CN101884638B - 5α-雄甾(烷)-3β,5,6β-三醇在制备神经元保护药物中的应用 - Google Patents
5α-雄甾(烷)-3β,5,6β-三醇在制备神经元保护药物中的应用 Download PDFInfo
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Abstract
本发明公开了5α-雄甾(烷)-3β，5，6β-三醇在制备神经元保护药物中的应用。本发明对脑缺血、脊髓缺血及缺氧损伤的保护作用。经体外三种原代培养神经元、大鼠局灶性脑缺血及兔脊髓缺血模型证实，5α-雄甾(烷)-3β，5，6β-三醇脑缺血、脊髓缺血及缺氧引起的神经元损伤具有明显的保护作用。在有效剂量下5α-雄甾(烷)-3β，5，6β-三醇未见明显的毒副反应。
Description
技术领域
本发明涉及化合物5α-雄甾(烷)-3β，5，6β-三醇(简称YC-6)的新药物用途。
背景技术
急性缺血性脑卒中的治疗主要通过两个途径：一为溶解血栓，二为神经保护，后者指在急性缺血性脑卒中的治疗中，阻止缺血引起的脑组织一系列的病理及生化反应，干扰缺血瀑布反应的各个环节，延长神经元存活的药物或措施。
当前，急性缺血性卒中的神经保护剂治疗已成为脑卒中治疗的研究热点，许多神经保护剂目前正在临床开发试验中，其作用机制在于通过阻断由缺血所致各种有害病理过程的发生，从而防止或局限缺血所引起的脑损害，减少脑组织死亡和促进功能恢复。由于神经保护剂可减少脑梗死面积，不引发出血，无溶栓、抗凝治疗过程中出现的出血并发症，用前无需进行详细的病因鉴别诊断，使得早期治疗成为可能，因而神经保护剂的治疗效果和前景，是令人鼓舞的。
然而，迄今为止还没有发现已证明为安全有效的神经保护剂，目前正在进行临床试验的、具有潜在临床应用前景的药物有钙通道阻滞剂(calcium channel blocker，CCB)、钙通道调节剂、谷氨酸释放抑制剂、γ-氨基丁酸(GABA)受体激动剂、自由基清除剂、抗细胞间黏附分子抗 体等。
在众多化合物中，神经活性甾体对神经保护具有广泛效应而日益受到关注。这些神经活性甾体水平与中枢神经系统(central nervous system，CNS)疾病的发生发展相关，对神经元损伤、死亡以及多种中枢神经系统疾病有显著调节作用。上世纪80年代，科学家们开始把这些天然存在或人工合成的，在神经组织具有活性的甾体激素命名为神经活性甾体(neuroactive steroids，NAS)。目前临床上已将这些甾体激素作为替代疗法运用于临床。雌激素是已知神经保护作用最强的NAS之一，绝经妇女卵巢停止产生雌激素，可引起β-淀粉样蛋(beta-amyloid protein，Aβ)沉积，导致阿尔茨海默病(AIzheimer s disease，AD)。而给予雌激素能明显降低大脑的Aβ水平，临床上将雌激素用于AD的治疗，收到良好的效果。有研究表明，别孕烯醇酮可以保护由缺氧和谷氨酸引起的体外培养海马神经元不可逆的神经毒性损伤。5α-雄甾(烷)-3β，5，6β-三醇(YC-6)是我们在神经甾体研究过程中发现的具有神经保护作用的化合物，其化学结构如图如示。据我们的文献检索，到目前为此，未见YC-6药理作用的报导，也没有YC-6对神经组织具有活性或具有神经保护作用的研究报导。
5α-雄甾(烷)-3β，5，6β-三醇的结构式
发明内容
本发明的目的在于提供5α-雄甾(烷)-3β，5，6β-三醇在制备神经元保护药物中的应用，从而为神经元疾病的治疗提供一种新药物。
