Skip to main content

Advertisement

SpringerLink
Log in

Phenytoin: a step by step insight into its multiple mechanisms of action—80 years of mechanistic studies in neuropharmacology

  • Pioneers in Neurology
  • Published:
Journal of Neurology Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Editorial (2010) Mechanism matters. Nat Med 16:347

    Article  Google Scholar 

  2. Yaari Y, Seltzer M, Pincus JH (1986) Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol 20:171–184

    Article  CAS  PubMed  Google Scholar 

  3. Goodman LS, Swinyard EA, Toman JE (1946) Studies on the anticonvulsant properties of diphenylhydantoin. Fed Proc 5:180

    CAS  PubMed  Google Scholar 

  4. Putnam TJ, Merritt HH (1937) Experimental determination of the anticonvulsant properties of some phenyl derivatives. Science 85(2213):525–526

    Article  CAS  PubMed  Google Scholar 

  5. Keppel Hesselink JM, Kopsky DJ (2017) Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action. J Neurol. doi:10.1007/s00415-017-8391-5

    Google Scholar 

  6. Williams D (1939) Treatment of epilepsy with sodium diphenyl hydantoinate. Lancet 234(6056):678–681

    Article  Google Scholar 

  7. Frost I (1939) Sodium diphenyl hydantoinate in the treatment of epilepsy: preliminary observations in severe cases. Br J Psychiatry 85:976–985

    Article  CAS  Google Scholar 

  8. Victor HG, Drake ME (1940) The effects of intravenous injection of sodium diphenyl hydantoinate (dilantin) on respiration, blood pressure, and the vagus nerve. J Pharmacol Exp Ther 68:36–40

    Google Scholar 

  9. Merritt H Houston, Brenner Charles (1947) Studies in new anticonvulsants. Bull N Y Acad Med 23(5):292

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Toman JE (1949) The neuropharmacology of antiepileptics. Electroencephalogr Clin Neurophysiol 1(1):33–44

    Article  CAS  PubMed  Google Scholar 

  11. Pratt CH (1939) Sodium diphenyl hydantoinate (dilantin) and its combination with phenobarbital in the treatment of epilepsy?: a review and preliminary report. BJP 85:986–998

    Article  Google Scholar 

  12. York GK, Steinberg DA (2011) Hughlings Jackson’s neurological ideas. Brain 134:3106–3113

    Article  PubMed  Google Scholar 

  13. Woodbury DM, Naisbitt MS (1955) Effect of diphenylhydantoin on electrolytes and radiosodium turnover in brain and other tissues of normal, hyponatremic and postictal rats. J Pharmacol Exp Ther 115:74–95

    CAS  PubMed  Google Scholar 

  14. Skou JC (1965) Enzymatic basis for active transport of Na+ and K+ across cell membrane. Physiol Rev 45:596–617

    CAS  PubMed  Google Scholar 

  15. Rawson MD, Pincus JH (1968) The effect of diphenylhydantoin on sodium, potassium, magnesium-activated adenosine triphosphatase in microsomal fractions of rat and guinea pig brain and on whole homogenates of human brain. Biochem Pharmacol 17:573–579

    Article  CAS  PubMed  Google Scholar 

  16. Korey SR (1951) Effect of dilantin and mesantoin on the giant axon of the squid. Proc Soc Exp Biol Med 76:297–299

    Article  CAS  PubMed  Google Scholar 

  17. Hille B (1971) The permeability of the sodium channel to organic cations in myelinated nerve. J Gen Physiol 58(6):599–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Armstrong CM (1971) Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol 58(4):413–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hille B (2001) Ionic channels of excitable membranes, 3rd edn. Sinauer Associates Inc., Sunderland

    Google Scholar 

  20. Lipicky RJ, Gilbert DL, Stillman IM (1972) Diphenylhydantoin inhibition of sodium conductance in squid giant axon. Proc Natl Acad Sci USA 69(7):1758–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Catterall WA (2012) Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol 590(Pt 11):2577–2589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Beneski DA, Catterall WA (1980) Covalent labeling of protein components of the sodium channel with a photoactivable derivative of scorpion toxin. Proc Natl Acad Sci USA 77:639–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Catterall WA (2000) From Ionic currents to molecular review mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26:13–25

    Article  CAS  PubMed  Google Scholar 

  24. Willow M, Kuenzel EA, Catterall WA (1984) Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 25(2):228–234

    CAS  PubMed  Google Scholar 

  25. Matsuki N, Quandt FN, Ten Eick RE, Yeh JZ (1984) Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J Pharmacol Exp Ther 228(2):523–530

    CAS  PubMed  Google Scholar 

  26. Courtney KR, Etter EF (1983) Modulated anticonvulsant block of sodium channels in nerve and muscle. Eur J Pharmacol 88(1):1–9

