CN101448805B - 抑郁障碍的治疗 - Google Patents
抑郁障碍的治疗 Download PDFInfo
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- CN101448805B CN101448805B CN2007800186530A CN200780018653A CN101448805B CN 101448805 B CN101448805 B CN 101448805B CN 2007800186530 A CN2007800186530 A CN 2007800186530A CN 200780018653 A CN200780018653 A CN 200780018653A CN 101448805 B CN101448805 B CN 101448805B
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Abstract
提供一种治疗抑郁障碍的方法,该方法包括单独或与附加的抗抑郁药物联合施用褪黑激素激动剂。所治疗的抑郁障碍是重性抑郁、精神抑郁症或双向性精神障碍中的一种或多种。也提供药剂盒,该药剂盒包含一个或多个药物剂量单元的褪黑激素激动剂以及一个或多个药物剂量单元的抗抑郁药。单体剂量单元可以各自进一步包含抗抑郁药或抗精神病药物并且任选包含一种或多种药物活性成分。
Description
相关申请的交叉参考
本申请要求2006年5月22日提交的共同未决的美国临时专利申请第60/747,843号的利益,由此将其并入本申请。
技术领域
本发明属于抑郁疾病的药物治疗的领域。
背景技术
仅在美国,抑郁障碍影响近两千万成年人。如果不进行治疗,抑郁障碍可能在情绪上和身体上使人虚弱。
抑郁障碍包括一系列症状,这些症状列在标题为“抑郁症”的美国国立精神健康研究所(U.S.National institute of Mental Health)(NIMH)出版的小册子中,所述症状如下:
“持续性悲伤、焦虑或“空虚”情绪
绝望感、悲观感
罪恶感、无价值感、无助感
失去曾经享受过的爱好和活动(包括性)的兴趣或快乐
精力减少、疲劳、变得“迟缓”
难于集中精神、记忆困难、难于作决定
失眠、早晨早醒或睡过度
无食欲和/或体重减轻或者吃得过多和体重增加
想到死亡或自杀;自杀企图
多动、易怒
对治疗无反应的持续性身体症状,例如头疼、消化障碍和慢性疼痛。”
根据NIMH小册子,最常见类型的抑郁疾病中的三种是:
“重性抑郁表现为症状的(参见症状列表)的组合,这些症状干扰工作、学习、睡眠、进食以及享受曾经令人快乐的活动的能力。抑郁的这种导致无能的事件在一生中可能只发生一次,但更常见地发生几次。
较不严重类型的抑郁,精神抑郁症涉及长期的慢性症状,该症状不会导致无能,但会使患者不能良好活动或不能感觉良好。很多患有精神抑郁症的人在他们的一生中有时也经历重性抑郁发作。
另一种类型的抑郁是双向性精神障碍,也称为躁狂-抑郁性疾病。远非其它形式的抑郁障碍流行的那样,双向性精神障碍的特征为循环性情绪变化:非常高涨(躁狂)和低落(抑郁)。有时,所述情绪变化是显著的和快速的,但是最经常地它们是逐步的。当处于抑郁循环中时,个体可以具有抑郁障碍的任何一种症状或所有症状。当处于躁狂循环时,个体可以活动过度、说话过度并且有大量精力。躁狂症常常以引起严重的问题和窘迫的方式影响思考、判断和社会行为。例如,在躁狂阶段的个体可能感觉兴高采烈、充满从愚蠢的商业决定到不切合实际的狂热行为的大计划。躁狂症如果不进行治疗,可能恶化成精神病状态。”
本申请中称为MA-1的化合物是(1R-反式)-N-[[2-(2,3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺。该化合物是一种试验性褪黑素能激动剂,其对褪黑激素-1(MT1)和褪黑激素-2(MT2)受体二者都具有高亲和力并且因此可以有效地用于治疗失眠和昼夜节律睡眠障碍。在美国专利第5,856,529号中公开了MA-1,通过参考将该专利像完全列出一样地并入本申请。本申请中称为MA-2的化合物是N-[1-(2,3-二氢苯并呋喃-4-基)吡咯烷-3-基]-N-乙脲。该化合物也是一种试验性褪黑素能激动剂并被公开在美国专利第6,211,225号中,通过参考将该专利像完全列出一样地并入本申请。
