CN104507477B - 用于治疗人的抑郁症和精神病的组合物和方法 - Google Patents
用于治疗人的抑郁症和精神病的组合物和方法 Download PDFInfo
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- CN104507477B CN104507477B CN201380037202.7A CN201380037202A CN104507477B CN 104507477 B CN104507477 B CN 104507477B CN 201380037202 A CN201380037202 A CN 201380037202A CN 104507477 B CN104507477 B CN 104507477B
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Abstract
公开了用于治疗人类抑郁症和精神病的组合物和方法,更具体地,本发明涉及包含抗精神病药和/或抗抑郁药且还包含NMDAR拮抗剂的制剂。本发明还涉及通过给予抗抑郁和/或抗精神病有效量的本发明组合物来治疗患有抑郁症和包括精神分裂症在内的其它精神病的人的方法。
Description
相关申请的交叉引用
本申请要求2012年7月12日提交的临时申请61/741,114和2012年7月12日提交的临时申请61/741,115的权益,通过引用将其各自的内容引入本文。
发明背景
精神分裂症为与精神病症状相关的临床症状,例如妄想和幻觉,以及诸如工作、社会关系或自我护理等领域的功能衰弱。
精神分裂症的诊断可使用本领域标准教科书来确定,例如美国精神病学会出版的精神障碍的诊断和统计手册(Diagnostic and Statistical Manual of MentalDisorders)第四版(DSM-IV)。通常使用等级量表如阳性与阴性症状量表(Positive andNegative Syndrome Scale,PANSS)来测定精神分裂症的症状。
精神分裂症的症状用抗精神病药治疗,主要通过阻断多巴胺D2受体来起作用。
抗精神病药可基于受体结合、临床前作用和副作用谱分成典型的(例如氯丙嗪、氟哌啶醇、奋乃静)和非典型的(例如氨磺必利、阿立哌唑、阿塞那平、布南色林(bloanserin)、联苯芦诺(bifeprunox)、卡利拉嗪、氯噻平、氯氮平、伊潘立酮、鲁拉西酮、莫沙帕明、奥氮平、帕潘立酮、哌罗匹隆、喹硫平、瑞莫必利、利培酮、舍吲哚、舒必利、齐拉西酮、佐替平)。临床有效剂量的抗精神病药剂通常产生大于60%的占有多巴胺D2受体。非典型抗精神病药可为部分或全部D2拮抗剂并还可具有对附加的儿茶酚胺和5-羟色胺受体类型的活性,包括5-HT2A与5-HT2C受体和肾上腺素能α1和α2受体。非典型的抗精神病药还可影响其它受体类型,例如毒蕈硷胆碱能受体。
重性抑郁症为包括固执悲伤情绪或对活动丧失兴趣的临床症状,该临床症状在无治疗下持续至少两周。通常使用等级量表如汉密尔顿抑郁症等级量表(HAM-D)或贝克抑郁症量表(BDI)测定重性抑郁症的的症状。除了包括与沮丧情绪相关的症状以外,HAM-D还包含对精神病敏感的症状,包括内疚、人格解体/现实感丧失和偏执狂等项。重性抑郁症还可与焦虑症状相关,其可利用等级量表如焦虑用汉密尔顿抑郁症等级量表(HAM-A)来测定。抑郁症分为重性抑郁症(MDD)和双相情感障碍(BPD),可使用美国精神病学会出版的诊断和统计手册第四版(DSM-IV)中所述的标准来诊断,该手册还提供了精神病症的其它描述。重性抑郁症还可在有无忧郁特征下发生。另外,抑郁症状可发生在焦虑性障碍如广泛性焦虑障碍、解离性障碍、人格障碍或适应障碍伴有沮丧情绪的环境下(DSM-IV)。
目前对于重性抑郁症的治疗主要由以下组成:年久的抗抑郁药,例如首次在十九世纪六十年代开发的单胺氧化酶抑制剂(monoamine oxidase inhibitors,MAOI)和三环抗抑郁药(TCA)(如丙咪嗪、阿米替林、去甲丙咪嗪、氯米帕明),以及较新的试剂如四环抗抑郁药(TeCA)(例如阿莫沙平、司普替林、马普替林、米安色林、米氮平)、5羟色胺(SSRI)和5羟色胺/去甲肾上腺素(SNRI)重摄取抑制剂(例如氟西汀、氟伏沙明、帕罗西汀、西酞普兰、艾司西酞普兰、度洛西汀、文拉法辛、达泊西汀、吲达品、维拉佐酮(valzodone))。这些试剂通过调节脑单胺特别是去甲肾上腺素和5羟色胺的水平,和/或通过阻断5-HT2A受体来起作用。AOI和TCA被认为是比随后开发的SSRI/SNRI“更广谱”的试剂。MAOI、TCA、TeCA、SSRI和SNRI可统一认为是常规抗抑郁药。
抗精神病药还可在治疗抑郁症方面有效。潜在有益的抗精神病药包括但不限于利培酮、奥氮平、喹硫平、阿立哌唑、氯氮平、伊潘立酮、舍吲哚、阿塞那平、鲁拉西酮、卡利拉嗪。
其它开发中的抗精神病药和抗抑郁药包括维度新(Valdoxan)(阿戈美拉汀,AGO178)(Servier,Novartis)、Lu AA21004(Lundbeck,Takeda)、F2695,左旋体米那普仑(levomilnacipran)(Forest,Pierre Fabre)、SEP-227162(Sepracor)、LuAA24530(Lundbeck,Takeda)、SEP-225289(Sepracor)、依利色林(Epivanserine)(Sanofi-Aventis)、SR46349(Sanofi-Aventis)、LY12624803,HY10275(Lilly,Hypnion)、TIK-301/LY156735(Tikvah Therapeutics)、Lonasen(布南色林,Dainippon)、LU-31-130(Lundbeck)、SLV313(Solvay)、Edivoxetine(LY2216684,Lilly)、OPC-34712(Otsuka/Lundbeck)、Vyvanse(甲磺酸赖氨酸安非他明(lisdexamfetamine),Shire)、BCI-224(沙可美林(sacomeline),BrainCells)、BCI-540(考拉西坦(clouracetam),BrainCells)、BMS-82036(BMS/AMRI)。
