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. 2007 Jan;4(1):149–154. doi: 10.1016/j.nurt.2006.11.012

Retigabine

Roger J Porter 1,2,✉, Virinder Nohria 3, Chris Rundfeldt 4
PMCID: PMC7479689  PMID: 17199031

Summary

Retigabine is a novel antiseizure drug that acts through potassium channels and has activity in a broad range of animal models of epilepsy. It is also effective in several preclinical pain models. The drug has been extensively studied in phase I and II studies, with very promising results. The maximal tolerated dose for most patients is 1,200 mg/day. Adverse effects have been largely CNS-related and mild; most have occurred during the titration periods in the various studies. At present, retigabine is in two pivotal phase III studies.

Key Words: Retigabine, potassium channels, partial-onset seizures, epilepsy

References

  • 1.Löscher W. New visions in the pharmacology of anticonvulsion. Eur J Pharmacol. 1998;342:1–13. doi: 10.1016/S0014-2999(97)01514-8. [DOI] [PubMed] [Google Scholar]
  • 2.Rogawski MA. Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. Trends Pharmacol Sci. 1993;14:325–331. doi: 10.1016/0165-6147(93)90005-5. [DOI] [PubMed] [Google Scholar]
  • 3.Kupferberg HJ. Antiepileptic drug development program: a cooperative effort of government and industry. Epilepsia. 1989;30(suppl 1):S51–S56. doi: 10.1111/j.1528-1157.1989.tb05815.x. [DOI] [PubMed] [Google Scholar]
  • 4.Jakovlev V, Achterrath-Tuckermann U, von Schlichtegroll A, Stroman F, Thiemer K. General pharmacologic studies on the analgesic flupirtine [In German] Arzneimittelforschung. 1985;35:44–55. [PubMed] [Google Scholar]
  • 5.Seaman CA, Sheridan PH, Engel J, Molliere M, Narang PK, Nice FJ. Flupirtine. In: Meldrum BS, Porter RJ, editors. New anticonvulsant drugs. Current Problems in Epilepsy 4. London: Libbey; 1986. pp. 135–146. [Google Scholar]
  • 6.Seydel JK, Schaper KJ, Coats EA, et al. Synthesis and quantitative structure-activity relationships of anticonvulsant 2,3,6-triaminopy-ridines. J Med Chem. 1994;37:3016–3022. doi: 10.1021/jm00045a005. [DOI] [PubMed] [Google Scholar]
  • 7.Rostock A, Tober C, Rundfeldt C, et al. D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res. 1996;23:211–223. doi: 10.1016/0920-1211(95)00101-8. [DOI] [PubMed] [Google Scholar]
  • 8.Tober C, Rundfeldt C, Rostock A, Bartsch R. The phenyl carbamic acid ester D-23129 is highly effective against amygdale kindled seizures in rats. Eur J Pharmacol. 1994;7:212–212. [Google Scholar]
  • 9.Löscher W, Schmidt D. Strategies in antiepileptic drug development: is rational drug design superior to random screening and structural variation? Epilepsy Res. 1994;17:95–134. doi: 10.1016/0920-1211(94)90012-4. [DOI] [PubMed] [Google Scholar]
  • 10.Nickel B, Shandra A, Godlevsky L, Mazarati A, Kupferberg H, Szelenyi I. Anticonvulsant activity of D-20443. Naunyn Schmiedebergs Arch Pharmacol. 1993;347:R142–R142. [Google Scholar]
  • 11.Nickel B, Shandra A, Godlevsky L, Mazarati A, Kupferberg H, Szelenyi I. Antiepileptic activity of a new drug: D-20443. Epilepsia. 1993;34(suppl 1):95–95. [Google Scholar]
  • 12.Löscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res. 1988;2:145–181. doi: 10.1016/0920-1211(88)90054-X. [DOI] [PubMed] [Google Scholar]
  • 13.Dailey JW, Cheong JH, Ko KH, Adams-Curtis LE, Jobe PC. Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response. Neurosci Lett. 1995;195:77–80. doi: 10.1016/0304-3940(95)11783-S. [DOI] [PubMed] [Google Scholar]
  • 14.Tober C, Rundfeldt C, Rostock A, Bartsch R. The phenyl carbamic acid ester D-23129 is highly effective in epilepsy models for generalized and focal seizures at nontoxic doses. Abstr Soc Neurosci. 1994;20:1641–1641. [Google Scholar]
  • 15.Tober C, Rostock A, Rundfeldt C, Bartsch R. D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures. Eur J Pharmacol. 1996;303:163–169. doi: 10.1016/0014-2999(96)00073-8. [DOI] [PubMed] [Google Scholar]
  • 16.Engel J. Clinical aspects of epilepsy. Epilepsy Res. 1991;10:9–17. doi: 10.1016/0920-1211(91)90089-X. [DOI] [PubMed] [Google Scholar]
