CN104981265A - 丘脑皮层节律异常的治疗 - Google Patents
丘脑皮层节律异常的治疗 Download PDFInfo
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Abstract
一种用于治疗与丘脑皮层节律异常相关的疾病的方法。所述方法包括将经颅低压电刺激(TLVES)治疗或经颅磁刺激(TMS)治疗应用于需要该治疗的患者、以及在所述TLVES治疗或所述TMS治疗期间将分离型麻醉剂给药于该患者。可以用分离型麻醉剂如NMADR抑制剂,包括氯胺酮联合TLVES或TMS来治疗许多疾病如耳鸣、抑郁症和疼痛。
Description
相关专利申请的交叉引用
本专利申请要求于2013年3月14日提交的美国专利申请序列号13/826,250以及于2012年11月25日提交的美国临时专利申请序列号61/729,625的权益,以上两个专利申请以引用方式全文并入本文。
背景技术
全球有数百万人患有神经性障碍。许多这些不同的精神性障碍与丘脑皮层节律异常相关,一般通过由连接大脑丘脑和皮层的主要神经回路的异常振荡活动所产生的一系列神经和精神病症来鉴别丘脑皮层节律异常。根据大脑中发生节律破坏的位置产生不同的症状,但是神经元的机制相同。异常节律干扰大脑的不同区域中以及不同区域之间的正常通信,因此损伤受皮层的这些区域控制的运动和认知能力、以及其他神经系统功能。与丘脑皮层节律异常相关的疾病有神经性疼痛、也称为(RSD)的复合性局部疼痛综合征(CRPS)、强迫性神经失调、抑郁症、惊恐性障碍、帕金森氏病、精神分裂症、僵直、肌张力障碍、耳鸣、震颤、癫痫以及重型情感障碍。
许多患者对这些疾病的传统治疗都没有反应。例如,STAR-D(抑郁症序贯治疗)预测,甚至在尝试用各种各样的抗抑郁药试验进行治疗之后,在诊断为重型情感障碍的2千万美国人中仅三分之一得到完全缓解,而大部分患者群体依然难以通过药物干预进行治疗。参见“The Numbers Count:MentalDisorders in America,National Institute of Mental Health(2012)”。类似地,三分之一的美国人口遭受慢性、非缓解性疼痛。至少40%的人口在躯体和情感后遗症结合时经历过慢性疼痛。参见“Institute of Medicine of The National Academiesof Science,Report Brief,June 2011”。
应用新型大脑刺激技术治疗抑郁症以及可能的其他神经精神障碍是新并且快速发展的领域。这些技术如经颅磁刺激(TMS)和经颅低压电刺激(TLVES)(也称为经颅电刺激(tES))正逐渐成为有希望的方法,因为它们相对易于使用、安全且具有神经生物学效果。
TLVES涉及使用弱电流(1~4毫安),通过放在头皮的电极,弱电流穿过大脑组织。已知对电极放置有效的疾病有,例如,急性疼痛、预防偏头痛、抑郁症和幻听。tES可以以tDCS(直流电刺激)、tACS(交流电刺激)或者作为有意混乱的电流的tRNS(随机噪声刺激)的形式传递。由于使用tES,许多参数可以改变,包括频率和频率的范围、波形和偏移(振荡波的数学基础)。刺激可以影响背景电状态、或者有时影响振荡状态、或者甚至改变神经元放电。在生理研究中已经证实,它也会诱导神经元兴奋性的持续变化。参见临床基础研究,这大概是通过重复的刺激可以导致有意义的治疗效果的机制。
也已经用经颅磁刺激(TMS)治疗过抑郁症,在1985年首次引入经颅磁刺激以演示神经元系统的相对无痛激活。近年来,已经应用TMS来研究沿着皮层神经元系统传播的电磁刺激的完整性和后果。最近,已经开发了商用TMS系统来治疗严重抑郁障碍(MDD)。例如,NEUROSTAR TMS系统(Neuronetics,Inc.)是在精神病医生的监督下完成的37分钟门诊患者TMS程序。它不需要麻醉或镇静,并且在该程序期间患者保持清醒并且警觉。该治疗通常每天进行,持续约4-6周。