然而,现有治疗方法具有严重的限制。仅60-65%的患者应答初始方案,而在这些应答中,不足一半达到缓解或变得无症状。对抗抑郁治疗的第一疗程不应答的个体通常转到不同的药物,结果一般是适度和增加的。
5-HT2A受体为神经递质5羟色胺的受体类型。5-HT2A拮抗剂为抑制激动剂如5-HT2A受体上的5羟色胺作用的化合物。另外,反向激动剂为减少活性至基线水平以下的化合物。相对于其它5羟色胺受体(如5-HT2C),5-HT2A受体拮抗剂对于5-HT2A可为非选择性的,或者对于5-HT2A受体是选择性的。选择性的5-HT2A拮抗剂可使用标准测定步骤开发和表征,例如2010年5月11日授权的美国专利7,713,995中记载的那些,通过引用将其全部内容并入本文。
充当非选择性5羟色胺受体拮抗剂的试剂包括利坦色林、酮色林、斯更色林和ICI-169369。充当选择性5-HT2A拮抗剂或反向激动剂的试剂包括氟利色林(MDL100,907,也称为M100907)、普凡色林(EMD281014)、依利色林、CYR-101和匹莫范色林(ACP-103)。选择性5-HT2A受体拮抗剂和反向激动剂目前处在治疗抑郁症和精神病二者的发展中,并且被视为潜在的抗抑郁药/抗精神病药。
另外的5-HT2A受体拮抗剂或反向激动剂记载于2011年1月25日授权的美国专利7,875,632;2011年1月11日授权的美国专利7,868,176;2011年1月4日授权的美国专利7,863,296;2010年10月26日授权的美国专利7,820,695;和/或2010年5月11日授权的7,713,995中,通过引用将其全部内容并入本文。
治疗-不应性抑郁症是指对现有可得的治疗应答不良的抑郁症的形式(例如http://www.nimh.nih.gov/trials/practical/stard/index.shtml2011年6月),其与其它形式的抑郁症相比可具有不同的潜在的病因病理学(etiopathological)机理。抗抑郁药的组合还未显示优于对难治性抑郁症的单一疗法,且通常增加副作用的风险,是不推荐的。
自杀的风险在抑郁症中显著增加,但可对针对郁郁症状整体的药物有不同应答。当自杀发生时,通常伴随卑微感或不宜的内疚感,以及复发的死亡想法或自杀意念,并且内疚是自杀的可接受的代替。在患有抑郁症的个体的自杀风险增加时,迄今为止典型地用于治疗抑郁症的药剂反常地增加自杀倾向。
使用抗精神病药和抗抑郁药的主要限制是产生行为副作用的可能性,特别是焦虑、激动和失静症。这些可区别于考虑时间进程和特殊的症状模式的疾病症状。
除了失静症以外,抗精神病药还产生锥体束外症状如僵直、震颤或运动障碍。然而,失静症区别于锥体束外症状并且显示不同的治疗应答。目前,抗精神病药诱导的失静症没有批准的治疗。
使用抗抑郁药还受到产生焦虑、激动和失静症的倾向的限制。
抗抑郁药的限制总结于FDA要求的"黑匣子"警告中,如下:下述症状,焦虑、激动、无端恐惧症、失眠症、过激性、敌意、攻击性、冲动性、失静症(精神运动不安)、轻度躁狂和躁狂症已在用抗抑郁药治疗重性抑郁症以及治疗其它适应症(精神病治疗和非精神病治疗二者)的成人和儿科患者中报道。尽管此类症状的出现与抑郁症的恶化和/或自杀冲动的出现之间的因果关系还未建立,人们担心此类症状可能表示出现自杀的前兆"(Trivedi等人,JClin Psychiatry.72.765-774.2011)。
正如抗精神病药诱导的失静症,目前还没有已知的抗抑郁药诱导的焦虑、激动和失静症的治疗。
焦虑和失静症可在动物模型中研究,例如大鼠缺陷或不安模型,如例如综述Schdev&Brune,Animal models of acute drug-induced akathisa中所述(NeurosciBiobehav Rev 24:269-277.2000)。
包括5-HT2A受体拮抗剂的抗精神病药和抗抑郁药还可治疗上用于治疗双相情感障碍(躁狂抑郁性精神病)、阿尔兹海默病、帕金森氏病、痴呆、焦虑性障碍、疼痛和包括自闭症的发展障碍。
N-甲基-D-天冬氨酸盐受体(NMDAR)为一类脑神经递质谷氨酸盐的受体。NMDAR参与广泛的脑功能,包括感觉加工、认知和情绪调节。
NMDAR包括多个亚单位,命名为GluN1、GluN2和GluN3(原名NR1、NR2、NR3。存在多种形式的GluN1、GluN2和GluN3。特别地,GluN2亚单位分成GluN2A-D亚型,也命名为NR2A-D亚单位。NMDAR可由GluN1、GluN2和GluN3亚单位以各种量的各种组合组成。激动剂和拮抗剂可同样影响所有NMDAR,或可对包含特定亚单位类型的NMDAR为选择性的。
NMDAR包含神经递质谷氨酸盐和内源调节氨基酸甘氨酸和D-丝氨酸的结合位点。
谷氨酸盐结合位点还以高亲和力选择性地结合合成的谷氨酸盐衍生物N-甲基-D-天冬氨酸盐。该位点可选地称作NMDAR的NMDA识别位点的谷氨酸盐识别位点。
甘氨酸/D-丝氨酸结合位点已称作甘氨酸调节位点、变构调节位点或甘氨酸-B受体。
NMDAR形成被多种药物滥用阻断的离子通道,例如苯环利定(PCP)、克他命或地佐环平(MK-801)。这些化合物结合至已被称为PCP受体的位点。阻断NMDAR-相关离子通道的试剂统称为非竞争性NMDAR拮抗剂,或NMDAR通道阻断剂。NMDAR被通道阻断剂阻断导致接近类似的精神分裂症的临床精神病状态。
经通道位点阻断NMDA受体的其它化合物包括AZD6765(AstraZeneca)和Glyx-13(Naurex)、NRX-1059(Naurex)。
其它NMDAR拮抗剂记载于公开于2011年12月15日的美国专利申请#20110306586,通过引用将其全部内容并入本文。
低亲和性NMDAR拮抗剂,例如美金刚(memantine)可区别于高亲和性拮抗剂如PCP、克他命或地佐环平。一般而言,低亲和性NMDAR拮抗剂不包括精神分裂症样精神病或啮齿动物的PCP-样行为影响
