CN1224389C - 莨菪胺盐的用途 - Google Patents
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Abstract
莨菪胺盐用于预防癫痫发作的用途，其中所述癫痫可能是在癫痫持续状态，严重的头部创伤，包括由神经外科创伤所引起的那些，和急性的脑损害事件之后发生的。
Description
本发明涉及一种通过给予莨菪胺来预防癫痫发作的预防疗法，其中所述癫痫大多数是在癫痫持续状态，头部创伤，包括由神经外科操作所引起的那些，和急性损害事件之后发生的。
癫痫是一种即使在没有毒代谢或发热情况下的，运动或非运动性癫痫反复发作的疾病。上述定义清楚地将非癫痫性癫痫发作(通常是一种与代谢紊乱或中毒有关的单一的孤立的事件)与真正的癫痫区别开来。虽然癫痫和非癫痫性发作可具有相似的临床表现，如抽搐痉挛，但癫痫指的是一种永久性改变的疾病。因此，癫痫患者的神经系统与没有癫痫的人在解剖学，生理学和药理学上均有所不同。
癫痫比较普遍，其每年的发病率为11-131/100,000，占总人口的1.5％(Guerreiro和Guerreiro，1993)。虽然在大多数情况下，我们还不知道这种病的病因，但有时也可很清楚地将其与先前的损害事件联系在一起。就这一点而论，由于严重的头部创伤所导致的癫痫的发病率为15-80％，其取决于受损脑部区域的范围，位置和严重程度(Gumnit RJ.，癫痫和脑损伤，《癫痫》，修订：原因和治疗，P.Robb(编)，Symposia Specialists，Chicago，pp.177-183，1980)。事实上，在严重的头部创伤之后发展成癫痫的危险比一般人要高13倍。
某些癫痫患者难以用现有的药物疗法进行治疗，进而可能需要进行神经外科手术。然而，即使是在最好的医疗中心，外科手术也不是总能完全地抑制癫痫发作(Germano IM，Poulin N和Olivier A.复发的精神运动性癫痫的再次手术，《神经外科学杂志》，81：31-36，1994)。事实上，在那些情况下的癫痫病灶很可能已经被完全切除，然而在外科手术后，癫痫发作仍然在持续，也就是说外科手术行为自身很可能构成了能够引起癫痫的脑创伤(Sperling MR，Skolnick J和O’Connor MJ.，短暂叶切除术后的先兆预测值，《癫痫》38(增刊8)：80，1997)。就像已经提到的那样，人们可以很清楚地知道，前述严重的头部创伤与随后的癫痫发作有关。
目前所用的抗癫痫药能够控制70％癫痫患者的癫痫发作(Yacubian EMT.Tratamento medicamentoso das epilepsias.Lemos编，
Paulo，1990)。尽管它们在癞痫发作的控制方面比较成功，但目前所用的药物疗法并不能真正地抗癫痫，它只能抗癫痫发作。治疗癫痫所用的药物疗法不能改变或抑制下面的癫痫状况，而仅能抑制癫痫发作。事实上，迄今为止，为了在已经患有癫痫(能够抑制癫痫)的患者或在严重头部创伤(能够预防癫痫)后的患者中评估一种真正的抗癫痫剂而进行的所有对照试验均失败了(Temkin NR，Dikmen SS和Winn HR.，用于癫痫发作的预防的临床试验，《抗癫痫药物的发展》，J French，I Leppik和MA Dichter(编)，Lippincott-Raven Publishers，Philadelphia，pp.179-88，1998)。因此，尽管人们已经知道与神经系统损害有关的各种事件导致发展成癫痫的危险仍然存在，但目前还没有有效的预防策略(Mel1o LEAM，Odesenvolvimento medicamentoso de novas estruturas moleculares.In：Tratamento medicamentoso das epilepsias.EMT Yacubian(编)，LemosEditorial，
Paulo，pp.107-115，1999；Temkin等，1998 op.Cit.)。
本发明的目的在于预防严重的头部创伤之后可能发生的癫痫。它是以大鼠的癫痫试验模型结果为基础的。在第一组试验的大鼠中，观察到合成乙酰胆碱的特定神经元群(基础的前脑胆碱能神经元)的选择性破坏抑制了随后的癫痫发作。假定该结果是由于基础前脑胆碱能神经元的功能性阻滞，那么可对该系统的一种可逆药理拮抗剂进行试验。因而，我们使用莨菪胺，一种胆碱能拮抗剂，来评估它在大鼠癫痫模型中预防癫痫发作的可能性。
