Classical Antiepileptic Drugs Research Articles

Design and synthesis of novel cycloalkanecarboxamide parabanic acid hybrids as anticonvulsants

Aiming to develop novel anticonvulsant agents a new series of novel cycloalkanecarboxamide parabanic acid hybrids series 8, 9 and 10 possessing the essential structure requirements for anticonvulsant activity was synthesized starting from cycloalkanones. All final target compounds were primary screened for chemically and electrically induced seizures using pentylenetetrazole “scPTZ” and maximal electroshock seizure “MES” models. In phase I anticonvulsant evaluation compounds 8b and 10b exhibited the highest potency among all the target compounds with 100% protection towards chemically induced seizures. Results of phase II anticonvulsant screening showed that compounds 8b and 10b are more potent than standard drug ethosuximide by about 11 and 9 fold, respectively. Regarding MES test, compounds 8b and 9a-d exhibited 100% protection with ED50 values ranged between 0.107–0.177 mmol/Kg. All final compounds did not display any signs of motor impairment in the neurotoxicity screening test. Also, compounds 8a, 9a-d and 10b were devoid of hepatotoxicity as shown by measurement of serum levels of liver enzymes, albumin as well as total protein. Moreover, the cyclohexyl derivative 10b produced a significant increase of Gamma-aminobutyric acid “GABA” brain’s content of mice compared to control group confirmed its GABAergic modulating activity. Molecular docking, physicochemical and pharmacokinetic properties were carried out for all compounds as well. These outcomes support that cycloalkanecarboxamide parabanic acid hybrid is a promising scaffold to pave the way towards further development of novel class of antiepileptic drugs.

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.

Quercetin alleviates kainic acid-induced seizure by inhibiting the Nrf2-mediated ferroptosis pathway.

Epilepsy is one of the most common neurological disorders in childhood. However, classical antiepileptic drugs are linked with drug toxicity and cognitive function impairment in children. Hence, it is essential to develop a novel therapy to solve this problem. Currently, studies indicate regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis pathway represents a potential advanced therapy for seizures. Hence, the present study aimed to explore whether quercetin, a natural polyphenol, could alleviate seizure-induced neuron death and preserve cognitive function by inhibiting Nrf2-mediated ferroptosis. Kainic acid-induced epileptic mice model, morris water maze (MWM) test, cell counting kit-8 (CCK-8) assays, western blotting analysis, enzyme-linked immunosorbent assay, flow cytometry, quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence staining, and RNA sequencing analysis were employed to explore the potential mechanisms by which quercetin exerts protective effects on seizure-induced neuron death in kainic acid-induced epileptic mice model and glutamate-induced HT22 neuronal cell death. Our findings suggested the association between the Nrf2-mediated ferroptosis pathway and seizures in a clinical setting. Quercetin pretreatment alleviates seizure-like behaviors and cognitive impairment in KA-induced epileptic mice. Additionally, in vitro, co-treatment with quercetin effectively exerts neuroprotective effects in glutamate-induced HT22 neuronal cell death. These protective effects were also closely linked to regulating the Nrf2-mediated ferroptosis pathway. Furthermore, bioinformatic profiling revealed that the SIRT1/Nrf2/SLC7A11/GPX4 pathway plays a crucial role in the Glu-induced HT22cell death pretreated with quercetin. These findings indicated that quercetin effectively protects against seizure-induced neuron death in vivo and in vitro and alleviates cognitive function impairment via the SIRT1/Nrf2/SLC7A11/GPX4 pathway.

Low-Dose Digoxin is Associated with Anticonvulsant Effect Enhancement of Classical Antiepileptic Drugs in the Electro-Induced Seizures in Mice

The aim of the study was to determine the effect of low doses of cardiac glycoside digoxin on the anticonvulsant effect of five classical antiepileptic drugs, sodium valproate, topiramate, levetiracetam, clonazepam and phenobarbital, under experimental seizures in mice. Antiepileptic drugs were administered 30 min before to seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate – at doses of 300 and 150 mg/kg; levetiracetam – at doses of 100 and 50 mg/kg; phenobarbital – at doses of 20 and 10 mg/kg; clonazepam – at doses of 0.1 and 0.05 mg/kg body weight. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10-15 min before seizure induction. Maximal electroshock seizure model was reproduced by transmitting an electric current (strength – 50 mA, frequency – 50 Hz) through the corneal electrodes for 0.2 sec. It was found that low-dose digoxin potentiates the anticonvulsant effects of sodium valproate, topiramate and phenobarbital as well as modulates the effects of levetiracetam and clonazepam, showing a distinct pharmacological effect of their sub-effective doses and increasing their therapeutic potential even under incomplete seizure control – the equivalent of drug-resistant epilepsy. The obtained results substantiate the expediency of further study of digoxin as an anticonvulsant drug in the adjuvant therapy of epilepsy and other seizure conditions.