我们的研究表明，5α-雄甾(烷)-3β，5，6β-三醇(简称YC-6)可明显抑制谷氨酸诱导的小脑颗粒神经元、皮层神经元和脊髓运动神经元的兴奋性毒性损伤，提高神经元的存活率，降低乳酸脱氢酶的释放，并呈剂量依赖关系，最低有效浓度为1μM。YC-6可明显抑制缺氧引起的大脑皮层神经元损伤，呈剂量依赖关系，最低有效浓度为2.5μM。
为了证实YC-6在体内有无神经保护作用，我们采用1)局灶性大脑缺血模型及2)阻断腹主动脉引起的脊髓损伤模型，研究了YC-6对大鼠大脑缺血及兔脊髓缺血引起的神经元损伤的保护作用。
YC-6组在大鼠脑缺血前30分钟经尾静脉静脉注射1mg.Kg-1YC-6，其神经功能评分明显高于未处理的对照组，脑梗死体积明显小于未处理的对照组。说明YC-6对脑神经元损伤有明显的保护作用。
施行脊髓缺血前30分钟预先注射2mg.Kg-1YC-6，其神经功能评分明显高于未处理的对照组，且无动物出现瘫痪。而对照组全部动物呈现瘫痪。组织病理学显示，YC-6组的正常脊髓前角运动神经元的数量明显多于对照组，进一步说明YC-6对脊髓神经元损伤有明显的保护作用。
综上，YC-6对脑缺血、脊髓缺血及缺氧引起的神经元损伤有保护作用。到目前为此，还没有YC-6对神经组织具有活性或具有神经保护作用的研究报导。
附图说明
图1为YC-6对谷氨酸诱导的小脑颗粒神经元、脊髓运动神经元、大脑皮层神经元兴奋性损伤的保护作用图，其中A为小脑颗粒神经元，B为脊髓运动神经元，C为大脑皮层神经元，D为LDH释放率，E为神经元存活率；*与**分别表示小脑颗粒神经元YC-6组与谷氨酸(Glu)组相比存在显著性差别，*P＜0.05，**P＜0.01；#与##分别表示脊髓运动神经元YC-6组与谷氨酸(Glu)组相比存在显著性差别，#P＜0.05，##P＜0.01；$与$$分别表示大脑皮层神经元YC-6组与谷氨酸(Glu)组相比存在显著性差别，$P＜0.05，$$P＜0.01。
图2为YC-6对缺氧诱导的皮层神经元损伤的保护作用图，其中A为相差显微镜结果，B为神经元存活率，C为LDH释放值；##表示缺氧组与control组相比有显著性差别P＜0.01；*与**分别表示YC-6组与缺氧组相比有显著性差别*P＜0.05，**P＜0.01。
图3为YC-6对腹主动脉夹闭致兔脊髓缺血模型的神经保护作用图，其中A为神经功能评分，B为组织病理切片，C为正常脊髓运动神经元记数。
图4为YC-6对局灶性大鼠大脑缺血模型的神经保护作用图，其中A为神经功能评分，B为大脑梗死切片图，C为大脑梗死容积比较。
具体实施方式
下面通过具体实施例进一步解释本发明，但是本发明不仅限于实施例中。
实施例1.神经元的培养
1.大鼠小脑颗粒神经元
取出生7～8d，体重约15～20g大鼠的去除脑膜和血管的小脑，用0.25g/L胰酶消化后，用0.05g/L DNase I的吹散液将细胞吹散为单细胞悬液，离心，取沉淀，用含10％(v/v)FBS和25mM KCl的BME培养基稀释并接种于经多聚赖氨酸预包被的培养皿中。接种24小时后加入10μM Ara-C以抑制非神经元细胞的生长和增殖，使小脑颗粒神经元的纯度在95％以上。培养时加入葡萄糖补充细胞代谢所需能量。第8天进行实验。
2.大鼠脊髓运动神经元
孕15天SD大鼠分离脊髓，去除脊膜和血膜，取胎鼠脊髓组织用0.125％胰酶消化后，离心，取含有丰富运动神经元的中层，离心去掉细胞碎片后，差速贴壁1h，选取贴壁速度慢的，悬浮的脊髓运动神经元。接种24h后加入阿糖胞苷，第3天全量换液，以L-15无血清培养基继续培养，每2-3天半量换液。第3-5天进行实验。
3.大鼠皮层神经元
