CN1129399A - 氟吡氨酯在神经变性疾病中的初级和次级神经保护作用 - Google Patents
氟吡氨酯在神经变性疾病中的初级和次级神经保护作用 Download PDFInfo
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Abstract
氟吡氨酯的NMDA-拮抗作用允许其制备治疗脑缺血、神经变性疾病、创伤性大脑和骨髓损伤、癫痫发作及其它疾病的药物。
Description
氟吡氨酯(KatadolonR)是一新的，作用于中枢的非鸦片镇痛剂。(Jakovlev，V.Sofia，R.D.，Achterrath-Tuckermann，U.，VonSchlichtegroll，A.，Thiemer，K.，Arzneim.-Forsch./Drug Res.35(I)，30(1985)；Nickel，B.，Herz，A.，Jakovlev，V.，Tibes，U.，Arzneim.-Forsch/Drug Res.35(II)，1402(1985)。氟吡氨酯通过不同于鸦片/类鸦片镇痛剂的作用机制而发挥其的中枢镇痛效应。(Nickel，B.，Postgrad.med.J.63(Suppl.3)，19(1987)；Szelenyi，I.，Nickel，B.，Borbe，H.O.，Brune K.，Br.J.Phamacol.143，89(1989))。电生理研究表明，氟吡氨酯能在棘上和棘水平干涉感受伤害过程。(Carlsson，K.H.Jurna，I.，Eur.J.pharmacol.143，89(1987)；Bleyer，H.，Carlsson K.H.，Erkel H.J.，Jurna，I.，Eur.J.Pharmacol 151，259(1988)；Nikel，B.Aledter，A.，Postgrad Med.J.63(Suppl.3)41(1987))。
氟吡氨酯因此已用于治疗由于运动器官疾病引起的急性疼痛。氟吡氨酯也已成功地用于患有神经痛、癌痛、血管舒缩及偏头痛、术后痛、受伤、灼烧及糜烂到起的疼痛、痛经和牙痛的患者。这些适应症及使用剂量由专业信息提供(KatadolonR，单一镇痛，科学手册，第二修订版04/1992，由ASTA Medica AG出版)。
氟吡氨酯与非甾体抗炎药的联合药剂在EP 189 788中有描述。在这些适应症中，氟吡氨酯不仅可以镇痛，而且具有肌松性质，如德国公开说明书4122166,4中所述。
就化学而言，氟吡氨酯为2-氨基-3-乙基-乙氧羰基氨基-6[5-氟苯甲基]-氨基吡啶的马来酸盐。氟吡氨酯及其药用盐的合成在EP 160865和199 951中有描述。氟吡氨酯马来酸盐的化学结构不能归类于迄今已知的具镇痛作用的药剂。氟吡氨酯是一种无色、晶状、几乎无味的粉末，具有微苦甜的味道。其仅仅中度溶于水。氟吡氨酯的镇痛效果已在各种动物实验中的疼痛模型中证实，即在小鼠、大鼠和狗上的机械(Haffner试验)、热(热盘试验)、电(电痛试验，牙髓刺激)、化学(扭曲试验)及化学-机械刺激。单一镇痛的氟吡氨酯的更多的作用及副作用在科学手册上记载(KatadolonR，单一镇痛，科学手册，第二修订版04/1992，由ASTA Medica AG出版)。药理实验表明，氟吡氨酯具有棘和棘上的进攻。用拮抗剂的阻滞实验表明，含血清素的及类鸦片体系都不介导氟吡氨酯的抗感受伤害的效应。最可能的解释为，氟吡氨酯介导的镇痛参与下行去甲肾上腺素能痛觉-调节的途径(I.Szelenyi，B.Nickel，H.O.Borbe，K.Brune Br.J.pharmacol.(1989)，97，835-842)，尽管氟吡氨酯对α1或α2-肾上腺素能受体没有亲合力(B.Nickel et al.，Br.J.pharmacol.(1989)97，835)。
此外，对大鼠大脑鸦片受体的这种亲合力缺失也反对了氟吡氨酯类似鸦片的作用机制。根据这些结果，排除了氟吡氨酯与鸦片相同的作用机制。而且也没有观察到耐受性和依赖性。
