CN102920713B - Gypensapogenin B在制备抗雌激素缺乏导致的骨质疏松药物中的应用 - Google Patents
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Abstract
本发明公开了Gypensapogenin B用于防治骨质疏松的新用途。骨质疏松是危害人类健康的重要疾病之一，随着人口的老龄化，骨质疏松的病人日益增多，给全球带来了巨大的社会，医疗和经济负担。尽管国内外相关专家学者对此病的防治十分重视，但该病尚缺乏有效的治疗药物。本发明通过体内试验发现Gypensapogenin B有显著抗骨质疏松的作用。实验结果表明Gypensapogenin B能够抑制去卵巢引起的骨转化率增强，较少骨质破坏，同时可以提高血钙浓度，有利于骨的沉积。对于由于雌激素缺乏导致的骨质疏松具有治疗作用，并且无雌激素样副作用。
Description
技术领域
本发明涉及抗骨质疏松相关的药物领域，尤其涉及Gypensapogenin B用于防治骨质疏松的新用途。
背景技术
骨质疏松是一种全身性的、代谢性的骨疾病，其特征是骨量减少和丢失，骨脆性和骨折危险性增加。随着人口的老龄化，骨质疏松的发病率也随着迅速增加，已经成为危害人类健康的重要疾病，并给全球带来了巨大的社会和经济负担。尽管国内外相关专家学者对此病的防治十分重视，但该病尚缺乏有效的治疗药物。
目前临床上常用的防治骨质疏松的药物包括雌激素替代药物，双膦酸盐类，选择性雌激素受体调节剂，维生素D，甲状旁腺素和人重组甲状旁腺激素(1-34) 等。双磷酸盐类药物虽然效果不错，但可导致颌骨坏死、肌肉骨骼痛和肾功能衰竭等严重不良反应；激素替代疗法虽然是防治绝经后骨质疏松的重要方法，但长期使用有导致乳腺癌、子宫内膜癌的潜在危险且发生血栓的风险也增加；而选择性雌激素受体调节剂可以使血栓性事件明显增加。其他药物或价格昂贵，或远期疗效不确切，均不够理想。由于骨质疏松是一种慢性病，需要长期服药，因此价格便宜，毒副作用小的中草药已成为研究治疗骨质疏松的热点之一。
本发明涉及的化合物Gypensapogenin B是一个2012年发表（Li, N. et al., 2012. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. European Journal of Medicinal Chemistry 50, 173–178.）的新骨架化合物，该化合物拥有全新的骨架类型，目前的用途仅仅涉及人肿瘤细胞株的细胞毒活性（Li, N. et al., 2012. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. European Journal of Medicinal Chemistry 50, 173–178.），对于本发明涉及的Gypensapogenin B在制备抗雌激素缺乏导致的骨质疏松药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其抗雌激素缺乏导致的骨质疏松活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于骨质疏松的防治显然具有显著的进步。
发明内容
本发明提供Gypensapogenin B的抗骨质疏松新用途。
本发明通过体内实验发现Gypensapogenin B在制备抗骨质疏松药物中的应用。
进一步，所述的骨质疏松是由于雌激素缺乏导致。
本发明通过体内试验发现Gypensapogenin B有显著的预防骨质疏松的作用。Gypensapogenin B能够抑制去卵巢引起的骨转化率增强和骨质破坏，同时可以提高血钙浓度，有利于骨的沉积。是一种理想的防治骨质疏松的药物。
所述化合物Gypensapogenin B结构如式（Ⅰ）所示：
本发明涉及的Gypensapogenin B在制备抗雌激素缺乏导致的骨质疏松药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其抗雌激素缺乏导致的骨质疏松活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于骨质疏松的防治显然具有显著的进步。
具体实施方式
本发明所涉及化合物Gypensapogenin B的制备方法参见文献（Li, N. et al., 2012. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. European Journal of Medicinal Chemistry 50, 173–178.和Wei, J.X. et al., 1982. Two new dammaran sapogenins from leaves of Panax notoginseng. Planta Medica, 45(3): 167-171.）。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
实施例1：本发明所涉及化合物Gypensapogenin B片剂的制备：
取20克化合物Gypensapogenin B，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例2：本发明所涉及化合物Gypensapogenin B胶囊剂的制备：