取出生1d的大鼠的去除脑膜和血管的皮层，用0.25g/L胰酶消化后，用0.05g/L DNase I的吹散液将细胞吹散为单细胞悬液，离心，取沉淀，用含5％(v/v)FBS和2％B27的DMEM-F12培养基稀释并接种于经多聚赖氨酸预包被的培养皿中。接种24小时后加入10μM Ara-C以抑制非神经元细胞的生长和增殖，以后每周2-3次半量换液。第10天进行实验。
实施例2.YC-6对原代培养神经元细胞的保护作用
1.YC-6对谷氨酸诱导的小脑颗粒神经元兴奋性损伤的保护作用
培养8天的小脑颗粒神经元，分别设正常对照组、谷氨酸组、MK801+谷氨酸、YC-6+谷氨酸组。正常对照组不做任何处理，谷氨酸组加入200μM谷氨酸，其它组预先加入MK801(10μM)和不同浓度的YC-6，37℃孵育30分钟后加入谷氨酸，24h后用相差显微镜观察神经细胞形态；用FDA染色，倒置荧光显微镜观察，进行细胞计数，计算神经元的存活率。并测定各组乳酸脱氢酶的活性。
存活率＝各组活细胞数/对照组活细胞数×100％。
结果发现，YC-6+谷氨酸组和MK801+谷氨酸组大部分小脑颗粒神经元能保持胞体和突起的完整，细胞存活率增加，LDH释放值降低，与谷氨酸组比较呈现明显差异，且YC-6存在浓度依赖关系，见图1-A，D，E。而在上述剂量范围YC-6对正常神经细胞的存活率无影响。
2.YC-6对谷氨酸诱导的脊髓运动神经元兴奋性损伤的保护作用
培养5天的脊髓运动神经元，分别设正常对照组、谷氨酸组、MK801+谷氨酸、YC-6+谷氨酸组。正常对照组不做任何处理，谷氨酸组加入200μM谷氨酸，其它组预先加入MK801(10μM)和不同浓度的YC-6，37℃孵育30分钟后再加入谷氨酸，24h后用相差显微镜神经细胞形态，用FDA染色，倒置荧光显微镜进行细胞计数，计算神经元的存活率。并测定各组乳酸脱氢酶的活性。
存活率＝各组活细胞数/对照组活细胞数×100％。
结果发现，倒置相差显微镜下观察，对照组存活的脊髓运动神经元数目多，胞体丰满，呈三角形、多角形、立体感强，有光晕可见分枝和突起；谷氨酸组存活脊髓运动神经元数少，但有突起形成，细胞严重受 损；而YC-6+谷氨酸和MK801+谷氨酸组脊髓运动神经元数目明显增多，并有很多突起，但仍有少数死亡细胞。与对照组比，其余三组的脊髓运动神经元存活率均有不同程度下降，与谷氨酸组相比，YC-6+谷氨酸组存活率有明显提高，且与YC-6存在浓度依赖关系，见图1-B，D，E。而在上述剂量范围YC-6对正常神经细胞的存活率无影响。
3.YC-6对谷氨酸诱导的皮层神经元兴奋性损伤的保护作用
培养10天的皮层神经元，分别设正常对照组、谷氨酸组、MK801+谷氨酸、YC-6+谷氨酸组。正常对照组不做任何处理，谷氨酸组加入200μM谷氨酸，其它组预先加入溶剂、MK801(10μM)和不同浓度的YC-6，37℃孵育30分钟后加入谷氨酸，24h后用相差显微镜神经细胞形态，用FDA染色，倒置荧光显微镜观察，进行细胞计数，计算神经元的存活率。并测定各组乳酸脱氢酶的活性。
存活率＝各组活细胞数/对照组活细胞数×100％。
结果发现，YC-6+谷氨酸组和MK801+谷氨酸组大部分皮层神经元能保持胞体和突起的完整，细胞存活率增加，LDH释放值降低，与谷氨酸组比较呈现明显差异，且与YC-6存在浓度依赖关系，见图1-C，D，E。而在上述剂量范围YC-6对正常神经细胞的存活率无影响。
4.YC-6对缺氧诱导的皮层神经元兴奋性损伤的保护作用
培养到10天的原代皮层神经元正常对照组、缺氧组、MK801+缺氧组、YC-6+缺氧组。每组设置副孔3个，正常对照组置于二氧化碳箱正常孵育，缺氧组置于缺氧工作站(氧气浓度1％)。MK801+缺氧组、YC-6+缺氧组则在置入缺氧工作站(氧气浓度1％)前30min用MK801(10μM) 和不同浓度的YC-6预处理。12小时后于相差显微镜下观察并拍照。
