CN1372933A - N－乙酰－d－氨基葡萄糖在制备防治晕动病药物中的应用 - Google Patents
N－乙酰－d－氨基葡萄糖在制备防治晕动病药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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Abstract
本发明公开了N－乙酰－D－氨基葡萄糖在制备防治晕动病的药物中的应用。以N－乙酰－D－氨基葡萄糖为主要活性成分的制剂可用于预防或治疗晕动病,有效率可达90%以上。
Description
本发明涉及N-乙酰-D-氨基葡萄糖在制备防治晕动病(motionsickness)的药物中的应用。
晕动病是晕车、晕船、晕机和由摇摆、颠簸、旋转、加速运动等各种因素所致疾病的统称。本病常在乘车、航海、飞行和其他运行数分钟至数小时后发生。先感上腹不适，继有恶心、面色苍白、出冷汗；后有眩晕、精神抑郁、唾液分泌增多、呕吐。可有血压下降、呼吸深而慢、眼球震颤。严重的呕吐引起脱水和电解质紊乱。症状一般在停止运行或减速后数十分钟和几小时内消失或减轻，亦有持续数天后才逐渐恢复，并伴有精神萎靡、四肢无力。重复运行或加速运动后，症状又可出现。
此病主要与影响前庭功能有关。前庭器的内耳膜迷路的椭圆囊和球囊的囊斑毛细胞主要感受上下和左右的直线运动，三个半规管的壶腹嵴毛细胞主要感受旋转运动。每个毛细胞有许多静纤毛和一根动纤毛，它们又被糖蛋白、粘多糖组成的胶质膜所覆盖。胶质膜(壶腹帽、位砂膜)与纤毛相互作用，构成位觉感受器。旋转运动或直线运动发生或停止时，内淋巴的位移导致胶质膜位移，对纤毛施加刺激，毛细胞产生的兴奋通过前庭神经传入脑，产生位觉。正常人毛细胞的纤毛摆动是混沌节律，因此，很容易与外界运动引起的无规律刺激相耦合并适应。而晕动病患者毛细胞的纤毛摆动是准周期的，难以与外界运动引起的无规律刺激相耦合，导致毛细胞持续兴奋，依次由前庭神经传到前庭神经核，再传到小脑和下丘脑，引起一系列的临床症状。前庭受刺激后影响网状结构，引起血压下降和呕吐；前庭神经核通过内侧纵束纤维至眼肌运动核引起眼球震颤；小脑和下丘脑受神经冲动后引起全身肌肉张力的改变。小脑受刺激也可能是本病的又一机制。
目前对晕动病的防治尚无较好的办法，主要用抗组胺类和颠茄类药，或采用止吐药(如胃复安)、镇静药(如苯巴比妥)。这些药的副作用大，并且给旅游、生活带来诸多不便。
本发明的目的是提供一种新型的预防或治疗晕动病的方法和药物。
本发明人现令人惊异地发现N-乙酰-D-氨基葡萄糖和其药物可接受的盐能有效地预防和治疗晕动病。由于N-乙酰-D-氨基葡萄糖没有毒副作用且疗效独特，不影响旅游和生活，因而可长期、广泛地使用。
因此本发明涉及一种预防或治疗晕动病的方法，包括给予需要的患者预防或治疗有效量的N-乙酰-D-氨基葡萄糖或其药物可接受的盐。
本发明涉及N-乙酰-D-氨基葡萄糖和其药物可接受的盐在制备防治晕动病的药物中的应用。
本发明人在进行“生物波”理论的研究过程中，建立了细菌波动生长模型。经过研究认识到这种波动有其内在的调节机制：某些化学物质参与生物波动过程的调节，把病态的周期性慢波转变成正常的生理性混沌快波，这类物质称为促波因子。经分离提纯和鉴定，确定有一种因子为N-乙酰-D-氨基葡萄糖，其促波作用与其对细胞的润滑和保护作用有关。人体的许多生化和生理过程需要促波因子的参与，当体内这种促波因子缺乏时则会导致异常状况。
N-乙酰-D-氨基葡萄糖，分子式：C8H15NO6，结构表示如下：
N-乙酰-D-氨基葡萄糖可以在市场上买到或可以按已知方法制得。例如，专利申请WO97/31121公开了一种从壳多糖酶法制备N-乙酰-D-氨基葡萄糖的方法。日本专利申请JP63273493公开了一种将壳多糖部分酸水解为N-乙酰-壳寡糖，然后用酶处理得到N-乙酰-D-氨基葡萄糖的方法。
在N-乙酰-D-氨基葡萄糖的药物可接受的盐中，可提及与药物可接受的酸形成的那些，例如与无机酸形成的那些，如盐酸盐、氢溴酸盐、硼酸盐、磷酸盐、硫酸盐、硫酸氢盐和磷酸氢盐，以及与有机酸形成的那些，如柠檬酸盐、苯甲酸盐、抗坏血酸盐、甲基硫酸盐、萘-2-磺酸盐、苦味酸盐、富马酸盐、马来酸盐、丙二酸盐、草酸盐、琥珀酸盐、乙酸盐、酒石酸盐、甲磺酸盐、甲苯磺酸盐、羟乙磺酸盐、α-酮戊二酸盐、α-甘油磷酸盐和葡萄糖-1-磷酸盐。