Morphine ameliorates pentylenetetrazole-induced locomotor pattern in zebrafish embryos; mechanism involving regulation of opioid receptors, suppression of oxidative stress, and inflammation in epileptogenesis

Zebrafish (Danio rerio) is becoming an increasingly important model in epilepsy research. Pentylenetetrazole (PTZ) is a convulsant agent that induces epileptic seizure-like state in zebrafish and zebrafish embryos and is most commonly used in antiepileptic drug discovery research to evaluate seizure mechanisms. Classical antiepileptic drugs, such as valproic acid (VPA) reduce PTZ-induced epileptiform activities. Opioid system has been suggested to play a role in epileptogenesis. The aim of our study is to determine the effects of morphine in PTZ-induced epilepsy model in zebrafish embryos by evaluating locomotor activity and parameters related to oxidant-antioxidant status, inflammation, and cholinergic system as well as markers of neuronal activity c-fos, bdnf, and opioid receptors. Zebrafish embryos at 72 hpf were exposed to PTZ (20 mM), VPA (1 mM), and Morphine (MOR) (100 µM). MOR and VPA pretreated groups were treated with either MOR (MOR + PTZ) or VPA (VPA + PTZ) for 20 min before PTZ expoure. Locomotor activity was quantified as total distance moved (mm), average speed (mm/sec) and exploration rate (%) and analyzed using ToxTrac tracking programme. Oxidant-antioxidant system parameters, acetylcholinesterase activity, and sialic acid leves were evaluated using spectrophotometric methods. The expression of c-fos, bdnf, oprm1, and oprd1 were evaluated by RT-PCR. MOR pretreatment ameliorated PTZ-induced locomotor pattern as evidenced by improved average speed, exploration rate and distance traveled. We report the restoration of inflammatory and oxidant-antioxidant system parameters, c-fos, bdnf, and opioid receptor oprm1 as the possible mechanisms involved in the ameliorative effect of MOR against PTZ-induced epileptogenic process in zebrafish embryos.

Effects of antiepileptic drugs on sleep architecture parameters in adults

ObjectivesPhysiological and restorative sleep is fundamental for physical and mental well-being. Polysomnography parameters are objective methods to access sleep structure. Antiepileptic drugs (AEDs) are a group of drugs whose interference in the sleep structure is still not well known, especially in what concern the new ones. We did a systematic review of the literature to compare the effect of classic and newer AEDs on sleep architecture.Material and MethodsA search was performed in PubMed and Scopus, using keywords “sleep” and “antiepileptics”, and each AED combined with “sleep”. Only studies concerning objective measures were selected.Results63 articles were included, only 21 were randomized, controlled and double-blinded. Studies not only in epilepsy, but also in restless leg syndrome, bruxism, insomnia, fibromyalgia and obstructive sleep apnea were found. Among classic AEDs, carbamazepine has a negative effect on sleep while phenobarbitone has a slightly dose-dependent interference and is also the only one to reduce N3 stage. Valproic acid has little to no effect while clobazam and clonazepam have a positive effect. No conclusion can be drawn about phenytoin. All of them reduce REM stage. In the newer AEDs group gabapentine, lamotrigine, perampanel, pregabaline and tiagabine increase N3 sleep in best evidence. Lacosamide and zonisamide appear to be innocent while levetiracetam reduces REM sleep.ConclusionStudies found used different methodologies not always addressing the analysis on the same parameters. In spite of these, newer AEDs have less effects on sleep structure when compared with classic AEDs but furthermore robust evidence is needed.

Recent Developments on the Use of Nanomaterials for the Treatment of Epilepsy.

