Effects of marketed antiepileptic drugs and placebo in the human photosensitivity screening protocol.
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ABSTRACT:
SUBMITTER: French JA
PROVIDER: S-EPMC3996112 | biostudies-literature | 2014 Apr
REPOSITORIES: biostudies-literature
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Project description:Introduction:Seizures are one of the most common neurological disorders of neonates, which is also an emergency in the neonatal intensive care unit. For neonates, the recommended first-line antiepileptic drugs (AEDs) include phenobarbitone, which may be effective in only 50% of seizures. Some new AEDs, such as levetiracetam, have been shown to be effective in adults and older children. However, their efficacy for neonatal seizures remains uncertain. The aim of this investigation is to conduct a systematic review to evaluate the efficacy of all AEDs in neonates. Additionally, the long-term outcomes following neonatal seizures, in relation to the development of cerebral palsy and epilepsy, will be studied. Method:We will perform a systematic review including randomised controlled studies (RCTs), cohort studies, case-controlled studies and case series studies which evaluated the efficacy of AEDs and short-term and long-term outcomes in neonatal seizures. PubMed, Embase, Web of Science, Cochrane Library and Clinical trial.gov will be searched. There will be no language restriction. Risk bias in RCTs will be evaluated by the Cochrane risk-of-bias tool, while cohort and case-control studies will be evaluated by the Newcastle-Ottawa Scale. A network meta-analysis will be performed by the Bayesian model using WinBUGS V.1.4.3 and R software if there is a high degree of homogeneity among studies. Otherwise, we will perform a narrative review without pooling. Subgroup analyses will be performed in different AEDs and dosage groups. Outcome:The primary outcomes will be seizure cessation confirmed by electroencephalogram and long-term neurodevelopmental outcome. Secondary outcomes will be neonatal mortality during hospitalisation and suspected drug toxicity. Ethics and dissemination:Formal ethical approval is not required as no primary data are collected. This systematic review will be disseminated through a peer-reviewed publication.
| S-EPMC7326240 | biostudies-literature
Project description:Cortical network functioning critically depends on finely tuned interactions to afford neuronal activity propagation over long distances while avoiding runaway excitation. This importance is highlighted by the pathological consequences and impaired performance resulting from aberrant network excitability in psychiatric and neurological diseases, such as epilepsy. Theory and experiment suggest that the control of activity propagation by network interactions can be adequately described by a branching process. This hypothesis is partially supported by strong evidence for balanced spatiotemporal dynamics observed in the cerebral cortex; however, evidence of a causal relationship between network interactions and cortex activity, as predicted by a branching process, is missing in humans. Here this cause-effect relationship is tested by monitoring cortex activity under systematic pharmacological reduction of cortical network interactions with antiepileptic drugs. This study reports that cortical activity cascades, presented by the propagating patterns of epileptic spikes, as well as temporal correlations decline precisely as predicted for a branching process. The results provide a missing link to the branching process theory of cortical network function with implications for understanding the foundations of cortical excitability and its monitoring in conditions like epilepsy.
| S-EPMC7245074 | biostudies-literature
Project description:Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis.
| S-EPMC4733155 | biostudies-literature
Project description:AimsExperimental studies show that some antiepileptic drugs (AEDs) may modify natural immune defences, thus influencing the risk of developing infectious diseases. The aim of this meta-analysis was to explore whether AEDs as a class of drugs or singularly may increase risk of infectious diseases.MethodsA meta-analysis of all randomized, double-blind, placebo-controlled trials (RCTs) investigating any AED in any condition was performed. All terms that could be coded in the System Organ Classes (SOCs) of infections and infestations using the Medical Dictionary for Regulatory Activities were recorded. Additional subanalyses were performed also pooling together AEDs sharing similar mechanisms of action.ResultsTwo hundreds and sixty-nine double-blind, placebo-controlled studies were identified and, among them, 127 RCTs with 16 AEDs (brivaracetam, gabapentin, lacosamide, levetiracetam, lamotrigine, oxcarbazepine, perampanel, pregabalin, phenytoin, remacemide, retigabine, rufinamide, tiagabine, topiramate, valproate, zonisamide) reported at least one of 19 symptoms or diseases that could be included in the Medical Dictionary for Regulatory Activities SOC term infections and infestations. These terms were singularly recorded and then pooled together in the SOC term infection and infestation. Topiramate was significantly associated with an increased risk of infection (risk difference = 0.04; 95% confidence interval = 0.01/0.06), while oxcarbazepine was significantly associated with a lower risk (-0.005; -0.09/-0.01). Risk difference of all studies with all AEDs showed a slight, but significantly increased risk of infection (0.01; 0.00/0.002). Levetiracetam and brivaracetam RCTs, when pooled together, were associated with a significantly increased risk of infection (0.03; 0.01/0.05).ConclusionsSome AEDs are associated with a mild increased risk of infection.
| S-EPMC5555858 | biostudies-literature
Project description:ObjectiveAn epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed.MethodsTsc1 deletion was induced in CAMK2A-expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs.ResultsMice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine.InterpretationThis novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and -epileptogenic drugs to treat mTORC1-dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1-mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.
