CN100500146C - 长春西汀及其衍生物在癫痫及其并发症的治疗和预防中的应用 - Google Patents
长春西汀及其衍生物在癫痫及其并发症的治疗和预防中的应用 Download PDFInfo
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Abstract
本发明涉及长春西汀及其衍生物的用途,这些衍生物从长春西汀的结构式衍生而来,它们在癫痫及其并发症的治疗中保持相同效果。我们的结果表明,长春西汀防止伴随癫痫性脑皮质层活动的ABR波的所有异常,这种现象在2个体内癫痫症实验模型的发作期和发作后时期观察到,长春西汀还抑制2种不同作用机制的痉挛剂诱发的显著性的听力损失和特征性的EEG变化。这些发现也表明长春西汀作为一种抗癫痫类药物不会伴随继发性的反作用。
Description
技术领域
本发明涉及长春西汀及其衍生物的用途,这些衍生物从长春西汀的结构式衍生而来,它们在癫痫及其并发症、特别是与听觉通路有关的那些病症的治疗中保持相同效果。
背景技术
癫痫的一个主要问题是由癫痫(Prevey等,1998 Epilepsy Res.30:1;Jokeit和Ebner 1999 J.Neurol.Neurosurg.Psychiatry 67:44;Theodore等,1999 Neurology 52:132;Meador 2001 Epilepsy Behav.2:307)及可用的抗癫痫的药物治疗(Gates 2000 Epilepsy Behav.1:153;Kwan和Brodie 2001Lancet 357:216;Brunbech和Sabers 2002 Drugs 62:593;Schmidt 2002Epilepsy Res.50:21)引起的有害的认知和行为后果。
从全身性癫痫患者上观察到的听觉脑干反应(ABR)的潜伏期和/或后继波的振幅改变暗示听觉脑干核与全身性癫痫病理生理学有关(Rodin等,1982 Clin.Electroencephalogr.13:154;Mervaala等,1986 Epilepsia 27:542;Phillips等,1990 Clin.Electroencephalogr.21:135;Soliman等,1993Ear Hear 14:235;Kohsaka等,1999 Brain Res.837:277;Kohsaka等,2001Brain Res.903:53)。非加药动物中由2种痉挛剂引起的急性癫痫伴随着听觉脑干反应(ABR)后继波(later wave)异常和显著的听力下降(Nekrassov和Sitges 2003 Epilepsy Res.53:245)。
听觉脑干反应(ABRs)是一种远场-诱发电势,该电势包含一些发生在听觉刺激后10毫秒之内的波。由于听觉脑干反应(ABR)后继波的变化表明听觉脑干中特定核的改变(Hughes,J.R.,Fino,J.J.,1985 J.Clin.Neurophysiol.2:355),听觉脑干反应(ABRs)通常用于耳蜗后损伤的临床诊断。而且,ABR阈值也用于听力敏感性的临床诊断,因为激发ABR需要逐渐增强的较高强度(dB)的刺激而听力敏感性降低。因此,ABR阈值升高是听力损害的一个客观判断标准。
包括卡马西平(carbamazepine)、丙戊酸盐(valproate)、苯妥英(phenytoin)、苯巴比妥(phenobarbital)、氯硝西泮(clonazepam)和氨己烯酸(vigabatrin)在内的抗癫痫药物也会引起ABR波的异常和听力下降(Mervaala et al.1987 Electroencephalogr.Clin.Neurophysiol.68:475;Armon et al.1990 Neurology 40:1896;Hirose et al.1990 Electroencephalogr.Clin.Neurophysiol.75:543;Yuksel et al.1995 Childs Nerv.Syst.11:474;Dela Cruz和Bance 1999 Arch Otolaryngol Head Neck Surg.125:225;Zgorzalewicz和Galas-Zgorzalewicz 2000 Clin.Neurophysiol.111:2150)。