二十世纪九十年代以来该化合物陆续被用于治疗牙周炎(WO9102530A1)、微生物感染(WO9718790A3)、炎性肠病(WO9953929A1)、角膜疾病(JP10287570A2)、前列腺肥大(US05116615)、下消化道粘膜器质性病变(WO93/14765)等疾病以及美容(JP59013708A2)、洗发制剂(JP2011505A2)、组织生长调节剂(WO/8702244)等。目前尚无在制备治疗晕动病药物方面的应用。
本申请人现发现N-乙酰-D-氨基葡萄糖可以有效地预防和治疗晕动病，由于N-乙酰-D-氨基葡萄糖的毒副作用很小，因而用其防治晕动病可以避免现有晕动病药物的不利副作用，并可以根据需要以小剂量长期治疗或以大剂量进行临时的短期防治。
为了用于晕动病的防治，可以单独使用N-乙酰-D-氨基葡萄糖或与药学上可接受的赋形剂或/和载体结合制成药物制剂使用。这种制剂可以是任何便于给药的常规形式，优选为液态或固态的口服制剂。可以采用常规的方法制备药学上适宜制剂形式的药物组合物，例如混合、粒化、成片、糖包衣和膜包衣等方法。口服用的液态形式的制剂可以以无菌水或无菌盐水为载体，还可以以酒精饮料如酒类为载体。在一个优选实施方案中，N-乙酰-D-氨基葡萄糖在酒精饮料中的浓度为0.1-4％(重量)。固体口服制剂，例如片剂或胶囊，除N-乙酰-D-氨基葡萄糖外，还可包括稀释剂，如乳糖、葡萄糖、纤维素、淀粉；润滑剂，如硅、滑石、硬脂酸镁或钙和或聚乙二醇；粘接剂，如淀粉、阿拉伯树胶、甲基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮；解聚剂，如淀粉、藻酸、藻酸盐、淀粉甘醇酸钠；起泡混合物；着色剂；甜味剂；润滑剂，如卵磷脂、多乙氧脂醚等。
优选地，所述药物以每日口服1000-10000mg N-乙酰-D-氨基葡萄糖的剂量从乘坐车、船、飞机前2-3天起至旅途结束给予需要的患者，用于晕动病的短期预防或治疗。
同样优选地，所述药物以每日口服200-2000mg N-乙酰-D-氨基葡萄糖的剂量给予需要的患者，用于晕动病的长期预防或治疗。
更优选地，以酒精饮料为载体的药物以每日口服200-1000mg N-乙酰-D-氨基葡萄糖的剂量从乘坐车、船、飞机前2-3天起至旅途结束给予需要的患者。
虽无意拘于任何理论，但申请人认为，晕动病实质上是一种振荡失耦合疾病。N-乙酰-D-氨基葡萄糖作为一种生物波调控因子，对生物波动具有广泛调节作用。它可能通过以下三个方面发挥防治晕动病的作用：(1)调节内耳毛细胞纤毛的节律性波动。毛细胞纤毛群体的摆动具有节律性，是可以调节的。而N-乙酰-D-氨基葡萄糖可以将患者毛细胞纤毛摆动的准周期波动调整为混沌波动，使其易于与外界的非节律运动相耦合，从而提高患者对外界运动的适应力。(2)调节壶腹帽和位砂膜的粘度。壶腹帽和位砂膜均是糖蛋白为主构成的胶质膜，它们传递外界的运动而对毛细胞纤毛产生作用。N-乙酰-D-氨基葡萄糖是形成糖蛋白的基本前体物质，它可促进毛细胞分泌糖蛋白，从而增加胶质膜的粘度。粘度增加可加强胶质膜与纤毛之间的耦合，有利于纤毛摆动与外界运动的耦合。(3)调节植物神经、前庭神经的兴奋性。N-乙酰-D-氨基葡萄糖能调节神经细胞及其网络的波动，将毛细胞传到前庭神经、小脑、下丘脑、植物神经的持续性单一波动调整为分形的混沌波动，使植物神经、迷走神经的活动受到扰动后仍能趋于吸引点(稳态)，从而缓解或消除恶心、呕吐、面色苍白、出冷汗、眩晕、血压下降、眼球震颤等症状。
以下试验实施例用以说明N-乙酰-D-氨基葡萄糖(NAG)的促波特性、低毒特性和防治晕动病的有效性。
一、N-乙酰-D-氨基葡萄糖的促波试验
1.实验材料和方法：
1.1.样品：N-乙酰-D-氨基葡萄糖纯品。
1.2.实验材料：
菌种：奇异变形杆菌(应符合如下生化反应特征：动力(+)、尿素酶(+)、乳糖(-)、葡萄糖(+)、H2S(-)、苯丙氨酸脱氨酶(+)。
培养基：改良LB培养基(组成成份为：1％胰蛋白胨、0.5％酵母提取物、1％氯化钠、0.1％葡萄糖、0.002％TTC、PH7.2-7.4)。
1.3.实验方法：
在LB平板中心点种奇异变形杆菌，37℃培养9小时，开始出现不断向外扩展间隔3小时的同心环，以此作为对照；在LB平板中加入终浓度为0.5％式(I)化合物同法点种奇异变形杆菌，37℃培养，结果不但形成每隔3小时出现的同心环，而且与对照相比，可见在每条环上有许多细小的波动也表现出来。
