CN100450475C - 用于治疗注意力缺陷多动障碍及多发性硬化症疲劳的含有莫达非尼的组合物 - Google Patents
用于治疗注意力缺陷多动障碍及多发性硬化症疲劳的含有莫达非尼的组合物 Download PDFInfo
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- CN100450475C CN100450475C CNB008111820A CN00811182A CN100450475C CN 100450475 C CN100450475 C CN 100450475C CN B008111820 A CNB008111820 A CN B008111820A CN 00811182 A CN00811182 A CN 00811182A CN 100450475 C CN100450475 C CN 100450475C
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Abstract
莫达非尼在改善注意力缺陷多动障碍及多发性硬化症疲劳的症状中是有效的。给药莫达非尼也显示出激活后下丘脑的结节性乳头状神经元,并因此在与正常的清醒功能相关的大脑区域表现出活性。
Description
发明背景
1.发明领域
本发明涉及神经药物,包括用于治疗注意力缺陷多动障碍及与多发性硬化症相关的疲劳的药剂领域。
2.对相关技术的描述
注意力缺陷/多动障碍(ADHD)是一种儿童慢性神经精神疾病,其特征是发育不当的机能亢进、冲动和注意力缺陷。据估计,ADHD影响3%-5%的学龄儿童。传统上,人们认为ADHD不会持续至青春期;但是,目前的研究表明,10%-60%的ADHD儿童发病病例持续至成年阶段。ADHD的持续与学术和职业机能障碍的高发病率以及精神病的合病症(例如,品行障碍、重度抑郁症和焦虑性障碍)的高发病率有关。据估计,大约1%-3%的成年人具有ADHD的症状。患有ADHD的成年人具有人口统计、社会心理、精神病学和认识特征的模式,这些特征在患有此种疾病的儿童中被充分地证实。这进一步支持了对成年人的诊断的有效性。在成年人中ADHD的核心症状包括频繁和持续的注意力缺陷/注意力分散和/或多动冲动模式。ADHD成年人中最常见的症状表现为明显的注意力缺陷、集中精神缺乏、注意力易于分散、白日梦、多忘和频繁改变活动。ADHD成年人也表现出明显的冲动、侵略性行为、挫折/压力承受力低下、脾气暴躁、烦躁和极度不耐烦。较少报道的成年人的症状包括多动,这可能被限制在烦躁或神经过敏或坐立不安的内心感受。除核心ADHD症状外,患有ADHD的成年人还经常表现出相关的临床特征,例如厌倦、不能溶入社会和在社会情景中的长期冲突。这些特征可能是由于1)分居和离婚和2)尽管具有足够的知识能力,但学术业绩和职业成就仍然低下的高发生率造成的。此外,患有ADHD的成年人具有药物滥用疾病的高发病率。
虽然ADHD的发病机理仍然不明确,但多巴胺能和去甲肾上腺素功能的变化似乎是该疾病的神经化学基础。对患有ADHD的成年人的大脑进行的正电子发射断层扫描表明涉及注意力和运动效能的大脑皮层区域,如额页的葡萄糖代谢发生变化。对成年人和儿童ADHD的最常见的治疗方法是使用兴奋剂(例如,右旋苯丙胺、苯哌啶醋酸甲酯和苯异妥英)。兴奋剂被认为是通过提高在神经元的突触中可用的多巴胺的量而发生作用。兴奋剂似乎在多个大脑解剖学位点作用。已经使用的其他治疗药物包括:抗抑郁药(例如,三环抗抑郁药,如丙咪嗪和去甲丙咪嗪;新型抗抑郁药,例如安非他酮(buproorion)和文拉法星),抗高血压药(例如,长压宁和胍法新),单胺氧化酶抑制剂([MAO’s]),例如,司立吉林),氨基酸(例如,左旋多巴,苯丙氨酸和L-.酪氨酸)和组合的药物疗法(例如,同时使用一种五羟色胺选择的再摄取抑制剂和一种兴奋剂药物;或一种兴奋剂和儿茶酚胺能(catelcholaminergic)抗抑郁剂服法)(Bhandary等PsychiatricAnnals(精神病学年报)27:545-555,1997年;Wilens等,J.Clin.Psychopharmacol.(临床精神药理学期刊)15:270-279,1995年;Frinkel,The Neurologist(神经病学家)3:31-34,1997年;Miller和Catellanos,Pediatrics in Review(儿科学回顾)19:373-384,1998年)。