在NeuroStar TMS治疗(NeuroStar TMS Therapy)期间,产生磁场脉冲并且瞄准左侧的前额叶皮层,此前额叶皮层是已经被证实为抑郁症患者存在功能异常的大脑区域。这些TMS磁场的类型和强度与磁共振成像(MRI)机器中使用的类型和强度相似。磁场脉冲畅通无阻地穿过头发、皮肤和头盖骨并且进入大脑中。
一旦进入大脑中,据信磁场脉冲在受影响的神经网络内引起电变化。产生的电位量很小,并且患者无法感受到,但是它能够改变神经组织的活性并且被认为引起神经递质化学物质如血清素、去甲肾上腺素和多巴胺的释放。此外,TMS可直接改变局部脑血流量(rCBF)。
TMS的一个显著缺点是需要几周严格的计划治疗,这在时间、金钱以及困难性方面对人来说是显著的负担,并且经常导致患者的依从性差。
除例如TLVES和TMS的技术以外,有很多现在可用于治疗神经性障碍的药物制剂。这些药物制剂包括但不限于:抗惊厥药、抗癫痫药、巴比妥类、巴比妥酸衍生物、麻醉剂、耳鸣治疗药、选择性血清素再摄取抑制剂、抗抑郁剂、精神安定剂、抗高血压药、抗精神病剂、钙通道阻滞剂、ACE抑制剂和β-阻滞剂、情绪稳定剂和兴奋剂以及致幻剂。然而,许多这种药受到它们的效果和显著的副作用的限制。例如,已知许多这些药会引起轻微头疼、抑郁、失眠、体重改变、性功能障碍、认知功能障碍、虚弱、疲劳、幻觉以及严格限制了它们在临床上使用的其他副作用。
最近,人们对使用NMDA受体拮抗剂治疗神经精神障碍感兴趣。NDMA抑制剂是一类精神药物制剂,该抑制剂拮抗或部分抑制N-甲基-D-天冬氨酸受体(NMDAR)的作用。它们常常用于动物和人体的麻醉。它们诱导的麻醉状态被称为分离型麻醉。几种合成的阿片类物质也起到NMDAR拮抗剂的作用,例如,哌替啶、美沙酮、右丙氧芬、曲马多和凯多米酮。一些NMDA受体拮抗剂包括但不限于氯胺酮、右美沙芬、苯环利定和一氧化二氮,因它们的分离、致幻和/或兴奋的特性而出名。
一种特定的NMDA抑制剂,即氯胺酮已经表现出对治疗双相障碍抑郁症患者有效,该双相障碍抑郁症对抗抑郁剂无效。详见Preskorn,生物精神病学(Biol.Psychiatry)(2012)72:第522-523页。在患有严重抑郁障碍和双相抑郁症的患者中,它在两小时内产生快速抗抑郁效果,相反,典型的抗抑郁药则要花上几周才能生效。在单独使用氯胺酮时,氯胺酮似乎提供4-7天缓解自杀。然而,氯胺酮似乎不会提供持续缓解自杀或抑郁。
因此,发明人认识到治疗与丘脑皮层节律异常相关的病症需要提供更强健且更连续改善的治疗。这种治疗也应当提供更大可能性的持续成功效果。更进一步,该治疗应当优选地减少药物疗法的不良后果。
这部分的上述描述不构成本申请的权利要求书的现有技术,并且不承认通过包括这部分内容而构成现有技术。
发明内容
在一个方面,本发明公开涉及一种用于治疗患者的与丘脑皮层节律异常相关的疾病的方法。所述方法包括:将经颅低压电刺激(TLVES)治疗或经颅磁刺激(TMS)治疗应用于所述患者;联合地,在所述TLVES治疗或所述TMS治疗期间将分离型麻醉剂给药于该患者。
在本发明公开的各个方面,与丘脑皮层节律异常相关的疾病可以是耳鸣;疼痛,包括复合性局部疼痛综合征或反射交感性营养不良;以及已知形式的抑郁症,包括双极抑郁症。
在另一方面,所述分离型麻醉剂是在可以约30分钟至60分钟的给药期间给药的N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂,例如氯胺酮。当所述NMDAR拮抗剂是氯胺酮时,剂量可以约为50~500mg。可替代地,可以使用其他NMDAR拮抗剂的相当的治疗剂量。
在又一方面,在给药所述NMDAR拮抗剂之前、期间以及之后间歇地或连续地应用TLVES治疗或TMS治疗。具体地讲,所述方法可以包括在联合应用分离型麻醉剂与TMS治疗之前进行的前治疗。
再者,本发明公开的另一个实施方式包括以3~7天的间隔重复所述治疗方法至少5次。