  • 17.Ganguly A, Wolf HH, White HS. Investigational anticonvulsant D-23129 inhibits limbic behavioral seizures in hippocampal kindled rats. Epilepsia. 1995;36(suppl 4):49–49. [Google Scholar]
  • 18.Armand V, Rundfeldt C, Heinemann U. Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by low magnesium in rat entorhinal cortex hippocampal slices. Epilepsia. 2000;41:28–33. doi: 10.1111/j.1528-1157.2000.tb01501.x. [DOI] [PubMed] [Google Scholar]
  • 19.Armand V, Rundfeldt C, Heinemann U. Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal cortex hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol. 1999;359:33–39. doi: 10.1007/PL00005320. [DOI] [PubMed] [Google Scholar]
  • 20.Straub H, Kohling R, Hohling J, et al. Effects of retigabine on rhythmic synchronous activity of human neocortical slices. Epilepsy Res. 2001;44:155–165. doi: 10.1016/S0920-1211(01)00193-0. [DOI] [PubMed] [Google Scholar]
  • 21.Tober C. Investigations of the effects of retigabine in the amygdala kindling model in rats [dissertation] Leipzig: Germany: University of Leipzig; 1997. [Google Scholar]
  • 22.Rundfeldt C, Netzer R. The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells transfected with human KCNQ2/3 subunits. Neurosci Lett. 2000;282:73–76. doi: 10.1016/S0304-3940(00)00866-1. [DOI] [PubMed] [Google Scholar]
  • 23.Rundfeldt C. The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur J Pharmacol. 1997;336:243–249. doi: 10.1016/S0014-2999(97)01249-1. [DOI] [PubMed] [Google Scholar]
  • 24.Rundfeldt C. Characterization of the K+ channel opening effect of the anticonvulsant retigabine in PC12 cells. Epilepsy Res. 1999;35:99–107. doi: 10.1016/S0920-1211(98)00131-4. [DOI] [PubMed] [Google Scholar]
  • 25.Rundfeldt C, Netzer R. Investigations into the mechanism of action of the new anticonvulsant retigabine: interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels. Arzneimittelforschung. 2000;50:1063–1070. doi: 10.1055/s-0031-1300346. [DOI] [PubMed] [Google Scholar]
  • 26.Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279:403–406. doi: 10.1126/science.279.5349.403. [DOI] [PubMed] [Google Scholar]
  • 27.Schroeder BC, Kubisch C, Stein V, Jentsch TJ. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1998;396:687–690. doi: 10.1038/25367. [DOI] [PubMed] [Google Scholar]
  • 28.Gribkoff VK. The therapeutic potential of neuronal KCNQ channel modulators. Expert Opin Ther Targets. 2003;7:737–748. doi: 10.1517/14728222.7.6.737. [DOI] [PubMed] [Google Scholar]
  • 29.Blackburn-Munro G, Jensen BS. The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur J Pharmacol. 2003;460:109–116. doi: 10.1016/S0014-2999(02)02924-2. [DOI] [PubMed] [Google Scholar]
  • 30.Dost R, Rostock A, Rundfeldt C. The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:382–390. doi: 10.1007/s00210-004-0881-1. [DOI] [PubMed] [Google Scholar]
  • 31.Ebert U, Brandt C, Löscher W. Delayed sclerosis, neuroprotection, and limbic epileptogenesis after status epilepticus in the rat. Epilepsia. 2002;43(suppl 5):86–95. doi: 10.1046/j.1528-1157.43.s.5.39.x. [DOI] [PubMed] [Google Scholar]
  • 32.Argentieri TM, Sheldon JH, Bowlby MR, inventors; American Home Products Corporation, assignee. Methods for modulating bladder function. US patent 6 348 486. Feb. 19, 2002.
  • 33.Burbridge SA, Clare JJ, Cox B, Dupere J, Hagan RM, Xie X. New uses for potassium channel openers. WO Patent WO1407768. January 11, 2001.
  • 34.Kharkovets T, Hardelin JP, Safieddine S, et al. KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci USA. 2000;97:4333–4338. doi: 10.1073/pnas.97.8.4333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Sachdeo RC, Ferron GM, Partiot AM, et al. An early determination of drug-drug interactions between valproic acid, phenytoin, carbamazepine, or topiramate and retigabine in epileptic patients. Neurology. 2001;56:A331–A332. [Google Scholar]
  • 36.Porter R, Alves W, Nohria V, on behalf of the 2005 study group Poster abstract 01175 [CD-ROM]. 2005 World Congress of Neurology, 5–11 Nov. 2005, Sydney, Australia. J Neurol Sci. 2005;15(suppl 1):S1–S526. [Google Scholar]

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