虽然兴奋剂是最常用的治疗药物,但大约30%-50%的ADHD成年患者在治疗中对兴奋剂不能产生积极的反应,具有不可接受的副作用或并发兴奋剂药疗法可能加重的抑郁或焦虑性障碍或无效。兴奋剂长期的副作用及其在ADHD药物滥用的高危群体中的使用仍然有待研究并且是人们所关注的;因此,仍然存在着ADHD的非兴奋剂药物疗法的需求。
另一种存在非兴奋剂药物治疗的长期需求的疾病是与多发性硬化症(MS)相关的疲劳。在美国,多发性硬化症是年轻人的一种最常见的残障性神经病之一,大约有400,000人患有此种疾病。虽然MS能够引起多种残障性神经损伤,例如失明、麻痹、不协调和肠或膀胱机能失调,但一种也可能成为严重残障的更不明显的症状是疲劳。在一项涉及656名MS患者的研究中,78%的患者自诉疲劳,60%每天都感到疲劳,22%的患者的日常活动受到干扰(Freal等,Arch.Phys.Med.Rehabil.65:135,1984年)。国家多发性硬化症学会评价了839名患有MS已超过10年,但仅有轻微的神经损伤的患者,在这类轻微损伤的患者群体中,疲劳是最常被报告的症状(Jones,纽约:全国多发性硬化症学会,保健事业研究报告,1991年)。在另一项研究中,40%的MS患者将疲劳列为他们疾病的最严重的症状(Murray,Can.J.Neurol.Sci.12:251,1985年)。在高达75%的MS患者中,疲劳被报告为至少是暂时性障碍的原因;英国MS学会发现疲劳是导致MS患者群失业的最重要的症状(Rolak,Curr.Neurol.9:109,1989年)。在美国,通过将与MS疲劳相关的残障作为残障津贴的标准包含在社会保障管理机构所制定的准则中强调了与MS疲劳相关的残障的流行。
人们还很不了解MS疲劳的机制。它已被归因于在中枢神经系统内的神经传导异常和由于神经残障所导致的提高的能量需求。MS疲劳的几个特征是妨碍身体机能和日常活动,受热加重以及在每天活动结束时恶化(Krupp等,Arch.Neurol.45:435,1988年)。用于治疗MS疲劳的处方药物包括氨基三环癸烷、匹莫林和其他兴奋剂。在一项双盲、随机研究中,氨基三环癸烷被证明在79%的患者中对MS疲劳有益,但其有益作用的机制仍然是未知的(Krupp等,Neurology(神经病学)45:1956,1995年)。虽然以严格的方式证明了氨基三环癸烷对MS疲劳有益,但对大多数患者而言该益处是部分的并且仍然存在无益报告的大量患者。相同的研究没有证明被经常用于治疗MS疲劳的匹莫林具有有益的效果。因此,强烈需要一种安全和有效的治疗方法用于治疗此种使人衰弱的疾病。
本发明概述
本公开文件提供了莫达非尼在治疗注意力缺陷多动障碍(ADHD)和改善由于多发性硬化症(MS)所导致的疲劳症状中的一种新型用途。
成为本公开文件的基础的研究工作意外地证明,向小鼠给药促清醒剂量的莫达非尼导致后下丘脑的结节性乳头状(tuberomamillary)神经核(TMN)的活性选择性地提高。给药莫达非尼降低了在下丘脑的脑侧室前视核区域(VLPO)的神经元的活性,已知在睡眠期间该活性抑制在TMN中的促清醒的被组胺激活的神经元的活性。通过莫达非尼将该被组胺激活的通路活化导致皮层的激活和清醒。因此,莫达非尼的促清醒作用的生理基础似乎涉及通过对VLPO的抑制作用解除对TMN的被组胺激活的神经元的抑制。这代表已知的通过选择性激活TMN而产生清醒的第一种药剂并且基于本领域的在先出版物是预料之外的。