本领域的普通技术人员通过阅读以下详细说明并适时结合附图将明白这些以及其他方面和优点以及替代形式。
具体实施方式
本文描述了示例性系统和方法。应当理解,本文中使用的词语“示例性”的意思是“作为实例、举例或举例说明。”本文中被描述为“示例性”或“实施例”的任何实施方式或特征未必被理解成优选于或优于其他的实施方式或特征。本文中描述的示例性实施方式并不意味着限制。容易理解的是,本发明公开的系统和方法的某些方面可以安排并且以各种各样的不同结构组合,本文中已设想包括所有这些内容。
在各方面,本发明涉及一种治疗患者的丘脑皮层节律异常障碍的方法。该方法包括联合将治疗有效量的分离型麻醉剂和经颅电或电磁刺激(例如TMS)或经颅低压电刺激(TLVES)应用于患者。
与丘脑皮层节律异常相关的神经性障碍的非限制性实例包括:抑郁症、慢性抑郁症、双相抑郁症、神经性疼痛或中枢性疼痛、又称为反射交感性营养不良(RSD)的复合性局部疼痛综合征(CRPS)、强迫性神经失调、惊恐性障碍、僵直、肌张力障碍、耳鸣、震颤、癫痫、癫痫小发作;失神性癫痫、孤独症、帕金森氏病;强迫性神经失调(OCD)、精神分裂症、分裂性情感精神病、偏头痛和多动腿综合征等等。另外,已知各种滥用药物的使用者患有丘脑皮层节律异常,滥用药物包括海洛因、阿片制剂、可卡因、精神兴奋药、酒精和安神药。
TMS涉及以受控的方式产生并且应用波动磁场。磁场的膨胀和收缩产生磁通量在受TMS头部线圈影响的患者组织中形成电变化。有时候这个效果被认为使神经元去极化并且生成动作电位。另一种可能的效果被认为是受到磁刺激影响的细胞的电状态的改变。TMS相比于TLVES的一个关键优势是TMS以空间上更集中的方式传送到大脑,尤其是在使用八字线圈时。本文描述的TMS治疗的一个参数是用于影响刺激大脑组织的电磁频率。例如,1Hz或以下的刺激频率可以与本文描述的TMS治疗联合使用。1Hz或以下的TMS治疗也被称为单脉冲TMS,尽管这个术语通常用于描述以随机间隔每几秒传送的TMS。以更高频率传送的TMS也可以联合本文描述的TMS治疗使用,尽管这种更高频率的TMS治疗有时被描述为重复性TMS(rTMS)。TMS的抑制和兴奋作用已经推测如同长时程增强和长时程抑制。另一方法是重复传送脉冲刺激,与θ脉冲刺激(TBS)的情况一样,使得初始刺激启动用于后续刺激的系统。
以低电压(通常小于约20伏特)进行经颅电刺激有几种形式,包括固定电流DC刺激(tDCS)、交流电刺激(tACS)或随机(噪声)电流生成(tRNS)。经颅低压电刺激(TLVES)有关的剂量可以参照头盖骨上的电极大小和位置以及电流的持续时间、频率和强度(毫安)进行定义。在这些技术中常用小于约4毫安的电流。在一些实施方式中,可以使用市售的计算机控制的DC激励器。
尽管本文中描述的经颅电刺激和电磁刺激的参数可以对较宽范围的个体一致,但是应当认识到,对于任何给定个体,对电刺激或电磁刺激的个体反应性存在差异。通常标定给定个体的刺激强度的一种方式是测试人体以得到施加在唤起运动反应的运动皮层(通常称为M1)上的最小刺激强度。该运动阈值通常报道为完成刺激所需的最小强度,并且可以以装置的可用输出量的百分比定义,或者可替代地以磁场测量强度,即,特斯拉单位进行定义。在任何情况下,刺激影响特定患者的治疗的程度会受刺激频率、治疗重复频率(包括以下描述的任何预治疗)以及特定患者的个人反应特性的影响。这些和类似的个体反应差异似乎可归因于个体的生理和化学特性,至少部分地是由基因决定的。具体的TMS参数包括系列脉冲之间的间隔时间(刺激的系列脉冲之间的时间)、每次治疗期的脉冲数量以及治疗期的持续时间。最常见的不适是头痛、头皮痛、恶心和短暂的听力困难(参与者戴耳塞以避免这种情况),并且这些因素也可以影响患者对治疗反应的方式。因此,应当理解的是,在任何患者上实施本文描述的方法将需要执业医师练习一定量的经验和判断以适应患者个体的敏感性。例如,当临床医生可能提前意识到某位患者似乎是在医学上或心理上脆弱而暗示该患者不是TMS的良好人选时,或者当患者可能想避免TMS治疗时,tES治疗提供有效的替代方法。tES治疗为那些可能不是TMS治疗的良好人选的患者提供重要的临床益处。另外,tES可以是对TMS治疗的副作用敏感的患者重要的有效的过渡治疗。