Epilepsy affects more than 40 million people worldwide, constituting one of the most debilitating disorders of the Central Nervous System (CNS). It results from an imbalance in the electrical activity of neurons, which is primarily mediated by calcium ions. In many cases, treatment with Antiepileptic Drugs (AEDs) that regulate calcium channel activity results in successful seizure control. However, AEDs frequently cause adverse effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure. Moreover, 30% of epileptic patients show drug-resistant epilepsy and do not respond to any form of medical treatment. In this context, nanotechnology has emerged as an excellent tool to overcome AEDs limitations. Numerous nano-strategies have been proposed as therapeutics and diagnostics for epilepsy through inhibition of different calcium channel types in the brain. In addition, limited brain access of classical AEDs in patients showing refractory epilepsy could be improved through the design of targeted drug delivery nanosystems. This report presents a review of the nanocarriers developed so far that could facilitate the interaction with calcium channels in the brain and the transport of AEDs through the blood-brain-barrier, mapping out a potential future direction in the research of epilepsy treatment.

Ex Vivo and In Vivo Studies of the Lysophospholipids Edelfosine and Mitelfosine to Develop Novel Anti‐Epileptic Therapies

Epilepsy is a chronic neurological disorder characterized by repeated seizures. Today, most anti‐epileptic therapies are a combination of anticonvulsant drugs that work on the excitability of neurons by inhibiting sodium and calcium channels, enhancing GABAergic transmission, inhibiting glutamate transmission or have several combined actions. However, these drugs have detrimental side effects, such as congenital disabilities and psychiatric comorbidities such as mood disorders, depression, and anxiety. In addition, ~35% of adults and ~15% of children epilepsy patients are resistant to these available therapies. Thus, it is critical to study new drugs against epileptic seizures that target neuronal mechanisms different from those used by classical anticonvulsants. Edelfosine (Ef) is a lysophospholipid that works as a phospholipase‐C‐β3 (PLCβ3) inhibitor. PLCβ3 is an effector of the G protein coupled to muscarinic acetylcholine receptors that produces inositol triphosphate and diacylglycerol increasing the release of calcium (Ca+2) from the calcium‐storing organelles. This cytoplasmic Ca2+ regulates several signaling cascades including opening of ion channels that leads neurons to excitotoxic death. Thus, Ef utilizes a neuroprotective mechanism against excitotoxicity that does not act directly on ion channels. This makes Ef a superior drug against muscarinic hyperstimulation. Unfortunately, Ef is not effective within the brain due to the blood‐brain barrier's (BBB) high selectivity, which does not allow its entry. Our project aims to deliver therapeutic concentrations of Ef to the brain to diminish neuronal excitotoxicity. Our first studies test the ex vivo effect of Ef in rat hippocampal slices after two different muscarinic hyperstimulation (excitotoxic insults). Our results showed that Ef could decrease brain excitotoxicity from both insults by inhibiting the PLCβ3 enzyme. This ex vivo preliminary data demonstrates for the first time in a brain model that exposure of hippocampal slices to Ef induced a significant recovery after a muscarinic hyperstimulation insult. For the next studies, we developed two non‐BBB‐targeted serum albumin (SA)‐based drug delivery system (DDS) loading Ef and the Ef analog, mitelfosine (Mf). We characterized the particle physical properties of these Ef‐SA DDS and Mf‐SA DDS using dynamic light scattering and circular dichroism. For both DDS, SA showed characteristic structural changes compared to the native SA, demonstrating the capacity of SA to load these two lysophospholipids. We also performed a short in vivo experiment for four days administrating these DDS to determine their safety in mice. From these in vivo preliminary results, we concluded that Ef‐SA DDS and Mf‐SA DDS showed no sign of toxicity and did not affect the weight, grooming or mobility. Future experiments will focus on the development of BBB‐targeted Ef‐SA DDS and Mf‐SA DDS and their in vivo effect in an epilepsy mouse model.

