Skip to content
2000
Volume 23, Issue 8
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Epilepsy is a neurological disorder affecting millions of people worldwide. Antiseizure medications (ASM) remain a critical therapeutic intervention for treating epilepsy, notwithstanding the rapid development of other therapies. There have been substantial advances in epilepsy medications over the past three decades, with over 20 ASMs now available commercially. Here we describe the conventional and unique mechanisms of action of ASMs, focusing on everolimus, cannabidiol, cenobamate, fenfluramine, and ganaxolone, the five most recently marketed ASMs. Major obstacles in the development of ASMs are also addressed, particularly drug-resistant epilepsy as well as psychiatric and behavioral adverse effects of ASMs. Moreover, we delve into the mechanisms and comparative efficacy of ASM polytherapy, with remarks on the benefits and challenges in their application in clinical practice. In addition, the characteristics of the ideal ASM are outlined in this review. The review also discusses the development of new potential ASMs, including modifying existing ASMs to improve efficacy and tolerability. Furthermore, we expound on the modulation of γ-aminobutyric acid type A receptor (GABAR) as a strategy for the treatment of epilepsy and the identification of a GABAR agonist, isoguvacine, as a potential ASM.

Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X323666241029171256
2025-01-24
2025-10-29
Loading full text...

Full text loading...

References

  1. PerkinsA. Epilepsy.Nurs. Made Incred. Easy2019174425010.1097/01.NME.0000559583.43254.ab
    [Google Scholar]
  2. BeghiE. The epidemiology of epilepsy.Neuroepidemiology202054218519110.1159/00050383131852003
    [Google Scholar]
  3. WHOEpilepsy fact sheets.2024Available from :https://www.who.int/news-room/fact-sheets/detail/epilepsy
  4. WHO Epilepsy Fact Sheets.WHO Collab. Cent. Drugs Stat. Methodolofy202215
    [Google Scholar]
  5. KhatebM. BosakN. HerskovitzM. The effect of anti-seizure medications on the propagation of epileptic activity: A review.Front. Neurol.20211267418210.3389/fneur.2021.67418234122318
    [Google Scholar]
  6. LöscherW. KleinP. The pharmacology and clinical efficacy of antiseizure medications: From bromide salts to cenobamate and beyond.CNS Drugs202135993596310.1007/s40263‑021‑00827‑834145528
    [Google Scholar]
  7. FrenchJ.A. PeruccaE. Time to start calling things by their own names? The case for antiseizure medicines.Epilepsy Curr.2020202697210.1177/153575972090551632077329
    [Google Scholar]
  8. ArulsamyA. GohB.H. ShaikhM.F. Current status of epilepsy in Malaysia and way ahead.Int. J. Pharm. Pharm. Sci.20157125
    [Google Scholar]
  9. DalicL. CookM. Managing drug-resistant epilepsy: Challenges and solutions.Neuropsychiatr. Dis. Treat.2016122605261610.2147/NDT.S8485227789949
    [Google Scholar]
  10. ChenB. ChoiH. HirschL.J. KatzA. LeggeA. BuchsbaumR. DetynieckiK. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.Epilepsy Behav.201776243110.1016/j.yebeh.2017.08.03928931473
    [Google Scholar]
  11. KanthK.M. ClarkS. BrittonJ.W. Antiseizure medication therapy.Epilepsy. CascinoG.D. SirvenJ.I. TatumW.O. USAWiley202117921510.1002/9781119431893.ch11
    [Google Scholar]
  12. GuidelliR. The common features of tetrameric ion channels and the role of electrostatic interactions.Electrochem. Commun.202012110686610.1016/j.elecom.2020.106866
    [Google Scholar]
  13. StriessnigJ. Voltage-gated Ca2+-Channel α1-Subunit de novo Missense mutations: Gain or loss of function – Implications for potential therapies.Front. Synaptic Neurosci.20211363476010.3389/fnsyn.2021.63476033746731
    [Google Scholar]
  14. XuL. DingX. WangT. MouS. SunH. HouT. Voltage-gated sodium channels: Structures, functions, and molecular modeling.Drug Discov. Today20192471389139710.1016/j.drudis.2019.05.01431129313
    [Google Scholar]
  15. CatterallW.A. SwansonT.M. Structural basis for pharmacology of voltage-gated sodium and calcium channels.Mol. Pharmacol.201588114115010.1124/mol.114.09765925848093
    [Google Scholar]
  16. BagalS.K. MarronB.E. OwenR.M. StorerR.I. SwainN.A. Voltage gated sodium channels as drug discovery targets.Channels (Austin)20159636036610.1080/19336950.2015.107967426646477
    [Google Scholar]
  17. CatterallW.A. Voltage‐gated sodium channels at 60: Structure, function and pathophysiology.J. Physiol.2012590112577258910.1113/jphysiol.2011.22420422473783
    [Google Scholar]
  18. PayandehJ. ScheuerT. ZhengN. CatterallW.A. The crystal structure of a voltage-gated sodium channel.Nature2011475735635335810.1038/nature1023821743477
    [Google Scholar]
  19. TikhonovD.B. ZhorovB.S. Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants.J. Gen. Physiol.2017149446548110.1085/jgp.20161166828258204
    [Google Scholar]
  20. AhernC.A. PayandehJ. BosmansF. ChandaB. The hitchhiker’s guide to the voltage-gated sodium channel galaxy.J. Gen. Physiol.2016147112410.1085/jgp.20151149226712848
    [Google Scholar]
  21. PalR. KumarB. AkhtarM.J. ChawlaP.A. Voltage gated sodium channel inhibitors as anticonvulsant drugs: A systematic review on recent developments and structure activity relationship studies.Bioorg. Chem.202111510523010.1016/j.bioorg.2021.10523034416507
    [Google Scholar]
  22. CaronaA. BickerJ. SilvaR. FonsecaC. FalcãoA. FortunaA. Pharmacology of lacosamide: From its molecular mechanisms and pharmacokinetics to future therapeutic applications.Life Sci.202127511934210.1016/j.lfs.2021.11934233713668
    [Google Scholar]
  23. RogawskiM.A. TofighyA. WhiteH.S. MatagneA. WolffC. Current understanding of the mechanism of action of the antiepileptic drug lacosamide.Epilepsy Res.201511018920510.1016/j.eplepsyres.2014.11.02125616473
    [Google Scholar]
  24. GuerriniR. Valproate as a mainstay of therapy for pediatric epilepsy.Paediatr. Drugs20068211312910.2165/00148581‑200608020‑0000416608372
    [Google Scholar]
  25. MantegazzaM. CuriaG. BiaginiG. RagsdaleD.S. AvoliM. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders.Lancet Neurol.20109441342410.1016/S1474‑4422(10)70059‑420298965
    [Google Scholar]
  26. WengertE.R. PatelM.K. The role of the persistent sodium current in epilepsy.Epilepsy Curr.2021211404710.1177/153575972097397833236643
    [Google Scholar]
  27. AdemuwagunI.A. RotimiS.O. SyrbeS. AjammaY.U. AdebiyiE. Voltage gated sodium channel genes in epilepsy: Mutations, functional studies, and treatment dimensions.Front. Neurol.20211260005010.3389/fneur.2021.60005033841294
    [Google Scholar]