本发明是以癫痫的试验模型为基础的，其中大鼠脑损害的产生是通过给予毛果芸香碱，一种胆碱能激动剂而实现的。根据此模型的原始描述，给大鼠或小鼠注射毛果芸香碱约20-30天后，产生自发的，反复的癫痫发作(Turski WA，Cavalheiro EA，Schwarz M，Czuczmar SJ，Kleinrok Z和Turski L.由毛果芸香碱引起的大鼠肢体癫痫发作，《行为，脑电图和神经病理的研究》，行为性脑研究，9：3l5-335，1983：Mello LEAM，Cavalherio EA，Babb TL，Kupfer WR，Pretorius JK，Tan AM和Finch DM.，在慢性癫痫的毛果芸香碱模型中癫痫发作的复发机理：细胞的损失及苔藓样纤维的生长，《癫痫》34：985-995，1993)。由于它的特殊特性，在癫痫的研究中，毛果芸香碱模型是目前3个最广泛使用的试验模型之一。
直到现在，在癫痫的毛果芸香碱或相似模型中，还没有试验过程显示出能够预防癫痫的进一步发展。在本发明人进行的研究工作中，已经证实了在癫痫的毛果芸香碱和钾盐镁矾(另一种能够诱导癫痫的药剂)模型中，莨菪胺的使用延缓甚或抑制了自发的，反复的癫痫发作，即癫痫。在最终继续且发展成癫痫发作的那些动物中，与没有用莨菪胺治疗过的动物相比，其癫痫发作的频率显著降低。
莨菪胺，和阿托品，是一种典型的胆碱能激动剂，且已知其可阻断毒蕈碱受体。这些药物阻滞胆碱能传导的能力是已知的，其中胆碱能的传导是通过毒蕈碱受体介导的。在试验中，我们使用Wistar成年雄性大鼠，这些大鼠是在温度，明/暗循环的可控条件下生长的，每个聚丙烯盒子中有6只动物，它们可自由地接触到自来水和大鼠的食物团块。给大鼠腹膜内注射320mg/Kg剂量的毛果芸香碱，以诱导癫痫持续状态。
正如我们所期望的，毛果芸香碱的全身给药导致行为的改变，如运动不能，身体震颤和/或头部的肌阵挛反射，及伴有多涎的口-面部刻板运动。癫痫持续状态，一种连续的癫痫发作状况，在注射毛果芸香碱后，平均持续19±5分钟。就癫痫持续状态发作的潜伏期而言，对照组(n＝12)与试验组(n＝8)没有什么不同。事实上，所述动物是根据其潜伏期而被随机分配到两组(对照组和试验组)中的一组的。在癫痫持续状态发作约90分钟后，以25mg/Kg的剂量给大鼠腹膜内注射硫贲妥钠，即毛果芸香碱模型中的一种标准操作，以降低较高的死亡率。
在癫痫持续状态发作两小时后，用莨菪胺的第一初始剂量(2mg/kg)对试验组的动物进行腹膜内注射。此剂量是诱导啮齿类动物记忆损伤所需的两倍(Rudy JW.在培养前和培养后给予莨菪胺可损害前后关系和听觉的恐惧条件反射，《学习和记忆的神经生物学》，65：73，1996；Elrod K和Buccafusco JJ.在两种消极回避方案中莨菪胺诱导的损害的机理评估，药理学生物化学和行为29：15，1998)。
在第一个连续的3天内，每6小时给予莨菪胺，以保持稳定的治疗水平，其半衰期一次为2.9±1.2小时。在这三天结束的时候(即对于癫痫持续状态所产生的应激反应而言，不确定是否存活所必需的时间)，然后将渗透泵(Alzet，2002型)皮下植入动物体内，以便在接下去的14天内确保莨菪胺稳定的治疗水平。就对照组的动物而言，在癫痫持续状态发作2小时后，开始以相似的方案给予无菌的生理盐水溶液(0.9％NaCl)，而不是莨菪胺。
在癫痫的毛果芸香碱模型中，在给予毛果芸香碱并诱导了癫痫持续状态几个星期后，所述动物发展成自发的，癫痫性癫痫发作，且在保证动物存活的条件下，这种发作反复出现。因而推测这种癫痫状况足以模拟人某些类型的癫痫性癫痫发作，且可以近似反映出在创伤后癫痫中所发生事件的续发事件。
癫痫持续状态发生约15-20天，即所报道的自发性癫痫发作的潜伏期持续时间后，开始用摄像机进行约12小时/周的行为性癫痫发作的监测。根据我们最初的假设，试验组(用莨菪胺治疗的)或者有较大的减轻，或者不再表现出自发的癫痫性癫痫发作，并因此避免了错误的阴性结果，这些动物摄像监测的采样率达24小时/周。在发生癫痫持续状态后，摄像监测这些动物约120天。在29英寸的宽屏幕电视机上常规地评估所记录下来的录象带，并记录所观察到的每只动物的癫痫发作。
对照组摄像记录开始期间的潜伏期为18.6±2.9天，试验组为18.4±2.8天，这样在所报道的这段时间内，自发性癫痫发作开始。虽然我们从癫痫持续状态发生后的第1天没有进行自发性癫痫发作的摄像监测，且尽管没有癫痫发作计数方法的采样基础，我们仍相信描述自发性癫痫发作的潜伏期是很有意义的。
自发性癫痫发作的潜伏期在表1中列出，其清楚地证实了两组间的差异。尽管有上述限制，即关于摄像监测的开始及这种记录的采样特征，对照组的值与在有关毛果芸香碱模型的各种文章中已经报道的那些值非常相似。因此这种相似性帮助我们验证了监测自发性癫痫发作的过程。