NMDA受体拮抗剂是一类分离型麻醉剂,其拮抗或抑制N-甲基-D-天冬氨酸受体的作用(NMDAR)。它们用于动物麻醉,不常用于人类。它们诱导的麻醉状态被称为分离型麻醉。NMDA受体是亲离子受体,其允许电信号在大脑和脊柱的神经元之间转移。为使电信号通过,NMDA受体必须打开。为了保持打开,谷氨酸和甘氨酸必须结合到NMDA受体上。谷氨酸和甘氨酸结合在上面且具有打开的离子通道的NMDA受体被称为“已激活”。
氯胺酮((RS)-2-(2-氯苯基)-2-(甲氨基)环己酮)是在人类医学和兽医学中使用的药物。氯胺酮经常与镇静剂联合主要用于诱导并维持全身麻醉。其他用途包括在重症监护内镇静、止痛(尤其是在紧急用药时)以及支气管痉挛的治疗。氯胺酮在人体中具有广泛的疗效,包括止痛、麻醉、幻觉、升高的血压以及支气管扩张,并且维持大脑和心脏组织的灌注。氯胺酮已被证明在治疗对抗抑郁药没有响应的双极障碍抑郁症患者具有疗效。尤其是,为人熟知的缓解自杀。在具有重度抑郁症的患者中,它将在两小时内产生快速抗抑郁效果,相反,典型的抗抑郁药则要经过几个星期才能见效。
氯胺酮也已经用于复合性局部疼痛综合征(CRPS)(也称为反射交感性营养不良(RSD))的试验性且有争议的治疗。CRPS/RSD是以知觉、自主神经系统、运动及营养不良的迹象和症状为特征的严重慢性疼痛病症。CPRS的疼痛是连续的,它会随着时间推移而加重,并且它经常与刺激诱因的严重程度和持续时间不相称。在输注氯胺酮的强迫性神经失调(OCD)患者中,其效果比上述疾病更为有限。(Pittenger等,生物精神病学(Biol.Psychiatry)(2012)72:第522-523页。)
其他NMDA受体拮抗剂包括金刚烷、金刚烷胺、美金刚、金刚乙胺、芳基环己胺、二乙环利定(dieticyclidine)、艾司氯胺酮、乙环利定、加环利定、梅塔菲它(metaphit)、2-(乙氨基)-2-(3-甲氧基苯基)环己酮(Methoxetamine)、奈拉美生(neramexane)、苯环利定、苯基己基环吡咯烷、咯环利定、替诺环定、替来他明、麦索克斯啶(Methoxydine)(4-MeO-PCP)、左吗喃、右美沙芬、右啡烷、甲吗喃、莫伐咯(Morphanol)、2-MDP、8A-PDHQ、阿替加奈、右奥沙屈、二乙醚、地佐环平、乙苯噁啶、伊波加因(在红月桂属中查找)、米达福太、NEFA、一氧化二氮、降伊波加因碱(noribogaine)、培净福太(perzinfotel)、瑞马西胺、塞福太和氙气。
在一个方面,本发明涉及一种用于治疗与丘脑皮层节律异常相关的病症的方法。该方法包括与分离型麻醉剂联合用经颅电刺激或电磁刺激(例如TMS或TLVES)治疗患者。在一个方面,分离型麻醉剂是NMDAR抑制剂,例如,氯胺酮。与在没有刺激的情况下进行治疗通常所需的剂量相比,联合分离型麻醉剂如氯胺酮使用电刺激或电磁刺激常常以减少剂量的分离型麻醉剂得到提高的治疗响应。例如,当联合TMS使用时,氯胺酮的剂量可以是在TMS治疗的疗程的标准商业配方中交付的约10mg~约500mg。更具体地,氯胺酮的剂量可以在约20mg~约400mg范围内变化,具体地在约50mg~约350mg的范围内变化,更具体地在约100mg~350mg的范围内变化,甚至更具体地在约200mg~约300mg的范围内变化。
联合治疗(即,刺激与麻醉剂联合)可以在合适的剂量水平从大约20分钟延长到约120分钟。具体地,刺激周期可以从大约20分钟延长到约100分钟,从约30分钟延长到约90分钟,从约40分钟延长到约100分钟,或者更具体地为约20分钟、30分钟、40分钟、50分钟、60分钟、70分钟、80分钟、90分钟、110分钟或120分钟。在一个具体的实施例中,在延长大约20分钟至60分钟的TMS治疗疗程中输注约50mg至350mg的氯胺酮。此外,更长的输注时间可以提供更温和地输送氯胺酮给患者,并且一般得到更好的情绪和更少的副作用。
