Identification of new epilepsy treatments: Issues in preclinical methodology

Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Epilepsia (Impact Factor: 4.57). 03/2012; 53(3):571-82. DOI: 10.1111/j.1528-1167.2011.03391.x
Source: PubMed


Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities.

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    • "Epilepsy is one of the most common serious chronic neurological disorders and it is estimated to affect more than 50 million people worldwide [1] [2] [3]. The pharmacotherapy with antiepileptic drugs (AEDs) is currently the therapeutic approach of choice regarding epilepsy [4] as it controls the occurrence of unpredictable epileptic seizures on approximately two thirds of the patients [3]. "
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    ABSTRACT: A new, sensitive and fast high-performance liquid chromatography–diode-array detection assay based on microextraction by packed sorbent (MEPS/HPLC-DAD) is herein reported, for the first time, to simultaneously quantify carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), and the active metabolites carbamazepine-10,11-epoxide (CBZ-E) and licarbazepine (LIC) in human plasma. Chromatographic separation of analytes and ketoprofen, used as internal standard (IS), was achieved in less than 15 min on a C18–column, at 35 °C, using acetonitrile (6%) and a mixture (94%) of water–methanol–triethylamine (73.2:26.5:0.3, v/v/v; pH 6.5) pumped at 1 mL/min. The analytes and IS were detected at 215, 237 or 280 nm. The method showed to be selective, accurate [bias ±14.8% (or ±17.8% in the lower limit of quantification)], precise [coefficient variation ≤9.7% (or ≤17.7% in the lower limit of quantification)] and linear (r2 ≥ 0.9946) over the concentration ranges of 0.1-15 μg/mL for CBZ; 0.1-20 μg/mL for LTG; 0.1-5 μg/mL for OXC and CBZ-E; 0.2-40 μg/mL for PB;0.3-30 μg/mL for PHT; and 0.4-40 μg/mL for LIC. The absolute extraction recovery of the analytes ranged from 57.8–98.1% and their stability was demonstrated in the studied conditions. This MEPS/HPLC-DAD assay was successfully applied to real plasma samples from patients, revealing to be a cost-effective tool for routine therapeutic drug monitoring of CBZ, LTG, OXC, PB and/or PHT.
    Journal of Chromatography B 09/2014; 971. DOI:10.1016/j.jchromb.2014.09.010 · 2.73 Impact Factor
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    • "Although many modern antiepileptic drugs (AEDs) have been discovered using target-based approaches, much of the success of this field comes from the early development of animal seizure models [3]–[5]. However, as the field moves from a primary focus of controlling seizures to the development of drugs able to address aspects of disease pathophysiology [6]–[8], this requires the adoption of much resource- and time-consuming chronic animal models that can longer sustain the testing of even moderate numbers of compounds [9]. In vitro models of epilepsy largely rely on electrophysiological measurements of epileptiform activity in brain slices or dissociated neuronal cultures [10], [11]. "
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    ABSTRACT: Research in the epilepsy field is moving from a primary focus on controlling seizures to addressing disease pathophysiology. This requires the adoption of resource- and time-consuming animal models of chronic epilepsy which are no longer able to sustain the testing of even moderate numbers of compounds. Therefore, new in vitro functional assays of epilepsy are needed that are able to provide a medium throughput while still preserving sufficient biological context to allow for the identification of compounds with new modes of action. Here we describe a robust and simple fluorescence-based calcium assay to measure epileptiform network activity using rat primary cortical cultures in a 96-well format. The assay measures synchronized intracellular calcium oscillations occurring in the population of primary neurons and is amenable to medium throughput screening. We have adapted this assay format to the low magnesium and the 4-aminopyridine epilepsy models and confirmed the contribution of voltage-gated ion channels and AMPA, NMDA and GABA receptors to epileptiform activity in both models. We have also evaluated its translatability using a panel of antiepileptic drugs with a variety of modes of action. Given its throughput and translatability, the calcium oscillations assay bridges the gap between simplified target-based screenings and compound testing in animal models of epilepsy. This phenotypic assay also has the potential to be used directly as a functional screen to help identify novel antiepileptic compounds with new modes of action, as well as pathways with previously unknown contribution to disease pathophysiology.
    PLoS ONE 01/2014; 9(1):e84755. DOI:10.1371/journal.pone.0084755 · 3.23 Impact Factor
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    • "Moreover, a third of the people with epilepsy do not get adequate seizure control with the current medications (Schmidt and Sillanpää, 2012). Thus, there is an urgent need for more effective (and better tolerated) treatments to control drug-resistant seizures, as well as for innovative therapies to prevent, stop or reverse the development of epilepsy in at-risk individuals (Galanopoulou et al., 2012). "
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    ABSTRACT: The transformation of a normal brain in epileptic (epileptogenesis) is associated with extensive morpho-functional alterations, including cell death, axonal and dendritic plasticity, neurogenesis, and others. Neurotrophic factors (NTFs) appear to be very strongly implicated in these phenomena. In this review, we focus on the involvement of fibroblast growth factor (FGF) family members. Available data demonstrate that the FGFs are highly involved in the generation of the morpho-functional alterations in brain circuitries associated with epileptogenesis. For example, data on FGF2, the most studied member, suggest that it may be implicated both in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring acute seizures but reducing seizure-induced cell death. Even if many FGF members are still unexplored and very limited information is available on the FGF receptors, a complex and fascinating picture is emerging: multiple FGFs producing synergic or antagonistic effects one with another (and/or with other NTFs) on biological parameters that, in turn, facilitate or oppose transformation of the normal tissue in epileptic. In principle, identifying key elements in these phenomena may lead to effective therapies, but reaching this goal will require confronting a huge complexity. One first step could be to generate a "neurotrophicome" listing the FGFs (and all other NTFs) that are active during epileptogenesis. This should include identification of the extent to which each NTF is active (concentrations at the site of action); how it is active (local representation of receptor subtypes); when in the natural history of disease this occurs; how the NTF at hand will possibly interact with other NTFs. This is extraordinarily challenging, but holds the promise of a better understanding of epileptogenesis and, at large, of brain function.
    Frontiers in Cellular Neuroscience 09/2013; 7:152. DOI:10.3389/fncel.2013.00152 · 4.29 Impact Factor
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