| S-EPMC6649373 | biostudies-literature
Project description:BackgroundA recent comparison showed the extensive similarities between the structural properties of metabolites in the reconstructed human metabolic network ("endogenites") and those of successful, marketed drugs ("drugs").ResultsClustering indicated the related but differential population of chemical space by endogenites and drugs. Differences between the drug-endogenite similarities resulting from various encodings and judged by Tanimoto similarity could be related simply to the fraction of the bitstrings set to 1. By extracting drug/endogenite substructures, we develop a novel family of fingerprints, the Drug Endogenite Substructure (DES) encodings, based on the ranked frequency of the various substructures. These provide a natural assessment of drug-endogenite likeness, and may be used as descriptors with which to derive quantitative structure-activity relationships (QSARs).Conclusions"Drug-endogenite likeness" seems to have utility, and leads to a simple, novel and interpretable substructure-based molecular encoding for cheminformatics.
| S-EPMC4429554 | biostudies-literature
Project description:Background and purposeIt has been reported that taking antiepileptic drugs (AEDs) may increase the risk of atherosclerosis. We performed a meta-analysis to evaluate the carotid artery intima-media thickness (CA-IMT) as a surrogate factor for atherosclerosis in epileptic patients.MethodsWe searched NCBI (PubMed), ISI Web of Knowledge, EMBASE, and the Cochrane Library databases for studies of the association between AEDs and CA-IMT in epileptic patients. A random-effects meta-analysis was used to pool results across studies.ResultsFifteen studies involving 1,775 epileptic patients were included in the analysis. The overall CA-IMT was significantly larger among users of AEDs [mean difference (MD)=0.09 mm, 95% confidence interval (CI)=0.06-0.12 mm). When stratified by age, the MD was similar in adult patients (MD=0.09 mm, 95% CI=0.06-0.13 mm), but no significant difference was observed in children (MD=0.03 mm, 95% CI=0.00-0.07 mm). Regarding specific AEDs, monotherapy with carbamazepine (CBZ) or valproic acid (VPA) was associated with a larger CA-IMT, while phenytoin monotherapy was not and the result for lamotrigine was inconclusive.ConclusionsThis study suggests that using AEDs is associated with the CA-IMT in patients with epilepsy, particularly for adult patients. In particular, CBZ and VPA may be related to a significant increase in CA-IMT.
| S-EPMC5653625 | biostudies-literature
Project description:BackgroundPharmacotherapy of epilepsy including antiepileptic drugs (AEDs) is one of the main treatment approaches. As a biological target, sodium channels (Nav channels) and glutamate receptor genes are playing a major role in the etiology and treatment of epilepsy.ObjectiveThis study aims to investigate the genetic associations of certain genetic polymorphisms with increased risk of epilepsy susceptibility and variability in response to AEDs treatment in a Jordanian Arab population.MethodA pharmacogenetics and case-control study on 296 unrelated epileptic Jordanian patients recruited from the pediatric neurology clinic at the Queen Rania Al-Abdullah Hospital (QRAH) in Amman, Jordan and 299 healthy individuals was conducted. Children up to 15 years old which receiving AEDs for at least three months were scanned for genetic association of 7 single nucleotide polymorphisms (SNPs) within three candidate genes (SCN2A, SCN3B and GRM4) with epilepsy susceptibility.ResultsSCN2A rs2304016 (P = 0.04) and GRM4 rs2499697 (P = 0.031) were statistically significant with generalized epilepsy. Haplotype of CAACG GRM4 was genetically associated with epilepsy and partial epilepsy (P = 0.036; P = 0.024, respectively). This study also found that TGTAA genetic haplotype formed within GRM4 gene was associated with generalized epilepsy susceptibility (P = 0.006). While, no significant linkage of SCN3B rs3851100 to either disease susceptibility or drug responsiveness was found.ConclusionThis study identified no significant associations of allelic or genotypic SNPs with the susceptibility of epilepsy and medication response with an exception of rs2304016 and rs2499697 SNPs that were associated with the generalized type of epilepsy among Jordanian population. Further studies are required in different populations to confirm our results and identify genetic factors that involved in susceptibility and treatment response.
| S-EPMC6598501 | biostudies-literature
Project description:Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients' quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM.
| S-EPMC9953000 | biostudies-literature
Project description:Drug-induced photosensitivity, the development of phototoxic or photoallergic reactions due to pharmaceuticals and subsequent exposure to ultraviolet or visible light, is an adverse effect of growing interest. This is illustrated by the broad spectrum of recent investigations on the topic, ranging from molecular mechanisms and culprit drugs through epidemiological as well as public health related issues to long-term photoaging and potential photocarcinogenic consequences. The present review summarizes the current state of knowledge on the topic while focusing on culprit drugs and long-term effects. In total, 393 different drugs or drug compounds are reported to have a photosensitizing potential, although the level of evidence regarding their ability to induce photosensitive reactions varies markedly among these agents. The pharmaceuticals of interest belong to a wide variety of drug classes. The epidemiological risk associated with the use of photosensitizers is difficult to assess due to under-reporting and geographical differences. However, the widespread use of photosensitizing drugs combined with the potential photocarcinogenic effects reported for several agents has major implications for health and safety and suggests a need for further research on the long-term effects.
| S-EPMC7898394 | biostudies-literature