NMDAR还可被结合至谷氨酸盐识别位点、甘氨酸识别位点或通道结合位点的拮抗剂所抑制。
塞福太(Selfotel)(CGS19755)为结合至谷氨酸盐识别位点的拮抗剂的实例。针对CNS适应症如中风或癫痫开发了几种这类化合物。当以足以充分抑制NMDAR的剂量使用时,这些化合物,如通道阻断剂,导致临床拟精神病症状。
充当谷氨酸盐识别位点的拮抗剂的其它化合物包括阿替加奈(aptiganel)(Cerestat,CNS-1102)和Reddy等人描述的相关化合物,J Med Chem 37:260-7.1994。
充当谷氨酸盐识别位点的拮抗剂的其它化合物包括被各种间隔子单元分隔的α-氨基-羧酸和磷酸官能团。未修饰的实例为2-氨基-5-磷酸基戊酸(AP5)(Watkins,J.C;Evans,R.H.,Annu.Rev.Pharmacol.Toxicol.1981,21,165),其包含饱和碳链。包含增强结构刚性和由此的潜能的元件的更复杂的实例包括CPP、顺式-4-(膦酸基甲基)-2-哌啶甲酸(CGS-19755)(Lehman,J.等人,J.Pharmacol.Exp.Ther.1988,246,65)和(E)-2-氨基-4-甲基-5-膦酸基-3-戊烯酸(CGP-37849)(Schmutz,M.等人,Abs.Soc.Neurosci.1988,14.864)。参见2008年5月18日授权的美国专利7,345,032,和美国专利5,168,103,通过引用将其全部内容并入本文。
NMDAR还可被结合至甘氨酸识别位点的拮抗剂抑制。
D-环丝氨酸为充当部分甘氨酸位点拮抗剂的化合物。D-环丝氨酸剂量可分成低剂量(0-250mg)、中等剂量(≥250-500mg)或高剂量(≥500mg)。在低剂量下,D-环丝氨酸可起到净NMDAR激动剂的作用。在高剂量下,D-环丝氨酸可起到净NMDAR拮抗剂的作用。与中等或高剂量给药相关的血浆浓度为大于25微克/ml。
非尔氨酯(Felbamate)为可经甘氨酸结合位点起作用的化合物的另一实例。当给予人时,非尔氨酯产生精神病作用,限制了其临床应用(例如Besag FM,Expert Opin DrugSaf 3:1-8,2004)。
加维斯替奈(Gavestinel)(GV-150,526)为甘氨酸结合位点拮抗剂的另一实例。其它化合物记载于DiFabrio等人,J Med Chem 40:841-50,1997,通过引用将其并入本文。
适用于本发明的药物组合物和方法的甘氨酸位点拮抗剂的其它实例为下述所指的那些:2003年12月23日授权的美国专利6,667,317;2000年6月27日授权的美国专利6,080,743;1999年11月23日授权的美国专利5,990,108;1999年7月15日授权的美国专利5,942,540;1999年7月15日授权的国际专利申请WO 99/34790;1998年10月29日公布的WO 98/47878;1998年10月1日公布的国际专利申请WO 98/42673;1991年1月29日公布的欧洲专利申请EP 966475A1;1998年9月11日公布的国际专利申请98/39327;1998年2月5日公布的国际专利申请WO 98/04556;1997年10月16公布的国际专利申请WO 97/37652;1996年10月9日授权的美国专利5,837,705;1997年6月12日公布的国际专利申请WO 97/20553;1999年3月23日授权的美国专利5,886,018;1998年9月1日授权的美国专利5,801,183,1995年3月23日授权的国际专利申请WO 95/07887;1997年11月11日授权的美国专利5,686,461;1997年4月22授权的美国专利5,622,952;1997年3月25日授权的美国专利5,614,509;1996年4月23日授权的美国专利5,510,367;1992年12月9日公布的欧洲专利申请517,347A1;1993年11月9日公布的美国专利5,260,324。通过引用将前述专利和专利申请以其全部内容并入本文。
用于本发明的药物组合物和方法甘氨酸位点拮抗剂的其它实例为N-(6,7-二氯-2,3-二氧-1,2,3,4-四氢-喹喔啉-5-基)-N-(2-羟基-乙基)-甲烷磺酰胺和6,7-二氯-5-[3-甲氧基甲基-5-(1-氧基吡啶-3-基)-[1,2,4]三唑-4-基]-1,4-二氢-喹喔啉-2,3-二酮。
其它的NMDAR拮抗剂记载于Schiene等人,美国专利申请US2001/0306674A1,通过引用将其全部内容并入本文,包括,但不限于,含N膦酸,如正缬氨酸(AP5)、D-正缬氨酸(D-AP5)、4-(3-膦酸基-丙基)-哌嗪-2-羧酸(CPP)、D-(E)-4-(3-膦酸基丙-2-丙烯基)哌嗪-2-羧酸(D-CPPene)、顺式-4-(膦酸基甲基)-2-哌啶羧酸(塞福太,CGS 19755)、SDZ-220581、PD-134705、LY-274614和WAY-126090;喹啉酸,如犬尿酸、7-氯-犬尿酸、7-氯-硫代犬尿酸和5,7-二氯-犬尿酸,其前药,如4-氯犬尿素和3-羟基-犬尿素;4-氨基四氢喹啉-羧酸酯,如L-689,560;4-羟基喹啉-2(1H)-酮,如L-701,324;喹喔啉二酮,如利可替奈(ACEA-1021)和CGP-68,730A;4,6-二氯-吲哚-2-羧酸酯衍生物,如MDL-105,519、加维斯替奈(gavestinel)(GV-150,526)和GV-196,771A;三环化合物,如ZD-9,379和MRZ-2/576、(+)-HA-966、吗啡喃衍生物,如右美沙芬和右羟吗喃;苯基吗啡类,如BIII-277CL;其它阿片类,如右旋丙氧芬、凯托米酮、右美沙酮和D-吗啡;氨基-金刚烷,如金刚烷胺和美金刚;氨基-烷基-环己烷,如MRZ-2/579;艾芬地尔和艾芬地尔样化合物如依利罗地和PD-196,860;亚氨基嘧啶类;或其它NMDA-拮抗剂如硝普盐、D-环丝氨酸、1-氨基环丙烷-羧酸、地佐环平(MK 801)和其类似物、苯环己哌啶(PCP)、克他命((R,S)-2-(2-氯苯基)-2-(甲基氨基)环己酮-1肟)、(R)-克他命、(S)-克他命、瑞马西胺(remacemide)和其脱-甘氨酸-代谢物FPL-12,495、AR-R-15,896、美沙酮、柳氮磺吡啶(sulfazocine)、AN19/AVex-144、AN2/AVex-73、贝生罗地(Besonprodil)、CGX-1007、EAB-318、非尔氨酯和NPS-1407。