CN1261095C - 脑、脊髓和神经损伤治疗方法 - Google Patents
脑、脊髓和神经损伤治疗方法 Download PDFInfo
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- CN1261095C CN1261095C CNB018037208A CN01803720A CN1261095C CN 1261095 C CN1261095 C CN 1261095C CN B018037208 A CNB018037208 A CN B018037208A CN 01803720 A CN01803720 A CN 01803720A CN 1261095 C CN1261095 C CN 1261095C
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Abstract
本发明提供脑、脊髓和神经损伤的治疗方法,包括使用P物质受体拮抗剂,并任选地联合使用镁化合物。本发明还提供用于该治疗方法中包含P物质受体拮抗剂和镁化合物的制剂。
Description
发明领域
本发明涉及脑、脊髓和神经损伤的治疗方法。还提供在该方法中尤其有用的制剂。
脑的损伤导致出现运动和认知缺陷,其使脑损伤存活者出现显著的病态。而且,它是在社会的年轻成员中具有最高发生率的事件。因此,脑损伤比任何其它疾病过程要造成更多的生产性生活丧失。尽管这样,仍没有有效的治疗方法可以改善脑损伤后的后果。我们公开了在脑损伤治疗中强药物干涉疗法的用途。使用该疗法显著地改善了中等至严重程度的实验性脑损伤后的运动和认知后果,而且我们发现其对脊髓和神经损伤的治疗也有有益的作用。
发明背景
正如熟知的,脑损伤通过两种机制导致神经缺陷的出现。其中第一种被称作原发性机制。这发生在损伤事件的同时,并包括机械性过程例如神经纤维的割裂、撕断、拉长和压缩。对于此类损伤一旦其发生几乎是无能为力。第二种机制是继发损伤,它包括由原发性损伤引起的、但在时间上出现在该损伤之后的生化和生理过程。已证明,脑损伤后的大多数病态与继发损伤的出现有关。如果继发损伤在原发性事件后的数分钟至数天内出现,则存在药物预防此类损伤并显著改善所致后果的机会。然而,必需首先鉴定出造成继发损伤的因子,然后开发出“抗因子”以抑制此损伤过程。
我们的研究集中在鉴定脑损伤后的继发损伤因子并开发干扰疗法。我们以前鉴定了一些决定损伤后后果的关键因子1-4,其中之一是脑的镁离子浓度。该离子是脑损伤后被激活的许多生化和生理过程的调节因子。实际上,已观察到镁离子浓度的降低使损伤过程恶化,同时也注意到镁离子浓度的增加可缓解损伤过程并导致后果的改善5。自此证明使用镁治疗脑损伤是有效的1,6-10,甚至在原发性事件后多达24小时施用也仍有效,并且该疗法在实验动物研究中的成功已导致随后在人脑损伤上进行临床试验。
尽管施用镁可以减轻脑损伤后的缺陷,但明显地治疗后仍持续存在运动和认知缺陷。我们尤其注意到以下事实,即年青动物中仍存在脑内积水(脑肿胀)而且这可以构成一个显著的危险因素。实际上,在近来的临床研究中,迟发性脑肿胀是导致50%年青脑损伤受害者中记录在案的所有死亡的原因。
发明陈述
由此,本发明的一个目的是提供有关脑损伤的治疗方法以及用于该方法的制剂。
在本发明一个方面中,该制剂包含P物质受体拮抗剂和镁化合物。
根据本发明的一个实施方案,所述制剂中的镁化合物的剂量足以使脑中游离镁的浓度增加至约1.0nM。
本发明方法包括步骤:给患有脑损伤的患者施用该制剂。或者,分别地,或以不影响疗效的时间延搁如1-30分钟依次地给予该制剂的各个成分。
P物质是兴奋性神经递质,在疼痛的传递中起作用,并是具有RPKPEEFFGLM-NH2结构的肽。其来自于下丘脑、CNS和肠,并增强平滑肌G1束的收缩。
已知P物质可与许多受体结合,包括NK1受体(即神经激肽1受体)、NK2受体和NK3受体。这些受体被认为在血液向脑的流动中起作用。
因此,P物质拮抗剂是抑制P物质与上述任何一种受体结合的物质。此处所附表1、2和3中给出了一系列适当的P物质拮抗剂。
