CN103202845B - 钠通道阻滞剂和选择性5-羟色胺摄取抑制剂的药物组合物 - Google Patents
钠通道阻滞剂和选择性5-羟色胺摄取抑制剂的药物组合物 Download PDFInfo
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- CN103202845B CN103202845B CN201310073166.1A CN201310073166A CN103202845B CN 103202845 B CN103202845 B CN 103202845B CN 201310073166 A CN201310073166 A CN 201310073166A CN 103202845 B CN103202845 B CN 103202845B
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Abstract
本发明涉及钠通道阻滞剂和选择性5-羟色胺摄取抑制剂的药物组合物,其具有改善的钠通道阻滞作用,另外,本发明涉及所述药物组合在慢性疼痛、运动系统障碍、癫痫以及其它其中钠通道阻滞剂的使用是可接收的治疗领域中的应用。
Description
本申请为国际申请PCT/HU2004/000123于2006年8月18日进入中国国家阶段、申请号为200480041830、发明名称为“钠通道阻滞剂和选择性5-羟色胺摄取抑制剂的药物组合物”的分案申请。
技术领域
本发明涉及具有增强的钠通道阻滞作用的新的药物组合。此外,本发明涉及该药物组合在慢性疼痛、运动系统障碍、癫痫以及其他应用钠通道阻滞剂是可接受的治疗领域中的用途。
背景技术
众所周知电压敏感性钠通道在产生和传导动作电位的过程中起着关键的作用,在调节神经元的兴奋性方面起关键作用。钠通道在神经细胞膜的表面形成小孔并且响应细胞膜的去极化通道将短时开放以便钠离子流入细胞引起电位改变。在神经系统的某些疾病中,可以观察到由于通道作用改变而通常导致神经元的兴奋性异常提高。通过阻滞电压依赖性钠通道而对此类疾病产生有益作用的多种药物正在上市或研发中。
钠通道阻滞剂如利多卡因,常规性地用于局部麻醉剂。某些结构相似的物质(例如美西律)用作抗心率失常的药物。目前有一些更新的分子正处于研发阶段,其中的crobenetine(克劳奈汀)被证实即使在很低的剂量下也有效(Carter,A.J.等,Potent blockade of sodium channelsand protection of brain tissue from ischemia by BIII890CL,Proc.Natl.Acad.Sci.USA97:4944-4949;2000)。后一种化合物看起来对神经性疼痛也有效。(Laird,J.M.A.等,Analgesic activity of a noveluse-dependent sodium channel blocker,crobenetine,in mono-arthriticrats,Br.J.Pharmacol134:1742-1748;2001)。多种其他的钠通道阻滞剂对慢性疼痛有效(Hunter,J.C,Loughhead,D.,Voltage-gated sodiumchannel blockers for the treatment of chronic pain,Curr.Opin.CPNS.Invest.Drugs1:72-81;1999)。用于治疗神经退行性疾病的利鲁唑具有相同的作用机理(Hurco,O.,Walsh,F.S.,Novel drug development foramyotrophic lateral sclerosis。J.Neurol.Sci.180:21-28;2000)。最近发现钠通道阻滞剂能够治疗伴随疼痛性肌肉痉挛阻碍病人正常活动的疾病(Kocsis,P.等,Mydeton:a centrally acting muscle relaxant drug ofGedeon Richter Ltd,Acta Pharm Hung72:49-61;2002)。