Flupirtine, a re-discovered drug, revisited

Inflammation Research

Volumn 62, Issue 3, 2013, Pages 251-258

  Szelenyi, Istvan ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

Analgesia; GABA; Potassium channels; Retigabine; Skeletal muscle relaxation

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; ALPHA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BENZODIAZEPINE DERIVATIVE; BETA1A INTERFERON; BICUCULLINE; DIZOCILPINE; FLUMAZENIL; FLUPIRTINE; IMIPRAMINE; LINOPIRDINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROTRANSMITTER RECEPTOR; NONSTEROID ANTIINFLAMMATORY AGENT; NORADRENALIN; OPIATE DERIVATIVE; OXALIPLATIN; POTASSIUM CHANNEL KCNQ; RESERPINE; RETIGABINE; UNCLASSIFIED DRUG; VINCA ALKALOID; VOLTAGE GATED POTASSIUM CHANNEL; W 2964M;

ANALGESIC ACTIVITY; ANTICONVULSANT ACTIVITY; ANTINOCICEPTION; ARTHRALGIA; CANCER PAIN; CHRONIC PAIN; CLINICAL TRIAL (TOPIC); DRUG ANTAGONISM; DRUG APPROVAL; DRUG BINDING SITE; DRUG RECEPTOR BINDING; DRUG RESEARCH; DRUG STRUCTURE; DYSMENORRHEA; EPILEPSY; FIBROMYALGIA; HUMAN; MULTIPLE SCLEROSIS; MUSCLE RELAXATION; MYALGIA; NEUROPATHIC PAIN; NEUROPROTECTION; NONHUMAN; NORADRENERGIC SYSTEM; OPTIC NEURITIS; PERIPHERAL NEUROPATHY; POSTOPERATIVE PAIN; PROTEIN SYNTHESIS INHIBITION; REVIEW; STRUCTURE ANALYSIS; TENSION HEADACHE;

AMINOPYRIDINES; ANALGESICS; EPILEPSY; HUMANS; KCNQ POTASSIUM CHANNELS; NEURALGIA; NEUROMUSCULAR AGENTS; URINARY BLADDER, OVERACTIVE;

EID: 84877155031     PISSN: 10233830     EISSN: 1420908X     Source Type: Journal    
DOI: 10.1007/s00011-013-0592-5     Document Type: Review

References (74)

