CN1886127A - 用于治疗精神分裂性精神病的脱氧鸭嘴花碱的用途 - Google Patents
用于治疗精神分裂性精神病的脱氧鸭嘴花碱的用途 Download PDFInfo
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Abstract
游离碱形式或酸加成盐形式的脱氧鸭嘴花碱,或脱氧鸭嘴花碱的衍生物,只要所述的衍生物同时为乙酰胆碱酯酶和单胺氧化酶的抑制剂,可用于制备治疗精神分裂性精神病的药剂。
Description
技术领域
本发明涉及用于治疗精神分裂性精神病的脱氧鸭嘴花碱的用途,特别是涉及用于治疗精神分裂性精神病的包含该脱氧鸭嘴花碱的药物。
背景技术
精神分裂症是一种影响深远的内源性精神疾病(神经病),该疾病伴随有患者的思想、知觉和行为的变化。
在精神分裂性精神病的病例中,几乎各种精神功能都可能有变化。发生大量在所有精神分裂症患者中强度不同的症状。基本上,就精神分裂症而言,基本症状和副症状之间就有不同。
在由精神分裂性精神病直接导致的紊乱的基本症状中,是指思维过程的受阻、情感生活(感情)和驱动力的紊乱、真实性的丧失(自闭症)和所谓的“自我混乱”,其被理解为个人自身性格遭受分裂。
在副症状中,即可由精神分裂症患者伴随基本症状发展的疾病,是指妄想症、幻觉、呆板和狂妄症。
精神病患者丧失了与其它人理智和情感上交流的能力,也无法真实地理解正在发生的事情的涵义和重要性。实质在于精神分裂症患者不能将对应现实世界中的事件的原因及结果联想在一起的逻辑方式进行思考。例如,精神分裂症患者可能会有与现实缺乏联系的怪异妄想。精神分裂症患者还会有幻觉,且通常为幻听。
除了上述思考过程阻碍以外,大量的精神分裂症患者还伴随有严重情感缺陷(emotional impairments)的患者,并且这些患者通常缺乏并害怕与他人接触。
精神分裂症的上述症状应与情感失调相区别,情感失调不只是与精神分裂症有关。这些“非精神分裂症的”症状是指焦虑、紧张、激动、罪恶感、抑郁、定向障碍和心身失调(psychosomatic symptoms)症状。
在精神分裂症和其它情感失调中的症状类型非常相似且经常不能被区分开。因此,根据可以被容易观察到的具体行为模式的缺乏或出现,已经开发出用于精神分裂症诊断的具有特殊指导原则的目录分类。所以,根据(Deutsche Gesellschaft für Psychiatrie,Psychotherapie undNervenheilkunde(DGPPN))的指导原则,诊断精神分裂症必须包含下面症状组的至少一种明确的症状:
1、思维化声;思维插入或思维被夺,将自己的思维传播给别人;
2、被控妄想,被影响妄想、感觉已完成某事-与身体行动、思想、活动或知觉有关;诠释妄想;
3、评论或对话性声音;和
4、持续、缺乏修养(culturally inadequate)且完全非真实性的妄想;
或者必须包含下面症状组的至少两种症状:
5、所有感觉形态的持续的幻觉;
6、在思维流中思维阻碍或插入;
7、紧张性症状,如激动、姿势呆板;消沉或恍惚;和
8、“阴性”症状,如明显的冷漠、语言匮乏、单调(flattened)及不当的反应。
关于这一点必须考虑的是,精神分裂症状的病因也必须与其它症状发展的可能性区别开,例如毒品和药物滥用、脑部肿瘤和其它神经方面的疾病。
估计全世界1%的人口患有典型的精神分裂症,即,患有这种精神病形式的疾病,其症状严重而明显,所以在诊断上不会有疑义。