  28. ZaccaraG. LattanziS. LeoA. RussoE. Critical appraisal of Cenobamate as adjunctive treatment of focal seizures in adults.Neuropsychiatr. Dis. Treat.2021173447345710.2147/NDT.S28149034876814
    [Google Scholar]
  29. Aboul-EneinM.N. El-AzzounyA.A. SalehO.A. MakladY.A. On chemical structures with potent antiepileptic/anticonvulsant profile.Mini Rev. Med. Chem.201212767170010.2174/13895571280062666522512548
    [Google Scholar]
  30. DolphinA.C. Voltage‐gated calcium channels and their auxiliary subunits: Physiology and pathophysiology and pharmacology.J. Physiol.2016594195369539010.1113/JP27226227273705
    [Google Scholar]
  31. RajakulendranS. HannaM.G. The role of calcium channels in epilepsy.Cold Spring Harb. Perspect. Med.201661a02272310.1101/cshperspect.a02272326729757
    [Google Scholar]
  32. DolphinA.C. Voltage-gated calcium channels: Their discovery, function and importance as drug targets.Brain Neurosci. Adv.20182239821281879480510.1177/239821281879480530320224
    [Google Scholar]
  33. CainS.M. SnutchT.P. T-type calcium channels in burst-firing, network synchrony, and epilepsy.Biochim. Biophys. Acta Biomembr.2013182871572157810.1016/j.bbamem.2012.07.02822885138
    [Google Scholar]
  34. NelsonM. TodorovicS. Perez-ReyesE. The role of T-type calcium channels in epilepsy and pain.Curr. Pharm. Des.200612182189219710.2174/13816120677758518416787249
    [Google Scholar]
  35. ZamponiG.W. LoryP. Perez-ReyesE. Role of voltage-gated calcium channels in epilepsy.Pflugers Arch.2010460239540310.1007/s00424‑009‑0772‑x20091047
    [Google Scholar]
  36. HanrahanB. CarsonR.P. Ethosuximide.Elsevier202110.1016/B978‑008055232‑3.61720‑9
    [Google Scholar]
  37. BitonV. Clinical pharmacology and mechanism of action of zonisamide.Clin. Neuropharmacol.200730423024010.1097/wnf.0b013e3180413d7d17762320
    [Google Scholar]
  38. KwanS.Y. ChuangY.C. HuangC.W. ChenT.C. JouS.B. DashA. Zonisamide: Review of recent clinical evidence for treatment of epilepsy.CNS Neurosci. Ther.201521968369110.1111/cns.1241826205514
    [Google Scholar]
  39. KimD.M. NimigeanC.M. Voltage-gated potassium channels: A structural examination of selectivity and gating.Cold Spring Harb. Perspect. Biol.201685a02923110.1101/cshperspect.a02923127141052
    [Google Scholar]
  40. KöhlingR. WolfartJ. Potassium Channels in Epilepsy.Cold Spring Harb. Perspect. Med.201665a02287110.1101/cshperspect.a02287127141079
    [Google Scholar]
  41. WickendenA.D. Potassium channels as anti-epileptic drug targets.Neuropharmacology20024371055106010.1016/S0028‑3908(02)00237‑X12504910
    [Google Scholar]
  42. D’AdamoM.C. CatacuzzenoL. Di GiovanniG. FrancioliniF. PessiaM. K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy.Front. Cell. Neurosci.2013713410.3389/fncel.2013.0013424062639
    [Google Scholar]
  43. VillaC. CombiR. Potassium channels and human epileptic phenotypes: An updated overview. Front. Cell. Neurosci20161011410.3389/fncel.2016.00081
    [Google Scholar]
  44. LiJ. MagheraJ. LamotheS.M. MarcoE.J. KurataH.T. Heteromeric assembly of Truncated Neuronal Kv7 Channels: Implications for neurologic disease and pharmacotherapy.Mol. Pharmacol.202098319220210.1124/mol.120.11964432580997
    [Google Scholar]
  45. RogawskiM.A. BazilC.W. New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels.Curr. Neurol. Neurosci. Rep.20088434535210.1007/s11910‑008‑0053‑718590620
    [Google Scholar]
  46. GunthorpeM.J. LargeC.H. SankarR. The mechanism of action of retigabine (ezogabine), a first‐in‐class K + channel opener for the treatment of epilepsy.Epilepsia201253341242410.1111/j.1528‑1167.2011.03365.x22220513
    [Google Scholar]
  47. YogeeswariP. SriramD. VaigundaragavendranJ. The GABA shunt: an attractive and potential therapeutic target in the treatment of epileptic disorders.Curr. Drug Metab.20056212713910.2174/138920005358607315853764
    [Google Scholar]
  48. GoetzT. ArslanA. WisdenW. WulffP. GABAA receptors: Structure and function in the basal ganglia.Prog. Brain Res.2007160214110.1016/S0079‑6123(06)60003‑417499107
    [Google Scholar]
  49. LiK. XuE. The role and the mechanism of γ-aminobutyric acid during central nervous system development.Neurosci. Bull.200824319520010.1007/s12264‑008‑0109‑318500393
    [Google Scholar]
  50. MeleM. CostaR.O. DuarteC.B. Alterations in GABAA-Receptor trafficking and synaptic dysfunction in brain disorders.Front. Cell. Neurosci.2019137710.3389/fncel.2019.0007730899215
    [Google Scholar]
  51. GalanopoulouA. GABA(A) receptors in normal development and seizures: Friends or foes?Curr. Neuropharmacol.20086112010.2174/15701590878376965319305785
    [Google Scholar]
  52. SieghartW. RamerstorferJ. Sarto-JacksonI. VaragicZ. ErnstM. A novel GABA A receptor pharmacology: Drugs interacting with the α + β ‐ interface.Br. J. Pharmacol.2012166247648510.1111/j.1476‑5381.2011.01779.x22074382
    [Google Scholar]
  53. SillsG.J. RogawskiM.A. Mechanisms of action of currently used antiseizure drugs.Neuropharmacology202016816810796610.1016/j.neuropharm.2020.10796632120063
    [Google Scholar]
  54. SankaraneniR. LachhwaniD. Antiepileptic drugs a review.Pediatr. Ann.2015442e36e4210.3928/00904481‑20150203‑1025658217
    [Google Scholar]
  55. BresnahanR. HounsomeJ. JetteN. HuttonJ.L. MarsonA.G. Topiramate add-on therapy for drug-resistant focal epilepsy.Cochrane Libr.2019201910CD00141710.1002/14651858.CD001417.pub431642054
    [Google Scholar]
  56. KarakasE. ReganM.C. FurukawaH. Emerging structural insights into the function of ionotropic glutamate receptors.Trends Biochem. Sci.201540632833710.1016/j.tibs.2015.04.00225941168
    [Google Scholar]
  57. TwomeyE.C. SobolevskyA.I. Structural mechanisms of gating in ionotropic glutamate receptors.Biochemistry201857326727610.1021/acs.biochem.7b0089129037031
    [Google Scholar]
  58. MihályA. The reactive plasticity of Hippocampal Ionotropic Glutamate receptors in animal epilepsies.Int. J. Mol. Sci.2019205103010.3390/ijms2005103030818767
    [Google Scholar]
  59. CrupiR. ImpellizzeriD. CuzzocreaS. Role of metabotropic glutamate receptors in neurological disorders.Front. Mol. Neurosci.2019122010.3389/fnmol.2019.0002030800054
    [Google Scholar]
  60. KölesL. KatóE. HanuskaA. ZádoriZ.S. Al-KhrasaniM. ZellesT. RubiniP. IllesP. Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems.Purinergic Signal.201612112410.1007/s11302‑015‑9480‑526542977
    [Google Scholar]
  61. HanadaT. The AMPA receptor as a therapeutic target in epilepsy: Preclinical and clinical evidence.J. Receptor Ligand Channel Res.201473910.2147/JRLCR.S51475
    [Google Scholar]