发明内容
发明概述
本发明的方法包括治疗动物中的一种或多种抑郁障碍以及治疗抑郁疾病的一种或多种症状。
本发明的方法也包括治疗或预防其它障碍,对该障碍某些抗抑郁药,例如5-羟色胺重摄取抑制剂被证明是有效的。这些障碍包括但不限于强迫观念与行为障碍、惊恐障碍、社交焦虑障碍、社交恐惧症、创伤后应激障碍、月经前焦虑障碍以及泛化性焦虑症。
发明详述
在下文中关于说明性实施方案描述的本发明构思了本申请中称为MA-1和MA-2的褪黑激素激动剂,包括其盐、前药、酯、代谢物、溶剂化物、水合物、对映体、立体异构体以及无定形形式和晶体形式的用途。MA-1是白色至灰白色粉末,熔点是约78℃(DSC),并且具有式1所示的结构。
式1:MA-1化学结构
MA-1代谢物包括,例如那些描述在“Preclinical Pharmacokineticsand Metabolism of BMS-214778,a Novel Melatonin ReceptorAgonist”,Vachharajani等人,J.Pharmaceutical Sci.,92(4):760-772中的代谢物,由此通过参考将其并入本申请。更具体地说,这些代谢物包括MA-1的羟基化的衍生物和脱氢的衍生物以及MA-1的葡糖苷酸衍生物和二醇衍生物。8个这类代谢物的结构具有式2-9。
式2-羟基化的MA-1代谢物1
式3-脱氢的MA-1代谢物2
式4-羟基化的MA-1代谢物3
式5-羟基化的MA-1代谢物4
式6-脱氢的MA-1代谢物5
式7-羟基化的MA-1代谢物6
式8-葡糖醛酸MA-1代谢物
式9-二醇MA-1代谢物
可以通过许多途径将有效量的MA-1或MA-2给予受试动物(通常是人,但是其它动物,例如耕作动物、宠物和竞赛动物也可被治疗)。有效量是在治疗过程中对抑郁障碍或其症状有预防或改善效果的量。例如,有效量是与其它抗抑郁药,例如选择性5-羟色胺重摄取抑制剂,诸如氟西汀、帕罗西汀、舍曲林等相同程度地预防抑郁障碍的症状的发生或复发的量。
有效量在数量上可以,例如根据受治疗的患者、障碍或症状的严重性以及给药途径变化。可用常规研究确定这类剂量。通常,对于全身给药,例如口服给药,给药的参考点是用于治疗人昼夜节律障碍的MA-1或MA-2的剂量,即当口服给予时的1-500mg/天。预期尽管为了避免可能的不良事件,优选使用更低的剂量,例如150、100、50、25、10或1mg/天,但是可以按1-500mg/天的剂量将MA-1或MA-2给予成年人。通常,MA-1的剂量在一个或多个单位剂型中在约10至约150mg/天,优选约10至约100mg/天的范围内。
可以理解,包括MA-1或MA-2的实际给予的量的给药方案由医师根据相关情况,包括,例如被治疗的状况、选择的给药途径、个体患者的年龄、体重和反应以及患者症状的严重性确定。当然应当监测患者的可能的不良事件。
为了治疗或预防用途,通常将MA-1或MA-2作为药物组合物给予,所述药物组合物包含使用标准技术和常规技术与药学上可接受的固体或液体载体以及任选与药学上可接受的助剂和赋形剂结合的作为所述(或一类)必要的活性成分的至少一种该化合物。
MA-1在95%乙醇、甲醇、乙腈、乙酸乙酯、异丙醇、聚乙二醇(PEG-300和PEG-400)中非常可溶或易溶,并且在水中仅仅微溶。MA-1在水中的饱和溶液的天然pH是8.5,并且它的水溶解性实际上不受pH影响。
