CN108014109B - 葫芦巴碱在制备治疗或预防缺氧性损伤的药物或食品中的应用 - Google Patents
葫芦巴碱在制备治疗或预防缺氧性损伤的药物或食品中的应用 Download PDFInfo
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- CN108014109B CN108014109B CN201711439967.XA CN201711439967A CN108014109B CN 108014109 B CN108014109 B CN 108014109B CN 201711439967 A CN201711439967 A CN 201711439967A CN 108014109 B CN108014109 B CN 108014109B
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Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种葫芦巴碱的新用途，即葫芦巴碱在制备治疗或预防缺氧性损伤的药物或食品中的应用，以及由葫芦巴碱制备的治疗或预防缺氧性损伤的药物或食品。本发明研究发现葫芦巴碱具有治疗或预防缺氧性损伤的功能，可以用于制备成治疗或预防缺氧性损伤的药物或食品，细胞实验及动物实验证明，葫芦巴碱可以防护缺氧性神经细胞损伤、减少缺氧导致的心肌细胞凋亡、延长小鼠常压耐缺氧试验中的存活时间和增加急性低压低氧试验中的存活率。
Description
技术领域
本发明涉及医药食品技术领域，特别是涉及葫芦巴碱在制备治疗或预防缺氧性损伤的药物或食品中的应用。
背景技术
缺氧是指机体生命活动所需的氧不能得到充足的供给时的一种病理状态。随着人们生活方式的改变和生活节奏的加快，缺氧已逐渐成为一类普遍的病理现象，严重地影响着人类的健康。高原低压低氧环境是人类感受缺氧最常见的情况之一，常常使急进到高原的人出现胸闷、呕吐、口渴、头晕、呼吸困难、疲劳感强、面容发紫等急性高原反应，严重时甚至引起高原病的发生，如高原肺水肿、高原脑水肿等，威胁生命。同时，缺氧还是一些神经性疾病(包括脑卒中、脑损伤和神经退行性疾病等)和心脏疾病(包括缺血再灌注损伤、心肌梗死等)的重要病理学因素，积极采取措施预防和治疗机体缺氧对包括急性高原病在内的诸多疾病的防治具有十分重要的作用。目前，对于抗缺氧药物主要有化学药和中成药，化学药如乙酰唑胺、地塞米松等，虽然具有较好的抗缺氧作用，但由于其副作用明显而受到限制；抗缺氧的中成药包括人参、红景天、雪莲等，虽然可以有效提高机体的低氧耐受力，但因资源有限且价格昂贵，也难以大范围推广使用。因此，迫切需要开发出高效经济的抗缺氧损伤防护药物。
葫芦巴碱(Trigonelline)最早发现于中药葫芦巴的种子中，是一种在自然界动植物中广泛存在且来源丰富的生物碱类化合物。由于其分子中同时存在带正负电荷的基团，因此是两性的季胺生物碱，具有降血糖、抗肿瘤、降血脂、退热、止咳等多种药理活性。但是目前尚无抗缺氧活性研究的报道。
发明内容
本发明经过研究发现了一种葫芦巴碱的新用途，即葫芦巴碱具有治疗或预防缺氧性损伤的作用，可以用于制备治疗或预防缺氧性损伤的药物或食品。
葫芦巴碱的结构式如式Ⅰ所示。
本发明提供了一种葫芦巴碱的新的用途，具体为：葫芦巴碱在制备治疗或预防缺氧性损伤的药物或食品中的应用。
本发明又提供了一种治疗或预防缺氧性损伤的药物，包含葫芦巴碱。
所述缺氧性损伤为高原低压性缺氧导致的急性高原病、脑缺血缺氧性疾病或心肌缺血缺氧性疾病。
所述药物为口服剂或注射剂。
所述口服剂由葫芦巴碱和药物学上可接受的载体组成，剂型可以是片剂、胶囊剂、分散剂或颗粒剂。
上述药物学上可接受的载体是指药学领域常规的药物载体，如填充剂、粘合剂、润滑剂、吸收剂、崩解剂、着色剂等。