在联合治疗期间,在给药麻醉剂期间以及任选地在此之前和/或之后进行电刺激或电磁刺激。例如,在给药麻醉剂之前可以刺激大约1分钟至15分钟的时间段,更具体地,大约3分钟至10分钟,或者甚至更具体地,在约5分钟的范围内。在先进行的刺激的时间段之后,可以开始给药麻醉剂,并且在给药麻醉剂期间可以继续进行刺激。在给药麻醉剂之后,此后可以继续刺激大约1分钟至15分钟,更具体地,大约3分钟至10分钟,或者甚至更具体地,在约5分钟的范围内。
在使用TMS进行联合治疗期间,TMS头部线圈朝向前扣带区,用于治疗与丘脑皮层节律异常相关的大多数疾病。当治疗耳鸣时,刺激联合皮质可能恰当。随着未来学习更多的有关大脑的哪个区域涉及附加的各种健康状况,将会更加清楚大脑的哪个区域应当是用于治疗这些附加的健康疾病的刺激重点。
TMS治疗合适的剂量可能是患者的运动阈值的大约80%至120%。正如本领域技术人员所理解的,患者的运动阈值反映当TMS针对运动带的相关区域时患者的拇指开始抽搐的TMS功率输出的量。提供一种在建立的安全参数内操作的简单方法与大脑刺激有关。更具体地,TMS治疗的合适剂量是患者的运动阈值的大约90%至120%,100%至120%,或105%至115%。一个具体的实例,TMS治疗的合适剂量是患者的运动阈值的110%。一般来讲,在本文描述的联合治疗期间,剂量的频率是1Hz并且刺激是连续的。
本领域的技术人员已知建立用于TLVES的合适的刺激程度和刺激位置的类似方法。例如,在使用TLVES时,电极的位置可以是一前一后(例如,在前额中间和头部或Oz的背面中心)。通常,患者可以在1000毫安至2500毫安治疗10分钟至50分钟,例如,在约1000毫安、1200毫安、1300毫安、1500毫安、2000毫安或2500毫安治疗约15分钟、25分钟、25分钟或45分钟。该刺激可以包括约800毫安至1200毫安的偏移,例如约1000毫安。在本文描述联合治疗期间,TLVES是连续的。此外,TLVES可以在输注分离型麻醉剂前开始,例如,在输注开始前约1分钟至15分钟开始,更具体地,例如,在输注开始前约1分钟、2分钟、5分钟、10分钟或15分钟开始。一旦完成输注,TLVES也可以继续有限的时间。
分离型麻醉剂可以通过任何传统的输送方法输送给患者,包括静脉注射、肌肉注射、口服、鼻饲以及吸入(在适当的时候)。根据麻醉剂及其半衰期、输送方法和吸收率,可以调节联合治疗期间的刺激时间以确保在刺激期间存在治疗有效量的麻醉剂。当麻醉剂通过静脉注射输送时,患者基本上立即能感受到它的效果。如果麻醉剂通过口服输送,可能需要增加附加时间来刺激,以确保在麻醉剂在治疗上有效时进行刺激。本领域技术人员已经较好地研究了氯胺酮和其他分离型麻醉剂的药代动力学,并且从这些研究得到的理解为预测时间、方法和药物剂量之间的关系以便确定麻醉剂进入血流并且变成可用于治疗患者组织的时间提供了合适的基础。
在联合治疗之前,患者可以经历大约10分钟至80分钟的预刺激治疗。例如,当TMS用于联合治疗时,在每次大约10分钟至40分钟的前治疗(primingtreatment)期间,TMS头部线圈对准左侧和右侧的前额叶背外侧皮层。TMS前治疗的频率对于右侧前额皮层,可以是约1Hz,对于左侧前额皮层,可以是约1Hz。联合治疗可以紧接在TMS前治疗完成之后,或者联合治疗可以在前治疗之后一天进行,这取决于患者的耐受性和依从性。根据患者的需要和耐受性,也可以使用预先进行的其他形式的电刺激或电磁刺激。
