CN1282584A - 淫羊藿甙在预防治疗性功能障碍以及与改善血管收缩有关疾病的用途 - Google Patents
淫羊藿甙在预防治疗性功能障碍以及与改善血管收缩有关疾病的用途 Download PDFInfo
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- CN1282584A CN1282584A CN00118336A CN00118336A CN1282584A CN 1282584 A CN1282584 A CN 1282584A CN 00118336 A CN00118336 A CN 00118336A CN 00118336 A CN00118336 A CN 00118336A CN 1282584 A CN1282584 A CN 1282584A
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Abstract
淫羊藿甙在预防治疗性功能障碍以及与改善血管收缩有关疾病的用途。
Description
本发明涉及淫羊藿甙在制备用于预防治疗性功能障碍药物中的用途，以及与改善血管收缩有关疾病的用途。
男性的性功能包括***、******、***和性快感，是在神经-内分泌***的调节下，***血管***的复杂的生理反映。故如果上述***的某一过程出现异常既可能引起***减退、******障碍、***障碍或***疲软障碍等疾病，而且，这种疾病可以单独出现或相互合并出现。男性性功能障碍的发病率大约占成人男性的30-60％，并有随着年龄增加而增加的趋势。传统的医学把性功能障碍通称为阳萎、早泄，直到最近十年以前，把性功能障碍的原因大部分被认为只是心理性原因。但是随着现代科学技术的发达已经明确了在50％以上的性功能障碍患者中发现有神经系、血管系、内分泌系疾病以及患有高血压病、糖尿病、服用各种药物等器质性原因。
男性的性功能主要是在有各种性刺激时，在神经-内分泌***的调节下通过血管***的复杂的生理反映使******。这种***的***过程首先是依靠***小动脉的扩张使***血流量增加，相继出现***海绵体平滑肌松弛而海绵体小孔膨胀，促使血液流入量近一步增加，导制***海绵体内压升高，压迫***白膜下的小静脉阻断血液流出，从而导致***海绵体内血液充盈而***坚硬***其强度可达到******，并维持***的时间足以达到性高潮而***。
这种******过程中***海绵体平滑肌的松弛作用起着关键作用，而且******过程受神经内分泌***的调节。动物实验表明许多局布因子影响******功能如去甲肾上腺素(NA)、神经肽Y(NPY)、乙酰胆碱(Ach)、***素(PGE)、五羟色胺(5-HT)、降钙素基因相关肽(CGRP)、血管活性肠肽(VIP)、内皮素(EDRF)等。
近来的研究表明，一氧化氮(NO)在******过程中起重要作用。当性刺激时NO由分布在***的副交感神经和非肾上腺素非乙酰胆碱能神经(NANC)末梢释放，而且NO也在分布于血管内皮层的内皮细胞和***海面体窦内皮细胞释放，NO可激活平滑肌细胞内鸟苷酸环化酶，使环磷酸鸟苷(cGMP)合成增加，也可激活蛋白酶G(PKG)，PKG可以使钙通道关闭和钾通道开放，两种作用均可引起***海面体平滑肌松弛导致******。环磷酸鸟甘(cGMP)又被磷酸二酯酶(PDE)灭活。
性功能障碍可分为***减退，***障碍，性高潮障碍和***障碍。性功能障碍的原因有血管神经性、内分泌性、心理性病变、糖尿病、高血压、脊髓神经损伤、吸烟等因素均可引起性功能障碍。
传统的观点认为性功能障碍主要是由于心理性原因引起。治疗上用口服药如安定剂曲唑酮，和育亨宾等。但是这种药物的作用机制尚不明确，其疗效不高，并有不同程度的副作用。
近年来随着弄清******机制，各种对***海绵体平滑肌有松弛作用的药物企图用来诊断和治疗男性性功能障碍，目前，已有用血管扩张剂如樱束碱(paparvarin)、芬托拉明(phentolamine)、***素E1(prostajlandin E1)等药物直接***海绵体内注射疗法来治疗******障碍获得较满意的疗效。但是，这种疗法可以引起局布疼痛、持续性******、***纤维化等副作用故临床上常被限制使用。
最近，美国发明的治疗***障碍的口服药物磷酸二酯酶V抑制剂(Viagra)被世人瞩目，上述药品作为化学性假体仅仅是用来一次诱发******，并有不同程度的副作用，如面红、头痛、视觉障碍、低血压等，特别是对有心血管疾病的患者安全性有争议值得留心。
因此，安全而有效的增进人体本能性***功能的药物有待于研究开发，最近的研究力求于开发安全有效的NO供体用来治疗性功能障碍。
