CN100348200C - 芍药甙的医药用途 - Google Patents
芍药甙的医药用途 Download PDFInfo
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- CN100348200C CN100348200C CNB2004100257178A CN200410025717A CN100348200C CN 100348200 C CN100348200 C CN 100348200C CN B2004100257178 A CNB2004100257178 A CN B2004100257178A CN 200410025717 A CN200410025717 A CN 200410025717A CN 100348200 C CN100348200 C CN 100348200C
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Abstract
本发明提供芍药甙的医药用途：芍药甙在制备治疗和预防中风及帕金森病等神经***疾病中的应用。
Description
技术领域
本发明涉及一种非嘌呤腺苷受体-1(Adenosine Receptor-1，A1R)的选择性激动剂——芍药甙的医药用途，具体指该化合物可选择性激动A1R受体，发挥治疗和预防中风及帕金森病等神经***疾病的作用，同时消除了传统的嘌呤类A1R激动剂的严重心血管副作用。
背景技术
芍药甙是一种天然活性化合物，源于毛茛科植物白芍、赤芍、及牡丹的根。其在源植物中的含量丰富，以山东曹县产白芍为例，该活性单体成分达1.95％；更甚之，芍药甙在牡丹根中的含量高达7％。再者，其源植物地域分布广泛，易于人工栽培，适于大规模产业化种植。药效学研究表明，其具有镇痛、镇静、解痉、抗炎、抗溃疡、扩张冠状动脉、对抗急性心肌缺血，以及抑制血小板凝聚等诸多方面的药效，且安全范围大。
大量研究发现，A1R受体激动剂一方面可激活突触前A1R受体，抑制谷氨酸等兴奋性氨基酸的释放，缓解细胞的兴奋毒性及Ca2+超负荷；另一方面，作用于突触后A1R受体，使K通道的电导增加，通过限制细胞膜去极化抑制神经元的兴奋。从而，发挥明显的神经保护作用(Heron A，Lekieffre D，Le Peillet E，Lasbennes F，Seylaz J，Plotkine M，Boulu RG.，Effects of an A1 adenosine receptor agonist on the neurochemical，behavioral and histologicalconsequences of ischemia.Brain Res.1994；641(2)：217-24.，Goldberg MP，Monyer H，Weiss JH，Choi DW.，Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivationin vitro.Neurosci Lett.1988；9(3)：323-7.，Mori M，Nishizaki T，Okada Y.，Protective effect ofadenosine on the anoxic damage of hippocampal slice.Neuroscience.1992；46(2)：301-7.，VonLubitz DK，Beenhakker M，Lin RC，Carter MF，Paul IA，Bischofberger N，Jacobson KA.，Reduction of postischemic brain damage and memory deficits following treatment with theselective adenosine A1 receptor agonist.Eur J Pharmacol.1996；302(1-3)：43-8.)，但A1R受体激动剂严重的心血管副作用，很大程度上限制了其临床应用(Collis MG，Hourani SM.，Adenosinereceptor subtypes.Trends Pharmacol Sci.1993；14(10)：360-6.Review.，Daval JL，Nehlig A，Nicolas F.，Physiological and pharmacological properties of adenosine：therapeutic implications.Life Sci.1991；49(20)：1435-53.Review.)。近年来，国际医药界投入大量的人力、物力，试图寻找神经保护作用确切，心血管副作用小的选择性A1R受体激动剂。