在又一种替代方式中,在联合治疗之前,可以用电刺激或电磁刺激对患者进行几周或几天的预治疗。对于经过预治疗的患者,不需要前治疗。因此,在一系列预治疗之后,例如,次日,可以开始联合治疗。当使用TMS进行联合治疗时,预治疗通常涉及为期约三天至两周(7天中的大约6天)的使用治疗方案的TMS治疗。例如,预治疗可能涉及每天高达四个历时半小时的TMS治疗期,治疗期之间的间隔为45分钟。举例来说,预治疗治疗期包括对准前额叶背外侧皮层(左侧)以1Hz刺激,再次对准左侧前额皮层以10Hz刺激,对准右侧前额皮层以20Hz刺激,并且对准覆盖前扣带区的区域以20Hz刺激。
一些患者对使用氯胺酮进行治疗感到忧虑并且可能容易恐惧。因此,使用抗抑郁药如安定(地西泮)或咪达唑仑针剂(咪达唑仑)是合适的。此外,抗恶心药如枢复宁(昂丹司琼),可能适用于一些患者。
当以每周或每两周为基础输送TMS治疗和氯胺酮的联合治疗时,显著的积极效果已经与这种联合有关。其他替代方式包括,例如,每2天、3天、4天、5天、6天、8天、9天、10天、11天、12天、13天、15天、16天、17天、18天、19天、20天、21天或更多天进行治疗。在某些情况下,患者因各种原因而放弃治疗,但是在许多个星期或者甚至许多个月之后恢复治疗。在约2天至20天之后,更具体地,在约5天至15天治疗之后,以约3天至11天的有规律间隔,更具体地,以约每周的有规律间隔,可以预期到积极的效果。此外,更长或更短的间隔已经得到积极的效果,这种积极的效果可能由于患者的日程安排和依从性问题而分散。在特定实施例中,以至少约5个治疗期,更具体地,约6-8个治疗期可以成功治疗抑郁症,而慢性疼痛可能要花几个附加治疗期来实现所希望的效果,尤其是当疼痛伴随着严重的抑郁症和/或癖嗜时。在某些情况下,为了维护目的,可能给患者进行持续不频繁的治疗(例如,每一个月至每四个月)。
据报道,对于治疗轻度至中度抑郁症,单独使用TMS对大约20%至30%的患者有效。据报道,TMS对治疗严重抑郁症甚至不太有效。研究已经表明,单独使用氯胺酮治疗抑郁症得到约60%至70%的成功率。然而,为了使单独使用氯胺酮获得这种成功,据报道,氯胺酮的剂量比当联合TMS使用氯胺酮时(如本文所述)所需的剂量高5至15倍。此外,在单独使用氯胺酮的研究中,单独使用氯胺酮所得的缓解似乎极为短暂。
相比之下,完成TMS联合氯胺酮的治疗并获得积极效果的患者的百分比高于单独使用TMS或单独使用氯胺酮所报道的成功率。此外,用TMS联合氯胺酮治疗而获得积极效果(如本文所述)的患者易于实现更有活力,即,长期的积极效果,并且获得这种积极效果的同时具有减少的不良副作用。积极效果包括回到工作中;恢复失败的生意;返回大学、婚姻;调和失败的关系;从药物滥用中回到可靠的清醒;以及显著减少使用破环性剂量的阿片类麻醉品。此外,在接受本文所述的联合治疗之后获得积极效果的许多患者此前用治疗他们的病症的所有其他治疗都没有成功。这些治疗包括rTMS、VNS、TLVES、ECT、高压氧治疗;药物包括氯胺酮(单独)输注;以及替代的医学疗法如顺势疗法。
因此,通过结合TMS或TLVES且使用更少的麻醉剂,上述治疗提供更好的效果。因为需要的麻醉剂越少,治疗就会得到更少的副作用。此外,需要越少的TMS或TLVES会导致更好的患者依从性,其本身有助于更积极的效果。实际上,最初经历由治疗所带来的缓解的患者趋向于被激励接受提供持久疗效的附加治疗。
TLVES/氯胺酮治疗给可能不是TMS/氯胺酮治疗的良好人选的患者提供临床疗效。具体地,临床医师可以提前辨别某些患者不是TMS的良好人选。例如,患者通过TLVES/氯胺酮可以获得更多疗效,因为TMS/氯胺酮对全部CBF(脑血流量)的强效作用会让患者变得过于疲劳。或者患者可能变得激动并且需要特殊护理以在漫长的TMS/氯胺酮治疗期内等待就绪。TLVES/氯胺酮治疗提供有效的替代方法。此外,就对TMS/氯胺酮的副作用敏感的患者而言,TLVES/氯胺酮可以作为重要的有效过渡疗法。TLVES/氯胺酮对于不是很健壮的患者来说可以更不费力,因此对于一旦正在稳定康复的这些人而言是很好的选择。
