CN1131036C - N－乙酰－d－氨基葡萄糖在制备抑制放化疗副反应药物中的应用 - Google Patents
N－乙酰－d－氨基葡萄糖在制备抑制放化疗副反应药物中的应用 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了N-乙酰-D-氨基葡萄糖在制备抑制放化疗副反应药物中的应用，以其为主要活性成分的制剂可用于抑制肿瘤患者的放化疗副反应，总有效率可达85%。
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抑制放化疗副反应药物中的应用。
肿瘤病人接受放化疗后，常可出现骨髓抑制、血象改变、贫血、白细胞减少、蛋白合成抑制等代谢低下反应并很快伴随全身放化疗副反应：恶心、呕吐、乏力、食欲减退、脱发等，严重者出现急性衰竭或呼吸窘迫；由于白细胞减少，引起免疫功能低下，可发生全身性感染；加之免疫细胞生成障碍，肿瘤病人最终多以全身衰竭、恶病质、感染等死亡，这些基本上均是放化疗副反应的结果。因此，对放化疗副反应的控制，有助于肿瘤的长期治疗和加强肿瘤患者对治疗的支持能力；同时也减轻治疗过程中病人的痛苦，避免肿瘤导致的严重并发症的发生。目前临床上常用的支持疗法主要是对症处理：如病人纳差时输入能量合剂；水电解质紊乱时补充水电解质；呕吐严重时服用止吐药，感染时采取抗感染治疗等。这些对症控制作用的效果不佳。放化疗后的副反应几乎发生在每一个接受治疗的肿瘤病人身上，使之承受着痛苦，也成为肿瘤治疗中的一大难题。因此，在肿瘤治疗领域迫切需要能够抑制肿瘤放化疗副反应的药物。
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(WO9102530)、微生物感染(WO9718790)、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。目前尚无人用于制备抑制放化疗副反应这种整体功能损伤过程的药物中。
本发明人现出人意料地发现N-乙酰-D-氨基葡萄糖和其药物可接受的盐能够有效地抑制肿瘤放化疗副反应的发生和降低其严重程度。
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抑制肿瘤放化疗副反应的药物中的应用。
另一方面，本发明涉及一种抑制肿瘤放化疗副反应的方法，包括给予有此需要的患者抑制所述副反应有效量的N-乙酰-D-氨基葡萄糖或其药物可接受的盐
N-乙酰-D-氨基葡萄糖为结构式如下的化合物：
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。
可将式(I)化合物或其药物可接受的盐作为活性成分，与多种药学上可接受的赋形剂或/和载体结合，采用混合、粒化、成片、糖包衣或膜包衣等方法制备成液态或固态制剂形式，用于抑制放化疗副反应。
式(1)化合物或其药物可接受的盐可通过非肠道途径给药，如静脉注射、肌肉注射，或口服给药。剂量取决于病人的年龄、体重、病状、给药途径和治疗肿瘤的具体放化疗方法。式(1)化合物或其药物可接受的盐可以在给予抗肿瘤放化疗之前一段时间(例如3-10天)给药，然后与抗肿瘤放化疗联合给药，或者直接与抗肿瘤放化疗联合给药，但在已经开始抗肿瘤放化疗并出现副反应时给药也是有效的。适宜剂量为成人给药量约200-10000mg/日，静脉注射优选每天一次，口服或肌肉注射优选每天分三次给药。建议七天为一个疗程，坚持2-3个疗程给药。
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，用于静脉注射用的或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。肌肉注射的悬浮液或溶液可采用无菌水、橄榄油、油酸乙酯、二醇类等医学上可接受的载体。固体口服形式中，例如片剂或胶囊，除式(I)活性化合物外，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。所说药物制剂可用已知方法制备，例如利用混合、粒化、成片、糖包衣或膜包衣等方法。
虽无意拘于任何理论，但本发明人基于生物波理论认为正常机体不断波动即以组织细胞节律性生命活动来执行生理功能。这个波动过程是一个混沌过程，以此维持着对外界环境的适应性。机体的混沌波动过程依赖于整体各个组织的协同统一。酶在肿瘤放化疗治疗过程中，除合成上受到影响外，而且现有酶蛋白的功能也出现障碍，进而代谢活动受到影响，使整体耦合振荡离散，无法出现宏大的功能活动，表现出非节律的生命活动过程，即连续反应，导致各种副反应发生。故此，放化疗副作用控制集中在保护现有蛋白功能。N-乙酰-D-氨基葡萄糖具有促进生物波的特性，相信它通过调节酶蛋白振荡来调节有机体整体功能，调节机体组织恢复节律过程。它一方面发挥有机体整体效果抵抗不利因素的刺激，适应外界环境；另一方面调节酶蛋白振荡，排除不利环境的影响，进而减轻或控制放化疗副作用。
以下试验实施例用于证明本发明式(I)化合物的促波特性、低毒性和抑制肿瘤放化疗副反应的有效性。
一、式(1)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粘膜上皮细胞、白细胞和肠道菌群的波动。
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、疗效观察
多年临床试用观察到生物波胶囊(每粒含N-乙酰-D-氨基葡萄糖600mg)对白血病、何杰金氏病以及肝癌、胃癌等多种肿瘤患者在放化疗中出现的副作用有良好的控制作用，总有效率85％，部分典型病例附后。
1.张某，男，患白血病。进行放化疗后，出现全身软弱无力，食欲减退，时常呕吐等身体不适现象，身体状况不佳。经服用生物波胶囊-周后，吃饭渐正常，同时改善了多梦，心悸等睡眠不佳状况。后继续服用，乏力和感冒次数较前明显减少。
2.陈某，四川南充人，女，胃癌。经放化疗后，身体消瘦，免疫力下降，伴有食欲下降，精神欠佳。经服用生物波胶囊，一日三次，一次1-2粒，一周后自我感觉有所好转，一些不良症状有明显改善，无副作用，继续服用未停。
Claims (3)
1.N-乙酰-D-氨基葡萄糖在制备抑制肿瘤病人放化疗副反应的药物中的应用。
2.按权利要求1的应用，其中所述药物为适于口服、静脉内或肌肉内给药的制剂。
3.按权利要求1或2的应用，其中所述药物对成人患者以每天200-10000mg N-乙酰-D-氨基葡萄糖的剂量给药。
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01104882A CN1131036C (zh) | 2001-02-28 | 2001-02-28 | N－乙酰－d－氨基葡萄糖在制备抑制放化疗副反应药物中的应用 |
| EP02703474A EP1374873B8 (en) | 2001-02-28 | 2002-02-28 | The use of n-acetyl-d-glucosamine in the manufacture of pharmaceutical useful for supressing side-effect of radiotherapy and chemotherapy |
| PCT/CN2002/000119 WO2002067946A1 (fr) | 2001-02-28 | 2002-02-28 | Utilisation de la n-acetyl-d-glucosamine dans la preparation de compositions pharmaceutiques utilisees dans la suppression des effets secondaires causes par la radiotherapie et la chimiotherapie |
| US10/469,327 US7037904B2 (en) | 2001-02-28 | 2002-02-28 | Use of N-acetyl-D-glucosamine in the manufacture of pharmaceutical useful for suppressing side-effect of radiotherapy and chemotherapy |