取20克化合物Gypensapogenin B，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000片。
下面通过药效学实验来进一步说明其药物活性。
1、材料与方法
将十周龄健康SD雌鼠（18只，江苏省动物中心）随机分成3组，每组6只：假手术组（Sham）、卵巢切除模型组（OVX）、Gypensapogenin B组。饲养条件：温度为(23 ±2) ℃，光照:黑暗为12∶12 。让各组大鼠适应环境2周后开始骨质疏松造模手术：各组大鼠均经腹腔注射20%乌拉坦麻醉(6ml/ kg 体重)，Sham组开腹后关腹，其余两组行双侧卵巢切除术。术后第4周起，Sham组和OVX组每天进食标准饲料和去离子水，Gypensapogenin B组每天进食标准饲料和去离子水，同时灌胃给与Gypensapogenin B 10 mg/kg，连续3个月，每周称一次体重。实验结束后，用乌拉坦麻醉，摘取眼球采血，2000r/min离心，吸取上清（即血清）。摘除大鼠子宫，迅速称重。取出大鼠双侧股骨和双侧胫骨，剔除软组织。两胫骨经800℃高温炉（由南京大学化学化工学院提供）中灰化8 h，冷却后称灰重。用研钵碾碎成灰状，取0.1g 骨灰溶于1 ml, 6 mol/l盐酸中，测骨钙和骨磷时取0.2 ml用超纯水稀释至1ml，用全自动生化分析仪检测骨钙和骨磷含量。左股骨用骨密度仪（江苏省人民医院核医学科提供）测量骨密度（BMD）。血清生化指标测定：取血清0.5 ml，用全自动生化分析仪（南京军区南京总医院普外科提供）检测血清碱性磷酸酶（ALP）、钙（Ca）和磷（P）。实验结果用 x±S表 示。
2、结果
（1）Gypensapogenin B对双侧卵巢切除大鼠体重及子宫系数的的影响
表1显示各组大鼠体重无明显差别，去卵巢模型组大鼠的子宫明显萎缩，给予Gypensapogenin B3个月后，并未引起子宫重量的明显增加，说明Gypensapogenin B对子宫生长无刺激作用。
表1 Gypensapogenin B对双侧卵巢切除大鼠体重及子宫系数的的影响
| 实验组别 | 体重 (g) | 子宫指数(mg/g) |
| Sham | 347.7±54.4 | 1.894±0.95 |
| OVX | 346.0±41.9 | 0.141±0.59 |
| Gypensapogenin B | 345.2±18.4 | 0.216±1.11 |
（2）Gypensapogenin B对双侧卵巢切除大鼠血清ALP，血清Ca和血清P的的影响
表2可以看出去卵巢后，模型组大鼠血清碱性磷酸酶活性增加。去卵巢后，体内雌激素缺乏，导致骨转化率增加，与绝经后妇女的高转化型骨质疏松症一致。给予Gypensapogenin B3个月后，碱性磷酸酶活性显著下降，可见Gypensapogenin B可以抑制去卵巢引起的骨转化率的增加，减少骨质的破坏。表中还显示与假手术组相比，模型组大鼠血清钙明显下降，而Gypensapogenin B可显著提升血清钙浓度。血清钙是骨形成的重要标记物，说明Gypensapogenin B可以有效逆转由于卵巢切除导致的血清钙的降低，有利于骨的形成。
表2 Gypensapogenin B对双侧卵巢切除大鼠血清ALP，血清Ca和血清P的的影响
*P<0.05vs OVX组
（3）Gypensapogenin B对双侧卵巢切除大鼠左股骨BMD的的影响
表3可以看出去卵巢后模型组大鼠左股骨骨密度较假手术组显著下降，给予Gypensapogenin B3个月后，骨密度有所增加。
表3 Gypensapogenin B对双侧卵巢切除大鼠左股骨BMD的的影响
| 实验组别 | 左股骨BMD(g/cm2) |
| sham | 0.332±0.027 |
| OVX | 0.215±0.037 |
| Gypensapogenin B | 0.292±0.021 * |
*P<0.05vs OVX组
（4）Gypensapogenin B对双侧卵巢切除大鼠双侧胫骨参数的影响
表4可以看出与假手术组相比，模型组大鼠双胫骨灰重显著降低，而Gypensapogenin B较模型组有所升高。各组骨钙和骨磷含量没有明显差别。
表4 Gypensapogenin B对双侧卵巢切除大鼠双侧胫骨参数的影响
*P<0.05vs OVX组
结论： Gypensapogenin B能够抑制去卵巢引起的骨转化率增强和骨质破坏，同时可以提高血钙浓度，有利于骨的沉积。对于由于雌激素缺乏导致的骨质疏松具有防治作用，并且无雌激素样副作用。Gypensapogenin B可以用于骨质疏松的防治。
Claims (1)
1.Gypensapogenin B在制备抗雌激素缺乏导致的骨质疏松药物中的应用，所述化合物Gypensapogenin B结构如式（Ⅰ）所示：
式（Ⅰ）。
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| Ning Li et. al..《Triterpenes possessing an unprecedented skeleton isolated from hydrolyzateof total saponins from Gynostemma pentaphyllum 》.《European Journal of Medicinal Chemistry》.2012,第50卷第173-178页. |
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