在另一方面,本发明公开涉及一种预防有关用分离型麻醉剂治疗与丘脑皮层节律异常相关的疾病的副作用的方法。例如,通过少用麻醉剂来治疗患者可以最小化或预防副作用。以这种方法,联合TMS或TLVES施用分离型麻醉剂。相似地,在另一方面,本发明公开涉及一种减少用于治疗与丘脑皮层节律异常相关的疾病的分离型麻醉剂的剂量的方法。在这些方面,麻醉剂的剂量可以比用于治疗该疾病所正常施用的量减少约2倍至20倍。在其他方面,所述剂量可以减少5倍至15倍,更具体地,减少10倍至15倍,甚至更具体地,减少约5倍、10倍或15倍。在分离型麻醉剂是氯胺酮的特定实施例中,用于治疗该疾病的剂量是约20mg至约400mg,约50mg至约350mg,更具体地,约100mg至约350mg,甚至更具体地,约200mg至约300mg。在分离型麻醉剂是氯胺酮的另一个实施例中,用于治疗该疾病的剂量是约0.1mg/kg至6.0mg/kg,更具体地,约0.5mg/kg至5.0mg/kg,甚至更具体地,约1.0mg/kg至4.0mg/kg。实施例
实例1:TMS/氯胺酮治疗
35位患者用氯胺酮联合TMS治疗。完成表1所示治疗的所有28名患者在完成表2所示治疗方案之后具有积极效果(表1和表2位于权利要求书之前的说明书结尾部分)。为了简化表2的表述,每周接受多于一次治疗的患者表示为那周接受一次治疗。同样,间隔被四舍五入到最近的周。
一些患者接受预治疗(PT)3天至两周(通常6天或7天),每天TMS治疗(图2中一般表示为“PT天”或“PT周”)。其他人在联合治疗前接受TMS前治疗。尽管大多数患者接受预治疗或前治疗,但是一些患者既不接受预治疗也不接受前治疗。由于前治疗比几天的预治疗更宽松,所以接受预治疗的所有患者最终都换成前治疗或者既不是预治疗也不是前治疗。基于诊断及患者依从性应用预治疗和/或前治疗。患有慢性疼痛的患者在应用预治疗或前治疗时一般反应更好,而抑郁症患者之间的差异不太明显。
基于先前研究中所报道的单独使用氯胺酮、单独使用TMS或单独使用TLVES没有成功,表1所示的积极效果表明氯胺酮和TMS联合治疗的协同增强效应。此外,接受联合治疗的患者似乎有持久的效果,这种效果此前尚未报告单独使用氯胺酮来获得,并且是以显著低于比此前所理解的氯胺酮的剂量来获得的。
实例2:TLVES/氯胺酮治疗
三位患者按照如上所述的方式先用TMS/氯胺酮进行治疗,并且有显著改善。然而,这些患者比该群体的其他成员更脆弱且不太强壮。
通过相对于净电流定义阳极在F3并且阴极在F8,用tACS或tRNS治疗患者。应用电极的电刺激进约20分钟。在5分钟之后开始使用氯胺酮并且连续输注总共0.5mg/kg至5.0mg/kg的剂量持续15-50分钟。对于tACS,参数是1200微安(无偏移)或1200微安(1000微安的偏移)。对于tRNS,参数是1300微安或2000微安(1000微安的偏移)。由于使用TLVES/氯胺酮,所有三位患者已经能够获得与TMS/氯胺酮相同的治疗效果,且治疗后疲劳更少。
尽管本文已经公开多个方面和实施方式,但是本领域技术人员会明白其他方面和实施例。在本文公开的多个方面和实施例是为了说明目的而并非旨在限制,其真实的保护范围和精神由以下权利要求书表示。
Claims (22)
1.一种用于治疗患者中的与丘脑皮层节律异常相关的疾病的方法,所述方法包括联合地进行如下步骤:
将经颅低压电刺激(TLVES)治疗或经颅磁刺激(TMS)治疗应用于所述患者;
在所述TLVES治疗或所述TMS治疗期间将分离型麻醉剂给药于所述患者。
2.根据权利要求1所述的方法,其中,所述分离型麻醉剂是N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂。
3.根据权利要求2所述的方法,其中,所述NMDAR拮抗剂是氯胺酮。
4.根据权利要求1所述的方法,其中,在给药所述NMDAR拮抗剂之前、期间以及之后应用所述TLVES或TMS。
5.根据权利要求1所述的方法,进一步包括前治疗。
