CN107213159A - Nadph在制备抗焦虑药物中的应用 - Google Patents
Nadph在制备抗焦虑药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明属于药品或保健品领域，具体涉及NADPH在制备抗焦虑药物中的应用。本发明通过研究发现，NADPH可以显著提高探索兴趣，显著降低大鼠的焦虑水平，逆转对慢性应激造成的焦虑样表现。这表明，NADPH具有抗焦虑的作用，可以作为潜在的预防或治疗广泛性焦虑障碍的药物。
Description
技术领域
本发明属于药品或保健品领域，具体涉及NADPH在制备抗焦虑药物中的应用。
背景技术
焦虑症是一种以急性焦虑反复发作为特征的神经官能症，包括广泛性焦虑及发作性惊恐状态等6种临床表现形式，常伴有头晕、胸闷、心悸、呼吸困难、口干、尿频、尿急、出汗、震颤和运动性不安以及睡眠障碍等，并伴有植物神经功能紊乱。焦虑症不仅直接影响人们的生活质量和身心健康,而且还可引起其他性质的疾病，如恐惧症、疑病症、神经衰弱等精神性疾病。随着现代社会的发展，人们的生活节奏普遍加快，人们将面临来自于社会、生活和工作等方面的压力，因此患焦虑症的人数呈增多趋势。无论是焦虑症或焦虑状态，临床上多用抗焦虑药物治疗，以苯并二氮卓类、丁螺环酮及其类似物为主。
还原型烟酰胺腺嘌呤二核苷酸磷酸(triphosphopyridine nucleotide，NADPH)由葡萄糖经过磷酸戊糖途径(PPP)代谢产生，作为细胞内最为重要的电子供体和生物合成的还原剂，可为还原性生物合成提供氢离子。NADPH是谷胱甘肽(GSH)的还原酶的辅酶，可使氧化型谷胱甘肽(GSSG)生成还原型GSH，维持还原型的GSH的正常含量。GSH是细胞内重要的抗氧化剂，可保护一些含巯基的蛋白质、脂肪和蛋白酶类免受氧化剂的破坏，特别在维持红细胞膜的完整性方面起着重要作用。NADPH除了参与胆固醇、脂肪酸、单加氧酶系、类固醇激素等的生物合成，还参与体内羟化反应和药物、毒物及某些激素的生物转化。例如，NADPH可利用解毒细胞的电子供体，通过体内代谢减少生物体氧化型化合物，维持其氧化还原的平衡，在氧化防御系统发挥重要作用。NADPH也可以借助于异柠檬酸穿梭作用进入呼吸链产生ATP：由于线粒体内膜对物质的通透性很低，线粒体外产生的NADPH不能直接进入呼吸链被氧化。NADPH上的H可以在异柠檬酸脱氢酶的作用下被交给NAD+，然后由NAD+进入呼吸链产生能量。细胞能量代谢的维持和减少ROS(活性氧簇)对细胞生存，特别对缺血缺氧的组织至关重要，普遍认为能量代谢障碍和氧化应激是心脑缺血疾病的重要机制，研究表明增加细胞能量代谢能力，降低细胞ROS产生可减轻缺血缺氧引起的细胞损伤。
目前，尚无NADPH用于焦虑症治疗的报道。
发明内容
为此，本发明提供NADPH在制备抗焦虑药物中的应用。
为解决上述技术问题，本发明是通过以下技术方案来实现的：
本发明提供NADPH在制备抗焦虑药物中的应用。
本发明提供NADPH在预防或治疗焦虑中的应用。
优选地，本发明上述应用，所述焦虑为广泛性焦虑障碍。
进一步优选地，本发明上述应用，所述药物包括药学上有效量的NADPH和药学上可接受的载体。
进一步优选地，本发明上述应用，所述载体选自常用的药用辅料、或者生理盐水、或者蒸馏水。
进一步优选地，本发明上述应用，所述药物为NADPH按照常规工艺，加入常规辅料制成临床上可接受的片剂、胶囊剂、散剂、合剂、丸剂、颗粒剂、糖浆剂、贴膏剂、栓剂、气雾剂、软膏剂或注射剂。
所述药学上可接受的辅料为：填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等；崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素纳等；润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等；助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等；粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等；矫味剂包括：甜味剂及各种香精；防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等；基质包括：PEG6000、PEG4000、虫蜡等。
进一步优选地，本发明上述应用，所述药物的给药方式选自口服给药、注射给药、舌下给药、直肠给药、经皮给药、喷雾吸入中的至少一种。
本发明的技术方案具有如下优点：
本发明通过研究发现，NADPH可以显著提高探索兴趣，显著降低大鼠的焦虑水平，逆转对慢性应激造成的焦虑样表现。这表明，NADPH具有抗焦虑的作用，可以作为潜在的预防或治疗广泛性焦虑障碍的药物。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍：
图1为本发明实验例1中旷场实验的实验结果，其中：与空白对照组相比，*P＜0.05，P＜0.01；与模型对照组相比，#P＜0.05，##P＜0.01；
图2为本发明实验例1中新奇抑制摄食实验的实验结果，其中：与空白对照组相比，*P＜0.05；与模型对照组相比，#P＜0.05。
具体实施方式
实施例1NADPH胶囊剂的制备
本实施例NADPH胶囊剂的组成为：NADPH 20g，助悬剂微晶纤维素60g，防腐剂叔丁基-4-羟基苯甲醚0.04g，润滑剂硬脂酸镁2g，填充剂乳糖加至200g。
其制备方法包括以下步骤：分别称取上述处方量的NADPH和各药用辅料，混合均匀，60目筛过筛3次，装入胶囊壳，即得。
实验例1NADPH对应激焦虑模型大鼠的抗焦虑作用研究
1、实验目的
研究NADPH的抗焦虑作用。
2、实验方法
2.1实验试剂与动物
NADPH，购自碧云天，纯度≥97％；NADPH用0.9％的生理盐水溶解，置于4℃冰箱避光保存，现配现用；
健康雄性3月龄SpragueDawley(SD)大鼠40只，体重250±15g，由苏州大学实验动物中心提供。
动物首先在光照时间8:00AM-8:00PM，室温22±2.5℃，相对湿度45％-55％的环境下适应性饲养1周，自由进食进水，为减少非实验因素对结果的影响，每日抚摸动物数次，以使其适应实验人员的操作。
2.2实验分组和给药方法
2.2.1实验分组
所有动物进行为期一周的糖水实验筛选，剔除对糖水偏爱测试极不敏感的大鼠，采用旷场试验测试5min内的大鼠的活动情况，将过于兴奋或安静的的大鼠筛除，再将筛选过后的大鼠按体重随机分为4组，分别为空白对照组、模型对照组、实验组1组、实验组2组，每组10只。
空白对照组每3-4只为一笼喂养，其他3组动物每只单笼喂养，所有的给药和行为学测试时间在上午8点至12点间进行。
2.2.2给药方法
实验组1组和实验组2组分别在每天上午9点给予NADPH4mg/kg、8mg/kg腹腔注射给药，腹腔注射体积为0.01mL/g体重，连续给药8周。
空白对照组和模型对照组均给予等体积的生理盐水。
2.3建模方法
慢性不可预料应激模型是目前最能结合表面效度、结构效度、预测效度复制做出的焦虑症模型，是观察焦虑发病机理、评价抗焦虑化学试剂的有效性的常用方法。
除空白对照组外，其他各组均建模。
参照文献，空白对照组动物除特定行为学实验需要与模型组动物饲养在同一个房间之外，其余时间均饲养在单独的房间里，由实验人员每隔两天抚摸五分钟，一方面减少焦虑模型组动物对对照动物潜在的干扰，一方面减少由实验人员操作对动物产生的影响；模型对照组动物每天遭受一种模拟人类社会环境中会出现的应激，刺激方式包括束缚、噪音、强光、频闪灯、食物剥夺、水分剥夺、倾斜鼠笼、足底电击、高温刺激、冷水刺激、颠倒日夜周期、夹尾等，这些应激是慢性且不可预料的，且同种刺激两天之内不重复出现。
各种刺激的具体操作如下：
束缚：大鼠被强制塞进一个与之体积差不多大的白色PVC圆柱体瓶子中(19cm高×9cm底面直径)束缚1h，然后被放回原来的笼子里；
白噪音：使用刺激分贝为110Db的噪声录音刺激2h，扬声器距离动物30cm；
频闪灯：使用频闪灯照射3h(每秒1次)；
食物剥夺：撤去大鼠饲料，禁食时间为前一天上午8点至次日上午8点；
水分剥夺：23小时分水剥夺后，空瓶放置1h，共计24h；
倾斜鼠笼：鼠笼倾斜45°，持续3h；
强光照射：冷光灯持续照射2h；
足底电击：将大鼠限制于特制的箱子中，给箱底通电，电压为25V，每隔1min刺激1次，每次持续刺激15s，共30次；
高温拥挤：将大鼠(7-9只1笼，除去水瓶)放于40°培养箱中，持续1h；
冷水刺激：将大鼠放于装有4°冷水的水箱中游泳10min，水深以大鼠既可以脚触地又可以游起来为宜；
颠倒日夜周期：前一天上午8点至当日上午8点白天将大鼠置于黑暗无光的环境中，在当日上午8点至次日上午8点将大鼠置于光照充足的环境中；
夹尾：用带弹簧的塑料夹子夹于动物尾巴末端1cm处持续夹尾1min(注意力度不能过大以夹破鼠尾)；
震荡拥挤环境：将5只大鼠放置在一个小盒子中在摇床上以240Hz的速度水平摇晃1小时。
2.4行为学实验
2.4.1旷场实验
旷场实验(Open field test，OFT)是用来观察实验动物神经精神变化、评价动物进入开阔环境后的各种活动、探索行为与紧张度的一种方法。
啮齿类实验动物的焦虑情绪主要基于其探索本性与外界环境的矛盾冲突，可分为状态焦虑和特质焦虑2类，其中OFT是评价啮齿类实验动状态焦虑行为的经典方法。通常，抗焦虑药物可明显增加OFT中央区(Ctime％，Ccross％)探索活性比例。
敞箱装置为无盖的立方体(100cm×100cm×42cm)，由不透明材料制成，底面的正方形被等分成4×4个等边方格，底面中央区域的正上方固定有摄像机，旷场实验视频分析系统与之相连接，可自动记录大鼠的活动轨迹和位置。实验在安静的环境下进行，由固定的实验员将每只大鼠放入箱内底面中心的方格内，与此同时由另一名实验员操作软件进行摄像和计时，观察大鼠5分钟内在中央格停留的时间(The time in the central square)、穿越的格子数(The number of crossing squares，四爪均进入的方格方可计数，为水平运动得分)、两前爪腾空或攀附墙壁使后肢直立的次数(The times of rearing，为垂直运动得分)、理毛次数(The times of grooming)和粪便粒数。
实验后，实验员将大鼠取出，清理干净箱底和四壁，并用75％的酒精擦拭以除去前一只大鼠的气味，更换大鼠，继续实验。
2.4.2新奇抑制摄食实验
新奇抑制摄食实验(novelty-suppressed feeding test，NSFT)是观察动物禁食后在饥饿状态下想要摄食的欲望和进入中央明亮区域的恐惧相矛盾冲突的行为，是观察给予抗焦虑药物后对动物的焦虑样行为和神经发生相关的行为影响的有效方法，以摄食潜伏期作为判定药物的抗焦虑的指标。该模型目前被广泛应用于抗焦虑药物的长期效应评价。
实验方法参照文献，具体如下所示：大鼠禁食24h(不禁水)之后，由固定的实验员将大鼠放入木制的顶部开放的旷场实验箱(敞箱大小为：76.5cm×76.5cm×40cm)，底部中央摆放一小部分食物，敞箱正上方架有一台摄像机，放入动物的同时开始摄像，记录大鼠8min内开始摄食的潜伏期(摄食的判定标准是动物开始咀嚼食物，而不是仅仅嗅闻或摆弄食物)，若8min仍未摄食的大鼠，摄食潜伏期记为8min。
实验测试环境为不同于饲养环境的全新环境，测试环境的光线强度大于饲养环境，测试时应尽量保持安静，每次放鼠的位和方向保持一致，每做完一只鼠清理粪便并以75％的酒精擦拭以减少动物留下的气味，实验员将动物放回原来的鼠笼子里，大鼠在笼子里1小时的食物摄入量也做为一个参考。
2.5数据统计处理
所有的结果均以平均值±标准差表示，各组件的数据比较用one-wayANOVA，P＜0.05被认为差异具有统计学意义。
3、实验结果
3.1旷场实验的实验结果
旷场实验的实验结果如图1所示。
由图1可知，(1)与空白对照组相比，模型对照组大鼠的水平得分、垂直得分、穿越中央格次数、中央格停留时间显著减少(P＜0.05、P＜0.05、P＜0.05、P＜0.05)，粪便粒数显著增多(P＜0.05)；
(2)与模型对照组相比，实验组2组大鼠的水平得分(P＜0.05)和垂直得分(P＜0.01)显著增加，穿越中央格的次数(P＜0.01)显著增加，在中央各停留的时间(P＜0.05)显著延长，这表明实验组2组大鼠的探索兴趣显著提高；
(3)与空白对照组相比，实验组1组和实验组2组大鼠的粪便粒数明显减少(P＜0.05、P＜0.05)，这表明实验组1组和实验组2组大鼠的焦虑水平显著降低。
3.2新奇抑制摄食实验的实验结果
新奇抑制摄食实验的实验结果如图2所示。
由图2可知，(1)在陌生环境中，与空白对照组相比，模型对照组大鼠的摄食潜伏期显著延长(P＜0.05)，显示出应激组大鼠焦虑样表现，对陌生环境表现为矛盾冲突样恐惧，探究行为明显减弱；
(2)与模型对照组相比，实验组2组大鼠的摄食潜伏期显著缩短(P＜0.05)，这表明实验组2组大鼠的慢性应激造成的焦虑样表现有所逆转。
4、实验结论
NADPH具有抗焦虑的作用，可以作为潜在的预防或治疗广泛性焦虑障碍的药物。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (7)
1.NADPH在制备抗焦虑药物中的应用。
2.NADPH在预防或治疗焦虑中的应用。
3.根据权利要求1或2所述的应用，其特征在于，所述焦虑为广泛性焦虑障碍。
4.根据权利要求1-3任一项所述的应用，其特征在于，所述药物包括药学上有效量的NADPH和药学上可接受的载体。
5.根据权利要求4所述的应用，其特征在于，所述载体选自常用的药用辅料、或者生理盐水、或者蒸馏水。
6.根据权利要求1-5任一项所述的应用，其特征在于，所述药物为NADPH按照常规工艺，加入常规辅料制成临床上可接受的片剂、胶囊剂、散剂、合剂、丸剂、颗粒剂、糖浆剂、贴膏剂、栓剂、气雾剂、软膏剂或注射剂。
7.根据权利要求1-6任一项所述的应用，其特征在于，所述药物的给药方式选自口服给药、注射给药、舌下给药、直肠给药、经皮给药、喷雾吸入中的至少一种。
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| CN109846900A (zh) * | 2018-05-25 | 2019-06-07 | 四川大学 | 还原型烟酰胺腺嘌呤二核苷酸磷酸在制备抗病毒药物中的用途 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1713916A (zh) * | 2002-11-19 | 2005-12-28 | 奴洛皮亚生态营养医学研究有限公司 | 含有nadh/nadph的组合物 |
| CN103340890A (zh) * | 2013-06-08 | 2013-10-09 | 苏州人本药业有限公司 | Nadph作为制备用于防治脑缺血性中风药物方面的应用 |
| WO2016176437A1 (en) * | 2015-04-28 | 2016-11-03 | Newsouth Innovations Pty Limited | Targeting nad+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1713916A (zh) * | 2002-11-19 | 2005-12-28 | 奴洛皮亚生态营养医学研究有限公司 | 含有nadh/nadph的组合物 |
| CN103340890A (zh) * | 2013-06-08 | 2013-10-09 | 苏州人本药业有限公司 | Nadph作为制备用于防治脑缺血性中风药物方面的应用 |
| WO2016176437A1 (en) * | 2015-04-28 | 2016-11-03 | Newsouth Innovations Pty Limited | Targeting nad+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity |
Non-Patent Citations (1)
| Title |
|---|
| FENG LIU等: "The link between angiotensin II-mediated anxiety and mood disorders with NADPH oxidase-induced oxidative stress", 《INT J PHYSIOL PATHOPHYSIOL PHARMACOL》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846900A (zh) * | 2018-05-25 | 2019-06-07 | 四川大学 | 还原型烟酰胺腺嘌呤二核苷酸磷酸在制备抗病毒药物中的用途 |
| CN109846900B (zh) * | 2018-05-25 | 2021-07-23 | 四川大学 | 还原型烟酰胺腺嘌呤二核苷酸磷酸在制备抗病毒药物中的用途 |
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