Digoxin at sub-cardiotonic dose modulates the anticonvulsive potential of valproate, levetiracetam and topiramate in experimental primary generalized seizures

The prevalence of epilepsy in the world population together with a high percentage of patients resistant to existing antiepileptic drugs (AEDs) stimulates the constant search for new approaches to the treatment of the disease. Previously a significant anticonvulsant potential of cardiac glycoside digoxin has been verified by enhancing a weak activity of AEDs in low doses under screening models of seizures induced by pentylenetetrazole and maximal electroshock. The aim of the present study is to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant activity of valproate, levetiracetam, and topiramate in models of primary generalized seizures with different neurochemical mechanisms. A total of 264 random-bred male albino mice have been used. AEDs were administered 30 min before seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate – at doses of 300 and 150 mg/kg; levetiracetam – at doses of 100 and 50 mg/kg. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10–15 min before seizure induction. Picrotoxin (aqueous solution 2.5 mg/kg, subcutaneously), thiosemicarbazide (aqueous solution 25 mg/kg, intraperitoneally), strychnine (aqueous solution 1.2 mg/kg, subcutaneously), camphor (oil solution 1000 mg/kg, intraperitoneally) have been used as convulsive agents for seizure induction. It was found that under the conditions of primary generalized seizures induced by picrotoxin, thiosemicarbazide, strychnine, and camphor, digoxin not only shows its own strong anticonvulsant activity but also significantly enhances the anticonvulsant potential of classical AEDs sodium valproate, levetiracetam, and topiramate. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant drug, in particular, the in-depth study of neurochemical mechanisms of its action.

Benzodiazepine partially reverses tonic-clonic seizures induced by thiocolchicoside.

Seizures are a disorder caused by structural brain lesions, life-threatening metabolic derangements, or drug toxicity. The present study describes the behavior related to proconvulsant activity induced by thiocolchicoside (TCC) in rats and investigates the electrocorticographic patterns of this behavior and the effectiveness of classic antiepileptic drugs used to control these seizures. Forty-nine adult male Wistar rats were used and divided into two phases of our experimental design: 1) evaluation of seizure-related behavior and electrocorticographic patterns induced by TCC and 2) evaluation of the efficacy of classical antiepileptic drugs to control the proconvulsive activity caused by TCC. Our results showed that TCC induced tonic-clonic seizures that caused changes in electrocorticographic readings, characteristic of convulsive activity, with average amplitude greater than that induced by pentylenetetrazole. Treatment with anticonvulsants, especially diazepam, reduced the electrocorticographic outbreaks induced by TCC. The results suggested that TCC caused seizures with increased power in brain oscillations up to 40 Hz and that diazepam may partially reverse the effects.

PCDH19 interplay with GABA(A) receptors: a window to DEE9 pathogenetic mechanisms.

PCDH19 interplay with GABA(A) receptors: a window to DEE9 pathogenetic mechanisms.

Effect of acute and chronic exposure to lovastatin on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Numerous studies indicate neuroprotective activity of statins, commonly used cholesterol lowering drugs in epilepsy and several other neurological diseases. Promising anti-convulsant and neuroprotective effects of statins, attributed to their anti-excitotoxic and anti-inflammatory action were reported in several animals’ seizure models.To determine the effects of acute (single) and chronic (once daily for 7 consecutive days) administration of lovastatin on the protective activity of four classical antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock seizure model.Seizure activity (maximal electroconvulsions) in mice were generated by alternating current delivered via ear-clip electrodes. Adverse-effect profile of lovastatin combinations with the tested antiepileptic drugs was assessed in the chimney test (motor performance). Total brain concentrations of antiepileptic drugs were evaluated with the fluorescence polarization immunoassay technique as a measure of the pharmacokinetic interaction between drugs.Lovastatin administered acutely or chronically (5–20 mg/kg) did not significantly affect the threshold for electroconvulsions in mice. Acute lovastatin (10 mg/kg) significantly enhanced the anticonvulsant effect of valproate, which was accompanied with a 34% significant increase in total brain concentration of valproate. Acute lovastatin in combination with phenytoin impaired motor performance by notably decreasing the TD50 value of phenytoin. Chronic lovastatin (10 mg/kg) markedly enhanced the anticonvulsant potential of phenytoin.Acute lovastatin increased anticonvulsant action of valproate but also significantly raised level of valproate in brain after combined administration suggesting pharmacokinetic nature of interaction. The combinations of chronic lovastatin combined with phenytoin can potentially enhance the anticonvulsant potency of phenytoin.

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.

Drosophila para bss Flies as a Screening Model for Traditional Medicine: Anticonvulsant Effects of Annona senegalensis.