根据这些机制研究,莫达非尼与通常用于ADHD和MS疲劳的兴奋剂相比具有明显不同的活性。他们是明显不同的药物,如本文所公开的,莫达非尼通过选择性地激活涉及正常清醒的下丘脑的神经核而促进清醒,相反,通常所使用的精神刺激剂,如安非他明主要是通过促进在中脑缘、结节性延髓(tuberoinfundibular)和黑质纹状体系统中的多巴胺能的神经元的神经传递提高向皮层和其他脑区域的多巴胺能的输入而发挥作用。在这些主要多巴胺能的通路中,起源自腹侧大脑脚盖的中脑缘系统最直接地涉及皮层活化,而结节性延髓和黑质纹状体系统分别涉及垂体和运动功能。由安非他明同时促进这些通路产生与安非他明给药相关的具有明显特征的皮层刺激和机能亢进。与涉及正常清醒的下丘脑系统相比,促进多巴胺能的神经传递似乎诱导了清醒状态,该清醒状态由于与情绪和安宁的知觉的变化以及运动效能的提高相关而是不正常的。
因为使用莫达非尼激活后下丘脑的结节性乳头状神经元这一令人惊奇的发现,揭示了莫达非尼的一种新的用途,并且此种用途是本发明的一个方面。例如,莫达非尼是一种能够为ADHD患者提供重要的益处的新型治疗剂是本发明的一个方面。因为莫达非尼激活下丘脑,还因为从下丘脑的抑制的被组胺能激活的神经元通路在抑制的Υ-氨基丁酸(GABA)额叶中间神经元上形成突触,下丘脑的激活有助于接下来的锥体细胞的激活并为莫达非尼在ADHD中的应用提供了一种机制。此外,TMN神经元的激活也能够通过直接的组胺能激活提高皮层的作用。换句话说,TMN的激活对皮层是直接或间接刺激性的。额侧皮层不足的活性已被包含在ADHD病因学中(Castellanos,F.X.,Clinical Pediatrics(临床儿科学),381-393(1997);Swanson,J.等,Current Opinion in Neurobiology(神经生物学的最新见解),8:263-271(1998);Barkley,R.A.,Scientific American(科学的美国人),66-71(1998))。
因此,可以将本公开文件的一个方面描述为治疗注意力缺陷多动障碍的一种治疗方法,该治疗方法包括向患有或易患注意缺陷多动障碍的患者给予一种含有莫达非尼化合物的组合物,该给药量是能够改进或阻止所述患者的注意缺陷多动障碍症状的有效剂量。
本公开文件的另一个方面是治疗与多发性硬化症相关的疲劳的治疗方法,该治疗方法包括向患有多发性硬化症疲劳的患者给予含有莫达非尼化合物的组合物,给药量是能够改进或阻止患者的多发性硬化症疲劳症状的有效剂量。在此所述的“疲劳”包括失去对刺激做出反应的力量或能力。这样,本文指出莫达非尼作为一种治疗方法在缓解与多发性硬化症相关的疲劳或失眠发面是有效的,并且也作为一种促进多发性硬化症患者清醒的方法。
本公开文件的又一个方面是治疗忍受注意缺陷多动障碍或多发性硬化症疲劳症状的患者的方法,该治疗方法包括向患者给药有效剂量的含有莫达非尼化合物的药物组合物,以刺激在患者大脑中的结节性乳头状神经元的活性。
本公开文件的再一个方面是用于治疗患有或易患注意缺陷多动障碍的患者的注意缺陷多动障碍的单位剂量形式的药物组合物,该药物组合物包括一定量的莫达非尼化合物,以使在定期给药后,其一个或多个单位剂量能够有效地稳定或改善患者的注意力缺陷多动障碍的症状。
本公开文件的一个方面是一种用于治疗多发性硬化症患者的疲劳的单位剂量形式的药物组合物,其中该组合物包含一定量的莫达非尼化合物,以使在定期给药后,其一个或多个单位剂量能够有效地稳定或改善患者的多发性硬化症疲劳症状。
如在此所公开的以及本发明的组合物和方法所使用的,莫达非尼化合物可以包括一种消旋混合物并且可以是酸的形式,例如莫达非尼的代谢的酸或二苯甲基亚硫酰基乙酸,砜形式,羟基化形式,共轭形式,例如莫达非尼化合物与蛋白质、多糖、葡糖醛酸糖苷或硫酸脂的共轭体或者是多晶形式,它也可以包括含有莫达非尼的苯基基团的电子等排替代基团的化合物和莫达非尼的多晶型种或同系物,或者是同类物的衍生物或前体药物,特别是那些向哺乳动物给药时能够刺激在TMN中的活性的制剂。在优选的实施方案中,莫达非尼化合物是莫达非尼。前体药物是本领域已知的在患者的体内转变为活性剂(莫达非尼)的化合物。