| AT02703474T ATE293983T1 (de) | 2001-02-28 | 2002-02-28 | Verwendung von n-acetyl-d-glucosamin bei der herstellung eines arzneimittels zur unterdrückung der nebenwirkungen von strahlentherapie und chemotherapie |
| DE60203895T DE60203895T2 (de) | 2001-02-28 | 2002-02-28 | Verwendung von n-acetyl-d-glucosamin bei der herstellung eines arzneimittels zur unterdrückung der nebenwirkungen von strahlentherapie und chemotherapie |
| HK04104522A HK1061530A1 (en) | 2001-02-28 | 2004-06-24 | The use of n-acetyl-d-glucosamine in the manufacture of pharmaceutical useful for supressing side-effect of radiotherapy and chemotherapy. |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01104882A CN1131036C (zh) | 2001-02-28 | 2001-02-28 | N－乙酰－d－氨基葡萄糖在制备抑制放化疗副反应药物中的应用 |
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| CN1372929A CN1372929A (zh) | 2002-10-09 |
| CN1131036C true CN1131036C (zh) | 2003-12-17 |
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| Country | Link |
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| US (1) | US7037904B2 (zh) |
| EP (1) | EP1374873B8 (zh) |
| CN (1) | CN1131036C (zh) |
| AT (1) | ATE293983T1 (zh) |
| DE (1) | DE60203895T2 (zh) |
| HK (1) | HK1061530A1 (zh) |
| WO (1) | WO2002067946A1 (zh) |
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| CN1210038C (zh) * | 2003-03-27 | 2005-07-13 | 中国人民解放军第三军医大学 | N－乙酰氨基葡萄糖在制备用于治疗毒物和药物中毒致脏器损伤的药物中的应用 |
| JP2007506645A (ja) * | 2003-09-17 | 2007-03-22 | 中国人民解放▲軍▼第三▲軍▼医大学 | 抗腫瘍および抗転移のための製剤の製造におけるｎ−アセチル−ｄ−グルコサミンの使用 |
| CN101155591B (zh) * | 2005-08-03 | 2012-01-18 | 国立癌中心 | 可用作tg抑制剂的葡萄糖胺及其衍生物 |
| 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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| US4216208A (en) * | 1978-07-31 | 1980-08-05 | Proter S.P.A. | N-Acyl derivatives of glucosamines having antitumor chemotherapeutic activity |
| US4710493A (en) * | 1984-08-14 | 1987-12-01 | Albert Landsberger | Therapeutic agent for the use in cancer treatment |
| CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
| US5229374A (en) | 1992-01-28 | 1993-07-20 | Burton Albert F | Method for treatment of lower gastrointestinal tract disorders |
| EP0630251A1 (en) | 1992-03-19 | 1994-12-28 | University Of British Columbia | Method and composition for suppression of side effects of anti-inflammatory drugs |
| 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 |
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2001
- 2001-02-28 CN CN01104882A patent/CN1131036C/zh not_active Expired - Fee Related
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2002
- 2002-02-28 AT AT02703474T patent/ATE293983T1/de not_active IP Right Cessation
- 2002-02-28 EP EP02703474A patent/EP1374873B8/en not_active Expired - Lifetime
- 2002-02-28 WO PCT/CN2002/000119 patent/WO2002067946A1/zh not_active Application Discontinuation
- 2002-02-28 DE DE60203895T patent/DE60203895T2/de not_active Expired - Lifetime
- 2002-02-28 US US10/469,327 patent/US7037904B2/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| HK1061530A1 (en) | 2004-09-24 |
| EP1374873B8 (en) | 2005-06-29 |
| EP1374873B1 (en) | 2005-04-27 |
| CN1372929A (zh) | 2002-10-09 |
| EP1374873A4 (en) | 2004-08-11 |
| US7037904B2 (en) | 2006-05-02 |
| DE60203895T2 (de) | 2005-09-29 |
| US20040077596A1 (en) | 2004-04-22 |
| WO2002067946A1 (fr) | 2002-09-06 |
| ATE293983T1 (de) | 2005-05-15 |
| DE60203895D1 (de) | 2005-06-02 |
| EP1374873A1 (en) | 2004-01-02 |
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