CN101610774B - 治疗脱髓鞘疾病的方法 - Google Patents
治疗脱髓鞘疾病的方法 Download PDFInfo
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- CN101610774B CN101610774B CN2007800491552A CN200780049155A CN101610774B CN 101610774 B CN101610774 B CN 101610774B CN 2007800491552 A CN2007800491552 A CN 2007800491552A CN 200780049155 A CN200780049155 A CN 200780049155A CN 101610774 B CN101610774 B CN 101610774B
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Abstract
本发明涉及治疗脱髓鞘疾病例如多发性硬化的方法,其包括向有此需要的个体给药非典型抗精神病药物(例如喹硫平或其类似物)。
Description
发明领域
本发明涉及治疗脱髓鞘疾病的方法。特别地,所述方法包括给药非典型抗精神病药物,例如喹硫平或其结构类似物,以在有此需要的个体中治疗脱髓鞘疾病例如多发性硬化。
发明背景
覆盖许多神经纤维的髓鞘由在早期生命中形成的脂蛋白层组成。在CNS中由少突胶质细胞形成的髓磷脂与在外周由神经鞘细胞(Schwanncell)形成的髓磷脂在化学和免疫学上不同,但是两种类型都具有相同的功能:促进神经冲动沿着轴突传递。
许多先天性代谢紊乱(例如:苯丙酮尿和其他氨基酸尿;泰-萨克斯病、尼曼-皮克病和高歇氏病;赫尔勒氏综合症;球形细胞脑白质营养不良(Krabbe′s disease)以及其他脑白质营养不良)影响髓鞘的形成,其主要在CNS中。除非生化缺陷能被纠正或者补偿,否则发生持久、常常广泛分布的神经病学缺陷。
脱髓鞘疾病在晚期生命中是许多神经病学障碍的特征;它可以来自于由于局部损伤、缺血、毒性药物或代谢紊乱所引起的对神经或髓鞘的损伤。大量的髓磷脂损失通常随轴索变性而来并且时常随细胞体变性而来,它们两者可能是不可逆的。然而,髓鞘再生在许多病例中出现,并且神经功能的修复、再生以及完全恢复会是迅速的。复原经常在节段性脱髓鞘后发生,它以许多周围神经病为特征;该过程可以说明多发性硬化(MS)的加重和减轻。中枢脱髓鞘(即:脊索、脑或视神经的脱髓鞘)在初期脱髓鞘疾病中是主要的发现,它的病原学未知。最熟知的是MS。其他疾病包括,例如:急性播散性脑脊髓炎(感染后脑脊髓炎)、肾上腺脑白质营养不良、肾上腺脊髓神经病、莱伯遗传性视神经萎缩以及相关的线粒体病症和人类T细胞亲淋巴病毒(HTLV)感染相关的脊髓病。
多发性硬化(MS)是中枢神经系统(CNS)的慢性炎性疾病。在病理学上,该疾病以分散的脱髓鞘损害、轴索损耗以及在脑和脊髓中的损伤为特征(Lassmann,2005),其导致许多神经病学缺陷。目前用于处理患有MS患者的疗法首先针对该疾病的炎性方面(Zamvil和Steinman,2003)并且仅部分有效且被副作用限制。现有的研究提出了谷氨酸介导的细胞毒性(兴奋性中毒)(Stover等人,1997;Barkhatova等人,1998;Smith等人,1999;Pitt,2000)、氧化性应激(Gilgum-Sherki等人,2004)和线粒体损害(Andrews等人,2005)可能在MS的发病机制中起重要作用。
髓鞘再生一般被认为是MS损害中的常规事件(Prineas等人,1993;Raine等人,1993);然而,这对于髓磷脂修复是不足的并且在MS患者中轴突仍然在脱髓鞘(Prineas等人,1993;Lovas等人,2000)。对此的可能的解释包括少突胶质细胞祖细胞(OPCs)募集或存活的失败、OPCs的分化/成熟的干扰以及髓磷脂形成能力的丧失(Wolswijk等人,1998;Chang等人,2003)。因此,有效干预MS应不仅预防疾病的发展,而且应促进髓鞘再生。
喹硫平是非典型抗精神病药物,它具有好的效能和耐受性,且它在精神分裂症的治疗中有用。喹硫平在帕金森氏病(Goldstein,2004)和药物滥用(Brown,2004)治疗中的用途也已经被提出。
非典型抗精神病药物(APDs),例如氯氮平和喹硫平,已被广泛用于治疗一系列严重的精神病(Thanvi等人,2004;Gao等人,2005)和在神经学疾病中的精神症状(Baum等人,2003;Bosboom等人,2004;Altschuler等人,2005;Carson等人,2006)。APDs的神经保护作用最近在体内和体外研究中都已经突出表现为它们治疗的新特征。在1993年,Farber和同事报道了由N-甲基-D-天冬氨酸(NMDA)受体拮抗剂地佐环平所产生的神经毒性,氯氮平预处理可以显著减少大鼠中的压部后皮质(Farber等人,1993)。后来的研究显示奥氮平在预防MK-801诱导的神经毒性中具有同样的作用(Farber等人,1996)。其他组也报道了用氯氮平或者奥氮平进行的预处理阻止了神经元的空泡形成并显著减弱了由地佐环平诱导的大鼠压部后皮质中Fos样蛋白的表达(Fujimura等人,2000;Hashimoto等人,2000)。
已证明喹硫平和奥氮平可以减弱大鼠海马中BDNF的表达中的固定应激诱导减少(Xu等人,2002;Luo等人,2004),并调节大鼠中长期给药dl-安非他命的短期和长期行为后果(He等人,2005)。体外研究也支持APDs氯氮平、奥氮平、喹硫平和利培酮可以减少由抽取血清或加入过氧化氢、β-淀粉样肽或者1-甲基-4-苯基吡啶鎓(MPP+)所引起的PC12细胞死亡。这些保护效应可能与PC12细胞中通过所述药物进行的低亲和力NGF受体p75和SOD1表达的调节有关(Bai等人,2002;Wei等人,2003,Qing等人,2003)。来自临床试验的结果表明:与从未被治疗过的患者或者用典型药物进行治疗的患者相比,非典型药物治疗显著地增加在精神分裂症患者中的血浆NGF浓度(Parikh等人,2003)。
