生物活性

• 描述Flupirtine (D 9998) is a selective neuronal potassium channel opener that also has NMDA receptor antagonist properties. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 mM) at -70 mV with an lC50 against steady-state responses of 182.1+/-12.1 mM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely^[3]. Therapeutic flupirtine concentrations (≤10 µM) did not affect voltage-gated Na(+) or Ca(2+) channels, inward rectifier K(+) channels, nicotinic acetylcholine receptors, glycine or ionotropic glutamate receptors. Flupirtine shifted the gating of K(V)7 K(+) channels to more negative potentials and the gating of GABA(A) receptors to lower GABA concentrations. In dorsal root ganglion and dorsal horn neurons, the facilitatory effect of therapeutic flupirtine concentrations on K(V)7 channels and GABA(A) receptors was comparable, whereas in hippocampal neurons the effects on K(V)7 channels were more pronounced^[4]. Rats were trained to discriminate the novel analgesic flupirtine (10.0 mg/kg i.p., 10 min) from no drug under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.87 mg/kg^[5]. Cell exposure to flupirtine decreased the amplitude of delayed rectifier K(+) current (I(K(DR))) with a concomitant raise in current inactivation in NSC-34 neuronal cells^[6]. Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation^[7].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00623415	Relapsing Remitting Multiple S... more >>clerosis Collapse <<	Phase 2	Terminated	-	Germany ... more >> NeuroCure Clinical Research Center, Charité Berlin Berlin, Germany, 10117 Carl-Thiem-Clinic Cottbus Cottbus, Germany, 03048 University of Göttingen, Department of Neurology Göttingen, Germany, 37075 University of Ulm, Department of Neurology Ulm, Germany Collapse <<
  NCT01676246	Pain Pharmaco... more >>kinetics Flupirtine Collapse <<	Phase 1	Completed	-	Germany ... more >> Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald Greifswald, Mecklenburg-Vorpommern, Germany, 17487 Collapse <<
  NCT01450865	Axonal Change, Neuronal ... more >> Pain Collapse <<	Phase 1	Completed	-	Germany ... more >> Multidisciplinary Pain Unit Department of Anaesthesiology University of Munich Pettenkoferstr. 8a Munich, Bavaria, Germany, 80336 Collapse <<

• 参考文献

• [1] Swedberg MD, Shannon HE, et al. Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat. J Pharmacol Exp Ther. 1988 Sep;246(3):1067-74.

  [2] Wu SN, Hsu MC, et al. Evidence for inhibitory effects of flupirtine, a centrally acting analgesic, on delayed rectifier k(+) currents in motor neuron-like cells. Evid Based Complement Alternat Med. 2012;2012:148403.

  [3] 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 (Vienna). 1999;106(9-10):857-867

  [4] Klinger F, Geier P, Dorostkar MM, et al. Concomitant facilitation of GABAA receptors and KV7 channels by the non-opioid analgesic flupirtine. Br J Pharmacol. 2012;166(5):1631-1642

  [5] Swedberg MD, Shannon HE, Nickel B, Goldberg SR. Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat. J Pharmacol Exp Ther. 1988;246(3):1067-1074

  [6] Wu SN, Hsu MC, Liao YK, Wu FT, Jong YJ, Lo YC. Evidence for inhibitory effects of flupirtine, a centrally acting analgesic, on delayed rectifier k(+) currents in motor neuron-like cells. Evid Based Complement Alternat Med. 2012;2012:148403

  [7] Kolosov A, Goodchild CS, Williams ED, Cooke I. Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis. Pain Med. 2012;13(11):1444-1456

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