CN1372931A - N－乙酰－d－氨基葡萄糖在制备治疗宫颈糜烂药物中的应用 - Google Patents
N－乙酰－d－氨基葡萄糖在制备治疗宫颈糜烂药物中的应用 Download PDFInfo
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Abstract
本发明公开了N－乙酰－D－氨基葡萄糖在制备治疗宫颈糜烂的药物中的应用。N－乙酰－D－氨基葡萄糖具有抗微生物定植和控制微生物感染、改善局部渗出、组织炎性水肿和疼痛等症状。
Description
本发明涉及N-乙酰-D-氨基葡萄糖在制备治疗宫颈糜烂的药物中的应用。
宫颈糜烂(cervical erosion)是一种妇科常见病症，由慢性子宫颈炎症过程中发生的子宫颈阴道部鳞状上皮坏死脱落形成的表浅缺损或子宫颈管粘膜外翻引起，表现为渗出及分泌物增多、宫颈粘膜充血水肿并溃烂、微生物感染等。这种病症不仅迁延难愈，极大地影响正常生活，而且有发展为癌症的可能。
目前，国内外对于宫颈糜烂的治疗，临床上多采用物理疗法如电熨、冷冻、激光等手段使糜烂组织坏死脱落，或采用腐蚀药剂如重铬酸钾、硝酸银等破坏糜烂组织，严重者甚至手术切除宫颈或子宫。上述疗法给患者带来极大的痛苦，在去除糜烂组织的同时也累及大量的正常组织。目前市售的其他药物制剂，一般以乙醇作溶剂，刺激性强，溶质本身也产生刺激，引起疼痛，并损伤正常皮肤。另外，这些产品在功能上多限于杀菌，有控制感染的效果，但破坏了微生态平衡，使感染得不到根治。因此，本领域一直需要能有效治疗宫颈糜烂的药物。
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)、下消化道粘膜器质性病变(WO93/14765)等疾病以及组织生长调节剂(WO/8 702244)、美容(JP59013708A2)、洗发制剂(JP2011505A2)等。目前尚无在制备治疗宫颈糜烂药物方面的应用。
本发明现发现N-乙酰-D-氨基葡萄糖能有效地治疗宫颈糜烂，这一发现是非常出人意料的，因为要治愈宫颈糜烂需要控制微生物感染、抗局部渗出、消除组织炎性水肿和疼痛以及促进组织修复等多方面配合，医生必须为患者开出多种药物联合治疗，而现发现单独以N-乙酰-D-氨基葡萄糖为活性成分的药物能够治愈宫颈糜烂。虽然现有技术中公开过N-乙酰-D-氨基葡萄糖的抗微生物感染和组织生长调节作用，这一发现仍然是令人惊异的。
基于上述发现，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治疗宫颈糜烂的药物中的应用。
另一方面，本发明涉及一种治疗宫颈糜烂的方法，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-氨基葡萄糖为结构如下的化合物：
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。
将式(I)的化合物或其药物可接受的盐作为主要活性成分，与多种药学上可接受的赋形剂或/和载体结合，制备成外用水剂、乳剂、霜剂、膏剂、栓剂等制剂形式，用于治疗宫颈糜烂。活性物质的用量为整个制剂量的0.2-6％。所述药物的日剂量为每人100-2000mg N-乙酰-D-氨基葡萄糖。
虽无意拘于任何理论，但本发明人认为本发明式(I)化合物治疗宫颈糜烂的功效是通过调节机体的细胞再分布来实现的。细胞再分布指机体组织细胞或微生物细胞的位置不断更替，胞内生物大分子的节律性凝-溶状态的更替。N-乙酰-D-氨基葡萄糖通过调节不同层次的细胞再分布发挥其特殊的功效。宏观细胞位置的更替表现波动生长特征。N-乙酰-D-氨基葡萄糖通过调节机体细胞及微生物细胞波动生长的正常进行，使微生物不能在局部定植。在微生态学功效上，主要扶持正常菌群生长，而不采用补充生态菌群方法，避免了补充菌群存在着定植条件的适应性问题。在促进皮肤粘膜组织修复方面，其对炎症、损伤、感染、渗出具有控制效果，这是本产品独有的特色。可广泛适用于控制症状，以及从根本问题上进行治疗。
以下试验实施例用于证明本发明式(I)化合物的促波特性、低毒性、抗微生物定植活性和治疗宫颈糜烂的临床观察。
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、乳酸杆菌。
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。
液体培养结果表明，式(I)化合物能促进乳酸杆菌的生长。
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，这种促波作用可参与皮肤细胞的修复和再分布作用。
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，属无毒物质。
三、以抗定植作用排除病原微生物的试验
原位细菌定植、定性、定量检测试验结果表明，式(I)化合物基本无杀菌抑菌作用，它是通过抗定植的作用使得病原微生物如白色念珠菌、阴道嗜血杆菌等不能定植生长，从而达到抗感染的目的。
四、临床试验
采用2％N-乙酰-D-氨基葡萄糖喷雾剂试用于人群，截至一九九九年八月止，共观察病人123例。从试用结果看，与空白对照组(不用药)和阳性药物(AgNO3)对照组比较，统计分析表明治疗组在痊愈率、有效率方面与阳性药物对照组和空白对照组相差显著，N-乙酰-D-氨基葡萄糖喷雾剂对宫颈糜烂的治疗效果是显著的，疗效统计结果如下：
| 例数 | 痊愈 | 有效 | |
| 治疗组 | 83 | 48 | 15 |
| 阳性药物对照组 | 60 | 5 | 8 |
| 空白对照组 | 40 | 2 | 6 |
Claims (3)
1.N-乙酰-D-氨基葡萄糖和其药物可接受的盐在制备治疗宫颈糜烂的药物中的应用。
2.权利要求1的应用，其中所述药物为外用水剂、乳剂、霜剂、膏剂、栓剂形式的制剂。
3.权利要求1或2的应用，其中所述药物的日剂量为100-2000mg N-乙酰-D-氨基葡萄糖。
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| CNB011048840A CN1173706C (zh) | 2001-02-28 | 2001-02-28 | N-乙酰-d-氨基葡萄糖在制备治疗宫颈糜烂药物中的应用 |
| PCT/CN2002/000118 WO2002067945A1 (fr) | 2001-02-28 | 2002-02-28 | Utilisation de n-acetyl-d-glucosamine dans la fabrication d'un produit pharmaceutique destine au traitement de l'erosion cervicale |
| US10/469,268 US6992073B2 (en) | 2001-02-28 | 2002-02-28 | Use of N-acetyl-D-glucosamine in the manufacture of a medicament for treating cervical erosion |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004084916A1 (fr) * | 2003-03-27 | 2004-10-07 | Third Military Medical University, Chinese People's Liberation Army, P.R. Of China | Utilisation de n-acetyle-d-aminoglycosamine dans le traitement de lesions locales et de symptomes systematiques lies aux infections virales ou bacteriennes |
| WO2004084915A1 (fr) | 2003-03-27 | 2004-10-07 | Third Military Medical University, Chinese People's Liberation Army, P.R. Of China | Utilisation de n-acetyl-d-aminoglycosamine dans le traitement d'inflammations non specifiques associees a des facteurs physiques ou chimiques |
| EP1666046A1 (en) * | 2003-09-17 | 2006-06-07 | Third Military Medical University Chinese People's Liberation Army P.R. of China | Use of n-acetyl-d-aminoglycosamine in preparation of drugs for the treatment of cacer and metastasis |
| EP1669076A1 (en) * | 2003-09-17 | 2006-06-14 | Third Military Medical University Chinese People's Liberation Army P.R. of China | Use of n-acetyl-d-aminoglycosamine in preparation of drugs for modulating microorganisms on mucous membrane |
| EP1669077A1 (en) * | 2003-09-18 | 2006-06-14 | Third Military Medical University Chinese People's Liberation Army P.R. of China | Antibacterial compositions of n-acetyl-d-aminoglycosamine and antibiotics |
| CN107334782A (zh) * | 2017-07-26 | 2017-11-10 | 吉林省始祖生物波医学研究院有限公司 | 一种抑菌消炎剂及其制备方法和应用 |
| CN113912656A (zh) * | 2021-09-30 | 2022-01-11 | 上海玉曜生物医药科技有限公司 | N-乙酰基-d-氨基葡萄糖的晶型及其制备方法、应用 |
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| AU2003261624A1 (en) * | 2003-09-05 | 2005-03-29 | Shenyang Sunbellcom Bio-Pharmaceutical Co., Ltd. | A red nocardia cell wall skeleton preparation process and its therapeutic use on treating cervical erosion |
| US20100152304A1 (en) * | 2008-12-17 | 2010-06-17 | Geng Funeng | Pharmaceutical composition comprising periplaneta americana or its ethanol extract and a method of using the same for treating inflammations |
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| JPS5913708A (ja) | 1982-07-14 | 1984-01-24 | Shiseido Co Ltd | 化粧料 |
| GB8524807D0 (en) | 1985-10-08 | 1985-11-13 | Hendry N G C | Tissue growth regulation |
| JPS63273493A (ja) | 1987-04-30 | 1988-11-10 | Kyogyo Kumiai N F I | Ｎ−アセチル−ｄ−グルコサミンの製造法 |
| JP2552536B2 (ja) | 1988-06-29 | 1996-11-13 | 川研ファインケミカル株式会社 | ヘアリンス剤 |
| US5116615A (en) * | 1989-01-27 | 1992-05-26 | Immunolytics, Inc. | Method for treating benign prostatic hypertrophy |
| JPH0383927A (ja) | 1989-08-25 | 1991-04-09 | Sunstar Inc | 歯周組織再生促進剤 |
| 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 |
| WO1997018790A2 (en) | 1995-11-22 | 1997-05-29 | The Research And Development Institute, Inc. | Therapeutic and diagnostic agents for the treatment of microbial infections |