还可以参考美国专利5990125中(该专利并入本文作为参考)描述的NK1受体拮抗剂,其是组成型P物质拮抗剂,可以用于本发明方法的制剂中。具体参考具有la、lb、lc、ld、le、X、XVI、XVII、XVIII、XIX、XX和XXI结构的化合物、以及包括奎宁环、乙二胺哌啶、吡咯烷和氮杂莰烷衍生物的其它拮抗剂、和表现出美国专利5990125第33栏中所述P物质受体拮抗剂的活性的相关化合物。
可以根据美国专利4990125第34栏中提及的剂量、并以美国专利5990125第34栏中提及的各种施用形式(即单独地或各种可药用载体或稀释剂一起通过口服施用或肠胃外施用),使用这些受体拮抗剂。
还可以通过美国专利5990125第35-36栏中提及的测试方法,确定用于本发明的各种作为P物质受体拮抗剂的物质的活性。
还可以参考美国专利5977104中描述的P物质受体拮抗剂,包括在该参考文献(其也完整地并入本文作为参考)中提及的各种剂型和剂量。
还可以参考美国专利4481139,其描述了多种肽拮抗剂,也完整地并入本文作为参考。
还应理解,正如本文所用,术语“P物质”在其范围内还可以包括美国专利4481139中所述的各种截短形式或类似物,该专利完整地并入本文作为参考。
还可以参考美国专利4985896,其提及了可以在本发明中作为P物质拮抗剂使用的各种哌啶和吗啉衍生物,或参考美国专利5981520中描述的哌嗪并衍生物。所有这些参考文献均完整地并入本文作为参考。
还可以参考美国专利5998444中提及的可以用于本发明中作为NK1或NK2拮抗剂的哌啶基化合物,该专利也完整地并入本文作为参考。
还应理解,也可以在本发明中使用美国专利4981744中提及的速激肽拮抗剂作为P物质拮抗剂,因此也将该参考文献完整地并入本文。
还可以参考EP-A-1035115(其完整地并入本文作为参考),其涉及可以在本发明中用作NK1受体拮抗剂的N-苄基-4-甲苯基烟酰胺和相关化合物。
可以参考国际公开文本WO 0050398(其完整地并入本文作为参考),其涉及可以在本发明中用作NK1受体拮抗剂的各种苯基和吡啶基衍生物。
还可以参考国际公开文本WO 0050401、WO 0053572、WO 0073278和WO 0073279,它们分别涉及到3-苯基吡啶、二苯基衍生物、5-苯基嘧啶衍生物和4-苯基嘧啶衍生物,这些说明书也完整地并入本文作为参考。这些说明书提及到可以用于本发明中的NK1受体拮抗剂。
还可以参考1998年Sigma产品目录、更具体地第1194-1997页,其描述了P物质或P物质片段的修饰物,它们可以作为P物质拮抗剂用于本发明。该出版物也完整地并入本文作为参考。
关于镁化合物,可以包含任何适当来源的镁离子,例如氯化镁、硫酸镁、草酸镁、葡糖酸镁或其它非毒性镁盐。
根据本发明这些药物制剂还可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、改变渗透压的盐、缓冲液、掩蔽剂或抗氧化剂。它们还可以含有其它具有治疗价值的物质。因此,本说明书中术语“包含”应根据上下文进行解释。剂量可以在一宽范围内变动,当然也可以与每种具体情况下的各种要求相配合。一般地,每个患者接受1至20000mg剂量、优选地10至5000mg剂量、更优选地50至2000mg剂量的P物质受体拮抗剂应当是适当的。
与本发明构思的发展相关,本发明人确立了损伤后脑中急性积水的一个原因是血管源性脑水肿的形成。这是由血脑屏障通透性的增加,由此允许血管蛋白质和水进入脑部细胞外空间并引起肿胀而导致的。几乎还没有研究检测过这种血脑屏障通透性的增加在损伤后神经缺陷的出现中起着怎样的作用,而且也没有研究调查过抑制脑肿胀是否可改善后果。偏头痛的研究12,13提示,硬脑脊膜(脑脊膜外层)的血管系统由于P物质的释放变得更容易通透血管成份。因此,我们推测P物质可能对脑血管系统具有相似的作用,在此处这种作用可以导致血脑屏障通透性和血管源性脑水肿的增加。我们还推测,施用P物质受体拮抗剂可以防止脑肿胀以及损伤后迟发性神经缺陷的出现。该假设是上述我们的发现(即血管源性脑水肿的形成导致了脑积水)的结果。