在此所公开的组合物和方法优选用于治疗哺乳动物类患者,特别优选用于人类。因为已经知道MS和ADHD会使成年人、青少年和儿童受到困扰,在此所公开的的方法和组合物也针对这一群体。虽然可以以毫克/天向人类口服给药有效的剂量,但应当理解的是,除非另外说明,该剂量针对成年人类,对儿童的剂量应做相应的调整。
本发明的一个目的是提供包括使用有效剂量的莫达非尼化合物用于治疗ADHD和MS疲劳的治疗方法,并且优选该有效的量为每天约1至约400毫克的剂量。本领域已知,例如从约200毫克/天至约400毫克/天的剂量是有效的促清醒剂量,预计该剂量可用于治疗ADHD和MS疲劳。还已知约100毫克/天的剂量是促清醒剂量的低限,但预计该剂量可用于治疗ADHD和MS疲劳。在其他地方报告的研究也表明了莫达非尼在低于促清醒剂量时的有益的活性,特别是在改善认知功能方面。这样,用于在此所公开的方法的莫达非尼化合物的有效量可以包括从约1毫克/天至约400毫克/天,或从约100至约400毫克每天,或从约200至约400毫克每天,或者甚至是200毫克每天是本公开文件的一个方面。还应当理解的是,在上述范围内,但没有明确指出的剂量,例如30毫克、50毫克、75毫克等包括在上述范围内,稍微超出上述范围界限的剂量也如此。
在优选的实施方案中,将含有莫达非尼化合物的组合物制成口服制剂,特别优选制成片剂口服。如下文的描述,含有莫达非尼的片剂制剂是本领域已知的,并可以优选此类片剂含有不同的惰性成分,例如,任意组合形式的乳糖、玉米淀粉、硅酸镁、交联羧甲纤维素钠、聚烯吡酮、硬脂酸镁、或滑石粉。
本公开文件的一个方面也可以被描述成一种用于向接受注意力缺陷多动障碍或多发性硬化症疲劳治疗的哺乳动物配药,或在配药中所使用的治疗用试剂盒,该试剂盒包括(1)一个或多个单位剂量的药剂,每个该单位剂量的药剂含有一定量的莫达非尼化合物,以使在定期给药和定期给予该单位剂量药剂后,所述的一个或多个单位剂量药剂能够有效地稳定或改善该哺乳动物中的注意力缺陷多动障碍或多发性硬化症疲劳的症状,和(2)上述药物的一种最终的药物容器,所述的容器包括(a)所述的一个或多个单位剂量药剂,和(b)指导该试剂盒在所述哺乳动物的治疗中的使用的标签。在优选的实施方案中,该试剂盒适于口服。
虽然按照特定的实施方案描述了在此所公开的组合物和方法,但应当理解的是,例如可以使用惰性稀释剂或可吸收的可咀嚼载体口服在此所描述的莫达非尼化合物。也可以将该组合物封入硬或软壳的白明胶胶囊中,压成片剂或直接加入日常食物中。对于口服治疗剂,虽然片剂是通常优选的给药莫达非尼的方法,但也可以将活性化合物,例如莫达非尼与赋形剂结合并以可消化的片剂、颊含片、锭剂、胶囊、酏剂、混悬液、糖浆剂、包药干糊片等形式使用。此种组合物和制剂应含有至少0.1%的活性化合物。当然,组合物和制剂的比例可以变化,并且可以方便地在单位重量的约2至60%之间。
片剂、锭剂、丸剂、胶囊等例如也可以含有任何下列成分:一种粘合剂,如黄芪树胶、阿拉伯胶、玉米淀粉或白明胶;赋形剂,如磷酸二钙;一种崩解剂,如玉米淀粉、马铃薯淀粉、褐藻酸等;一种润滑剂,如硬脂酸镁;和一种甜味剂,如可以加入蔗糖、乳糖或糖精或一种调味剂,如薄荷、冬青油或樱桃调味剂。当剂量单元的形式是胶囊时,除上述类型的物质外,它可以含有一种液体载体。其他不同的物质可以作为包衣使用或者以其他方式改进剂量单元的外观。例如,可以使用虫胶、糖或二者包被片剂、丸剂或胶囊。糖浆或酏剂可以含有活性化合物,作为甜味剂的蔗糖和作为防腐剂的对羟基苯甲酸甲酯或丙酯,一种染料和调味剂,例如樱桃或柑桔调味剂。当然,在制备任何剂量单元形式中所使用的任何物质均应是药学纯的并且在所使用的剂量基本无毒。此外,可以将活性化合物掺合在持续释放的制剂和配方中。