    Article  CAS  PubMed  Google Scholar 

  27. Qiao X, Sun G, Clare JJ, Werkman TR, Wadman WJ (2014) Properties of human brain sodium channel alpha-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine. Br J Pharmacol 171(4):1054–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Terragni B, Scalmani P, Colombo E, Franceschetti S, Mantegazza M (2016) Ranolazine vs phenytoin: greater effect of ranolazine on the transient Na(+) current than on the persistent Na(+) current in central neurons. Neuropharmacology 110(Pt A):223–236

    Article  CAS  PubMed  Google Scholar 

  29. Smith NE, Corry B (2016) Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins. Channels (Austin) 10(3):225–237

    Article  Google Scholar 

  30. Silver K, Soderlund DM (2005) State-dependent block of rat Nav1.4 sodium channels expressed in xenopus oocytes by pyrazoline-type insecticides. Neurotoxicology 26(3):397–406

    Article  CAS  PubMed  Google Scholar 

  31. Nelson M, Yang M, Millican-Slater R, Brackenbury WJ (2015) Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo. Oncotarget 6(32):32914–32929

    Article  PubMed  PubMed Central  Google Scholar 

  32. Boerma RS, Braun KP, van den Broek MP (2016) Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics 13(1):192–197

    Article  CAS  PubMed  Google Scholar 

  33. Black JA, Liu S, Waxman SG (2009) Sodium channel activity modulates multiple functions in microglia. Glia 57(10):1072–1081

    Article  PubMed  Google Scholar 

  34. Zhao F, Li X, Jin L (2016) Development of a rapid throughput assay for identification of hNav1.7 antagonist using unique efficacious sodium channel agonist, antillatoxin. Mar Drugs 14(2):36

    Article  PubMed Central  Google Scholar 

  35. Patejdl R, Leroux AC, Noack T (2015) Phenytoin inhibits contractions of rat gastrointestinal and portal vein smooth muscle by inhibiting calcium entry. Neurogastroenterol Motil 27(10):1453–1465

    Article  CAS  PubMed  Google Scholar 

  36. Chou MY, Lee CY, Liou HH, Pan CY (2014) Phenytoin attenuates the hyper-exciting neurotransmission in cultured embryonic cortical neurons. Neuropharmacology 83:54–61

    Article  CAS  PubMed  Google Scholar 

  37. Deisz RA, Lux HD (1977) Diphenylhydantoin prolongs postsynaptic inhibition and iontophoretic GABA action in the crayfish stretch receptor. Neurosci Lett 5(3–4):199–203

    Article  CAS  PubMed  Google Scholar 

  38. Ayala GF, Lin S, Johnston D (1977) The mechanism of action of diphenylhydantoin or invertebrate neurons. Effects on basic membrane properties. Brain Res 121(2):245–258

    Article  CAS  PubMed  Google Scholar 

  39. Connors BW (1981) A comparison of the effects of pentobarbital and diphenylhydantoin on the GABA sensitivity and excitability of adult sensory ganglion cells. Brain Res 207(2):357–369

    Article  CAS  PubMed  Google Scholar 

  40. Granger P, Biton B, Faure C (1995) Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin. Mol Pharmacol 47(6):1189–1196

    CAS  PubMed  Google Scholar 

  41. Kimball OP, Horan TN (1939) The use of Dilantin in the treatment of epilepsy. Ann Intern Med 13:787–793

    Article  Google Scholar 

  42. Shapiro M (1957) Preprinted abstract, annual meeting, Internat Assn for Dental Research. In: Shafer WG (1960) Effect of dilantin sodium on growth of human fibroblast-like cell cultures. Exp Biol Med 104(2):198–201

  43. Shapiro M (1958) Acceleration of gingival wound healing in non-epileptic patients receiving diphenylhydantoin sodium (dilantin, epanutin). Exp Med Surg 16(1):41–53

    CAS  PubMed  Google Scholar 

  44. Bhatia A, Prakash S (2004) Topical phenytoin for wound healing. Dermatol Online 10(1):5

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Neuropathic Pain, Spoorlaan 2a, 3735 MV, Bosch en Duin, The Netherlands

    Jan M. Keppel Hesselink

Authors
  1. Jan M. Keppel Hesselink
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan M. Keppel Hesselink.

Ethics declarations

Conflicts of interest

The author is one of the patent holder of two patents related to topical phenytoin formulations: ‘topical phenytoin for use in the treatment of peripheral neuropathic pain’ and ‘topical pharmaceutical composition containing phenytoin and a (co-)analgesic for the treatment of chronic pain’.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keppel Hesselink, J.M. Phenytoin: a step by step insight into its multiple mechanisms of action—80 years of mechanistic studies in neuropharmacology. J Neurol 264, 2043–2047 (2017). https://doi.org/10.1007/s00415-017-8465-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-017-8465-4

Keywords

Search

Navigation