Advertisement

Novel Molecular Targets for Drug-Treatment of Epilepsy

  • Vincenzo BelcastroEmail author
  • Alberto Verrotti
Chapter
Part of the Contemporary Clinical Neuroscience book series (CCNE)

Abstract

Nowadays several antiepileptic drugs (AEDs) are available for the treatment of patients with epilepsy. Nevertheless, up to 30 % of patients continue to present recurrent seizures. So, the challenge for new more efficacious and better tolerated drugs is continuing. Advances in understanding of pathophysiology of epilepsy and in the physiology of ion channels and other molecular targets provide opportunities to create new and improved AEDs. Potentially interesting molecular targets include KCNQ-type K+ channels, SV2A synaptic vesicle protein, ionotropic and metabotropic glutamate receptors. The pipeline for the development of new AEDs with novel mechanisms of action is narrowing with only a few interesting compounds on the immediate horizon. In fact, only perampanel (modulates AMPA mediated neurotransmission) and brivaracetam (binds to SV2A protein and sodium channel) are likely to reach the market-place in the next 3 years. Eslicarbazepine has approved in the last year as add-on treatment for partial onset seizures.

This chapter reviews the available information on various classes of molecules that are in the pipeline for the treatment of epilepsy.

Keywords

Antiepileptic drugs Epilepsy treatment KCNQ-type K+ channels SV2A synaptic vesicle protein Ionotropic Metabotropic glutamate receptors 