NMDA-拮抗剂例如公开于“Analgesics”,由H.Busc mann、T.Christoph、E.Friderichs、C.Maul、B.Sundermann编辑,2002,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,特别是第389-428页。通过引用将说明的相应部分并入本文并形成本公开的一部分。
拮抗剂可对GluN2B(NR2B)(包含亚型)是选择性的。对包含受体的NR2B选择性的化合物的实例包括艾芬地尔、曲索罗地(CP-101,606)、贝生罗地、Ro25-6981、MK-0657和EVT-101。
与已鉴定的NMDAR拮抗剂一起,可使用公知确认的电生理学测定或放射性受体测定来鉴定其它NMDAR拮抗剂,电生理学测定如NMDA-受体介导的对NMDA谷氨酸盐-位点激动剂的应答的调制,放射性受体测定如结合至NMDA PCP-受体通道结合位点的调制。甘氨酸位点激动剂和拮抗剂还可基于电生理学和来自与通道位点结合的化合物如苯环己哌啶(PCP)或克他命的受体结合来区别。部分激动剂定义为具有相对于完全激动剂减少的诱导受体构象改变的效力(通常为40-80%)的化合物,其可以低剂量诱导激动剂效果,但以高剂量诱导拮抗剂效果。
NMDAR拮抗剂克他命目前批准为麻醉剂。还有报道显示小规模临床试验中治疗抗抑郁症的有益效果。然而,其实用性受限于拟精神病效果。低亲和性NMDAR拮抗剂美金刚批准用于痴呆。另外,NMDAR拮抗剂不具有确定的临床实用性。
一般而言,NMDAR拮抗剂被认为用于精神分裂症或抑郁症是忌用的。例如,NMDAR拮抗剂D-环丝氨酸用于抑郁症、严重焦虑或精神病被FDA认为是忌用的。
这里我们出乎意料地显示NMDAR拮抗剂出乎意料地减少与抗抑郁药和/或抗精神病药治疗相关的失静症和焦虑。
这里我们出乎意料地显示抗抑郁药防止与NMDAR激动剂使用相关的精神病症状。
这些发现提供用于改善需要用抗精神病药、抗抑郁药或NMDAR拮抗剂药剂治疗的人的治疗方法。
附图简述
图1为下文描述的实施例中记载的结果的图示,示出对于特定药物或药物组合,在测试装置的开放臂(open arms)中花费的时间百分比。
发明概述
本发明涉及用于治疗人类抑郁症和精神病的组合物。更具体地,本发明涉及包含抗精神病药和/或抗抑郁药并且还包含NMDAR拮抗剂的制剂,抗精神病药和/或抗抑郁药包括选择性5-HT2A受体拮抗剂/反向激动剂。本发明还涉及用于通过给予抗抑郁和/或抗精神病有效量的本发明组合物来治疗患有抑郁症和包括精神分裂症等的其它精神病的人的方法。
在一实施方案中,本发明提供口服或肠胃外给药方案,其基本上由两种治疗剂组成,其中所述两种活性成分的第一种为抗抑郁药或抗精神病药,第二试剂由NMDAR受体拮抗剂组成。
在本发明的某些实施方案中,第一化合物由典型的或非典型的抗精神病药组成。
在本发明的某些实施方案中,第一治疗剂从包括下述物质的列表中得到:氨磺必利、阿立哌唑、阿塞那平、联苯芦诺、布南色林、卡利拉嗪、氯噻平、氯氮平、伊潘立酮、鲁拉西酮、莫沙帕明、奥氮平、帕利哌酮、哌罗匹隆、喹硫平、瑞莫必利、利培酮、舍吲哚、舒必利、齐拉西酮、佐替平。
在某些实施方案中,第一治疗剂包括四环抗抑郁药(TeCA)、选择性5羟色胺重摄取抑制剂(SSRI)、5羟色胺/去甲肾上腺素重摄取抑制剂(SNRI)、5-HT2A拮抗剂/反向激动剂或其组合。
5-HT2A受体拮抗剂/反向激动剂可从包括下述物质的列表中得到:氟利色林(MDL100,907,也称为M100907)、普凡色林(EMD281014)、依利色林、CYR-101和匹莫范色林(ACP-103)。
NMDAR拮抗剂可从甘氨酸识别位点、谷氨酸盐识别位点或通道识别位点的拮抗剂得到。
NMDAR拮抗剂可为对包含特定亚单位如NR2A或NR2B亚单位的NMDAR的非选择性拮抗剂或选择性拮抗剂,。
在本发明的某些实施方案中,抗抑郁药可选自包括丙咪嗪、阿米替林、去甲丙咪嗪、氯米帕明、阿莫沙平、司普替林、马普替林、米安色林、米氮平、氟西汀、氟伏沙明、帕罗西汀、西酞普兰、艾司西酞普兰、度洛西汀、文拉法辛、达泊西汀、吲达品、维拉佐酮。
在本发明的某些实施方案中,第一治疗剂从包括下述物质的列表中得到:阿戈美拉汀、Lu AA21004、F2695、左旋体米那普仑、SEP-227162、LuAA24530、SEP-225289、依利色林、SR46349、LY12624803、HY10275、TIK-301/LY156735、Lonasen、LU-31-130、SLV313、Edivoxetine、OPC-34712、甲磺酸赖氨酸安非他明、沙可美林、考拉西坦和BMS-82036。
在某些实施方案中,第二治疗从包括下述物质的列表中得到:克他命、右美沙芬、CNS-1102、AZD6765或CGS-19755。
在本发明优选的实施方案中,第二治疗剂由D-环丝氨酸组成,以每天至少500mg的剂量给药。
在某些实施方案中,NMDA受体拮抗剂由D-环丝氨酸组成,以产生超过25微克/mL的血清水平的剂量给药。
在某些实施方案中,本发明提供治疗有需要的个体的精神病的方法,所述方法向所述个体提供本文描述的口服或肠胃外给药方案。
在某些实施方案中,本发明提供治疗有需要的个体的抑郁症的方法,所述方法向所述个体提供本文描述的口服或肠胃外给药方案。
在某些实施方案中,个体患有狂躁症,或者在某些实施方案中,个体患有双相情感障碍。
