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      Difficulties in Treatment and Management of Epilepsy and Challenges in New Drug Development

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      Author(s):
      Publication date (Electronic):
      Journal: Pharmaceuticals
      Publisher: MDPI
      Keywords: antiepileptic, anticonvulsant, seizure, pharmacoresistance, refractory seizures

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          Abstract

          Epilepsy is a serious neurological disorder that affects around 50 million people worldwide. Almost 30% of epileptic patients suffer from pharmacoresistance, which is associated with social isolation, dependent behaviour, low marriage rates, unemployment, psychological issues and reduced quality of life. Currently available antiepileptic drugs have a limited efficacy, and their negative properties limit their use and cause difficulties in patient management. Antiepileptic drugs can provide only symptomatic relief as these drugs suppress seizures but do not have ability to cure epileptogenesis. The long term use of antiepileptic drugs is limited due to their adverse effects, withdrawal symptoms, deleterious interactions with other drugs and economic burden, especially in developing countries. Furthermore, some of the available antiepileptic drugs may even potentiate certain type of seizures. Several in vivo and in vitro animal models have been proposed and many new antiepileptic drugs have been marketed recently, but large numbers of patients are still pharmacoresistant. This review will highlight the difficulties in treatment and management of epilepsy and the limitations of available antiepileptic drugs and animal seizure models.

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          The pilocarpine model of temporal lobe epilepsy

          Giulia Curia, Daniela Longo, Giuseppe Biagini … (2008)
          Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of models of status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epileptic foci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv) the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SE is followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). These processes are, however, influenced by experimental conditions such as rodent species, strain, gender, age, doses and routes of pilocarpine administration, as well as combinations with other drugs administered before and/or after SE. In the attempt to limit these sources of variability, we evaluated the methodological procedures used by several investigators in the pilocarpine model; in particular, we have focused on the behavioural, electrophysiological and histopathological findings obtained with different protocols. We addressed the various experimental approaches published to date, by comparing mortality rates, onset of SRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we propose that the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and even more so when standardized to reduce mortality at the time of pilocarpine injection, differences in latent period duration, variability in the lesion extent, and SRS frequency.
          Article 0 comments Cited 254 times – based on 0 reviews     Review now
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            Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy.

            Matthew E. Barton, Brian Klein, Harold Wolf … (2001)
            Originally described as a model of 'psychomotor seizures' (J. Pharmacol. Exp. Ther. (1953) 107-273), the 6 Hz corneal stimulation model was abandoned shortly after its description because of its lack of sensitivity to phenytoin. This observation is the basis for the present study designed to validate the 6 Hz seizure as a model of therapy-resistant epilepsy. The pharmacological profile of the 6 Hz seizure was determined at varying current intensities using seven established AEDs (phenytoin, carbamazepine, clonazepam, phenobarbital, ethosuximide, trimethadione, valproic acid) and five second-generation AEDs (lamotrigine, levetiracetam, felbamate, tiagabine, topiramate). The immediate early gene c-Fos was used as a marker of seizure-induced neuronal activation to help define those brain structures that were activated by 6 Hz corneal stimulation. At the current intensity required to produce a seizure in 97% of the population (CC97=22 mA), the 6 Hz seizure did not discriminate between clinical classes of AEDs tested. Increasing the current intensity by 50% (i.e. 32 mA) decreased the sensitivity of the 6 Hz seizure to phenytoin and lamotrigine. At a current intensity of 2 x CC97 (i.e. 44 mA), only two AEDs, levetiracetam and valproic acid, displayed complete protection against the 6 Hz seizure, though the efficacy of these drugs was reduced when compared to the lower stimulation intensities. Intense c-Fos staining from 6 Hz seizures induced by 22 and 32 mA stimulus intensities remained localized to the amygdala and piriform cortex. Increasing the stimulus intensity to 44 mA resulted in additional heavy staining of the dentate gyrus. This recruitment of the dentate gyrus may account for the decrease in potency of levetiracetam and valproic acid at 44 mA. The pharmacological results combined with the c-Fos immunohistochemistry suggest that the 6 Hz stimulation may provide a useful model of therapy-resistant limbic seizures.
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              Refractory epilepsy: clinical overview.

              Jacqueline French (2007)
              The incidence of refractory epilepsy remains high despite the influx of many new antiepileptic drugs (AEDs) over the past 10 years. Epidemiological data indicate that 20-40% of the patients with newly diagnosed epilepsy will become refractory to treatment. Factors that may be used to predict whether or not a patient will respond favorably to AED therapy include the type of epilepsy, underlying syndrome, etiology, and the patient's history of seizure frequency, density, and clustering. Environmental factors, such as trauma and prior drug exposure, and genetic factors that predetermine the rate of absorption, metabolism, and uptake of a drug by target tissue may also uniquely impact an individual and influence their response to AED therapy. Treatment resistance is, therefore, a multifaceted phenomenon. Since individuals with refractory epilepsy do not share a common reason for their treatment resistance, the use of targeted drug therapies may be our best option for improving treatment outcomes in this patient population. Pharmacogeneticists are currently attempting to understand the genetic basis of refractory epilepsy so that they can identify subgroups of patients who share a common genetic background and then target drug therapies to meet their specific needs.
              Article 0 comments Cited 92 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmaceuticals (Basel)
                Journal ID (iso-abbrev): Pharmaceuticals (Basel)
                Journal ID (publisher-id): pharmaceuticals
                Title: Pharmaceuticals
                Publisher: MDPI
                ISSN (Electronic): 1424-8247
                Publication date (Electronic): 05 July 2010
                Publication date Collection: July 2010
                Volume: 3
                Issue: 7
                Pages: 2090-2110
                Affiliations
                Institute of Neurophysiology, Charité Berlin Medical University, Tucholskystrasse 2, D-10117 Berlin, Germany; E-Mail: abdul.wahab@ 123456charite.de ; Tel.: +49 30 44707274; Fax: +49 30 450528962
                Article
                Publisher ID: pharmaceuticals-03-02090
                DOI: 10.3390/ph3072090
                PMC ID: 4036655
                PubMed ID: 27713344
                SO-VID: 493c062b-9573-4976-a3d8-52b0283ab331
                Copyright © © 2010 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 10 June 2010
                Date revision received : 28 June 2010
                Date accepted : 02 July 2010
                Categories
                Subject: Review

                Keywords: antiepileptic,anticonvulsant,seizure,pharmacoresistance,refractory seizures
                Data availability:
                Keywords: antiepileptic, anticonvulsant, seizure, pharmacoresistance, refractory seizures

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