本研究基于配体-受体竞争性结合试验的高通量筛选平台，首次发现芍药甙选择性竞争结合A1R受体；其化学结构区别于传统的A1R受体激动剂，为一种新型的非嘌呤类A1R受体选择性激动剂；经典的试验动物模型证实，芍药甙具有治疗和预防中风及帕金森病等神经***疾病的作用；进一步的研究证明，其心血管副作用小，具有临床应用价值。
中风和帕金森病等神经***疾病是对人类健康威胁最大的杀手之一，在老年人中患病率和致残率居高不下。仅以中风为例，45-89岁的群体中，其发生率约为0.35％。其中约20％中风患者的存活期低于1个月；存活期超过6个月的患者中，超过30％的生活不能自理。个人、家庭、及社会承担着极大的心理上和经济上的双层负担。
本发明提供了一种治疗和预防中风及帕金森病等神经***疾病的新型药物，具有巨大的社会效益和经济效益。
发明内容
1.本发明的目的在于公开芍药甙是一种非嘌呤类A1受体选择性激动剂。
2.本发明的又一目的在于提供芍药甙在预防和治疗中风和帕金森症等神经***疾病中的应用。
本发明采用化学方法从毛茛科植物白芍、赤芍、及牡丹的根中提取分离出一种天然活性化合物芍药甙，经过药理试验发现芍药甙作为一种非嘌呤类腺苷受体-1的选择性激动剂，可以在制备预防和治疗中风和帕金森症等神经***疾病药物中得到应用。
本发明采用白芍、赤芍、及牡丹的根为原料，制备过程如下：
白芍、赤芍、或牡丹的根，经乙醇回流提取，得干浸膏，浸膏加水充分溶解，通过大孔树脂，水洗脱至糖反应阴性，加2倍柱体积乙醇洗脱，得浸膏，经硅胶柱层析分离得纯化合物芍药甙。
芍药甙化学结构如下：
它的分子式为：C23H28O11，分子量为480.48化学名为β-D-Glucopyranoside，56-[(benzoyloxy)methyl]tdtrahydro-5-hydroxy-2-methyl-2，5-methano-1H-3，4-dioxacyclobuta[cd]Pentalen-la(2H)-yl，[lar-cla α，2β，3aα，5α，5aα，5bα]]。
芍药甙的提取纯化方法参考文献(金继曙 都述虎 种明才 用大孔吸附树脂分离白芍总甙，中国中药杂志1994年01期 1994.VOL.19 NO.1：31)。
本发明采用上述方法提取获得的芍药甙进行了相关的药理药效试验。
一.芍药甙的配体-受体竞争性结合试验：
采用大鼠大脑皮层突触膜，将大鼠断头后，分离出大脑皮层，随后在1∶15(W/V)的蔗糖溶液中充分匀浆，离心，取上清离心。弃上清后，用1∶30(W/V)的Tris-Hcl缓冲液(50mM，PH 7.4)重悬沉淀，匀浆洗涤后再离心，洗涤过程重复3次后，用1∶5(W/V)的Tris-Hcl缓冲液(50mM，PH 7.4)再次重悬沉淀，分装保存于-80℃，并采用Bradford法测定蛋白浓度((Bradford MM.A rapid and sensitive method for the quantitation of microgram quantities ofproteins utilizing the principle of protein-dye binding.Anal Biochem.1976；72：248-254.)，上述操作均在4℃进行。
用上述模型分别验证芍药甙与A1R和A2aR受体混合型激动剂[3H]-乙基酰胺腺苷([3H]-NECA)及A1R受体选择性激动剂[3H]-CCPA的竞争性结合。
实验证明芍药甙可竞争结合[3H]-CCPA，同时对[3H]-NECA的竞争结合具有典型的双位点竞争特性(EC501＝13.9nM，EC502＝5.00μM)。结果提示芍药甙同时结合A1R和A2AR受体；并具有较高的选择性(EC502/EC501＝360倍)，低浓度选择性结合A1R，高浓度结合A2AR。
二.芍药甙预防和治疗中风的药效试验：
