eslicarbazepine and Epilepsy

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

The prevalence of epilepsy is estimated 5-10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds.

Topics: Animals; Anticonvulsants; Biomarkers; Brain; Dibenzazepines; Epilepsy; Humans; Levetiracetam; Piracetam

Topics: Adult; Anticonvulsants; Dibenzazepines; Epilepsy; Humans; Isoxazoles; Zonisamide

Variants in SCN8A, the Na. We investigated the therapeutic potential of eslicarbazepine (S-licarbazepine; S-lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain-of-function (G1475R and M1760I) and one variant with biophysical gain-of-function but neuronal loss-of-function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of Na. Similar to known effects on Na. S-lic has not only substance-specific effects but also variant-specific effects. Personalized treatment regimens optimized to achieve such variant-specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A-related disease.

Topics: Animals; Dibenzazepines; Epilepsy; Mice; Mutation; NAV1.6 Voltage-Gated Sodium Channel

Brain tumor-related epilepsy (BTRE) is frequent in patients affected with glioma. Most patients have refractory seizures and require polytherapy. Promising treatment options derive from the development of novel anti-epileptic drugs (AEDs), like Eslicarbazepine (ESL), whose role in BTRE has not yet been explored. Our aim was to report a retrospective cohort of patients affected by BTRE treated with ESL as an adjunctive therapy and to discuss the potential role of this third-generation AED in this clinical context.. We analyzed a single-center, retrospectively collected cohort of patients affected by glioma and BTRE, treated with ESL as an adjunctive therapy.. This single-center experience suggests that ESL may be a well-tolerated, efficacious option as an add-on drug in the treatment of BTRE.

Topics: Adult; Aged; Anticonvulsants; Brain Neoplasms; Dibenzazepines; Epilepsy; Female; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood.. In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats.. We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca. These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.

Topics: Adamantane; Animals; Anticonvulsants; CA1 Region, Hippocampal; Calcium; Dibenzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Feedback, Physiological; Hippocampus; Inhibitory Postsynaptic Potentials; Interneurons; Long-Term Potentiation; Muscarinic Agonists; Neural Inhibition; Neuronal Plasticity; Neurons; Pilocarpine; Pyramidal Cells; Rats; Receptors, AMPA

Metabolic bone disease and fractures are a great problem for patients with epilepsy. The use of antiepileptic drugs (AEDs) is known to play an essential role in the progression of bone loss by various pathophysiological mechanisms. The aim of this study was to evaluate the effects of AEDs on bone microstructure as an additional cause of an increased fracture risk in patients with epilepsy.. Five groups of each of 12 female rats were orally dosed daily for 8 weeks with either carbamazepine (CBZ) (60 mg/kg), eslicarbazepine (ESL) (80 mg/kg), valproic acid (VPA) (300 mg/kg), levetiracetam (LEV) (50 mg/kg) or saline (control (CTL)). Following killing, dissected femurs were analyzed using X-ray micro-computed tomography (µCT), dual-energy X-ray absorptiometry (DXA) and biomechanical testing. In addition, serum bone turnover markers (BTM) were monitored throughout the experiment.. Compared to CTL treatment, VPA decreased bone volume fraction by 19%, decreased apparent density by 14% and increased structural model index by 41%. No changes were observed in bone biomechanics nor mineral density evaluated by DXA or in levels of BTM.. Our findings suggest that VPA affects the microarchitectural properties of the bone. The AEDs CBZ, ESL and LEV appear to have less adverse effects on bone biology and may be a better choice when treating patients with respect to bone health.

