CN1713900A - 去甲肾上腺素再摄取抑制剂在治疗认知障碍中的应用 - Google Patents
去甲肾上腺素再摄取抑制剂在治疗认知障碍中的应用 Download PDFInfo
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Abstract
将选择性去甲肾上腺素再摄取抑制剂,特别是托莫西汀、瑞波西汀和2-烷硫基取代的苯氧基苯丙胺,用于治疗认知障碍,其中包括由痴呆、谵妄和精神分裂症引发的认知障碍。
Description
本发明属于药物化学和中枢神经系统药物的领域,并提供一种治疗认知障碍的方法。
认知障碍就是认知功能即获取、保留和应用知识过程的失调或丧失。估计全美国有2%的人患有不同形式和程度的认知障碍,其中大约有15%65岁以上的人患有该种疾病。认知障碍通常主要是由于谵妄(delirium)或痴呆(dementia)造成的,但也可能由其它一些疾病引发。
谵妄的特点在于短时期内发生意识障碍和认知改变。痴呆则是智能和其它认知技能的长期衰退严重到妨碍其日常生活行为能力。尽管痴呆可能发生在任何年龄段,但主要还是发生在老龄阶段,超过15%的65岁以上的人,40%80岁以上的人都身患此症。疗养院收纳人员有一半以上是痴呆患者。阿尔茨海默氏病引发的痴呆就困扰着4百万美国人,平均每年为此花费约900亿美元,包括医疗和疗养院护理、社会公益服务、损失的生产力和早亡。在老年人中,超过65%的痴呆患者是阿尔茨海默氏病患者。
非阿尔茨海默痴呆患者包括卢伊体(Lewy body)痴呆、溢血性痴呆和宾斯万格氏痴呆(皮质下动脉硬化性脑病)。痴呆也可能出现在患有帕金森氏症、进行性核上麻痹、亨廷顿舞蹈病(舞蹈病)、皮克病、额叶痴呆综合症、拳击员痴呆、正常颅压脑积水、硬脑膜下血肿、克-雅综合症、格-施-沙病、麻痹性痴呆、艾滋病和精神分裂症的患者身上。
目前对于认知障碍的治疗包括促进胆碱能神经传导的化合物如杜尼匹次(donepezil)、雷司替名(rivastigmine)和他克林。这些试剂的应用由于其副作用而受到限制,该副作用包括使视觉或平衡发生变化、腹泻、头晕、昏厥或跌倒、尿频或失禁、神经质、激动、意识错乱增强、皮疹或荨麻疹、心跳减慢或心悸、胃痛、出汗、控制不住的运动、异常出血或碰伤、皮肤上出现红色或紫色部位、呕吐和体重减轻。另一种治疗方法就是施用氢麦角碱。而氢麦角碱治疗需要六个月的时间来确定其是否有效以及是否会产生恶心等副作用。
对于认知障碍的治疗,需要一些比目前所用治疗方法更为有效、更具耐受性的其它治疗方法。
本发明提供一种治疗认知障碍的方法,该方法包括对需要该种治疗的哺乳动物给予一种有效量的选择性去甲肾上腺素再摄取(reuptake)抑制剂。
本发明提供一种依赖新的作用机制治疗认知障碍的方法。该方法包括采用一种化合物,即选择性去甲肾上腺素再摄取抑制剂,治疗患有认知障碍的哺乳动物。这种作用机制对于哺乳动物是有效的,其中哺乳动物优选人。
本发明还提供选择性去甲肾上腺素再摄取抑制剂在制备用于治疗或预防认知障碍的药物中的应用。
本发明提供一种治疗认知障碍的方法。如本文所用的术语“认知障碍”,是指认知功能障碍谱(spectrum)从轻度认知损伤到智能和其它认知技能严重衰退到妨碍其日常生活行为能力。