References

  1. Almeida L, Soares da Silva P (2007) Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics 4:88–96PubMedCrossRefGoogle Scholar
  2. Almeida L, Minciu I, Nunes T, Falcão A, Magureanu SA, Soares-da-Silva P (2008) Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescent with epilepsy. J Clin Pharmacol 48:966–977PubMedCrossRefGoogle Scholar
  3. Almeida L, Bialer M, Soares da Silva P (2009) Eslicarbazepine acetate. In: Shorvon S, Perucca E, Engel J (eds) The treatment of Epilepsy, 3rd edn. Blackwell, Oxford, pp 485–498CrossRefGoogle Scholar
  4. Ambrosio AF, Silva AP, Araujo I, Malva JO, Soares-da-Silva P, Carvalho AP et al (2000) Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and two new putative antiepileptic drugs, BIA 2-093 and BIA 2-024. Eur J Pharmacol 406:191–201PubMedCrossRefGoogle Scholar
  5. Ambrosio AF, Silva AP, Malva JO, Soares-da-Silva P, Carvalho AP, Carvalho CM (2001) Inhibition of glutamate release by BIA 2-093 and BIA 2-024, two novel derivates of carbazepine, due to blockade of sodium but not calcium channel. Biochem Pharmacol 61:1271–1275PubMedCrossRefGoogle Scholar
  6. Benes J, Parada A, Figueiredo AA, Alves PC, Freitas AP, Learmonth DA et al (1999) Anticonvulsivant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz(b,f)azepine-5-carboxamide derivative. J Med Chem 42:2582–2587PubMedCrossRefGoogle Scholar
  7. Ben-Menachem E, Gabbai AA, Hufnagel A, Maia J, Almeida L, Soares-da-Silva P (2010) Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilesy Res 89:278–285CrossRefGoogle Scholar
  8. Bennett B, Matagne A, Michel P, Leonard M, Cornet M, Meeus MA et al (2007) Seletracetam (UCB 44212). Neurother 4(1):117–122CrossRefGoogle Scholar
  9. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS (2013) Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res 103(1):2–30PubMedCrossRefGoogle Scholar
  10. Binnie CD, Kasteleijn-Nolst Trenité DGA, De Korte RA (1986) Photosensitivity as a model for acute antiepileptic drug studies. Electroencephalogr Clin Neurophysiol 63:35–41PubMedCrossRefGoogle Scholar
  11. Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S (2014) Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia 55(1):57–66PubMedCrossRefGoogle Scholar
  12. Brodie MJ (2010) Antiepileptic drug therapy the story so far. Seizure 19(10):650–655PubMedCrossRefGoogle Scholar
  13. Brown ME, El-Mallakh RS (2010) Role of eslicarbazepine in the treatment of epilepsy in adult patients with partial-onset seizures. Ther Clin Risk Manag 6:103–109PubMedCentralPubMedGoogle Scholar
  14. Cunha RA, Coelho JE, Costenla AR, Lopes LV, Parada A, de Mendonça A et al (2002) Effects of carbazepine and novel 10,11-dihidro-5H-dibenz(b,f)azepine-5-carboxamide derivatives on synaptic transmission in rat hippocampal slices. Pharmacol Toxicol 90:208–213PubMedCrossRefGoogle Scholar
  15. Di Prospero NA, Gambale JJ, Pandina G, Ford L, Girgis S, Moyer JA et al (2014) Evaluation of JNJ-26489112 in patients with photosensitive epilepsy: A placebo-controlled, exploratory study. Epilepsy Res 108(4):709–716PubMedCrossRefGoogle Scholar
  16. Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-Silva P (2007) Eslicarbazepine acetate: a double blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 48:497–504PubMedCrossRefGoogle Scholar
  17. Elger C, Halasz P, Maia J, Almeida L Soares-da-Silva P (2009) BIA-2093–301 Investigators Study Group. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase 3 study. Epilepsia 50:454–463PubMedCrossRefGoogle Scholar
  18. Falcao A, Pinto R, Nunes T, Soares-da-Silva P (2013a) Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects. Epilepsy Res 106(1–2):244–249CrossRefGoogle Scholar
  19. Falcao A, Vaz-da-Silva M, Gama H, Nunes T, Almeida L, Soares-da-Silva P (2013b) Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healty women. Epilepsy Res 105:368–376CrossRefGoogle Scholar
  20. Faught E, Holmes GL, Rosenfeld WE, Novak G, Neto W, Greenspan A et al (2008) Randomized, controlled, dose ranging trial of carisbamate for partial-onset seizures. Neurology 71:1586–1593PubMedCrossRefGoogle Scholar
  21. Franco V, Crema F, Iudice A, Zaccara G, Grillo E (2013) Novel treatment options for epilepsy: focus on perampanel. Pharmacol Res 70(1):35–40PubMedCrossRefGoogle Scholar
  22. Francois J, Ferrandon A, Koning E, Nehlig A (2005) A new drug RWJ 333369 protects limbic areas in the lithium-pilocarpine model of epilepsy and delays or prevents the occurrence of spontaneous seizures. Epilepsia 46(Suppl 8):269–270Google Scholar
  23. French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A et al (2012) Adjunctive Perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 79:589–596PubMedCentralPubMedCrossRefGoogle Scholar