所述填充剂可采用淀粉、预胶化淀粉、糊精、糖粉、甘露醇或微晶纤维素；所述粘合剂可采用淀粉浆、羟丙基纤维素、聚维酮、糖浆或聚乙二醇；所述润滑剂可采用硬脂酸镁、微粉硅胶、聚乙二醇、滑石粉、氢化植物油；所述吸收剂可采用硫酸钙、磷酸氢钙、轻质氧化镁或碳酸钙；所述崩解剂可采用干淀粉、羟甲基淀粉钠、低取代羟丙基纤维素、泡腾崩解剂或交联聚维酮；所述着色剂可采用二氧化钛、日落黄、亚甲蓝或药用氧化铁红。另外，还可以加入其它辅剂如香味剂、甜味剂等。
所述注射剂为注射液或注射液冻干粉针剂，由葫芦巴碱和药物学上可接受的药剂辅料组成。
上述药物学上可接受的药剂辅料是指药学上注射剂常用药剂辅料，如溶剂、pH调节剂/缓冲剂、抗氧剂、抑菌剂、等渗调节剂等。
所述溶剂可采用注射用水、乙醇、丙二醇、异丙醇、异丁醇、聚乙二醇和甘油；所述pH调节剂/缓冲剂可采用盐酸、磷酸盐、乳酸、氢氧化钠、枸缘酸、枸缘酸钠、酒石酸或酒石酸钠；所述抗氧剂可采用亚硫酸钠、焦亚硫酸钠或硫代硫酸钠；所述抑菌剂可采用苯酚、苯甲醇、硫柳汞；所述等渗调节剂可采用氯化钠、葡萄糖。
每剂药物中含葫芦巴碱10～500mg。
本发明还提供了一种预防缺氧性损伤的食品，包含葫芦巴碱。
本发明研究发现葫芦巴碱具有治疗或预防缺氧性损伤的功能，可以用于制备成治疗或预防缺氧性损伤的药物或食品，细胞实验及动物实验证明，葫芦巴碱可以防护缺氧性神经细胞损伤、减少缺氧导致的心肌细胞凋亡、延长小鼠常压耐缺氧试验中的存活时间和增加急性低压低氧试验中的存活率。
附图说明
图1为葫芦巴碱对缺氧条件下dPC12细胞形态的影响结果图，其中图A为正常对照组；图B为缺氧模型组；图C、D、E为实验组，葫芦巴碱的给药浓度分别为0.1μg/mL、1.0μg/mL和10.0μg/mL。
具体实施方式
试验药物：葫芦巴碱(购自Sigma-aldrich试剂公司，纯度≥95％)。
细胞株：类神经细胞——高分化型大鼠的嗜铬细胞瘤(differentiatedPC12cell，dPC12)细胞株购于中国科学院典型培养物保藏委员会细胞库；大鼠心肌细胞系H9C2细胞株购于中国科学院典型培养物保藏委员会细胞库。
昆明种雄性小白鼠：由浙江大学动物中心提供。
培养液：RPMI 1640培养基(Hyclone)；10％胎牛血清(Hyclone)；DMEM培养基(Hyclone)。
其它材料：胰酶(Hyclone)；CCK-8试剂盒(南京建成生物研究所)；培养皿(Corning)；移液管(Corning)；96孔板(Corning)；CO2细胞培养箱(Heal Force生物医疗科技控股有限公司)；三气培养箱(长沙华曦电子科技有限公司)；酶标仪(Biotek Eon)等。
实施例1
缺氧神经细胞损伤防护试验。
试验方法：
1)接种100μL(约5×103个)dPC12细胞于96孔板中，在37℃、5％CO2条件的正常培养箱中培养24h使细胞贴壁及正常生长。
2)小心地吸去培养基，加入样品液，设立葫芦巴碱低剂量组(0.1μg/mL)、中剂量组(1.0μg/mL)、高剂量组(10.0μg/mL)、缺氧对照和正常对照组各5个复孔，于37℃、5％CO2条件的正常培养箱中孵育3h后，除正常对照组外，将其余组的培养板转入37℃、0.5％O2+5％CO2+94.5％N2的三气培养箱中条件下培养36h。
3)超净工作台中(注意避光)小心地向每孔加入10μL CCK-8溶液，混匀。在培养箱内孵育3h，用酶标仪测定450nm波长下的吸光度。
试验结果：
结果如表1所示，持续缺氧36h会显著降低dPC12细胞活力(p＜0.01)，而用浓度为1.0、10.0μg/mL的葫芦巴碱共孵育则可以显著降低因缺氧造成的dPC12细胞损伤(p＜0.01)。
