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OBJECTIVE: Seizures due to epilepsy in any form cause a wide range of problems in a patient\'s physical, psychological, and social health. This study aimed to investigate piperine\'s anti-seizure and antiepileptic effects and mechanisms.
METHODS: In this systematic review study, which was conducted according to the principles of PRISMA 2020, the initial search was conducted on November 2, 2023, using EndNote software. Various databases such as PubMed, Cochrane Library, Web of Science, Embase, and Scopus were searched using specific keywords. After screening the articles, a form was designed according to the objectives of the study, and the information related to the included articles was entered in the form, and the studies were reviewed.
RESULTS: Piperine showed its antiepileptic activity by affecting the brain\'s antioxidant, anti-inflammatory, and anti-apoptotic activity. It also, by modulating brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA)ergic activity, can control seizures. In addition, piperine can help treat seizures and epilepsy by elevating 5-HT levels in the brain, modulating astrocyte and microglia function, modulatory effects on Ca2+ and NA+ channels, increasing antiepileptic drugs bioavailability and influencing protein and gene expression.
CONCLUSIONS: In vivo and in vitro studies showed beneficial effects on treating epilepsy. Although clinical studies also showed similar results, these needed to be increased, and more clinical studies needed to be designed in this field.

The growing interest in Kv7.2/7.3 agonists originates from the involvement of these channels in several brain hyperexcitability disorders. In particular, Kv7.2/7.3 mutants have been clearly associated with epileptic encephalopathies (DEEs) as well as with a spectrum of focal epilepsy disorders, often associated with developmental plateauing or regression. Nevertheless, there is a lack of available therapeutic options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016. This is why several efforts have been made both by both academia and industry in the search for suitable chemotypes acting as Kv7.2/7.3 agonists. In this context, in silico methods have played a major role, since the precise structures of different Kv7 homotetramers have been only recently disclosed. In the present review, the computational methods used for the design of Kv.7.2/7.3 small molecule agonists and the underlying medicinal chemistry are discussed in the context of their biological and structure-function properties.

Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.

BACKGROUND: Despite new anti-seizure medications (ASMs) being introduced into clinical practice, about one-third of people with epilepsy do not reach seizure control. Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. In randomized controlled trials, adjunctive cenobamate reduced the frequency of focal seizures in people with uncontrolled epilepsy. Studies performed in real-world settings are useful to complement this evidence and better characterize the drug profile.
METHODS: The Italian BLESS (\"Cenobamate in Adults With Focal-Onset Seizures\") study is an observational cohort study aimed to evaluate the effectiveness, tolerability, and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy in the context of real-world clinical practice. The study is ongoing and conducted at 50 centers in Italy. This first interim analysis includes participants enrolled until June 2023 and with 12-week outcome data available.
RESULTS: Forty participants with a median age of 36.5 (interquartile range [IQR] 26.0-47.5) years were included. The median monthly seizure frequency at baseline was 6.0 (IQR 2.5-17.3) seizures and 31 (77.5%) participants had failed four or more ASMs before cenobamate. At 12 weeks from starting cenobamate, the median reduction in monthly seizure frequency was 52.8% (IQR 27.1-80.3%); 22 (55.0%) participants had a ≥ 50% reduction in baseline seizure frequency and six (15.0%) reached seizure freedom. The median number of concomitant ASMs decreased from 3 (IQR 2-3) at baseline to 2 (IQR 2-3) at 12 weeks and the proportion of patients treated with > 2 concomitant ASMs decreased from 52.5% to 40.0%. Seven (17.5%) patients reported a total of 12 adverse events, 11 of which were considered adverse drug reactions to cenobamate.
CONCLUSIONS: In adults with uncontrolled focal seizures, the treatment with adjunctive cenobamate was well tolerated and was associated with improved seizure control and a reduction of the burden of concomitant ASMs.
BACKGROUND: NCT05859854 (ClinicalTrials.gov Identifier).

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

Imepitoin is a low-affinity partial agonist for benzodiazepine binding sites of gamma-aminobutyric acid receptors with anxiolytic effects. It has been shown to reduce anxiety during noise-related events in dogs when given at 30 mg/kg PO BID, although this dose was associated with ataxia and increased appetite in some cases. The objective of this study was to assess its safety and efficacy for storm anxiety when started at 10 mg/kg PO BID and titrated to effect up to 30 mg/kg PO BID during storm season. Significant decreases in anxiety scores were seen in weekly surveys and storm logs (SLs) at 10, 20 and 30 mg/kg PO BID. Serious adverse events (AEs) were not reported in any subject. Ataxia was the most commonly reported non-serious AE (14/33), followed by increased hunger (13/33). The frequency of AEs was higher in the 20 mg/kg PO BID group than in the 10 mg/kg group PO BID. No clinically significant changes were seen in lab work pre- and post-study. In conclusion, Imepitoin given during storm season at doses ranging from 10 to 30 mg/kg PO BID reduced clinical signs of fear and anxiety during storms for the dogs in this study. These findings support the use of an individually titrated dose.