采用可逆性大鼠中动脉栓塞法分别制成暂时性和永久性两种局灶脑缺血模型(Belayev L，Alonso OF，Busto R，Zhao W，Ginsberg MD.Middle cerebral artery occlusion in the rat byintraluminal suture.Neurological and pathological evaluation of an improved model.Stroke，1996；27：1616-22.，Takano K，Tatlisumak T，Bergmann AG，Gibson DG 3rd，Fisher M.Reproducibilityand reliability of middle cerebral artery occlusion using a silicone-coated suture(Koizumi)in rats.J Neurol Sci.1997；153：8-11.)，分别检验芍药甙对脑缺血大鼠神经缺损体征及对大脑损伤体积的影响。腹腔注射氯醛糖麻醉，右股动脉插管监测血压，保持36.5～37.5℃肛温，颈部切口，游离颈外动脉，电凝切断其分支动脉，并在远端结扎，取颈头部呈鼓锤状4～0号的单丝尼龙线，由颈外动脉经颈内动脉***大脑前动脉以阻断大脑中动脉起始处，同时也阻断了大脑前动脉以阻断大脑中动脉起始处，同时也阻断了大脑前、后动脉及颈内动脉的侧支血流。暂时性MCAO模型组，缺血1.5hr后拔出栓线，再灌注22.5hr，于缺血后15分钟和6小时，分别皮下注射生理盐水、不同剂量的芍药甙；永久性MCAO模型组，不拔出栓线，连续缺血24hr，于缺血后15分钟和6小时，分别皮下注射生理盐水、芍药甙、和DPCPX+芍药甙，其中DPCPX在缺血前15min预先给予。
根据Syderff神经缺损体征判别法进行综合等级评分(Sydserff SG，Borelli AR，Green AR，Cross AJ.，Effect of NXY-059 on infarct volume after transient or permanent middle cerebralartery occlusion in the rat；studies on dose，plasma concentration and therapeutic time window.BrJ Pharmacol.2002；135(1)：103-12.)。根据前肢弯曲、自发旋转、及异侧搔挠刺激反应缺失的程度，分别评以0-2分(0＝正常，2＝严重)。此外，肢体异侧旋转的扭矩也被作为一个单独的指标，评以0-2分(0＝大扭矩，2＝小扭矩)。因此损伤评分值在0-8之间。
试验结果表明芍药甙在中剂量浓度(5mg.kg-1s.c.)下明显改善暂时性中动脉栓塞大鼠的神经症状，同时显著降低缺血引起的大脑皮层下核团及大脑皮层的损伤；芍药甙剂量依赖性的减轻缺血引起的大脑皮层下核团及大脑皮层的损伤，且此作用可被选择性AiR受体拮抗剂DPCPX所拮抗。提示芍药甙可能通过激活A1R受体，发挥神经保护作用，可用于中风的临床治疗和预防。
三.芍药甙在预防和治疗帕金森病(PD)的应用：
采用N-甲基苯四氢吡啶(1-methyl-4-phenyl-1，2，3，6-tetrahydro-pyridine，MPTP)诱导的小鼠PD模型，分别检测芍药甙对PD模型小鼠爬杆能力及中脑黑质多巴胺神经元缺失的影响。用20-25g雄性C57B1/6J小鼠，实验开始前测定按小鼠爬杆时间，以按爬杆时间随机分5组，每组8只。用低剂量和中剂量芍药甙分别连续11天皮下注射给药，于实验第8天以2小时为间隔腹腔注射(ip)4次N-甲基苯四氢吡啶(1-methyl-4-phenyl-1，2，3，6-tetrahydro-pyridine，MPTP)诱导小鼠PD模型。
通过爬杆法测定小鼠运动能力，将小鼠头向下，置于长55cm，直径为8mm的垂直粗糙的杆上，记录小鼠从杆向下爬至四肢全部接触地面的时间(Hamaue N，Minami M，Terado M，Hirafuji M，Endo T，Maehida M，Hiroshige T，Ogata A，Tashiro K，Saito H，Parvez SH.Comparative study of the effects of isatin，an endogenous MAO-inhibitor，and selegiline onbradykinesia and dopamine levels in a rat model of Parkinson′s disease induced by the Japaneseencephalitis virus.Neurotoxicology.2004 Jan；25(1-2)：205-13.)。
试验结果表明芍药甙中剂量组(5mg.kg-1s.c.)显著改善MPTP引起的运动功能障碍，对抗MPTP诱发的多巴胺能神经元的缺失，提示芍药甙可用于帕金森病的临床治疗和预防。