在某些实施方案中,本发明提供治疗有需要的个体的自闭症症状的方法,所述方法向所述个体提供本文描述的口服或肠胃外给药方案。
在某些实施方案中,本发明将减少与抗精神病药相关的副作用的方法提供给需要此类治疗的个体,所述方法包括向所述个体提供本文描述的口服或肠胃外给药方案。
在某些实施方案中,本发明将减少与抗抑郁药相关的副作用的方法提供给需要此类治疗的个体,所述方法包括向所述个体提供本文描述的口服或肠胃外给药方案。
在某些实施方案中,本发明将减少与NMDAR拮抗剂药剂相关的副作用的方法提供给需要此类治疗的个体,所述方法包括向所述个体提供本文描述的口服或肠胃外给药方案。
在某些实施方案中,凝胶剂如羟丙基甲基纤维素,与一种或多种药学可接受赋形剂一起,用于制造缓释剂。
在某些实施方案中,缓释制剂包含包括凝胶剂、优选羟丙基甲基纤维素的亲水基质,NMDA受体拮抗剂,抗抑郁药及其药学可接受盐,以及一种或多种药学上可接受的赋形剂。
在某些实施方案中,NMDA受体拮抗剂和抗抑郁或抗精神病药剂将用于共同缓释而制造。
在某些实施方案中,NMDA受体拮抗剂将用于缓释而制造,并结合有抗抑郁药或抗精神病药。
在某些实施方案中,抗抑郁药或抗精神病药将用于缓释而制造,并结合有NMDA受体拮抗剂。
在一实施方案中,NMDA受体拮抗剂和抗抑郁药或抗精神病药将选择性释放特征,允许组合药剂的每日一次的剂量,并将不需要单独的缓释制造。
发明详述
在某些实施方案中,本发明提供肠胃外或静脉给药方案,在治疗有需要的个体的精神分裂症或抑郁症中有用,或者在减少有需要的个体或群体的失静症或焦虑的发病率中有用。
在某些实施方案中,本发明提供口服或肠胃外给药方案,基本上由两种活性成分组成,其中所述成分的第一种为抗精神病药或抗抑郁药。
根据该方面,在某些实施方案中,第一治疗剂包括本文所述的任何试剂,例如,四环抗抑郁药(TeCA)、选择性5羟色胺重摄取抑制剂(SSRI)、5羟色胺/去甲肾上腺素重摄取抑制剂(SNRI)、选择性5-HT2A受体拮抗剂、选择性5-HT2A受体反向激动剂、批准用于治疗抑郁症的抗精神病药,或其组合。
在某些实施方案中,选择性5-HT2A拮抗剂/反向激动剂选自氟利色林(MDL100,907,M100907)、普凡色林(EMD281014)、依利色林、CYR-101和匹莫范色林(ACP-103)。
在某些实施方案中,第一治疗剂为抗精神病药,由典型的或非典型的抗精神病药组成。
在某些实施方案中,抗精神病药选自氨磺必利、阿立哌唑、阿塞那平、布南色林、联苯芦诺、卡利拉嗪、氯氮平、氯氮平、伊潘立酮、鲁拉西酮、莫沙帕明、奥氮平、帕利哌酮、哌罗匹隆、喹硫平、莫瑞必利、利培酮、舍吲哚、舒必利、齐拉西酮、佐替平。
在某些实施方案中,第二治疗剂为NMDAR拮抗剂。
在某些实施方案中,第二治疗剂对甘氨酸识别位点、谷氨酸盐识别位点或通道识别位点起作用。
在某些实施方案中,第二治疗剂对含有NR2A亚单位的NMDAR起作用。
在某些实施方案中,第二治疗剂对含有NR2B亚单位的NMDAR起作用。
在某些实施方案中,第二治疗剂从包括下列物质的列表中得到:克他命、塞福太、阿替加奈、CPP、CGP-37849、非尔氨酯、加维斯替奈、N-(6,7-二氯-2,3-二氧-1,2,3,4-四氢-喹喔啉-5-基)-N-(2-羟基-乙基)-甲烷磺酰胺和6,7-二氯-5-[3-甲氧基甲基-5-(1-氧基吡啶-3-基)-[1,2,4]三唑-4-基]-1,4-二氢-喹喔啉-2,3-二酮、4-(3-膦酸基-丙基)-哌嗪-2-羧酸(CPP)、D-(E)-4-(3-膦酸基丙-2-丙烯基)哌嗪-2-羧酸(D-CPPene)、SDZ-220581、PD-134705、LY-274614和WAY-126090;喹啉酸,如犬尿酸、7-氯-犬尿酸、7-氯-硫代犬尿酸和5,7-二氯-犬尿酸,其前药,如4-氯犬尿素和3-羟基-犬尿素;4-氨基四氢喹啉-羧酸酯,如L-689,5604;4-羟基喹啉-2(1H)-酮,如L-701,324;喹喔啉二酮,如利可替奈(ACEA-1021)和CGP-68,730A;4,6-二氯-吲哚-2-羧酸酯衍生物,如MDL-105,519,加维斯替奈(GV-150,526)和GV-196,771A;三环化合物,如ZD-9,379和MRZ-2/576、(+)-HA-966、吗啡喃衍生物,如右美沙芬和右羟吗喃;苯基吗啡类,如BIII-277CL;其它阿片类,如右旋丙氧芬、凯托米酮、右美沙酮和D-吗啡;氨基-金刚烷,如金刚烷胺和美金刚;氨基-烷基-环己烷,如MRZ-2/579;艾芬地尔和艾芬地尔样化合物如依利罗地和PD-196,860;亚氨基嘧啶类;或其它NMDA-拮抗剂如硝普盐、D-环丝氨酸、1-氨基环丙烷-羧酸、地佐环平(MK 801)和其类似物、苯环己哌啶(PCP)、克他命((R,S)-2-(2-氯苯基)-2-(甲基氨基)环己酮-1肟)、(R)-克他命、(S)-克他命、瑞马西胺和其脱-甘氨酸-代谢物FPL-12,495、AR-R-15,896、美沙酮、柳氮磺吡啶、AN19/AVex-144、AN2/AVex-73、贝生罗地、CGX-1007、EAB-318、非尔氨酯和NPS-1407。
在某些实施方案中,第二化合物为D-环丝氨酸,以500mg或更高的剂量给药。
在某些实施方案中,两种活性成分以单一药物组合物提供,在某些实施方案中,本发明预期包含各两种活性成分的试剂盒或组合的药剂包(dispenser packet)。
要理解的是,本发明预期向个体同时给药两种活性成分中的每个,无论此类给药以单一制剂结合还是以单独制剂结合,无论此类给药是同时发生还是交错发生。
本发明的组合物可通过各种公知既定的药用途径给药,包括静脉、腹膜内、肠胃外、肌内或口服。
在某些实施方案中,本发明提供用于治疗有需要的个体的抑郁症的方法,所述方法包括以本文所述的口服制剂或肠胃外制剂或肠胃外注射的形式给予有效量的本发明组合物。
在某些实施方案中,个体患有精神分裂症,或者在某些实施方案中,个体患有双相情感障碍。在某些实施方案中,本发明提供用于对有需要的个体或人群减少发病率或治疗自杀或自杀意念的方法,所述方法包括向所述个体提供本文所述的口服或肠胃外给药方案。