在96孔板中如上分组以及处理，然后加入MTT储存液200μl，作用4h，存活的细胞中形成紫蓝色结晶。去除各孔中的液体，加入DMSO150μl，溶解紫蓝色结晶。半小时后，待结晶完全溶解，用酶联仪570nm波长测定OD值。损伤组与对照组各时间点留取培养液50μL，依试剂盒说明书检测各孔培养液LDH含量。各组数据以mean±SD表示，采用多个样本均数间方差分析及两两比较的t检验检验进行统计学分析。参考文献[1]和[2]。[1]Brewer G.J.Isolation and culture of aldut rathippocampal neurons.J.Neurosci.Meth.1997，71：143-155.[2]Lee M.M.，Hseih M.T.Magnolol protects cortical neuronal cells from chemical hypoxiain rats.Neuroreport 1998，9：3451-3456.
结果表明，大鼠皮层神经元培养10天后，细胞呈锥形或多极形，胞体清晰明亮，边界清楚，有很强的折光性，神经元突起相互交织成网，细胞核明显。缺氧处理的皮层神经元完整性受到破坏，折光性降低，突触断裂、消失，胞质颗粒性变，部分胞体肿胀甚至消失。MK801预处理组与YC-6预处理组与正常对照组相比，皮层神经元基本无形态学差异。神经元保护作用与YC-6呈浓度依赖关系(图2A)。MTT法结果表明，缺氧处理明显减低了神经元的存活率(P＜0.05)，而YC-6呈浓度依赖性提高高了缺氧损害造成的神经元存活率(图2B)。LDH释放结果与MTT法相符，YC-6预处理组浓度依赖性地降低了缺氧造成的神经元损伤(图2-C，P＜0.05)。
实施例3.YC-6对腹主动脉夹闭致兔脊髓缺血模型的神经保护作用
40只雄性新西兰大白兔分为4组(n＝10)：Control组制作兔脊髓缺血模型；YC-6组在脊髓缺血前30分钟经耳缘静脉注射2mg.Kg-1甾体YC-6；Vehicle组在脊髓缺血前30min同样方式注射等容量羟丙基环糊精(1ml·Kg-1)；Sham组仅仅暴露腹主动脉，不实施阻断。
兔脊髓缺血模型制作参照文献报道[3，4]和我们先前的研究[5]。[3]CelikM.，et al.Erythropoietin prevents motor neuron apoptosis and neurologicdisability in experimental spinal cord ischemic injury.Proc Natl Acad Sci US A，2002，99：2258-2263.[4]Johnson SH，Kraimer J.M.，Graeber G.M.Effects of flunarizine on neurological recovery and spinal cord blood flow inexperimental spinal cord ischemia in rabbits.Stroke，1993，24：1547-1553.[5]Sang H.，Cao L.，Qiu P.，Xiong L.，Wang R.，Yan G.Isoflurane producesdelayed preconditioning against spinal cord ischemic injury via release offree radicals in rabbits.Anesthesiology.2006，105：953-960.