此外可能的应用领域为脑缺血、遗传性通道疾病、耳鸣、偏头痛以及药物滥用(Clare,J.J.等,Voltage-gated sodium channels as therapeutic targets,Drug Discov.Today5:506-520;2000)。很多抗癫痫药物(苯妥英、卡马西平)已经应用了很长时间。钠通道抑制活性被认为是它们的作用机理的主要组成部分(Willow,M.等,Voltage clamp analysis of the inhibitory actions ofdiphenylhydantoin and carbamazepine on voltage-sensitive sodiumchannels in neuroblastoma cells,Molecular Pharmacology27:549-558,1985)。在此作用机理的启发下开发了拉莫三嗪(Leach,M.J.等,Pharmacological studies on lamotrigine,a novel potential antiepilepticdrug:II Neurochemical studies on the mechanism of action,Epilepsia27:490-497,1986;Clare,J.J.等,Voltage-gated sodium channels astherapeutic targets,Drug Discov.Today5:506-520;2000)。
leander的研究表明在小鼠的最大电休克惊厥试验(MES)中氟西汀增强了卡马西平、苯妥英和氨托利的抗惊厥作用。(leander,J.D.,Fluoxetine,a selective serotonin-uptake inhibitor enhances theanticonvulsant effects of phenytoin,carbamazepine,and ameltolide(LY201116),Epilepsia33:573-576,1992)。作者总结到由于同时给予氟西汀可以提高抗癫痫药物的作用,氟西汀也可以用于治疗那些有癫痫问题的抑郁患者。然而作者没有提到其可能的作用机理。与此相似,Raju等(Raju,S.S.等,Effect of fluoxetine on maximal electroshockseizures in mice:acute vs.chronic administration,PharmacologicalResearch39:451-454,1999。)发现急性应用的氟西汀导致苯妥英抗惊厥作用的ED50值降低。另一方面,Dailey及其合作者在其试验中发现单独给予氟西汀显示了抗惊厥活性(Dailey,J.W.等。Neurochemicalcorrelates of antiepileptic drugs in the genetically epilepsy-prone rat(GEPR).Life Sciences58:259-266,1996。)。更进一步的数据表明5-羟色胺的损耗降低了某些抗癫痫药物(卡马西平、抗痫灵)的有效性,但是对苯妥英的效力没有影响。另一方面,其他的研究者强调关于抗惊厥作用去甲肾上腺素能系统是单胺能系统中最重要的部分(Fisher,W.,Müller,M.,Pharmacological modulation of central monoaminergicsystems and influence on the anticonvulsant effectiveness of standardantiepileptics in maximal electroshock seizure,Biomedica BiochimicaActa47:631-645,1988。)。而拟交感作用导致某些抗癫痫药物(苯妥英、卡马西平)的有效性显著提高,去甲肾上腺素能系统的作用减弱导致所研究的抗癫痫药物的效力减弱。根据他们的结论调节5-羟色胺能系统对抗癫痫药物的效力不产生主要影响。