Epilepsy is among the most common serious neurological disorders and affects around 50 million people worldwide, 80% of which live in developing countries. Despite the introduction of several new Anti-Epileptic Drugs (AEDs) in the last two decades, one third of treated patients have seizures refractory to pharmacotherapy. This highlights the need to develop new treatments with drugs targeting alternative seizure-induction mechanisms. Traditional medicine (TM) is used for the treatment of epilepsy in many developing countries and could constitute an affordable and accessible alternative to AEDs, but a lack of pre-clinical and clinical testing has so far prevented its wider acceptance worldwide. In this study we used Drosophila melanogaster paralytic bangsensitive (parabss) mutants as a model for epileptic seizure screening and tested, for the first time, the anti-seizure effect of a non-commercial AED. We evaluated the effect of the African custard-apple, Annona senegalensis, which is commonly used as a TM for the treatment of epilepsy in rural Africa, and compared it with the classical AED phenytoin. Our results showed that a stem bark extract from A. senegalensis was significantly more effective than a leaf extract and similar to phenytoin in the prevention and control of seizure-like behavior. These results support that Drosophila constitutes a robust animal model for the screening of TM with potential value for the treatment of intractable epilepsy.

Aggression as psychiatric side effect of newer AEDs in patients with epilepsy: Cross-sectional study based on Buss-Perry Aggression Questionnaire

PurposeAggression-irritability is the most commonly encountered antiepileptic-drug-induced psychiatric adverse effects. In this cross-sectional study, we tried to assess antiepileptic-drug-induced aggression in patients with epilepsy (PWE) with a standardized rating scale. MethodsTwo hundred sixty-six consecutive outpatients receiving treatment for epilepsy with antiepileptic drugs (AEDs) were initially examined, and the effects of the investigated drugs in regard to aggression were investigated using the Buss-Perry Aggression Questionnaire (BAQ). We compared BAQ scores as a function of a specific class of AEDs, levetiracetam (LEV), lacosamaide (LCM), perampanel (PER), and carbamazepine (CBZ), and determined whether AED type had a relationship with aggression. Additionally, the association of BAQ score with other clinico-demographic variables was also assessed. ResultsOne-way ANOVA revealed that the LEV group had a significantly higher mean BAQ score as compared to the CBZ (P = 0.001) and LCM (P = 0.029) groups for total score. In subscale analysis, the LEV group had higher scores than the CBZ group for the physical aggression (p = 0.01), verbal aggression (p = 0.02) and hostility (p = 0.01) subscales, while the LEV group had a significantly higher mean score than the LCM group for hostility (p = 0.025). In multiple regression analysis, LEV had a statistically significant impact on increased total BAQ score (B = 0.119, p = 0.049). In contrast, CBZ (B = −0.191, p = 0.002), older age at epilepsy onset (B = −0.269, p = 0.000) and female gender (B = −0.210, p = 0.000) had a significant association with lower total BAQ score. ConclusionsOur results indicate that LEV is associated with increased aggression, while CBZ and LCM showed effects to reduce aggression.

Iatrogenic phenytoin toxicity – Newer lessons learnt

Phenytoin is a widely prescribed anti-epileptic drug (AED), but overdoses are common given its narrow therapeutic index. A 24-year-old male, a previously diagnosed case of seizure disorder on multiple AEDs, including phenytoin presented with breakthrough seizures to the medical emergency. The subsequent medical management of this patient led to an inadvertent iatrogenic overdose of phenytoin resulting in encephalopathy in this patient. Given our experience in this patient, we suggest using a newer class of AED for seizure control in a patient already on phenytoin, particularly if immediate therapeutic plasma phenytoin level monitoring is not readily available.

Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice

Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED50 values) and acute neurotoxic effects of TPL-16 (as TD50 values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD50 and ED50 values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.

Prescription patterns of antiepileptic drugs for adult patients with newly diagnosed focal epilepsy from 2006 to 2017 in Japan

