Traditional Antiepileptic Drugs Research Articles

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations.

To explore the mechanism involved in variable phenotypes of epilepsy models induced by γ-aminobutyric acid type A γ2 subunit (GABRG2) mutations. The zebrafish carrying wild-type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video-Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio-signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations. The established Tg(hGABRG2P282S ) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2P282S ) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2P282S ) zebrafish. In addition, the behavioral activity, production of pro-inflammatory factors, and activation of the IL-2 receptor signal pathway varied among the three mutant zebrafish lines. We successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.

Reactive A1 Astrocyte-Targeted Nucleic Acid Nanoantiepileptic Drug Downregulating Adenosine Kinase to Rescue Endogenous Antiepileptic Pathway.

Resistance to traditional antiepileptic drugs is a major challenge in chronic epilepsy treatment. MicroRNA-based gene therapy is a promising alternative but has demonstrated limited efficacy due to poor blood-brain barrier permeability, cellular uptake, and targeting efficiency. Adenosine is an endogenous antiseizure agent deficient in the epileptic brain due to elevated adenosine kinase (ADK) activity in reactive A1 astrocytes. We designed a nucleic acid nanoantiepileptic drug (tFNA-ADKASO@AS1) based on a tetrahedral framework nucleic acid (tFNA), carrying an antisense oligonucleotide targeting ADK (ADKASO) and A1 astrocyte-targeted peptide (AS1). This tFNA-ADKASO@AS1 construct effectively reduced brain ADK, increased brain adenosine, mitigated aberrant mossy fiber sprouting, and reduced the recurrent spontaneous epileptic spike frequency in a mouse model of chronic temporal lobe epilepsy. Further, the treatment did not induce any neurotoxicity or major organ damage. This work provides proof-of-concept for a novel antiepileptic drug delivery strategy and for endogenous adenosine as a promising target for gene-based modulation.

The clinical, sociodemographic, and pharmacotherapeutic characteristics influencing quality of life in patients with epilepsy

Background: It is becoming widely understood that evaluating a patient’s quality of life (QOL) is crucial to managing their epilepsy. The study aimed to explore the impact of sociodemographic, clinical, and pharmacotherapy factors on QOL in patients with epilepsy. Methods: This was a cross-sectional study conducted over 2 years at the outpatient and inpatient Department of Medicine (Neurology Division) of SMHS Hospital, affiliated with Government Medical College, Srinagar. The patients with epilepsy with a definite diagnosis of epilepsy as per the International League Against Epilepsy (ILAE) guidelines were included. Results: Patients on polytherapy had significantly lower scores for overall QOL, energy/fatigue, medication effects, social functioning, and overall score. Patients on monotherapy scored significantly lower for the said domains, including the seizure worry domain, compared to those patients with epilepsy who were antiepileptic drugs (AEDs) naive. Conclusion: Individuals who were receiving monotherapy had greater QOL scores than those who were receiving traditional AEDs and had focal epilepsy. Furthermore, in patient with epilepsy, all QOL domains were significantly predicted by increased seizure frequency and the presence of adverse drug reactions (ADRs).

Forward Genetics-Based Approaches to Understanding the Systems Biology and Molecular Mechanisms of Epilepsy

Epilepsy is a highly prevalent, severely debilitating neurological disorder characterized by seizures and neuronal hyperactivity due to an imbalanced neurotransmission. As genetic factors play a key role in epilepsy and its treatment, various genetic and genomic technologies continue to dissect the genetic causes of this disorder. However, the exact pathogenesis of epilepsy is not fully understood, necessitating further translational studies of this condition. Here, we applied a computational in silico approach to generate a comprehensive network of molecular pathways involved in epilepsy, based on known human candidate epilepsy genes and their established molecular interactors. Clustering the resulting network identified potential key interactors that may contribute to the development of epilepsy, and revealed functional molecular pathways associated with this disorder, including those related to neuronal hyperactivity, cytoskeletal and mitochondrial function, and metabolism. While traditional antiepileptic drugs often target single mechanisms associated with epilepsy, recent studies suggest targeting downstream pathways as an alternative efficient strategy. However, many potential downstream pathways have not yet been considered as promising targets for antiepileptic treatment. Our study calls for further research into the complexity of molecular mechanisms underlying epilepsy, aiming to develop more effective treatments targeting novel putative downstream pathways of this disorder.

Маркетинговые исследования национального рынка противоэпилептических препаратов

Introduction. The anticonvulsant drug range expansion, the change in the treatment strategies, and person-oriented approach to choosing the optimal drug dictates the need for marketing research to update and systematize data on the state of the national pharmaceutical market of anticonvulsants. Carrying out a marketing analysis of the antiepileptic drugs (AEDs) market, including determining the market situation and the qualitative characteristics of this group of drugs, is necessary to prescribe optimal and rational pharmacotherapy regimens for patients with epilepsy, as well as to meet the demand and needs of consumers. Aim. To perform an analysis of the national market of AEDs and determine its main parameters and development trends. Materials and methods. The methodology for research of the AEDs market included methods of content-analysis and ATC/DDD methodology, structural-logical, graphic-analytical, and statistical methods of analysis. The objects of content analysis were: the State Register of Medicines; the unified structured directory-catalog of medicines; Internet sites; price-lists of the main distributors of medicines. The objects of the study were the sales data on AEDs in the Russian Federation for 2020 provided by the IQVIA agency (IMS Health). Results. An analysis of the AED range in the Russian market showed sufficient assortment saturation of AEDs of the 1st and 2nd generations, and an insufficient number of the latest AEDs. It has been established that the largest share (50%) of the AEDs in the home pharmaceutical market is represented by Russian manufacturers. At the same time, India makes the maximum contribution to the structure of imports (11%). In 2020, the leading positions in consumption continued to be held by valproates (36%) and carbamazepine (27%), however, the AEDs’ consumption structure has been changing in recent years, the share of the newest anticonvulsants was 13% in physical terms (in volume) and 23% in monetary terms (in values), respectively, an increase in the cost of the newest anticonvulsants amounted to 19%. Conclusion. The growth driver of the AED market is the subsidized segment. The growth of public antiepileptic therapy spending, despite the entry of ever cheaper generic drugs, was provided by medicines of the new and newest generations, the price of which differs up to a hundred times from traditional AEDs. The revealed dynamics of sales of AEDs, the social orientation of the policy of the Russian state, and the legal norms for subsidized drug provision of patients with epilepsy with all drugs, suggest a further increase in government expenditures on AEDs in the coming years.

Low-dose digoxin enhances the anticonvulsive potential of carbamazepine and lamotrigine in chemo-induced seizures with different neurochemical mechanisms

"Non-antiepileptic" drugs have a strong potential as adjuvants in multidrug-resistant epilepsy treatment. In previous study the influence of low doses of digoxin, which do not affect the myocardium, on the anticonvulsant potential of classical commonly used anti-epileptic drugs under conditions of seizures, induced by pentylenetetrazole and maximal electroshock, has been investigated.
 The aim of the study was to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant potential of carbamazepine and lamotrigine in experimental seizures with different neurochemical mechanisms.
 Material and methods: A total of 192 random-bred male albino mice weighting 22–25 g were used. Carbamazepine and lamotrigine were administered intragastrically in conditionally effective (ED50) and sub-effective (½ ED50) doses: carbamazepine at doses of 100 and 50 mg/kg; lamotrigine at doses of 25 and 12.5 mg/kg. Digoxin was administered subcutaneously at a sub-cardiotonic dose of 0.8 mg/kg as an adjuvant to carbamazepine and lamotrigine in ½ ED50. Picrotoxin (2.5 mg/kg subcutaneously); thiosemicarbazide (25 mg/kg intraperitoneally); strychnine (1.2 mg/kg subcutaneously); camphor (1000 mg/kg intraperitoneally) were used as convulsant agents.
 Results: It was found that digoxin not only has its own permanent anticonvulsant effect on different models of paroxysms with different neurochemical mechanisms of development, but also significantly enhances the anticonvulsant potential of carbamazepine (to a lesser extent – lamotrigine) regardless of the pathogenesis of experimental paroxysms.
 Conclusion: Based on the results, it can be concluded that digoxin has a high potential as an adjuvant medicine in complex epilepsy treatment because it enhances the efficiency of low-dose traditional anticonvulsants carbamazepine and lamotrigine

Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers.

Mutations in N-methyl-d-aspartate receptors (NMDAR) subunits have been implicated in a growing number of human neurodevelopmental disorders. Previously, a de novo mutation in GRIN2A, encoding the GluN2A subunit, was identified in a patient with severe epilepsy and developmental delay. This missense mutation, which leads to GluN2A-P552R, produces significant dendrotoxicity in transfected rodent cortical neurons, as evidenced by pronounced dendritic blebbing. This injurious process can be prevented by treatment with the NMDA antagonist memantine. Given the increasing use of FDA approved NMDA antagonists to treat patients with GRIN mutations, who may have seizures refractory to traditional anti-epileptic drugs, we investigated whether additional NMDA antagonists were effective in attenuating neurotoxicity associated with GluN2A-P552R expression. Intriguingly, we found that while treatment with memantine can effectively block GluN2A-P552R-mediated dendrotoxicity, treatment with ketamine does not, despite the fact that both drugs work as open NMDAR channel blockers. Interestingly, we found that neurons expressing GluN2A-P552R were more vulnerable to an excitotoxic insult—an effect that, in this case, could be equally rescued by both memantine and ketamine. These findings suggest that GluN2A-P552R induced dendrotoxicity and increased vulnerability to excitotoxic stress are mediated through two distinct mechanisms. The differences between memantine and ketamine in halting GluN2A-P552R dendrotoxicity could not be explained by NMDA antagonist induced changes in MAP or Src kinase activation, previously shown to participate in NMDA-induced excitotoxicity. Our findings strongly suggest that not all NMDA antagonists may be of equal clinical utility in treating GRIN2A-mediated neurological disorders, despite a shared mechanism of action.

Modified Atkins Diet for Infantile Spasms

Modified Atkins Diet for Infantile Spasms

A Comparison of Seizure Prophylaxis: Phenytoin Versus Levetiracetam

Phenytoin and levetiracetam are both antiepileptic drugs (AEDs) used for seizure prophylaxis. However, to date, there is a paucity of literature comparing their relative efficacies. In this narrative review, we seek to determine if there is greater advantage between the two AEDs, levetiracetam and phenytoin. Phenytoin is the more traditional AED of the two as it has been medically used for a much longer time than levetiracetam. However, levetiracetam, the newer AED of the two, has fewer side effects than phenytoin and fewer drug-drug interactions. Although past studies have aimed to compare the efficacy of phenytoin versus levetiracetam, there is no clear consensus as to if there is a clinical advantage to one over the other. Here, we have analyzed several studies published between 2013 and 2020 in the hopes of having a better understanding of which AED is more efficient in preventing seizures. Many factors can contribute to determining which AED is the better fit for patients, including pricing, risk for adverse drug effects, and level of patient monitoring. After analysis of past research, the more advantageous AED still remains unclear. Future research must be conducted that involve large patient populations, stratifying age populations, and studies analyzing cost-effectiveness to clearly determine if there is indeed a more advantageous AED between levetiracetam and phenytoin.

Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances.

Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.

Effects of atorvastatin and aspirin on post-stroke epilepsy and usage of levetiracetam.

Objective:Atorvastatin and aspirin have been used in treating different forms of epilepsy. However, their effect on post-stroke epilepsy (PSE) still needs to be validated by large-scale clinical studies. In addition, their impact on the use of the antiepileptic drug levetiracetam for post-stroke epilepsy remains to be explored. Thus, the aim of this study was to further evaluate the effect of atorvastatin and aspirin on PSE and their effect on the usage of the antiepileptic drug levetiracetam in PSE patients.Methods:Patients, aged 65 to 85 years, with newly diagnosed post-ischemic stroke epilepsy from August 30, 2014 to August 30, 2018 were included in the study, with the exclusion of those with coexisting conditions.Results:Initially, 1321 patients were included, and 780 remained in the study at the 1-year follow-up. During the study, atorvastatin treatment with or without aspirin reduced the number of clinical epileptic episodes in PSE patients. It also reduced the dosage of levetiracetam and achieved better control of epilepsy compared to levetiracetam mono-treatment. Aspirin co-treatment with levetiracetam did not result in a significant improvement. However, the combination of aspirin with atorvastatin significantly reduced the number of seizures compared to atorvastatin treatment alone.Conclusion:Atorvastatin and aspirin co-treatment with levetiracetam can reduce epilepsy in PSE patients and reduce the dosage of levetiracetam required for effective control of PSE.

Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice.

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.

Case series: Fetomaternal outcome with polytherapy in pregnant women with epilepsy at a rural tertiary care hospital

Epilepsy is most common major neurological complication encounterd in pregnancy. The etiology of seizures covers a wide range of diseases, vascular insults,infectious sequelae, malignant processes and primary central nervous dysfunction. A wide range of obstetric complications have been reported including spontaneous abortion , preterm labour, stillbirth, neonatal death, hemorrhagic disease of the newborn; low apgar and low birth weight. The incidence of malformations increase from 2.9% in the non drug user group to 3.7% in patient on monotherapy and 6.6% in patients on polytherapy. To study the maternal and perinatal outcome in pregnant women with epilepsy on polytherapy. This retrospective observational study was conducted in R.L. Jalappa Hospital Kolar India over a period of 6 months (December 2017-june2018). Five pregnant women with epilepsy attending the antenatal clinic or admitted in labour ward in a tertiary care hospital taking two or more antiepileptic drugs were evaluated. Cases included in this study concludes that, despite the increased risks of pregnancy in woman with epilepsy, with appropriate clinical management with newer drugs, more than 90 percent woman with epilepsy can have successful pregnancies and better neonatal outcome. Moreover because of prepregnancy planning, counselling and optimisation of antiepileptic drug regimens and use of preconception folic acid, pregnancy outcome have become better.A higher teratogenic potential was confirmed for traditional antiepileptic drugs, particularly Valproate. Lower rates of congenital malformations were found for levetiracetam(1.7%) than in association with VPA (6.9%)

The Impact of Antiepileptic Drugs on Thyroid Function in Children with Epilepsy: New Versus Old.

To investigate the effects of traditional antiepileptic drugs (AEDs) versus newer AEDs on the thyroid hormone profile of children with epilepsy. A total of 80 children with epilepsy were included in this study and were divided into two groups. Group 1 included 40 children with epilepsy on traditional AEDs, and group 2 included 40 children with epilepsy on newer AEDs. Forty healthy children were also included as the control group (group 3). We analyzed the serum levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). In epileptic children treated with traditional drugs, there was a significant reduction in the serum level of FT4 and a significant increase in TSH concentration, compared to the control group (P<0.001). Conversely, epileptic children treated with newer AEDs showed no significant changes in the serum concentrations of FT3, FT4, and TSH, compared to the control group. Traditional AEDs have more significant effects on thyroid hormone profile, compared to newer AEDs.

Factors Influencing Plasma Concentrations of Phenytoin, Phenobarbitone, Carbamazepine and Sodium Valproate in Epileptic Patients Attending a Tertiary Care Hospital

Objective: The traditional anti-epileptic drugs like phenytoin, sodium valproate and carbamazepine continue to be used widely in the low to middle income countries due to their time tested efficacy and low costs. The factors which affect the AED concentrations in non-toxicity indications has not been reported so far. Hence, we studied the factors that could influence the plasma concentrations of these AEDs. Methods: This is a retrospective record based study and a short term prosepective study. Requisition forms of epileptic patients referred for TDM 2012-2014 were compared with the AED concentrations reported. Epileptic patients who were referred during May-June 2015 for TDM were evaluated for their seizure history and anthropometic measurements for calculation of extracellular volume (VECW) and compared with the AED concentrations. Results: Out of the 170 requisitions for TDM, 68.2% were monotherapy and 31.8% received two or more antiepileptic drugs. In 44% of patients, the plasma concentrations of the AED correlated with clinical response. In our study the plasma level of carbamazepine was found to be reduced by phenytoin, sodium valproate concentration was reduced by carbamazepine and phenytoin levels were reduced by sodium valproate. In male, phenytoin levels were significantly lower than in female, Phenytoin decreased carbamazepine levels significantly in female. Carbamazepine significantly decreased sodium valproate concentrations in females. Carbamazepine dose adjusted for weight and VECW was found to show a trend of correlation to the blood levels, Conclusion: TDM for AEDs is an indispensable investigation that guides the clinicians to tailor dose of drugs in individual patients. Factors such as age, gender, concomitant drugs in general and VECW in patients on carbamazepine needs to be considered while interpreting AED plasma concentrations for monitoring therapy.

Influence of new versus traditional antiepileptic drugs on course and outcome of status epilepticus

PurposeNew antiepileptic drugs (AEDs) are increasingly applied in second-line therapy of status epilepticus (SE). In our study, we analyzed the impact of the choice of second-line AEDs on the course and prognosis of SE. MethodsThis retrospective single- center study used data of an 8 year cohort of SE in adults from 2007 to 2014. Based on the year of market introduction with a cutoff at 1990, we classified AEDs as traditional or new. Prescription pattern associated differences in prognosis were measured through univariate and multivariable analysis of 3 endpoints: occurrence of refractory SE (RSE), functional outcome in survivors to discharge (good: mRS at discharge <3 or identical to admission mRS; otherwise poor), and in-hospital mortality. ResultsFrom 362 SE episodes during the study period, 222 episodes were included into the study, among those 150 episodes treated with new and 72 with traditional AEDs. Use of new AEDs increased during the study period. After adjustment for confounders, treatment with new AEDs was on the one hand associated with higher rate of RSE occurrence (OR 1.95, 95 % CI 1.05–3.62, p = 0.03), but, on the other hand, also with better functional outcome at discharge (OR 2.64, 95 % CI 1.16–6.00, p = 0.02), while it was not an independent predictor of in- hospital mortality (OR 0.88, 95 % CI 0.33–2.33, p = 0.80). ConclusionOur observation that new AEDs may be associated with a higher rate of RSE development and relatively better functional outcome when adjusted for the premorbid mRS needs confirmation in prospective studies.

Anti-epileptic effect of 16-O-acetyldigitoxigenin via suppressing mTOR signaling pathway

Epilepsy is a common chronic disease of the central nervous system that can last for years or even decades, causing serious adverse effects on the body, mind, and psychology of patients. Traditional antiepileptic drugs can effectively control seizures, but because of large individual differences, serious adverse reactions, narrow therapeutic window and other shortcomings, more effective, new treatment drugs are looked for. Streptocaulon griffithii is a plant of Asclepiadaceae. 16-O-acetyldigitoxigenin (ACE) is a strong cardiac glycoside isolated from methanol extract of Streptocaulon griffithii. The aim of this study was to investigate the antiepileptic effect of ACE on Pilocarpine (Pilo) induced epilepsy in mice, and to explore the effect of mTOR signaling pathway on its antiepileptic effect. The results showed that ACE had antiepileptic and neuroprotective effects on Pilo induced epilepsy mice. ACE attenuates Pilo induced seizures by inhibiting the activation of p-mTOR/p-70S6K pathway, and inhibits Pilocarpine induced brain damage by inhibiting mTOR signaling pathway. These results suggest that ACE has a promising future in the treatment of epilepsy and other nervous system diseases.

Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis.

Posttraumatic epilepsy (PTE) is a prevalent type of acquired epilepsy secondary to traumatic brain injury, and is characterized by repeated seizures. Traditional antiepileptic drugs have minimal response in preventing posttraumatic epileptic seizures. It is essential for the development of new therapeutic strategy. Our previous work disclosed a potent neuroprotective role of baicalein, a flavonoid extracted from Scutellaria baicalensis Georgi, against inherited epilepsy in rats. Whether baicalein has protective potential in posttraumatic epileptic seizures and the possible molecular mechanism remain elusive. Additionally, the brain is vulnerable to lipid peroxidation-induced damage due to high consumption of oxygen and abundant polyunsaturated fatty acids in neuronal membranes. Our present investigation aimed to elucidate whether baicalein exerts neuroprotective effects on posttraumatic epileptic seizures by inhibiting ferroptosis, a newly discovered lipid peroxidation-dependent cell death modality. We found that baicalein significantly reduced seizure score, number of seizures, and average seizure duration in an iron chloride (FeCl3)-induced PTE mouse model. The neuroprotective effect of baicalein was also validated in a ferric ammonium citrate (FAC)-induced HT22 hippocampal neuron damage model. Moreover, in vitro, baicalein could remarkably decrease ferroptotic indices (lipid reactive oxygen species, 4-hydroxynonenal, and prostaglandin endoperoxide synthase 2) and inhibit the expression of 12/15-lipoxygenase (12/15-LOX) in an iron-induced HT22 cell damage model. These findings were also validated in a mouse PTE model. It was concluded that baicalein exerted neuroprotective effects against posttraumatic epileptic seizures via suppressing ferroptosis and 12/15-LOX was likely to be involved in baicalein’s neuroprotection.

Use of Newer Anticonvulsants for the Treatment of Status Epilepticus.

Status epilepticus (SE) has a high mortality rate and is one of the most common neurologic emergencies. Fast progression of this neurologic emergency and lack of response to traditional antiepileptic drugs (AEDs) in most cases has challenged clinicians to use new agents. This article evaluates the efficacy and safety of AEDs released to the market after 2000 for SE, refractory status epilepticus (RSE), and super-refractory status epilepticus (SRSE). The PubMed database was searched for clinical trials published between January 2000 and July 2018 using the search terms status epilepticus, refractory status epilepticus, super refractory status epilepticus, brivaracetam, clobazam, cannabidiol, eslicarbazepine, lacosamide, perampanel, rufinamide, stiripentol, and zonisamide. Trials that evaluated these agents in adults with SE, RSE, and SRSE were included. Brivaracetam use was identified in two retrospective reviews with success rates of 27% and 57%. One unsuccessful case report of cannabidiol use in SE was found. Four clobazam studies were identified in SE and RSE with success rates ranging from 25-100%. No evidence for the use of eslicarbazepine and zonisamide was found. Using the search terms for lacosamide identified 38 articles: 1 systematic review, 5 prospective studies, 15 retrospective reviews, and 17 case reports. Success rates and dosing varied, but studies that included focal or partial types of SE showed higher success rates. Five articles were identified regarding perampanel use in this setting. Three were retrospective reviews with success rates ranging from 17-60%, and two were case reports. Only one case report regarding the use of rufinamide was found; rufinamide titrated up to 4.4mg/day allowed discontinuation of barbiturate and clobazam. One case report and two case series of stiripentol were found with reported efficacy between 60% and 100% in SRSE. Evidence is currently insufficient to support the use of these agents in this setting.

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS-001 (huperzine A), 2-deoxy-d-glucose, FV-082, FV-137, JNJ-40411813, JNJ-55511118 and analogs, ketone-enhanced antiepileptic drugs, oxynytones, OV329, TAK-935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease-modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.