几十年来,发现于20世纪60年代后期的长春西汀(阿扑长春胺-22-酸乙酯)已经成功地应用于脑血管源性的中枢神经系统病症的治疗。在缺氧和局部缺血的动物模型中,长春西汀表现出有利的抗神经元损伤的作用(King 1987 Arch.Int.Pharmacodyn.Ther.286:299;Araki et al.1990Res..Exp..Med.190:19)。
最近,基于早先的动物和人体试验研究,长春西汀也已经应用于改善记忆力(Subhan和Hindmarch 1985 Eur.J.Clin.Pharmacol.28:567;Bhatti和Hindmarch 1987 Int.Clin.Psychopharmacol.2:325;DeNoble 1987Pharmacol.Biochem.Behav.26:183)。
长春西汀是一种钠离子通道阻断剂( et al.1996 Europ.J.Pharmacol.314:69)。在脑分离神经末端,我们观察到长春西汀可以选择性抑制由突触前钠离子通道通透性增加诱发的神经传递素的释放(Sitges和Nekrassov,1999 Neurochem.Res.24:1587;Trejo et al.2001 Brain Res.909:59)。而且,我们在豚鼠的体内实验观察到长春西汀对阿米卡星(Nekrassov和Sitges 2000 Brain Res.868:222)和其它氨基糖苷类抗生素(未发表结果)引起的ABR波的改变、听力丧失和死亡有长期的抑制作用。
癫痫的治疗存在显而易见的药物需要。尽管“老的和新一代的”抗癫痫药物的药物治疗对发作控制表现出积极的效果(至少在约70%的癫痫患者中有效),应用这些抗癫痫药物治疗却能损伤认知功能(Vermeulen和Aldenkamp 1995 Epilepsy Res.22:65;Gates 2000 Epilepsy Behav.1:153;Brunbech和Sabers 2002 Drugs 62:593;Schmidt 2002 Epilepsy Res.50:21),这种恶化可能加剧疾病本身带来的认知水平下降(Prevey et al.1998Epilepsy Res.30:1;Jokeit和Ebner 1999 J.Neurol.Neurosurg.Psychiatry 67:44;Theodore et al.1999 Neurology 52:132;Meador 2001 Epilepsy Behav.2:307)。这些抗癫痫药物也能引起ABR波的改变(Mervaala et al.1987Electroencephalogr.Clin.Neurophysiol.68:475;Armon et al.1990 Neurology40:1896;Hirose et al.1990 Electroencephalogr.Clin.Neurophysiol.75:543;Yuksel et al.1995 Childs Nerv.Syst.11:474;De la Cruz和Bance 1999 ArchOtolaryngol Head Neck Surg.125:225;Zgorzalewicz和Galas-Zgorzalewicz2000 Clin.Neurophysiol.111:2150),ABR波的改变能导致听力下降(Nekrassov和Sitges 2003 Epilepsy Res.53:245);而且,在癫痫首次发作之后,这些药物并不能产生有效的预防作用(Hernandez 1997 TrendsPharmacol.Sci.18:59;Temkin et al.2001 Drugs 61:1045;Schmidt 2002Epilepsy Res.50:21)。
目前可用的抗癫痫药物促发一些继发性反作用,这些重要改变将限制患者的日常生活,患者往往因此而停止治疗。
本发明涉及长春西汀及其衍生物的用途,这些衍生物从长春西汀结构式衍生而来,而且对治疗癫痫同样有效,为癫痫的治疗提供了药物选择性。本发明描述了长春西汀的有益作用,可以防止发作期和发作后时期癫痫性的脑皮质活动,也可以防止癫痫本身引起的和可用抗癫痫药物加重的非常重要的病症。