  62. RogawskiM.A. AMPA receptors as a molecular target in epilepsy therapy.Acta Neurol. Scand.201312719791810.1111/ane.1209923480151
    [Google Scholar]
  63. NarangodaC. SakipovS.N. KurnikovaM.G. AMPA receptor noncompetitive inhibitors occupy a promiscuous binding site.ACS Chem. Neurosci.201910114511452110.1021/acschemneuro.9b0034431596070
    [Google Scholar]
  64. HansenK.B. YiF. PerszykR.E. FurukawaH. WollmuthL.P. GibbA.J. TraynelisS.F. Structure, function, and allosteric modulation of NMDA receptors.J. Gen. Physiol.201815081081110510.1085/jgp.20181203230037851
    [Google Scholar]
  65. LeeC.H. LüW. MichelJ.C. GoehringA. DuJ. SongX. GouauxE. NMDA receptor structures reveal subunit arrangement and pore architecture.Nature2014511750819119710.1038/nature1354825008524
    [Google Scholar]
  66. DasV. An introduction to pain pathways and pain “Targets.”.Molecular and Cell Biology of Pain.Elsevier Inc.201513113010.1016/bs.pmbts.2015.01.003
    [Google Scholar]
  67. KumarA. NMDA receptor function during senescence: Implication on cognitive performance.Front. Neurosci.2015947310.3389/fnins.2015.0047326732087
    [Google Scholar]
  68. JaneD.E. LodgeD. CollingridgeG.L. Kainate receptors: Pharmacology, function and therapeutic potential.Neuropharmacology20095619011310.1016/j.neuropharm.2008.08.02318793656
    [Google Scholar]
  69. PinheiroP. MulleC. Kainate receptors.Cell Tissue Res.2006326245748210.1007/s00441‑006‑0265‑616847640
    [Google Scholar]
  70. ChałupnikP. SzymańskaE. Kainate receptor antagonists: Recent advances and therapeutic perspective.Int. J. Mol. Sci.2023243190810.3390/ijms2403190836768227
    [Google Scholar]
  71. Kainate receptors: Role in epilepsy.Front. Mol. Neurosci.2018111710.3389/fnmol.2018.00217
    [Google Scholar]
  72. ChenT.S. HuangT.H. LaiM.C. HuangC.W. The role of glutamate receptors in epilepsy.Biomedicines202311378310.3390/biomedicines1103078336979762
    [Google Scholar]
  73. BartholomeO. Van den AckervekenP. Sánchez GilJ. de la Brassinne B.O. LeprinceP. FranzenR. RogisterB. Puzzling out synaptic vesicle 2 family members functions.Front. Mol. Neurosci.20171014810.3389/fnmol.2017.0014828588450
    [Google Scholar]
  74. RossiR. ArjmandS. BærentzenS.L. GjeddeA. LandauA.M. Synaptic vesicle glycoprotein 2A: Features and functions.Front. Neurosci.20221686451410.3389/fnins.2022.86451435573314
    [Google Scholar]
  75. ZhangY. HeylenL. PartoensM. MillsJ.D. KaminskiR.M. GodardP. GillardM. de WitteP.A.M. SiekierskaA. Connectivity mapping using a novel sv2a Loss-of-function zebrafish epilepsy model as a powerful strategy for anti-epileptic drug discovery.Front. Mol. Neurosci.20221588193310.3389/fnmol.2022.88193335686059
    [Google Scholar]
  76. OhnoY. TokudomeK. Therapeutic role of synaptic vesicle glycoprotein 2A (SV2A) in modulating epileptogenesis.CNS Neurol. Disord. Drug Targets201716446347110.2174/187152731666617040411502728393712
    [Google Scholar]
  77. KleinP. BourikasD. Narrative review of brivaracetam: Preclinical profile and clinical benefits in the treatment of patients with epilepsy.Adv. Ther.20244172682269910.1007/s12325‑024‑02876‑z38811492
    [Google Scholar]
  78. Contreras-GarcíaI.J. Cárdenas-RodríguezN. Romo-MancillasA. BandalaC. ZamudioS.R. Gómez-ManzoS. Hernández-OchoaB. Mendoza-TorreblancaJ.G. Pichardo-MacíasL.A. Levetiracetam mechanisms of action: From molecules to systems.Pharmaceuticals202215447510.3390/ph1504047535455472
    [Google Scholar]
  79. YanH.D. IshiharaK. SekiT. HanayaR. KurisuK. AritaK. SerikawaT. SasaM. Inhibitory effects of levetiracetam on the high-voltage-activated L-type Ca2+ channels in hippocampal CA3 neurons of spontaneously epileptic rat (SER).Brain Res. Bull.20139014214810.1016/j.brainresbull.2012.10.00623107646
    [Google Scholar]
  80. DowlingR.J.O. TopisirovicI. FonsecaB.D. SonenbergN. Dissecting the role of mTOR: Lessons from mTOR inhibitors.Biochim. Biophys. Acta. Proteins Proteomics20101804343343910.1016/j.bbapap.2009.12.00120005306
    [Google Scholar]
  81. SaxtonR.A. SabatiniD.M. mTOR signaling in growth, metabolism, and disease.Cell2017168696097610.1016/j.cell.2017.02.00428283069
    [Google Scholar]
  82. LaplanteM. SabatiniD.M. mTOR signaling in growth control and disease.Cell2012149227429310.1016/j.cell.2012.03.01722500797
    [Google Scholar]
  83. LiptonJ.O. SahinM. The neurology of mTOR.Neuron201484227529110.1016/j.neuron.2014.09.03425374355
    [Google Scholar]
  84. KennedyB.K. LammingD.W. The mechanistic target of Rapamycin: The grand conductor of metabolism and aging.Cell Metab.2016236990100310.1016/j.cmet.2016.05.00927304501
    [Google Scholar]
  85. ZouZ. TaoT. LiH. ZhuX. mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges.Cell Biosci.20201013110.1186/s13578‑020‑00396‑132175074
    [Google Scholar]
  86. WangX. ProudC.G. The mTOR pathway in the control of protein synthesis.Physiology (Bethesda)200621536236910.1152/physiol.00024.200616990457
    [Google Scholar]
  87. GoldsteinH.E. HauptmanJ.S. The putative role of mTOR inhibitors in non-tuberous sclerosis complex-related Epilepsy.Front. Neurol.20211263931910.3389/fneur.2021.63931933643212
    [Google Scholar]
  88. CuratoloP. MoaveroR. mTOR inhibitors as a new therapeutic option for epilepsy.Expert Rev. Neurother.201313662763810.1586/ern.13.4923739000
    [Google Scholar]
  89. MengX.F. YuJ.T. SongJ.H. ChiS. TanL. Role of the mTOR signaling pathway in epilepsy.J. Neurol. Sci.20133321-241510.1016/j.jns.2013.05.02923773767
    [Google Scholar]
  90. SumadewiK.T. HarkitasariS. TjandraD.C. Biomolecular mechanisms of epileptic seizures and epilepsy: A review.Acta Epileptol.2023512810.1186/s42494‑023‑00137‑0
    [Google Scholar]
  91. AliN.H. Al-kuraishyH.M. Al-GareebA.I. AlnaaimS.A. AlexiouA. PapadakisM. SaadH.M. BatihaG.E.S. Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator.Mol. Med.202329114210.1186/s10020‑023‑00742‑237880579
    [Google Scholar]
  92. SadowskiK. Kotulska-JóźwiakK. JóźwiakS. Role of mTOR inhibitors in epilepsy treatment.Pharmacol. Rep.201567363664610.1016/j.pharep.2014.12.01725933981
    [Google Scholar]
  93. SvarrerE.M.M. FischerC.M. FrederiksenM.G. BornA.P. Hoei-HansenC.E. Everolimus as adjunctive treatment in tuberous sclerosis complex-associated epilepsy in children.Dan. Med. J.201966121631791480
    [Google Scholar]
  94. BastT. SteinhoffB.J. Anticonvulsant agents: Potassium bromide.NeuroPsychopharmacotherapy.ChamSpringer International Publishing20201710.1007/978‑3‑319‑56015‑1_304‑1
    [Google Scholar]
  95. RhoJ.M. WhiteH.S. Brief history of anti‐seizure drug development.Epilepsia Open20183Suppl. 211411910.1002/epi4.1226830564769
    [Google Scholar]
