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International Journal of Molecular... Dec 2023Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials... (Review)
Review
Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.
Topics: Animals; Male; Female; Pregnancy; Humans; Valproic Acid; Cleft Lip; Cleft Palate; Fetus; Teratogenesis; Anticonvulsants; Teratogens; Epilepsy
PubMed: 38203562
DOI: 10.3390/ijms25010390 -
Current Neuropharmacology 2022Epilepsy is a chronic neurological disorder, characterized by the predisposition of unprovoked seizures affecting the neurobiological, psychological, cognitive,... (Review)
Review
Epilepsy is a chronic neurological disorder, characterized by the predisposition of unprovoked seizures affecting the neurobiological, psychological, cognitive, economic, and social wellbeing of the patient. As per the 2019 report by World Health Organization, it affects nearly 80% of the population, which comes from middle to low-income countries. It has been suggested that 70% of such cases can be treated effectively if properly diagnosed. It is one of the most common neurological diseases affecting 50 million people globally. Most of the antiepileptic drugs used in clinical practice are only 60-80% effective in controlling the disease. These drugs suffer from serious drawbacks of non-selectivity and toxicity that limit their clinical usefulness. Hence, there is a need to search for safe, potent, and effective anti-epileptic drugs. One of the emerging strategies to discover and develop selective and non-toxic anticonvulsant molecules focuses on the design of non-nitrogen heterocyclic compounds (NNHC). Drugs such as valproic acid, gabapentin, viagabatrin, fluorofelbamate, tiagabine, progabide, pregabalin, gamma amino butyric acid (GABA), etc. do not contain a nitrogen heterocyclic ring but are as effective anticonvulsants as conventional heterocyclic nitrogen compounds. This review covers the various classes of NNHC which have been developed in the recent past as anticonvulsants along with their chemistry, percentage yield, structure-activity relationship and biological activity. The most potent compound in each series has been identified for comparative studies, for further structural modification and to improve the pharmacokinetic profile. Various optimized synthetic pathways and diverse functionalities other than nitrogen-containing rings discussed in the article may help medicinal chemists to design safe and effective anticonvulsant drugs in near future.
Topics: Anticonvulsants; Epilepsy; Humans; Nitrogen; Seizures; Structure-Activity Relationship
PubMed: 34344289
DOI: 10.2174/1570159X19666210803144815 -
Revista Medica de Chile Jan 2016Pediatric Status Epilepticus (SE) is an emergency situation with high morbidity and mortality that requires early and aggressive management. The minimum time criterion... (Review)
Review
Pediatric Status Epilepticus (SE) is an emergency situation with high morbidity and mortality that requires early and aggressive management. The minimum time criterion to define SE was reduced from 30 to 5 minutes, defined as continuous seizure activity or rapidly recurrent seizures without resumption of consciousness for more than 5 minutes. This definition considers that seizures that persist for > 5 minutes are likely to do so for more than 30 min. Those that persist for more than 30 minutes are more difficult to treat. Refractory SE is the condition that extends beyond 60-120 minutes and requires anesthetic management. Super-refractory SE is the state of no response to anesthetic management or relapse during withdrawal of these drugs. The aim of this review is to provide and update on convulsive SE concepts, pathophysiology, etiology, available antiepileptic treatment and propose a rational management scheme. A literature search of articles published between January 1993 and January 2013, focused on pediatric population was performed. The evidence about management in children is limited, mostly corresponds to case series of patients grouped by diagnosis, mainly adults. These publications show treatment alternatives such as immunotherapy, ketogenic diet, surgery and hypothermia. A 35% mortality, 26% of neurological sequelae and 35% of recovery to baseline condition is described on patients evolution.
Topics: Anticonvulsants; Child Health; Disease Management; Humans; Seizures; Status Epilepticus
PubMed: 26998986
DOI: 10.4067/S0034-98872016000100011 -
Epilepsia Open Aug 2022Drug-resistant epilepsy remains to this day as a highly prevalent condition affecting around one-third of patients with epilepsy, despite all the research and the... (Review)
Review
Drug-resistant epilepsy remains to this day as a highly prevalent condition affecting around one-third of patients with epilepsy, despite all the research and the development of several new antiseizure medications (ASMs) over the last decades. Epilepsies are multifactorial complex diseases, commonly associated with psychiatric, neurological, and somatic comorbidities. Thus, to solve the puzzling problem of pharmacoresistance, the diagnosis and modeling of epilepsy and comorbidities need to change toward a complex system approach. In this review, we have summarized the sequence of events for the definition of epilepsies and comorbidities, the search for mechanisms, and the major hypotheses of pharmacoresistance, drawing attention to some of the many converging aspects between the proposed mechanisms, their supporting evidence, and comorbidities-related alterations. The use of systems biology applied to epileptology may lead to the discovery of new targets and the development of new ASMs, as may advance our understanding of the epilepsies and their comorbidities, providing much deeper insight on multidrug pharmacoresistance.