许多化合物,包括下面详细讨论的化合物,均为选择性的去甲肾上腺素再摄取抑制剂,毫无疑问,将来还会确定出更多。在实施本发明的过程中,按照Wong等,药物发展研究(Drug Development Research),6,397(1985)记载的方案,要求包含显示50%有效浓度约1000nM或更低的去甲肾上腺素再摄取抑制剂。用于本发明方法的去甲肾上腺素再摄取抑制剂的特征在于,相对于其作为其它受体直接激动药或拮抗药的能力而言,对神经递质再摄取的抑制作用具有选择性。优选地,用于本发明方法的化合物相对于作为其它受体的直接激动药或拮抗药而言至少10倍的选择性抑制去甲肾上腺素再摄取。优选地,用于本发明方法的化合物相对于作为其它受体的直接激动药或拮抗药而言至少100倍的选择性抑制去甲肾上腺素再摄取。可用于本发明所述方法的去甲肾上腺素再摄取抑制剂包括,但不限于:
托莫西汀(Atomoxetine)(以前称之为tomoxetine),即(R)-(-)-N-甲基-3-(2-甲基苯氧基)-3-苯丙胺,通常以盐酸盐的形式给药。托莫西汀首次公开于美国专利US4314081。本文所用的术语“托莫西汀”是指该分子的任何酸加成盐或游离碱。参见,如Gehlert等,神经科学通讯(Neuroscience Letters),157,203-206(1993)中关于托莫西汀作为去甲肾上腺素再摄取抑制剂的活性的讨论;
通式I所示的化合物,或其药学上可接受的盐:
I
其中X是C1-C4烷硫基,Y是C1-C2烷基。式I化合物记载于Gehlert,Robertson和Wong的美国专利US5281624,以及Gehlert等,生命科学(Life Science),55(22),1915-1920(1995)。其中提到这些化合物是大脑中去甲肾上腺素再摄取的抑制剂。还阐述了该化合物是以立体异构体形式存在,因此不仅包括外消旋体,还包括分离后的单个异构体以及单个异构体的混合物。例如式I化合物包括下面的示例:
N-乙基-3-苯基-3-(2-甲硫基苯氧基)丙胺苯甲酸盐;
(R)-N-甲基-3-苯基-3-(2-丙硫基苯氧基)丙胺盐酸盐;
(S)-N-乙基-3-苯基-3-(2-丁硫基苯氧基)丙胺;
N-甲基3-苯基-3-(2-乙硫基苯氧基)丙胺丙二酸盐;
(S)-N-甲基-3-苯基-3-(2-叔丁硫基苯氧基)丙胺萘-2-磺酸盐;
(R)-N-甲基-3-(2-甲硫基苯氧基)-3-苯丙胺;和
瑞波西汀(EdronaxTM),即2-[α-(2-乙氧基)苯氧基苄基]吗啉,通常以外消旋体的形式给药。由美国专利US4229449首次报道,其中记载了它治疗抑郁症的作用。瑞波西汀是一种选择性的去甲肾上腺素再摄取抑制剂。本文所用的术语“瑞波西汀”是指其以外消旋体或任何一种对映体形式存在的该分子的任何酸加成盐或游离碱。
虽然所有具备去甲肾上腺素再摄取抑制作用的化合物均可用于本发明的方法,但有些是优选的。优选对去甲肾上腺素再摄取比其它神经递质再摄取更具选择性的去甲肾上腺素再摄取抑制剂。还优选对其它受体不具有显著的直接激动剂或拮抗剂活性的去甲肾上腺素再摄取抑制。特别优选的去甲肾上腺素再摄取抑制剂选自托莫西汀、瑞波西汀或(R)-N-甲基-3-(2-甲硫基苯氧基)-3-苯丙胺。托莫西汀在本发明方法中的应用是本发明最优选的实施方式。
本发明另外一个实施方式包括给予具有选择性去甲肾上腺素再摄取抑制剂活性的组合物。该组合物可由一种或多种试剂组成,所述试剂单独或合起来是去甲肾上腺素再摄取的选择性抑制剂。
本发明所用药物的剂量最终必须由主治医师运用药物知识、结合临床试验确定的组合药物性质和患者的特征包括并非医师正在治疗的疾病来确定。本文将给出这些药物一般的剂量和一些优选的剂量。
托莫西汀:对成人和年龄较大的青少年:约5mg/日~约200mg/日;优选约60~约150mg/日;更优选约60~约130mg/日;更优选约50~约120mg/日;对儿童和年龄较小的青少年:约0.2-约3.0mg/kg/日,优选约0.5~约1.8mg/kg/日;
式I化合物:约0.01mg/kg~约20mg/kg;优选日剂量为约0.05mg/kg~10mg/kg;理想剂量为约0.1mg/kg~约5mg/kg;
瑞波西汀:约1~30mg,每日一至四次;优选约5~30mg,一日一次。
很多其它疾病的患者也会出现认知障碍。本发明包括去甲肾上腺素再摄取抑制剂在治疗单一的或与其它疾病相关的认知障碍中的应用。例如精神分裂症患者通常就会表现出认知障碍等症状。因此,本发明的一个实施方式就是去甲肾上腺素再摄取抑制剂在治疗与精神分裂症有关的认知障碍中的应用。精神分裂症患者经常也表现出负性症状如乏力、无社会性、无反应性、无意志和快感缺乏。本发明另外一个实施方式就是去甲肾上腺素再摄取抑制剂在治疗精神分裂症负性症状中的应用。
本发明还提供一种对精神病患者或易患精神病的人进行治疗的方法,该方法包括对上述患者给予有效量的第一组分即抗精神病药,联合应用有效量的第二组分即去甲肾上腺素再摄取抑制剂。本发明还提供一种包含第一组分即抗精神病药和第二组分即去甲肾上腺素再摄取抑制剂的药物组合物。
本发明这方面总的来说,第一组分(component)就是作为抗精神病药的化合物,所述抗精神病药可以是典型性抗精神病药如氟哌啶醇,或非典型性抗精神病药。非典型性抗精神病药的必要特征就是相对于典型性抗精神病药如氟哌啶醇具有更轻微的与治疗有关的锥体束外综合征,尤其是张力失常。氯氮平,原型的非典型性抗精神病药,不同于典型性抗精神病药,具有以下特征:(1)在典型性抗精神病药对其无效的精神分裂症患者的整个精神病理学治疗过程中具有更好的效果;(2)对精神分裂症负性症状疗效更佳;和(3)更低频率和更少量地增加与治疗有关的血清促乳素浓度(Beasley等,神经心理药物学(Neuropsychopharma-cology),14(2),111-123,(1996))。虽然典型和非典型性抗精神病药均可用于本发明的这些方法和制剂,但是优选非典型性抗精神病药作为第一组分。
典型性抗精神病药包括,但不限于:
氯丙嗪,2-氯-10-(3-二甲氨基丙基)吩噻嗪,记载于美国专利US2645640。其药理学已经得到验证(Crismon,精神药理学公报(Psychopharma-col.Bul.),4,151(1967年10月);
氟哌利多,1-(1-[3-(p-氟苯甲酰)丙基]-1,2,3,6-四氢-4-吡啶基)-2-苯并咪唑啉酮,记载于美国专利US3141823;
氟哌啶醇,4-[4-(4-氯苯基)-4-羟基-1-哌啶基]-1-(4-氟苯基)-1-丁酮,记载于美国专利US3438991。其对精神病的疗效已有报道(Beresford和Ward,药物(Drugs),33,31-49(1987));
甲硫哒嗪,1-羟基-10-[2-(1-甲基-2-吡啶基)乙基]-2-(甲硫基)吩噻嗪盐酸盐,记载于Bourquin等,(Helv.Chim.Acta,41,1072(1958))。其作为抗精神病药已有报道(Axelsson等,Curr.Ther.Res.,21,587(1977));和
三氟拉嗪,10-[3-(4-甲基-1-哌嗪基)丙基]-2-三氟甲基吩噻嗪盐酸盐,记载于美国专利US2921069。
非典型性抗精神病药包括,但不限于:奥氮平,2-甲基-4-(4-甲基-1-哌嗪基)-10H-噻吩并[2,3-b][1,5]苯并二氮杂(benzodiazepine),是一种已知的化合物,并记载于美国专利US5229382中用于治疗精神分裂症、精神分裂症样疾病、急性躁狂、轻度焦虑状态和精神病。
氯氮平,8-氯-11-(4-甲基-1-哌嗪基)-5H-二苯[b,e][1,4]二氮杂,记载于美国专利US3539573。其治疗精神分裂症的临床效果也有记载(Hanes等,精神药理学公报(Psychopharmacol.Bull.),24,62(1988));
利培酮,3-[2-[4-(6-氟-1,2-苯并异噁唑-3-基)哌啶子基]乙基]-2-甲基-6,7,8,9-四氢-4H-吡啶并-[1,2-a]嘧啶-4-酮,其治疗精神病的应用记载于美国专利US4804663
舍吲哚,1-[2-[4-[5-氯-1-(4-氟苯基)-1H-吲哚-3-基]-1-哌啶基]乙基]咪唑烷基-2-酮,记载于美国专利US4710500。其治疗精神分裂症的应用记载于美国专利US5112838和5238945;
喹迪平(Quetiapine),5-[2-(4-二苯并[b,f][1,4]硫杂(thiazepin)-11-基-1-哌嗪基)乙氧基]乙醇,证实其治疗精神分裂症作用而测定的活性记载于美国专利US4879288。喹迪平通常以其(E)-2-丁烯二酸(2∶1)盐的形式给药。
齐拉西酮(Ziprasidone),5-[2-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]乙基]-6-氯-1,3-二氢-2H-吲哚-2-酮,通常以盐酸盐一水合物的形式给药。该化合物在美国专利US4831031和US5312925中已有记载。证实其治疗精神分裂症作用而测定的活性记载于美国专利US4831031。
同样地,本发明的这个方面从广义上来讲,第二组分就是上述起去甲肾上腺素再摄取抑制剂作用的化合物。
可以理解,虽然优选采用单一的抗精神病药作为第一组分化合物,但是如有必要,也可采用两种或多种抗精神病药的组合作为第一组分。同样地,虽然优选使用单一的去甲肾上腺素再摄取抑制剂作为第二组分化合物,但是如有必要,也可采用两种或多种去甲肾上腺素再摄取抑制剂的组合作为第二组分。
虽然第一组分和第二组分的所有组合均可适用且有价值,但是某些组合特别有价值且属优选,如下所示:
奥氮平/托莫西汀
奥氮平/瑞波西汀
奥氮平/(R)-N-甲基-3-(2-甲硫基苯氧基)-3-苯丙胺
氯氮平/托莫西汀
利培酮/托莫西汀
舍吲哚/托莫西汀
喹迪平/托莫西汀
齐拉西酮/托莫西汀
总之,优选采用奥氮平作为第一组分的治疗方法和组合物。此外,优选以托莫西汀作为第二组分的治疗方法和组合物。特别优选的是以奥氮平作为第一组分,托莫西汀作为第二组分的治疗方法和组合物。特别优选的,以奥氮平作为第一组分时,该奥氮平是如US5769541所述的II型奥氮平。
更优选的,II型奥氮平多晶型物是以基本纯的II型奥氮平多晶型物(polymorph)给药。本文所用的“基本纯的”是指型II中伴有低于约5%的形I,优选低于约2%的I形,更优选低于约1%的I形。而且,“基本纯的”II型包含低于约0.5%的有关物质,其中“有关物质”是指不希望存在的化学杂质或残余溶剂或水。具体而言,“基本纯的”II型应该包含低于约0.05%的乙腈,更优选的,低于0.005%的乙腈。此外,本发明的该多晶型物应包含低于0.5%的缔合水。
虽然优选II型奥氮平,但是应该可以理解,除非特别说明,本文所用的术语“奥氮平”包括所有的溶剂合物和多晶型奥氮平。
本领域技术人员应该可以理解,本发明所用的大部分或所有的化合物都能够形成盐,因为盐比游离碱更容易结晶和纯化,所以通常都是使用盐形药物。就一切情况而言,本文所描述的以盐的形式应用上述药物属于预期情况,通常也是优选的,所有化合物的药学上可接受的盐均在此范围内。特别优选的药学上可接受的盐是其与盐酸形成的盐。
本发明这方面所用第一组分药物的剂量最终必须由主治医师运用药物知识、结合临床试验确定的组合药物性质和患者的特征包括并非医师正在治疗的疾病来确定。本文可以并将在此给出这些药物的一般剂量和一些优选剂量。将首先分别给出一些药物的指导剂量,那么就可以选择每一种成份药物的指导剂量来得到任意期望组合的指导剂量。
氯丙嗪:约25-75mg/日~约75-150mg/日;
氟哌利多:注射约5mg;
氟哌啶醇:约1-15mg/日~约100mg/日口服或注射;
甲硫哒嗪:约75-150mg/日;
三氟啦嗪:约4-10mg/日~约15-20mg/日;
奥氮平:约0.25-50mg,1次/日;优选,1-30mg,1次/日;最优选1-25mg,1次/日;
氯氮平:约12.5-900mg/日;优选,约150-450mg/日;
利培酮:约0.25-16mg/日;优选约2-8mg/日;
舍吲哚:约0.0001-1.0mg/kg/日;
喹迪平:约1.040mg/kg,1次/日或分剂量;
齐拉西酮:约5-500mg/日;优选约50-100mg/日。
更概括地来说,可以根据上述指导准则的精神,通过选择第一组分和第二组分化合物的剂量来得到本发明的组合物。
通过第一组分与第二组分一起给药来实施本发明的附加治疗,其中可以采用任何同时在体内提供有效量化合物的方式给药。优选口服附加组合物。两种组分可以单独剂型一起给药,也可分别给药。但是口服不是唯一的途径,也不是唯一优选的途径。例如,健忘或不愿口服药物的患者可能就非常希望通过皮肤给药。在特定情况下,可通过皮下、静脉内、肌内、鼻内或直肠给药。根据药物的物理性质、患者和护理人员的方便以及其他相关情况(Remington′sPharmaceutical Sciences,18th Edition,Mack Publishing Co.(1990))可以任意改变给药途径。
附加组合物(adjunctive combination)可以单独的药物组合物形式给药,因此两种化合物混合的组合物是本发明重要的实施方式。这些组合物可呈药学上可接受的任何物理形式,但特别优选口服药物组合物。这些附加药物组合物包含有效量的每一种化合物,其有效量与给予化合物的日剂量有关。每个附加剂量单位可能包含日剂量的所有化合物,或者包含部分日剂量,如1/3剂量。可供选择的,每个剂量单位可能包含整个剂量的一种化合物和部分剂量的其它化合物。在这种情况下,患者每天要服用一个组合物剂量单位,和一个或多个仅含其它化合物的剂量单位。在每个剂量单位中所含每一种药物的量取决于选用来进行治疗的药物的同一性以及其它因素如进行附加治疗的适应症。
该药物组合物以药学领域公知的方法进行制备。其载体或赋形剂可以是能作为活性成分媒介物或介质的固体、半固体或液体物质。合适的载体或赋形剂是本领域公知的。该药物组合物可适于口服、吸入、非肠道给药或局部给药,也可以片剂、胶囊、气雾剂、吸入剂、栓剂、溶液、悬浮液等形式对患者给药。
例如,用于本发明方法的化合物可以利用惰性稀释剂或胶囊或压成片剂口服。为了便于口服治疗给药,该化合物可与赋形剂组合制成片剂、锭剂、胶囊、酏剂、悬浮液、糖浆剂、糯米纸囊剂、口香糖等形式。这些制品应该包含至少4%本发明的化合物,即活性成份,但可以根据具体形式在4%-约70%重量单位的范围内灵活变化。组合物中化合物的量就是以获得合适的剂量为准。用于本发明方法优选的组合物和制剂可由本领域普通技术人员确定。
所述片剂、丸剂、胶囊、锭剂等也可包含一种或多种下面的辅剂:可加入粘合剂如微晶纤维素、黄蓍树胶或明胶;赋形剂如淀粉或乳糖;崩解剂如褐藻酸、原生凝胶(Primogel)、玉米淀粉等;润滑剂如硬脂酸镁或氢化植物油(Sterotex);助流剂如胶态二氧化硅;和甜味剂如蔗糖或糖精;或者芳香剂如薄荷、水杨酸甲酯或桔子香料。剂量单位形式是胶囊时,除了上述材料外,其中还可包含液态载体如聚乙二醇或脂肪油。其它剂量单位形式可包含其它多种改变剂量单位物理形态的物质,例如,作为涂层。因此,片剂或丸剂可表面包糖、虫胶或其它涂布剂。除了本化合物以外,糖浆剂还可包含蔗糖作为甜味剂和某些防腐剂、染料、颜料和调味剂。用于制备上述各种组合物的物质应是药用纯度,且所用量的该种物质应无毒。
用于R-(-)-N-甲基3-((2-甲基苯基)氧基)-3-苯基-1-氨基丙烷盐酸盐(托莫西汀)给药的制剂包括R-(-)-N-甲基3-((2-甲基苯基)氧)-3-苯基-1-氨基丙烷盐酸盐与稀释剂和润滑剂的干混合物。淀粉,如预糊化玉米淀粉,是一种适用于硬明胶胶囊的稀释剂,硅油,如二甲基硅氧烷是一种合适的润滑剂。制备了包含约0.4-26%R-(-)-N-甲基3-((2-甲基苯基)氧)-3-苯基-1-氨基丙烷盐酸盐、约73-99%淀粉和约0.2-1.0%硅油的合适制剂。下表列出了特别优选的托莫西汀制剂:
组成(%) | 2.5mg | 5mg | 10mg | 18mg | 20mg | 25mg | 40mg | 60mg |
R-(-)-N-甲基3-((2-甲基苯基)氧)-3-苯基-1-氨基丙烷盐酸盐 | 1.24 | 2.48 | 4.97 | 8.94 | 9.93 | 12.42 | 19.87 | 22.12 |
二甲基硅氧烷 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
预糊化玉米淀粉 | 98.26 | 97.02 | 94.53 | 90.56 | 89.57 | 87.08 | 79.63 | 77.38 |
组成(mg/胶囊) | 2.5mg | 5mg | 10mg | 18mg | 20mg | 25mg | 40mg | 60mg |
R-(-)-N-甲基3-((2-甲基苯基)氧)-3-苯基-1-氨基丙烷盐酸盐 | 2.86 | 5.71 | 11.43 | 20.57 | 22.85 | 28.57 | 45.71 | 68.56 |
二甲基硅氧烷 | 1.15 | 1.15 | 1.15 | 1.15 | 1.15 | 1.15 | 1.15 | 1.15 |
预糊化玉米淀粉 | 225.99 | 223.14 | 217.42 | 208.28 | 206.00 | 200.28 | 183.14 | 239.89 |
胶囊填充重量(gm) | 230 | 230 | 230 | 230 | 230 | 230 | 230 | 310 |
胶囊尺寸 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 |
为了实现非肠道治疗给药,可以将本发明的化合物加入到溶液或悬浮液中。这些制品通常包含至少0.1%本发明的化合物,但可在其0.1-约90%重量的范围内变化。组合物中式I化合物的量就是以获得合适的剂量为准。该溶液或悬浮液还可包含一种或多种下述辅剂:无菌稀释剂如用于注射的水、盐水、不挥发性油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗菌剂如苄醇或羟苯甲酸甲酯;抗氧化剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲剂如醋酸盐、柠檬酸盐或磷酸盐,以及调节肌肉弹性的试剂如氯化钠或葡萄糖。非肠道注射产品可包封于由玻璃或塑料制成的安瓿、一次性注射器或多倍剂量的小瓶中。优选的组合物和产品可由本领域普通技术人员确定。
抑制或去甲肾上腺素再摄取
化合物抑制去甲肾上腺素再摄取的能力可通过Wong等(出处同上)中的常规方法进行测定。
将重150-250gm的雄性Sprague-Dawley大白鼠去头,并立即取出其脑组织。将大脑皮质在9倍体积含0.32M蔗糖和10mM葡萄糖的介质中匀浆。经过1000xg离心10分钟和17,000xg离心28分钟,差速离心后分离得到突触体粗制品。将最终的沉淀物悬浮于同样的介质中并保存在冰中至使用当天。
突触体再摄取的3H-去甲肾上腺素可通过如下方法进行测定。将皮质突触体(相当于1mg蛋白质)置于1mL Krebs-碳酸氢盐培养基中37℃下保温5分钟,该培养基中还含有10mM葡萄糖、0.1mM异丙异烟肼、1mM抗坏血酸、0.17mMEDTA和50nM 3H-去甲肾上腺素。立即将反应混合物用2mL冰冷的Krebs-碳酸氢盐缓冲液稀释并用细胞捕获器真空过滤。过滤器用约5mL冰冷的0.9%盐水冲洗2遍,通过液体闪烁计数估计再摄取的3H-去甲肾上腺素。可将4℃下3H-去甲肾上腺素的积聚物视为基底,并从所有的测量结果中减去该量。通过线性回归分析确定抑制50%3H-去甲肾上腺素积聚物(IC50值)所需试样化合物的浓度。
本发明提供一种治疗认知障碍的方法。患有多种疾病的患者都可能出现认知障碍。本发明的方法可用于治疗与分入诊断的精神病统计手册(第4卷,美国精神病治疗协会(DSM-IV)出版)的疾病有关的认知障碍。为方便读者,下面列出其DSM序列号。
一般医药条件引发的谵妄 293.0
未另作说明的谵妄 780.09
阿尔茨海默型痴呆
早期伴随谵妄 290.11
早期伴随妄想症 290.12
早期无并发症 290.10
晚期伴随谵妄 290.3
晚期伴随妄想症 290.20
晚期无并发症 290.0
溢血性痴呆
伴随谵妄 290.41
伴随妄想症 290.42
无并发症 290.40
艾滋病引发的痴呆 294.1
头部外伤引发的痴呆 294.1
帕金森氏症引发的痴呆 294.1
亨廷顿氏舞蹈病引发的痴呆 294.1
皮克病引发的痴呆 290.10
克罗伊茨费尔特一雅各病引发的痴呆 290.10
其它医疗条件引起的痴呆 294.1
未另作说明的痴呆 294.8
一般医疗条件引起的遗忘症 294.0
未另作说明的遗忘症 294.8
未另作说明的认知障碍 294.9
偏执型精神分裂症 295.30
错乱型精神分裂症 295.10
紧张型精神分裂症 295.20
未分化型精神分裂症 295.90
残留型精神分裂症 295.60
精神分裂症样疾病 295.40
分裂情感性疾病 295.70
有经验的技术人员非常清楚上述疾病例举了可能出现认知障碍的适应症,但绝不会限制本发明的范围。
采用本发明的附加治疗方法进行治疗的的精神病包括精神分裂症、精神分裂症样疾病、急性躁狂以及分裂情感性疾病。这种疾病的名称表示多种疾病状态。下面列举了多种这样的疾病状态,其中有些被分入了诊断的精神病统计手册,第4卷,美国精神病治疗协会(DSM)出版。为方便读者需要的时候可以得到,下面列出这些疾病状态的DSM序列号。
偏执型精神分裂症 295.30
错乱型精神分裂症 295.10
紧张型精神分裂症 295.20
未分化型精神分裂症 295.90
残留型精神分裂症 295.60
精神分裂症样疾病 295.40
分裂情感性疾病 295.70
本发明也适用于与更年期发作有关的认知障碍的治疗。
本发明的方法对于儿童、青少年或成人患者的治疗都很有效,不同年龄患者的症状和具体治疗方法上不存在显著差异。但一般来说,对本发明而言,儿童是指青春期以下年龄阶段的患者,青少年是指青春期到大约18岁年龄阶段的患者,成人则是18岁以上的患者。
实施例1
立即早期基因c-fos及其蛋白质产物已经日益广泛地用作神经元激活的标记物(Dragunow and Faull,J.Neurosci.Methods,29,261-265(1989);Morgan andCurran,Prog.In Brain Res.,86,287-294(1990);Robertson,et al.,J.Pharmacol.Exp.Ther.,271,1058-1066(1994)).对应用托莫西汀时C-fos的活化作用进行如下测定。
给予托莫西汀(3mg/kg,i.p.)两小时后,将大白鼠用戊巴比妥钠(60mg/kg,i.p.)深度麻醉,用100ml磷酸缓冲盐水(PBS)进行经心脏(transcardially)灌流,然后换用100ml含4%多聚甲醛的PBS。立即取下其大脑后置于4%多聚甲醛后固定90分钟,然后移至4℃下30%蔗糖中至饱和。快速冷冻后,切割成一系列30μm切片,并置于PBS中至进行免疫组织化学检查。简而言之,切片在包含封闭血清和0.5%Triton-X 100的PBS中浸泡1小时。然后将切片置于抗-Fos抗体(Santa CruzBiotechnology,Inc.)中4℃下浸泡一夜。利用Vectastain ABC Elite Kit(Vector Labs,Burlingame,CA)并根据该试剂盒提供的标准方法对Fos样免疫反应进行显色,采用镍增强二氨基联苯胺(DAB)作为嗜铬剂(chromagen)获得灰黑色的沉淀产物。Fos免疫反应显色后,再将切片固定到明胶涂敷的玻璃片上干燥。然后使该切片脱水,盖上盖片。利用MCID M2成像系统(Imaging Research,St.Catherines,Ontario)对表达Fos的细胞进行计数。
出人意料,通过下表的数据可以证实托莫西汀仅增加了c-fos在皮质区的表达。
治疗药品 | 前额皮质** | 伏隔核** | 纹状体** |
赋形剂 | 80±28 | 129±33 | 118±26 |
托莫西汀 | 296±26* | 152±44 | 102±35* |
*=p<0.001
**Fos正细胞数/mm2
Claims (7)
1.选择性去甲肾上腺素再摄取抑制剂在制备治疗认知障碍的药物中的应用。
3.根据权利要求2的应用,其中所述的选择性去甲肾上腺素再摄取抑制剂是托莫西汀。
4.根据权利要求2的应用,其中所述的选择性去甲肾上腺素再摄取抑制剂托莫西汀盐酸盐。
5.根据权利要求1-4中任一项的应用,其中被治疗的是痴呆引发的认知障碍。
6.根据权利要求1-4中任一项的应用,其中被治疗的是谵妄引发的认知障碍。
7.根据权利要求1-4中任一项的应用,其中被治疗的是精神分裂症引发的认知障碍。
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