Biomarkers for antiepileptic drug response.
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ABSTRACT:
SUBMITTER: Glauser TA
PROVIDER: S-EPMC3263405 | biostudies-literature | 2011 Oct
REPOSITORIES: biostudies-literature
Publications
The identification and validation of genetic factors ('biomarkers') that reliably predict the efficacy and toxicity of specific pharmacological agents for individual patients would significantly improve the current treatment of patients with epilepsy. A pharmacogenetic biomarker classification has been proposed that identifies three biomarker types involved in drug response: 'known valid biomarkers', 'probable valid biomarkers' and 'exploratory or research biomarkers'. The only known valid antie ...[more]
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Project description:INTRODUCTION:Antiepileptic drugs, which are also called anticonvulsants, are used in the therapy and prophylaxis of epileptic seizures. The purpose of this paper was to investigate the relevant epidemiological data and to determine which of these drugs was the most frequent cause of intoxication. Another purpose of this study was to determine the neurological, cardiac, and biochemical problems caused by antiepileptics. MATERIAL AND METHOD:This retrospective study included 95 consecutive patients under 18 years of age with antiepileptic intoxication, presenting to and being followed-up in, the Toxicology Unit between January 2010 and February 2013. The data were obtained by screening the patient files. RESULTS:Of the cases, 67 (70.5%) were self-poisoned by first generation antiepileptics (FGAEs) and 28 (29.5%) by second generation antiepileptics (SGAEs). The Glasgow Coma Scale (GCS) scores and the serum lactate levels of the patients poisoned by FGAEs and SGAEs on admission to emergency department were 15 (25th: 12; 75th: 15; 95th: 15; IQR: 3) and 1.9 (25th: 1.4; 75th: 3.1; 95th: 5.6; IQR: 1.7), and 15 (25th: 14.3; 75th: 15; 95th: 15; IQR: 0.75) and 1.07 (25th: 0.9; 75th: 1.6; 95th: 5.5; IQR: 0.71), respectively. The serum lactate levels of patients poisoned by FGAEs were significantly higher (p < 0.001). Among the cases poisoned by carbamazepine, the most frequent cause of intoxication, the GCS score was significantly lower and serum lactate level was significantly higher in the group with high serum levels of carbamazepine (p = 0.004 and p < 0.001, respectively). In cases poisoned by valproic acid (VPA), the second frequent cause of intoxication, there was neither a significant association between the serum VPA level and the GCS score, nor between the serum lactate level and the systolic blood pressure (p = 0.470, p = 0.897, and p = 0.088, respectively). However, there was a positive correlation between the serum VPA level and the serum ammonia level (kk = 0.742, p < 0.001). CONCLUSION:First generation antiepileptics are more toxic than SGAEs. In patients with serum carbamazepine level, particularly those over 30 mg/L, serious disorders of consciousness, cardiovascular toxicity, and metabolic disorders may occur. In VPA intoxication, there is a positive correlation between the serum VPA levels and ammonia levels. On account of this finding, one should be more careful about hyperammonemic hepatic encephalopathy as the serum VPA level rises.
| S-EPMC5598106 | biostudies-literature
Project description:Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1?year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication.
| S-EPMC4672179 | biostudies-literature
Project description:Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice.
| S-EPMC2741411 | biostudies-other
Project description:ObjectiveThe aim of the study was to determine sociodemographic, biological epilepsy-specific, and adherence predictors of long-term pediatric seizure outcomes.MethodsThis study is a prospective, longitudinal, observational study of antiepileptic drug (AED) adherence and seizure outcomes in children with newly diagnosed epilepsy. Patients were recruited from April 2006 to March 2009 and followed for 2 years. Objective, electronic monitors were used to assess AED adherence. Medical chart reviews assessed medical variables and seizure outcomes.ResultsParticipants (n = 109) were 7.3 ± 2.9 years of age, and 62% male. Four adherence trajectory groups were identified: severe early nonadherence (n = 10), variable nonadherence (n = 16), moderate nonadherence (n = 40), and high adherence (n = 43). Two seizure probability trajectory groups were identified: high seizure (n = 28) and low seizure probability (n = 81). Participants with recognizable syndromes were less likely to be a member of the high seizure probability group (b = -2.372; odds ratio [OR] = 0.093; 95% confidence interval [CI]OR = 0.015, 0.595); those with the presence of epileptiform discharges on EEG were more likely to be in the high seizure probability group (b = 1.649; OR = 5.203; 95% CIOR = 1.422, 19.037). Adherence trajectory group status was a significant predictor of seizure trajectory group status (partial max-rescaled R(2) = 0.13).ConclusionsAdherence trajectories and 2 biological epilepsy-specific variables explain a similar proportion of the variability in longitudinal seizure outcomes. The relationship between AED nonadherence and seizure outcomes is not linear. Early adherence interventions could change the course of seizure outcomes, particularly if variability in adherence was minimized postdiagnosis.