葫芦巴碱对缺氧条件下dPC12细胞形态的影响见图1，可见正常dPC12细胞呈不规则的梭形，突触较多，结构完整，折光度高，贴壁生长，缺氧处理36h的模型组细胞则出现细胞折光度显著降低，细胞边缘模糊，细胞变圆，突触显著减少，粘附度降低等，而经葫芦巴碱预处理的dPC12细胞，这些不良生长症状有了一定的改善，且随着药物浓度的增加，改善效果也逐渐显著。
表1葫芦巴碱对缺氧条件下dPC12细胞活力的影响(Mean±SD)
| 给药浓度(μg/mL) | 细胞活力(OD<sub>450nm</sub>) |
| 正常对照组 | 1.273±0.087 |
| 缺氧模型组 | 0.704±0.060<sup>##</sup> |
| 0.1 | 0.772±0.066 |
| 1.0 | 0.919±0.075<sup>**</sup> |
| 10.0 | 1.023±0.099<sup>**</sup> |
注：**表示与缺氧模型组相比，p＜0.01；##表示缺氧模型组与正常组相比，p＜0.01。
实施例2
缺氧心肌细胞损伤防护试验。
试验方法：
1)接种100μL(约1×104个)H9C2细胞于96孔板中，在37℃、5％CO2条件的正常培养箱中培养24h使细胞贴壁及正常生长。
2)小心地吸去培养基，加入样品液，设立葫芦巴碱低剂量组(0.1μg/mL)、中剂量组(1.0μg/mL)、高剂量组(10.0μg/mL)、缺氧对照和正常对照组各5个复孔，于37℃、5％CO2条件的正常培养箱中孵育3h后，除正常对照组外，将其余组的培养板转入37℃、0.5％O2+5％CO2+94.5％N2的三气培养箱中条件下培养24h。
3)超净工作台中(注意避光)小心地向每孔加入10μL CCK-8溶液，混匀。在培养箱内孵育3h，用酶标仪测定450nm波长下的吸光度。
结果如表2所示，持续缺氧24h会显著降低心肌细胞H9C2的活力(p＜0.01)，而中(1.0μg/mL)、高(10.0μg/mL)剂量的葫芦巴碱共孵育则可以显著降低因缺氧造成的心肌细胞损伤(p＜0.05)。
表2葫芦巴碱对缺氧条件下心肌细胞活力的影响(Mean±SD)
| 给药浓度(μg/mL) | 细胞活力(OD<sub>450nm</sub>) |
| 正常对照组 | 1.138±0.075 |
| 缺氧模型组 | 0.804±0.044<sup>##</sup> |
| 0.1 | 0.842±0.097 |
| 1.0 | 0.920±0.068<sup>*</sup> |
| 10.0 | 1.028±0.066<sup>**</sup> |
注：*表示与缺氧模型组相比，p＜0.05，**p＜0.01；##表示缺氧模型组与正常组相比，p＜0.01。
实施例3
常压耐缺氧小鼠试验。
取健康的昆明种雄性小白鼠60只，体重18～22g，由浙江大学动物中心提供，试验前适应环境7天。按体重随机分为4组：空白对照组(蒸馏水)、阳性对照组(乙酰唑胺：200mg/kg.bw/d)、葫芦巴碱低剂量组(100mg/kg.bw/d)和葫芦巴碱高剂量组(300mg/kg.bw/d)，每组15只。将各样品用蒸馏水充分分散溶解，口服灌胃给药7天后，进行常压耐缺氧小鼠试验。试验期间，自由饮水、进食，并观察小鼠摄食、生理及精神状况。
根据《功能食品检验与评价技术规范》(2003版)功能学评价检验方法中的提高缺氧耐受力功能的检验方法，将实验小鼠最后一次灌胃给药后，分别放入装有5g钠石灰的250mL的具塞磨口广口瓶中(每瓶1只)，瓶盖周围涂抹凡士林密封，加盖后立即计时，进行观察。以小鼠呼吸停止为终点，停止计时，记录小鼠因缺氧而死亡的时间。结果如表3所示，与空白对照组相比，葫芦巴碱低、高剂量组均能显著延长小鼠在常压耐缺氧试验中的存活时间(p＜0.05)，其中，葫芦巴碱高剂量组的存活时间延长率达到43.3％，效果显著优于乙酰唑胺阳性对照组(p＜0.05)。
表3各组小鼠常压耐缺氧存活时间的比较(Mean±SD)
注：*表示与空白对照组相比，p＜0.05，**p＜0.01；#表示与乙酰唑胺组相比，p＜0.05。