由于开放后很快失去活性,所以钠通道的开放时间极短(1-2毫秒)。通过调节失活过程可以有效地影响神经元的兴奋性。目前的研究结果表明某些神经递质(例如乙酰胆碱、5-羟色胺、去甲肾上腺素)可以通过G-蛋白偶联受体调节通道的作用(Carr,D.B.等,Transmittermodulation of slow,activity-dependent alterations in sodium channelavailability endows neurons with a novel form of cellular plasticity.Neuron39:793-806;2003,与Li,P.,Zhuo,M.,Cholinergic,noradrenergic,and serotonergic inhibition of fast synaptic transmission in spinal lumbardorsal horn of rat.Brain Res.Bull.54:639-947;2001)。尽管有些作者报道5-羟色胺受体激动剂可能通过激活5-羟色胺受体而间接抑制钠通道的作用(Carr,D.B等,Serotonin receptor activation inhibits sodium currentand dendritic excitability in prefrontal cortex via a protein kinaseC-dependent mechanism.J.Neurosci.22:6846-6855;2002)他们并没有研究钠通道阻滞剂和5-羟色胺能药物之间可能的协同作用。另一方面,Rapeport报道了在5-羟色胺摄取抑制剂和钠通道阻滞剂之间没有发现协同作用(Rapeport,W.G.等,Absence of a sertraline-mediated effect onthe pharmacokinetics and pharmacodynamics of carbamazepine.Journal ofClinical Psychiatry57(Suppl.1):20-23;1996)。美国专利公开申请US2002/0147196A1公开了儿茶酚胺摄取抑制剂与钠通道阻滞剂组合治疗神经性疼痛的有益效果。
总之,已发表的有关5-羟色胺摄取抑制剂可能加强钠通道阻滞剂作用的试验数据相互矛盾。尽管偶尔发现有些组合有加强作用的情况,其他的结果又提出了相反的倾向。
然而,钠通道阻滞剂具有多种副作用,其中有些是钠通道阻滞作用本身造成的后果:例如对心血管(例如心搏徐缓、张力减退)或中枢神经系统(CNS)(例如共济失调、镇静作用)等的副作用。
其他的副作用与钠通道无关而与其化学结构有关,例如较大剂量的拉莫三嗪可能引起肠胃失调、肝脏损害或皮肤病等。如果设法降低药物的有效剂量就能够减少这些副作用。显然,与能加强钠通道阻滞作用的药物结合是达到此目的合适途径。
发明内容
在试验中,我们惊奇地发现同时给予5-羟色胺摄取抑制剂化合物可显著增强钠通道的阻滞活性。而至于副作用,5-羟色胺能在此方面的活性增强作用没有那么明显。因此,本发明的药物组合物比单用钠通道阻滞剂具有更多有利的治疗指数。正如旋转运动测试中所显示的那样,5-羟色胺摄取抑制剂更少或甚至可能不表现增强作用,因此,给予药物组合与单独给予钠通道阻滞剂相比治疗指数就相当高了。例如拉莫三嗪的治疗指数(旋转运动测试ED50/MES ID50)为7.6,其在10mg/kg氟西汀的存在下治疗指数增加约3倍。应用本发明的组合可能带来癫痫治疗的副作用上的进步。
因此本发明的目的是新的药物组合,该组合在作为钠通道阻滞剂的治疗靶标的疾病(例如慢性疼痛,某些运动系统障碍、癫痫、毒瘾或酒瘾、大小便失禁、炎症、搔痒、颅内水肿、缺血和/或由再灌注引起的继发性损害、或作为青光眼并发症的视网膜病变)的治疗中显示了较高的活性,并且比单用钠通道阻滞剂具有更加有利的副作用特性(side effect profile)。本发明的药物组合物,能够分别降低钠通道阻滞剂的有效治疗剂量和提高其临床效果。
上述的药物组合物包含作为活性成分的钠通道阻滞剂结合5-羟色胺摄取抑制剂。