| S-EPMC4248449 | biostudies-literature
Project description:Danio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established using the common convulsant agent pentylenetetrazole (PTZ). Larval PTZ-exposed zebrafish exhibit clear behavioral convulsions and abnormal electrographic activity, reminiscent of interictal and ictal epileptiform discharge. By using this model, our laboratory developed simple locomotion-based and electrophysiological assays to monitor and quantify seizures in larval zebrafish. Zebrafish also offer multiple advantages for rapid genetic manipulation and high-throughput phenotype-based drug screening. Combining these seizure assays with genetically modified zebrafish that represent Dravet syndrome, a rare genetic epilepsy, ultimately contributed to a phenotype-based screen of over 3500 drugs. Several drugs identified in these zebrafish screens are currently in clinical or compassionate-use trials. The emergence of this 'aquarium-to-bedside' approach suggests that broader efforts to adapt and improve upon this zebrafish-centric strategy can drive a variety of exciting new discoveries.
| S-EPMC8277967 | biostudies-literature
Project description:ObjectiveThe 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure-free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re-analyzed this trial to account for crossover between arms using contamination-adjusted intention to treat (CA ITT) methods, to explore dose-response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as-treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing.MethodsCA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic).ResultsThe trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre-seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p < .01). Adjusted odds ratios of a 2-year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9-1.9) in the as-treated analysis, 2.5 (95% CI 1.9-3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1-4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as-treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1-year seizures). As-treated dose-response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70).SignificanceCA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.
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Project description: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 (?flow-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 ?flow-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 ?flow-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.
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Project description:OBJECTIVE:To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE). METHODS:Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency???15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide. RESULTS:Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not-seizure-free participants (p?=?0.011, odds ratio [OR]?=?2.63, 95% confidence limits [CL]?=?1.25-5.56; p?=?0.026, OR?=?2.38, 95% CL?=?1.11-5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p?=?0.015, OR?=?2.22, 95% CL?=?1.16-4.17) was more common in not-seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p?=?0.038, OR?=?0.52, 95% CL?=?0.28-0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of ethosuximide. Ethosuximide's effect on rate of decay of CaV 3.2 was significantly less for P640L channel compared to wild-type channel. INTERPRETATION:Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444-453.
| S-EPMC6171340 | biostudies-literature
Project description:Although long granted the status of immune privilege, the central nervous system is not completely isolated from the immune system. Increasing evidence suggests that this system contributes to seizures and epilepsy and that the molecular mediators of inflammation and immunity may serve as appropriate targets in the quest to develop novel antiepileptic drugs that are more efficacious and potentially disease modifying.
| S-EPMC3220427 | biostudies-literature
Project description:We assessed the likelihood of 12-month seizure remission and treatment failure after failure of a first antiepileptic drug, and identified factors influencing these outcomes.SANAD (Standard and New Antiepileptic Drug) was a randomized controlled trial comparing monotherapy with standard and new antiepileptic drugs. Patients were followed up to study completion, even if they were switched from their randomized treatment. After a first treatment failure, we assessed the probability of 12-month seizure remission and treatment failure. Prognostic modeling identified predictors of these outcomes.Forty-four percent of patients in the SANAD trial had a first treatment failure. Seventy-five percent of these subsequently achieved 12-month remission by 6 years of follow-up. Significant prognostic factors included sex, age at treatment failure, time on randomized treatment at treatment failure, neurologic insult, total number of tonic-clonic seizures at treatment failure, reason for treatment failure, seizure type, and CT/MRI scan result. After a first treatment failure, young patients without tonic-clonic seizures, with a normal CT/MRI scan and failing their treatment because of unacceptable adverse events, had the highest likelihood of 12-month remission. Approximately 50% of patients who failed a first treatment also failed their second. Significant prognostic factors included total number of tonic-clonic seizures at first treatment failure, reason for first treatment failure, and CT/MRI scan result. Patients with tonic-clonic seizures and failing because of inadequate seizure control had the highest risk of a second treatment failure.A high proportion of patients will achieve 12-month remission after a first treatment failure. Clinical factors can stratify patients according to likely outcome.
| S-EPMC4142004 | biostudies-literature