1. Jakovlev V, Sofia RD, Achterrath-Tuckermann U, von Schlichtegroll A, Thiemer K. Untersuchungen zur pharmakologischen Wirkung von Flupirtin, einem strukturell neuartigen Analgetikum. Arzneimittelforschung [The pharmacologic effect of flupirtine, a structurally new analgesic]. Arzneimittelforschung. 1985;35:30-43 (in German).
2. Gordon R, Sofia RD, Diamantis W. Effect of flupirtine maleate on the nociceptive pathway, EEG, evoked potentials and polysynaptic reflexes in laboratory animals. Postgrad Med J. 1987;63(Suppl 3):49-55.
3. Carlsson KH, Jurna I. Depression by flupirtine, a novel analgesic agent, of motor and sensory responses of the nociceptive system in the rat spinal cord. Eur J Pharmacol. 1987;143:89-99.
4. Bleyer H, Carlsson KH, Erkel HJ, Jurna I. Flupirtine depresses nociceptive activity evoked in rat thalamus. Eur J Pharmacol. 1988;151:259-65.
5. Nickel B, Herz A, Jakovlev V, Tibes U. Untersuchungen zum Wirkmechanismus des Analgetikums Flupirtin [Mechanism of action of the analgesic flupirtine]. Arzneimittelforschung. 1985;35:1402-9 (in German).
6. Nickel B, Borbe HO, Szelenyi I. Investigations with the novel non-opioid analgesic flupirtine in regard to possible benzodiazepine-like abuse inducing potential. Arzneimittelforschung. 1990;40:905-8.
7. Darius H, Schrör K. The action of flupirtine on prostaglandin formation and platelet aggregation in vitro. Arzneimittelforschung. 1985;35:55-9.
8. Yeung SY, Greenwood IA. Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells. Br J Pharmacol. 2005;146:585-95.
9. Mani BK, Brueggemann LI, Cribbs LL, Byron KL. Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery. Br J Pharmacol. 2011;164:237-49.
10. Joshi S, Sedivy V, Hodyc D, Herget J, Gurney AM. KCNQ modulators reveal a key role for KCNQ potassium channels in regulating the tone of rat pulmonary artery smooth muscle. J Pharmacol Exp Ther. 2009;329:368-76.
11. Mackie AR, Brueggemann LI, Henderson KK, Shiels AJ, Cribbs LL, Scrogin KE, Byron KL. Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance. J Pharmacol Exp Ther. 2008;325:475-83.
12. Szelenyi I, Nickel B. Putative site(s) and mechanism(s) of action of flupirtine, a novel analgesic compound. Postgrad Med J. 1987;63(Suppl 3):57-60.
13. Szelenyi I, Nickel B, Borbe HO, Brune K. Mode of antinociceptive action of flupirtine in the rat. Br J Pharmacol. 1989;97:835-42.
14. Nickel B, Shandra A, Godlevsky L, Mazarati A, Kupferberg H, Szelenyi I. Antiepileptic effects of a new drug: D-20443. 20th Int Epilepsy Congress, Oslo, 13-16 August 1993. Epilepsia. 1993;34(Suppl. 2):95.
15. Aghajanian GK, VanderMaelen CP. Alpha 2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science. 1982;215:1394-6.
16. Jakob R, Krieglstein J. Flupirtine activates an inwardly rectifying potassium current in hippocampal neurons. Naunyn-Schmied Arch Pharmacol. 1995;351:R162.
17. Jakob R, Krieglstein J. Influence of flupirtine on a G-protein coupled inwardly rectifying potassium current in hippocampal neurones. Br J Pharmacol. 1997;122:1333-8.
18. North RA. Twelfth Gaddum memorial lecture. Drug receptors and the inhibition of nerve cells. Br J Pharmacol. 1989;98:13-28.
19. Ocaña M, Del Pozo E, Baeyens JM. ATP-dependent K+ channel blockers antagonize morphine- but not U-504,88H-induced antinociception. Eur J Pharmacol. 1993;230:203-7.
20. Ocaña M, Baeyens JM. Differential effects of K+ channel blockers on antinociception induced by alpha 2-adrenoceptor, GABAB and kappa-opioid receptor agonists. Br J Pharmacol. 1993;110:1049-54.
21. Andrade R, Aghajanian GK. Opiate- and alpha 2-adrenoceptor-induced hyperpolarizations of locus ceruleus neurons in brain slices: reversal by cyclic adenosine 3':5′-monophosphate analogues. J Neurosci. 1985;5:2359-64.
22. Kornhuber J, Bleich S, Wiltfang J, Maler M, Parsons CG. Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication. J Neural Transm. 1999;106:857-67.
23. Crozier RA, Ajit SK, Kaftan EJ, Pausch MH. MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability. J Neurosci. 2007;27:4492-6.
24. Klinger F, Geier P, Dorostkar MM, Chandaka GK, Yousuf A, Salzer I, Kubista H, Boehm S. Concomitant facilitation of GABA(A) receptors and K(V) 7 channels by the non-opioid analgesic flupirtine. Br J Pharmacol. 2012;166:1631-42.