在实践本发明中有用的药物组合物包括用于口服、肠胃外(包括皮下、肌肉内、皮内和静脉内)、透皮、支气管的或鼻给药的适合的剂型。因此,如果使用固体载体,可将制剂压片、以粉或小丸的形式放入硬胶囊或呈糖锭或锭剂的形式。固体载体可包含常规赋形剂,诸如黏合剂、填充剂、压片润滑剂、崩解剂、湿润剂等。如果需要,可将片用常规技术薄膜包衣。如果使用液体载体,所述制剂可以呈糖浆、乳液、软明胶胶囊、注射用无菌介质、含水或无水液体悬浮液的形式,或可以是在使用前用水或其它适当的介质重建的干燥产品。液体制剂可以包含常规添加剂,诸如悬浮剂、乳化剂、湿润剂、非水介质(包括食用油)、防腐剂以及矫味剂和/或着色剂。为了肠胃外给药,尽管可以使用盐溶液、葡萄糖溶液等,但是,介质通常包含无菌水,其占至少大部分。也可以使用注射用悬浮液,其中可以使用常规的悬浮剂。也可以将常规防腐剂、缓冲剂等加入肠胃外用剂型。给予在口服给药制剂中的式I的化合物是特别有用的。可以通过适合的常规技术将药物组合物制备成含有适当量的MA-1或MA-2的期望的制剂。参见,例如Remington’s Pharmaceutical Sciences,Mack Publishing Company,Easton,Pa.,17th版,1985。
当制备本发明使用的药物组合物时,活性成分通常与载体混合、或被载体稀释、或包含在可呈胶囊、小药袋、纸容器或其它容器的形式的载体中。当载体充当稀释剂时,它可以是固体、半固体或液体材料,其作为活性成分的载体、赋形剂或介质起作用。因此,所述组合物可以呈片剂、丸剂、粉剂、锭剂、小药袋、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆剂、气雾剂(以固体的形式或在液体介质中)、含有例如至多10%重量的活性化合物的软膏剂、软明胶胶囊和硬明胶胶囊、栓剂、无菌注射溶液以及无菌被包装的粉剂的形式。
适当的载体和稀释剂的某些实例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉类、阿拉伯树胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲基酯和羟基苯甲酸丙基酯、滑石、硬脂酸镁和矿物油。所述制剂可以附加地包括润滑剂、湿润剂、乳化剂和悬浮剂、防腐剂、甜味剂或矫味剂。可以制备本发明的组合物以在对患者给药后提供活性成分的快速、持续或延迟的释放。
优选地将组合物制备成单位剂型,每个剂量包含从约0.1至约100mg的活性成分。术语“单位剂型”指适合作为人受试者和其它哺乳动物的单一剂量的物理上离散的单位,每个单位包含与需要的药物载体结合的经计算可在治疗期间的过程中产生期望的预防或治疗效果的预定量的活性物质。因此,例如可以给患有抑郁障碍的成年患者开的药方为1-4片,每片含有10-100mg MA-1,每天服用一次、两次或三次,并且在约1至约12周内可以期望改善他或她的状况。
典型的单位剂型可以是尺寸0或尺寸1的胶囊,其除了无水乳糖、微晶纤维素、胶体二氧化硅、交联羧甲纤维素钠和硬脂酸镁以外,还含有10、20、50或100mg MA-1。推荐在15-20℃避免湿气和日光下保存。
也可将MA-1制备成控释形式,例如延迟的、持续或脉冲式释放。也可以将MA-1与其它药物治疗同时给予,所述的其它药物治疗包括但不限于其它抗抑郁药治疗或其它用于治疗其它情绪障碍的药物治 疗。因此,例如本发明包括将MA-1或MA-2与其它褪黑激素能激动剂或其它睡眠诱发性药剂组合给予。其它抗抑郁药包括,但不限于在下列药物种类中的药剂:
-褪黑激素激动剂
-选择性5-羟色胺重摄取抑制剂(SSRIs)
○5-HT1A拮抗剂
○5-HT1A/β-肾上腺素能受体拮抗剂
○5-HT1B拮抗剂
○5-HT2C拮抗剂
○5-HT2C激动剂
○5-HT6激动剂
○α-2肾上腺素能拮抗剂
-5-羟色胺和去甲肾上腺素重摄取抑制剂(SNRIs)
-单胺氧化酶抑制剂(MAOIs)
-三环类抗抑郁药(TCAs)
-三重单胺摄取阻断剂
-NMDA受体拮抗剂
-吡咯啉酮类
-苯并噻二嗪类(Benzothiadiazides)
-苯甲酰基哌啶类(Benzoylpiperidnes)
-联芳丙基磺酰胺类
-代谢型谷氨酸受体(mGluRs)
-GABA拮抗剂
-NK1拮抗剂
-NK2拮抗剂
-CRF1拮抗剂
-精氨加压素V1b拮抗剂
-MCH受体拮抗剂
-NGF拮抗剂
-BDNF拮抗剂
-NT-3拮抗剂
-NT-4拮抗剂
-CREB拮抗剂
这类药剂的说明性的并且不是限制性的是:
褪黑激素能激动剂:褪黑激素,阿戈美拉汀,(1R-反式)-N-[[2-(2,3-二氢-4-苯并呋喃基)环丙基]甲基]丙-酰胺,和N-[1-(2,3-二氢苯并呋喃-4-基)吡咯烷-3-基]-N-乙脲],雷美替胺,2-苯基褪黑激素,8-M-PDOT,2-碘褪黑激素,6-氯褪黑激素;
5-羟色胺重摄取抑制剂:帕罗西汀、氟西汀、舍曲林、文拉法辛、西酞普兰、依他普仑、氟伏沙明、曲唑酮、奈法唑酮、米那普仑、地西帕明、度洛西汀、YM992;
SSRI/5-HT1A拮抗剂:WAY-100635、吲哚洛尔;
SSRI/5-HT1B拮抗剂:SB-224289;
SSRI/5-HT2C拮抗剂;
选择性的:SB242084,RS102221;
非选择性的:酮色林、茚达酮;
SSRI/5-HT2C激动剂:Org37684、Ro60-0175、WAY-161503、YM348、WAY-629、WAY-163909;
SSRI/5-HT6激动剂:LY586713、WAY-466、WAY-1811187;
α-2肾上腺素能拮抗剂:米氮平(瑞美隆);
三重单胺摄取阻断剂:DOV21,947;
NMDA受体拮抗剂:MK-801、美金刚、氯胺酮、非尔氨酯、甘氨酸、D-丝氨酸、D-环丝氨酸、L-谷氨酸艾芬地尔;
吡咯烷酮类:吡拉西坦、茴拉西坦;
三环类:阿米替林、氯米帕明、地昔帕明、度硫平、多赛平、丙咪嗪、洛非帕明、去甲替林、普罗替林、曲米帕明、伊普吲哚、奥匹 哌醇;
四环类:马普替林、米安色林、米氮平、阿莫沙平、曲唑酮、奈法唑酮;
5-羟色胺重摄取增强剂:噻奈普汀;
单胺氧化酶抑制剂:哈马灵、尼亚拉胺、司来吉兰、异卡波肼、异丙烟肼、异丙氯肼、吗氯贝胺、苯乙肼、托洛沙酮、反苯环丙铵;
多巴胺重摄取抑制剂:安非他酮、安咪奈丁、哌醋甲酯、芬美曲秦、伐诺司林;
去甲肾上腺素重摄取抑制剂:托莫西汀、瑞波西汀、维洛沙秦、马普替林、安非他酮、瑞波西汀;
5-羟色胺-去甲肾上腺素重摄取抑制剂:地昔帕明、度洛西汀、米那普仑、奈法唑酮、文拉法辛;
苯并噻二嗪类:环噻嗪;
苯甲酰基哌啶类:CX516、CX546;
联芳丙基磺酰胺类:LY392098、LY404187、LY451646;
代谢型谷氨酸受体(mGluRs):2-甲基-6-(苯基乙炔基)-吡啶(MPEP)、3-[(2-甲基-1,3-噻唑-4-基)乙炔基]-吡啶(MTEP)、JNJ16259685、CPCOOEt、MGS0039、LY341495、LY354740、ACPT-1/L-SOP(L-丝氨酸-O-磷酸盐)、高(Homo)AMPA、N-苯基-7-(肟基)环丙[b]色烯-1a-甲酰胺;
GABA拮抗剂:CGP36742、CGP56433、CGP56999;
NK1拮抗剂:GW823296、GW679769、GW597599(维替匹坦)、R673、CP-122,721、L-759274、GR205171、L733060;
NK2拮抗剂:SR48968;
CRF1拮抗剂:DMP696、DMP904、GW876008、AAG561、TS-041、CP-154,526(antalarmin)、SSR125543、R278995/CRA0450、R121919;
精氨加压素V1b拮抗剂:SSR149415;
MCH受体拮抗剂:T-226296。
在某些患者中,据报道,用锂或三碘甲状腺原氨酸增强抗抑郁治 疗是有用的。
因此,在另一个说明性的实施方案中,本发明包括含有一个或多个药物剂量单元的MA-1或MA-2以及一个或多个药物剂量单元的抗抑郁药的药剂盒(kit),其中MA-1或MA-2单位剂型和抗抑郁药单位剂型中任一个或两者也可以分别包含抗抑郁药或抗-精神病药和任选一种或多种附加的药学活性成分。在另一个实施方案中,本发明包括将MA-1或MA-2和其它药剂在不同时间间隔给予,以使在患者血流中在适当的时间以适当的量保持每个药剂的有效量。与其它药剂相比,这类药剂盒可以有利于,例如给予在不同时间间隔服用的MA-1或MA-2。在一个相关实施方案中,药剂盒包含单独的一种药剂的药物剂量单元以及包含两种药剂的其它药物剂量单元。以这种方式,例如,可以在白天单独服用MA-1或MA-2,并且在晚上服用MA-1或MA-2和另一种药剂。
当在这类组合中使用时,预期每个药剂的剂量与单独任一药剂的有效量大约相同或更小。例如,可以每种成分单独给予时的剂量的约20%至约80%的剂量给予每种药学活性成分。
可以大约同时,即伴随地(例如,在互相约0至约5分钟内,优选在间隔约1分钟内)给予所述两种(或更多种)药剂,或将它们在不同时间给予。例如,在一方面,本发明是包含抗-精神病药剂和其它药剂的药物组合物。这个实施方案,例如,包含丸剂或胶囊,所述丸剂或胶囊具有混合在一起的两种活性药物成分或具有在所述丸剂或胶囊的离散部分中的每个活性药物成分。
本发明的单位剂型,无论它们包含MA-1或MA-2或其活性代谢物作为单独的活性药物成分或与其他药剂,例如抗精神病药或抗抑郁药组合,也可以制成控释形式,例如延迟、持续或脉冲释放。使用这类形式,在组合的情况下,MA-1或MA-2或其活性代谢物可以与其它药剂相同或不同的速率和时间释放。
具体实施方式
下列实施例是说明性的,不限制本发明,并且说明MA-1在预防和治疗抑郁障碍的症状中的有用性。
实施例1-3.在下列3个模型中测试MA-1:(1)应激-诱导的cGMP升高,(2)小鼠强迫游泳试验以及(3)大鼠强迫游泳试验。下列是使用的试验方案和从这些研究中得到的结果。
应激-诱导的小脑cGMP升高
试验方案:将动物放置在装有钢栅形地板的电击箱中,以1mA电击10秒。在刺激物后一分钟,将动物放入塑料限制管中,并用微波照射处死(在3.5kW1.8秒)。迅速取出小脑,速冻并且在cGMP测定前保存在-80℃。将未应激的动物直接从它们的笼子取出,用微波照射处死,并且使用类似方法处理组织。在足-电击应激前30-60分钟进行药物给药。为了cGMP测定,使用Brinkman Polytron在#5设定下在2ml1%高氯酸中将每个组织搅匀大约15秒,并且放在冰上直到所有的样品都被匀化。然后将样品放置在85℃水浴中5分钟,在2500G离心15分钟,收集~0.5ml上清液用于分析。根据125I-cGMP闪光板(flashplates)的制造商的说明书,在乙酸钠缓冲液中按1:20稀释上清液。用125I-cGMP将稀释的样品在闪光板孔中培养过夜,在γ-计数器板阅读器上检测,并且使用在相同试验中生成的标准曲线将其转化为pmol cGMP/mg组织。
结果:接受电击的大鼠显示小脑cGMP水平~2.5x增加。通过用剂量为0.1-10mg/kg的MA-1处理,减弱这个增长~50%。尽管该效果看起来是最大的,没有剂量-反应,但是没有尝试更低的剂量。
小鼠强迫游泳试验
试验方案:将动物以在0600时光照的12:12LD循环饲养。在试验开始前至少1小时将小鼠放入试验房间。在下列三种情况之一下给予介质、阿米替林和MA-1:A)急性治疗,在试验前30分钟对动物给药;B)4天亚-慢性AM治疗,在早上较早期间(0900-1100时)进行给药,在试验前30分钟进行最终给药;并且C)亚慢性PM治疗在晚上期间 (1730-1800时,恰好在熄灯前)进行给药,并且在第二天早上进行强迫游泳试验。使用Porsolt等(1978)最初描述的试验方案的改良方案在强迫游泳试验中检测动物。在7分钟游泳期间,将小鼠放入盛有800ml水(20-22℃)的1L烧杯(KIMAX#14005)中。仅在所述试验的后5分钟给动物打分,如果动物积极地游泳,则给它们的分数为“0”,如果除了保持漂浮需要的小移动以外,动物不动,则给它们的分数为“1”。在5分钟打分期间内,每只小鼠有总可能得分为0-10的十个30秒打分间隔。以中位数(四分点间距(interquartile range))的形式报告数据。每个研究用未受过试验的小鼠的单独的组独立进行。使用Statview(SAS,Cary,NC)通过Kruskal-Wallis分析,然后用Mann-Whitney U-检验,显著性水平设置为p<0.05对数据进行分析。
结果:在三种情况下在小鼠强迫游泳模型中测试MA-1的功效,所述三种情况包括(A)急性治疗,在给药后30分钟测试;(B)4天亚-慢性治疗,AM给药,在最终给药后30分钟测试;并且(C)4天亚慢性治疗,PM给药,并且在第二天早上测试。在这个试验中使用阿米替林作为阳性对照,并且阿米替林在情况A和B下有活性,但是在情况C下没有显示活性。然而,MA-1在任何测试的情况下都没有在这个试验中显示活性。
大鼠强迫游泳试验
试验方案:使用Porsolt等(Eur.J.Pharmacol.,47,379-391,1978)最初描述的试验方案在强迫游泳试验中测试动物。在试验的第一天将大鼠单个地放入含有13cm水(25℃)的桩形物(高=40cm,直径=20cm)中15分钟(试验期1),然后在24小时后再放回入水中进行5分钟测试(试验期2)。测量在所述5分钟测试期间不动的持续时间。每组研究6只大鼠。在盲化下进行试验。在光照循环期间,即在开灯后2.5至5.5小时或在黑暗循环期间,即在熄灯后2.5至5.5小时进行试验期1和试验期2。因此,在9:30am至12:30pm之间进行光照循环期间的试验,但是,因为光照循环转换,在14:30pm至17:30pm之间进行黑暗循环期间的试验。
为了允许在相同的天由相同的试验室技术员进行所述试验的2阶段(光照阶段和黑暗阶段),将在黑暗阶段期间测试的动物在强迫游泳试验的第一试验期前12天经历光照循环转换,由此将光照/黑暗循环提前了7小时(开灯:0:00am,熄灯:12:00pm)。估计12天期间对于黑暗-循环动物来说足以调节至转换。为了使大鼠习惯光照循环转换,将黑暗-循环动物在试验期1前12天经历所述转换。为了保证在光循环和黑暗循环动物之间的其它条件相似,所有在试验中使用的动物来自相同递送批次并且在相同时间,即在试验期1前12天放入它们的试验生活笼。
在光照阶段期间的测试是在正常试验室光照下进行的,在黑暗阶段期间的测试是在红外的光照下进行的。MA-1、阿戈美拉汀和褪黑激素各自以2个口服(p.o.)剂量进行评价,给药两次(在试验期2前24小时和1小时)。在试验期1后立即进行第一次给药。在相同试验条件下给予两次的丙咪嗪(64mg/kg p.o.)被用作参照物质。
结果:在24小时循环的黑暗阶段(表1)或光照阶段(表2)期间对大鼠给药并测试,以研究对昼夜节律时间的敏感性的潜能。测试的化合物包括作为阳性对照的丙咪嗪(64mg/kg)、褪黑激素(10和50mg/kg)、阿戈美拉汀(10和50mg/kg)以及MA-1(1和10mg/kg)。选择与在文献中关于这个或其它行为试验已报道活性的范围相一致的剂量。所有褪黑激素激动剂在黑暗阶段的活性更强,阿戈美拉汀分别在10和50mg/kg显示不动时间减少60%和33%。MA-1也在两个测试剂量下显示显著的不动时间减少,在1和10mg/kg分别观察到不动时间减少37%和41%。尽管在测试的剂量中效果更弱并且更不一致,在光照阶段(表2)期间测试的动物中也观察到活性。
表1
阿戈美拉汀、MA-1、褪黑激素和丙咪嗪在大鼠行为绝望试验(黑暗循环)中的效果
(每组6只大鼠)
学生t检验:*=p<0.05;**=p<0.01;***=p<0.001
#1:逃跑(1/6)。
#2:死亡(1/6)。
表2
阿戈美拉汀、MA-1、褪黑激素和丙咪嗪在大鼠行为绝望试验(光照循环)中的效果
(每组6只大鼠)
学生t检验:NS=不显著;*=p<0.05;**=p<0.01;***=p<0.001
结论:设计该系列研究是为了测试MA-1是否在应激和行为绝望 的啮齿类动物行为模型中显示与其它褪黑激素激动剂相似的活性。在其它褪黑激素激动剂显示活性的那些模型中,MA-1具有活性。在应激-诱导的cGMP试验(没有显示数据)中褪黑激素和阿戈美拉汀以前显示的活性的水平与观察到的MA-1的相似。另外,MA-1在大鼠FST(Porsolt试验室)中显示的活性与阿戈美拉汀和褪黑激素显示的活性在数量上相似。尽管MA-1在小鼠FST中没有活性,但是我们在这个试验中没有显示其它褪黑激素激动剂的活性。与Porsolt试验室进行的大鼠试验相比,在小鼠FST中缺少效果不简单地是由物种不同引起的,因为我们在另一种形式的大鼠FST中也没有观察到褪黑激素激动剂的活性。这表明试验设计的细微不同、给药途径或给药时间可能对于褪黑激素激动剂在本试验中发挥作用来说是关键的。在另一个本文未报道的研究中,在5mg/kg和10mg/kg在改良的强迫游泳试验中在大鼠中测试MA-1,并且其没有显示对不动、游泳或攀爬的与介质有统计学上差异的效果。
Claims (3)
1.(1R-反式)-N-[[2-(2,3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺在制备药物组合物中的用途,其中所述药物组合物用于治疗人的重性抑郁。
2.权利要求1的用途,其中所述重性抑郁表现为以下症状的组合:持续性悲伤、焦虑或空虚情绪;绝望感;悲观;罪恶感、无价值感或无助感;失去曾经享受过的爱好和活动的兴趣或快乐;精力减少、疲劳或迟缓;难于集中精神、记忆困难或难于作决定;失眠、早晨早醒或睡过度;无食欲和/或体重减轻或者吃得过多和体重增加;想到死亡;自杀企图;多动;易怒;对治疗无反应的持续性身体症状,其选自头疼、消化障碍和慢性疼痛。
3.权利要求1或2的用途,其中在制备所述药物组合物中使用第二种抗抑郁药物。
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US11090285B2 (en) | 2013-11-12 | 2021-08-17 | Vanda Pharmaceuticals Inc | Treatment of circadian rhythm disorders |
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IL300422A (en) * | 2016-03-08 | 2023-04-01 | Sage Therapeutics Inc | Neuroactive steroids, preparations and their uses |
WO2018205935A1 (zh) | 2017-05-09 | 2018-11-15 | 浙江大学 | 治疗抑郁症的方法和药物组合物 |
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RU2268725C2 (ru) * | 2000-01-19 | 2006-01-27 | Акцо Нобель Н.В. | Комбинация лекарственных препаратов, включающая миртазапин, для лечения депрессии и связанных расстройств |
US20050203130A1 (en) * | 2003-12-02 | 2005-09-15 | Erik Buntinx | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists |
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CN101448805A (zh) | 2009-06-03 |
US20090209638A1 (en) | 2009-08-20 |
AU2007253704A2 (en) | 2009-01-08 |
EP2029564A2 (en) | 2009-03-04 |
KR20090024140A (ko) | 2009-03-06 |
JP2009538334A (ja) | 2009-11-05 |
WO2007137247A3 (en) | 2008-01-24 |
RU2008150621A (ru) | 2010-06-27 |
ZA200809527B (en) | 2009-11-25 |
MX2008014840A (es) | 2008-12-05 |
CA2652421A1 (en) | 2007-11-29 |
BRPI0712014A2 (pt) | 2011-12-27 |
WO2007137247A2 (en) | 2007-11-29 |
EP2029564A4 (en) | 2010-01-13 |
RU2445973C2 (ru) | 2012-03-27 |
AU2007253704A1 (en) | 2007-11-29 |
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