Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Pharmacological Reviews
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Pharmacological Reviews

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit Pharm Rev on Facebook
  • Follow Pharm Rev on Twitter
  • Follow ASPET on LinkedIn
Review ArticleReview Article
Open Access

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

Wolfgang Löscher, Heidrun Potschka, Sanjay M. Sisodiya and Annamaria Vezzani
Eric L. Barker, ASSOCIATE EDITOR
Pharmacological Reviews July 2020, 72 (3) 606-638; DOI: https://doi.org/10.1124/pr.120.019539
Wolfgang Löscher
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, Hannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for Pharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy (A.V.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heidrun Potschka
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, Hannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for Pharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy (A.V.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sanjay M. Sisodiya
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, Hannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for Pharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy (A.V.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Annamaria Vezzani
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, Hannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for Pharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy (A.V.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric L. Barker
Roles: ASSOCIATE EDITOR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Fig. 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 1.

    Introduction of antiseizure drugs (ASDs) to the market from 1853 to 2019. Licensing varied from country to country. We give here the year of first licensing or the first mention of clinical use in a country of Europe, the United States, or Japan. We have not included all derivatives of listed ASDs nor ASDs used solely for treatment of status epilepticus. The first generation of ASDs, entering the market from 1857 to 1958, includes potassium bromide, phenobarbital, and a variety of drugs that were mainly derived by modification of the barbiturate structure, including phenytoin, primidone, trimethadione, and ethosuximide. The second-generation ASDs, including carbamazepine, valproate, and the benzodiazepines, which were introduced between 1960 and 1975, differed chemically from the barbiturates. The era of the third-generation ASDs started in the 1980s with “rational” (target-based) developments such as progabide, vigabatrin, and tiagabine, i.e., drugs that were designed to selectively target a mechanism that was thought to be critical for the occurrence of epileptic seizures. The figure also illustrates the impact of preclinical seizure models on ASD development. The use of seizure models for drug screening started with the experiments performed by Merritt and Putnam in the 1930s, who used an electroshock seizure model in cats, leading to the discovery of phenytoin. Subsequently, the electroshock model was adapted to rodents and, together with chemical seizure models, used for drug screening in diverse laboratories, leading to discovery of various additional ASDs. In 1975, the NIH/NINDS ASP was established in the United States as part of a larger Antiepileptic Drug Development program to promote industry interest in ASD development. Since its start, the seizure tests have been performed at a contract facility based at the University of Utah, using three rodent models, i.e., the maximal electroshock seizure (MES) test, the pentylenetetrazole (PTZ) seizure test, and the rotarod test for assessing neurotoxicity. Later, other seizure models were added. The seizure tests were performed on a blinded and confidential basis and at no cost to the ASP participants, thus providing opportunities for researchers from academia and industry in the United States and abroad to submit compounds for screening in a battery of well established rodent seizure models. Approximately 32,000 compounds from more than 600 participants from 38 countries have been screened by this program, and the ASP has contributed to bringing nine currently available ASDs to market since 1990 (Kehne et al., 2017). More recently (2016), the ASP has been renamed Epilepsy Therapy Screening Program (ETSP) with the refocused mission to identify novel agents that will help address the considerable remaining unmet medical needs in epilepsy, particularly ASD-resistant seizures (Kehne et al., 2017). Figure modified from Löscher and Schmidt (2011). For further details, see text and Löscher et al. (2013a).

  • Fig. 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 2.

    Pharmacoresistant epilepsy workflow for the Epilepsy Therapy Screening Program (ETSP). The figure has been provided by John Kehne and slightly modified for consistency with the text of this review. For details, see text and Kehne et al. (2017) and Wilcox et al. (2020).

  • Fig. 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 3.