在特定的实施方案中,可以将在此公开的组合物配制成通过使用皮肤贴片或经皮给药系统给药。可以通过本领域已知的任何系统实现在此所描述的莫达非尼组合物的经皮给药。适于使用在此所描述的组合物的系统的例子包括在美国专利U.S.No.4,816,252;U.S.No.5,122,382;U.S.No.5,198,223;U.S.No.5,023,084;U.S.No.4,906,169;U.S.No.5;145,682;U.S.No.4,624,665;U.S.No.4,687,481;U.S.No.4,834,978和U.S.No.4,810,499(在此全部引入作为参考)中所描述的经皮给药系统。
这些方法通常包括一种粘合剂基质或药物储存系统并可以包括一种皮肤渗透增强剂,如乙醇、聚乙二醇200二月桂酸酯、肉豆蔻酸异丙酯、甘油三油酸酯、亚麻酸饱和乙醇、油酸单甘油酯、月桂酸单甘油酯、正癸醇、癸酸和特定的饱和和不饱和脂肪酸及其酯、醇、单甘油酯、乙酸酯、二乙醇酰胺和N,N-二甲基酰胺化合物(例如见美国专利U.S.No.4,906,169)。
本发明进一步涉及一种识别在后下丘脑的TMN中刺激活性的化合物的方法。该方法包括标准的用于上文所述新发现的筛选技术的应用。因此,提供了通过本方法识别出的本发明的化合物及其作为药物的应用,其中该药物在后下丘脑的TMN中的刺激作用将对接受治疗的动物和人类保持良好状态产生有益的效果。
详细描述
莫达非尼是在中枢神经系统中具有活性的试剂并已被作为治疗药品开发用于与发作性睡眠症相关的过度的日间嗜睡。与安非他明类药剂类似,莫达非尼的主要药物活性是促进清醒。莫达非尼在小鼠(Touret等,Neuroscience Letters(神经科学学报),189:43-46(1995);Edgar和Seidel,J.Pharmacol.Exp.Ther.283:757-69(1997))、猫科动物(Lin等,Brain Research(大脑研究)591:319-326(1992))、犬科动物(Shelton等,Sleep(睡眠)18(10):817-826,(1995))和非人灵长类动物(DS-93-023,pp180-181;Hernant等,Psychopharmacology(精神性药理学),103:28-32(1991))中促进清醒,在模仿临床情况的模型中,例如睡眠呼吸暂停(英国牛头犬睡眠障碍呼吸模型)(Panckeri等,1996)和发作性睡眠症(发作性睡眠的犬科动物)(Shelton等,Sleep(睡眠)18(10)817-826,(1995))也促进清醒。莫达非尼也已被证实是在帕金森氏症的治疗中(美国专利U.S.No.5,180,745);在保护大脑组织免受局部缺血中(美国专利U.S.No.5,391,576);在大小便失禁的治疗中(美国专利U.S.No.5,401,776)和在中枢神经系统起端的睡眠呼吸暂停的治疗中(美国专利U.S.No.5,612,378)是有用的药剂。美国专利U.S.No.5,618,845描述了一种粒子尺寸被限定在低于200微米的莫达非尼制剂,该制剂比含有较大比例的更大粒子的制剂更有效和更安全。
已经研究了不同的神经解剖学通路在诱导和维持清醒方面的作用,有些研究工作是针对结节性乳头状神经核(TMN)的潜在作用的(Sherrin等,Science(科学)271:216-219,1996)。Lin等人的研究(Proceedings of the National Academy of Science(国家科学院学报),美国93:14128-14133,1996)证实了莫达非尼对前下丘脑选择性的激活作用,该研究报告的作者还证实了向猫科动物给药促清醒剂量的莫达非尼不能激活后下丘脑的TMN。一项向小鼠给药促清醒剂量的莫达非尼的类似研究(Engber等Neuroscience(神经科学),87:905-911(1998))也证实了莫达非尼诱导的清醒与TMN的激活无关。因此,虽然正常的清醒状态涉及TMN的激活,但这些研究者的研究清楚地教导了在莫达非尼诱导的清醒状态中不涉及TMN激活。