附图简述
图1本图显示的是代表性动物的ABR记录,(a)在PTZ之前4小时预先注射载体的动物中,注射戊四氮(PTZ)之前,(b)注射PTZ后50分钟的ABR,(c)在PTZ之前4小时预先注射长春西汀的动物中,注射PTZ后50分钟的ABR。如箭头所示,动物受到高频率(8kHz)和高强度(100dB)的纯音单耳刺激。
图2本图显示的是长春西汀抑制PTZ诱发的ABR P2,P3和P4波的峰值潜伏期的增长。分别记录动物在注射PTZ之前和注射PTZ之后10,20,30和50分钟,在8kHz音频(左侧曲线)和4kHz音频(右侧曲线)由100dB强度的刺激诱发的ABR波潜伏期,实验组动物在注射PTZ之前按2mg/kg体重预先注射长春西汀(空心圆圈),对照组动物注射载体(黑色圆圈)。结果取自8只独立动物的平均值±SEM值。
图3本图显示的是长春西汀抑制发作期PTZ诱发的脑电图(EEG)变化。记录在注射PTZ前4小时预先注射载体的模式动物在注射PTZ前(上部曲线)和注射PTZ后约2分钟(中间曲线)的脑电图变化,底部曲线记录的是在注射PTZ之前4小时预先注射长春西汀的动物中注射PTZ后约2分钟的脑电图变化。
图4本图显示的是长春西汀抑制发作后时期PTZ诱发的脑电图(EEG)变化。记录预先注射载体的代表性动物在注射PTZ前(上部曲线)和注射PTZ后10,20,30和50分钟的脑电图变化,也记录预先注射长春西汀的代表性动物在注射PTZ前(上部曲线)和注射PTZ后10,20,30和50分钟的脑电图变化。
图5本图显示的是长春西汀抑制由另外一种痉挛剂,4-氨基吡啶(4-AP)诱发的ABR后继波的振幅改变。ABR波由8kHz音频100dB强度的刺激诱发产生。如图所示,对照组动物注射4-氨基吡啶(4-AP)后观察到的ABR P3波振幅渐进性升高现象(a)在预先注射长春西汀的动物中被消除(b),对照组动物注射4-氨基吡啶(4-AP)后观察到的ABRP4波振幅显著降低现象(c)在注射长春西汀的动物中被极大的减弱了(d)。
图6本图显示的是长春西汀抑制发作期4-氨基吡啶(4-AP)诱发的脑电图(EEG)变化。(a)记录预先注射载体的代表性动物在注射4-AP前和注射4-AP后约20分钟的脑电图变化,(b)记录预先注射长春西汀(2mg/kg体重)的代表性动物在注射4-AP前和注射4-AP后约20分钟的脑电图变化。
图7本图显示的是长春西汀抑制发作后时期4-氨基吡啶(4-AP)诱发的脑电图(EEG)变化。(a)记录预先注射载体的代表性动物在注射4-AP前(上部曲线)和注射4-AP后30,60和80分钟的脑电图变化,(b)记录预先注射长春西汀的代表性动物在注射4-AP前(上部曲线)和注射4-AP后30,60和80分钟的脑电图变化。
发明详述
在早先的研究中我们证明以ABR后继波的参数(振幅和潜伏期)异常反映的上橄榄复合体外侧核和内侧核活动与癫痫症引发的听力下降相关(Nekrassov和Sitges,2003 Epilepsy Res.53:245)。
本发明论证了长春西汀抑制ABR后继波振幅和潜伏期变化,听力的降低和特征性的癫痫性脑皮层活动,这些现象可在2种癫痫实验动物模型体内观察到。
通过体内试验降低大脑抑制性传递介素水平或者升高大脑兴奋传递介素水平可以诱发实验动物的癫痫症。这可以通过分别注射GABA拮抗剂、PTZ或谷氨酸释放剂、4-氨基吡啶(4-AP)引起。豚鼠试验结果显示,当在注射PTZ 4小时前或注射4-AP 1小时前长春西汀的腹膜内给予量为2mg/kg时,这些痉挛剂都不能诱发ABR后继波的振幅和潜伏期改变、激发听力下降或诱发癫痫性的大脑皮质层活动。
豚鼠的ABR P3和P4波分别代表上橄榄核内侧核和外侧核活动(Wada和Starr,1983,Electroencephalog.Clin.Neurophysiol.56:326;56:340;56:352)。在上橄榄核中,P4波发生器决定声源的定位(Tollin 2003Neuroscientist 9:127)。ABR后续波的这些变化预示耳蜗后(retro-cochlear)的变化。长春西汀取消了PTZ或4-AP诱发的所有耳蜗后异常(P3和/或P4参量的变化可以证实),并且通过这种方式防止了这两种痉挛剂诱发的听力下降。