用于本发明的药物组合物中的钠通道阻滞剂是已知具有该作用机理的物质。这些物质的例子为拉莫三嗪、克劳奈汀、卡马西平、苯妥英、托哌酮、乙哌立松、奥卡西平、磷苯妥英,优选拉莫三嗪、奥卡西平、磷苯妥英或克劳奈汀。用于进行本发明而任选的这些物质的混合物也在本发明的范围之内。
能够应用的5-羟色胺摄取抑制剂为已知具有该作用机理的物质。优选应用的选择性5-羟色胺摄取抑制剂为氟西汀、帕罗西汀、度洛西汀、舍曲林、西酞普兰、依地普仑。最优选氟西汀、舍曲林或西酞普兰。用于进行本发明而任选的这些物质的混合物也在本发明的范围之内。
所述的钠通道阻滞剂的盐、溶剂化物、结晶变体或立体异构体及其混合物的应用也在本发明的范围之内。
本发明的药物组合物能够有效治疗和/或预防慢性疼痛(例如神经性疼痛、炎症或风湿引起的疼痛、三叉神经痛、头痛、纤维肌痛)和肠易激综合症(IBS),治疗和预防运动系统障碍(例如痉挛性疾病、特发性震颤、肌张力障碍、耳鸣、锥体束外障碍、抽动)和神经退行性疾病(例如ALS、HIV引发的痴呆、帕金森综合症、阿尔茨海默病、亨廷顿舞蹈病、多发性硬化、朊病毒疾病、中风、大脑和脊髓损伤、脑缺血),也能够治疗和预防毒瘾或酒瘾、大小便失禁、炎症、搔痒、颅内水肿、缺血和/或由再灌注引起的继发性损害、或作为青光眼并发症的视网膜病变,进一步治疗和预防不同类型的癫痫,例如部分性发作如简单部分性发作(运动症状表现、体感觉中枢-感觉中枢症状表现、自主神经症状表现、精神症状表现),复杂部分性发作(局部发作和/或意识丧失)或伴随继发性全身发作的部分性发作(全身性强直或阵挛性发作)、全身性发作如精神不集中(典型或非典型)、肌阵挛、阵挛、强直-阵挛(癫痫大发作)发作、肌紧张消失(起立不能发作),还有无法归类的其他形式的发作(癫痫发作的国际分类,Epilepsia,22,489-501,1981)。
上述疾病能够得到成功的治疗不仅需要通过将钠通道阻滞剂和5-羟色胺摄取抑制剂(在此情况下所述的物质以两种独立的组合物或以单一组合物如组合的形式存在)同时给药,而且需要连续给药,此时可以优先给予任一活性成分。
活性药物或其药学上可接受的衍生物可以不需配制成分进行应用或优选以适合于药物应用的形式应用,尤其是对人体施治。
除了将活性药物制成合适的形式以外,组合物也可以包含一种或多种药学可接受的辅料。
药物组合物可以口服形式、肠胃外给药形式,包括静脉内、皮下、皮内、肌内、直肠、局部、口颊、皮肤或舌下的形式应用,也可以适合吸入的方式应用。
适合口服给药的制剂可以是单位剂量的形式,例如胶囊、片剂(例如用于儿科的咀嚼片)、可以是粉末或颗粒的形式、水溶液或非水溶液的形式或悬浮液和油包水或水包油的乳剂形式。
片剂可经任选使用一种或多或种辅料制备成压缩片或塑制片。压缩片由合适的压片机制备而成,其中粉末状或粒状的活性成分任选与已知的辅料如粘合剂、填充剂、润滑剂、崩解剂、湿润剂和调味剂混合。粘合剂的例子为糖浆、阿拉伯树胶、明胶、山梨醇和聚乙烯吡咯烷酮。填充剂的例子为不同的羟甲基纤维素填充剂、乳糖、蔗糖、微晶纤维素、玉米淀粉、磷酸钙或羟甲基纤维素。润滑剂的例子为硬脂酸镁、硬脂酸、滑石、聚乙二醇或硅胶。崩解剂的例子为土豆淀粉或羟基乙酸钠。塑制片可以通过将粉末状活性药物与惰性液体溶剂的混合物置于合适的成型机中制备而成。任选将片剂按照制药工业中已知的方法进行包衣。也可以制备缓释或控释片剂。
口服给药用组合物也可以是液体形式,例如水悬浮液或油悬浮液、溶液、乳剂、糖浆剂或酊剂。该组合物也可以制备成干燥形式,在刚好治疗前能够通过合适的方法将其转化成液体形式。
所述的液体制剂可以包含已知的添加剂例如悬浮剂(山梨醇、糖浆、甲基纤维素、葡萄糖、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝胶或食用氢化脂肪)、乳化剂(卵磷脂、单油酸失水山梨醇酯、阿拉伯树胶)、非水物质(甜杏仁油、分馏椰子油、酯、丙二醇、乙醇)、防腐剂(对羟基苯甲酸的甲基酯或丙基酯、山梨醇)或调味添加剂。
栓剂形式的组合物可以含有常规的赋形剂,例如可可油、固体脂肪、聚乙二醇或甘油及其衍生物。
肠胃外给药用组合物是注射用水性或非水性溶液且可以含有抗氧化剂、缓冲剂、杀菌剂和溶于等渗溶液的物质。然后将组合物装于如安瓿(一个或多个单位剂量)中或以冻干形式保存。