发明概述
在本申请中,使用已确立的脱髓鞘和髓鞘再生模型,已证明非典型抗精神病药物(APD)喹硫平减少铜宗(cuprizone)诱导的脱髓鞘和在小鼠脑内髓鞘再生过程中促进在脱髓鞘区域中成熟少突胶质细胞重置。具体而言,在本发明的研究中,证明了:(1)同时给药喹硫平弱化铜宗诱导的脱髓鞘;(2)补给铜宗引起小鼠的空间记忆障碍,其可以通过喹硫平治疗逆转;(3)喹硫平减轻少突胶质细胞祖代应答脱髓鞘而发生的活化和蓄积;(4)喹硫平不改变成熟的少突胶质细胞在脱髓鞘区域中的消耗;以及(5)在髓鞘再生过程中,喹硫平治疗促进成熟的少突胶质细胞在损伤中的再生。
相应地,本发明包括治疗脱髓鞘疾病的方法,其包括向有此需要的个体给药有效量的选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物,所述化合物在所述个体中对脱髓鞘的缓解有效。
本发明还包括选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物用于治疗脱髓鞘疾病的用途,所述化合物在所述个体中对脱髓鞘的弱化有效。此外,本发明包括选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物用于制备治疗脱髓鞘疾病的药物的用途,所述药物在所述个体中对脱髓鞘的弱化有效。
在本发明的实施方案中,所述脱髓鞘疾病为多发性硬化。
喹硫平弱化脱髓鞘和逆转铜宗诱导的记忆障碍。在髓鞘再生过程中,喹硫平促进在脱髓鞘损害中成熟少突胶质细胞再生。这是第一次关注喹硫平对脱髓鞘和髓鞘再生的作用。由于MS的复杂发病机理,现有的免疫调节治疗在预防脱髓鞘和促进髓鞘再生中具有有限的效果。通过利用神经保护、作用于少突胶质细胞调节和认知功能障碍管理,非典型抗精神病药物,例如喹硫平,是用于治疗患有脱髓鞘疾病如多发性硬化的患者的候选药物。
本发明概述部分罗列了几个本发明的实施方案,并在许多实例中列出了这些实施方案的变更和变换。该概述仅仅是众多且不同的实施方案的示例。给出的实施方案提到的一个或多个特定特征同样是示例性的。这样的实施方案可以典型地具有或没有提到的特征的形式而存在;同样地,那些特征可以用于本发明的其他实施方案,而不论在本概述中是否列出。为避免过度重复,本概述没有列出或提出这样的特征的全部可能组合。
为了概括本发明和相对于现有技术所达到的优点,本发明的一些目标和优势已在上文描述。当然,要理解的是依照本发明的任何特定具体实施方案,所有这样的目标或优点都实现是不必要的。因此,例如,本领域技术人员会认识到,本发明可以按这样一种方式体现或实现:达到或优化本文教授的一个优点或一组优点而不必然达到本文可能教授或建议的其他目标或优点。
其他本发明的特征和优点将在下面详细的描述中变得明白。然而应理解,详细的描述和具体的实施例尽管指示了本发明优选的实施方案,但仅是通过举例方式给出的,因为对本领域技术人员来说,从该详细描述中在本发明的主旨和范围内的多种变化和修饰会变得显而易见。
附图简述
现将对本发明进行与附图相关的描述,其中:
图1表示在8分钟Y-迷宫试验中喹硫平对铜宗诱导的自发变换行为损害(A)和进入臂的总次数(B)的作用。小鼠用0.2%铜宗饲养5周,具有载体(水)(cup)或喹硫平治疗(cup+que);年龄一致的小鼠用正常食物进行饲养(con)和进行单独喹硫平治疗(que)。Y-迷宫试验在治疗结束后进行。对于髓鞘再生,给予铜宗6周,并随后恢复正常饮食用喹硫平(que)(10mg/kg/天在水中)或载体(水)治疗2周。数据以平均值±S.E.M.表达。对每组的6-8只小鼠进行检查。**相对于对照组P<0.01,++相对于单独铜宗组P<0.01(图基检验)。
图2表示在小鼠胼胝体中的脱髓鞘和髓鞘再生。MBP免疫染色表示铜宗处理5周后在胼胝体中的脱髓鞘(C)。喹硫平治疗显著弱化脱髓鞘(D)。对照组(A)和单独喹硫平组(B)在髓鞘形成方面没有表现出不同。为评价髓鞘再生的程度,在铜宗饲养5周后,小鼠在髓鞘再生过程中用正常食物再饲养两周。脱髓鞘损害迅速复原。喹硫平(F)与载体(水,E)在髓磷脂修复方面(MBP染色,放大倍数,×4)没有区别。对MBP染色区域计数(G)。结果代表对照组的MBP染色区域百分比的均值(平均值±S.E.M.)。对每组的6-8只小鼠进行检查。**相对于对照组P<0.01,++相对于单独铜宗组P<0.01(图基检验)。
图3表示给药喹硫平以防铜宗引起的脱髓鞘。小鼠用0.2%铜宗饲养5周,具有载体(水)(C)或喹硫平治疗(D);年龄一致的小鼠用正常食物进行饲养(A)和进行单独喹硫平治疗(B)。在胼胝体水平的冠状脑切片用LFB-PAS染色。为了评价髓鞘再生的程度,在铜宗饲养5周后,小鼠在髓鞘再生过程中用正常食物再饲养两周。用LFB/PAS进行染色的代表性脑冠状缝切面(放大倍数,×4)表示的是载体(水,E)和喹硫平治疗的小鼠(F)在铜宗饲养6周后用正常食物饲养2周。
图4表示喹硫平减少铜宗处理后脱髓鞘过程中OPCs的蓄积。A:冰冻的冠状脑切片用NG2抗体进行染色。相比于cup+que组(D),在铜宗处理(C)5周后观察到OPCs的较高蓄积。少量NG2+细胞在对照组(A)和单独喹硫平组(B)中被观察到。铜宗处理刺激NG2+细胞分化为星形未成熟少突胶质细胞(E)。在髓鞘再生过程中,OPCs的蓄积减少,在水(F)和喹硫平治疗(G)之间没有观察到差异。该数据代表在胼胝体中的NG2+细胞的均值(平均值±S.E.M.)。对每组的6-8只小鼠进行检查。**相对于对照组P<0.01,++相对于单独铜宗组P<0.01(图基检验)。放大倍数,A、B、C和D为×10;E为×40;F和G为×20。