  96. GouveiaD. MandigersP. CherubiniG.B. Bromide: the good, the bad, and the ugly of the oldest antiseizure medication.Front. Vet. Sci.202411143319110.3389/fvets.2024.143319138988980
    [Google Scholar]
  97. MansoorS. KhanS.Y. KhanS. KakarN. SaadatS. A brief history of epilepsy.SAS J. Med.201841118618810.21276/sasjm.2018.4.11.3
    [Google Scholar]
  98. TolchinB. HirschL.J. LaFranceW.C.Jr Neuropsychiatric aspects of epilepsy.Psychiatr. Clin. North Am.202043227529010.1016/j.psc.2020.02.00232439022
    [Google Scholar]
  99. HakamiT. Efficacy and tolerability of antiseizure drugs.Ther. Adv. Neurol. Disord.2021141756286421103743010.1177/1756286421103743034603506
    [Google Scholar]
  100. AndersonG.D. SanetoR.P. Current oral and non-oral routes of antiepileptic drug delivery.Adv. Drug Deliv. Rev.2012641091191810.1016/j.addr.2012.01.01722326840
    [Google Scholar]
  101. WhelessJ.W. PhelpsS.J. A clinician’s guide to oral extended-release drug delivery systems in epilepsy.J. Pediatr. Pharmacol. Ther.201823427729210.5863/1551‑6776‑23.4.27730181718
    [Google Scholar]
  102. PeruccaE. Introduction to the choice of antiepileptic drugs.The Treatment of Epilepsy. ShorvonS. PeruccaE. EngelJ. Oxford, UKWiley-Blackwell200938739810.1002/9781444316667.ch30
    [Google Scholar]
  103. CharlierB. CoglianeseA. De RosaF. de GraziaU. OpertoF.F. CoppolaG. FilippelliA. Dal PiazF. IzzoV. The effect of plasma protein binding on the therapeutic monitoring of antiseizure medications.Pharmaceutics2021138120810.3390/pharmaceutics1308120834452168
    [Google Scholar]
  104. MarvanovaM. Pharmacokinetic characteristics of antiepileptic drugs (AEDs).Ment. Health Clin.20166182010.9740/mhc.2015.01.00829955442
    [Google Scholar]
  105. RobertiR. De CaroC. IannoneL.F. ZaccaraG. LattanziS. RussoE. Pharmacology of Cenobamate: Mechanism of action, pharmacokinetics, drug–drug interactions and tolerability.CNS Drugs202135660961810.1007/s40263‑021‑00819‑833993416
    [Google Scholar]
  106. BrodieM.J. MintzerS. PackA.M. GidalB.E. VechtC.J. SchmidtD. Enzyme induction with antiepileptic drugs: Cause for concern?Epilepsia2013541112710.1111/j.1528‑1167.2012.03671.x23016553
    [Google Scholar]
  107. ZaccaraG. PeruccaE. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.Epileptic Disord.201416440943110.1684/epd.2014.071425515681
    [Google Scholar]
  108. Abou-KhalilB.W. Update on antiseizure medications 2022.Continuum (Minneap. Minn.)202228250053510.1212/CON.000000000000110435393968
    [Google Scholar]
  109. HovingaC.A. Levetiracetam: A novel antiepileptic drug.Pharmacotherapy200121111375138810.1592/phco.21.17.1375.3443211714211
    [Google Scholar]
  110. BurakgaziE. FrenchJ.A. Treatment of epilepsy in adults.Epileptic Disord.201618322823910.1684/epd.2016.083627435035
    [Google Scholar]
  111. PengJ. FanM. AnC. NiF. HuangW. LuoJ. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD).Basic Clin. Pharmacol. Toxicol.2022130443945610.1111/bcpt.1371035083862
    [Google Scholar]
  112. MartinP. ReederT. SourbronJ. de WitteP.A.M. GammaitoniA.R. GalerB.S. An emerging role for sigma-1 receptors in the treatment of developmental and epileptic encephalopathies.Int. J. Mol. Sci.20212216841610.3390/ijms2216841634445144
    [Google Scholar]
  113. TomsonT. ZelanoJ. DangY.L. PeruccaP. The pharmacological treatment of epilepsy in adults.Epileptic Disord.202325564966910.1002/epd2.2009337386690
    [Google Scholar]
  114. LechugaL. FranzD.N. Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures.Expert Rev. Neurother.2019191091392510.1080/14737175.2019.163545731335226
    [Google Scholar]
  115. YasiryZ. ShorvonS.D. How phenobarbital revolutionized epilepsy therapy: The story of phenobarbital therapy in epilepsy in the last 100 years.Epilepsia201253Suppl. 8263910.1111/epi.1202623205960
    [Google Scholar]
  116. ThibaultC. MasseyS.L. AbendN.S. NaimM.Y. ZoraianA. ZuppaA.F. Population pharmacokinetics of phenobarbital in neonates and infants on extracorporeal membrane oxygenation and the influence of concomitant renal replacement therapy.J. Clin. Pharmacol.202161337838710.1002/jcph.174332960986
    [Google Scholar]
  117. HeL.Y. HuM.B. LiR.L. ZhaoR. FanL.H. HeL. LuF. YeX. HuangY. WuC.J. Natural medicines for the treatment of epilepsy: Bioactive Components, Pharmacology and mechanism.Front. Pharmacol.20211260404010.3389/fphar.2021.60404033746751
    [Google Scholar]
  118. AlqahtaniS. AlzaidiT. AlotaibiM. AlsultanA. Estimation of Phenytoin pharmacokinetic parameters in Saudi epileptic patients.Pharmacology20191041-2606610.1159/00050031431067540
    [Google Scholar]
  119. St LouisE.K. Minimizing AED adverse effects: Improving quality of life in the interictal state in epilepsy care.Curr. Neuropharmacol.20097210611410.2174/15701590978884885719949568
    [Google Scholar]
  120. CalcaterraN.E. BarrowJ.C. Classics in chemical neuroscience: Diazepam (valium).ACS Chem. Neurosci.20145425326010.1021/cn500005624552479
    [Google Scholar]
  121. GreenblattD.J. HarmatzJ.S. ZhangQ. ChenY. ShaderR.I. Slow accumulation and elimination of Diazepam and its active metabolite with extended treatment in the elderly.J. Clin. Pharmacol.202161219320310.1002/jcph.172632856316
    [Google Scholar]
  122. Tolou-GhamariZ. ZareM. HabibabadiJ.M. NajafiM.R. A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012.J. Res. Med. Sci.201318Suppl. 1S81S8523961295
    [Google Scholar]
  123. AndradeC. The practical importance of half-life in psychopharmacology.J. Clin. Psychiatry2022834222710.4088/JCP.22f1458435900254
    [Google Scholar]
  124. KeränenT. SiveniusJ. Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy.Acta Neurol. Scand.1983681698010.1111/j.1600‑0404.1983.tb01536.x6424398
    [Google Scholar]
  125. de PaulaN.C. Araujo CordeiroK.C.F. de Melo SouzaP.L. NogueiraD.F. da Silva e SousaD.B. CostaM.B. NoëlF. de OliveiraV. Biosynthesis of human Diazepam and Clonazepam metabolites.Bioorg. Med. Chem. Lett.20152551026102910.1016/j.bmcl.2015.01.02525655722
    [Google Scholar]
  126. Tolou-GhamariZ. PalizbanA.A. Review of Sodium valproate clinical and biochemical properties.Zahedan J. Res. Med. Sci.201517881310.17795/zjrms‑2207
    [Google Scholar]
  127. Cotterman-HartS. Antiepileptic drugs.Epilepsy and Brain Tumors.Elsevier201517119310.1016/B978‑0‑12‑417043‑8.00012‑2
    [Google Scholar]
  128. PeruccaE. BrodieM.J. KwanP. TomsonT. 30 years of second-generation antiseizure medications: Impact and future perspectives.Lancet Neurol.202019654455610.1016/S1474‑4422(20)30035‑132109411
    [Google Scholar]