缺血前即刻，缺血后10min及再灌注后20min测定组间各生理学参数。用Talov评分法[5]进行各组兔的功能评分：0分，后肢完全瘫痪；1分，可以觉察的后肢关节运动；2分，后肢可以自由运动但无法站立；3分，可以站立但无法行走；4分，后肢运动功能完全恢复，可以正常行走。
神经功能评分完毕后，在麻醉状态下取腰段脊髓组织(L5-L7)，行石腊包埋后切片，HE染色，光镜下由一不了解分组情况的观察者观察脊髓病理学改变并对脊髓前角正常运动神经元计数。每只动物脊髓前角正常神经元计数为3张切片计数的均值。
结果表明，缺血前即刻，缺血后10min及再灌注后20min测定各组间生理学参数无明显差异(P＞0.05)。各组动物神经功能评分结果详见图3-A。假手术组兔的后肢神经功能在整个观察期间完全正常(4分)；而Control和Vehicle组中没有一只兔能够站立；YC-6组中有7只兔能够站立(大于或等于3分)。YC-6组和Sham组的神经功能评分均明显高于Control和Vehicle组(P＜0.05)。
在Control和Vehicle组，腰段脊髓有严重的损伤，表现为正常运动神经元基本消失、大量空泡变性；而在YC-6组，腰段脊髓损伤明显减轻，可见正常的运动神经元，图3-B。YC-6组和Sham组的脊髓前角正常神经细胞数明显增多(P＜0.05)。见图3-C。
综上，YC-6对脊髓缺血具明显的保护作用。
实施例4.YC-6对大鼠局灶性脑缺血模型(MCAO)的神经保护作用
30只雄性SD大鼠随机均分为3组(n＝10)：Control组制作大鼠局灶性脑缺血模型；YC-6组在脑缺血前30分钟经尾静脉静脉注射1mg.Kg-1YC-6；Vehicle组在脊髓缺血前30钟同样方式注射等容量的羟丙基环糊精(2ml·Kg-1)。
术前禁食12h，自由饮水。采用线栓法制作大脑中动脉阻闭(MCAO)模型[6]。[6]Wang Q.，Peng Y.，Chen S.，Gou X.，Hu B.，Du J.，Lu Y.，XiongL.Pretreatment with electroacupuncture induces rapid tolerance to focalcerebral ischemia through regulation of endocannabinoid system.Stroke，2009，40(6)：2157-2164.阻闭120min后抽出尼龙线，恢复再灌注。激光多普勒血流仪监测局部脑血流。术毕麻醉苏醒后，将动物放回鼠笼，自 由饮食。脑缺血再灌注后72h，由一不了解分组情况的观察者根据Longa评分法[7]。[7]Longa E.Z.，Weinstein P.R.，Carlson S.，Cummins R.Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke，1989，20(1)：84-91.评估并记录神经功能评分：0级，无功能障碍；1级，不能伸展左侧前肢；2级，向左侧旋转；3级，向左侧倾倒；4级，无自主活动伴意识抑制；5级，死亡。
神经功能评分完成后，断头处死大鼠，迅速取出鼠脑，切片后迅速用TTC溶液染色30min，然后用多聚甲醛缓冲液固定。24h后用数码相机拍照，输入计算机，用图像处理软件(ADOBE，PHOTOSHOP 8.0)计算梗死面积(粉红色区为正常脑组织，白色区为梗死区)。为校正脑水肿带来梗死容积的偏差，用占对侧正常容积的百分比表示梗死容积。
梗死容积百分比＝(对侧正常组织容积-同侧正常组织的容积)/对侧正常组织容积×100％。
神经行为学评分(NBS)采用非参(Kruskal-Wallis)检验，若存在组间差异，以Mann-Whitney U检验Bonferroni校正进行两两比较。梗死容积和生理学参数采用均数±标准差(mean±SD)表示，采用单因素方差分析(ANOVA)，多组间两两比较采用SNK(post hocStudent-Newman-Keuls)检验。*P＜0.05表示有显著的统计学差异。
各组动物神经功能评分结果详见图5。与Control和Vehicle组相比，YC-6组神经功能明显改善，脑梗死容积明显减少(*P＜0.05)。
综上，YC-6，即雄甾(烷)-3β，5α，6β-三醇对低氧、脑缺血、脊髓缺血引起的神经元损伤有保护作用。
Claims (1)
1.5α-雄甾(烷)-3β，5，6β-三醇在制备神经元保护药物中的应用，所述神经元保护药物为治疗脑缺血药物、治疗脊髓缺血药物或治疗由于缺氧引起的神经元损伤药物。
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| CN2010102241733A CN101884638B (zh) | 2010-07-09 | 2010-07-09 | 5α-雄甾(烷)-3β,5,6β-三醇在制备神经元保护药物中的应用 |
| KR1020127032524A KR101463477B1 (ko) | 2010-07-09 | 2011-07-08 | 5a-안드로스탄(알킬)-3β,5,6β-트리올의 신경보호 약물 제조에서의 용도 |
| HUE11803155A HUE032159T2 (en) | 2010-07-09 | 2011-07-08 | The use of 5-alpha-androstane-3β, 5,6ß-triol in the manufacture of neuroprotective drugs |