图5表示在铜宗诱导的脱髓鞘期间,喹硫平对成熟少突胶质细胞数目的影响。在胼胝体中的成熟少突胶质细胞通过用抗-GST-pi抗体进行染色分析。铜宗处理显著减少在胼胝体中的GST-pi+细胞(C);喹硫平似乎不保护成熟少突胶质细胞的耗竭(D)。相比于对照组(A),单独喹硫平治疗组(B)没有区别。有趣的是,相比于水(E),喹硫平(F)在髓鞘再生过程中增加了GST-pi+细胞的数目。结果表示在胼胝体中每平方毫米GST-pi阳性细胞的平均数目(G)**相对于对照组p<0.01;+相对于水组p<0.05。T检验(Student’s t test)。放大倍数,×20。
发明详述
喹硫平是治疗神经精神性疾病方面广泛应用的非典型抗精神病药物。先前的研究已经证明在动物或培养细胞的多种损伤后,喹硫平提供神经保护作用。体外研究数据表明喹硫平选择性地促进神经干细胞分化为少突胶质细胞列,并促进髓磷脂形成。为检查喹硫平对体内脱髓鞘和髓鞘再生的作用,让幼年的C57BL/6小鼠接触铜宗中毒(0.2%w/w在食物中)5周,并用喹硫平(10mg/kg/天,p.o.)或载体(水)持续治疗。相比于载体治疗,喹硫平治疗的小鼠的脑中脱髓鞘显著地减少。脱髓鞘的这种减少与少突胶质细胞祖细胞蓄积的减少相互关联。喹硫平也改善了小鼠中由铜宗处理所引起的工作记忆障碍。当铜宗从日常饮食中移除时,髓鞘再生自然地发生。在髓鞘再生过程中,喹硫平治疗显著地增加在脱髓鞘区域中成熟少突胶质细胞的重置;它可能是通过少突胶质细胞祖细胞增殖和分化来促进的。此数据表明喹硫平对脱髓鞘和髓鞘再生均有有益的作用,这表明喹硫平和它的类似物将是用于治疗脱髓鞘疾病例如多发性硬化(MS)的候选药物。
相应地,本发明包括治疗脱髓鞘疾病的方法,其包括向有此需要的个体给药有效量的选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物,所述化合物在所述个体中对脱髓鞘的弱化有效。
本发明还包括选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物用于治疗脱髓鞘疾病的用途,所述化合物在所述个体中对脱髓鞘的弱化有效。此外,本发明包括选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物用于制备治疗脱髓鞘疾病的药物的用途,所述化合物在所述个体中对脱髓鞘的弱化有效。
所述化合物在个体中对脱髓鞘的弱化有效。“脱髓鞘的弱化”表示当同另外的同样的病情比较时,作为所述疾病的结果或所述疾病的症状在个体中脱髓鞘的数量减少了,和/或当同其他同样的病情比较时在个体中髓鞘再生的数量增加了。“减少”表示脱髓鞘的数量或者归因于脱髓鞘的任何脱髓鞘疾病症状的任何可测量或可观察的减少。同样地,术语“增加”表示髓鞘再生数量任何可测量或可观察的增加,它也表现为归因于脱髓鞘的任何脱髓鞘疾病症状的减少。在本发明的实施方案中,个体中脱髓鞘的弱化是相对于对照组得出的。归因于脱髓鞘的症状会根据疾病而变化,例如它可能包括但不限于神经机能缺损,如认知损害(包括记忆力、注意力、概念化和问题求解技巧)和信息处理;一处或更多骨端、躯干或者脸的一侧上感觉异常;腿或手的虚弱或笨拙;或者视觉障碍,如部分盲和一只眼的疼痛(球后视神经炎)、视觉不清或者暗点。
化合物弱化脱髓鞘的能力可以通过现有技术已知的测定方法来检测或测量,例如,如本文所述的铜宗诱导的脱髓鞘模型。
喹硫平为11-(4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基二苯并[b,f][1,4]硫氮杂,也被称为思瑞康TM(SeroquelTM),并具有如下结构:
在美国专利4,879,288(Warawa等人)中对此化合物、其药学可接受的盐和它在治疗精神分裂症中的用途进行了描述。在美国专利申请公布20040242562(Parthasaradhi等人)中描述了喹硫平的新的多晶型物。本发明扩大到所有形式的喹硫平(包括无定形和结晶形式)的方法和用途。
在本发明的实施方案中,所述化合物选自喹硫平及其药学可接受的盐、溶剂合物和前药,合适的是其药学可接受的盐。在本发明的另一实施方案中,所述化合物选自喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药,合适的是其药学可接受的盐。喹硫平的类似物,例如那些在美国专利申请公布20060094705(Edgar等人)中描述的化合物。喹硫平的类似物还包括喹硫平的代谢物,包括相应的N-去烷基化类似物、相应的亚砜和砜类似物以及相应的酚化类似物。
在本发明的实施方案中,所述喹硫平的类似物选自式I的化合物及其药学可接受的盐、溶剂合物和前药:
其中R1、R2、R3、R4、R5、R6、R7和R8中的一至四个,合适的是一至三个独立地选自Br、Cl、I、F、OH、OCH3、CF3、OCF3、CH3、CH2CH3、CH2CH2CH3、CH2(CH3)2、CH2CH2CH2CH3、CH2CH2(CH3)2和C(CH3)3。
在本发明的一个实施方案中,所述脱髓鞘疾病为导致对围绕脑和脊髓中的神经的保护罩(髓鞘)的损伤的任何疾病或病症。在本发明的又一实施方案中,所述脱髓鞘疾病选自多发性硬化、横贯性脊髓炎、格-巴二氏综合征、进行性多灶性白质脑病、横贯性脊髓炎、苯丙酮尿和其他氨基酸尿、泰-萨克斯病、尼曼-皮克病、高歇氏病、赫尔勒综合征、球形细胞脑白质营养不良和其他脑白质营养不良、急性播散性脑脊髓炎(感染后脑脊髓炎)、肾上腺脑白质营养不良、肾上腺脊髓神经病、视神经炎、德维克病(视神经脊髓炎)、莱伯遗传性视神经萎缩和相关的线粒体病症以及HTLV相关脊髓病或者所述脱髓鞘疾病是局部损伤、缺血、毒性药物或代谢紊乱的结果。在本发明的又一实施方案中,所述脱髓鞘疾病为多发性硬化。