精神分裂性精神病的确切病因仍然未知,但传递神经信号的化学信使物质(神经递质)起到重要作用。过去认为精神分裂症是神经递质多巴胺的过量产生的结果。但是近来的研究表明多巴胺的部分信号转导途径过分活跃。这证明,例如,用于治疗精神分裂症的神经镇静药通过与突触后的多巴胺受体结合,从而消除了多巴胺在脑中的作用。
在大多数对应的研究中,相对于非精神分裂症先证者(proband),在精神分裂症患者中已发现降低的或不变的单胺氧化酶(monoaminoxidase)活性,其与过度活跃多巴胺信号转导通道的假说一致。通过与大多数研究比较,Lewine和Meltzer通过未给药的精神分裂症男性的血小板能够证明,阴性症状与单胺氧化酶的活性之间的明显的正相关(Lewine,R.J.和Meltzer;H.Y.,Psychiatry Res.12,99-109(1984))。Schildkraut和其助手也发现在遭受精神分裂症相关的抑郁患者的血小板中升高的单胺氧化酶活性(Schildkraut等,Schizophr.Bull.6,220-225(1980);Schildkraut等,Am J Psychiatry 135,110-112(1978))。
除上述情况外,最近从流行病学的分析和行为研究也认为神经元烟碱性受体(nAChRs)在包括精神分裂症的神经疾病的发病机理中起到重要作用。例如,已经报道了在精神分裂症中烟碱乙酰胆碱受体,且尤其是烟碱乙酰胆碱受体的α7亚型的降低被认为与精神分裂性障碍有关。这些发现引起了对烟碱乙酰胆碱受体的异构调节剂的关注,例如,用于治疗与烟碱乙酰胆碱受体功能或表达的变化有关的神经障碍的加兰他敏(galanthamine)(Deutsch,S.I.等,Life Sciences 73,2333-2361(2003))。
除心理治疗外,以抗精神病药,主要用神经镇静药进行药物治疗,构成了治疗精神分裂性精神病状的基础。通过施用精神病药物,可以减轻精神分裂症的症状。神经镇静药可以减轻紧张,并能够使患者面对他人而不产生妄想,所以对于超过50%的精神分裂症病人而言,预后结果良好。这些患者能够再次将自己溶入社会环境中,并也可以再次工作。但是,精神病药不能治愈精神分裂症。
另外,现有的药物疗法具有发生相当多的副作用的缺点。因而,神经镇静药具有一系列严重的副作用,例如运动障碍、非自主的肌肉痉挛、感觉迟钝、疲倦、缺乏动力、及体重增加,除了非自主的肌肉痉挛外,大部分副作用在停药后会消失,这是确实的,但发生这些副作用的情况也说明仍然需要具有更少副作用或其副作用不严重的更好的治疗药物,或者通过其不仅抑制精神分裂病的症状而且也能治愈疾病。
发明内容
因而本发明的目的是提供用于开发治疗精神分裂性精神病的改进的精神病药物的活性物质。
根据本发明,通过使用用于治疗精神分裂症的脱氧鸭嘴花碱或使用用于制备治疗精神分裂症的药物的脱氧鸭嘴花碱,从而实现该目的。
具体实施方式
脱氧鸭嘴花碱(1,2,3,9-四氢吡咯[2,1-b]喹唑啉)(1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline)是一种分子式为C11H12N2的生物碱,其存在于蒺藜科植物中。优选通过从叙利亚芸香(骆驼蓬(Peganum harmala))中分离或通过化学合成得到脱氧鸭嘴花碱。对于药学领域而言,可从文献,尤其是专利说明书中得知。
DE-A 199 06 978(对应WO 00/48582),公开了用于治疗毒瘾和药物依赖的基于脱氧鸭嘴花碱的药物。
DE-A 199 06 979(对应WO 00/48445),公开了用于治疗尼古丁依赖的基于脱氧鸭嘴花碱的药物。
DE-A 199 06 975(对应WO 00/48599),公开了用于治疗阿耳茨海默痴呆症(Alzheimer’s dementia)的脱氧鸭嘴花碱的应用。
DE-A 101 63 667(对应WO 03/053445),公开了用于治疗临床抑郁症的脱氧鸭嘴花碱的用途。
基于其药理学性质,脱氧鸭嘴花碱属于可逆性作用的胆碱脂酶抑制剂的组。脱氧鸭嘴花碱不仅可以抑制乙酰胆碱酯酶而且还可以抑制单胺氧化酶,这在上述公开文献中已普遍提及。在所有这些文献中脱氧鸭嘴花碱对单胺氧化酶的抑制作用被描述成为加强脱氧鸭嘴花碱抑制乙酰胆碱酯酶作用的单纯补充作用,而后者的抑制作用被认为是最重要的。
由于其双重作用机理,据说加兰他敏优选用于精神分裂症的治疗,或用于治疗精神分裂症的药物的制备,其中的精神分裂症与单胺氧化酶活性增加和/或烟碱乙酰胆碱受体、尤其是α7亚型的功能降低(活性降低或表达减少)有关。
脱氧鸭嘴花碱的给药可以为经口或非肠道式的。对于口服给药,可以使用已知的给药剂型,例如片剂、包衣片剂、胶囊、锭剂。例如饮用溶液的液体或半液体剂型也是适合的,在该情况中,药物以溶液或悬浮液的形式存在。可以使用的溶剂或悬浮剂为水、液体介质或药理学上可接受的油(植物或矿物油)。
含有脱氧鸭嘴花碱的药物优选制成缓释药物,其能够以可控的方式并在一段延长的时间中向身体传递该药物。
此外,根据本发明的脱氧鸭嘴花碱也可以由以下方式给药,直肠(例如,通过插入栓剂)、吸入(通过吸入具有特定浓度和微粒尺寸分布的气雾剂)、经皮(通过含活性物质的贴片、擦剂溶液、凝胶等)、经粘膜(通过口或鼻粘膜吸收的方式,活性物质通过在唾液中溶出释放进口腔,或者通过喷雾溶液等进入鼻腔)、以植入导管的方式(其被动渗透地释放活性物质,或通过微型泵等控制的方式释放活性物质)、经静脉注射、经肌肉注射或皮下注射和经脑室(intracerebroventricularly)的方式。
关于非肠道给药,根据本发明,可以使用经皮或经粘膜的剂型用于脱氧鸭嘴花碱的给药是有特别的优势的,特别是,在DE-A 199 06 977中具体描述的用于脱氧鸭嘴花碱的粘性经皮治疗系统(活性物质贴片)。这些方式能够以控制的方式在一段延长的时间内通过皮肤向接受治疗的患者传送药物。
根据本发明,脱氧鸭嘴花碱可以其游离碱和作为酸加成盐的形式用于治疗;优选的盐为盐酸脱氧鸭嘴花碱或氢溴酸脱氧鸭嘴花碱。另外,也可以使用其它药理学上可接受的酸的盐,例如柠檬酸盐、酒石酸盐或醋酸盐。
在文献中描述的代替脱氧鸭嘴花碱的衍生物也被认为具有相同作用,只要其同时为乙酰胆碱脂酶和单胺氧化酶的抑制剂。这些衍生物包括在Synthetic Communs.25(4),569-572(1995)中描述的7-溴脱氧鸭嘴花碱,以及在Drug Des.Disc.14,1-14(1996)中描述的7-卤素-6-羟基-5-甲氧基脱氧鸭嘴花碱,并且其通式为
7-溴-6-羟基-5-甲氧基脱氧鸭嘴花碱
7-氯-6-羟基-5-甲氧基脱氧鸭嘴花碱
7-氟-6-羟基-5-甲氧基脱氧鸭嘴花碱
7-碘-6-羟基-5-甲氧基脱氧鸭嘴花碱
也可进一步使用在Ind.J.Chem.24B,789-790(1985)中描述的脱氧鸭嘴花碱衍生物,即1,2,3,9-四氢-6,7-亚甲基二氧吡咯[2,1-b]喹唑啉(chinazoline)和2,3-二氢-6,7-二甲氧基吡咯[2,1-b]喹唑啉(quinazoline)-9(1H)-酮(2,3-dihydro-6,7-dimethyoxypyrrolo[2,1-b]quinazoline-9(1H)-on)。
根据本发明可用于脱氧鸭嘴花碱给药的药剂形式可以包括下面的一种或多种添加剂:
-抗氧化剂、增效剂、稳定剂;
-防腐剂;
-口味调整剂;
-着色剂;
-溶剂、溶解剂;
-表面活性剂(乳化剂、溶解剂、润湿剂、消泡剂);
-调节粘度和稠度的物质、凝胶形成剂;
-吸收促进剂;
-吸附剂、保湿剂、润滑剂;
-影响崩解及溶出的物质、填充剂(增量剂)、胶溶剂;
-延迟释放剂。
该列表并非限制性的,适合的生理上可接受的物质对本领域技术人员而言是已知的。
优选以药物制剂施用脱氧鸭嘴花碱,该制剂包含0.1~90%重量的药物,特别优选为2~20%的重量,在各情况中以游离的脱氧鸭嘴花碱计算。根据本发明所使用的含脱氧鸭嘴花碱的药物制剂可以对本领域技术人员而言公知的用量额外包含添加剂,例如非活性成分或辅料、赋形剂或载体、和/或稳定剂。
每天给药剂量优选在0.1~100mg的范围内,特别优选在10~50mg。其可以根据个人的需要适当地调节。
Claims (15)
1、脱氧鸭嘴花碱在制备用于治疗精神分裂性精神病的药剂中的用途,该脱氧鸭嘴花碱为游离碱形式或酸加成盐形式,或者其衍生物形式,只要所述衍生物同时为乙酰胆碱脂酶和单胺氧化酶的抑制剂。
2、根据权利要求1的用途,其特征在于,以游离的脱氧鸭嘴花碱计算,所述的药剂包含0.1~90%重量的活性物质脱氧鸭嘴花碱,优选为2~20%重量。
3、根据权利要求1或2的用途,其特征在于,所述的药剂具有缓释效果。
4、根据前述任意一项权利要求的用途,其特征在于,所述的药剂为可口服给药的药剂。
5、根据权利要求1至3任意一项的用途,其特征在于,所述的药剂为可非肠道给药的药剂。
6、根据权利要求5的用途,其特征在于,所述的药剂为可经皮给药的药剂。
7、脱氧鸭嘴花碱在治疗精神分裂性精神病中的用途,该脱氧鸭嘴花碱为游离碱形式或酸加成盐形式,或者其衍生物形式,只要所述衍生物同时为乙酰胆碱脂酶和单胺氧化酶的抑制剂。
8、根据权利要求7的用途,其特征在于,日给药剂量在0.1~100mg,优选在10~50mg范围内。
9、根据权利要求7或8的用途,其特征在于,脱氧鸭嘴花碱以药物制剂给药,按游离的脱氧鸭嘴花碱计算,该药物制剂包含0.1~90%重量,优选为2~20%的重量的活性物质。
10、根据权利要求9的用途,其特征在于,脱氧鸭嘴花碱以具有缓释效果的药物制剂给药。
11、根据权利要求9或10的用途,其特征在于,脱氧鸭嘴花碱为口服给药。
12、根据权利要求9或10的用途,其特征在于,脱氧鸭嘴花碱为非肠道给药。
13、根据权利要求12的用途,其特征在于,脱氧鸭嘴花碱为经皮给药。
14、根据前述任意一项权利要求的用途,其特征在于,所述的精神分裂性精神病与单胺氧化酶活性增加和/或烟碱乙酰胆碱受体,尤其是α7亚型,的功能降低(活性降低或表达减少)有关。
15、根据前述任意一项权利要求的用途,其特征在于,所述的脱氧鸭嘴花碱衍生物,只要该脱氧鸭嘴花碱衍生物同时为乙酰胆碱脂酶和单胺氧化酶的抑制剂,选自包含以下物质的组:7-溴脱氧鸭嘴花碱、7-溴-6-羟基-5-甲氧基脱氧鸭嘴花碱、7-氯-6-羟基-5-甲氧基脱氧鸭嘴花碱、7-氟-6-羟基-5-甲氧基脱氧鸭嘴花碱、7-碘-6-羟基-5-甲氧基脱氧鸭嘴花碱、1,2,3,9-四氢-6,7-亚甲基二氧吡咯[2,1-b]喹唑啉和2,3-二氢-6,7-二甲氧基吡咯[2,1-b]喹唑啉-9(1H)-酮。
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