  129. HanayaR. AritaK. The new antiepileptic drugs: Their neuropharmacology and clinical indications.Neurol. Med. Chir. (Tokyo)201656520522010.2176/nmc.ra.2015‑034426935782
    [Google Scholar]
  130. Schulze-BonhageA. Pharmacokinetic and pharmacodynamic profile of pregabalin and its role in the treatment of epilepsy.Expert Opin. Drug Metab. Toxicol.20139110511510.1517/17425255.2013.74923923205518
    [Google Scholar]
  131. LiJ. SunM. WangX. The adverse-effect profile of lacosamide.Expert Opin. Drug Saf.202019213113810.1080/14740338.2020.171308931914330
    [Google Scholar]
  132. PandaP.K. PandaP. DawmanL. SharawatI.K. Efficacy of lacosamide and phenytoin in status epilepticus: A systematic review.Acta Neurol. Scand.2021144436637410.1111/ane.1346933999428
    [Google Scholar]
  133. BitonV. Rufinamide.The Treatment of Epilepsy. ShorvonS. PeruccaE. EngelJ. Oxford, UKJohn Wiley & Sons, Ltd201561762710.1002/9781118936979.ch47
    [Google Scholar]
  134. BrunbechL. SabersA. Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: A comparative review of newer versus older agents.Drugs200262459360410.2165/00003495‑200262040‑0000411893228
    [Google Scholar]
  135. MahmoudS.H. RansC. Systematic review of Clobazam use in patients with status epilepticus.Epilepsia Open20183332333010.1002/epi4.1223030187002
    [Google Scholar]
  136. HuddartR. LeederJ.S. AltmanR.B. KleinT.E. PharmGKB summary.Pharmacogenet. Genomics201828411011510.1097/FPC.000000000000032729517622
    [Google Scholar]
  137. HarrisJ.A. MurphyJ.A. Retigabine (ezogabine) as add-on therapy for partial-onset seizures: An update for clinicians.Ther. Adv. Chronic Dis.20112637137610.1177/204062231142154223251762
    [Google Scholar]
  138. BaulacM. Retigabine.The Treatment of Epilepsy. ShorvonS. PeruccaE. EngelJ.Jr Wiley201560661610.1002/9781118936979.ch46
    [Google Scholar]
  139. PeruccaE. The pharmacological treatment of epilepsy: Recent advances and future perspectives.Acta Epileptol.2021312210.1186/s42494‑021‑00055‑z
    [Google Scholar]
  140. PackA.M. Brivaracetam, a novel antiepileptic drug: Is it effective and safe? Results from one phase iii randomized trial.Epilepsy Curr.201414419619810.5698/1535‑7597‑14.4.19625170316
    [Google Scholar]
  141. OverwaterI.E. RietmanA.B. van EeghenA.M. de WitM.C.Y. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives.Ther. Clin. Risk Manag.20191595195510.2147/TCRM.S14563031440057
    [Google Scholar]
  142. FranzD.N. LawsonJ.A. YapiciZ. IkedaH. PolsterT. NabboutR. CuratoloP. de VriesP.J. DlugosD.J. HerbstF. PeyrardS. PelovD. FrenchJ.A. Adjunctive everolimus therapy for tuberous sclerosis complex‐associated refractory seizures: Results from the postextension phase of EXIST‐3.Epilepsia202162123029304110.1111/epi.1709934693520
    [Google Scholar]
  143. ArenaC. BizzocaM. CaponioV. TroianoG. ZhurakivskaK. LeuciS. Lo MuzioL. Everolimus therapy and side‑effects: A systematic review and meta‑analysis.Int. J. Oncol.20215915410.3892/ijo.2021.523434132370
    [Google Scholar]
  144. AncionesC. Gil-NagelA. Adverse effects of cannabinoids.Epileptic Disord.202022S1293210.1684/epd.2019.112531941644
    [Google Scholar]
  145. LatimerD.R. EdinoffA.N. RuffR.D. RooneyK.C. PennyK.M. PatelS.B. SabbenahalliS. KayeA.M. CornettE.M. ViswanathO. UritsI. KayeA.D. Cenobamate, a Sodium channel inhibitor and positive allosteric modulator of GABAA Ion channels, for partial onset seizures in adults: A comprehensive review and clinical implications.Neurol. Int.202113225226510.3390/neurolint1302002634207493
    [Google Scholar]
  146. SchmitzB. LattanziS. VonckK. KälviäinenR. NashefL. Ben-MenachemE. Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations.Epilepsia Open2023841241125510.1002/epi4.1283037743544
    [Google Scholar]
  147. GogouM. CrossJ.H. Fenfluramine as antiseizure medication for epilepsy.Dev. Med. Child Neurol.202163889990710.1111/dmcn.1482233565102
    [Google Scholar]
  148. SamantaD. Fenfluramine: A review of pharmacology, clinical efficacy, and safety in epilepsy.Children202298115910.3390/children908115936010049
    [Google Scholar]
  149. YawnoT. MillerS.L. BennetL. WongF. HirstJ.J. FaheyM. WalkerD.W. Ganaxolone: A new treatment for neonatal seizures.Front. Cell. Neurosci.20171124610.3389/fncel.2017.0024628878622
    [Google Scholar]
  150. DeS.K. Ganaxolone: First FDA-approved medicine for the treatment of seizures associated with cyclin-dependent Kinase-like 5 deficiency disorder.Curr. Med. Chem.202431438839210.2174/092986733066623032012395236959132
    [Google Scholar]
  151. KimK.T. KimD.W. YangK.I. LeeS.T. ByunJ.I. SeoJ.G. NoY.J. KangK.W. KimD. ChoY.W. Drug Committee of Korean Epilepsy Society Refining general principles of antiepileptic drug treatments for epilepsy.J. Clin. Neurol.202016338338910.3988/jcn.2020.16.3.38332657058
    [Google Scholar]
  152. VerrottiA. TambucciR. Di FrancescoL. PavoneP. IapadreG. AltobelliE. MatricardiS. FarelloG. BelcastroV. The role of polytherapy in the management of epilepsy: Suggestions for rational antiepileptic drug selection.Expert Rev. Neurother.202020216717310.1080/14737175.2020.170766831855066
    [Google Scholar]
  153. BrigoF. AussererH. TezzonF. NardoneR. When one plus one makes three: The quest for rational antiepileptic polytherapy with supraadditive anticonvulsant efficacy.Epilepsy Behav.201327343944210.1016/j.yebeh.2013.03.01023591263
    [Google Scholar]
  154. GlauserT.A. CnaanA. ShinnarS. HirtzD.G. DlugosD. MasurD. ClarkP.O. CapparelliE.V. AdamsonP.C. Childhood Absence Epilepsy Study Group Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy.N. Engl. J. Med.2010362979079910.1056/NEJMoa090201420200383
    [Google Scholar]
  155. RoksG. DeckersC.L.P. MeinardiH. DirksenR. van EgmondJ. van RijnC.M. Effects of polytherapy compared with monotherapy in antiepileptic drugs: An animal study.J. Pharmacol. Exp. Ther.199928824724779918547
    [Google Scholar]
  156. St LouisE.K. Truly “rational” polytherapy: Maximizing efficacy and minimizing drug interactions, drug load, and adverse effects.Curr. Neuropharmacol.2009729610510.2174/15701590978884892919949567
    [Google Scholar]
  157. SarhanE.M. WalkerM.C. SelaiC. Evidence for efficacy of combination of antiepileptic drugs in treatment of epilepsy.J. Neurol. Res.20155626727610.14740/jnr356w
    [Google Scholar]
  158. MattsonR.H. CramerJ.A. CollinsJ.F. SmithD.B. Delgado-EscuetaA.V. BrowneT.R. WilliamsonP.D. TreimanD.M. McNamaraJ.O. McCutchenC.B. HomanR.W. CrillW.E. LubozynskiM.F. RosenthalN.P. MayersdorfA. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.N. Engl. J. Med.1985313314515110.1056/NEJM1985071831303033925335
    [Google Scholar]