在本文使用的术语“本发明的化合物”是指选自喹硫平和喹硫平的类似物及它们的药学可接受的盐、溶剂合物和前药的化合物。
如在本文所使用的以及如现有技术中所充分理解的,“处理”或“治疗”为获得有益或期望的结果(包括临床结果)的方法。有益或期望的临床结果可以包括但不限于,一种或更多症状或病症的减轻和改善、病变范围的减小、疾病状况的稳定(即没恶化)、预防疾病的传播、疾病进程的延迟或减慢、疾病状况的改善或缓和,以及痊愈(无论部分或全部),无论这些结果可被检测或者不能被检测。“治疗”也可以表示同如果没接受治疗所预期的存活时间相比,延长的存活时间。
“缓和”疾病或病症表示,同未治疗所述病症相比,减弱病症或疾病状况的程度和/或不期望的临床表现和/或减缓或延长发展的时间过程。
术语“药学可接受的”表示在动物特别是人类的治疗方面是适合的。
术语“药学可接受的盐”表示适于或者与患者的治疗相容的酸或碱加成盐。
本文使用的术语“药学可接受的酸加成盐”表示本发明任何碱性化合物的任何无毒的有机盐或无机盐。可以形成酸加成盐的碱性化合物包括那些具有碱性氮的化合物。用作说明的形成合适盐的无机酸包括盐酸、氢溴酸、硫酸和磷酸,以及金属盐例如磷酸一氢钠和硫酸氢钾。用作说明的形成合适盐的有机酸包括一、二和三羧酸例如羟乙酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、苯甲酸、苯乙酸、桂皮酸和水杨酸,以及磺酸类例如对甲苯磺酸和甲磺酸。可以形成单酸式盐或二酸式盐,并且这样的盐可以按水合物、溶剂合物或基本上无水的形式存在。通常,所述化合物的酸加成盐在水中和各种亲水性有机溶剂中更易溶,并且与它们游离碱形式相比通常表现出更高的熔点。选择合适的盐对本领域技术人员来说会是公知的。其他非药学可接受的盐,如草酸盐,可以例如在化合物的分离中用于实验室用途或用于随后转化为药学可接受的酸加成盐。在本发明的实施方案中,所述药学可接受的盐是盐酸盐、马来酸盐、延胡索酸盐、柠檬酸盐、磷酸盐、甲磺酸盐或硫酸盐。在本发明的另一实施方案中,所述药学可接受的盐为延胡索酸盐,例如半胡索酸盐。
本文使用的术语“药学可接受的碱加成盐”表示本发明的任何酸性化合物的任何无毒有机碱加成盐或无机碱加成盐。可以形成碱加成盐的酸性化合物包括例如那些具有酸性氢原子(如C(O)OH)的化合物。用作说明的能形成合适盐的无机碱包括氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁或氢氧化钡。用作说明的形成合适盐的有机碱包括脂族胺、脂环族胺或芳族有机胺如甲胺、三甲胺和甲基吡啶或氨。选择合适的盐对本领域技术人员来说会是公知的。其他非药学可接受的盐可以例如在本发明化合物的分离中用于实验室用途或用于随后转化为药学可接受的酸加成盐。
通过使用标准技术来形成所希望的化合物盐。例如,中性化合物在合适的溶剂中用酸进行处理并通过过滤、萃取、重结晶或任何其他合适的方法对形成的盐进行分离。
本文使用的术语“溶剂合物”表示其中合适的溶剂的分子被引入晶格中的本发明化合物。合适的溶剂在所给药的剂量下是生理学耐受的。合适的溶剂的实例为乙醇、水等。当水为溶剂时,分子被称为“水合物”。本发明化合物的溶剂合物的形成会根据所述化合物和所述溶剂合物的特性而变化。一般而言,通过将所述化合物溶解在合适的溶剂中并经冷却或使用抗溶剂分离溶剂合物而形成溶剂合物。所述溶剂合物通常在环境条件下干燥或共沸。
本发明的方法也可以使用喹硫平的前药来实现。前药为喹硫平的衍生物或喹硫平类似物,将其设计为在个体中经过化学或生化转化以释放出活性化合物。喹硫平的前药或喹硫平类似物可以是例如与可用的羟基形成的常见酯。例如,可用的羟基可以在碱存在下且任选在惰性溶剂中使用活化的酸(例如在吡啶中的酰基氯)来酰化。一些已经被用作前药的常见酯为苯酯、脂族(C8-C24)酯、酰氧基甲酯、氨基甲酸酯和氨基酸酯。
制备喹硫平的方法在美国专利4,879,288(Warawa等人)、美国专利申请公布20040220400(Diller等人)、美国专利申请公布20060063927(Etlin等人)和美国专利申请公布20060189594(Puig等人)中被报道。
在本文使用的术语“个体”包括所有动物界的成员,包括人类。个体合适地是人类。
本发明化合物的“治疗有效量”、“有效量″”或“充分量”为当给药至包括哺乳动物例如人类的个体时,足以产生包括临床结果的有益或期望结果的量,并且如同这样,“有效量”或其同义词取决于正在应用它的环境。例如,在治疗脱髓鞘疾病的环境下,例如,它是相比于没有给药所述化合物所得到的反应,足以达到这样的治疗的化合物的量。在疾病的环境下,治疗有效量的本发明化合物被用于在哺乳动物中治疗、调节、减弱、逆转或影响脱髓鞘疾病。“有效量”意在表示足以治疗、预防或抑制脱髓鞘疾病的化合物的量。在一些合适的实施方案中,对应于这样的量的给定的本发明化合物的量会取决于多种因素而变,所述因素例如给定的药物或化合物、药物制剂、给药途径、疾病或病症的类型、被治疗的个体或宿主的特性等,但是这些还是可以由本领域技术人员常规确定。并且,如本文所使用,本发明化合物的“治疗有效量”为相比于对照,在个体中预防、抑制、遏制或减少脱髓鞘疾病的量。如在本文所定义,本发明化合物的治疗有效量可以由普通技术人员以本领域已知的常规方法轻易地确定。
本文使用的术语“预防”或其同义词是指患者变得易患脱髓鞘疾病或者表现出与脱髓鞘疾病相关的症状的风险或可能性降低。