四.药甙对清醒大鼠血压的影响
以清醒大鼠为研究对象，采用尾套传感器，将压力脉冲传至光电三极管，转换为相应的血压和心率值。待大鼠恢复平静后，记录其血压和心率，作为基础值。随后，经尾静脉分别注射生理盐水、不同剂量芍药甙和利血平(reserpine)。
记录给药前(0min)及给药后(5min至2hr)的血压和心率的变化。
试验结果显示不同剂量的芍药甙(10，40，160mg kg-1，i.v.)均不影响大鼠血压和心率，显然在其发挥治疗和预防中风及帕金森病等神经***疾病的治疗剂量范围内，无显著的心血管副作用。
附图说明：
图1.1是分别用不同浓度的芍药甙、CPA(选择性A1R受体激动剂)和CV-1808(选择性A2AR受体激动剂)竞争[3H]-NECA(A1R和A2AR混合型激动剂)在大鼠大脑皮层突触膜上的结合位点。结果显示芍药甙剂量依赖性地竞争[3H]-NECA于大鼠大脑皮层突触膜上的结合位点，并具有双位点竞争特性(EC501＝13.9nM，EC502＝5.00μM)。
图1.2是分别用不同浓度的芍药甙竞争[3H]-CCPA(选择性A1R受体激动剂)在大鼠大脑皮层突触膜上的结合位点。结果显示芍药甙剂量依赖性地竞争[3H]-CCPA于大鼠大脑皮层突触膜上的结合位点(EC50＝19.8nM)。
图2.1(a)芍药甙(2.5mg·kg-1，5mg·kg-1)对暂时性MCACO大鼠神经症状的改善(n＝6，*p＜0.05，**p＜0.01 vs Sal)；(b)芍药甙(2.5mg·kg-1，5mg·kg-1)对暂时性MCACO大鼠皮层下核团及皮层的保护(n＝6，*p＜0.05，**p＜0.01 vs Sal)。
图2.2芍药甙(2.5mg·kg-1，5mg·kg-1，10mg·kg-1s.c.)对暂时性MCACO大鼠皮层下核团及皮层的保护，DPCPX(0.25mg·kg-1s.c.)阻断芍药甙的保护作用(n＝6，*p＜0.05，**p＜0.01 vs Sal；#p＜0.05 vs芍药甙10mg·kg-1 s.c.)。
图3.1芍药甙(PF)(2.5mg·kg-1，5mg·kg-1s.c.)对MPTP引起小鼠运动徐缓的影响。
图3.2芍药甙(PF)(2.5mg·kg-1，5mg·kg-1s.c.)对MPTP引起的多巴胺能神经元的缺失及纹状体多巴胺神经纤维的减少的影响。
图4.1芍药甙(10，40，160mg kg-1，i.v.)不影响清醒大鼠血压的影响(n＝6；*p＜0.05，**p＜0.01)。
图4.2芍药甙(10，40，160mg kg-1，i.v.)不影响清醒大鼠心率的影响(n＝6；*p＜0.05，**p＜0.01)。
从上述实验可以看出，本发明所提供的化合物芍药甙竞争结合A1R受体，并具有高选择性。就其化学结构而言，区别于传统的A1R受体激动剂，为一种新型的非嘌呤类A1R受体激动剂。通过相关动物实验确证，芍药甙具有治疗和预防中风及帕金森病等神经***疾病的作用；进一步的研究证明，其心血管副作用小，具有临床应用价值，可以在中风及帕金森病等神经***疾病的治疗和预防中得以应用。
具体实施方式
实施例1：芍药甙是一种非嘌呤类A1受体的选择性激动剂
1.1.大鼠大脑皮层突触膜制备
将大鼠断头后，立即分离出大脑皮层，置于冰冷的生理盐水。随后，在1∶15(W/V)的蔗糖溶液(0.32mol/L)中充分匀浆，离心(1,000×g，10分钟)，取上清离心(30,000×g，30分钟)。弃上清后，用1∶30(W/V)的Tris-Hcl缓冲液(50mM，PH 7.4)重悬沉淀，匀浆洗涤后再离心(48,000×g，10分钟)。此洗涤过程重复3次后，用1∶5(W/V)的Tris-Hcl缓冲液(50mM，PH 7.4)再次重悬沉淀，分装保存于-80℃，并采用Bradford法测定蛋白浓度上述操作均在4℃进行。
1.2.配体-受体竞争结合
选用A1R和A2aR受体混合型激动剂[3H]-NECA(NEN；15.3 Ci/mmol＝0.57 TBq/mmol)以及A1R受体选择性激动剂[3H]-CCPA(NEN；30 Ci/mmol＝2.9PBq/mol)，检验芍药甙与A1R和A2aR受体的结合。反应体系为200μL，其中预试药物5μL，分别为芍药甙、A1R选择性激动剂(CPA)和A2aR受体选择性激动剂(CV-1808)，终浓度均从0，10-10到10-4mol/L；大脑皮层突触膜悬液20μL；25nmol/L的[3H]-NECA或0.2nmol/L的[3H]-CCPA 20μL；分析缓冲液(50mmol/L Tris-HCl，1mmol EDTA，0.5％BSA，pH 7.4)155μL。样品于25℃孵育3小时后，采用细胞收集器抽吸反应液，使之透过GF/C滤膜，以中止反应，再用过滤缓冲液(50mmol/LTris-HCl，0.1％BSA，pH 7.4)冲洗滤膜3次，随后于40℃干燥1小时。再将滤膜装入密封袋，加入5mL MicroScint 20，压匀后加以封条，进行放射活性计数(Microβ，PerkinElmer)。统计结果按双位点竞争模型进行拟合。