因此,在本发明的另一方面,提供了P物质受体拮抗剂在降低脑屏障通透性和/或血管源性脑水肿中的用途。
实验
正如表1、2和3所示,许多商业合成的P物质受体拮抗剂目前可以从标准的科学性化学药品提供者处获得。基于其低脂溶性(这限制了其天然跨越血脑屏障的能力)以及相对便宜这一事实,我们选择了使用化合物N-乙酰基L-色氨酸。脑损伤后30分钟按246mg/kg剂量静脉内施用N-乙酰基-L-色氨酸(盐水载体),导致脑损伤动物认知结果的显著改善(通过巴恩斯圆形迷宫(Barnes Circular Maze)评价的)。类似地,正如rotarod测试所评价的,动物的运动结果也有显著改善。结果的这些改善在脑损伤后24小时表现出来并在14天的评价期中持续存在。在所有测试的时间点上,对照(测试载体)动物比治疗过的动物都有糟得多的神经学结果。
与载体处理的对照相比,用N-乙酰基L-色氨酸处理过的动物在脑损伤后24小时脑积水(即脑水肿)显著减少。这与如下观察结果,即损伤后5小时(该时间与脑损伤后的最大血脑屏障通透性有关)N-乙酰基-L-色氨酸减少伊文思蓝的脑透过量,是一致的。因此,脑损伤后30分钟施用N-乙酰基L-色氨酸降低血脑屏障的通透性并降低血管源性脑水肿的形成。使用NK1拮抗剂的非可通透性制剂我们观察到这些效果,这一事实提示,这些效果主要是由血管受体所介导的并且不依赖于中枢受体。
施用24.6mg/kg的N-乙酰基L-色氨酸也显著地改善脑损伤动物的认知结果。然而,该药物对运动结果的有益作用较少。而且,因为在所有治疗过的动物中总观察到有一些残余的认知和运动缺陷,所以与性质严重的损伤不同,使用NK1拮抗剂治疗的有益效果在轻度严重的损伤中较不明显。考虑到脑损伤患者中轻度头部损伤的发生率最大,这就成为了一个主要的限制。
镁和N-乙酰基L-色氨酸的组合
脑损伤的最通常形式是轻度的头部损伤。世界神经外科医生联盟在下一年(2000)提出的指南中建议,具有任何并发症如呕吐、恶心、丧失知觉或健忘症的所有轻度头部损伤患者都必须送往医院。这就极大地迫使健康系统要充分地治疗这些患者以便不再出现继发损伤。目前,还没有这样的疗法。
我们使用N-乙酰基-L-色氨酸得到的结果提示,该化合物在头部损伤后封闭血脑屏障并减少脑肿胀或脑水肿。对于尤其易于出现迟发性脑肿胀的年轻头部损伤患者而言,这极为重要。而且,我们使用镁治疗得到的结果提示,镁治疗可有效地减少不一定与血脑屏障通透性增加有关的神经缺陷。因此,我们提出,P物质拮抗剂和镁化合物或盐的组合将是一种尤其有效的治疗任何严重程度的脑损伤的疗法。
联合施用246mg/kg N-乙酰基L-色氨酸及30mg/kg硫酸镁(静脉内)导致运动和认知缺陷的极大减少,这比单独施用任一种药物所获得的减少都要大得多(图1和图2)。
该组合制剂中的所有化合物都具有许多对于用于脑损伤而言极其具有吸引力的性质。
已证实P物质(SP)拮抗剂可通过拮抗P物质诱导的焦虑而快速改善情绪。因此,它们对于治疗损伤后的抑郁是有效的。从上述工作来看,明显地SP拮抗剂减低血脑屏障通透性并抑制血管源性脑水肿的形成和损伤后的脑肿胀或脑水肿。这些拮抗剂也表现出可以抑制疼痛。在海马和纹状体中有大量的P物质受体,而已知脑的这些部分与学习和记忆有关。因此,使用SP拮抗剂抑制结合可以防止P物质诱导的学习和记忆缺陷。我们在以上提供的证据提示,这可能确是事实。这在以前从未被显示过。实际上,还没有关于P物质或任何神经肽在脑损伤中作用的文献。
镁影响超过300种的细胞酶。因此,毫不令人惊奇地,镁具有许多靶标,在这些靶标处其可以改善结果。其中,这些包括阻断谷氨酸诱导的兴奋性毒性、提高膜的稳定性并降低活性氧种类的产生、改善能量状态、抑制钙通道、减少神经递质释放、抑制线粒体转运孔的开放、和抑制细胞凋亡。值得注意的是,它还阻断谷氨酸诱导的P物质释放。生理上,镁显示出14-17改善脑的血流,减少脑血管痉挛、并减少脑神经酰胺和前列腺素的产生。
镁和P物质拮抗剂的联合使用比单独使用任一种药物对神经损伤产生更大的保护。