本发明部分地起因于当以促清醒剂量给药时,莫达非尼的确在后下丘脑的TMN中产生活性刺激作用这一发现。在小鼠中给药莫达非尼降低了在下丘脑的脑侧室前视核区域(VLPO)的神经元的活性,已知在睡眠期间该活性抑制在TMN中的促清醒的被组胺激活的神经元的活性。通过莫达非尼将该被组胺能激活的通路活化导致皮层的激活和清醒。因此,莫达非尼的促清醒作用的生理基础似乎涉及通过在VLPO的抑制作用解除对TMN的被组胺激活的神经元的抑制。这代表了已知的通过TMN的激活而获得清醒的第一种药剂。此外,因为莫达非尼激活下丘脑,还因为从下丘脑的抑制的被组胺能激活的神经元通路在抑制的Υ-氨基丁酸(GABA)额叶中间神经元上形成突触,本发明的发明人预计下丘脑的激活有助于接下来的锥体细胞的激活并提供了一种莫达非尼在ADHD和MS疲劳中的应用机制(Swanson,J.等,Current Opinion in Neurobiology(神经生物学的最新见解),8:263-271(1998);Roelke,U.等,Neurobiology(神经生物学),48:1566-1571(1997))。
在本文所公开或要求的任何发明之前,在本领域中已知治疗用试剂盒形式的莫达非尼,以的名字营销。是一种由宾夕法尼亚州West Chester的Cephalon公司制造的药物产品,也由Cephalon公司销售。作为含有100毫克或200毫克莫达非尼的片剂供应。在商业应用中,现有技术中含有莫达非尼的治疗用试剂盒以标签或其他形式标明用于发作性睡眠症患者。
因此,现有技术中已知的是提供作为一种活性成分的莫达非尼的一个或多个单位剂量药剂的治疗用试剂盒,该活性成分提供在含有所述单位剂量药剂的最终的药物容器中,该药物容器还含有或包括指示所述试剂盒在治疗上述人类疾病或不适中的应用的标签。在随着药物容器所提供的说明中指示莫达非尼每天的剂量为200毫克/天,在早晨以单一剂量形式给药。虽然在临床实验中,400毫克/天的剂量也是可以很好地耐受的,但200毫克/天是在成年人中最佳的促清醒剂量。
根据本公开文件无需过多的实验,可以制造和实施在此所公开和要求的所有组合物和方法。虽然本发明的组合物和方法是以优选的实施方案的形式描述的,但可以对在此所描述的组合物和/或方法以及该方法的步骤或步骤的顺序进行改变而不会偏离本发明的概念、精神和范围对于本领域中的技术人员而言是明显的。更具体地说,使用在化学和生理学上相关的特定试剂取代在此所描述的试剂,同时仍可获得相同或类似的效果将是显而易见的。所有此类本领域的技术人员显而易见的类似取代和改进均被认为在后附的权利要求所定义的本发明的精神、范围和概念之内。
实施例
通过下列实施例进一步说明本发明。仅为说明的目的提供实施例,并不得将实施例解释为对本发明范围或内容的限制。
实验设计:在下列实施例中,在治疗后2小时杀死小鼠并通过Fos免疫组织化学分析大脑。在实施例1和2中,对小鼠做脑电图(EEG)和肌电图(EMG)记录。为避免在给药莫达非尼或赋形剂过程中触摸的压力,在腹膜腔中安置长期导管用于给药莫达非尼或赋形剂。
动物和记录环境:将65只体重为270-330克的雄性Sprague-Dawley小鼠(Harlan)分别关在无病菌的栅栏内,维持室温在21.5℃-22.5℃之间,在上午7:00打开光源,下午7:00关闭光源。小鼠可随意地取食和饮水。在每次实验前至少3天,将小鼠置于一个隔离的房间中不透光的、无声的记录室(生物小室(Biocube))中。在每个笼子中,光密度的中值为100-150勒克司。Beth Israel Deaconess MedicalCenter和Harvard Medical School(哈佛医学院)的InstitutionalAnimal Care and Use Committees(动物护理和使用学会委员会)批准了所有实验过程。