在某些实施方案中,关于本文引用的治疗剂的“有效”量或“治疗有效量”,其意指无毒的但足以提供期望效果的治疗剂量。在本发明的组合疗法中,组合中的一个组分的“有效量”为当与组合中的其它组分组合使用时有效提供期望效果的化合物量。“有效”的该量将在个体之间变化,依赖于个体的年龄和一般情况,具体的活性剂或试剂等。因此,不总是可规定精确的“有效量”。然而,在任何个体情况下的适当的“有效”量可由本领域普通技术人员使用常规实验确定。
本文使用的术语“治疗(treating)”和“治疗(treatment)”是指降低症状的严重程度和/或频率、消除症状和/或根本病因,预防症状的发生和/或它们的根本病因,和改善或补救损伤。因此,例如,“治疗”患者涉及预防易感个体的特定病况或不利生理事件以及有临床症状的个体的治疗。
D-环丝氨酸或DCS是指化学制品D-环丝氨酸(CA索引名,3-异噁唑烷酮(Isoxazolidinone),4-氨基-,(4R)-(9CI);CAS注册号68-41-7),或其药学可接受盐。DCS为FDA(美国食品药品管理局)-批准的用于治疗肺结核的药物,并由Eli Lilly and Company以商标名销售。DCS为D-丙氨酸的结构类似物,且为兰花链霉菌(Streptomyces orchidaceus)和S.garphalus的某些菌株产生的广谱抗生素。在某些实施方案中,本发明的组合可用于治疗肺结核。
标记被提供并设置在相邻的行和列中,用于显示常见天数和连续周数。因此,包装提供递增方案,防止错误剂量造成的不良反应。结果,根据本发明的包装提供安全性且因而更有益的方法用于使得方案能够具有依从性。
根据该方面,在某些实施方案中,第一治疗剂以一定剂量给药,所述剂量被认为是在用所述第一治疗剂单独治疗所述个体时治疗所述个体的抑郁症或精神病的次优剂量。
利用本发明的方法进行治疗的个体可体验显著的抑郁症改善。相对于用其他抑郁症疗法治疗的个体,在某些实施方案中,根据本发明的方法治疗的个体将体验到更大的改善,或更持久改善,如通过任意临床认可的抑郁症评价法所测定的(例如,21-项汉密尔顿抑郁症等级量表)。应注意的是,不是每个个体都将从本发明的方法中获益,正如其它药剂通常不能有益于每个患者一样。
用本发明的方法进行治疗的个体可体验到显著的焦虑改善。相对于用其他焦虑疗法治疗的个体,在某些实施方案中,根据本发明的方法治疗的个体将体验到更大的改善,或更持久改善,如通过任意临床认可的焦虑评价法所测定的(例如,汉密尔顿焦虑等级量表)。应注意的是,不是每个个体都将从本发明的方法中获益,正如其它药剂通常不能有益于每个患者一样。
用本发明的方法进行治疗的个体可体验到显著的失静症改善。相对于用其他失静症疗法治疗的个体,在某些实施方案中,根据本发明的方法治疗的个体将体验到更大的改善,或更持久改善,如通过任意临床认可的失静症评价法所测定的(例如,汉密尔顿失静症等级量表)。应注意的是,不是每个个体都将从本发明的方法中获益,正如其它药剂通常不能有益于每个患者一样。
用本发明的方法进行治疗的个体可体验到显著的精神病改善。相对于用其他精神病疗法治疗的个体,在某些实施方案中,根据本发明的方法治疗的个体将体验到更大的改善,或更持久改善,如通过任意临床认可的精神病评价法所测定的(例如,汉密尔顿精神病等级量表)。应注意的是,不是每个个体都将从本发明的方法中获益,正如其它药剂通常不能有益于每个患者一样。
实施例
实施例:NMDAR拮抗剂对由5-HT2A拮抗剂诱导的失静症的作用
背景:药物诱导的失静症是抗精神病和抗抑郁药剂二者常见的副作用,并且甚至可见于新近的非典型抗精神病药中(Iqbal等人,CNS Spectrums,12:1-13,2007)。该症状还描述于焦虑/神经过敏症状(Sinclair等人,Br J Psychiatry,194:483-90,2009),也见于下述SSRI和三环抗抑郁药二者中。
尽管目前没有精确的动物模型,但评价局部不安的啮齿动物活动测量已表明具有判定它们的用途的表面有效性(face validity)(Sachdev和Brune.Neurosci Biobehav Rd24:269-277,2000)。5-HT2A受体的激动剂如(+/-)-1-(2,5-二甲氧基-4-吲哚苯基)-2-氨基丙烷(DOI)已很好地描述了抗焦虑性质,可在啮齿动物测定如四板试验或高架十字迷宫(elevated plus maze)(Nic Dhonnchadha等人,Behavioural brain research.147:175-84,2003)中检测。5-HT2A配体的作用可部分经GABA体系调节(Masse等人,Behav Brain Res177:214-26.2007),增加该机理与失静症的相关性。
本调查试验了以下假设:NMDA受体拮抗剂可反转完全或部分通过5-HT2A阻断起作用的试剂的失静症诱导作用,所述试剂包括选择性5-HT2A拮抗剂/反向激动剂、抗抑郁药和非典型抗精神病药。对于该研究,主要使用的NMDA受体拮抗剂为D-环丝氨酸(DCS)。
方法:所有研究在PsychoGenics,Inc.进行(总部设在765Old Saw Mill RiverRoad,Tarrytown,NY),使用高架十字迷宫(EPM)设备评价药剂的行为影响。
准备:来自Jackson Laboratories(Bar Harbor,Maine)的雄性C57BI/6J小鼠用于本研究。小鼠接收时为6周龄。在收到时,为小鼠分配唯一标识数(尾部标记)并以4小鼠/笼成组居住在OPTI小鼠通风笼中。在研究的剩余时间里,所有动物保持四个一组居住。在测试前,所有小鼠适应于新居住室(colony room)至少1周,并随后以平均7周龄试验。
在适应环境期间,小鼠定期检查、处理并称重,从而确保足够的健康和适应性。将动物保持在12/12光照/黑暗循环中;在光照阶段进行试验。室温保持在20至23℃之间,相对湿度保持在30%和70%之间。在研究持续期间提供食物和水自由采食。在各试验中,动物随机分配至治疗组。所有动物在研究完成后安乐死。