当研究氟吡氨酯在大鼠中的肌松效果时，惊奇地发现氟吡氨酯的效果能被兴奋性氨基酸N-甲基-D-天冬氨酸(NMDA)所抑制。这些发现表明。氟吡氨酯的效果至少部分通过抑制NMDA-介导的兴奋来调节。这就使氟吡氨酯作为兴奋性氨基酸的拮抗剂来治疗由兴奋性氨基酸介导的疾病，例如脑缺血、神经变性疾病和癫痫发作成为可能。
在大鼠上进行体内实验。将雄性Wistar大鼠(体重250-280g)用乌拉坦(400mg/kg，腹膜内)和α-choralose(80mg/kg，腹膜内)麻醉。用透皮针电极刺激胫骨肌神经进行H-反射导程(0.2ms持续时间的单方脉冲，刺激强度为反射阈的两倍)。用一对皮下Klippel电极从足底肌记录EMG导程。
以低刺激强度对胫骨肌神经的电刺激通过类似于人Hoffinann(H)-反射的反射应答产生，(H)-反射是一种棘α-运动神经元的单突触兴奋，特别是通过初级肌梭传入神经产生。随着刺激强度的提高，H-反射通过一种称为M-波的第二个短潜伏期的EMG波产生，该波可归因于直接刺激α运动神经元的轴突。在腹膜内注射溶剂或不同的物质之前(对照)及之后或者在鞘内注射之后，利用计算机程序将10个连续的反射应答平均。M-波以及H-反射的大小通过测量峰-峰间的振幅而确定。
为引起屈肌反射，用一对精密的皮下针电极(刺激频率为500Hz的5个连续方脉冲，其中每个为0.2ms的持续时间，刺激强度为反射阈的三倍)刺激一只后爪。用一对精密针电极从同侧胫骨肌神经记录EMG导程。校正7个连续的EMG应答，在腹膜内注射溶剂或不同的物质之前及之后或者在鞘内注射之后，利用PC平均。屈肌反射的大小从反射曲线和基线之间的区域得到。
在所有的反射研究中，在注射溶剂或物质之后即得到注射前适当对照值百分数的测量值。利用Mann-Whitney U-试验进行统计学分析。
将聚乙烯导管(PE10)装在大鼠上以便鞘内注射。暴露寰椎-枕肌膜，在中线区域小心切开。然后将导管引入棘腔，末端推到腰髓区。以每分钟1μl的灌注速率注射入5μl溶剂或物质。随后注入10μl溶剂以确保所有的物质经导管进入棘腔。
当完成实验后，经导管注入2％的Evans蓝墨水而确定导管末端的确切位置。
将氟吡氨酯(ASTA Medica AG，德国)，盐酸育亨宾(SigmaChemicals，美国)和哌唑嗪(RBI，美国)溶于生理盐水溶液中。将NMDA(Sigma)，甲磺化毕扣扣灵(Sigma)，6，7-硝基喹喔啉-2，3-二酮(DNQX)(RBI，美国)及ATPA(由Dr.Tutski，Schering，德国提供)溶于少量1摩尔的NaOH中，用盐水补足。Phaclofen(Tocris，大不列颠)溶于0.2N HCl中，总体积也用盐水补足。
将Flumazenil(由Haefelv教授提供，Hoffmann-La Roche，瑞士)溶于吐温80和蒸馏水中。调节所有溶液的pH值至7.2-7.4。在腹膜内注射溶剂过程中，单突触H-反射和多突触屈肌反射都未受影响，每公斤体重以1至10mg剂量系统给予氟吡氨酯以剂量依赖的方式降低屈肌反射(图1至图3)。在10分钟内氟吡氨酯产生作用，注射后10至30分钟达最大并持续20至60分钟(依赖剂量)。
不同的是，H-反射不受氟比氨酯的影响。即使是氟吡氨酯的最大剂量(每公斤10mg)(其可将屈肌反射减弱至约50％的初始值)，也对H-反射无影响(图3)。
鞘内给药后也同样确证了氟吡氨酯对屈肌反射和H-反射的不同影响。在33-330nmol的剂量，氟吡氨酯在鞘内注射后减弱了屈肌反射而不改变H-反射(图4)。这一效应同样在10分钟内出现并持续40-60分钟(依选择的剂量而定，图5)。鞘内注射溶剂对屈肌反射和H-反射都无影响。给予溶剂及注射氟吡氨酯都不改变M波。这证明了所选择的制剂的稳定性。人的药理反射研究证实了动物的药理学数据。在人体中(口服给药)，氟吡氨酯也仅仅减弱屈肌反射，而H-反射不受影响。