  159. LuszczkiJ.J. MazurkiewiczL.P. Wroblewska-LuczkaP. WlazA. OssowskaG. SzpringerM. ZolkowskaD. Florek-LuszczkiM. Combination of phenobarbital with phenytoin and pregabalin produces synergy in the mouse tonic-clonic seizure model: An isobolographic analysis.Epilepsy Res.201814511612210.1016/j.eplepsyres.2018.06.00329940514
    [Google Scholar]
  160. BrodieM.J. SillsG.J. Combining antiepileptic drugs—Rational polytherapy?Seizure201120536937510.1016/j.seizure.2011.01.00421306922
    [Google Scholar]
  161. LuszczkiJ.J. CzuczwarS.J. Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy.Prog. Neuropsychopharmacol. Biol. Psychiatry200731252953810.1016/j.pnpbp.2006.11.02017204358
    [Google Scholar]
  162. HardenC.L. ZisfeinJ. Atos-RadzionE.C. TuchmanA.J. Combination valproate—carbamazepine therapy in partial epilepsies resistant to carbamazepine monotherapy.J. Epilepsy199362919410.1016/S0896‑6974(05)80094‑5
    [Google Scholar]
  163. WalkerJ. Carbamazepine versus Valproate versus combined therapy for refractory partial complex seizures with secondary generalization.Epilepsia198829693
    [Google Scholar]
  164. DeanJ.C. PenryJ.K. Carbamazepine/Valproate therapy in 100 patients with partial seizure failing Carbamazepine monotherapy: Long-term follow-up.Epilepsia198829687
    [Google Scholar]
  165. SunM.Z. DeckersC.L.P. LiuY.X. WangW. Comparison of add-on valproate and primidone in carbamazepine-unresponsive patients with partial epilepsy.Seizure2009182909310.1016/j.seizure.2008.06.00918672385
    [Google Scholar]
  166. DeckersC.L.P. HeksterY.A. KeyserA. Van LierH.J.J. MeinardiH. RenierW.O. Monotherapy versus polytherapy for epilepsy: A multicenter double-blind randomized study.Epilepsia200142111387139410.1046/j.1528‑1157.2001.30800.x11879339
    [Google Scholar]
  167. NicolsonA. AppletonR.E. ChadwickD.W. SmithD.F. The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies.J. Neurol. Neurosurg. Psychiatry2004751757914707312
    [Google Scholar]
  168. BrodieM.J. YuenA.W.C. Lamotrigine substitution study: Evidence for synergism with sodium valproate?Epilepsy Res.199726342343210.1016/S0920‑1211(96)01007‑89127723
    [Google Scholar]
  169. MoellerJ.J. RaheyS.R. SadlerR.M. Lamotrigine–valproic acid combination therapy for medically refractory epilepsy.Epilepsia200950347547910.1111/j.1528‑1167.2008.01866.x19054403
    [Google Scholar]
  170. PeruccaE. Clinically relevant drug interactions with antiepileptic drugs.Br. J. Clin. Pharmacol.200661324625510.1111/j.1365‑2125.2005.02529.x16487217
    [Google Scholar]
  171. FowlerT. BansalA.S. LozsádiD. Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting.Seizure201972617010.1016/j.seizure.2019.07.00331708349
    [Google Scholar]
  172. BesagF.M.C. VaseyM.J. SharmaA.N. LamI.C.H. Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: A systematic review.Ther. Adv. Psychopharmacol.20211162045125321104587010.1177/2045125321104587034646439
    [Google Scholar]
  173. BrodieM.J. BarryS.J.E. BamagousG.A. NorrieJ.D. KwanP. Patterns of treatment response in newly diagnosed epilepsy.Neurology201278201548155410.1212/WNL.0b013e3182563b1922573629
    [Google Scholar]
  174. PeruccaP. BahloM. BerkovicS.F. The genetics of epilepsy.Annu. Rev. Genomics Hum. Genet.202021120523010.1146/annurev‑genom‑120219‑07493732339036
    [Google Scholar]
  175. ChenZ. BrodieM.J. LiewD. KwanP. Treatment Outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs.JAMA Neurol.201875327928610.1001/jamaneurol.2017.394929279892
    [Google Scholar]
  176. KannerA.M. AshmanE. GlossD. HardenC. BourgeoisB. BautistaJ.F. Abou-KhalilB. Burakgazi-DalkilicE. Llanas ParkE. SternJ. HirtzD. NespecaM. GidalB. FaughtE. FrenchJ. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy.Neurology2018912829010.1212/WNL.000000000000575629898974
    [Google Scholar]
  177. MargolisJ.M. ChuB.C. WangZ.J. CopherR. CavazosJ.E. Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action.JAMA Neurol.201471898599310.1001/jamaneurol.2014.80824911669
    [Google Scholar]
  178. FriedmanD. FrenchJ.A. MaccarroneM. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders.Lancet Neurol.201918550451210.1016/S1474‑4422(19)30032‑830910443
    [Google Scholar]
  179. RosenbergE.C. TsienR.W. WhalleyB.J. DevinskyO. Cannabinoids and epilepsy.Neurotherapeutics201512474776810.1007/s13311‑015‑0375‑526282273
    [Google Scholar]
  180. BalachandranP. ElsohlyM. HillK.P. Cannabidiol interactions with medications, Illicit substances, and alcohol: A comprehensive review.J. Gen. Intern. Med.20213672074208410.1007/s11606‑020‑06504‑833515191
    [Google Scholar]
  181. AndersonL.L. AbsalomN.L. AbelevS.V. LowI.K. DoohanP.T. MartinL.J. ChebibM. McGregorI.S. ArnoldJ.C. Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.Epilepsia201960112224223410.1111/epi.1635531625159
    [Google Scholar]
  182. LöscherW. SillsG.J. WhiteH.S. The ups and downs of alkyl‐carbamates in epilepsy therapy: How does cenobamate differ?Epilepsia202162359661410.1111/epi.1683233580520
    [Google Scholar]
  183. WhelessJ.W. Adjunctive cenobamate for the treatment of focal onset seizures in adults with epilepsy: A critical review.Expert Rev. Neurother.202020111085109810.1080/14737175.2020.183485533031714
    [Google Scholar]
  184. OdiR. InvernizziR.W. GallilyT. BialerM. PeruccaE. Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know.Pharmacol. Ther.202122610786610.1016/j.pharmthera.2021.10786633895186
    [Google Scholar]
  185. MartinP. CzerwińskiM. LimayeP.B. MuranjanS. OgilvieB.W. SmithS. BoydB. In vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions.Pharmacol. Res. Perspect.2022103e0095810.1002/prp2.95835599345
    [Google Scholar]
  186. BialerM. JohannessenS.I. KoeppM.J. LevyR.H. PeruccaE. PeruccaP. TomsonT. WhiteH.S. Drugs in More Advanced Clinical Development Progress report on new antiepileptic drugs: A summary of the sixteenth eilat conference on new antiepileptic drugs and devices ( EILAT XVI ): II. Drugs in more advanced clinical development.Epilepsia202263112883291010.1111/epi.1737635950617
    [Google Scholar]
  187. LambY.N. Ganaxolone: First approval.Drugs202282893394010.1007/s40265‑022‑01724‑035596878
    [Google Scholar]
  188. AronsonJ.K. FernerR.E. Clarification of terminology in drug safety.Drug Saf.2005281085187010.2165/00002018‑200528100‑0000316180936
    [Google Scholar]
  189. GaitatzisA. SanderJ.W. The long-term safety of antiepileptic drugs.CNS Drugs201327643545510.1007/s40263‑013‑0063‑023673774
    [Google Scholar]
  190. PeruccaP. GilliamF.G. Adverse effects of antiepileptic drugs.Lancet Neurol.201211979280210.1016/S1474‑4422(12)70153‑922832500
    [Google Scholar]
  191. KennedyG.M. LhatooS.D. CNS adverse events associated with antiepileptic drugs.CNS Drugs200822973976010.2165/00023210‑200822090‑0000318698874
    [Google Scholar]
  192. TsujiA. TamaiI. Carrier-mediated or specialized transport of drugs across the blood–brain barrier.Adv. Drug Deliv. Rev.1999362-327729010.1016/S0169‑409X(98)00084‑210837720
    [Google Scholar]
  193. GaoZ. ChenY. CaiX. XuR. Predict drug permeability to blood–brain-barrier from clinical phenotypes: Drug side effects and drug indications.Bioinformatics201733690190810.1093/bioinformatics/btw71327993785
    [Google Scholar]
  194. UpadhyayR.K. Drug delivery systems, CNS protection, and the blood brain barrier.BioMed Res. Int.2014201413710.1155/2014/86926925136634
    [Google Scholar]
  195. ShaL. YongX. ShaoZ. DuanY. HongQ. ZhangJ. ZhangY. ChenL. Targeting adverse effects of antiseizure medication on offspring: Current evidence and new strategies for safety.Expert Rev. Neurother.202323214115610.1080/14737175.2023.217675136731825
    [Google Scholar]
  196. ThakkarK. BillaG. RaneJ. ChudasamaH. GoswamiS. ShahR. The rise and fall of felbamate as a treatment for partial epilepsy – aplastic anemia and hepatic failure to blame?Expert Rev. Neurother.201515121373137510.1586/14737175.2015.111387426566191
    [Google Scholar]
  197. LonjouC. ThomasL. BorotN. LedgerN. de TomaC. LeLouetH. GrafE. SchumacherM. HovnanianA. MockenhauptM. RoujeauJ-C. RegiSCAR Group A marker for Stevens-Johnson syndrome: Ethnicity matters.Pharmacogenomics J.20066426526810.1038/sj.tpj.650035616415921
    [Google Scholar]
  198. KwanP. ArzimanoglouA. BergA.T. BrodieM.J. Allen HauserW. MathernG. MoshéS.L. PeruccaE. WiebeS. FrenchJ. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies.Epilepsia20105161069107710.1111/j.1528‑1167.2009.02397.x19889013
    [Google Scholar]
  199. LaxerK.D. TrinkaE. HirschL.J. CendesF. LangfittJ. DelantyN. ResnickT. BenbadisS.R. The consequences of refractory epilepsy and its treatment.Epilepsy Behav.201437597010.1016/j.yebeh.2014.05.03124980390
    [Google Scholar]
  200. TangF. HartzA.M.S. BauerB. Drug-resistant epilepsy: Multiple hypotheses, few answers.Front. Neurol.2017830110.3389/fneur.2017.0030128729850
    [Google Scholar]
  201. LöscherW. PotschkaH. Drug resistance in brain diseases and the role of drug efflux transporters.Nat. Rev. Neurosci.20056859160210.1038/nrn172816025095
    [Google Scholar]
  202. FangM. XiZ.Q. WuY. WangX.F. A new hypothesis of drug refractory epilepsy: Neural network hypothesis.Med. Hypotheses201176687187610.1016/j.mehy.2011.02.03921429675
    [Google Scholar]
  203. RogawskiM.A. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs.Epilepsia201354Suppl. 2334010.1111/epi.1218223646969
    [Google Scholar]
  204. LöscherW. PotschkaH. SisodiyaS.M. VezzaniA. Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options.Pharmacol. Rev.202072360663810.1124/pr.120.01953932540959
    [Google Scholar]
  205. RemyS. BeckH. Molecular and cellular mechanisms of pharmacoresistance in epilepsy.Brain20061291183510.1093/brain/awh68216317026
    [Google Scholar]
  206. SchmidtD. LöscherW. New developments in antiepileptic drug resistance: An integrative view.Epilepsy Curr.200992475210.1111/j.1535‑7511.2008.01289.x19421380
    [Google Scholar]
  207. Pérez-PérezD. Frías-SoriaC. L. RochaL. Drug-resistant epilepsy: From multiple hypotheses to an integral explanation using preclinical resourcesEpilepsy Behav202112110643010.1016/j.yebeh.2019.07.031
    [Google Scholar]
  208. AbbottN.J. PatabendigeA.A.K. DolmanD.E.M. YusofS.R. BegleyD.J. Structure and function of the blood–brain barrier.Neurobiol. Dis.2010371132510.1016/j.nbd.2009.07.03019664713
    [Google Scholar]
  209. KeaneyJ. CampbellM. The dynamic blood–brain barrier.FEBS J.2015282214067407910.1111/febs.1341226277326
    [Google Scholar]
  210. EricksonM.A. BanksW.A. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer’s disease.J. Cereb. Blood Flow Metab.201333101500151310.1038/jcbfm.2013.13523921899
    [Google Scholar]
  211. LiuJ.Y.W. ThomM. CatarinoC.B. MartinianL. Figarella-BrangerD. BartolomeiF. KoeppM. SisodiyaS.M. Neuropathology of the blood–brain barrier and pharmaco-resistance in human epilepsy.Brain2012135103115313310.1093/brain/aws14722750659
    [Google Scholar]
  212. WeissN. MillerF. CazaubonS. CouraudP.O. The blood-brain barrier in brain homeostasis and neurological diseases.Biochim. Biophys. Acta Biomembr.20091788484285710.1016/j.bbamem.2008.10.02219061857
    [Google Scholar]
  213. SalarS. MaslarovaA. LippmannK. NichtweissJ. WeissbergI. SheintuchL. KunzW.S. ShorerZ. FriedmanA. HeinemannU. Blood–brain barrier dysfunction can contribute to pharmacoresistance of seizures.Epilepsia20145581255126310.1111/epi.1271324995798
    [Google Scholar]
  214. van VlietE.A. AronicaE. GorterJ.A. Role of blood–brain barrier in temporal lobe epilepsy and pharmacoresistance.Neuroscience201427745547310.1016/j.neuroscience.2014.07.03025080160
    [Google Scholar]
  215. MarchiN. BettoG. FazioV. FanQ. GhoshC. MachadoA. JanigroD. Blood–brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edema.Epilepsia200950466467710.1111/j.1528‑1167.2008.01989.x19175391
    [Google Scholar]
  216. de BiaseS. NiloA. BernardiniA. GigliG.L. ValenteM. MerlinoG. Timing use of novel anti-epileptic drugs: Is earlier better?Expert Rev. Neurother.2019191094595410.1080/14737175.2019.163664931257949
    [Google Scholar]
  217. PitkänenA. EngelJ.Jr Past and present definitions of epileptogenesis and its biomarkers.Neurotherapeutics201411223124110.1007/s13311‑014‑0257‑224492975
    [Google Scholar]
  218. PitkänenA. LukasiukK. Mechanisms of epileptogenesis and potential treatment targets.Lancet Neurol.201110217318610.1016/S1474‑4422(10)70310‑021256455
    [Google Scholar]
  219. PitkänenA. LukasiukK. DudekF.E. StaleyK.J. Epileptogenesis.Cold Spring Harb. Perspect. Med.2015510a02282210.1101/cshperspect.a02282226385090
    [Google Scholar]
  220. RakhadeS.N. JensenF.E. Epileptogenesis in the immature brain: Emerging mechanisms.Nat. Rev. Neurol.20095738039110.1038/nrneurol.2009.8019578345
    [Google Scholar]
  221. KnottS. FortyL. CraddockN. ThomasR.H. Epilepsy and bipolar disorder.Epilepsy Behav.201552Pt A26727410.1016/j.yebeh.2015.07.00326316422
    [Google Scholar]
  222. MoaveroR. BombardieriR. MarcianoS. CerminaraC. CuratoloP. Epilepsy in tuberous sclerosis complex.J. Pediatr. Epilepsy20155206406910.1055/s‑0035‑1570070
    [Google Scholar]
  223. VignoliA. La BriolaF. PeronA. TurnerK. VannicolaC. SaccaniM. MagnaghiE. ScornavaccaG.F. CaneviniM.P. Autism spectrum disorder in tuberous sclerosis complex: Searching for risk markers.Orphanet J. Rare Dis.201510115410.1186/s13023‑015‑0371‑126631248