| SG2012088688A SG186135A1 (en) | 2010-07-09 | 2011-07-08 | Use of 5a-androstane (alkyl)-3b,5,6b-triol in preparing neuroprotective drugs |
| EP11803155.8A EP2591785B1 (en) | 2010-07-09 | 2011-07-08 | Use of 5-androstane (alkyl)-3,5,6 -triol in preparing neuroprotective drugs |
| RU2012151400/15A RU2541093C2 (ru) | 2010-07-09 | 2011-07-08 | Применение 5а-андростан-3в,5,6в-триола для изготовления нейропротекторных лекарственных средств |
| LTEP11803155.8T LT2591785T (lt) | 2010-07-09 | 2011-07-08 | 5-androstan(alkil)-3,5,6-triolio panaudojimas neuroprotekcinių vaistų gamybai |
| DK11803155.8T DK2591785T3 (en) | 2010-07-09 | 2011-07-08 | USE OF 5-ANDROSTANE (ALKYL) -3,5,6-TRIOL FOR THE PREPARATION OF NEURO PROTECTIVE MEDICINE |
| JP2013516989A JP5681931B2 (ja) | 2010-07-09 | 2011-07-08 | ニューロン保護薬の製造のための５α−アンドロスタン−３β，５，６β−トリオールの使用 |
| CA2802133A CA2802133C (en) | 2010-07-09 | 2011-07-08 | Use of 5.alpha.-androstane(alkyl)-3.beta.,5,6.beta.-triol in preparation of neuroprotective drugs |
| AU2011276800A AU2011276800B2 (en) | 2010-07-09 | 2011-07-08 | Use of 5a-androstane (alkyl)-3B,5,6B-triol in preparing neuroprotective drugs |
| ES11803155.8T ES2620754T3 (es) | 2010-07-09 | 2011-07-08 | Uso de 5-androstano (alquil)-3,5,6-triol en la preparación de fármacos neuroprotectores |
| PCT/CN2011/076967 WO2012003802A1 (zh) | 2010-07-09 | 2011-07-08 | 5α-雄甾（烷）-3β，5，6β-三醇在制备神经元保护药物中的应用 |
| US13/805,436 US8809309B2 (en) | 2010-07-09 | 2011-07-08 | Use of 5α-androstane (alkyl)-3β,5,6β-triol in preparation of neuroprotective drugs |
| BR112012031861A BR112012031861B1 (pt) | 2010-07-09 | 2011-07-08 | uso de 5a-androstano-3ß,5,6ß-triol |
| SI201131126A SI2591785T1 (sl) | 2010-07-09 | 2011-07-08 | Uporaba 5-androstan(alkil)-3,5,6-triola pri pripravi nevroprotektivnega zdravila |
| PL11803155T PL2591785T3 (pl) | 2010-07-09 | 2011-07-08 | Zastosowanie 5-androstano(alkilo)-3,5,6-triolu do wytwarzania leków neuroprotekcyjnych |
| PT118031558T PT2591785T (pt) | 2010-07-09 | 2011-07-08 | Utilização de 5-androstano(alquilo)-3,5,6-triol na preparação de fármacos neuroprotetores |
| RS20170319A RS55845B1 (sr) | 2010-07-09 | 2011-07-08 | Upotreba 5-androstan (alkil)-3,5,6 -triola u pripremanju neuroprotektivnih lekova |
| US14/332,338 US9320743B2 (en) | 2010-07-09 | 2014-07-15 | Use of 5α-androstane-3β,5,6β-triol in preparation of neuroprotective drugs |