为获得在传递GABA、去甲肾上腺素或兴奋性氨基酸时的变化是否与氟吡氨酯的肌松作用有关，我们研究了不同物质(其作为激动剂或拮抗剂攻击受体)对氟吡氨酯肌松作用的影响。鞘内注射氟吡氨酯(165nmol)后对屈肌反射的降肌作用不受同时给予GABAA-拮抗剂毕扣扣灵(1nmol)和GABAB-拮抗剂Phaclofen及α1-拮抗剂哌唑嗪(100nmol)(图6)或者兴奋性氨基酸ATPA(α-氨基-3-羟基-5-叔基-4-异恶唑-丙酸proprionic酸))(0.1pm)(图8)，其为quisqualate受体的潜在激动剂。腹膜内注射苯并二氮卓类拮抗剂flumazenil(5mg/kg)也不影响氟吡氨酯的作用。flumazenil应系统给药，因为其水不溶性不能鞘内给药。相比而言，联合给予混合的α1-α2-拮抗剂育亨宾(10nmol)(图7)或兴奋性氨基酸NMDA(0.1nmol)(图8)阻止了氟吡氨酯对屈肌反射的作用。毕扣扣灵、phaclofen、哌唑嗪、ATPA、flumazenil、育亨宾及NMDA分别按不影响反射大小的剂量给药(图6-9)，但是其足以拮抗GABAA-激动剂蝇覃醇、α2-激动剂咪噻二唑及NMDA-拮抗剂2-氨基-膦酰基-庚酸酯(AP7)的降肌作用以及拮抗二甲金刚胺对棘的反射。
随后的实验表明，多突触屈肌反射在腹膜内(1-10mg/kg体重)和鞘内(33-330nmol)给予氟吡氨酯后降低而不破坏单突触Hoffmann(H)-反射(以依赖于剂量的方式)。
在这些实验中，联合给予兴奋性氨基酸N-甲基-D-天冬酰胺(NMDA)降低了氟吡氨酯的肌松作用。与这些发现相符合，氟吡氨酯的作用，是通过抑制兴奋性氨基酸的传递而介导的。在这种情况下，经NMDA受体介导的传递尤其受到破坏。
附图说明
图1：由后爪的电刺激引起(5个刺激，频率500Hz，3倍于反射阈)的胫骨肌神经的屈肌反射(上图)及Hoffmann(H)-反射和M-波(下图)，其来自对胫骨肌(前药)电刺激(单一刺激，两倍于反射阈)后并且在腹膜内注射10mg/kg氟吡氨酯后的足底肌。刺激现象用箭头标出。
图2：腹膜内注射溶剂或不同氟吡氨酯剂量后对屈肌反射的作用时间。横坐标：注射后的时间(分钟)，纵坐标：屈肌反射的大小相对于注射前的百分数(平均值+SEM，每组6-8只动物)。显著性**p＜0.001 vs.溶剂(Mann-Whitney U-试验)
图3：腹膜内注射氟吡氨酯(1-10mg/kg)对屈肌反射(上)及H-反射(下)大小的作用。大小以注射前适当值的百分数表示(平均值+SEM，每组6-8只动物)。
C：溶剂，显著性**p＜0.01，***p＜0.001vs。溶剂(Mann-WhitneyU-试验)
图4：鞘内内注射氟吡氨酯(33-330nmol)对屈肌反射(土)及H-反射(下)大小的作用。大小以注射前适当值的百分数表示(平均值+SEM，每组7-10只动物)。
C：溶剂，剂量为nmol，显著性**p＜0.01，***p＜0.00lvs。溶剂(Mann-Whitney U-试验)
图5：鞘内注射溶剂或不同氟吡氨酯剂量(33-330nmol)后对屈肌反射的作用时间。横坐标：注射后的时间(分钟)，纵坐标：屈肌反射的大小相对于注射前的百分数(平均值+SEM，每组7-10只动物)。显著性*p＜0.05，**p＜0.01，***p＜0.001 vs.溶剂(Mann-Whitney U-试验)
图6：鞘内注射毕扣扣灵(Bic；上)或phaclofen(phac；下)及氟吡氨酯对屈肌反射的作用，剂量为nmol，显著性**p＜0.01，***p＜0.001vs.溶剂(Mann-Whitney U-试验)
图7：鞘内注射育亨宾(Yoh；上)或哌唑嗪(praz；下)及氟吡氨酯对屈肌反射的作用，剂量为nmol，显著性**p＜0.01，***p＜0.001vs。溶剂：+p＜0.05，++p＜0.01vs。氟吡氨酯(Mann-Whitney U-试验)
图8：鞘内注射NMDA(上)或ATPA(下)及氟吡氨酯对屈肌反射的作用，剂量为nmol，显著性**p＜0.01，***p＜0.001vs.溶剂；+p＜0.05，++p＜0.01vs.氟吡氨酯(Mann-Whitney U-试验)
图9：腹膜内注射flumazenil(Flum)及鞘内注射氟吡氨酯对屈肌反射大小的作用。剂量为mg/kg(Flum)和nmol(氟吡氨酯)。显著性**p＜0.01，***p＜0.001(Mann-Whitney U-试验)