    Various potential mechanisms of ASD resistance or factors predicting poor outcome have been implicated in patients with epilepsy and animal models of medically resistant seizures, indicating that intrinsic or acquired resistance to ASDs is a multifactorial phenomenon. Based on these findings, a number of hypotheses of ASD resistance, including the target, transporter, network, intrinsic severity, and genetic variant hypotheses, have been suggested (see text). These hypotheses are not mutually exclusive but may be relevant for the same patient, thus complicating any strategy to counteract or reverse pharmacoresistance. Modified from Löscher et al. (2013a).

  • Fig. 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 4.

    Differences between ASD responders and nonresponders in two animal models of DRE. For comparison, alterations associated with ASD resistance in patients are shown. Those alterations that occur both in the models and in patients are highlighted by the colored boxes. For details, see Löscher (2011), Löscher et al. (2013a), and Löscher (2016).

  • Fig. 5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 5.

    Selection and characterization of ASD responders and nonresponders by phenobarbital in a rat model of TLE in which spontaneous recurrent seizures (SRS) develop following sustained electrical stimulation of the basolateral amygdala. (A) Schematic illustration of selection of drug-resistant and drug-responsive epileptic rats by prolonged administration of phenobarbital. (B) Effect of phenobarbital (PB) on SRS. About 5 months after the electrically induced SE, SRS were recorded over a period of 2 weeks before onset of PB treatment (predrug control), followed by drug treatment of 2 weeks and then a 2-week postdrug control period. All data are shown as means ± S.E.M. The graphs in (B) show 1) average seizure data from 33 epileptic rats from three prospective experiments, 2) respective data from 20 responders, 3) data from 13 nonresponders, and 4) average plasma concentration of PB from the blood samples taken at the end of the treatment period. The shaded area indicates the therapeutic plasma concentration range of PB. In the responder group, PB significantly suppressed SRS compared with the pre- and postdrug periods (*P < 0.001). Note the higher average frequency of SRS in nonresponders versus responders. (C) Pgp expression in brain capillary endothelial cells of responders and nonresponders. Significant differences are indicated by asterisk (*P < 0.05). (D) Coadministration of PB and the Pgp inhibitor tariquidar lead to a significant (*P < 0.05) suppression of SRS in PB nonresponders. Three different doses of tariquidar (10, 15, and 20 mg/kg) were used, demonstrating a dose-dependent effect. Data are from Brandt et al. (2004), Volk and Löscher (2005), Brandt et al. (2006), Bethmann et al. (2007), and Brandt and Löscher (2014).

  • Fig. 6.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 6.

    Schematic representation of the evidence-based pathologic links between inflammatory mediators and mechanisms of drug resistance. Inflammatory mediators (including but not limited to cytokines) may contribute to drug-resistant seizures mainly by three (nonmutually exclusive) pathways: 1) the induction of BBB dysfunction by promoting breakdown of tight junctions or inducing transocytosis, aberrant angiogenesis generating “leaky” vessels, and oxidative stress. The inflammatory phenotype of astrocytes is pivotal for these actions to take place, and reciprocally, BBB permeability changes may promote the expression of inflammatory molecules in astrocytes. This vicious cycle contributes to recurrent seizures, cell loss, and maladaptive neuronal network plasticity, therefore contributing to increase the “intrinsic severity” of the disease. Morever, BBB dysfunction will enhance albumin brain extravasation into the brain parenchyma and potentially increase the “buffering” effect of albumin binding to drugs, thus decreasing functionally relevant unbound drug levels at brain target sites. 2) Another mechanism is the induction of Pgp in endothelial cells, and likely in perivascular astrocytes, by specific inflammatory pathways involving COX2-PGE2-EP1R and the IL-1beta-IL-1R1 axis, thus contributing to the transporter hypothesis of drug resistance. 3) Inflammatory mediators can also induce post-translational modifications in voltage-gated and receptor-operated ion channels resulting in less responsive ASD targets, which may contribute to the pharmacodynamic (target) hypothesis of drug resistance. Details and references are reported in the main text.