适合于局部用药的组合物的例子为霜剂(cream)、凝胶剂、膏剂(ointment)或透皮贴膏剂形式。
鼻内给药的组合物的例子为喷射剂、粉末剂(dust)或滴剂。
适用于治疗的组合物可以是气雾喷射剂,它含有除活性成分以外的推进剂,例如二氧化碳、1,1,1-三氟乙烷、1,1,1,2,3,3,3-七氟丙烷等。
生物学数据
脊髓反射抑制
我们的试验按照Otsuka和Konishi所描述的方法(Otsuka,M.,Konishi S.,Electrophysiology of mammalian spinal cord in vitro,Nature252,733-734;1974))来进行,并稍作改进(Kocsis,P.等,Participation ofAMPA-and NMDA-type excitatory amino acid receptors in the spinalreflex transmission,in rat,Brain Research Bulletin60:81-91;2003)。使用超大的电脉冲刺激分离后的脊髓半横断标本的L5背根并记录L5前根的反射电位。根据刺激后的反应时间和持续时间,得到的反射电位的不同构成是可以完全区分开来的。
钠通道阻滞剂通常是且尤其是在结构和活性上密切相关的托哌酮和乙哌立松,它们在体外的脊髓半横断标本中显示了相当的脊髓反射抑制作用。这是研究两种物质之间的药效学相互作用的理想标本,因为代谢作用的因素没有参与其中。
附图说明
图1表示不同的5-羟色胺摄取抑制剂增加钠通道阻滞剂克劳奈汀的反射抑制活性的效果。Cont(对照组)=单用克劳奈汀的效果;还表示了有氟西汀(Fluo;1μM)、舍曲林(Sert;0.5μM)、帕罗西汀(Paro;10nM)和西酞普兰(Cital;5nM)存在时的效果。
图2表示不同的5-羟色胺摄取抑制剂增加钠通道阻滞剂拉莫三嗪的反射抑制活性的效果。Cont(对照组)=单用拉莫三嗪的效果;还表示了有氟西汀(Fluo;1μM)、舍曲林(Sert;0.5μM)、帕罗西汀(Paro;10nM)和西酞普兰(Cital;5nM)存在的效果。
图3表示5-羟色胺摄取抑制剂(1μM氟西汀)增加不同钠通道阻滞剂的反射抑制活性的效果。从中可以看出拉莫三嗪(Lamo)、克劳奈汀(Cro)、托哌酮(Tolp)、乙哌立松(Eper)和卡马西平(Carba)不加和加上1μM氟西汀的反射抑制效果。
图4中表示单用钠通道阻滞剂拉莫三嗪和克劳奈汀的作用和在5-羟色胺摄取抑制剂以单用没有显著效果的剂量存在时钠通道阻滞剂增加的效力。即,将震颤试验中得到的单用拉莫三嗪和克劳奈汀(Cont)及与10mg/kg氟西汀(Fluo)或10mg/kg舍曲林(Sert)合用的ID50值绘图;所有的物质都经腹膜内给药。
图5显示在5-羟色胺摄取抑制剂存在时钠通道阻滞剂拉莫三嗪的止痛效力增强,其中将扭体试验中获得的单用拉莫三嗪(Cont)与合用10mg/kg的氟西汀(Fluo)的ID50值分别绘于图中。
具体实施方式
在各种情况下,加入5-羟色胺摄取抑制剂都导致钠通道阻滞剂的活性显著增加。
在体内也测量了5-羟色胺的用量(tone)增加后钠通道阻滞剂效力的变化,即在GYKI20039诱导的震颤试验中测试了其震颤抑制作用。
震颤试验
对小鼠中由药物诱导的震颤的抑制作用是化合物对人体弛缓作用的很好的表征。可以通过给予GYKI20039(3-(2,6-二氯苯基)-2-亚氨基噻唑烷)诱导震颤。该方法公开于Kocsis P.,Tarnawa I.,Kovács Gy.,Szombathelyi Zs.,Farkas S.,2002;Acta Pharmaceut.Hung.,72:49-61;US53408231994、US5198446、JP1992270293、EP0468825、1990HU4647。
我们的试验显示将GYKI20039以10mg/kg的剂量对小鼠腹膜内给药引起小鼠强烈的震颤,其持续30-60分钟并在第4至8分钟达到顶峰。其作用方式还不完全清楚,但其与引发震颤(tremorogen)的化合物LON-954的结构类似,表明牵涉减弱多巴胺能和5-羟色胺能系统(Mohanakumar,K.P.,Ganguly,D.K.,1989;Brain Res.Bull.22:191-5)。