BACKGROUND: Epilepsy is one of the most common in all age groups and disabling neurologic disorders around the world.
OBJECTIVE: This systematic review was to explore whether berberine (BBR) has any anti-seizure or anti-epileptic effects and also reviewed this possible mechanism.
METHODS: The EMBASE, Scopus, Cochrane Library, PubMed, and Web of Science databases were searched before Sep 2023. All types of studies that investigated the effects of BBR on epilepsy or chemical-induced seizures were eligible for inclusion. Two authors independently evaluated and reviewed titles/abstracts to identify publications for potential eligibility, and a third team member resolved discrepancies. Data were extracted in an Excel form, and the outcomes were discussed.
RESULTS: BBR showed its neuroprotective properties by reducing oxidative stress, neuroinflammation, and anti-apoptosis effects. It also increases brain-derived neurotrophic factor (BDNF) release and reduces transforming growth factor-beta (TGF-β1) and hypoxia-inducible factor 1α (HIF-1α). BBR by increasing scavenging reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), endogenous antioxidant enzymes, heme oxygenase-1 (HO-1), and inhibition of lipid peroxidation insert its antioxidant activity. Moreover, BBR showed antiinflammatory activity by reducing Interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels and through inhibiting cyclooxygenase-2 (COX-2), and including nuclear factor κB (NF-κB). In addition, it modulated c-fos expression and neuronal excitability in the brain.
CONCLUSIONS: BBR indicated promising anti-seizure effects with remarkable antioxidant, antiinflammatory, anti-apoptotic, and neuroprotective activity. Future studies should be based on well-designed clinical trial studies that are integrated with new methods related to increasing bioavailability.

Background: Migraine is considered as one of the most common and disabling diseases of the nervous system that has a great impact on quality of life (QOL) and a little risk of neurologic complications such as stroke. Migraine aura is known to be the result of cortical spreading depression and is associated with higher risk of this complication. Thus, the present study was conducted with the aim to compare the effects of topiramate as an antiepileptic, and propranolol in patients with migraine with aura. Methods: The present randomized clinical trial was conducted on patients with migraine with aura referred to the neurology clinic of Golestan Hospital, Ahvaz, Iran, in the period of 2019-2020. The patients were randomized into two groups and received either topiramate or propranolol. The Migraine Disability Assessment Scale (MIDAS) score was evaluated before and at the end of three months after initiating the treatment. Results: Reduction in the MIDAS score in patients taking topiramate (-16.94) was greater than that in the propranolol group (-14.5), but this difference was not statistically significant (P > 0.005). No significant relationship was found between gender and changes in the MIDAS score after the treatment of both groups (P > 0.050). However, the changes in the MIDAS score were greater in younger patients, and this relationship was statistically significant (P < 0.050). Conclusion: There was no significant difference in the efficacy of topiramate and propranolol in patients with migraine with aura. No significant relationship was found between gender and changes in the MIDAS score after the treatment in both groups, but the reduction in the MIDAS scores was significantly higher in younger patients of both groups.

OBJECTIVE: To review and summarize the pharmacology of the antiepileptic drug (AED), levetiracetam (LEV), and to discuss its clinical utility in dogs and cats.
METHODS: Veterinary and human peer-reviewed medical literature and the authors\' clinical experience.
CONCLUSIONS: LEV is an AED with mechanisms of action distinct from those of other AEDs. In people and small animals, LEV exhibits linear kinetics, excellent oral bioavailability, and minimal drug-drug interactions. Serious side effects are rarely reported in any species. LEV use is gaining favor for treating epilepsy in small animals and may have wider clinical applications in patients with portosystemic shunts, neuroglycopenia, and traumatic brain injury. In people, LEV may improve cognitive function in patients with dementia.
CONCLUSIONS: LEV is a well-tolerated AED with well-documented efficacy in human patients. Although its use is becoming more common in veterinary medicine, its role as a first-line monotherapy in small animal epileptics remains to be determined. This review of the human and animal literature regarding LEV describes its role in epileptic people and animals as well as in other disease states and provides recommendations for clinical usage.