本发明化合物可以按游离碱、盐、溶剂合物和/或前药的形式使用。所有形式都属于本发明的范围。适合地,所述化合物是以游离碱或药学可接受的盐的形式使用。
根据本发明的方法,本发明的化合物和/或其盐、溶剂合物和/或其前药可以通过取决于所选给药途径的不同形式向患者给药,正如会被本领域技术人员所理解的。本发明化合物和/或其盐、溶剂合物和/或前药可以例如通过口服、肠胃外、含服、舌下、鼻腔、直肠、贴皮、泵或经皮给药形式给药,并且相应地配制药物组合物。肠胃外给药包括静脉内、腹膜内、皮下、肌内、经上皮、鼻腔、肺内、鞘内、直肠和局部的给药方式。肠肠胃外给药可以是在选定的一段时间内通过连续输注进行。
本发明化合物和/或其盐、溶剂合物和/或前药,可以口服给药,例如,与惰性稀释剂或与可同化可食用的载体一起,或者它可以被包附在硬壳或软壳明胶胶囊中,或者它可以被压制为片剂,或者它可以直接掺入饮食的食物中。为了口服治疗给药,所述化合物可以与赋性剂混合并且以可吸收的片剂、含化片剂、糖锭剂、胶囊剂、酏剂、混悬剂、糖浆剂、糯米纸囊剂(wafers)等形式使用。
本发明化合物和/或其盐、溶剂合物和/或前药,也可以肠胃外给药。本发明化合物的溶液可以在水中适当地与表面活性剂例如羟丙纤维素混合来制备。分散液也可以在甘油、液体聚乙烯二醇类、DMSO和其混合物中制备,具有或没有乙醇,以及在油类中制备。在存储和使用的普通条件下,这些制剂含有防腐剂以避免微生物的生长。本领域技术人员会知道如何制备合适的制剂。用于选择和制备合适制剂的常规程序和成份例如在Remington′s Pharmaceutical Sciences(2000,第20版)和在TheUnited States Pharmacopeia:The National Formulary(USP 24 NF19)中被描述。
适于注射用途的药物形式包括无菌水溶液或分散液以及用于临时制备无菌注射溶液或分散液的无菌粉剂。在所有实例中,所述形式必须是无菌的并且必须是流动性达到存在容易注射能力的程度。
用于鼻腔粘膜给药的组合物可以方便地配制成为气雾剂、滴剂、凝胶剂和散剂。气雾剂制剂典型地包括活性物质在生理学可接受的含水或非水溶剂中的溶液或均匀的悬浮液,并且通常单剂量或多剂量地以无菌形式存在于密封容器中,其可以利用雾化设备采取药筒或替换物的形式来使用。可选地,所述密封容器可以是单一的配药装置,例如单剂量鼻用吸入器或带有计量阀门的气雾剂分配器,所述计量阀门在使用后用于配药。其中所述药物剂型包括气雾剂分配器,它含有可以是压缩气体如压缩空气的抛射剂或者如氟氯烷的有机抛射剂。气雾剂剂型也可以采取泵压喷雾剂的形式。
适于含服或舌下给药的组合物包括片剂、锭剂和软锭剂,其中活性成份与如糖、阿拉伯胶、黄蓍胶或明胶和甘油的载体配制而成。直肠给药的组合物适合以含有例如可可脂的常规栓剂基质的栓剂形式。
本发明化合物和/或其盐、溶剂合物和/或前药,也可以按脂质体递药系统的形式给药,例如单层小泡脂质体、单层大泡脂质体和多室脂质体。脂质体可以形成自许多种磷脂类化合物,例如胆固醇、硬脂酰胺或磷脂酰胆碱类。
本发明化合物和/或其盐、溶剂合物和/或前药,也可以通过使用化合物分子所要配对的单克隆抗体作为独立载体将其递送。本发明化合物和/或其盐、溶剂合物和/或前药也可以偶联有可溶性聚合物作为靶向药物载体。这样的聚合物可以包括聚维酮、吡喃共聚物、聚羟基丙基异丁烯酰胺-苯酚、聚羟基-乙基天冬酰胺-苯酚或者棕榈酰残基取代的聚环氧乙烷-聚赖氨酸。此外,本发明化合物和/或其盐、溶剂合物和/或前药,可以同在达到药物控释方面有效的这类可生物降解的聚合物偶联,所述聚合物例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、多正酯类、缩醛树脂、聚二氢吡喃、聚腈基丙烯酸酯和水凝胶类的交联或两亲嵌段共聚物。
含有喹硫平的制剂是现有技术中已知的(参见例如,美国专利申请公布20040228914、20050158383和20060159768)。
本发明化合物和/或其盐、溶剂合物和/或前药,可以单独使用或者与其他已知用于治疗或预防脱髓鞘疾病的药物相组合使用。
当与其他用于治疗脱髓鞘疾病的药物相组合使用时,本发明化合物和/或其盐、溶剂合物和/或前药适当地与那些药物同时给药。本文使用的两种物质的“同时给药”是指各自提供这两种物质以便它们都是同时独立地产生生物学活性。确切的给药细节会取决于这两种物质彼此存在时的药代动力学,并且可以包括在几小时内各自给药这两种物质,或者甚至如果药代动力学合适的话,给药一种药物是在另外的药物给药24小时之内。设计适合的给药方案对本领域技术人员来说是常规的。在具体实施方案中,两种物质会基本上是同时给药,即彼此给药间隔在几分钟之内,或者在含有这两种物质的单一组合物中。
如上所述,本发明化合物和/或其盐、溶剂合物和/或前药单独给药至动物或者也可以与药学可接受载体组合给药,载体比例由所述化合物的溶解度和化学性质、选择的给药途径和标准的制药实践来决定。
本发明化合物和/或其盐、溶剂合物和/或前药的剂量可以依赖许多因素进行变化,所述因素例如所述化合物的药效性质、给药方式、接受者的年龄、健康状况和体重、症状的本质和程度、治疗的频率以及同时进行的治疗的类型,如果有这些因素的话,以及化合物在将被治疗的动物中的清除率。基于上述因素本领域技术人员可以确定合适的剂量。本发明化合物和/或其盐、溶剂合物和/或前药最初可以按合适的剂量给药,并且它可以随着需要进行调整,这取决于临床反应。作为代表性的实例,本发明化合物和/或其盐、溶剂合物和/或前药的口服剂量对于成年人将在约1mg/天至约400mg/天的范围内,合适地为约1mg/天至约200mg/天,更合适地为约1mg/天至约20mg/天。当配制供口服给药时,所述化合物适合地为每片含有0.25、0.5、0.75、1.0、5.0、10.0、20.0、25.0、30.0、40.0、50.0、60.0、70.0 75.0、80.0、90.0、100.0、150、200、250、300、350或400mg活性成分的片剂形式。合适地,对于口服给药,所述化合物适合地为每片含有0.25、0.5、0.75、1.0、5.0或10.0mg活性成分的片剂形式。本发明化合物和/或其盐、溶剂合物和/或前药可以按单一日剂量给药或者日总剂量可以分成两、三或四份日剂量。如果本发明化合物和/或其盐、溶剂合物和/或前药经皮给药,例如使用那些本领域技术人员熟知的经皮药物贴剂的形式,该剂量给药在整个剂量范围内将是持续的而非间断的。