GYKI20039诱导的震颤能够被肌松药以不同的作用方式剂量依赖性抑制,因此其为用于比较药物肌松效力的合适方法。该模型通过临床实践中应用的多种不同的肌松药得到了证实。其中所有的药物都产生剂量依赖性抑制作用,这与肌松药的临床抗痉挛效力有关。
我们的研究证明了钠通道阻滞剂具有震颤抑制作用,也证实了5-羟色胺水平提高时钠通道阻滞剂效力发生变化。试验在雄性NMRI小鼠(19-21g)中进行,同时腹膜内给予活性物质。
还将包含固定比例活性成分的组合进行了试验。在这种情况下,也发现了作用增强的现象。下述表1表示通过加入固定比例的5-羟色胺摄取抑制剂(氟西汀),钠通道阻滞剂(拉莫三嗪)的作用增强了。
表1
抑制最大电休克惊厥
抑制最大电休克惊厥(MES;Swinyard,E.A.,Brown,W.C.,Goodman L.S.,Comparative assay of antiepileptic drugs in mice and rats.Journal of Pharmacology and Experimental Therapeutics106,319-330;1952)试验显示了化合物的抗癫痫效力。这项试验在雄性NMRI小鼠(19-21g)中进行。使用SSRI化合物对动物进行预处理后引起钠通道阻滞剂的作用显著增强。而在本试验中单独给予相同剂量的SSRI化合物几乎无效。
下表2表示在自身单用无明显作用的5-羟色胺摄取抑制剂存在的情况下钠通道阻滞剂的效力增强。5-羟色胺摄取抑制剂在电休克前45分钟腹膜内给药而钠通道阻滞剂在30分钟前给药。
表2
我们的结果显示5-羟色胺摄取抑制剂增强了作用机理为阻滞钠通道的抗癫痫药物的效力。另一方面,在研究运动副作用的旋转运动测试中这种加强作用极少表现表明也提高了副作用的分布。因此两种物质组合应用产生了具有更有益的副作用特性、更加有强效的药物。
旋转运动测试
通过旋转运动测试(Dunnham,N.W.,Miya,T.S.J.Am.Pharm.Assoc.46,208,1957)可以研究作为可能的副作用的自主运动的协调性损害和障碍。在这方面由5-羟色胺引起的电压依赖性钠通道阻滞剂的效力变化远不显著,从而导致与母体化合物相比,组合的副作用特性更有益。
本试验使用雄性NMRI小鼠(19-21g)来进行。采用不同的预处理时间进行的试验产生了相似的结果。下述表3表明在5-羟色胺摄取抑制剂存在的情况下钠通道阻滞剂的效力略有增加。
表3
*未测定
苯醌诱导的急性疼痛(扭体(writhing)试验)
本试验采用Hndershot和Forsaith在1959年描述的方法(KazukoGoto等,Analgesic Effect of Mofezolac,a Non-SteroidalAnti-Inflammatory Drug,Against Phenylquinone-Induced Acute Pain inMice,Prostaglandins&other Lipid Mediators56:245-254;1998,PremPrakash Singh等,Acetic Acid and Phenylquinone WrithingTest:A CriticalStudy in Mice,Meth and Find Exptl Clin Pharmacol5(9):601-606;1983)通过将刺激物苯醌注射进腹腔(0.02%的溶液,0.1ml/10g体重)诱导急性疼痛。在给予拉莫三嗪(腹膜内)前15分钟给予氟西汀。试验在雄性NMRI小鼠(19-21g)中进行。
Claims (2)
1.药物组合物,其包含选择性5-羟色胺摄取抑制剂氟西汀和钠通道阻滞剂拉莫三嗪。
2.选择性5-羟色胺摄取抑制剂氟西汀和钠通道阻滞剂拉莫三嗪在制备适合治疗和/或预防哺乳动物的疾病的药物组合物中的应用,所述疾病包括慢性疼痛或癫痫,或由运动系统障碍和/或损伤引起的症状或疾病。
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