Dost R, Rundfeldt C
Department of Pharmacology, Arzneimittelwerk Dresden GmbH, Corporate R&D, ASTA Medica Group, Radebeul, Germany.
Epilepsy Res. 2000 Jan;38(1):53-66. doi: 10.1016/s0920-1211(99)00065-0.
Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester, D-23129) is a broad acting anticonvulsant currently undergoing phase II clinical trials. An opening effect on leakage conductance K+ channels, potentiation of GABA induced currents and a weak blocking effect on Na+ and Ca++ channels were previously reported. The goal of this study was to investigate whether retigabine is capable of blocking epileptiform discharges in the low Ca++ and low Mg++ model in the hippocampal slice preparations and whether the anti-burst activity can be related to the K+ channel opening effect. In the low Ca++ model, synaptic transmission is blocked and discharges evolve from ephaptically-coupled neurons. Compounds which directly interfere with the threshold for action potential induction via alteration of ion channel function (i.e. Na+ channel blocker) may alter the discharges, while compounds interfering with synaptic transmission are not active. Retigabine suppressed the discharges in a concentration-dependent manner. A significant reduction in frequency without effect on amplitude was observed after application of 1 microM, and a full block of all discharges after application of 25 microM. The opener of the ATP sensitive K+ channels cromakalim was also active. Application of 300 microM cromakalim yielded to a lower frequency with no effects on the amplitude of discharges. Treatment with phenytoin and carbamazepine resulted in a marked reduction in amplitude accompanied by a rise in frequency; only at higher concentrations was a full block observed. The effect of retigabine therefore differs from sodium channel blockers and can be related to the K+ channel opening effect. In the low Mg++ model, excitatory neurotransmission is augmented by reducing the Mg++ block of NMDA channels. This results in development of interictal-like epileptiform activity in area CA1 in isolated hippocampal slices. Treatment with retigabine 10 microM resulted in a significant reduction of the discharges, and discharges were fully blocked after application of 25 microM. Qualitatively similar effects were observed with cromakalim and valproate, albeit at higher concentrations. The data indicate that retigabine exerts potent broad spectrum activity making it an interesting candidate for treatment of drug resistant patients.
瑞替加滨（N-(2-氨基-4-(4-氟苄基氨基)-苯基)氨基甲酸乙酯，D-23129）是一种正在进行II期临床试验的广谱抗惊厥药。此前有报道称其对钾离子渗漏电导通道有开放作用，能增强γ-氨基丁酸（GABA）诱导的电流，对钠离子和钙离子通道有微弱的阻断作用。本研究的目的是探究瑞替加滨是否能够阻断海马脑片制备中低钙和低镁模型中的癫痫样放电，以及其抗爆发活动是否与钾离子通道开放作用有关。在低钙模型中，突触传递被阻断，放电由电突触耦合神经元产生。直接通过改变离子通道功能（如钠离子通道阻滞剂）来干扰动作电位诱导阈值的化合物可能会改变放电，而干扰突触传递的化合物则无活性。瑞替加滨以浓度依赖性方式抑制放电。应用1微摩尔后，频率显著降低，幅度无影响；应用25微摩尔后，所有放电完全被阻断。ATP敏感性钾离子通道开放剂克罗卡林也有活性。应用300微摩尔克罗卡林可使频率降低，对放电幅度无影响。苯妥英和卡马西平治疗导致幅度显著降低，频率升高；仅在较高浓度时才观察到完全阻断。因此，瑞替加滨的作用不同于钠离子通道阻滞剂，可能与钾离子通道开放作用有关。在低镁模型中，通过减少NMDA通道的镁离子阻断来增强兴奋性神经传递。这导致在分离的海马脑片CA1区出现发作间期样癫痫样活动。用10微摩尔瑞替加滨治疗可使放电显著减少，应用25微摩尔后放电完全被阻断。克罗卡林和丙戊酸盐也观察到定性相似的效果，尽管浓度更高。数据表明瑞替加滨具有强大的广谱活性，使其成为治疗耐药患者的一个有吸引力的候选药物。