Tables

  • Figures
    • View popup
    TABLE 1

    Molecular targets of clinically used ASDs

    Adapted from Rogawski and Löscher (2004), Rogawski et al. (2016), and Sills and Rogawski (2020)

    Molecular targetASDs that act on target
    Voltage-gated ion channels
    Voltage-gated sodium channelsPhenytoin, fosphenytoin,a carbamazepine, oxcarbazepine,b eslicarbazepine acetate,c lamotrigine, lacosamide; possibly topiramate, zonisamide, rufinamide
    Voltage-gated calcium channels (T-type)Ethosuximide
    Voltage-gated potassium channels (Kv7)Retigabine (ezogabine)
    GABA-mediated inhibition
    GABAA receptorsPhenobarbital, primidone, stiripentol, benzodiazepines, (including diazepam, lorazepam, midazolam and clonazepam), possibly topiramate, felbamate, retigabine (ezogabine)
    GAT1 GABA transporterTiagabine
    GABA transaminaseVigabatrin
    Glutamic acid decarboxylasePossibly valproate, gabapentin, pregabalin
    Presynaptic release machinery
    SV2ALevetiracetam, brivaracetam
    α2δ subunit of calcium channelsGabapentin, pregabalin
    Ionotropic glutamate receptors
    AMPA receptorPerampanel
    Carbonic anhydratase inhibitionAcetazolamide, topiramate, zonisamide, possibly lacosamide
    Disease-specific
    mTORC1 signalingdEverolimus
    Lysosomal enzyme replacementeCerliponase alfa (recombinant tripeptidyl peptidase 1)
    Mixed/unknownValproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorticotrophin (ACTH), cannabidiol, cenobamate
    • AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate.

    • ↵a Fosphenytoin is a prodrug for phenytoin.

    • ↵b Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine.

    • ↵c Eslicarbarbazepine acetate is a prodrug for S-licarbazepine.

    • ↵d In patients with epilepsy because of tuberous sclerosis complex (TSC).

    • ↵e In patients with epilepsy because of neuronal ceroid lipofuscinosis type 2.

    • View popup
    TABLE 2

    In vivo models of drug-resistant seizures

    For references, see text.

    Seizure or epilepsy modelSpeciesMode of seizure or epilepsy inductionChronic modelDevelopment of spontaneous seizuresSelection of responders and nonresponders reportedThroughput
    6-Hz seizure modelMouseTranscorneal electrical stimulationNoNon.a.High
    6-Hz seizure modelRatTranscorneal electrical stimulationNoNon.a.High
    Allylglycine-induced seizuresMouseIntraperitoneal administration of chemoconvulsantNoNon.a.High
    Allylglycine-induced seizuresZebrafish larvaeBath application of chemoconvulsantNoNon.a.Very high
    6-Hz kindlingMouseTranscorneal electrical stimulationYesNoNoIntermediate
    Lamotrigine-resistant kindled animalsRatRepeated electrical stimulation of the amygdalaYesNoNoIntermediate
    Lamotrigine-resistant kindled animalsMouseRepeated electrical stimulation of the amygdalaYesNoNoIntermediate
    Intrahippocampal kainate modelMouseIntracerebral injection of kainateYesYesYesIntermediate
    Post-traumatic seizuresRatFluid percussion injuryYesYesNoLow
    Cortical dysplasia modelRatIn utero exposure to methylazoxymethanol acetate plus kainate exposureYesNoNoLow
    Dravet modelsMiceGenetic modulationYesYesNoLow
    NMDA model of epileptic spasmsRat (immature)Intraperitoneal administration of chemoconvulsantNoNoNoHigh
    Multiple-hit model of infantile spasmsRatPN3 unilateral i.c.v. doxorubicin and intracortical lipopolysaccharide plus PN5 intraperitoneal p-chlorophenylalanine (→ increases spasm frequency)YesYesNoLow
    Phenytoin-selected kindled animalsRatRepeated electrical stimulation of the amygdalaYesNoYesLow
    Phenobarbital-selected animals with spontaneous seizuresRatProlonged electrical stimulation of amygdala induction of a status epilepticusYesYesYesLow
    Canine patients with DREDogNatural disease (structural or idiopathic according to IVETF guidelines)YesYesYes (based on clinical response)Very low
    • i.c.v., intracerebroventricular; IVETF, International Veterinary Epilepsy Task Force; n.a., not applicable; PN, postnatal day.

