CN1372932A - N－乙酰－d－氨基葡萄糖在制备辅助治疗肛周疾病药物中的应用 - Google Patents
N－乙酰－d－氨基葡萄糖在制备辅助治疗肛周疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了N－乙酰－D－氨基葡萄糖在制备辅助治疗肛周疾病的药物中的应用。通过稳定细胞溶酶体膜,减轻由于细胞溶酶体中各种酶类的释放而扩大的损伤程度和范围;促进损伤组织的愈合;对抗微生物在创面上的定植,防止感染的发生。以其为主要活性成分的药物制剂可用于辅助治疗肛周疾病,产生显著疗效。
Description
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辅助治疗肛周疾病的药物中的应用。
肛周疾病包括肛裂、肛周脓肿、瘘管、痔疮、直肠息肉、直肠癌等，这些疾病的共同特点是存在原位组织损伤，平常症状轻，急性发作时出现疼痛、红肿、瘙痒、渗出增加等炎症症状。给人们生活工作带来许多烦恼和痛苦。此种病症需要消除急性水肿、减轻疼痛、稳定膜结构以阻止炎症加剧，同时要控制感染。多年来临床上该病以小病症大难题而著称。因此，本领域一直需要能有效治疗或辅助治疗肛周疾病的药物。
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-氨基葡萄糖是一种化学试剂，二十世纪九十年代以来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)等疾病以及美容(JP59013708A2)、洗发制剂(JP2011505A2)、组织生长调节剂(WO/8702244A)等。但尚没有有关治疗肛周疾病的报道。
申请人研究发现，N-乙酰-D-氨基葡萄糖能够对抗微生物在局部的定植并稳定细胞溶酶体膜结构，从而对肛周疾病具有辅助治疗作用，这已在临床观察中得到证实。
因此，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辅助治疗肛周疾病的药物中的应用。
另一方面，本发明涉及一种辅助治疗肛周疾病的方法，包括给予有此需要的患者治疗有效量的N-乙酰-D-氨基葡萄糖或其药物可接受的盐。
N-乙酰-D-氨基葡萄糖为如下结构的化合物：
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。
可以将N-乙酰-D-氨基葡萄糖或其药物可接受的盐制备成液态制剂形式，喷洒于局部，以辅助治疗肛周疾病。也可以将其与其他治疗肛周疾病的活性成分一起制成药物制剂，用于治疗肛周疾病。本发明的药物可用于男女肛周会阴部皮肤粘膜的清洁卫生，除臭止痒、消炎止痛、抗感染，对肛裂、肛周脓肿、肛瘘、内外痔以及直肠息肉和直肠癌引起的疼痛红肿、瘙痒，脓样分泌渗出等症状能迅速消除或减轻。对坐定工作引起的会阴不适也有速效。
以下试验实施例用于说明本发明化合物(式(I)化合物)的促波特性、低毒性、抗微生物定植活性和稳定溶酶体膜的活性。一、式(I)化合物的促波试验1.实验材料和方法：1.1.样品：式(I)化合物纯品。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，用以研究式(I)化合物的促波作用，结果可见式(I)化合物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，表明式(I)化合物对生物波动是有促进作用的，这种促波作用可调节肠道平滑肌和肠道菌群的波动。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：式(I)化合物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，证明式(I)化合物对小鼠受孕妊娠、分娩、哺乳及仔鼠发育均无影响。证明式(I)化合物属无毒物质。三、抗定植实验：
1动物：
昆明种小鼠，中国第三军医大学动物所提供
2方法：
首先给实验动物灌胃绿脓杆菌悬液造成绿脓杆菌定植模型，以连续三天在粪便标本中培养出绿脓杆菌为阳性。取造模阳性的小鼠共32只，分为四组，即三个剂量的实验组和一个对照组，每组各8只，实验组每日按设定剂量灌胃给予N-乙酰-D-氨基葡萄糖，对照组灌胃生理盐水。每日做粪便培养，观察绿脓杆菌定植情况。
3.结果：
高中低三个剂量的N-乙酰-D-氨基葡萄糖均能有效对抗绿脓杆菌对肠道的定植。
四、稳定溶酶体膜实验：
1动物：wistar大鼠，第三军医大学动物所提供
2方法：建立内毒素休克大鼠模型，并同时对大鼠肝溶酶体进行体内外稳膜实验，模型动物分两组，实验组以N-乙酰-D-氨基葡萄糖进行治疗，对照组以生理盐水做相同处理。以酸性磷酸酶(ACP)的活性反应肝溶酶体膜的状况。
3结果：对照组游离ACP活性与实验组比较有显著性差异。
4结论：N-乙酰-D-氨基葡萄糖能有效稳定内毒素休克大鼠的肝溶酶体膜，减少酸性磷酸酶的释放。
五、人群试用
在对有肛周疾患的人群所作的临床试用实验表明，式(I)化合物制成的药物制剂能迅速消除或减轻由于各种原因引起的肛周不适，疼痛，渗出，瘙痒等症状。
Claims (2)
1.N-乙酰-D-氨基葡萄糖和其药物可接受的盐在制备辅助治疗肛周疾病药物中的应用。
2.权利要求1的应用，其中所述药物为外用液态制剂。
Priority Applications (3)
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| CN01104885A CN1131038C (zh) | 2001-02-28 | 2001-02-28 | N－乙酰－d－氨基葡萄糖在制备辅助治疗肛周疾病药物中的应用 |
| US10/469,284 US20050119224A1 (en) | 2001-02-28 | 2002-02-28 | Use of n-acetyl-d-glucosamine in the manufacture of pharmaceutical useful for adjuvant treatment of perianal disease |
| PCT/CN2002/000120 WO2002067947A1 (fr) | 2001-02-28 | 2002-02-28 | Utilisation de n-acetyl-d-glucosamine dans la preparation de compositions pharmaceutiques utilisees dans le traitement adjuvant d'une maladie anoperineale |
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| CN01104885A CN1131038C (zh) | 2001-02-28 | 2001-02-28 | N－乙酰－d－氨基葡萄糖在制备辅助治疗肛周疾病药物中的应用 |
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| Country | Link |
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| US (1) | US20050119224A1 (zh) |
| CN (1) | CN1131038C (zh) |
| WO (1) | WO2002067947A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104267185A (zh) * | 2014-09-12 | 2015-01-07 | 范飞舟 | 检测肿瘤的试剂盒及其专用识别n-乙酰氨基葡萄糖的物质 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5116615A (en) * | 1989-01-27 | 1992-05-26 | Immunolytics, Inc. | Method for treating benign prostatic hypertrophy |
| 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 |
| 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 |
| 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 |
| US6046179A (en) * | 1998-04-17 | 2000-04-04 | Murch; Simon | Composition for and treatment of inflammatory bowel disease by colon administration of N-acetylglucosamine |
| AU2001280891A1 (en) * | 2000-08-01 | 2002-02-13 | Schering Corporation | Uses of mammalian genes and related reagents |
-
2001
- 2001-02-28 CN CN01104885A patent/CN1131038C/zh not_active Expired - Fee Related
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2002
- 2002-02-28 US US10/469,284 patent/US20050119224A1/en not_active Abandoned
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104267185A (zh) * | 2014-09-12 | 2015-01-07 | 范飞舟 | 检测肿瘤的试剂盒及其专用识别n-乙酰氨基葡萄糖的物质 |
| CN104267185B (zh) * | 2014-09-12 | 2016-05-18 | 范飞舟 | 检测肿瘤的试剂盒及其专用识别n-乙酰氨基葡萄糖的物质 |
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| Publication number | Publication date |
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| US20050119224A1 (en) | 2005-06-02 |
| WO2002067947A1 (fr) | 2002-09-06 |
| CN1131038C (zh) | 2003-12-17 |
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