25. Ilyin VI, Carlin KP, Hodges DD, Robledo S, Woodward RM. Flupirtine - a positive modulator of heteromeric KCNQ2/Q3 channels. Neurosci. Meet. Program No. 758.10, July 10, 2002 (Abstract).
26. Martire M, Castaldo P, D'Amico M, Preziosi P, Annunziato L, Taglialatela M. M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci. 2004;24:592-7.
27. Wladyka CL, Kunze DL. KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons. J Physiol. 2006;575:175-89.
28. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58:32-45.
29. Löscher W, Fredow G, Ganter M. Comparison of pharmacodynamic effects of the non-competitive NMDA receptor antagonists MK-801 and ketamine in pigs. Eur J Pharmacol. 1991;192:377-82.
30. Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD. The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol. 1989;167:127-35.
31. Harish S, Bhuvana K, Bengalorkar GM, Kumar T. Flupirtine: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2012;28:172-7.
32. Osborne NN, Schwarz M, Pergande G. Protection of rabbit retina from ischemic injury by flupirtine. Invest Ophthalmol Vis Sci. 1996;1996(37):274-80.
33. Osborne NN, Cazevieille C, Wood JP, Nash MS, Pergande G, Block F, Kosinski C, Schwarz M. Flupirtine, a nonopioid centrally acting analgesic, acts as an NMDA antagonist. Gen Pharmacol. 1998;30:255-63.
34. Perovic S, Schleger C, Pergande G, Iskric S, Ushijima H, Rytik P, Müller WE. The triaminopyridine flupirtine prevents cell death in rat cortical cells induced by N-methyl-D-aspartate and gp120 of HIV-1. Eur J Pharmacol. 1994;288:27-33.
35. Osborne NN, Pergande G, Block F, Schwarz M. Immunohistochemical evidence for flupirtine acting as an antagonist on the N-methyl-d-aspartate and homocysteic acid-induced release of GABA in the rabbit retina. Brain Res. 1994;667:291-4.
36. Lorenz B, Schlüter T, Bohnensack R, Pergande G, Müller WE. Effect of flupirtine on cell death of human umbilical vein endothelial cells induced by reactive oxygen species. Biochem Pharmacol. 1998;56:1615-24.
37. Müller WE, Laplanche JL, Ushijima H, Schröder HC. Novel approaches in diagnosis and therapy of Creutzfeldt-Jakob disease. Mech Ageing Dev. 2000;116:193-218.
38. Schröder HC, Müller WE. Neuroprotective effect of flupirtine in prion disease. Drugs Today (Barc). 2002;38:49-58.
39. Malan TP, Mata HP, Porreca F. Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology. 2002;96:1161-7.
40. A receptor subtypes. Nature. 2008;451:330-4.
41. Tucker AP, Mezzatesta J, Nadeson R, Goodchild CS. Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain. Anesth Analg. 2004;98:1521-7.
42. A receptors in primary afferent depolarization and spinal pain control. J Neurosci. 2011;31:8134-42.
43. Wienrich M, Szelenyi I. The muscle relaxant effect of flupirtine - indications from electrophysiological studies (abstract). Soc Neurosci. 1991;Part 2:537.5(1341).
44. Wienrich M, Szelenyi I. Der Mechanismus der muskelrelaxierenden Wirkung von Flupirtin - erste Hinweise aus elektrophysiologischen Untersuchungen (abstract). Der Schmerz. 1991;5:161(H 2.5).
45. Weiser T, Nickel B, Szelenyi I, Wienrich M. In-vivo and in vitro findings about the muscle relaxing properties of flupirtine. Arch Pharmacol. 1992; 346(Suppl 1):R22 (P27).
46. Popovici F, Dorostkar M, Boehm S. The non-opioid analgesic flupirtine is a modulator of GABAA receptors involved in pain sensation (abstract). BMC Pharmacol. 2008;8(Suppl 1):A14.
47. Hummel T, Friedmann T, Pauli E, Niebch G, Borbe HO, Kobal G. Dose-related analgesic effects of flupirtine. Br J Clin Pharmacol. 1991;32:69-76.
48. Nickel B, Kolasiewicz W, Szelenyi I. Quantification of rigidity and tremor activity in rats by using a new device and its validation by different classes of drugs. Arzneimittelforschung. 1997;47:1081-6.
49. Szelenyi I, Nickel B. Pharmacological profile of flupirtine, a novel centrally acting, non-opioid analgesic drug. Agents Actions. 1991;32(Suppl):119-23.
50. Emig P, Nickel B, Weischer CH, Szelenyi I, Engel J. Neue zentralanalgetisch wirksame Triaminopyridine. Arzneimittelforschung. 1993;43:627-31.
51. Nickel B, Jakovlev V, Szelenyi I. Einfluss von Flupirtin, verschiedener Analgetika und Muskelrelaxantien auf den Skelettmuskeltonus wacher Ratten. Arzneimittelforschung. 1990;40:909-11.