6.根据权利要求1所述的方法,其中,所述方法以3~7天的间隔进行重复。
7.根据权利要求1所述的方法,其中,所述与丘脑皮层节律异常相关的疾病是耳鸣。
8.根据权利要求1所述的方法,其中,所述与丘脑皮层节律异常相关的疾病是药物滥用。
9.一种用于治疗个体中的疼痛的方法,所述方法包括联合地进行如下步骤:
将经颅低压电刺激(TLVES)治疗或经颅磁刺激(TMS)治疗应用于所述个体;
在所述TLVES治疗或所述TMS治疗期间将N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂给药于所述个体。
10.根据权利要求9所述的方法,其中,在给药所述NMDAR拮抗剂之前、期间以及之后应用所述TLVES或TMS。
11.根据权利要求9所述的方法,其中,所述NMDAR拮抗剂是氯胺酮,剂量约为50~500mg。
12.根据权利要求11所述的方法,其中,所述氯胺酮在约30分钟至60分钟之间的时间段内输注。
13.根据权利要求9所述的方法,进一步包括前治疗。
14.根据权利要求9所述的方法,其中,所述方法以3~7天的间隔重复至少5次。
15.根据权利要求9所述的方法,其中,所述疼痛与复合性局部疼痛综合征或反射交感性营养不良相关。
16.一种用于治疗抑郁症的方法,包括联合地进行如下步骤:
将经颅低压电刺激(TLVES)治疗或经颅磁刺激(TMS)治疗应用于患有抑郁症的患者;
在所述TLVES治疗或所述TMS治疗期间将N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂给药于患者。
17.根据权利要求16所述的方法,其中,在给药所述NMDAR拮抗剂之前、期间以及之后应用所述TLVES或TMS。
18.根据权利要求16所述的方法,其中,所述NMDAR拮抗剂是氯胺酮,剂量约为50~500mg。
19.根据权利要求18所述的方法,其中,所述氯胺酮在约30分钟至60分钟之间的时间段内输注。
20.根据权利要求16所述的方法,进一步包括前治疗。
21.根据权利要求16所述的方法,其中,所述方法以3~7天的间隔重复至少5次。
22.根据权利要求16所述的方法,其中,所述抑郁症是双极抑郁症。
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WO2014081948A1 (en) | 2014-05-30 |
JP2022188221A (ja) | 2022-12-20 |
JP2016501865A (ja) | 2016-01-21 |
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EP2922591A4 (en) | 2016-08-10 |
CA2896568A1 (en) | 2014-05-30 |
US10716950B2 (en) | 2020-07-21 |
IL273912A (en) | 2020-05-31 |
US20140148636A1 (en) | 2014-05-29 |
KR20200117062A (ko) | 2020-10-13 |
JP2019065021A (ja) | 2019-04-25 |
ES2882619T3 (es) | 2021-12-02 |
EP2922591A1 (en) | 2015-09-30 |
US20180001104A1 (en) | 2018-01-04 |
KR20230141875A (ko) | 2023-10-10 |
HK1215687A1 (zh) | 2016-09-09 |
IL238979B (en) | 2020-08-31 |
MX2015006444A (es) | 2015-10-29 |
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