2.实验结果及评价：
本实验采用生物波动模型，用以研究NAG的促波作用，结果可见NAG不仅可以使细菌细胞表现正常的生物波特征，而且使这种波动表现出更加微细的波动方式，使波动周期缩短，表明NAG对生物波动有促进作用，这种促波作用可调节内耳毛细胞和神经系统神经冲动传导的耦合振荡波动过程。
二、式(I)化合物的毒理试验包括：
1.急性毒性试验：包括口服、静脉注射和最大极限量给药试验；
2.Ames试验；
3.小鼠骨髓细胞微核试验；
4.鼠精子畸性试验
5.小鼠睾丸染色体畸变试验；
6.慢性致死试验；
7.亚慢性毒性(90天喂养)试验；
8.传统致畸试验；
试验结论表明：NAG急性毒性试验剂量超过2g/kg，是人注射剂量的300倍，仍未出现急性中毒反应；在长期毒性试验中，最高剂量已达到1g/kg，经四周试验观察，未出现中毒反应；在生殖试验中，从常规剂量7mg/kg喂小鼠，经三次传代，证明NAG对小鼠受孕妊娠、分娩、哺乳及仔鼠发育均无影响。证明NAG属无毒物质。
三、疗效观察
选择80名晕动病患者，随机分为4组：N-乙酰-D-氨基葡萄糖(NAG)长期服用组(800mg NAG/人/天)，NAG短期服用组(6000mg NAG/人/天)，安慰药组(6000mg葡萄糖/人/天)，不用药组。采用双盲法，以坐100公里汽车(速度20公里/小时)和100公里小轮船进行疗效观察。和坐车前相比，下列症状缓解或消除者判断为有效：眩晕、恶心、呕吐。结果见下表：
如表所示：统计结果表明，N-乙酰-D-氨基葡萄糖对晕动病的治疗和预防有效率在90％以上，与安慰药组和不用药组相差显著(p＜0.05)。
| 人数(人) | 有 效 | 无 效 | |
| NAG长期服用组 | 20 | 18 | 2 |
| NAG短期服用组 | 20 | 19 | 1 |
| 安慰药组 | 20 | 3 | 17 |
| 不用药组 | 20 | 2 | 18 |
Claims (6)
1.N-乙酰-D-氨基葡萄糖和其药物可接受的盐在制备用于预防或治疗晕动病的药物中的应用。
2.权利要求1的应用，其中所述药物为口服液体或固体制剂。
3.权利要求2的应用，其中所述药物为含0.1-4％重量N-乙酰-D-氨基葡萄糖的酒精饮料。
4.权利要求1的应用，其中所述药物以每日口服1000-10000mg N-乙酰-D-氨基葡萄糖的剂量从乘坐车、船、飞机前2-3天起至旅途结束给予需要的患者，用于晕动病的短期预防或治疗。
5.权利要求1的应用，其中所述药物以每日口服200-2000mg N-乙酰-D-氨基葡萄糖的剂量给予需要的患者，用于晕动病的长期预防或治疗。
6.权利要求3的应用，其中所述药物以每日口服200-1000mg N-乙酰-D-氨基葡萄糖的剂量从乘坐车、船、飞机前2-3天起至旅途结束给予需要的患者。
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| Application Number | Priority Date | Filing Date | Title |
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| CNB011048921A CN1168453C (zh) | 2001-02-28 | 2001-02-28 | N-乙酰-d-氨基葡萄糖在制备防治晕动病药物中的应用 |
| PCT/CN2002/000117 WO2002067944A1 (fr) | 2001-02-28 | 2002-02-28 | Utilisation de n-acetyl-d-glucosamine dans la fabrication d'un produit pharmaceutique destine au traitement du mal des transports |
| US10/469,326 US6946452B2 (en) | 2001-02-28 | 2002-02-28 | Use of N-acetyl-D-glucosamine in the manufacture of pharmaceutical useful for treating motion sickness |