本发明的一个目的是提供用于神经变性疾病以及类似疾病的含有活性物质氟吡氨酯的药物制剂。
以氟吡氨酯的药理学结论为基础的可治疗疾病有，例如脑缺血、特发性帕金森病、毒性或药物诱导的帕金森综合症、阿尔茨海默病和不同起因的大脑痴呆症、亨廷顿舞蹈病；多发性硬化、肌萎缩性脊髓侧索硬化、感染性神经变性疾病如AIDS-脑病、克罗伊茨费尔特-雅各布综合症、由rubiola和疱疹病毒以及borrelioses引起的脑病、代谢毒性性神经变性疾病如肝性、醇性、低或高血糖性脑病，以及由溶剂或药物导致的脑病、不同起因的变性性视网膜疾病、创伤性大脑和骨髓损伤、不同起因的大脑过度兴奋综合症如在对药物、毒素、病原及毒品上瘾和/或戒除后，精神及创伤性大脑过度兴奋状态、周围神经系统的神经变性综合症如代谢、药物、毒性及感染性多神经病及多神经炎，也可用于支气管痉挛。
也可以将氟吡氨酯与抗帕金森药物例如L-多巴及各种多巴胺激动剂分别或连续使用，或者以联合药物的形式使用。本发明中将L-多巴用于联合药物时使用的剂量为2mg-200mg L-多巴1(与羟苄丝肼或甲基多巴肼固定结合)和5mg-100mg氟吡氨酯，当使用多巴胺激动剂如溴麦角隐亭作为联合药物时，其为0.5mg-10mg，氟吡氨酯为5mg-100mg；当使用麦角乙脲作为联合药物时，其为0.05mg-0.2mg，氟吡氨酯为5mg-100mg；当使用硫丙麦角林作为联合药物时，其为0.01mg-1mg，氟吡氨酯为5mg-100mg；当使用单胺氧化酶-B抑制剂丙炔苯丙胺时，其为0.1mg-5mg，氟吡氨酯为5mg-100mg。类似地，氟吡氨酯可以与抗氧剂、抗癫痫药、循环促进药物以及精神抑制药分别使用，或者以联合药物给药。
氟吡氨酯的性质也允许其可单独或与其它精神抑制药一起用于精神抑制性痛觉缺失。剂量形式可以是，例如片剂、膜包衣片、硬明胶胶囊、软明胶胶囊、丸、颗粒剂、包衣片、栓剂、微囊、水或油性混悬剂、油溶液、肌内及鞘内给药的注射溶液、静脉内给药的注射溶液及输注溶液。用于制备药物的适当盐为所有氟吡氨酯生理上可接受的盐。例如，可使用氟吡氨酯的氯化物、马来酸盐、硫酸盐及葡糖酸盐。以下的剂量信息视氟吡氨酯为一个碱。如果使用氟吡氨酯的盐，应根据分子量加以换算。
也可以用德国公开说明书39 12 292中所述的方法将氟吡氨酯转化为一种持续释放的形式。本发明药物中氟吡氨酯的用量为：
10mg-3000mg，优选20mg-2000mg，更优选50mg-1500mg。所述药物的单一剂量可以是口服、直肠、静脉内、鞘内或肌内给药，每日1-5次，优选1-3次，最好每日1-2次。
Claims (16)
1.将活性物质氟吡氨酯用于制备治疗脑缺血药物的用途。
2.将活性物质氟吡氨酯用于制备治疗神经变性疾病药物的用途。
3.将活性物质氟吡氨酯用于制备治疗癫痫发作药物的用途。
4.将活性物质氟吡氨酯用于制备治疗帕金森病药物的用途。
5.将活性物质氟吡氨酯用于制备治疗阿尔茨海默病药物的用途。
6.将活性物质氟吡氨酯用于制备治疗亨廷顿舞蹈病药物的用途。
7.将活性物质氟吡氨酯用于制备治疗多发性硬化症药物的用途。
8.将活性物质氟吡氨酯用于制备治疗肌萎缩性脊髓侧索硬化药物的用途。
9.将活性物质氟吡氨酯用于制备抗感染性神经变性疾病药物的用途。
10.将活性物质氟吡氨酯用于制备治疗代谢毒性神经变性疾病药物的用途。
11.将活性物质氟吡氨酯用于制备治疗视网膜变性和局部缺血药物的用途。
12.将活性物质氟吡氨酯用于制备治疗创伤性大脑及骨髓损伤药物的用途。
13.将活性物质氟吡氨酯用于制备治疗大脑过度兴奋综合症药物的用途。
14.将活性物质氟吡氨酯用于制备治疗周围神经系统的神经变性综合症药物的用途。
15.将活性物质氟吡氨酯用于制备精神抑制性痛觉缺失药物的用途。
16.将活性物质氟吡氨酯用于制备治疗帕金森病的氟吡氨酯和L-多巴及多巴胺拮抗剂联合药物的用途。
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| DE19539861A1 (de) * | 1995-10-26 | 1997-04-30 | Asta Medica Ag | Verwendung von 4-Amino-4-(4-fluorbenzylamino)-1-ethoxy-carbonylaminobenzen zur Prophylaxe und Behandlung der Folgen der akuten und chronischen zerebralen Minderdurchblutung sowie neurodegenerativer Erkrankungen |
| DE19541405A1 (de) * | 1995-11-07 | 1997-05-15 | Asta Medica Ag | Verwendung von Flupirtin zur Prophylaxe und Therapie von Erkrankungen, die mit einer Beeinträchtigung des hämatopoetischen Zellsystems einhergehen |
| DE19625582A1 (de) * | 1996-06-27 | 1998-01-02 | Asta Medica Ag | Verwendung von Flupirtin zur Prophylaxe und Therapie von Erkrankungen die mit einer unphysiologisch hohen Zellsterberate einhergehen |
| ATE284684T1 (de) | 1997-10-27 | 2005-01-15 | Sumitomo Pharma | Amidderivate zur behandlung neurodegenerativer erkrankungen der netzhaut |
| WO2001034172A2 (en) * | 1999-11-05 | 2001-05-17 | Vela Pharmaceuticals Inc. | Methods and compositions for treating reward deficiency syndrome |
| WO2001039760A2 (en) * | 1999-12-01 | 2001-06-07 | Duke University | Method of treating batten disease |
| US6821995B1 (en) | 1999-12-01 | 2004-11-23 | Duke University | Method of treating batten disease |
| DE10327674A1 (de) | 2003-06-20 | 2005-01-05 | Awd.Pharma Gmbh & Co. Kg | Injizierbare Darreichungsform von Flupirtin |
| DE10328260A1 (de) * | 2003-06-23 | 2005-01-27 | Schmidt, K.-G., Dr. med. | Flupirtine-Präparat |
| CA2550023C (en) * | 2003-12-16 | 2011-04-12 | Cnsbio Pty Ltd | Treatment of neuropathic pain |
| WO2006065204A1 (en) * | 2004-12-14 | 2006-06-22 | Astrazeneca Ab | Substituted aminopyridines and uses thereof |
| EP1688141A1 (en) | 2005-01-31 | 2006-08-09 | elbion AG | The use of flupirtine for the treatment of overactive bladder and associated diseases, and for the treatment of irritable bowel syndrome |