表1试验组和对照组第一次记录的自发性癫痫性癫痫发作的潜伏期长
| 对照组 | 潜伏期(天)24.9±10.5(15-44) |
| 试验组 | 54.6±37.5*(18-117) |
数据是以平均值±标准偏差表示的；括号中的数字表示潜伏期天数的范围；*p＜0.03(Mann-Whitney)
正如我们所看到的，表1中的数据清楚地表明了所采用的治疗方法(缓慢注入莨菪胺14天)对于此模型中自发的癫痫性癫痫发作的保护作用。事实上，试验组的平均潜伏期是对照组的两倍。如果此作用能够在人类的临床研究中重现，则其代表了在控制创伤后癫痫方面的重大进步。
对照组和试验组关于癫痫发作频率的对比在统计学上也体现出显著的差异(见表2)。
表2对照组和试验组自发的癫痫性癫痫发作的频率
| 对照组(n＝12) | 自发的癫痫发作/h×100074.49±67.89(20-220) |
| 试验组(n＝8) | 24.98±28.60*(0-74) |
数据是以平均值±标准偏差表示的；括号中的
数字表示潜伏期天数的范围：*p＜0.02(Mann-Whitney)
表2清楚的显示出对照组自发的癫痫性癫痫发作的平均频率比试验组(用莨菪胺治疗的)高3倍。然而对于每一个体的癫痫发作而言，我们发现两组间的定性或定量特性没有差异。120天后，除了已经提到的差异外，两组间癫痫发作的暂时分配是相似的。在两组中，具有较高的自发性癫痫发作频率的动物，趋向于在一群中显示那些癫痫发作，在一个时期内有多次癫痫发作，而在接下来的时期内没有癫痫发作。然而，只有2只(25％)莨菪胺治疗组的动物有癫痫的聚集，有7只对照组的动物(58％显示出癫痫的聚集。因此，用莨菪胺进行治疗可产生一种保护作用。在临床中，毫无疑问癫痫发作可使癫痫患者的生命质量恶化。
最重要的一个结果是，在产生癫痫持续状态，及对每一只试验组动物进行摄象监测200-300小时后的4个月观察期结束时，记录到有一只动物没有癫痫发作，而另一只动物仅有1次癫痫发作。尽管癫痫发作采样时间的总数较少，相比之下，对照组具有最小绝对值的动物有3次自发性癫痫发作(与表2中，在对照组低偏差范围中表示的值20相对应)。
我们的结果表明，在严重的头部创伤后，莨菪胺14天的缓慢给药(例如：持续输液、多样给药、经由皮肤给药)具有减轻或阻滞随后发展成癫痫的潜力。在成年的雄性Wistar大鼠中，每6小时以2mg/kg的剂量给药，随后是与渗透泵等剂量的缓慢给药，其产生了一种清楚的抗致癫痫作用。本发明在人类中应用的可能性依赖于建立适宜剂量及获得最佳结果时的治疗持续时间的临床试验。本发明支持了在人类严重的头部创伤发生后，用莨菪胺进行治疗的临床研究的发展。有了严重头部创伤的频率及随后发展成癫痫的强有力的有关临床证据后，补充必需的患者数，从而进行暗示疗法的初步评估应当不难。最后，记住目前还没有治疗这种疾病的有效方法这一点是非常重要的。
Claims (3)
1.东莨菪碱盐在制备用于预防非先天性癫痫发生的药物中的应用。
2.权利要求1所述的应用，其特征在于将所述东莨菪碱盐用于制备在头部创伤后使用从而预防非先天性癫痫发生的药物。
3.权利要求1所述的应用，其特征在于将所述东莨菪碱盐用于制备在切除具有致癫痫性的解剖学结构的外科手术后使用从而预防非先天性癫痫发生的药物。
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| CN1454087A (zh) | 2003-11-05 |
| EP1259241A1 (en) | 2002-11-27 |
| WO2001043745A1 (en) | 2001-06-21 |
| EP1259241B8 (en) | 2006-09-06 |
| ATE332137T1 (de) | 2006-07-15 |
| BR9906220A (pt) | 2001-06-26 |
| CA2395037A1 (en) | 2001-06-21 |
| DE60029252D1 (de) | 2006-08-17 |
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| JP2003530315A (ja) | 2003-10-14 |
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| EP1259241B1 (en) | 2006-07-05 |
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