我们以前已显示,当静脉内施用16至60mg/kg范围内的剂量时镁对外伤有有益的作用。当作为肌内注射剂施用时,有效剂量在45至90mg/kg间变动。目的是将血液中的游离镁离子浓度增加至约1.0mM,该浓度是正常血液游离镁浓度的两倍。无论所用的镁盐是什么,均观察到有益的结果。
我们使用P物质拮抗剂进行的研究证明,有效的静脉内剂量在24.6mg/kg至240.6mg/kg或更高之间变动,而且更高的剂量对运动结果有更为有益的作用。而且,这些剂量与具有低脂溶性而由此具有有限的血脑屏障通透性的拮抗剂是相称的。高脂溶性制剂应也起到相同的有益作用,然而,可能会出现可能是不适当的中枢介导的副作用。
当组合使用时,该制剂可以在上述用于各成份的范围内变化。我们使用上述针对各成份的最大静脉内剂量,获得了极好的结果。
镁/SP拮抗剂组合预期在以下情况中是有用的:
·外伤性脑损伤后作为“急救”预防治疗
·轻微头部损伤,包括脑震荡后作为“急救”预防治疗
·非外伤性脑损伤,包括中风、缺氧和涉及水肿的任何形式脑损伤后,作为一种疗法
·脑损伤后作为一种持续疗法
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表1
NK1受体拮抗剂
化学药品编号 | 化学药品名称 |
CGP49823 | (2R,4S)-2-苄基-1-(3,5-二甲基苯甲酰基)-N-[(4-喹啉基)甲基]-4-胡椒碱胺)二盐酸盐 |
CP-96,345 | (2S,3S)-顺-(2(二苯甲基)-N-[(2-甲氧基苯基)甲基]-1-氮杂二环[2.2.2]辛-3-胺 |
CP-99,994 | ((2S,3S)-顺-3-(2-甲氧基苄基氨基)-2-苯基哌啶)二盐酸盐 |
CP-122,721 | (+)-(2S,3S)-3-(2-甲氧基-5-三氟甲氧基苄基)氨基-2-苯基哌啶 |
FK 888 | (N2-[(4R)-4-羟基-1-(1-甲基-1H-吲哆-3-基)羰基-L-丙基-N-甲基-N-苯甲基-L-3-(2-萘基)-丙氨酰胺 |
GR 203040 | (2S,3S和2R,3R)-2-甲氧基-5-四唑-1-基苄基-(2-苯基哌啶-3-基)胺 |
GR-205171 | 3-哌啶胺,N-[[2-甲氧基-5-[5-(三氟甲基)-1H-四唑-1-基]苯基]甲基]-2-苯基-,(2S-顺)- |
GR 82334 | [D-Pro9,]螺-γ-内酰胺]亮氨酸10,色氨酸11]泡蛙肽-(1-11) |
GR 94800 | PhCO-Ala-Ala-D Trp-Phe-D Pro-Pro-Nle-NH2 |
HSP-117 | 3-哌啶胺,N-[[2,3-二氢-5-(1-甲基乙基)-7-苯并呋喃基]甲基]2-苯基-,二盐酸盐,(2S-顺)- |
L 703,606 | 1-氮杂二环[2.2.]辛-3-胺,2-(二苯甲基)-N-[2-碘苯基)甲基]-,(2S-顺)-,草酸盐 |
L 732,138 | N-乙酰基L-色氨酸 |
L 733,060 | ((2S,S)-3-((3,5-双(三氟甲基)苯基)甲氧基)-2-苯基哌啶 |
L 742,694 | (2-(S)-(3,5-双(三氟甲基)苄氧基)-3-(S)-苯基-4-(5-(3-氧-1,2,4-三唑并)甲基吗啉 |
L 754,030 | 2-(R)-(1-(R)-3,5-双(三氟甲基)苯基乙氧基)-3-(S)-(4-氟)-苯基-4-(3-氧-1,2,4-三唑-5-基)甲基吗啉 |
L 668,169 | L-苯丙氨酸,N-[2-[3-[[N-[2-(3-氨基-2-氧-1-吡咯烷基)-4-甲基-1-氧戊基]-L-甲硫氨酰-L-谷氨酰胺酰-D-色氨酰-N-甲基-L-苯丙氨酰基]氨基]-2-氧-1-吡咯烷基]-4-甲基-1-氧戊基]-L-甲硫氨酰-L-谷氨酰胺酰-D-色氨酰-N-甲基-,环(8->1)肽,[3R-[1[S*[R*(S*)]],3R*]]- |
LY 303241 | 1-哌嗪乙酰胺,N-[2-[乙酰基[(2-甲氧基苯基)甲基]氨基]-1-(1H-吲哆-3-基甲基)乙基]-4-苯基-,(R)- |