Topics: Anticonvulsants; Drug Resistance; Drug Resistant Epilepsy; Epilepsy; Humans; Systems Biology
PubMed: 35253410
DOI: 10.1002/epi4.12588 -
Neurologia 2023Advances in the development of drugs with novel mechanisms of action have not been sufficient to significantly reduce the percentage of patients presenting... (Review)
Review
INTRODUCTION
Advances in the development of drugs with novel mechanisms of action have not been sufficient to significantly reduce the percentage of patients presenting drug-resistant epilepsy. This lack of satisfactory clinical results has led to the search for more effective treatment alternatives with new mechanisms of action.
DEVELOPMENT
The aim of this study is to examine epidemiological aspects of the use of cannabis-based products for the treatment of epilepsy, with particular emphasis on the main mechanisms of action, indications for use, clinical efficacy, and safety. We conducted a narrative review of articles gathered from the PubMed, EMBASE, and Google Scholar databases and from the reference sections of relevant publications.
CONCLUSIONS
In recent years there has been growing interest in the use of cannabis-based products for the treatment of a wide range of diseases, including epilepsy. The cannabis plant is currently known to contain more than 100 terpenophenolic compounds, known as cannabinoids. The 2 most abundant are delta-9-tetrahydrocannabinol and cannabidiol. Studies of preclinical models of epilepsy have shown that these cannabinoids have anticonvulsant properties, and 100% purified cannabidiol and cannabidiol-enriched cannabis extracts are now being used to treat epilepsy in humans. Several open-label studies and randomised controlled clinical trials have demonstrated the efficacy and safety of these products.
Topics: Humans; Cannabinoids; Cannabidiol; Epilepsy; Anticonvulsants; Cannabis; Hallucinogens; Treatment Outcome
PubMed: 34824031
DOI: 10.1016/j.nrleng.2020.02.012 -
The Cochrane Database of Systematic... Sep 2015The prevalence of epilepsy among people with intellectual disabilities is much higher than in the general population. Seizures in this population are often complex and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The prevalence of epilepsy among people with intellectual disabilities is much higher than in the general population. Seizures in this population are often complex and refractory to treatment and antiepileptic medication may have a profound effect upon behaviour (Kerr 1997).This is an updated version of a Cochrane Review first published in Issue 3, 2007.
OBJECTIVES
To assess the data available from randomised controlled trials (RCTs) of the efficacy of antiepileptic drug (AED) interventions in people with epilepsy and intellectual disabilities.
SEARCH METHODS
For the latest update of this review, we searched the Cochrane Epilepsy Group Specialised Register (2 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) (2 September 2014), MEDLINE (Ovid, 1946 to 3 September 2014) and PsycINFO (EBSCOhost, 1887 to 3 September 2014).
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials (RCTs) of pharmacological interventions for people with epilepsy and a learning disability.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We assessed epilepsy/seizure, behavioural and cognitive outcomes, as well as quality of life and adverse effects.
MAIN RESULTS
We included 14 RCTs (1116 participants) in the present review. Data were heterogenous and a descriptive analysis is presented. In the majority of cases where antiepileptic drugs (AEDs) were trialled in this population, we found moderate reductions in seizure frequency in that there was a significantly higher rate of responders (reduction of 50% or more) in the treatment group compared with the placebo group, with some studies reporting a higher incidence of seizure freedom in the treatment group. In general, AEDs that are proven to be effective in the general epilepsy population are also effective for refractory epilepsy in people with intellectual disability. It is not possible to comment on the relative efficacy of medications, making clinical decisions difficult.In trial settings patients continued on treatment in the majority of cases. Placebo groups often experienced fewer adverse events. Where adverse events were experienced they appeared similar to those in the general population. The methods by which adverse events were recorded and reported appeared to be inconsistent, resulting in very large variation between studies. This is problematic as clinically relevant interpretation of these findings is limited.The quality of evidence provided in the present review is low to moderate. Additionally the majority of studies lacked or used non-reliable measures of behavioural exacerbation. However, where measured, little obvious impact on behaviour was seen in terms of behaviour disorder.
AUTHORS' CONCLUSIONS
This review broadly supports the use of AEDs to reduce seizure frequency in people with refractory epilepsy and intellectual disability. The evidence suggests that adverse events are similar to those in the general population and that behavioural adverse events leading to discontinuation are rare; however, other adverse effects are under-researched.
Topics: Anticonvulsants; Epilepsy; Humans; Persons with Mental Disabilities; Randomized Controlled Trials as Topic
PubMed: 26333428
DOI: 10.1002/14651858.CD005399.pub3 -
Frontiers in Endocrinology 2020Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been...
Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline- pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3beta-methylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebo-controlled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.
Topics: Allosteric Regulation; Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Agonists; Humans; Neurosteroids; Seizures; Treatment Outcome
PubMed: 33117274
DOI: 10.3389/fendo.2020.541802 -
IEEE Transactions on Bio-medical... May 2019Hippocampal slice cultures spontaneously develop chronic epilepsy several days after slicing and are used as an in vitro model of post-traumatic epilepsy. Here, we...
OBJECTIVE
Hippocampal slice cultures spontaneously develop chronic epilepsy several days after slicing and are used as an in vitro model of post-traumatic epilepsy. Here, we describe a hybrid microfluidic-microelectrode array (μflow-MEA) technology that incorporates a microfluidic perfusion network and electrodes into a miniaturized device for hippocampal slice culture based antiepileptic drug discovery.
METHODS
Field potential simulation was conducted to help optimize the electrode design to detect a seizure-like population activity. Epilepsy-on-a-chip model was validated by chronic electrical recording, neuronal survival quantification, and anticonvulsant test. To demonstrate the application of μflow-MEA in drug discovery, we utilized a two-stage screening platform to identify potential targets for antiepileptic drugs. In Stage I, lactate and lactate dehydrogenase biomarker assays were performed to identify potential drug candidates. In Stage II, candidate compounds were retested with μflow-MEA-based chronic electrical assay to provide electrophysiological confirmation of biomarker results.
RESULTS AND CONCLUSION
We screened 12 receptor tyrosine kinases inhibitors, and EGFR/ErbB-2 and cFMS inhibitors were identified as novel antiepileptic compounds.
SIGNIFICANCE
This epilepsy-on-a-chip system provides the means for rapid dissection of complex signaling pathways in epileptogenesis, paving the way for high-throughput antiepileptic drug discovery.
Topics: Anticonvulsants; Brain; Drug Discovery; Electrophysiology; Epilepsy; Humans; Microfluidic Analytical Techniques; Tissue Array Analysis
PubMed: 30235116
DOI: 10.1109/TBME.2018.2871415 -
Journal of Medicinal Chemistry Aug 2022Neuronal Kv7 channels represent important pharmacological targets for hyperexcitability disorders including epilepsy. Retigabine is the prototype Kv7 activator...
Neuronal Kv7 channels represent important pharmacological targets for hyperexcitability disorders including epilepsy. Retigabine is the prototype Kv7 activator clinically approved for seizure treatment; however, severe side effects associated with long-term use have led to its market discontinuation. Building upon the recently described cryoEM structure of Kv7.2 complexed with retigabine and on previous structure-activity relationship studies, a small library of retigabine analogues has been designed, synthesized, and characterized for their Kv7 opening ability using both fluorescence- and electrophysiology-based assays. Among all tested compounds, emerged as a potent and photochemically stable neuronal Kv7 channel activator. Compared to retigabine, compound displayed a higher brain/plasma distribution ratio, a longer elimination half-life, and more potent and effective anticonvulsant effects in an acute seizure model in mice. Collectively, these data highlight compound as a promising lead compound for the development of novel Kv7 activators for the treatment of hyperexcitability diseases.
Topics: Animals; Anticonvulsants; Carbamates; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Mice; Phenylenediamines; Seizures
PubMed: 35972998
DOI: 10.1021/acs.jmedchem.2c00911 -
Acta Pharmaceutica (Zagreb, Croatia) Sep 2020Results from numerous pre-clinical studies suggest that a well known anticonvulsant drug valproic acid (VPA) and other short-chain fatty acids (SCFAs) cause significant... (Review)
Review
Results from numerous pre-clinical studies suggest that a well known anticonvulsant drug valproic acid (VPA) and other short-chain fatty acids (SCFAs) cause significant inhibition of cancer cell proliferation by modulating multiple signaling pathways. First of all, they act as histone deacetylase (HDAC) inhibitors (HDIs), being involved in the epigenetic regulation of gene expression. Afterward, VPA is shown to induce apoptosis and cell differentiation, as well as regulate Notch signaling. Moreover, it up-regulates the expression of certain G protein-coupled receptors (GPCRs), which are involved in various signaling pathways associated with cancer. As a consequence, some pre-clinical and clinical trials were carried out to estimate anticancer effectiveness of VPA, in monotherapy and in new drug combinations, while other SCFAs were tested in pre-clinical studies. The present manuscript summarizes the most important information from the literature about their potent anticancer activities to show some future perspectives related to epigenetic therapy.
Topics: Anticonvulsants; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Proliferation; Epigenesis, Genetic; Fatty Acids, Volatile; Histone Deacetylase Inhibitors; Humans; Neoplasms; Valproic Acid
PubMed: 32074065
DOI: 10.2478/acph-2020-0021