在本发明的实施方案中,长期地给药或使用本发明化合物和/或其盐、溶剂合物和/或前药。这里使用的术语“长期(long term和chronic)”或使用或给药表示本发明化合物和/或其药学可接受的盐、溶剂合物和/或前药是基于连续有规则、长期的治疗学基础向个体给药的。例如,本发明化合物和/或其药学可接受的盐、溶剂合物和前药可以连续向个体给药而基本上没有间断,比如例如,为了在需要所述治疗的个体中治疗脱髓鞘疾病,持续至少几周或几个月至几年每天给药。在本发明的一个实施方案中,本发明化合物和/或其药学可接受的盐、溶剂合物和前药至少向个体给药约2个月。在本发明的另一实施方案中,本发明化合物和/或其药学可接受的盐、溶剂合物和前药基于不确定的基础向个体给药,例如个体的剩余生命,或者直到这样的给药不再具有有益的效果或治疗。
在理解本公布的范围时,本文使用的术语“包括”及其衍生词,意味着开放性术语,它详细说明了所要叙述的特征、元素、组分、基团、整体和/或步骤的存在,但是没有排除其他未叙述的特征、元素、组分、基团、整体和/或步骤的存在。上述内容也适用于具有类似含义的词语,例如术语“包括”、“具有”以及它们的衍生词。最后,本文使用的程度术语如“基本上”、“约”和“大致”是指被修饰的术语的合理数量的偏差,这样最终结果不会有显著变化。如果偏差不会否定这些程度术语所修饰的词语的含义,则这些程度术语解释为包括被修饰的术语至少±5%的偏差。
实施例
材料和方法
动物
C57BL/6小鼠(8周大,20-25g)从Charles River Canada(蒙特利尔,QC,加拿大)获得并饲养在萨斯喀彻温大学动物实验中心(University ofSaskatchewan animal facility)。所有执行的操作过程均遵循由加拿大动物保护协会(Canadian Council on Animal Care,CCAC)制定的指南并被萨斯喀彻温大学的大学动物保护和供应委员会(University Committee onAnimal Care and Supply,UCACS)批准。
铜宗诱导的脱髓鞘/髓鞘再生和喹硫平的给药
为了测试喹硫平是否可以保护小鼠大脑不被铜宗诱导产生脱髓鞘,如上所描述8周大的小鼠用含有0.2%铜宗(w/w)(Sigma-Aldrich,圣路易斯,MO,USA)的磨好的LabDiet啮齿类动物食物(PMI nutritioninternational LLC,Brentwood,MO,USA)喂养5周(Morell等人,1998)。在该处理中动物没有表现出严重的副作用。研究包括下面4组(6-8只动物/组):第1组:对照,用常规食物进行喂养(con);第2组:用喹硫平(10mg/kg/天在饮用水中)预给药1周,随后5周喹硫平与正常饮食一起给药(que);第3组:喂养含有铜宗的食物5周(cup)并将常用自来水作为饮用水;第4组:用喹硫平(10mg/kg/天在饮用水中)预给药1周,随后5周喹硫平治疗与给予铜宗一起进行(cup+que)。
为研究喹硫平对髓鞘再生过程的作用,另外两组(6-8只动物/组)的小鼠用在磨成粉的食物中的0.2%铜宗处理6周,然后恢复为不含铜宗的饮食(Matsushima和Morell,2001)。在再食用不含铜宗的饮食后,小鼠立即用载体(水)或喹硫平(10mg/kg/天在水中,que)喂养两周。
行为试验
运动行为试验
在这些实验结束前的一天,对自发性运动用装配有光束的运动检测系统进行测量。小鼠被独立地放在透明笼里(40×40×25cm)6分钟,在1分钟的适应期之后,随后5分钟内被小鼠所中断的光束频率被记录为运动的总数目(水平和垂直的)(Bushnell等人,1986)。
Y迷宫自发变换
在运动行为试验后,立即通过记录在Y迷宫中的自发性变换行为来评价空间工作记忆,该迷宫包括标记为A、B和C臂的三个30-cm小室。自发变换行为是基于啮齿类探索新环境的自然趋势。在Y迷宫中,小鼠趋向通过系统地进入每个臂来探索迷宫。为了有效的变换,要求小鼠知道哪个臂已经被探访过。因此,变换行为被认为是包括空间工作记忆的量度。工作记忆受损的小鼠不能记住哪个臂刚刚已经探访过,并因此表现出减少的自发变换(Wietrzych等人,2005)。每只小鼠被放在一个臂的末端并允许在8分钟的时间内自由地移动通过该迷宫。观察记录进入臂的总数和次序(series)。重复进入顺序的数目(例如,ABC,BCA)被定义为变换的数目。结果根据下式被计算为变换的百分数:变换百分数=(变换的数目)/(进入臂的总数-2)×100(Wall等人,2002)。总进入次数作为在Y迷宫中移动行为的指数被评分,并且表现出低于6次进入的评分的小鼠将被排除。
组织制备和免疫组织化学分析