| US20060258708A1 (en) * | 2005-05-16 | 2006-11-16 | Andrulis Peter J Jr | Method for treating Parkinson's disease and other neurological diseases |
| US20080279930A1 (en) * | 2007-05-07 | 2008-11-13 | Bernd Terhaag | Controlled-Release Flupirtine Compositions, Compacts, Kits and Methods of Making and Use Thereof |
| DE102011006425A1 (de) | 2010-03-31 | 2011-10-06 | Awd.Pharma Gmbh & Co. Kg | Pharmazeutische Zubereitung und deren Verwendung |
| DE102010030053A1 (de) | 2010-06-14 | 2011-12-15 | Awd.Pharma Gmbh & Co.Kg | Injizierbare Darreichungsform von Flupirtin |
| MX2016001177A (es) * | 2013-07-31 | 2016-04-29 | Teva Pharma | Tratamiento de esclerosis multiple con la combinacion de laquinimod y flupirtina. |
| WO2019014547A1 (en) * | 2017-07-14 | 2019-01-17 | Texas Tech University System | FUNCTIONALIZED PYRIDINE CARBAMATES HAVING ENHANCED NEUROPROTECTOR ACTIVITY |
| DE102017007385A1 (de) | 2017-08-02 | 2019-02-07 | Christoph Hoock | Maleatfreie feste Arzneimittelformen |
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| US4481205A (en) * | 1980-09-13 | 1984-11-06 | Degussa Aktiengesellschaft | 2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate |
| ATE25078T1 (de) * | 1982-10-27 | 1987-02-15 | Degussa | 2-amino-3-acylamino-6-benzylamino-pyridinderivate mit anti-epileptischer wirkung. |
| DE3337593A1 (de) * | 1982-10-27 | 1984-05-03 | Degussa Ag, 6000 Frankfurt | 2-amino-3-acylamino-6-benzylamino-pyridin-derivate mit antiepileptischer wirkung |
| NO860825L (no) * | 1985-03-23 | 1986-09-24 | Degussa | Fremgangsmaate til fremstilling av 2-amino-3-nitro-6-(4-fluor-benzylamino)-pyridin samt 2-amino-3-karbetoksyamino-6-(4-fluor-benzylamino)-pyridin. |
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