    • View popup
    TABLE 3

    Proof-of-concept of drug resistance hypotheses

    As suggested by Sisodiya (2003), at least four criteria must be satisfied for a proposed drug-resistance mechanism of epilepsy to be accepted; the mechanism must 1) be detectable in epileptogenic brain tissue, 2) have appropriate functionality, 3) be active in drug resistance (and not be an epiphenomenon), and 4) drug resistance should be affected when the mechanism is overcome. These criteria are based on the famous Koch’s postulates, which were originally proposed by Robert Koch in 1890 to establish a causal relationship between a bacterium and a disease.

    Drug-resistance hypothesis in epilepsyDetectable in brain (or peripheral) tissues of nonrespondersAppropriate functionalityActive in ASD resistanceResistance reversed when mechanism is overcome
    Target hypothesis+ (rat)+ (rat)? (rat)? (rat)
    + (human)+ (human)? (human)? (human)
    Transporter hypothesis+ (rat)+ (rat)+ (rat)+ (rat)
    + (human)+ (human)+ (human)? (human)
    Pharmacokinetic hypothesis- (rat)- (rat)? (rat)? (rat)
    + (human)? (human)? (human)? (human)
    Neural network hypothesis+ (rat)? (rat)? (rat)? (rat)
    + (human)? (human)? (human)+ (human)
    Intrinsic severity hypothesis+ (rat)a? (rat)? (rat)? (rat)
    + (human)a? (human)? (human)? (human)
    Gene variant hypothesis+ (rat)+ (rat)? (rat)? (rat)
    + (human)+ (human)+/? (human)+/? (human)
    Epigenetic hypothesis+ (rat/mouse)+/? (rat/mouse)+/? (rat/mouse)+/? (rat/mouse)
    + (human)? (human)? (human)? (human)
    Neuroinflammation/blood-brain barrier+ (rat, mouse)+ (rat)+ (rat)+ (rat)
    + (human)? (human)? (human)? (human)
    • ↵a Increased seizure frequency/density compared with ASD responders.

    • View popup
    TABLE 4

    Potential etiology-specific drugs (“precision medicine”) that are currently used or discussed for treatment of severe pediatric-onset epilepsies

    Drugs are listed according to mutated genes. For a source of references, please refer to Wang et al. (2017) and Mesraoua et al. (2019). Note that mutations of the same gene may result in different clinical phenotypes, as recently shown for KCNQ2 mutation, in which the majority of patients have loss-of-function mutations but a small percentage have gain-of-function mutations associated with a different phenotype (Demarest and Brooks-Kayal, 2018). Except for everolimus in TSC-associated focal epilepsy and for cannabidiol and fenfluramine in Dravet syndrome, none of the treatments listed in this table have been validated in randomized controlled trials in patients with the indicated mutations, and for some of these treatments, evidence for efficacy is speculative or controversial, with most entries being anecdotal or in fact not “precision” (see comments). Clinicians should not consider this table as constituting support for treatment with these agents.