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| CNB011048921A CN1168453C (zh) | 2001-02-28 | 2001-02-28 | N-乙酰-d-氨基葡萄糖在制备防治晕动病药物中的应用 |
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| CN102199513A (zh) * | 2011-03-01 | 2011-09-28 | 邱阳 | 一种抗氧化保健酒 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4777170A (en) * | 1987-02-03 | 1988-10-11 | Heinrich William A | Method to prevent and treat the signs and symptoms of motion sickness |
| US5229374A (en) | 1992-01-28 | 1993-07-20 | Burton Albert F | Method for treatment of lower gastrointestinal tract disorders |
| AU3881493A (en) | 1992-03-19 | 1993-10-21 | University Of British Columbia, The | Method and composition for suppression of side effects of anti-inflammatory drugs |
| GB9513972D0 (en) * | 1995-07-08 | 1995-09-06 | Merck Sharp & Dohme | Pharmaceutical compositions |
| CN1067246C (zh) | 1996-12-27 | 2001-06-20 | 中国人民解放军第三军医大学 | N－乙酰－d－氨基葡萄糖在制备治疗皮肤癣菌的药物中的应用 |
| CN1049006C (zh) * | 1996-12-27 | 2000-02-02 | 中国人民解放军第三军医大学 | 以n-乙酰-d-氨基葡萄糖作为添加剂的保健酒 |
| CN1067245C (zh) * | 1996-12-27 | 2001-06-20 | 中国人民解放军第三军医大学 | N－乙酰－d－氨基葡萄糖在制备治疗呼吸道疾病的药物中的应用 |
| CN1095366C (zh) | 1996-12-27 | 2002-12-04 | 中国人民解放军第三军医大学 | N－乙酰－d－氨基葡萄糖在制备治疗肠道疾病药物中的应用 |
| US6159485A (en) * | 1999-01-08 | 2000-12-12 | Yugenic Limited Partnership | N-acetyl aldosamines, n-acetylamino acids and related n-acetyl compounds and their topical use |
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2001
- 2001-02-28 CN CNB011048921A patent/CN1168453C/zh not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102199513A (zh) * | 2011-03-01 | 2011-09-28 | 邱阳 | 一种抗氧化保健酒 |
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| WO2002067944A1 (fr) | 2002-09-06 |
| US20040116383A1 (en) | 2004-06-17 |
| CN1168453C (zh) | 2004-09-29 |
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