设备:高架十字迷宫试验评价焦虑。迷宫(Kinder Scientific;Poway,CA)由两个封闭臂(14.5cm h×5cm w×35cm l)和两个开放臂(6cm w×35cm l)组成,形成交叉,含有方形中心平台(6×6cm)。所有可见的表面由黑色丙烯酸塑料制成。迷宫的各臂置于地板上方56cm的支持柱上。抗静电黑色乙烯基窗帘(7'高)围绕EPM以造成5'w×5'l的围栏。在试验前允许动物适应试验室至少1小时。小鼠置于高架十字迷宫的中心面对封闭臂5分钟运行。所有动物试验一次。由计算机自然记录所花费的时间、游历的距离和进入各臂。EPM在各试验后完全清洁。
药剂:药剂通过静脉注射给药。所有药剂溶于适当的载体中。剂量表示为毫克/千克(mpk)。
统计分析:本研究的主要依赖性测定由在开放臂中花费的时间的%组成,将其理解为抗焦虑效果的测定。使用post-hoc LSD在单尾检验显著性p<0.05下进行状况之间的比较。
结果:使用开放臂中时间的百分比%的测定评价NMDA受体拮抗剂对焦虑/失静症相关症状的具体作用,其测定进入EPM的开放的vs.封闭的部分的意愿。由于其代表在开放和封闭臂中的活动之间的比例,对于总体活动水平的变化相对不敏感。使用总游历距离评价潜在的非特异性作用,这是总体活动的测定。NMDA拮抗剂诱导的移动活跃过度被认为是精神病的啮齿动物模型。5-HT2A拮抗剂已知为逆转高亲和性NMDAR通道阻断剂对啮齿动物活动的作用,反映了它们作为抗精神病药的潜在用途。然而,在先没有研究调查竞争性NMDAR激动剂对甘氨酸或谷氨酸盐位点起作用以逆转高亲和性5-HT2A产生的潜在失静症-相关的焦虑效应的能力。
拮抗剂,或其它化合物如抗抑郁药或非典型抗精神病药潜在地与5-HT2A受体激动剂相关。
结果的描述
前述描述的实验的结果示于表1。个体代表性实验的结果示于表2并描绘于图1中。
表1
表2
与盐水相比,DOI(2mpk)以1mpk(p<0.05)和2mg(p<0.05)两种剂量显著增加在开放臂中花费的时间%。DCS在以30mpk或300mpk的剂量单独加入DOI时不具有显著作用,表明在该测定体系中非特异性行为影响的缺失。DCS(300mpk)显著逆转了MDL100709的作用(p<0.05),而DCS(30mpk)的作用是非显著性的。此外,组合的DCS(300mpk)与酮色林和EMD281014二者在开放臂中花费的时间%在数值上大于单独使用各试剂。当在实验中进行分析时,观察到D-环丝氨酸(300mpk)vs.DOI(2mpk)和单独MDL100,907(0.3mpk)的高度显著的作用(p<0.01)(图1)。
在DOI(2mpk)的存在下,5-HT2A拮抗剂/反向拮抗剂MDL100907(p=0.001)和酮色林(p<0.001)和EMD281014(p<0.05)均显著减少了在开放臂中花费的时间%,表明失静症的显著倾向。
竞争性谷氨酸盐位点拮抗剂D-CPPene在开放臂中花费的时间%上产生与MDL100,907的作用相反的倾向水平(p<0.1)。其它NMDA受体拮抗剂,包括CGS19755和CP101606产生数值改善。没有观察到通道位点拮抗剂PCP的显著效果,尽管倾向是效果恶化。此外,在组合的D-丝环霉素/DOI/MDL100907的存在下在开放臂中的时间%显著大于在组合的PCP/DOI/MDL100907(p<0.05)的存在下。
除了选择性5-HT2A拮抗剂/反向激动剂以外,非典型抗精神病药喹硫平(p<0.001)和鲁拉西酮(p<0.05)也显著减少了开放臂中的时间%,表明诱导失静症的可能性。通过DCS300mpk显著逆转了喹硫平(p<0.05)和鲁拉西酮(p<0.05)二者的作用。
最后,在D-环丝氨酸(300mpk)和DOI(2mpk)的存在下试验三种抗抑郁药-度洛西汀、米氮平和文拉法辛。与DOI单独相比,所有3种都显示显著减少的开放臂进入%,与临床诱导失静症的能力一致。
游历的距离(DT)
与开放臂中的时间%相反,DOI(2mpk)显著减少了总游历距离。与单独DOI(2mpk)相比(p<0.05),MDL100907显著增加了DT,且该作用被D-环丝氨酸(300mpk)增强(而不是逆转)(p<0.001)。其它5-HT2A和NMDAR拮抗剂以与开放臂中花费的时间%测定中观察到的相反的模式,在单独和组合下具有不一致性的效果,反映了抗-失静症效果的特异性。总体而言,与DOI(2mpk)和D-环丝氨酸(300mpk)单独相比(p<0.05),加入DOI(2mpk)和D-环丝氨酸(300mpk)的度洛西汀、文拉法辛和米氮平显著增强了DT。
总结:
这些发现表明D-环丝氨酸的非预期能力,在高剂量下逆转由5-HT2A拮抗剂如MDL100709、酮色林或非典型抗精神病药诱导的高架十字迷宫的开放臂中花费时间%的减少的能力。不仅对于D-环丝氨酸,而且对于其它NMDA受体拮抗剂如D-CPPene、CGS19755或CP101606,发现促-疗效效果。相反,常规通道阻断剂PCP相对于DCS的较低的性能,表明该试剂作用于谷氨酸盐或甘氨酸结合位点,或者较低亲和性的通道阻断剂如GlyX-13,可优于较高亲和性的非竞争性拮抗剂如PCP或ΜΚ-801。此外,尽管5-HT2A拮抗剂已知逆转由NMDA通道阻断剂如克他命、MK-801或PCP诱导的活跃过度,但开放臂%测定(比较开放vs.封闭臂中游历的距离)纠正了活性水平方面的总体改变。
尽管本动物模型未解决在啮齿动物中观察到的现象的程度是与人类中药物诱导的失静症和/或神经过敏/焦虑症状同形的,该问题对于要求保护的发明是不重要的,然而这表示,5-HT2A拮抗剂和非典型抗精神病化合物产生焦虑的性质被D-环丝氨酸和其它NMDA受体拮抗剂高度有效的和意料之外的逆转。这些发现因而表明,添加NMDA受体拮抗剂至包括典型/非典型拮抗剂和抗抑郁药在内的5-HT2A拮抗剂的独特的意料之外的益处,并表明这些化合物的不合需要的产生焦虑的副作用可通过使用NMDAR拮抗剂而被最小化。