目前可用的抗癫痫类药物诱发ABR波参量变化和听力下降,这将加剧癫痫本身诱发的异常症状和听力损失。尽管抗癫痫药物的药物治疗在发作控制方面表现出积极的效果,但同时也引发了继发性的副作用,这些副作用中尤其以认知水平下降和听力损失为严重。长春西汀具有很好的耐受性,没有禁忌征,人类的服用量可以高达60毫克/天(Hindmarch et al.1991Int.Clin.Psychopharmacol.6:31),我们的试验结果表明合理剂量(2mg/kg)的长春西汀可以完全取消PTZ和4-AP诱发的发作时和发作后时期的脑皮质活动和这两种痉挛剂诱发的听力损失。长春西汀可以防止癫痫本身及传统抗癫痫类药物引发的听力损失和下降,这代表了长春西汀用作抗癫痫药物相对于传统抗癫痫治疗的优越性。
目前可用抗癫痫类药物的另一个问题是它们不能对癫痫的发生或进展产生明显的影响。在早先的研究中我们已经证明长春西汀对高剂量阿米卡星治疗诱发的ABR波改变、听力损失和死亡表现出长期的(大于半年)保护作用(Nekrassov和Sitges 2000 Brain Res.868:222),这表明长春西汀对癫痫的治疗也表现出重要的预防作用。
概括来说,我们的发现表明长春西汀防止发作期和发作后时期癫痫性脑皮质活动,并能防止ABR波改变,ABR波改变将导致听力损失,而且有助于癫痫本身及可用抗癫痫类药物引发的对认知的副作用。这些发现和长春西汀的长期保护作用,表明长春西汀是一种更好的治疗和预防癫痫的替换药物。
实施例
实验使用初始体重349±38克的有颜色的成年雄性豚鼠。ABR记录用来评估每只动物的听力状况,脑电图EEG记录用来评估脑皮质兴奋度的变化。ABR波和脑电图EEG记录按照我们早先发表的方法(Nekrassov和Sitges,2003)获得。所有的实验程序由Institutional Animal Use and CareCommittee核准认可。
在麻醉动物身上记录3类数据,即为高强度声波(100dB)刺激引起的ABR记录,确定听阈的ABR记录和脑电图EEG。
ABR波参量的确定。记录指定时间不同实验条件下的ABR,从记录中测量ABR每个波成分的潜伏期和振幅,听觉刺激为纯音频4和8kHz、强度100dB的声波。ABR波的潜伏期(单位ms)是指听觉刺激开始到ABR波出现正向峰值的时间间隔。图1上记录底部的竖直箭头所指处为刺激开始的时刻。ABR每个波的最大振幅(单位μV)是波的正峰值和参考基线(图1中刺激和ABR波第一次出现点之间的连线)之间的距离。
ABR阈值的确定。强度(单位dB)逐渐降低的声波刺激诱发的ABR记录可以用于确定听阈。阈值定义为在三次连续试验中仍然能够记录到ABR P3波的最低的刺激强度(单位dB)。
Student’s t-检验用于评估注射痉挛剂之前和之后特定时刻获得的结果之间的差异。所有测量值的统计学显著性标准都是P≤0.05。所有数据表示为平均值±平均值标准误差。图和表格中*用于表示有统计学显著差异。
实施例1.用于检验长春西汀影响大脑抑制性传递介素水平降低引起的癫痫症诱发的ABR和脑电图EEG的变化的实验设计。
本研究中使用8只雄性豚鼠。PTZ溶解于生理盐水,长春西汀溶解于用盐酸酸化的生理盐水中后再用氢氧化钠调节到pH 4。豚鼠注射载体后4小时(酸化的生理盐水用于溶解长春西汀)该动物被麻醉,记录腹膜内注射痉挛剂PTZ之前的第一组ABR和脑电图EEG。给动物注射PTZ(100mg/kg),记录注射PTZ后约2分钟(发作期)的脑电图EEG。接着记录发作后时期特定时刻的其它系列的ABR和脑电图EEG。2周后获得同样系列的记录,但是在注射PTZ之前4小时用长春西汀(2mg/kg)而不是载体注射动物。
下面的表格显示长春西汀抑制PTZ诱发的P4波峰值振幅降低。在对照组动物中(预先注射载体),音频8和4kHz、强度100dB的刺激引发的ABR P4波振幅逐渐的被PTZ降低(左列),而在预先注射长春西汀的动物中,没有观察到这种PTZ诱发的P4波振幅降低现象(右列)。表格中显示的值是P4波振幅(单位μV)的平均值±标准误差,其从注射痉挛剂(PTZ)之前和之后特定时刻的8只动物获得。
长春西汀也抑制4和8kHz音频、100dB强度的刺激诱发的ABR P2,P3和P4波在注射PTZ后产生的潜伏期增长(图2)。
