psychobiotics and their metabolites as metabiotics, especially as an adjuvant to antidepressants, improves mental disorders. It is a new approach to the prevention, management, and treatment of mental and emotional illnesses, particularly major depressive disorder and metabolic depression. For the effectiveness of antidepressant therapy, psychobiotics should be administered at a dose higher than 1 billion CFU/day for at least 8 weeks.

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.

Effects of Antiarrhythmic Drugs on Antiepileptic Drug Action-A Critical Review of Experimental Findings.

Severe cardiac arrhythmias developing in the course of seizures increase the risk of SUDEP (sudden unexpected death in epilepsy). Hence, epilepsy patients with pre-existing arrhythmias should receive appropriate pharmacotherapy. Concomitant treatment with antiarrhythmic and antiseizure medications creates, however, the possibility of drug-drug interactions. This is due, among other reasons, to a similar mechanism of action. Both groups of drugs inhibit the conduction of electrical impulses in excitable tissues. The aim of this review was the analysis of such interactions in animal seizure models, including the maximal electroshock (MES) test in mice, a widely accepted screening test for antiepileptic drugs.

Activity of Selected Group of Monoterpenes in Alzheimer's Disease Symptoms in Experimental Model Studies-A Non-Systematic Review.

Alzheimer's disease (AD) is the leading cause of dementia and cognitive function impairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes-low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes and monoterpenoids for which possible mechanisms of action have been explained. The main body of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic and sleep-regulating effects as determined by in vitro and in silico tests-followed by validation in in vivo models.

How Antidepressant Drugs Affect the Antielectroshock Action of Antiseizure Drugs in Mice: A Critical Review.

Depression coexists with epilepsy, worsening its course. Treatment of the two diseases enables the possibility of interactions between antidepressant and antiepileptic drugs. The aim of this review was to analyze such interactions in one animal seizure model-the maximal electroshock (MES) in mice. Although numerous antidepressants showed an anticonvulsant action, mianserin exhibited a proconvulsant effect against electroconvulsions. In most cases, antidepressants potentiated or remained ineffective in relation to the antielectroshock action of classical antiepileptic drugs. However, mianserin and trazodone reduced the action of valproate, phenytoin, and carbamazepine against the MES test. Antiseizure drug effects were potentiated by all groups of antidepressants independently of their mechanisms of action. Therefore, other factors, including brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) modulation, should be considered as the background for the effect of drug combinations.

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.

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.

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.

Interactions of antiepileptic drugs with drugs approved for the treatment of indications other than epilepsy.

Introduction: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics. Areas covered: This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I-IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.Expert opinion: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.

Role of oxidative stress in epileptogenesis and potential implications for therapy.

In a state of balance between oxidants and antioxidants, free radicals play an advantageous role of "redox messengers". In a state of oxidative stress, they trigger a cascade of events leading to epileptogenesis. During this latent, free of seizures period, a cascade of neurological changes takes place and finally leads to spontaneous recurrent seizures. The main processes involved in seizure generation are: neuroinflammation, neurodegeneration with anomalous neuroregeneration and lowering seizure threshold. Time of epileptogenesis offers a unique therapeutic window to prevent or at least attenuate seizure development. Animal data indicate that some antioxidants (for instance, resveratrol) may bear an anti-epileptogenic potential.

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.