在本发明的某些特征已在此说明和描述的同时,本领域普通技术人员现将想到许多修改、替换、改变和等同形式。因此,要理解的是,所附权利要求意欲覆盖所有此类落在本发明的真实原意内的修改和改变。
本领域技术人员将理解的是,可在不偏离如所附权利要求中阐述的本发明的精神和范围下对其进行形式和细节的各种改变。本领域技术人员将意识到,或仅仅使用常规实验能够确定,本文所述的本发明特定实施方案的许多等同形式。此类等同形式意欲包括在权利要求的范围内。
通过引用将本文提及的所有公报、专利和专利申请的全部内容并入本文,犹如各独立的公报或专利具体且单独提及通过引用并入本文一样。在说明书与并入的参考冲突的情况下,说明书应有支配地位。本文件中给出的数值范围,除非另有说明,否则包括范围内的端点。此外,要理解的是,除非另有说明,或从上下文来看是显而易见的,并且本领域普通技术人员理解,表示为范围的值可涵盖在指定范围内的任何特定值和子集,在本发明的不同实施方案中,任选地包括或排除一个或两个端点至范围下限的单位的十分之一,除非上下文明确指出其它方面。在百分比引入关于基本上具有为整数的单位的值的情况下,任何产生的分数可四舍五入至最接近的整数。
在权利要求中,冠词如“一(a)”、“一(an)”和“所述(the)”意指一种或超过一种,除非另有相反说明,或上下文来看显而易见是相反的。一组成员间包括“或”或者“和/或”的权利要求或说明书如果存在、采用一个、超过一个或所有组员,或另外与给定产品或方法相关,则被认为是合适的,除非另有相反说明或上下文来看显而易见是相反的。本发明包括其中存在、采用恰好该组的一个成员或另外与给定产品或方法相关的实施方案。本发明还包括其中存在、采用超过一个或所有组员或另外与给定产品或方法相关的实施方案。此外,要理解的是,本发明在各种实施方案中提供所有变化、组合和交换,其中来自一个或多个所列权利要求的一个或多个限定、元素、从句、描述性术语等引入引用同一基础权利要求的另一权利要求,除非另有说明或除非这对于本领域普通技术人员而言显而易见将产生矛盾或不一致。在元素以例如马库什基团形式中列出存在的情况下,要理解的是,各元素子集也被公开了,且任何元素可从该组中除去。应理解的是,一般而言,本发明或本发明的方面是指包括特定元素、特征等,本发明的某些实施方案或本发明的方面由此类元素、特征等组成或基本组成。出于简化的目的,在此这些实施方案未在每个实例中用同样的话具体陈述。某些权利要求为了方便起见以从属的形式示出,但申请人保留将任意从属权利要求改写为独立形式的权利,包括独立权利要求或该权利要求引用的任何其它权利要求中的元素或限定,并且此类改写的权利要求无论以何种形式(修改的或未修改的)都被认为与被改写成独立形式之前的从属权利要求在所有方面是等价的。
Claims (11)
1.NMDAR拮抗剂在制备用于降低与给予人个体用于治疗精神疾病的选择性5-HT2A受体拮抗剂/反向激动剂相关的失静症的药物中的用途,所述药物包含有效量的由以下组成的口服制剂或肠胃外制剂:
-第一化合物,选自选择性5-HT2A受体拮抗剂/反向激动剂;和
-第二化合物,选自NMDAR受体拮抗剂。
2.如权利要求1所述的用途,其中所述NMDAR受体拮抗剂选自非选择性拮抗剂、选择性拮抗剂及其组合。
3.如权利要求1所述的用途,其中所述选择性5-HT2A受体拮抗剂/反向激动剂选自MDL100,907、普凡色林、依利色林、CYR-101、OPC-34712和匹莫范色林。
4.如权利要求1所述的用途,其中所述NMDAR拮抗剂选自甘氨酸识别位点、谷氨酸盐识别位点和通道识别位点的拮抗剂。
5.如权利要求1所述的用途,其中所述NMDAR拮抗剂对于包含NR2B亚单位的NMDAR是选择性的。
6.如权利要求1所述的用途,其中所述NMDAR拮抗剂由D-环丝氨酸组成,以净NMDAR拮抗剂剂量给药。
7.如权利要求6所述的用途,其中所述净NMDAR拮抗剂剂量产生D-环丝氨酸的血浆水平大于25微克/mL。
8.如权利要求1所述的用途,其中所述NMDAR拮抗剂选自CGS-19755、D-CPPene、MK-0657、AZD6765、Glyx-13、NRX-1059或EVT-101。
9.如权利要求1所述的用途,其中:
-所述第一化合物选自MDL 100,907和鲁拉西酮,且所述第二化合物为以净NMDAR拮抗剂剂量提供的D-环丝氨酸;或者
-所述第一化合物为MDL 100,907,且所述第二化合物选自以净NMDAR拮抗剂剂量提供的D-环丝氨酸、CGS-19755、D-CPPene、CP101606、GV150526和L701324。
10.如权利要求1所述的用途,其中所述药物被配制用于口服、肌内、静脉、腹膜内或肠胃外给药。
11.如权利要求1所述的用途,其中所述药物为缓释剂型的形式。
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EP3263108B1 (en) | 2019-10-02 |
US9737531B2 (en) | 2017-08-22 |
CN107875389B (zh) | 2021-02-02 |
US10660887B2 (en) | 2020-05-26 |
DK2872139T3 (en) | 2018-02-05 |
EP3263108A1 (en) | 2018-01-03 |
CN104507477A (zh) | 2015-04-08 |
US20150374684A1 (en) | 2015-12-31 |
JP6416762B2 (ja) | 2018-10-31 |
EP2872139B1 (en) | 2017-11-01 |
JP2019014740A (ja) | 2019-01-31 |
CN107875389A (zh) | 2018-04-06 |
CA2878565A1 (en) | 2014-01-16 |
AU2013288827B2 (en) | 2018-03-08 |
AU2013288827A1 (en) | 2015-02-19 |
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