动物手术:在水合氯醛麻醉(350毫克/千克,腹膜注射)后,对实施例1和2的小鼠手术植入4个轻微接触硬脑脊膜的脑电图螺钉(距离前囟点AP:+3,-4;RL:+2,-2)并在颈部肌肉下面植入2条肌电图线(Plastics One,Roanoke,VA)。导线与一个6通道的连接器(Plastics One)相连,该连接器通过牙科用的丙烯酸粘附在头骨上。除5只小鼠外,向所有小鼠的腹腔中植入一种遥感的温度传感器(TA10TA-F40,Data Sciences International,St.Paul,MN)。为了不需触摸小鼠给药,将一条80厘米长的硅橡胶导管(1毫米内径,Baxter Scientific Products)插入小鼠腹腔中,经皮下通向头皮,使用牙科用丙烯酸粘合固定并通过一个弹簧外部保护。此种腹膜内导管中充满肝素化的无热原物的生理盐水并每周及在实验前3天冲洗。动物至少恢复14天,然后在开始生理记录前使他们适应记录电缆3天。
给药:将莫达非尼(批次:#PA008;Cephalon,Inc.,West Chester,PA)悬浮在0.25%的甲基纤维素(Ph=7.4,Dow Chemical Inc.,Midland,MI)在0.9%的无热原物的生理盐水中所形成的溶液中。以150毫克/千克的剂量以2.0毫升/千克的体积给药。向对照动物给予等量体积的甲基纤维素赋形剂。然后用1毫升0.9%的生理盐水冲洗导管以确保药物被输送至腹腔。使用一盏红色的闪光灯帮助在黑暗中进行注射。
组织学和免疫组织化学:在注射药物后2小时,使用水合氯醛(600毫克/千克,腹膜注射)深麻醉动物并用100毫升0.9%的生理盐水,然后用500毫升磷酸盐缓冲的10%的福尔马林,pH=7.0(Sigma)穿心灌注。除去大脑,在福尔马林中后固定4小时,然后在4℃下,用0.02%的叠氮化钠(Sigma)在20%蔗糖的0.1M磷酸盐缓冲生理盐水(PBS)的溶液中均衡。将大脑在冷冻切片机上切片(1∶5系列,30μm)并于4℃保存在PBS-叠氮化物中。使用在先描述的方法(Elmquist等,1996)对每个大脑的一个系列进行Fos染色。简要地说,在4℃下,用0.25%Triton X-100(PBT-Az)在抗-Fos兔多克隆抗血清(Ab-5,OncogeneResearch Products,1∶100,000稀释)、3%猴血清(JacksonImmunoResearch)和PBS-叠氮化物中温育切片48小时。然后在PBS中漂洗组织,在室温下在生物素化的猴抗-兔IgG(1∶1,000,JacksonImmunoResearch)中温育1小时,用过氧化物酶共轭的抗生物素生物素复合体(ABC,载体)温育1小时,然后使用0.05%的二氨基联苯胺四氢氯化物(DAB)和含有1%NiSO4和0.5%CoCl2的0.01%的H2O2,在细胞核中获得黑色反应产物。
细胞计数:测试选定的大脑区域的Fos-免疫反应性模式。为量化这些区别,由不了解实验条件的检验员在可能具有莫达非尼诱导的Fos区域计数Fos-免疫阳性(Fos-IR)神经元。对于所有细胞核,对含有最多细胞核区域的3个连续的、相隔120μm的切片上进行双向计数并平均所获得的6个数字。在实施例1中,对涉及行为状态控制的区域:脑侧室前视核区域(VLPO)、TMN、腹侧被盖区(VTA)和前带状束皮层进行Fos-IR细胞核计数。
统计分析:使用Bonferroni校正的Mann-Whitney排列合计试验(rank-sum test)对比Fos-IR细胞计数;如果p<0.05,则认为p是显著的。
实施例1:为确定由莫达非尼诱导的神经激活的模式,我们在午夜,即正常的清醒期间给药莫达非尼(150毫克/千克)或赋形剂。数据示于表1。
表1
赋形剂 | 莫达非尼150毫克/千克 | Kruskal-WallisP值 | |
n | 6 | 6 | |
带状束皮层 | 52±13 | 191±38 | 0.008 |
TMN | 13±7 | 46±4 | 0.005 |