  24. French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D et al (2013) Evalutation of adjunctive Perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 54:117–125PubMedCrossRefGoogle Scholar
  25. Gillard M, Fuks B, Leclercq K, Matagne A (2011) Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol 664(1–3):36–44PubMedCrossRefGoogle Scholar
  26. Gil-Nagel A, Lopes-Lima J, Almeida L, Maia J Soares-da-Silva P (2009) BIA-2093–303 Investigators Study Group. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand 120:281–287PubMedCrossRefGoogle Scholar
  27. Gil-Nagel A, Elger C, Ben-Menachem E, Halász P, Lopes-Lima J, Gabbai AA et al (2013) Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia 54:98–107PubMedCrossRefGoogle Scholar
  28. Gormsen L, Finnerup NB, Almqvist PM, Jensen TS (2009) The efficacy of the AMPA receptor antagonist NS1209 and lidocaine in nerve injury pain: a randomized, double-blind, placebo-controlled, three-way crossover study. Anesth Analg 108(4):1311–1319PubMedCrossRefGoogle Scholar
  29. Halasz P, Cramer JA, Hodoba D, Członkowska A, Guekht A, Maia J et al (2010) Long term efficacy of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy. Epilepsia 51:1963–1969PubMedCrossRefGoogle Scholar
  30. Hufnagel A, Ben-Menachem E, Gabbai AA, Falcão A, Almeida L, Soares-da-Silva P (2013) Long-term safety and efficacy of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy: results of a 1-year open-label extension study. Epilepsy Res 103:262–269PubMedCrossRefGoogle Scholar
  31. Kaminski RM, Matagne A, Leclercq K, Gillard M, Michel P, Kenda B et al (2008) SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 54(4):715–720PubMedCrossRefGoogle Scholar
  32. Kasteleijn-Nolst Trenité D Rubboli G, Hirsch E, Martins da Silva A, Seri S, Wilkins A et al (2012) Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory. Epilepsia 53:16–24PubMedCrossRefGoogle Scholar
  33. Kasteleijn-Nolst Trenité DG, Biton V, French JA, Abou-Khalil B, Rosenfeld WE, Diventura B et al (2013) Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy. Epilepsia 54(8):1437–1443PubMedCentralPubMedCrossRefGoogle Scholar
  34. Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J et al (2012a) Randomized phase 3 study 306: adjunctive Perampanel for refractory partial-onset seizures. Neurology 78:1408–1415CrossRefGoogle Scholar
  35. Krauss GL, Bar M, Biton V, Klapper JA, Rektor I, Vaiciene-Magistris N et al (2012b) Tolerability and safety of Perampanel: two randomized dose-escalation studies. Acta Neurol Scand 125:8–15CrossRefGoogle Scholar
  36. Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S (2014) Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 55(1):38–46PubMedCrossRefGoogle Scholar
  37. Löscher W, Klitgaard H, Twyman RE, Schmidt D (2013) New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 12(10):757–756PubMedCrossRefGoogle Scholar
  38. Margineanu DG, Klitgaard H (2009) Brivaracetam inhibits spreading depression in rat neocortical slices in vitro. Seizure 18(6):453–456PubMedCrossRefGoogle Scholar
  39. Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H (2008) Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br J Pharmacol 154(8):1662–1671PubMedCentralPubMedCrossRefGoogle Scholar
  40. Matagne A, Margineanu DG, Potschka H, Löscher W, Michel P, Kenda B et al (2009) Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy. Eur J Pharmacol 614(1–3):30–37PubMedCrossRefGoogle Scholar
  41. Mattson RH, Cramer JA, Collins JF (1992) A comparison of valproate with carbamazepine for the treatment of partial seizures and secondary generalized tonic-clonic seizures in adults. N Eng J 327:765–771CrossRefGoogle Scholar
  42. Meldrum BS, Rogawski MA (2007) Molecular targets for antiepileptic drug development. Neurother 4(1):18–61CrossRefGoogle Scholar
  43. Parada A, Soares da Silva P (2002) The novel anticonvulsivant BIA2-093 inhibits transmitter release during opening of voltage-gated sodium channels: a comparison with carbamazepine and oxcarbazepine. Neurochem Int 40:435–440PubMedCrossRefGoogle Scholar
  44. Perucca E (2009) What is the promise of new antiepileptic drugs in status epilepticus? Focus on brivaracetam, carisbamate, lacosamide, NS-1209, and topiramate. Epilepsia 50(Suppl 12):49–50PubMedCrossRefGoogle Scholar
  45. Perucca E, Tomson T (2011) The pharmacological treatment of epilepsy in adults. Lancet Neurol 10(5):446–456PubMedCrossRefGoogle Scholar
  46. Perucca E, French J, Bialer M (2007) Development of new antiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol 6(9):793–804PubMedCrossRefGoogle Scholar