    Mutated geneGene nameEncoded protein functionType of epilepsyPotentially beneficial therapyComments
    CHRNA4Cholinergic receptor nicotinic alpha 4 subunitNicotinergic acetylcholine receptorNocturnal frontal lobe epilepsyZonisamide, acetazolamide, and nicotine patchesZonisamide and acetazolamide are not really “precision.” Nicotinergic agents are theoretically of possible use, but none have been proven to be of value currently
    GRIN2AGlutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit 2AGlutamate (NMDA) receptorFocal epilepsy and speech disorder with or without mental retardationMemantineHas been proposed on the basis of two studies only, none published since 2015
    KCNQ2Potassium voltage-gated channel subfamily Q member 2Potassium channelBenign familial neonatal seizures or, in infancy and childhood, EIEERetigabine/ezogabineHas in vitro evidence to support its use in gain-of-function mutants, but prospective controlled trials are still lacking
    KCNT1Potassium sodium-activated channel subfamily T member 1Potassium channelEIEEQuinidineThe evidence is equivocal, with many negative reports after the initial reports of benefit
    PCDH19Protocadherin 19Cell adhesion moleculeEIEEPotassium bromide, clobazamOnly anecdotal evidence. Better rationale for hormonal treatment with allopregnanolone.
    PLCB1Phospholipase C beta 1EnzymeEIEEInositolNot any evidence for this in humans
    PRRT2Proline-rich transmembrane protein 2UnclassifiedBenign familial infantile seizuresCarbamazepine, oxcarbazepineNot really precision (mechanism-based) treatments
    SCN1ASodium voltage-gated channel alpha subunit 1Voltage-gated sodium channelDravet syndromeGABAergic drugs, fenfluramine, cannabidiolFenfluramine and cannabidiol cannot be considered precision (mechanism-based) treatments
    SCN2ASodium voltage-gated channel alpha subunit 2Voltage-gated sodium channelBenign familial infantile seizures or EIEEHigh levels of phenytoin; levetiracetamNot yet clear whether levetiracetam can be considered precision (mechanism-based) treatment
    SCN2ASodium voltage-gated channel alpha subunit 2Voltage-gated sodium channelEIEE, status epilepticusLidocaine, acetazolamideEvidence for precision (mechanism-based) treatment status limited
    SCN8ASodium voltage-gated channel alpha subunit 8Voltage-gated sodium channelBenign familial infantile seizures or EIEEHigh levels of phenytoin or carbamazepine; amitriptyline, nilvadipine, carvedilolBased on one study for one mutation in SCN8A
    SLC2A1Solute carrier family 2 member 1TransporterIdiopathic generalized epilepsyKetogenic dietBypasses the pathophysiology to provide an alternative energy supply to the brain
    STXBP1Syntaxin-binding protein 1Membrane traffickingEIEELevetiracetam, folinic acid, vigabatrinOnly anecdotal evidence
    TSC1 and 2TSC (tuberous sclerosis complex) subunits 1 and 2Unclassified; mutations lead to increased activity of mTORTuberous sclerosisEverolimusA precision treatment with support from clinical trials and licensed for particular uses in tuberous sclerosis complex
    • EIEE, early infantile epileptic encephalopathy.

PreviousNext
Back to top

In this issue

Pharmacological Reviews: 72 (3)
Pharmacological Reviews
Vol. 72, Issue 3
1 Jul 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Pharmacological Reviews article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options
(Your Name) has forwarded a page to you from Pharmacological Reviews
(Your Name) thought you would be interested in this article in Pharmacological Reviews.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Review ArticleReview Article

Drug-Resistant Epilepsy

Wolfgang Löscher, Heidrun Potschka, Sanjay M. Sisodiya and Annamaria Vezzani
Pharmacological Reviews July 1, 2020, 72 (3) 606-638; DOI: https://doi.org/10.1124/pr.120.019539

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Review ArticleReview Article

Drug-Resistant Epilepsy

Wolfgang Löscher, Heidrun Potschka, Sanjay M. Sisodiya and Annamaria Vezzani
Pharmacological Reviews July 1, 2020, 72 (3) 606-638; DOI: https://doi.org/10.1124/pr.120.019539
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • I. Introduction
    • II. Pharmacology of Antiseizure Drugs
    • III. In Vivo and In Vitro Models of Drug Resistance
    • IV. Current Hypotheses of Mechanisms of Drug Resistance
    • V. How to Overcome Drug Resistance?
    • VI. Conclusions
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Endocannabinoid System as a Therapeutic Target
  • Protein SUMOylation and LLPS
  • Endoplasmic Reticulum Pharmacology in Neurodegeneration
Show more Review Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Pharmacological Reviews
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacology Research & Perspectives
ISSN 1521-0081 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics