-
Drug Design, Development and Therapy 2015Eslicarbazepine acetate (ESL) is a new antiepileptic drug whose mechanism of action is blockade of the voltage-gated sodium channel (VGSC). However, in respect to... (Review)
Review
Eslicarbazepine acetate (ESL) is a new antiepileptic drug whose mechanism of action is blockade of the voltage-gated sodium channel (VGSC). However, in respect to carbamazepine and oxcarbazepine, the active ESL metabolite (eslicarbazepine) affects slow inactivation of VGSC and has a similar affinity for the inactivated state and a lower affinity for the resting state of the channel. This new antiepileptic drug has been recently approved in Europe (trade name Zebinix) and in the United States (trade name Stedesa) for adjunctive treatment in adult subjects with partial-onset seizures, with or without secondary generalization. Following oral administration, ESL is rapidly and extensively metabolized by hepatic esterases to eslicarbazepine. This active metabolite has a linear pharmacokinetic profile, a low binding to plasma proteins (<40%), and a half-life of 20-24 hours and is mainly excreted by kidneys in an unchanged form or as glucuronide conjugates. ESL is administered once a day and has a low potential for drug-drug interactions. Efficacy and safety of this drug in patients with focal seizures have been assessed in four randomized clinical trials, and responder rates (percentage of patients with a ≥50% improvement of their seizures) ranged between 17% and 43%. Adverse events were usually mild to moderate, and the most common were dizziness, somnolence, diplopia, abnormal coordination, blurred vision, vertigo, headache, fatigue, nausea, and vomiting. ESL may be considered an interesting alternative to current antiepileptic drugs for the treatment of drug-resistant focal epilepsies. Additionally, it is under investigation in children with focal epilepsies, in patients with newly diagnosed focal epilepsies, and also in other neurological and psychiatric disorders.
Topics: Animals; Anticonvulsants; Dibenzazepines; Humans; Seizures
PubMed: 25709402
DOI: 10.2147/DDDT.S57409 -
Annals of the New York Academy of... Aug 2016This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve... (Review)
Review
This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABA receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABA receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure.
Topics: Animals; Anticonvulsants; Humans; Neuroprotective Agents; Neurotransmitter Agents; Organophosphate Poisoning; Organophosphates; Status Epilepticus
PubMed: 27450921
DOI: 10.1111/nyas.13160 -
Neuro-oncology Jun 2016Seizures are a well-recognized symptom of primary brain tumors, and anticonvulsant use is common. This paper provides an overview of epilepsy and the use of... (Review)
Review
Seizures are a well-recognized symptom of primary brain tumors, and anticonvulsant use is common. This paper provides an overview of epilepsy and the use of anticonvulsants in glioma patients. Overall incidence and mechanisms of epileptogenesis are reviewed. Factors to consider with the use of antiepileptic drugs (AEDs) including incidence during the disease trajectory and prophylaxis along with considerations in the selection of anticonvulsant use (ie, potential side effects, drug interactions, adverse effects, and impact on survival) are also reviewed. Finally, areas for future research and exploring the pathophysiology and use of AEDs in this population are also discussed.
Topics: Anticonvulsants; Brain Neoplasms; Drug Interactions; Epilepsy; Glioma; Humans; Treatment Outcome
PubMed: 26527735
DOI: 10.1093/neuonc/nov269 -
Current Opinion in Critical Care Dec 2019Status epilepticus is a neurological emergency associated with high morbidity and mortality. There is a lack of robust data to guide the management of this neurological... (Review)
Review
PURPOSE OF REVIEW
Status epilepticus is a neurological emergency associated with high morbidity and mortality. There is a lack of robust data to guide the management of this neurological emergency beyond the initial treatment. This review examines recent literature on treatment considerations including the choice of continuous anesthetics or adjunctive anticonvulsant, the cause of the status epilepticus, and use of nonpharmacologic therapies.
RECENT FINDINGS
Status epilepticus remains undertreated and mortality persists to be unchanged over the past 30 years. New anticonvulsant choices, such as levetiracetam and lacosamide have been explored as alternative emergent therapies. Anecdotal reports on the use of other generation anticonvulsants and nonpharmacologic therapies for the treatment of refractory and super-refractory status epilepticus have been described.Finally, recent evidence has examined etiology-guided management of status epilepticus in certain patient populations, such as immune-mediated, paraneoplastic or infectious encephalitis and anoxic brain injury.
SUMMARY
Randomized clinical trials are needed to determine the role for newer generation anticonvulsants and nonpharmacologic modalities for the treatment of epilepticus remains and evaluate the long-term outcomes associated with continuous anesthetics.
Topics: Anesthetics; Anticonvulsants; Humans; Status Epilepticus
PubMed: 31524720
DOI: 10.1097/MCC.0000000000000661 -
Molecules (Basel, Switzerland) Jun 2018GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This... (Review)
Review
GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This pentameric structure not only allows different receptor binding sites, but also various types of ligands, such as orthosteric agonists and antagonists, positive and negative allosteric modulators, as well as second-order modulators and non-competitive channel blockers. A fact, that is also displayed by the variety of chemical structures found for both, synthetic as well as nature-derived GABA(A)-receptor modulators. This review covers the literature for natural GABA(A)-receptor modulators until the end of 2017 and discusses their structure-activity relationship.
Topics: Allosteric Regulation; Allosteric Site; Animals; Anti-Anxiety Agents; Anticonvulsants; Catalytic Domain; GABA Antagonists; GABA-A Receptor Agonists; Humans; Kinetics; Ligands; Protein Domains; Protein Multimerization; Protein Subunits; Receptors, GABA-A; Structure-Activity Relationship
PubMed: 29932138
DOI: 10.3390/molecules23071512 -
International Journal of Toxicology Oct 2021Metabolomics is unique among omics technologies in being applicable to metabolism and toxicity studies broadly across organisms (e.g., humans, other mammals, model... (Review)
Review
Metabolomics is unique among omics technologies in being applicable to metabolism and toxicity studies broadly across organisms (e.g., humans, other mammals, model organisms, and even bacteria) and across biological materials (e.g., blood, urine, saliva, biopsy, and stool), including cultured cells and subcellular fractions. Metabolomics can be used to characterize biologic response patterns in humans as well as to support mechanistic studies in model systems and ex vivo studies. A broad range of resources are available, including publicly accessible data repositories (e.g., Metabolomics Workbench), tools for biostatistics and bioinformatics (e.g., MetaboAnalyst), metabolite identification (e.g., Metlin), and pathway analysis (e.g., Kyoto Encyclopedia of Genes and Genomes). Thus, metabolomics is more than a promise of the future; metabolomics is already available as a translational approach to facilitate precision medicine. This ACT Symposium review will contain an introduction to metabolomics in toxicity studies followed by sections on translational metabolic networks, translational metabolite biomarkers of acetaminophen-induced acute liver injury, translational framework using high-resolution metabolomics for integrated pharmacokinetics and pharmacodynamics, and precision medicine applications: extracting actionable targets from untargeted metabolomics data following one year in space.
Topics: Acetaminophen; Animals; Anticonvulsants; Biomarkers; Chemical and Drug Induced Liver Injury; Humans; Metabolomics; Precision Medicine
PubMed: 34514887
DOI: 10.1177/10915818211039436 -
Neurocritical Care Oct 2017Prophylactic anticonvulsants are routinely prescribed in the acute setting for intracerebral hemorrhage (ICH) patients, but some studies have reported an association...
BACKGROUND AND PURPOSE
Prophylactic anticonvulsants are routinely prescribed in the acute setting for intracerebral hemorrhage (ICH) patients, but some studies have reported an association with worse outcomes. We sought to characterize the prevalence and predictors of prophylactic anticonvulsant administration after ICH as well as guideline adherence. We also sought to determine whether prophylactic anticonvulsants were independently associated with poor outcome.