| HRP20170418TT HRP20170418T1 (hr) | 2010-07-09 | 2017-03-14 | Uporaba 5-androstan (alkil)-3,5,6-triola u pripravi neuroprotektivnih lijekova |
| CY20171100375T CY1118789T1 (el) | 2010-07-09 | 2017-03-27 | Χρηση 5α-ανδροστανο(αλκυλο)-3β,5-6β-τριολης σε παρασκευη νευροπροστατευτικων φαρμακων |
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| CN101961311B (zh) * | 2010-09-21 | 2012-11-21 | 中山大学 | 一种5α-雄甾(烷)-3β,5,6β-三醇注射剂及其制备方法 |
| CN103626819B (zh) * | 2012-03-08 | 2016-01-20 | 广州市赛普特医药科技有限公司 | 雄甾-3β,5α,6β-三醇的晶型化合物及其制备方法 |
| EP2653163A1 (en) * | 2012-04-19 | 2013-10-23 | Université de Liège | Estrogenic components for use in the treatment of neurological disorders |
| CN104072564B (zh) | 2013-03-28 | 2016-08-17 | 广州市赛普特医药科技股份有限公司 | 2β,3α,5α-三羟基-雄甾-6-酮及其制备方法与用途 |
| CN108125965B (zh) * | 2014-04-25 | 2020-04-10 | 广州市赛普特医药科技股份有限公司 | 5α-雄甾-3β,5,6β-三醇及其类似物在高原病中的应用 |
| CN109985049B (zh) * | 2017-12-29 | 2022-02-22 | 广州市赛普特医药科技股份有限公司 | 5α-雄甾-3β,5,6β-三醇在制备治疗脑小血管病的药物中的应用 |
| CN113350359B (zh) * | 2017-12-29 | 2022-08-16 | 广州市赛普特医药科技股份有限公司 | 5α-雄甾-3β,5,6β-三醇在制备治疗出血性脑卒中药物中的应用 |
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| EP2591785B1 (en) | 2017-01-04 |
| RU2541093C2 (ru) | 2015-02-10 |
| HUE032159T2 (en) | 2017-09-28 |
| US20140329790A1 (en) | 2014-11-06 |
| ES2620754T3 (es) | 2017-06-29 |
| BR112012031861B1 (pt) | 2020-02-04 |
| US20130157993A1 (en) | 2013-06-20 |
| KR20130038286A (ko) | 2013-04-17 |
| CY1118789T1 (el) | 2018-03-07 |
| SI2591785T1 (sl) | 2017-07-31 |
| CA2802133C (en) | 2014-01-14 |
| EP2591785A1 (en) | 2013-05-15 |
| AU2011276800A1 (en) | 2013-01-10 |
| CA2802133A1 (en) | 2012-01-12 |
| CN101884638A (zh) | 2010-11-17 |
| KR101463477B1 (ko) | 2014-11-19 |
| JP2013529657A (ja) | 2013-07-22 |
| BR112012031861A2 (pt) | 2016-11-08 |
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| CP03 | Change of name, title or address |
Address after: Moon Road, Science City high tech Industrial Development Zone of Guangzhou City, Guangdong province 510663 No. 3 Guangzhou international business incubator C District No. G401-415 room Patentee after: GUANGZHOU SAIPUTE PHARMACEUTICAL TECHNOLOGY CO., LTD. Address before: Guangzhou Science City skim Springs Road No. 3, Guangzhou international business incubator C208 Patentee before: Guangzhou Saipute Medical Technology Co., Ltd. |