1.3.试验结果
芍药甙可竞争结合[3H]-CCPA，其EC50＝19.8nM；同时对[3H]-NECA的竞争结合具有典型的双位点竞争特性(EC501＝13.9nM，EC502＝5.00μM)。结果提示芍药甙同时结合A1R和A2AR受体；并具有较高的选择性(EC502/EC501＝360倍)，低浓度选择性结合A1R，高浓度结合A2AR。
实施例2：芍药甙在预防和治疗中风中的应用
2.1.动物模型及给药方法
采用可逆性大鼠中动脉栓塞法分别制成暂时性和永久性两种局灶脑缺血模型，腹腔注射氯醛糖350mg·kg-1麻醉，右股动脉插管监测血压，保持36.5～37.5℃肛温，颈部切口，游离颈外动脉，电凝切断其分支动脉，并在远端结扎，取颈头部呈鼓锤状4～0号的单丝尼龙线，由颈外动脉经颈内动脉***大脑前动脉以阻断大脑中动脉起始处，同时也阻断了大脑前动脉以阻断大脑中动脉起始处，同时也阻断了大脑前、后动脉及颈内动脉的侧支血流。暂时性MCAO模型组，缺血1.5hr后拔出栓线，再灌注22.5hr，于缺血后15分钟和6小时，分别皮下注射生理盐水(2mL·kg-1)、芍药甙(2.5mg·kg-1，5mg·kg-1)；永久性MCAO模型组，不拔出栓线，连续缺血24hr，于缺血后15分钟和6小时，分别皮下注射生理盐水(2mL·kg-1)、芍药甙(2.5mg·kg-1，5mg·kg-1，10mg·kg-1)、和DPCPX(2.5mg·kg-1)+芍药甙(10mg·kg-1)，其中DPCPX在缺血前15min预先给予。
2.2.指标测定
2.2.1.神经缺损评价标准
根据Syderff神经缺损体征判别法进行综合等级评分根据前肢弯曲、自发旋转、及异侧搔挠刺激反应缺失的程度，分别评以0-2分(0＝正常，2＝严重)。此外，肢体异侧旋转的扭矩也被作为一个单独的指标，评以0-2分(0＝大扭矩，2＝小扭矩)。因此损伤评分值在0-8之间。
2.2.2.脑缺血的功能性酶组织化学染——TTC染色
将大鼠断头后，立即取出大脑，-20℃储存15min，连续冠状切片(片厚2mm)。脑片置于1％TTC(PH7.2)染色，37℃孵育10min，倾去染色液，固定于4％甲醛溶液。数码相机拍照，对脑切片的皮层及皮层下损伤区进行象素点扫描(Adobe ImageReady 7.0)，计算出皮层损伤区，皮层下损伤区及总损伤区所占的面积百分比，进一步参照全脑体积，推算皮层损伤区，皮层下损伤区及总损伤区的体积。
2.3.试验结果
实验结果显示芍药甙(5mg·kg-1s.c.)明显改善暂时性MCAO大鼠的神经症状，同时显著降低缺血引起的大脑皮层下核团及大脑皮层的损伤；芍药甙(2.5，5，10mg·kg-1s.c.)剂量依赖性的减轻缺血引起的大脑皮层下核团及大脑皮层的损伤，且此作用可被选择性A1R受体拮抗剂DPCPX所拮抗。提示芍药甙可能通过激活A1R受体，发挥神经保护作用，可用于中风及其后遗症中的临床治疗和预防。
实施例3：芍药甙在预防和治疗帕金森病的应用
3.1.动物模型及给药方法
20-25g雄性C57B1/6J小鼠，实验开始前测定按小鼠爬杆时间，以按爬杆时间随机分5组，每组8只。芍药甙(2.5mg kg-1，5mg kg-1)连续11天皮下注射给药，于实验第8天以2小时为间隔腹腔注射(ip)4次N-甲基苯四氢吡啶(1-methyl-4-phenyl-1，2，3，6-tetrahydro-pyridine，MPTP)诱导小鼠PD模型。给药方案如下：
| 组别 | 给药 | 剂量 | ip MPTP(on day 8) |
| 对照组 | Salme | 0.1ml/10g | |
| 模型组 | Saline | 0.1ml/10g | 4×20mg/kg·d |
| 低剂量组 | 芍药甙 | 2.5mg/kg | 4×20mg/kg·d |
| 中剂量组 | 芍药甙 | 5mg/kg | 4×20mg/kg·d |
3.2.指标测定
3.2.1爬杆法测定小鼠运动能力