下面的表格显示长春西汀抑制痉挛剂PTZ诱发的听力损失。在4和8kHz音频下,PTZ诱发的听阈显著上升(左列),而在PTZ给药前预先注射长春西汀的动物中听阈没有上升(右列)。表格中显示的数值是在8只动物中获得的听阈(单位dB)的平均值±标准误差。
长春西汀抑制PTZ引发的所有脑电图EEG的变化。所有的注射了PTZ的麻醉动物出现了全身性发作。发作活动的开始突发出现在注射PTZ之后的前2个第一分钟内,其特征在于脑电图EEG跟踪表现为重复的高振幅棘波尖波活动。麻醉动物在痉挛时PTZ诱发脑皮层活动的显著变化,之后伴随典型脑皮质活动模式,典型脑皮质活动的特征在于高振幅节律性棘峰脉冲。这种不伴随痉挛现象的典型脑皮质活动模式持续的时间称为发作后时期。
长春西汀完全抑制发作期和发作后时期PTZ诱发的脑皮质层活动的变化。图3和图4最上端的迹线显示对照情况下(即,注射PTZ之前)特征性的脑电图记录。在预先注射载体的动物中,注射PTZ后大约2分钟将诱发脑电图显著变化(发作期),而在预先注射长春西汀的动物中,脑电图没有这样的变化(图3)。同样的,注射PTZ后10,20,30和50分钟诱发的变化(图4a)在预先注射长春西汀的动物中也没有检测到(图4b)。
实施例2.用于检验长春西汀影响大脑兴奋传递介素水平升高引起的ABR和脑电图EEG的变化的实验设计。
本研究中使用5只豚鼠。在给豚鼠注射载体(酸化的生理盐水,用于溶解长春西汀)后1小时将该动物麻醉,此时记录腹膜内注射痉挛剂4-AP之前的第一组ABR和脑电图EEG。给动物注射4-AP(2mg/kg),记录4-AP注射后约20分钟(发作期)的脑电图。接着记录发作后时期特定时刻的其它系列的ABR和脑电图EEG。2周后重复同样系列的记录,但是在注射4-AP之前1小时用长春西汀(2mg/kg)而不是载体注射动物。
长春西汀也抑制4-AP诱发的P3和P4波振幅变化。例如,在对照组动物中,4-AP产生的ABR P3波振幅逐渐升高(图5a),而在长春西汀处理的动物中振幅没有升高(图5b),4-AP在对照组动物中产生的P4波振幅减小现象(图5c)在长春西汀处理的动物中也被显著的减弱了(图5d)。
下面的表格显示了音频8和4kHz、强度100dB的刺激引发的ABR P4波潜伏期变化,对照组动物中,注射4-AP后指定时刻ABR P4波潜伏期增长(左列),在预先用长春西汀处理的动物中,潜伏期的这种变化消失了(右列)。
长春西汀抑制4-AP诱发的听力损失。下面的表格显示在4和8kHz音频下,4-AP在对照组动物中诱发的听阈上升(左列)现象在长春西汀处理的动物中消失了(右列)。
长春西汀抑制4-AP诱发的所有脑电图变化。所有的注射了4-AP的麻醉动物出现了全身性发作,其特征是在注射4-AP后约20分钟脑电图跟踪出现重复的高振幅棘波尖波活动。4-AP引起的发作期的脑皮质层活动变化之后伴随以更高振幅孤立棘峰脑电图为特征的发作后时期,发作后时期出现在注射4-AP后大约1小时。长春西汀完全抑制4-AP诱发的发作期和发作后时期的脑皮质层活动。图6的最上部迹线显示注射4-AP前的特征性脑电图,(a)为预先注射载体动物的脑电图,(b)为预先注射长春西汀的动物。图6a的第二条迹线显示4-AP诱发的发作期变化。在长春西汀处理的动物中,4-AP不能诱发脑电图的发作活动(图6b的第二条迹线)。图7a显示4-AP诱发的发作后的活动,当动物用长春西汀预先处理时,痉挛剂4-AP不能诱发发作后的活动(图7b)。
Claims (5)
1.长春西汀在制备药物中的应用,所述药物能够拮抗伴随癫痫的听觉脑干反应(ABR)波的改变和听力损失。
2.权利要求1所述的应用,其中所述药物用于治疗耳蜗后源性改变,其是通过抑制所述ABR的后续波的振幅和潜伏期的改变来达到的,所述ABR的后续波即P3和P4。
3.权利要求1所述的应用,其中所述药物用于治疗耳蜗后源性听力损失,其是通过抑制由痉挛剂,即戊四唑和4-氨基吡啶,诱发的听阈升高来达到的。
4.权利要求1所述的应用,其中所述药物作为抗癫痫药,其是通过抑制发作期和发作后时期癫痫性脑皮质层活动来达到的。
5.权利要求1-4任何一项的应用,其特征在于它在药用载体中口服或肠胃外施用。
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