Topics: Animals; Anticonvulsants; Bone and Bones; Carbamazepine; Dibenzazepines; Disease Models, Animal; Epilepsy; Female; Levetiracetam; Rats; Rats, Sprague-Dawley; Valproic Acid; X-Ray Microtomography

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, -49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level-to-dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Carbamazepine; Child; Dibenzazepines; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Oxcarbazepine; Phenobarbital; Phenytoin; Pyrrolidinones; Retrospective Studies; Young Adult

Topics: Aged; Anticonvulsants; Dibenzazepines; Drug Hypersensitivity Syndrome; Epilepsy; Humans; Male

Pharmacoresistance is a problem affecting ∼30% of chronic epilepsy patients. An understanding of the mechanisms of pharmacoresistance requires a precise understanding of how antiepileptic drugs interact with their targets in control and epileptic tissue. Although the effects of (S)-licarbazepine (S-Lic) on sodium channel fast inactivation are well understood and have revealed maintained activity in epileptic tissue, it is not known how slow inactivation processes are affected by S-Lic in epilepsy.. We have used voltage clamp recordings in isolated dentate granule cells (DGCs) and cortical pyramidal neurons of control versus chronically epileptic rats (pilocarpine model of epilepsy) and in DGCs isolated from hippocampal specimens from temporal lobe epilepsy patients to examine S-Lic effects on sodium channel slow inactivation.. S-Lic effects on entry into and recovery from slow inactivation were negligible, even at high concentrations of S-Lic (300 μmol/L). Much more pronounced S-Lic effects were observed on the voltage dependence of slow inactivation, with significant effects at 100 μmol/L S-Lic in DGCs from control and epileptic rats or temporal lobe epilepsy patients. For none of these effects of S-Lic could we observe significant differences either between sham-control and epileptic rats, or between human DGCs and the two animal groups. S-Lic was similarly effective in cortical pyramidal neurons from sham-control and epileptic rats. Finally, we show in expression systems that S-Lic effects on slow inactivation voltage dependence are only observed in Na. From these data, we conclude that a major mechanism of action of S-Lic is an effect on slow inactivation, primarily through effects on slow inactivation voltage dependence of Na

Topics: Adult; Analysis of Variance; Animals; Anticonvulsants; Biophysics; Cells, Cultured; Dentate Gyrus; Dibenzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Epilepsy; Female; Humans; In Vitro Techniques; Male; Membrane Potentials; Middle Aged; Neurons; Patch-Clamp Techniques; Pilocarpine; Rats; Rats, Wistar; Sodium Channels

Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED) and an analogue to carbamazepine (CBZ) and oxcarbazepine (OXC). In this study, we evaluate initial therapeutic response to ESL and events in the change from CBZ and OXC.. We evaluated 61 patients with a broad spectrum of drug-resistant epilepsies in a cross-sectional study. The switch from CBZ and OXC to ESL was carried out in a single night at ratios of 1:1.3 and 1:1mg respectively.. The most common form of epilepsy was temporal lobe epilepsy (62.3%). The most common aetiology was mesial temporal sclerosis (26.2%). Mean follow-up time was 4.7±3.2 months. In 40 patients with a minimum follow-up period of 3 months, monthly median seizure frequency dropped by 63.6% (P<.001) and a reduction of 80% or more was recorded in 30%. Adverse events (AEs) occurred in 54%; all appeared during the titration phase. They were more frequent at doses in excess of 800mg (73.9% vs. 47.4%; P=.042). The most common AE was dizziness (34.4%), which was commonly associated with VPA, LTG and/or LCS consumption (19.2% vs. 45.7%; P=.031). The retention rate at 3 months was 75.4%. A total of 25 patients replaced CBZ or OXC treatment with ESL; any AEs were transient (69.2% for CBZ and 33% for OXC; P=.073). At 3 months after the treatment change, median seizure frequency had decreased by 20% (P<.075).. ESL is effective in the treatment of focal epilepsies and its early retention rate is > 70%. AEs occurred during the titration phase and corresponded to associated AEDs. A rapid change from CBZ and OXC to ESL treatment can be safely performed.

Topics: Adult; Anticonvulsants; Cross-Sectional Studies; Dibenzazepines; Drug Resistance; Epilepsy; Female; Humans; Male; Middle Aged