将小鼠头向下，置于长55cm，直径为8mm的垂直粗糙的杆上，记录小鼠从杆向下爬至四肢全部接触地面的时间
3.2.2中脑黑质多巴胺神经元免疫荧光染色——酪氨酸羟化酶(Tyrosine hydroxylase，TH)染色
心脏灌注4％多聚甲醛进行前固定，随后取出大脑，4％甲醛溶液后固定一周。于-20℃连续冠状切片(片厚30□m)，以酪氨酸羟化酶(Tyrosine hydroxylase，TH)作为多巴胺神经元的特异性标记。一抗为单克隆小鼠TH抗体(1∶1000，Sigma)，二抗为Alexa fluor 488荧光标记山羊抗小鼠(1∶1000，Molecular Probes)。荧光显微镜(Olympus DP70)拍照，并对黑质TH阳性细胞计数。
3.3.试验结果
芍药甙(5mg·kg-1 s.c.)明对抗MPTP引起的多巴胺能神经元的缺失及运动功能障碍，提示芍药甙可用于帕金森病的临床治疗和预防。
实施例4：芍药甙不影响清醒大鼠血压
4.1.动物模型及给药方法
以清醒大鼠为研究对象，采用尾套传感器，将压力脉冲传至光电三极管，转换为相应的血压和心率值。待大鼠恢复平静后，记录其血压和心率，作为基础值。随后，经尾静脉分别注射生理盐水、芍药甙(10，40，160mg kg-1)和利血平(reserpine)。
4.2.指标测定
记录给药前(0min)及给药后(5min至2hr)的血压和心率的变化。
4.3.试验结果
芍药甙(10，40，160mg kg-1，i.v.)不影响大鼠血压和心率，显然在其发挥治疗和预防中风及帕金森病等神经***疾病的治疗剂量范围内，无显著的心血管副作用。
Claims (4)
1、一种从毛莨科植物白芍、赤芍、牡丹根中提取分离结构如下的芍药甙
在制备一种非嘌呤类A1受体选择性激动剂药物中的应用。
2.根据权利要求1所述的芍药甙的医药用途，其特征在于所述的芍药甙在制备治疗和预防神经***疾病的药物中的应用。
3.根据权利要求2所述的芍药甙的医药用途，其特征在于所述的芍药甙在制备治疗和预防中风和中风后遗症的药物中的应用。
4.根据权利要求2所述的芍药甙的医药用途，其特征在于所述的芍药甙在制备治疗和预防帕金森症及其他相关的神经退行性病变的药物中的应用。
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| CNB2004100257178A CN100348200C (zh) | 2004-07-02 | 2004-07-02 | 芍药甙的医药用途 |
| JP2007519597A JP2008505128A (ja) | 2004-07-02 | 2005-06-27 | ペオニフロリンの医薬用途 |
| US11/631,123 US20080275226A1 (en) | 2004-07-02 | 2005-06-27 | Medical Use of Paeoniflorin |
| PCT/CN2005/000929 WO2006002589A1 (fr) | 2004-07-02 | 2005-06-27 | Utilisation medicale de paeoniflorine |
| EP05757963A EP1767210A4 (en) | 2004-07-02 | 2005-06-27 | MEDICAL USE OF PAEONIFLORIN |
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| CN102731522B (zh) * | 2011-04-01 | 2014-10-22 | 中国科学院上海药物研究所 | 一种具有环氧化酶-2异常表达抑制活性的芍药苷类化合物，其制备方法及其用途 |
| CN106565802B (zh) * | 2016-09-26 | 2020-05-15 | 中国人民解放军北部战区总医院 | 白芍醇提物、4-o-没食子酰基白芍苷及其制备和应用 |
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| JP2008505128A (ja) | 2008-02-21 |
| CN1714797A (zh) | 2006-01-04 |
| EP1767210A4 (en) | 2010-09-08 |
| US20080275226A1 (en) | 2008-11-06 |
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