VTA | 8±2 | 12±3 | 不明显 |
表1,对在午夜以莫达非尼或赋形剂处理的小鼠的细胞计数。数值为平均值±标准误差。黑体数值是通过post-hoc Scheffe实验与赋形剂相比具有统计学意义的数值。
在给药莫达非尼(150毫克/千克)后,TMN中Fos-IR神经元的数量是对照组的4倍(表1)。在睡眠期间,VLPO的神经元被激活(Sherin等,Science(科学)271:216-9(1996);Alam等,Annual Meeting ofthe Society for Neuroscience(神经科学学会年会),Washington,DC.1996),由于所有动物基本上均是清醒的,在所有小鼠中Fos-IRVLPO神经元是不寻常的并不奇怪。使用莫达非尼处理的小鼠比对照小鼠在皮层具有更高的Fos免疫活性。此种Fos的诱导性在大部分皮层上是明显的,但通常在带状束和梨状皮层上更明显,在额侧和顶骨皮层上具有中等数量。
实施例2:在实施例2中,在中午,正常的睡眠时间给予莫达非尼(150毫克/千克)。数据示于下表2中
表2
赋形剂 | 莫达非尼150毫克/千克 | Mann-WhitneyP值 | |
n | 6 | 7 | |
VLPO | 52±7 | 26±3 | 0.007 |
TMN | 8±4 | 43±5 | 0.003 |
表2,对在LD或DD条件下,在中午时间以莫达非尼或赋形剂处理的小鼠进行细胞计数。黑体数值是通过post-hoc Scheffe分析与赋形剂相比具有统计学意义的数值。
在维持正常LD周期的动物中,在中午时间给药莫达非尼(150毫克/千克)显著地增加了在TMN中的Fos-IR神经元数量,而在VLPO中则降低了该数量。莫达非尼处理也提高了Fos在额侧和带状束皮层中的表达。
Claims (11)
1.莫达非尼化合物在制备通过刺激患者大脑中的结节性乳头状神经元的活性而治疗选自注意力缺陷多动障碍和多发性硬化症疲劳的疾病的药物中的应用。
2.权利要求1所述的应用,其中所述的莫达非尼化合物是莫达非尼。
3.权利要求1所述的应用,其中所述的患者是成年人。
4.权利要求1所述的应用,其中所述的患者是儿童。
5.权利要求1所述的应用,其中所述的药物包含从1至400毫克所述莫达非尼化合物每日剂量。
6.权利要求1所述的应用,其中所述的药物包含从100至400毫克所述莫达非尼化合物每日剂量。
7.权利要求1所述的应用,其中所述的药物包括从200至400毫克所述莫达非尼化合物每日剂量。
8.权利要求1所述的应用,其中所述的药物包括200毫克所述莫达非尼化合物每日剂量。
9.权利要求1的应用,其中所述的药物被配制成口服给药制剂。
10.权利要求1的应用,其中所述的药物被配制成片剂。
11.权利要求10所述的应用,其中所述的片剂含有任意组合形式的乳糖、玉米淀粉、硅酸镁、交联羧甲纤维素钠、聚烯吡酮、硬脂酸镁或滑石粉。
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4177290A (en) * | 1977-03-31 | 1979-12-04 | Laboratoire L. Lafon | Acetamide derivatives |
US5180745A (en) * | 1990-06-14 | 1993-01-19 | Laboratoire L. Lafon | Method for providing a neuroprotective effect |
US5401776A (en) * | 1992-10-23 | 1995-03-28 | Laboratoire L. Lafon | Use of modafinil for the treatment of urinary and fecal incontinence |
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