在它们治疗期结束时,用戊巴比妥钠对小鼠以50mg/kg进行麻醉并用0.01M PBS继之以在PBS中的4%多聚甲醛进行贲门内灌注,并且之后固定脑在4%多聚甲醛中过夜。脑组织然后用0.01M PBS清洗3遍并在30%蔗糖中于4℃低温保护一天并于-80℃冰冻用于免疫染色。如在themouse brain atlas of Franklin and Paxinos(Franklin和Paxinos,1997)中所定义,在1至-1mm前卤点之间的水平切开连续冠状缝切面。在胼胝体的冷冻切片(30μm)中用勒克司坚牢蓝进行高碘酸-雪夫染色反应来评估脱髓鞘疾病。利用在0.01M PBS中的0.3%H2O2对漂浮的冰冻切片(30μm)于室温(RT)培养30分钟以消除内源过氧化物酶活性,然后用10%山羊血清/PBS或10%兔血清(用于MBP染色)于室温封闭1小时,并且随后用在封闭液中稀释的初级抗体温育过夜。清洗后,切片用合适的生物素结合的次级抗体于室温温育1小时(1∶1000;Vector实验室,Burlingame,CA)。切片随后利用亲和-生物素复合物试剂盒(Vector实验室,Burlingame,CA)进行显影并将抗体用DAB色原体显影(Sigma-Aldrich,圣路易斯)。
抗体
针对MBP的山羊多克隆抗体(1∶250;Santa Cruz Biotechnology,CA)被用于检测髓鞘。兔谷胱甘肽S-转移酶抗-pi亚型(GST-pi,1∶500;Stressgen,维多利亚,BC,加拿大)被用作成熟少突胶质细胞的标记物(Mason等人,2004);Ness等人,2005)。兔多克隆NG2抗体(1∶200;Chemicon,Temecula,CA)被用作少突胶质细胞祖细胞的标记物(Nishiyama等人,1996)。
图象分析
为了量化GST-pi和NG2,对三幅来自每个动物冠状缝切面的数字图像(包括各切片中胼胝体的中线和两个边缘)进行检查。依照the mousebrain atlas of Franklin and Paxinos(Franklin和Paxinos,1997),细胞计数表示为来自两个不同区域、500μm距离、在1至-1mm前卤点之间的三个冠状缝切面中的阳性细胞计数的平均值。结果表示为每组至少6只小鼠的平均值。为了MBP染色分析,对三幅来自每个动物冠状缝切面(包括大脑皮层)的数字图像进行检查,至少每组6只动物。在选定的区域计算MBP阳性区域的百分比(图2.G)。结果表示为与对照组相比MBP阳性区域的平均百分数(图2.H)。图像在有数字CCD捕捉系统的OlympusBX-51光学显微镜下完成(Diagnostic Instruments Inc.,Sterling Heights,MI)并且利用Image-Pro Plus软件(4.1版,Media Cybernetics公司,SilverSpring,MD)进行分析。
统计分析
结果表示为均值±SEM。P<0.05的概率被认为是统计学显著性的。统计学显著性通过方差分析(ANOVA)和随后用图基检验完成的治疗组之间的多重比较来确定(*P<0.05;**P<0.01;***P<0.001)。双尾配对t检验被用于单个治疗组与对照组的比较(*P<0.05,**P<0.01)。
结果
实施例1:铜宗显著损伤了自发变换行为,其可通过与喹硫平的共同给药来逆转
在本研究中,发现0.2%铜宗给药5周显著地损伤在Y迷宫中的自发变换行为并增加进入Y迷宫臂的总次数。同时给药喹硫平(10mg/kg/天,p.o.)显著性地弱化自发变换行为的损伤和减少铜宗诱导的进入臂的总次数的上升(图1.图基检验,**相对于对照组p<0.01,++相对于铜宗组p<0.01)。记忆障碍在从铜宗脱髓鞘疾病中恢复2周后仍然存在。在髓鞘再生过程中的喹硫平治疗并没有出现使记忆障碍好转或者改变在Y迷宫中的总臂进入次数(图1,双尾t检验,*p<0.05,**p<0.01)。组间的运动行为试验没有表现出显著性差异(数据没有显示)。
实施例2:共同给药喹硫平减少了铜宗诱导的脱髓鞘
为了评价喹硫平对铜宗诱导的脱髓鞘的作用,小鼠用0.2%铜宗喂养5周,共同给药或不共同给药喹硫平。随后通过用于髓磷脂蛋白的MBP免疫染色和用于髓磷脂的LFB-PAS组织学对脑切片进行染色研究。来自5周铜宗处理组的切片在MBP染色中显示明显的脱髓鞘;相反,来自共同给药喹硫平和铜宗组的切片表现出较少的脱髓鞘(减少35%)(图2.A-D)。LFB-PAS染色表现出和MBP染色相同的趋势(图3.A-D)。在从铜宗脱髓鞘中恢复两周后,MBP和LFB-PAS都在脱髓鞘损害区域表现出明显的髓鞘再生,但是在载体(水)组和喹硫平治疗组之间关于髓鞘再生没有差异(图2.E,F和3.E,F)。
实施例3:喹硫平改变祖细胞响应脱髓鞘的增殖
作为对脱髓鞘和成熟少突胶质细胞消耗的响应,NG2+少突胶质祖细胞快速蓄积在脱髓鞘胼胝体中并分化为星样形态(图4.E)(Morell等人,1998;Arnett等人,2001);然而,共同给药喹硫平显著减少了脱髓鞘区域中NG2+细胞的数量(图4.A-D)。不希望受限于理论,该结果提示脱髓鞘的减少可以抑制NG2+细胞的蓄积。NG2+细胞在从铜宗处理恢复2周后显著地减少。喹硫平对此变化只有很少的影响(图4.F,G)。
实施例4:喹硫平治疗促进髓鞘再生过程中成熟少突胶质细胞的再生
在治疗5周后,铜宗诱导胼胝体中成熟少突胶质细胞显著的损失,这部分是因为细胞凋亡(Mason等人,2000,Arnett等人,2002)。为了检查少突胶质细胞的损失,GST-pi作为成熟的生成髓鞘的少突胶质细胞标记物被染色。在铜宗组和cup+que组中,GST-pi+细胞在胼胝体中几乎完全消失,这表明喹硫平没有逆转成熟少突胶质细胞的损失(图5.A-D)。当铜宗从饮食中撤去时发生髓鞘再生并导致新的成熟少突胶质细胞存在于脱髓鞘损害区域(Mason等人,2000)。在关于神经祖细胞培养的体外研究中,喹硫平促进少突胶质细胞的增殖和分化。为研究喹硫平治疗是否也可以促进来自脱髓鞘损害区域的少突胶质细胞髓鞘再生,检查已经从脱髓鞘疾病中恢复2周的小鼠的胼胝体中的GST-pi+细胞。GST-pi+成熟少突胶质细胞在喹硫平治疗的小鼠中显著的增加(图5.E-F)。
讨论