52. Schwarz M, Block F, Pergande G. N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of flupirtine in rats. NeuroReport. 1994;5:1981-4.
53. Schwarz M, Schmitt T, Pergande G, Block F. N-methyl-d-aspartate and alpha 2-adrenergic mechanisms are involved in the depressant action of flupirtine on spinal reflexes in rats. Eur J Pharmacol. 1995;276:247-55.
54. Roura-Ferrer M, Solé L, Martínez-Mármol R, Villalonga N, Felipe A. Skeletal muscle Kv7 (KCNQ) channels in myoblast differentiation and proliferation. Biochem Biophys Res Commun. 2008;369:1094-7.
55. Iannotti FA, Panza E, Barrese V, Viggiano D, Soldovieri MV, Taglialatela M. Expression, localization, and pharmacological role of Kv7 potassium channels in skeletal muscle proliferation, differentiation, and survival after myotoxic insults. J Pharmacol Exp Ther. 2010;332:811-20.
56. Wieland SJ, Gong QH. Modulation of a potassium conductance in developing skeletal muscle. Am J Physiol. 1995;268:C490-5.
57. 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;50:1063-70.
58. Su TR, Zei WS, Su CC, Hsiao G, Lin MJ. The effects of the KCNQ openers retigabine and flupirtine on myotonia in mammalian skeletal muscle induced by a chloride channel blocker. Evid Based Complement Alternat Med. 2012;2012:803082.
59. Richter A, Sander SE, Rundfeldt C. Antidystonic effects of Kv7 (KCNQ) channel openers in the dtsz mutant, an animal model of primary paroxysmal dystonia. Br J Pharmacol. 2006;149:747-53.
60. Nickel B, Nagymajtenyi L, Desi I, Szelenyi I. Flupirtine a centrally acting analgesic with muscle relaxing activity (abstract). Scand J Rheumatol. 1992;21(s94):30.
61. Rose K, Ooi L, Dalle C, Robertson B, Wood IC, Gamper N. Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. Pain. 2011;152:742-54.
62. Passmore GM, Selyanko AA, Mistry M, Al-Qatari M, Marsh SJ, Matthews EA, Dickenson AH, Brown TA, Burbidge SA, Main M, Brown DA. KCNQ/M currents in sensory neurons: significance for pain therapy. J Neurosci. 2003;23:7227-36.
63. Blackburn-Munro G, Jensen BS. The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur J Pharmacol. 2003;460:109-16.
64. Mishra S, Choudhary P, Joshi S, Bhatnagar S. Successful use of flupirtine in refractory neuropathic pain due to small fiber neuropathy. Am J Hosp Palliat Care. 2013;30:91-93.
65. Sittl R, Carr RW, Schwarz JR, Grafe P. The Kv7 potassium channel activator flupirtine affects clinical excitability parameters of myelinated axons in isolated rat sural nerve. J Peripher Nerv Syst. 2010;15:63-72.
66. Sittl R, Carr RW, Fleckenstein J, Grafe P. Enhancement of axonal potassium conductance reduces nerve hyperexcitability in an in vitro model of oxaliplatin-induced acute neuropathy. Neurotoxicology. 2010;31:694-700.
67. Nielsen AN, Mathiesen C, Blackburn-Munro G. Pharmacological characterisation of acid-induced allodynia in rats. Eur J Pharmacol. 2004;487:93-103.
68. Wörz R. Flupirtine in chronic myofacial pain conditions. Fortschr Med. 1991;109:158-60 (in German).
69. Stoll AL. Fibromyalgia symptoms relieved by flupirtine: an open-label case series. Psychosomatics. 2000;41:371-2.
70. Block F, Pergande G, Schwarz M. Flupirtine reduces functional deficits and neuronal damage after global ischemia in rats. Brain Res. 1997;754:279-84.
71. Perovic S, Bohm M, Meesters E, Meinhardt A, Pergande G, Muller WE. Pharmacological intervention in age-associated brain disorders by flupirtine: Alzheimer's and prion diseases. Mech Ageing Dev. 1998;101:1-19.
72. Sättler MB, Williams SK, Neusch C, Otto M, Pehlke JR, Bähr M, Diem R. Flupirtine as neuroprotective add-on therapy in autoimmune optic neuritis. Am J Pathol. 2008;173:1496-507.
73. Michel M, Radziszewski P, Falconer C, Marschall-Kehrel D, Rundfeldt C, Vanhoutte F. The centrally acting ion channel modulator flupirtine improves bladder function in animal models and patients with overactive bladder syndrome. 2006. https://www.icsoffice.org/Abstracts/Publish/46/000406.pdf. Accessed 8 Aug 2012.
74. McCallum LA, Pierce SL, England SK, Greenwood IA, Tribe RM. The contribution of Kv7 channels to pregnant mouse and human myometrial contractility. J Cell Mol Med. 2011;15:577-86.