LY 303870 | (R)-1-[N-(2-甲氧基苄基)乙酰基氨基]-3-(1H-吲哆-3-基)-2-[N-(2-(4-(哌啶基)哌啶-1-基)乙酰基)氨基]丙烷 |
LY 306740 | 1-哌嗪乙酰胺,N-[2-’乙酰基[(2-甲氧基苯基)甲基]氨基]-1-(1H-吲哆-3-基甲基)乙基]-4-环己基-,(R)- |
MEN 11149 | 2-(2-萘基)-1-N-[(1R,2S)-2-N-[1(H)吲哆-3-基羰基]氨基环己烷羰基]-1-[N’-乙基-N’-(4-甲基苯基乙酰基)]二氨基乙烷 |
MK-869 | 3H-1,2,4-三唑-3-酮,5-[[2-[1-[3,5-双(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)-4-吗啉基]甲基]-1,2-二氢-,[2R[2α(R*),3α]]- |
PD 154075 | (2-苯并呋喃)-CH2OCO]-(R)-α-Me Trp-(S)-NHCH(CH3)Ph |
R-544 | Ac-Thr-D-Trp(FOR)-Phe-N-MeBzl |
RP-67580 | (3aR,7aR)-7,7-二苯基-2[1-亚氨基-2(2-甲氧基苯基)乙基]+++全氢异吲哆-4-酮盐酸盐 |
RPR 100893 | (3aR,4S,7aS)-7,7-二苯基-4-(2-甲氧基苯基)-2-[(S)-2-(2-甲氧基苯基)丙酰基]全氢异吲哆-4-醇 |
Spendide | Tyr-D-Phe-Phe-D-His-Leu-Met-NH2 |
Spantide II | D-NicLys1,3-Pa13,D-C12Phe5,Asn6,D-Trp7.0,Nle11-P物质 |
Spantide III | L-正亮氨酰胺,N6-(3-吡啶基羰基)-D-赖氨酰-L-脯氨酰-3-(3-吡啶基)-L-丙氨酰-L-脯氨酰-3,4-二氯-D-苯丙氨酰-L-天冬酰胺酰-D-色氨酰-L-苯丙氨酰-3(3-吡啶基)-D-丙氨酰-L-亮氨酰基- |
SR140333 | (S)-1-[2-[3-(3,4-二氯苯基)-1(3-异丙氧基苯基乙酰基)哌啶-3-基]乙基]-4-苯基-1-氮翁二环[2.2.2]辛烷 |
WIN-41,708 | (17β-羟基-17α-乙炔基-5α-雄甾烷并[3,2-b]嘧啶并[1,2-a]苯并咪唑 |
WIN-62,577 | 1H-苯并咪唑并[2,1-b]环戊[5,6]萘并[1,2-g]喹唑啉-1-醇,1-乙炔基-2,3,3a,3b,4,5,15,15a,15b,16,17,17a-十二氢-15a,17a-二甲基-,(1R,3aS,3bR,15aR,15bS,17aS)- |
表2
NK2受体拮抗剂
化学药品编号 | 化学药品名称 |
SR-48,968 | (S)-N-甲基-N-[4-(4-乙酰基氨基-4-(苯基哌啶子基)-2-(3,4-二氯苯基)-丁基)]苯甲酰胺 |
L-659,877 | 环[Gln,Trp,Phe,Gly,Leu,Met] |
MEN 10627 | 环(Met-Asp-Trp-Phe-Dap-Leu)环(2β-5β) |
SR 144190 | (R)-3-(1-[2-(4-苯甲酰基-2-(3,4-二氟苯基)-吗啉-2-基)-乙基]-4-苯基哌啶-4-基)-1-二甲基脲 |
GR 94800 | PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 |
表3
NK3受体拮抗剂
化学药品编号 | 化学药品名称 |
SR-142,801 | (S)-(N)-(1-(3-(1-苯甲酰基-3-(3,4-二氯苯基)哌啶-3-基)丙基)-4-苯基哌啶-4-基)-N-甲基乙酰胺 |
R820 | 3-吲哚基羰基-Hyp-Phg-N(Me)-Bzl |
R486 | H-Asp-Ser-Phe-Trp-β-Ala-Leu-Met-NH2 |