对年轻成年小鼠喂养铜宗5周引起再生的和明显的脱髓鞘。当撤去铜宗,广范的髓鞘再生在几周内发生(Blakemore等人,1973)。相比于作为炎症性脱髓鞘模型的实验性自身免疫性脑脊髓炎(EAE),铜宗模型由于不存在T细胞而具有简单的免疫应答(Bakker等人,1987;Hiremath等人,1998)。因此,由于具有更少的免疫应答,铜宗模型被认为是用于研究脱髓鞘和髓鞘再生过程的理想模型。
基于该模型,通过LFB-PAS染色(Pappas等人,1981)或MBP免疫染色(图2和3),发现喹硫平治疗显著地改善铜宗诱导的在小鼠大脑中的脱髓鞘。作为对脱髓鞘的应答,OPCs蓄积并在脱髓鞘损害区域展现出星样形态(Mason等人,2000)。在本研究中,OPCs的蓄积在cup+que组中也减少,并伴随着脱髓鞘的减少(图4)。该结果表明弱化脱髓鞘也抑制了OPCs的蓄积。尽管不希望受限于理论,在脱髓鞘中的不同可能是由于在喹硫平治疗的小鼠中髓磷脂产生的少突胶质细胞损失的延迟,但是GST-pi+成熟少突胶质细胞几乎不存在于铜宗处理或者共同给药喹硫平的小鼠中(图5)。如同McMahon与同事先前指出的那样(McMahon等人,2001),看起来脱髓鞘和成熟少突胶质细胞的损失在该时间点上不同时发生。可能的解释是虽然大量的GST-pi+成熟少突胶质细胞通过在脱髓鞘过程中的细胞凋亡而损失(Mason等人,2000),一些成熟少突胶质细胞还是可以通过下调GST-pi基因从而存活(Tansey等人,1997),并且因此不能通过GST-pi染色检测到,这要归因于GST-pi细胞的缺失(McMahon等人,2001)。
同样地,尽管不希望受限于理论,设想喂养铜宗导致细胞色素氧化酶的活性减少和线粒体中能量代谢的紊乱(Suzuki等人,1969;Wakabayashi等人,1978);它降低了SOD(Ljutakova等人,1985)和单胺氧化酶(Kesterson等人,1971)的活性,并且因此减少了少突胶质细胞凋亡和脱髓鞘。最近的研究已经指出炎症细胞因子例如干扰素(Mana等人,2006;Lin等人,2006,Gao等人,2000)和肿瘤坏死α因子(TNF-α)(Arnett等人,2001;McMahon等人,2001),以及生长因子如PDGF(Murtie等人,2005;Woodruff等人,2004)、FGF2(Armstrong等人,2002)和IGF-1(Mason等人,2000;Mason等人,2003)它们也都参与脱髓鞘和髓鞘再生过程。其他研究报道了喹硫平和其他APDs能够抑制细胞凋亡(He等人,2004;Luo等人,2004;Jarskog等人,2006)、保护细胞对抗氧化应激(Wang等人,2005)和NMDA医治兴奋性毒素伤害(Farber等人,1993;Farber等人,1996)并上调神经生长因子表达(例如NGF、GDNF、BDNF)(Xu等人,2002;Parikh等人,2003)。因此,人们猜测APDs的这些方面(包括喹硫平)可以促成保护髓鞘以避免脱髓鞘。
研究表明约40-60%的MS患者患有认知损害(Penman等人,1991;McIntosh-Michaelis等人,1991;Rao等人,1991),包括记忆力、注意力、概念化和问题求解技巧,以及信息处理(Petersen等人,1989)。在这些当中,最典型涉及的是记忆缺失,尤其是长期记忆和工作记忆(Grant等人,1984;Beatty等人,1988)。在铜宗模型中,发现在Y迷宫试验中表现出工作记忆障碍的减退通过喹硫平治疗被逆转(图1)。动物研究也已经表明喹硫平可以逆转苯环利定(He等人,2006)和卡英酸(Martin等人,2005)诱导的记忆缺失。
作为首个关于在铜宗模型中的记忆障碍的报告,猜测记忆障碍与脱髓鞘损害相关,因此,铜宗模型可以用作MS模型,不但用于脱髓鞘研究,而且用于评估脱髓鞘相关的记忆缺失。当铜宗的攻击终止后,髓鞘再生自然地发生。
虽然已经通过目前认为是优选的实施例来对本发明进行描述,但是要理解,本发明并不限于所公开的实施例。相反地,本发明意在覆盖包括在所附权利要求的主旨和范围之内的各种修改和等同排列。
如同各自独立的出版物、专利或专利申请被明确和独立地表明全部引入本文作为参考那样,所有出版物、专利和专利申请以同样的范围全部引入本文作为参考。如果在本申请中哪里的术语定义被发现不同于在本文引用作为参考的文件中的定义,本文提供的定义将作为术语的定义。
在说明书中所引用的全部参考文献
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Claims (4)
1.喹硫平或其药学可接受的盐在制备用于治疗铜宗诱导的脱髓鞘疾病的药物中的应用。
2.权利要求1的应用,其中所述铜宗诱导的脱髓鞘疾病是铜宗诱导的胼胝体中成熟少突胶质细胞的凋亡。
3.权利要求2的应用,其中所述铜宗诱导的脱髓鞘疾病是多发性硬化。
4.权利要求1、2或3的应用,其中所述喹硫平或其药学可接受的盐是喹硫平半延胡索酸盐。
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CA2704279C (en) | 2014-09-30 |
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US20100216771A1 (en) | 2010-08-26 |
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CA2704279A1 (en) | 2008-05-08 |
HK1139334A1 (en) | 2010-09-17 |
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