METHODS
We performed a retrospective study of primary ICH in our two academic centers. We used a propensity matching approach to make treated and non-treated groups comparable. We conducted multiple logistic regression analysis to identify independent predictors of prophylactic anticonvulsant initiation and its association with poor outcome as measured by modified Rankin score.
RESULTS
We identified 610 patients with primary ICH, of whom 98 were started on prophylactic anticonvulsants. Levetiracetam (97%) was most commonly prescribed. Age (OR 0.97, 95% CI 0.95-0.99, p < .001), lobar location (OR 2.94, 95% CI 1.76-4.91, p < .001), higher initial National Institutes of Health Stroke Scale (NIHSS) score (OR 2.31, 95% CI 1.40-3.79, p = .001), craniotomy (OR 3.06, 95% CI 1.51-6.20, p = .002), and prior ICH (OR 2.36, 95% CI 1.10-5.07, p = .028) were independently associated with prophylactic anticonvulsant initiation. Prophylactic anticonvulsant use was not associated with worse functional outcome [modified Rankin score (mRS) 4-6] at hospital discharge or with increased case-fatality. There was no difference in prescribing patterns after 2010 guideline publication.
DISCUSSION
Levetiracetam was routinely prescribed following ICH and was not associated with worse outcomes. Future investigations should examine the effect of prophylactic levetiracetam on cost and neuropsychological outcomes as well as the role of continuous EEG in identifying subclinical seizures.
Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Cerebral Hemorrhage; Drug Prescriptions; Female; Guideline Adherence; Humans; Levetiracetam; Male; Middle Aged; Outcome Assessment, Health Care; Piracetam; Prevalence; Retrospective Studies; Seizures
PubMed: 28324261
DOI: 10.1007/s12028-017-0385-8 -
International Journal of Molecular... Feb 2023Worldwide, prostate cancer (PC) is the second most frequent cancer among men and the fifth leading cause of death; moreover, standard treatments for PC have several... (Review)
Review
Worldwide, prostate cancer (PC) is the second most frequent cancer among men and the fifth leading cause of death; moreover, standard treatments for PC have several issues, such as side effects and mechanisms of resistance. Thus, it is urgent to find drugs that can fill these gaps, and instead of developing new molecules requiring high financial and time investments, it would be useful to select non-cancer approved drugs that have mechanisms of action that could help in PC treatment, a process known as repurposing drugs. In this review article, drugs that have potential pharmacological efficacy are compiled to be repurposed for PC treatment. Thus, these drugs will be presented in the form of pharmacotherapeutic groups, such as antidyslipidemic drugs, antidiabetic drugs, antiparasitic drugs, antiarrhythmic drugs, anti-inflammatory drugs, antibacterial drugs, antiviral drugs, antidepressant drugs, antihypertensive drugs, antifungal drugs, immunosuppressant drugs, antipsychotic drugs, antiepileptic and anticonvulsant drugs, bisphosphonates and drugs for alcoholism, among others, and we will discuss their mechanisms of action in PC treatment.
Topics: Male; Humans; Drug Repositioning; Antiviral Agents; Anticonvulsants; Anti-Bacterial Agents; Prostatic Neoplasms
PubMed: 36835564
DOI: 10.3390/ijms24044154 -
Current Neuropharmacology 2019Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a... (Review)
Review
BACKGROUND
Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways.
METHODS
CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions.
RESULTS
The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype.
CONCLUSION
Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy.
Topics: Adult; Age Factors; Anticonvulsants; Biosynthetic Pathways; Child; Cytochrome P-450 CYP2C9; Epilepsy; Genotype; Humans; Phenotype; Polymorphism, Genetic; Valproic Acid
PubMed: 29119932
DOI: 10.2174/1570159X15666171109143654 -
International Journal of Molecular... Mar 2023The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise... (Review)
Review
The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG's unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG's potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored.
Topics: Humans; Lamotrigine; Depressive Disorder, Major; Anticonvulsants; Epilepsy; Central Nervous System; Glutamic Acid; Ion Channels; Triazines
PubMed: 37047022
DOI: 10.3390/ijms24076050