实施例4
急性减压缺氧存活小鼠试验。
取健康的昆明种雄性小白鼠80只，体重18～22g，由浙江大学动物中心提供，试验前适应环境7天。按体重随机分为4组：空白对照组(蒸馏水)、阳性对照组(乙酰唑胺：200mg/kg.bw/d)、葫芦巴碱低剂量组(100mg/kg.bw/d)和葫芦巴碱高剂量组(300mg/kg.bw/d)，每组20只。将各样品用蒸馏水充分分散溶解，口服灌胃给药7天。小鼠最后一次灌胃给药后，禁食禁水，放入低压低氧氧舱中，关紧舱门，以20m/s的速度减压上升至相当于海拔5000m，停留5分钟，继续上升至海拔10000m，维持此高度的低压低氧环境1h，以20m/s降至正常海拔高度，统计小鼠的死亡率。结果如表4所示，与空白对照组相比，葫芦巴碱低、高剂量组均能提升小鼠在急性减压缺氧试验中的存活数量，存活率均高于40％。
表4各组小鼠在减压缺氧存活试验中的存活率的比较
实施例1～4的试验结果表明，葫芦巴碱具有显著的抗缺氧功效，而且效果可与美国食品药品管理局(FDA)唯一批准的抗缺氧药物乙酰唑胺相媲美，以其为活性成分制备的抗缺氧药物或食品，可用于防治缺氧性神经损伤或心肌损伤等相关病症，也可以用于预防和治疗高原低压性缺氧导致的急性高原病、脑缺血缺氧性疾病或心肌缺血缺氧性病。
实施例5
以葫芦巴碱为活性成分，按药剂学上的常规工艺制备成各种剂型的抗缺氧药物。
(1)葫芦巴碱注射液：
精确称取0.500g葫芦巴碱用5mL乙醇完全溶解，接着加入20mL甘油，混合均匀得药物溶液。将0.02g的EDTA-Na2加入到70mL注射用水中，使之完全溶解后，将该水溶解加入到药物溶液中，混合均匀，用0.1moL/L的氢氧化钠和稀盐酸调节pH至5.5±1.0，并用注射用水定容至100mL(pH＝5.5±1.0)，加入0.1％的针用活性炭在85℃下保温15分钟，G3垂熔玻璃漏斗过滤，0.22μm的微孔滤膜过滤，滤液分装成2mL/支的针剂50支，每支含葫芦巴碱10mg，分装好的注射剂可以直接压塞、压铝盖成针剂。
(2)葫芦巴碱注射液冻干粉剂：
精确称取1.000g葫芦巴碱用5mL乙醇完全溶解。配置50mL pH＝5.5±0.2的磷酸盐缓冲溶液，加入0.02g亚硫酸钠，混合均匀，将缓冲液加入到葫芦巴碱的乙醇溶液中，混合均匀，加入注射用水40mL，用0.1moL/L的氢氧化钠和稀盐酸调节pH至5.5±0.5，并用注射用水定容至100mL(pH＝5.5±0.5)，加入0.1％的针用活性炭，在100℃下保温30分钟，G3垂熔玻璃漏斗过滤，0.22μm的微孔滤膜过滤，滤液分装成2mL/支于西林瓶中，经冷冻干燥机干燥后制成干粉剂，每支含葫芦巴碱20mg。
(3)葫芦巴碱片剂：
按片剂常规方法制备，共制成200片，每片含葫芦巴碱500mg。
(4)葫芦巴碱胶囊剂：
按胶囊剂常规方法制备，共制成1000粒，每粒胶囊含葫芦巴碱100mg。
(5)葫芦巴碱颗粒剂：
按颗粒剂常规方法制备，共制成1000袋，每袋含葫芦巴碱50mg。
本发明的药物剂型也不完全限于此，它可以制备成更多的剂型，如滴丸、胶囊剂、软胶囊剂、分散剂、缓控释制剂、注射剂等。
Claims (1)
1.葫芦巴碱在制备治疗或预防缺氧性损伤的药物中的应用，
所述缺氧性损伤为高原低压性缺氧导致的急性高原病，所述药物为口服剂或注射剂，每剂药物中含葫芦巴碱10～500mg。
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| CN102697781B (zh) * | 2011-06-21 | 2013-12-04 | 中国人民解放军第三军医大学第二附属医院 | 胡芦巴碱作为制备防治糖尿病及其并发症药物的应用 |
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