  47. Pitkanen A, Mathiesen C, Ronn LC, Møller A, Nissinen J (2007) Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat. Epilepsy Res 74(1):45–54PubMedCrossRefGoogle Scholar
  48. Rascol O, Barone P, Behari M, Emre M, Giladi N, Olanow CW et al (2012) Perampanel in Parkinson disease fluctuations: a double-blind randomized trial with placebo and entacapone. Clin Neuropharmacol 35:15–20PubMedCrossRefGoogle Scholar
  49. Rocha JF, Vaz-da-Silva M, Almeida L, Falcão A, Nunes T, Santos AT et al (2009) Effect of eslicarbazepine acetate on the pharmacokinetics of metformin in healthy subjects. Int J Clin Pharmacol Ther 7:255–261CrossRefGoogle Scholar
  50. Roeloffs R, Wickenden AD, Crean C, Werness S, McNaughton-Smith G, Stables J et al (2008) In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluorobenzamide], a potent and selective KCNQ2/Q3 (Kv7.2/Kv7.3) activator in rodent anticonvulsant models. J Pharmacol Exp Ther 326:818–828PubMedCrossRefGoogle Scholar
  51. Rogawski MA (2002) Principles of antiepileptic drug action. In Levy RH, Mattson RH, Meldrum BS, Perucca E (eds) Antiepileptic drugs, 5th ed. Lippincot Williams & Wilkins, Philadelphia, pp 3–22Google Scholar
  52. Rogawski MA (2011) Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr 11:56–63PubMedCentralPubMedCrossRefGoogle Scholar
  53. Rogawski MA (2013) AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol Scand 197:9–18CrossRefGoogle Scholar
  54. Rogawski MA, Bazil CW (2008) New molecular targets for antiepileptic drugs: alpha (2) delta, SV2A, and K(v)7/KCNQ/Mpotassium channels. Curr Neurol Neurosci Rep 8:345–352PubMedCentralPubMedCrossRefGoogle Scholar
  55. Rogawski MA, Loscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5:553–564PubMedCrossRefGoogle Scholar
  56. Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A (2008) The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. Br J Clin Pharmacol 66(1):71–75PubMedCentralPubMedCrossRefGoogle Scholar
  57. Russo E, Gitto R, Citraro R, Chimirri A, De Sarro GB (2012) New AMPA antagonists in epilepsy. Expert Opin Investig Drugs 21(9):1371–1389PubMedCrossRefGoogle Scholar
  58. Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S (2014) Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia 55(1):47–55PubMedCrossRefGoogle Scholar
  59. Sander JW (2004) The use of antiepileptic drugs–principles and practice. Epilepsia 45(S6):28–34PubMedCrossRefGoogle Scholar
  60. Sargentini-Maier ML, Rolan P, Connell J, Tytgat D, Jacobs T, Pigeolet E et al (2007) The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males. Br J Clin Pharmacol 63(6):680–688PubMedCentralPubMedCrossRefGoogle Scholar
  61. Sargentini-Maier ML, Sokalski A, Boulanger P, Jacobs T, Stockis A (2012) Brivaracetam disposition in renal impairment. J Clin Pharmacol 52(12):1927–1933PubMedCrossRefGoogle Scholar
  62. Shorvon S (2000) Oxcarbazepine: a review. Seizure 9:75–79PubMedCrossRefGoogle Scholar
  63. Sperling MR, Greenspan A, Cramer JA, Kwan P, Kälviäinen R, Halford JJ et al (2010) Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized, placebo controlled trials. Epilepsia 51:333–343PubMedCrossRefGoogle Scholar
  64. Stockis A, Sargentini-Maier ML, Horsmans Y (2013) Brivaracetam disposition in mild to severe hepatic impairment. J Clin Pharmacol 53(6):633–641PubMedCrossRefGoogle Scholar
  65. Vaz-da-Silva M, Costa R, Soares E, Maia J, Falcão A, Almeida L et al (2009) Effects of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects. Fundam Clin Pharmacol 23:504–514CrossRefGoogle Scholar
  66. Verrotti A, Loiacono G, Rossi A, Zaccara G (2014) Eslicarbazepine acetate: an update on efficacy and safety in epilepsy. Epilepsy Res 108(1):1–10PubMedCrossRefGoogle Scholar
  67. Von Rosenstiel P (2007) Brivaracetam (UCB 34714). Neurother 4(1):84–87CrossRefGoogle Scholar
  68. Zaccara G, Franciotta D, Perucca P (2007) Idiosyncratic adverse reaction to antiepileptic drugs. Epilepsia 48:1223–1244PubMedCrossRefGoogle Scholar
  69. Zaccara G, Giovannelli F, Cincotta M, Verrotti A, Grillo E (2013) The adverse profile of Perampanel: meta-analysis of randomized controlled trials. Eur J Neurol 20:1204–1211PubMedCrossRefGoogle Scholar
  70. Zona C, Niespodziany I, Pieri M, Klitgaard H, Margineanu DG (2005) Seletracetam (ucb 44212), a new pyrrolidone derivative, lacks effect on Na + currents in rat brain neurons in vitro. Epilepsia 46(Suppl 8):116Google Scholar
  71. Zona C, Pieri M, Carunchio I, Curcio L, Klitgaard H, Margineanu DG (2010) Brivaracetam (ucb 34714) inhibits Na(+) current in rat cortical neurons in culture. Epilepsy Res 88(1):46–54PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Neurology UnitS. Anna HospitalComoItaly
  2. 2.Department of PaediatricUniversity of PerugiaPerugiaItaly

Personalised recommendations