SB 222200 | (S)-(-)-N-(a-乙基苄基)-3-甲基-2-苯基喹啉-4-甲酰胺 |
L 758,298 | 膦酸,[3-[[2-[1-[3,5-双(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)-4-吗啉基]甲基]-2,5-二氢-5-氧-1H-1,2,4-三唑-1-基]-,[2R-[2α(R*),3α]]- |
NK-608 | (2R,4S)-N-[1-{3,5-双(三氟甲基)-苯甲酰基}-2-(4-氯苄基)-4-哌啶基]-喹啉-4-甲酰胺 |
Claims (19)
1.治疗脑、脊髓和神经损伤的注射用制剂,其包含P物质受体拮抗剂以及镁化合物。
2.根据权利要求1的制剂,其特征在于镁化合物的剂量足以使血液中游离镁的浓度增加至约1.0mM。
3.根据权利要求1的制剂,其特征在于镁化合物的剂量足以使正常的血液游离镁浓度加倍。
4.根据权利要求1至3之任一项的制剂,其中P物质受体拮抗剂是NK1受体拮抗剂。
5.权利要求4中所要求的制剂,其中NK1受体拮抗剂选自:CG P49823、CP-96,345、CP99,994、CP-122,721、FK88、GR203040、G R205171、GR82334、GR94800、HSP-117、L-703,606草酸盐、L-732,138、L-733060、L-742,694、L-745,030、L-668,169、LY-303241、LY-303870、LY306740、MEN-11149、MK-869、PD-154075、R-544、RP-67580、RPR100893、Sendide、SpantideII、Spantide III、SR140333、WIN-41,7098、WIN-62,577。
6.权利要求1至3之任一项中所要求的制剂,其中镁化合物选自氯化镁、硫酸镁、草酸镁、葡糖酸镁或其它非毒性镁盐。
7.权利要求1至3之任一项中所要求的制剂,其中P物质受体拮抗剂的剂量是每患者1-20,000mg。
8.权利要求1至3之任一项中所要求的制剂,其中P物质受体拮抗剂的剂量是每患者10-5,000mg。
9.权利要求1至3之任一项中所要求的制剂,其中P物质受体拮抗剂的剂量是每患者50-2,000mg。
10.P物质受体拮抗剂在制备用于治疗脑、脊髓和神经损伤的注射用药物中的用途。
11.根据权利要求10的用途,其中损伤是由于神经纤维的割裂、撕断、拉长和压缩引起的。
12.根据权利要求10的用途,其中所述药物为改善脑损伤后的认知后果的药物。
13.根据权利要求10的用途,其中所述药物为防止脑损伤后P物质诱导的学习和记忆缺陷的药物。
14.根据权利要求10的用途,其中所述药物为改善轻度至严重的脑损伤后的运动和认知后果的药物。
15.根据权利要求10至14之任一项的用途,其中P物质受体拮抗剂是NK1受体拮抗剂。
16.根据权利要求15的用途,其中NK1受体拮抗剂选自:CGP49823、CP-96,345、CP99,994、CP-122,721、FK88、GR203040、GR205171、GR82334、GR94800、HSP-117、L-703,606草酸盐、L-732,138、L-733060、L-742,694、L-745,030、L-668,169、LY-303241、LY-303870、LY306740、MEN-11149、MK-869、PD-154075、R-544、RP-67580、RPR100893、Sendide、SpantideII、Spantide III、SR140333、WIN-41,7098、WIN-62,577。
17.根据权利要求10至14之任一项的用途,其中P物质受体拮抗剂与镁化合物一起施用。
18.根据权利要求17的用途,其中施用的镁化合物足以使正常的血液游离镁浓度加倍。
19.根据权利要求17的用途,其中施用的镁化合物足以使血液中的游离镁浓度增加至约1.0mM。
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