| US5998173A (en) | 1996-02-20 | 1999-12-07 | The University Of Bristish Columbia | Process for producing N-acetyl-D-glucosamine |
| 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 |
| 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 |
| JP4290231B2 (ja) | 1997-04-09 | 2009-07-01 | 生化学工業株式会社 | 角膜障害症治癒促進剤 |
| 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 |
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- 2001-02-28 CN CNB011048840A patent/CN1173706C/zh not_active Expired - Fee Related
-
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- 2002-02-28 WO PCT/CN2002/000118 patent/WO2002067945A1/zh not_active Application Discontinuation
- 2002-02-28 US US10/469,268 patent/US6992073B2/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004084916A1 (fr) * | 2003-03-27 | 2004-10-07 | Third Military Medical University, Chinese People's Liberation Army, P.R. Of China | Utilisation de n-acetyle-d-aminoglycosamine dans le traitement de lesions locales et de symptomes systematiques lies aux infections virales ou bacteriennes |
| WO2004084915A1 (fr) | 2003-03-27 | 2004-10-07 | Third Military Medical University, Chinese People's Liberation Army, P.R. Of China | Utilisation de n-acetyl-d-aminoglycosamine dans le traitement d'inflammations non specifiques associees a des facteurs physiques ou chimiques |
| EP1666046A1 (en) * | 2003-09-17 | 2006-06-07 | Third Military Medical University Chinese People's Liberation Army P.R. of China | Use of n-acetyl-d-aminoglycosamine in preparation of drugs for the treatment of cacer and metastasis |
| EP1669076A1 (en) * | 2003-09-17 | 2006-06-14 | Third Military Medical University Chinese People's Liberation Army P.R. of China | Use of n-acetyl-d-aminoglycosamine in preparation of drugs for modulating microorganisms on mucous membrane |
| EP1669076A4 (en) * | 2003-09-17 | 2007-10-03 | Univ Pla 3Rd Military Medical | USE OF N-ACETYL-D-AMINOGLYCOSAMINE IN THE MANUFACTURE OF MEDICAMENTS FOR MODULATING MICRO-ORGANISMS ON THE TISSUE |
| EP1666046A4 (en) * | 2003-09-17 | 2007-10-03 | Univ Pla 3Rd Military Medical | USE OF N-ACETYL-D-AMINOGLYCOSAMINE FOR THE PREPARATION OF DRUGS FOR THE TREATMENT OF CANCER AND METASTASES |
| EP1669077A1 (en) * | 2003-09-18 | 2006-06-14 | Third Military Medical University Chinese People's Liberation Army P.R. of China | Antibacterial compositions of n-acetyl-d-aminoglycosamine and antibiotics |
| EP1669077A4 (en) * | 2003-09-18 | 2007-10-03 | Univ Pla 3Rd Military Medical | ANTIBACTERIAL COMPOSITIONS BASED ON N-ACETYL-D-AMINOGLYCOSAMINE AND ANTIBIOTICS |
| CN107334782A (zh) * | 2017-07-26 | 2017-11-10 | 吉林省始祖生物波医学研究院有限公司 | 一种抑菌消炎剂及其制备方法和应用 |
| CN113912656A (zh) * | 2021-09-30 | 2022-01-11 | 上海玉曜生物医药科技有限公司 | N-乙酰基-d-氨基葡萄糖的晶型及其制备方法、应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20040138174A1 (en) | 2004-07-15 |
| CN1173706C (zh) | 2004-11-03 |
| WO2002067945A1 (fr) | 2002-09-06 |
| US6992073B2 (en) | 2006-01-31 |
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