    [Google Scholar]
  224. SpecchioN. PietrafusaN. TrivisanoM. MoaveroR. De PalmaL. FerrettiA. VigevanoF. CuratoloP. Autism and epilepsy in patients with tuberous sclerosis complex.Front. Neurol.20201163910.3389/fneur.2020.0063932849171
    [Google Scholar]
  225. CramerJ.A. MintzerS. WhelessJ. MattsonR.H. Adverse effects of antiepileptic drugs: A brief overview of important issues.Expert Rev. Neurother.201010688589110.1586/ern.10.7120518605
    [Google Scholar]
  226. BeghiE. Efficacy and tolerability of the new antiepileptic drugs: Comparison of two recent guidelines.Lancet Neurol.200431061862110.1016/S1474‑4422(04)00882‑815380158
    [Google Scholar]
  227. PeruccaE. FrenchJ. BialerM. Development of new antiepileptic drugs: Challenges, incentives, and recent advances.Lancet Neurol.20076979380410.1016/S1474‑4422(07)70215‑617706563
    [Google Scholar]
  228. BialerM. JohannessenS.I. LevyR.H. PeruccaE. TomsonT. WhiteH.S. Progress report on new antiepileptic drugs: A summary of the twelfth eilat conference (EILAT XII).Epilepsy Res.20151118514110.1016/j.eplepsyres.2015.01.001
    [Google Scholar]
  229. BialerM. JohannessenS.I. LevyR.H. PeruccaE. TomsonT. WhiteH.S. Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on new antiepileptic drugs and devices ( EILAT XIII ).Epilepsia201758218122110.1111/epi.1363428111749
    [Google Scholar]
  230. BialerM. JohannessenS.I. KoeppM.J. LevyR.H. PeruccaE. PeruccaP. TomsonT. WhiteH.S. Drugs in More Advanced Clinical Development Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New antiepileptic drugs and devices (EILAT XV). II. Drugs in more advanced clinical development.Epilepsia202061112365238510.1111/epi.1672633165915
    [Google Scholar]
  231. BialerM. PeruccaE. Lorcaserin for dravet syndrome: A potential advance over Fenfluramine?CNS Drugs202236211312210.1007/s40263‑022‑00896‑335094259
    [Google Scholar]
  232. NishiT. MetcalfC.S. FujimotoS. HasegawaS. MiyamotoM. SunaharaE. WatanabeS. KondoS. WhiteH.S. Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor.Epilepsia20226361580159010.1111/epi.1723235316533
    [Google Scholar]
  233. ElkommosS. MulaM. Current and future pharmacotherapy options for drug-resistant epilepsy.Expert Opin. Pharmacother.202223182023203410.1080/14656566.2022.212867036154780
    [Google Scholar]
  234. PeruccaE. WhiteH.S. BialerM. Treatments in Clinical Development New GABA-targeting therapies for the treatment of seizures and epilepsy: II.CNS Drugs202337978179510.1007/s40263‑023‑01025‑437603261
    [Google Scholar]
  235. PongA.W. RossJ. TyrlikovaI. GiermekA.J. KohliM.P. KhanY.A. SalgadoR.D. KleinP. Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials.Expert Opin. Emerg. Drugs2022271759010.1080/14728214.2022.205946435341431
    [Google Scholar]
  236. BialerM. Chemical properties of antiepileptic drugs (AEDs).Adv. Drug Deliv. Rev.2012641088789510.1016/j.addr.2011.11.00622210279
    [Google Scholar]
  237. BialerM. Why are antiepileptic drugs used for nonepileptic conditions?Epilepsia201253Suppl. 7263310.1111/j.1528‑1167.2012.03712.x23153207
    [Google Scholar]
  238. LandmarkC.J. JohannessenS.I. Modifications of antiepileptic drugs for improved tolerability and efficacy.Perspect. Medicin. Chem.200821177391X080020010.1177/1177391X080020000119787095
    [Google Scholar]
  239. SobolE. BialerM. YagenB. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives.J. Med. Chem.200447174316432610.1021/jm049835115294003
    [Google Scholar]
  240. DelageC. PalayerM. EtainB. HagenimanaM. BlaiseN. SmatiJ. ChouchanaM. BlochV. BessonV.C. Valproate, divalproex, valpromide: Are the differences in indications justified?Biomed. Pharmacother.202315811405110.1016/j.biopha.2022.11405136521249
    [Google Scholar]
  241. YangM.T. LinY.C. HoW.H. LiuC.L. LeeW.T. Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures.J. Neuroinflammation20171411510.1186/s12974‑017‑0797‑628109197
    [Google Scholar]
  242. LiM. ZhouY. ChenC. YangT. ZhouS. ChenS. WuY. CuiY. Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis.Orphanet J. Rare Dis.20191413910.1186/s13023‑019‑1012‑x30760308
    [Google Scholar]
  243. DeebT.Z. MaguireJ. MossS.J. Possible alterations in GABA A receptor signaling that underlie benzodiazepine‐resistant seizures.Epilepsia201253Suppl. 9798810.1111/epi.1203723216581
    [Google Scholar]
  244. HeissJ.D. ArgersingerD.P. TheodoreW.H. ButmanJ.A. SatoS. KhanO.I. Convection-enhanced delivery of Muscimol in patients with drug-resistant epilepsy.Neurosurgery2019851E4E1510.1093/neuros/nyy48030407567
    [Google Scholar]
  245. JankovićS.M. DješevićM. JankovićS.V. Experimental GABA a receptor agonists and allosteric modulators for the treatment of focal epilepsy.J. Exp. Pharmacol.20211323524410.2147/JEP.S24296433727865
    [Google Scholar]
  246. CoppolaM. MondolaR. OlivaF. Luigi PicciR. Areca alkaloids and schizophrenia.Neuropathology of Drug Addictions and Substance Misuse.Elsevier2016Vol. 379480210.1016/B978‑0‑12‑800634‑4.00079‑2
    [Google Scholar]
  247. IsaevD. IsaevaE. KhazipovR. HolmesG.L. Anticonvulsant action of GABA in the high potassium-low magnesium model of ictogenesis in the neonatal rat hippocampus in vivo and in vitro. J. Neurophysiol.20059442987299210.1152/jn.00138.200516000527
    [Google Scholar]
  248. SalazarP. TapiaR. Seizures induced by intracerebral administration of pyridoxal-5′-phosphate: effect of GABAergic drugs and glutamate receptor antagonists.Neuropharmacology200141554655310.1016/S0028‑3908(01)00110‑111587709
    [Google Scholar]
  249. WahabA. HeinemannU. AlbusK. Effects of γ-aminobutyric acid (GABA) agonists and a GABA uptake inhibitor on pharmacoresistant seizure like events in organotypic hippocampal slice cultures.Epilepsy Res.2009862-311312310.1016/j.eplepsyres.2009.05.00819535226
    [Google Scholar]
  250. OreficeL.L. MoskoJ.R. MorencyD.T. WellsM.F. TasnimA. MozeikaS.M. YeM. ChirilaA.M. EmanuelA.J. RankinG. FameR.M. LehtinenM.K. FengG. GintyD.D. Targeting peripheral somatosensory neurons to improve tactile-related phenotypes in ASD models.Cell20191784867886.e2410.1016/j.cell.2019.07.02431398341
    [Google Scholar]
  251. WanatK. Biological barriers, and the influence of protein binding on the passage of drugs across them.Mol. Biol. Rep.20204743221323110.1007/s11033‑020‑05361‑232140957
    [Google Scholar]
/content/journals/cn/10.2174/011570159X323666241029171256
Loading
/content/journals/cn/10.2174/011570159X323666241029171256
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test