ObjectiveThis study aimed to examine prescription patterns of antiepileptic drugs (AEDs) for adult patients with newly diagnosed focal epilepsy in Japan and whether these patterns adhere to the 2010 Japanese Society of Neurology Guidelines of Epilepsy Treatment. MethodsData from the JMDC Claims Database were obtained for patients aged between 20 and 65 years with newly diagnosed focal epilepsy who were prescribed AEDs between 2006 and 2017. Available prescription information up to the patient’s first year was recorded and longitudinal descriptive statistics, Cochran Armitage Trend (CAT) tests, and annual percentage change (APC) were used to analyze AED trends and overall guideline adherence. In addition, logistic regression analyses were used to compare these results across different health facilities. ResultsA total of 6024 adult patients with newly diagnosed focal epilepsy were enrolled. The prescription of new AEDs increased significantly (CAT, p < 0.001, APC = 28.74 %) up to 36.8 % of all prescriptions in 2017 when compared to 2006. Among new AEDs, prescriptions for levetiracetam increased most rapidly and were followed by lamotrigine. In contrast, prescriptions for older AEDs, especially valproate, decreased over this same time period. The average guideline adherence rate from 2010 to 2017 was 75.3 %, and was not significantly different over time (CAT, p = 0.55). Health facilities with either more than 500 beds or between 20–499 beds had higher odds of prescribing new AEDs and improved guideline adherence when compared to facilities with 0–19 beds. ConclusionPrescription patterns of AEDs for adult patients with newly diagnosed focal epilepsy exhibited a trend from older to new AED classes between 2006 and 2017, with consistent, high guideline adherence from 2010 to 2017. Health facilities with 0–19 beds were less likely to prescribe new AEDs and completely adhere to proposed guidelines.

Seizures in alcohol withdrawal syndrome

Alcohol withdrawal syndrome develops in individuals with alcohol dependence who discontinue or reduce alcohol intake after long-term or binge drinking. Withdrawal symptoms usually occur 6–8 hours after the last alcohol consumption and peak between 24–72 hours. Typical manifestations include tremor, nausea, vomiting, insomnia, agitation, and excess sweating. Complicated withdrawal syndrome may manifest with seizures (including cluster seizures), status epilepticus, acute psychosis and delirium, when hallucinations are accompanied by disorientation in time, place and situation. About 10–15% of patients develop complicated withdrawal syndrome. The seizures in alcohol withdrawal syndrome are triggered in the brain stem and have a mechanism other than that of classic epileptic seizures. Benzodiazepines, which are more effective than other classes of anticonvulsants (they primarily reduce the frequency of convulsions in the first two days after alcohol discontinuation and significantly reduce the risk of death), are the gold standard for the treatment of alcohol withdrawal syndrome. The Clinical Institute of Withdrawal Assessment for Alcohol Scale (CIWA-Ar) is a helpful tool for making decisions on treatment initiation or discontinuation. It should be noted that chronic use of benzodiazepines in the secondary prevention of alcohol withdrawal seizures is not recommended due to the addictive potential of these agents and a more severe course of alcohol withdrawal seizures with benzodiazepine co-dependence.

Micronized Resveratrol Shows Anticonvulsant Properties in Pentylenetetrazole-Induced Seizure Model in Adult Zebrafish.

Epilepsy affects 50 million people around the world, and the patients experience cognitive, psychological and social consequences. Despite the considerable quantity of antiepileptic drugs available, 30% of patients still suffer in seizure. Therefore, the advance in therapeutic alternatives is mandatory. Resveratrol has been attracting the attention of many researchers because of its pharmacological potential. However, despite its neuroprotective and anti-epileptic effects, clinical resveratrol use is impaired by its low bioavailability. Here, we applied the supercritical fluid micronization technology (SEDS) to overcome this deficit, and investigated the anticonvulsant potential of micronized resveratrol in a PTZ-induced seizure model in adult zebrafish (Danio rerio). SEDS permits obtaining significantly reduced particle size with a fine size distribution in comparison with the starting material. It can improve the pharmacotherapeutic efficacy. Our data showed that micronized resveratrol decreased the occurrence of the tonic-clonic seizure stage and slowed the development of the seizures in a similar manner of diazepam. Non-processed resveratrol was not able to protect the animals. Furthermore, diazepam decreased the locomotion and exploratory behavior. Differently from diazepam, the micronized resveratrol did not induce behavioral adverse events. In addition, our data showed that the PTZ-induced seizures increased the c-fos transcript levels following the neural excitability. However, the increase in c-fos levels was prevented by micronized resveratrol. In conclusion, our results demonstrate that the micronized resveratrol shows anticonvulsant effect, like the classical antiepileptic drug diazepam in a PTZ-induced seizure model. Excitingly, different from diazepam, micronized resveratrol did not provoke behavioral adverse events.