生药淫羊藿在传统医学界里用来滋补强壮剂的处方中常常作为一种成份，但是其作用机制尚未弄清。近来的对淫羊藿有效成份研究证明淫羊藿中含有许多成份，如淫羊藿甙、挥发油、蜡醇、州一烷、植物甾醇、鞣质、亚油酸等。近来又分离出微量的magnoflorin、淫羊藿糖甙A、epimedin A，B， C、槲皮素、脱水淫羊藿甙-3-O-鼠李糖甙等。其中淫羊 藿甙目前仅被用做淫羊藿成份分析用标准试剂。一些研究报告淫羊藿具有抗疲劳作用、增进免疫功能以及改善肝脏功能。但是到目前为止，还没有关于淫羊藿甙单体用来治疗性功能障碍的研究报告。
本发明的目的是寻找并开发淫羊藿甙新的医药用途
本发明人经研究发现，淫羊藿甙出人意料的具有强烈松弛***海绵体平滑肌的作用，还具有对大动脉平滑肌轻度的松弛作用，其药理作用与平滑肌细胞内一氧化氮(NO)-cGMP通路的活性增强有关。从而可用于改善和增进******功能以及与改善血管收缩有关疾病的症状。
因此，本发明涉及淫羊藿甙在制备用于预防治疗性功能障碍的药物中的用途以及与改善血管收缩有关疾病用途。
本发明涉及下试本发明涉及淫羊藿甙在制备用于预防治疗性功能障碍的药物中的用途以及制备与改善血管收缩有关疾病药物中的用途。
本发明涉及用于预防或治疗性功能障碍和血管收缩有关疾病的药物组合物，其包括作为活性成分的淫羊藿甙及药用载体和赋形剂。
本发明涉及预防或治疗性功能障碍和血管收缩有关疾病的方法，包括给需要预防或治疗性功能障碍和血管收缩有关疾病的患者预防或治疗有效量的淫羊藿甙或含淫羊藿甙的药物组合物。
淫羊藿甙由生药淫羊藿分离出来的属于黄酮甙类单体，其化学结构式：C33H40O15分子量：676．67，熔点：225-230℃。
根据本发明，本发明中使用的淫羊藿甙可以单独使用或以药物组合物形式使用。药物组合物包括作为活性成份的淫羊藿甙及药用载体。
根据本发明，本发明的药物组合物，可按本领域以知方法制备并可以通过口服或非肠道或局部途经给药。口服制剂包括如片剂、口嚼剂，胶囊、悬浮液、溶液等，非肠道给药制剂包括如注射液。局部给药制剂包括如霜剂、软膏剂、贴剂，喷雾剂等。
根椐本发明，淫羊藿甙是从淫羊藿生药中通过有机溶剂或有机溶剂与水的混合物提取得到。可使用的有机溶剂包括醇类如甲醇、乙醇等、卤代烷类如二氯甲烷、氯仿、醚类如***、酮类如丙酮、脂类如乙酸甲脂、乙酸乙脂、烃类如己烷等。
下面的实施例用来更详细的说明本发明，但不意味着本发明仅限于此。实施例1淫羊藿甙的制备
提取方法(1)
取干燥淫羊藿(地上部分)500克加MeOH 10升，加温提取3日，共3回。过泸回收溶媒，减压浓缩获得MeOH提取物。MeOH提取物加水混悬后用同量的己烷提取共4次，取水层浓缩到1／3量。在此浓缩水层中加5％柠檬酸混悬(pH=5．5)，再用同等量的CHCl3提取，再加适量NH4OH混悬(pH=10)，再用同等量的CHCl3提取。此过程反复3次。最终碱性水层用同等量丁醇反复提取3次，获得淫羊藿甙粗品(icariin richfraction，IRF)(利用HPLC分析法测定结果淫羊藿甙含量为8％)。
提取方法(2)
取干燥淫羊藿(地上部分)500克加EtOH 10升，80℃加温汇流提取3次，每次1小时，共3回。过滤，减压回收乙醇浓缩成浆状。加4倍量水分散后静止3小时除去叶绿素几蜡脂等，正丁醇翠取4次后合并滤液，减压浓缩。用40-60目聚酰氨柱吸附，30％乙醇洗脱至无色，洗脱液减压浓缩。加70％乙醇(1∶20)溶解，静止8小时，过滤得淫羊藿总甙。淫羊藿总甙与无水乙醇(1∶15)反复洗脱重结晶得淫羊藿总甙粗品。淫羊藿总甙含量52％。
淫羊藿甙分离
淫羊藿甙或淫羊藿总甙粗品溶化在MeOH，吸附在硅胶干燥，再加入已备好的硅胶柱(8×60cm)中，以CHCl∶MeOH=5∶1，4∶1，3∶1，2∶1的顺序溶出，各溶出的分液浓缩，再用MeOH／H2O混和液析出淡黄色结晶。
该结晶在UV发色，pauly试剂显阳性反映，TLC分析结果Rf值为0．6，熔点：239℃。确认为是纯品淫羊藿甙(淫羊藿甙，利用HPLC分析法测定结果淫羊藿甙含量为99．8％))。实验1安全性实验
按照急性毒性试验规则利用SD系大白鼠雌雄各5只为1组，共分4组，第1组口服给药量为淫羊藿甙3g／kg，第2组2g／kg，第3组1g／kg，第三组0．5g／kg。投药后观察7目的结果，LD50雄性为1．88g／kg，雌性为1．95g／kg。实验2药效及药理作用机制实验原理
男性的性功能主要是在有各种性刺激下时，在神经-内分泌***的调节下通过血管***的复杂的生理反映促使******。这种***的***过程首先是依靠***小动脉的扩张作用和***海绵体平滑肌松弛作用，***海绵体窦膨胀促使***海绵体血液流入量增加，导制***海绵体内压升高而压迫***白膜下的小静脉以阻断血液流出，从而导致***海绵体内血液充盈而***坚硬***。这种******过程中，***海绵体平滑肌的松弛作用起着关键作用。故具对***海棉体平滑肌有松弛作用的药品有助于******功能。***海绵体平滑肌的松弛作用也受非肾上腺素非已酰胆碱(NANC)能神经和内皮细胞松弛因子(EDRF)的调节，而这种EDRF中一氧化氮(NO)起着重要的作用。NO或含有NO的物质扩散到平滑肌细胞内，激活可溶性鸟苷酸环化酶，使cGMP合成增加而诱发***海绵体平滑肌松弛促使******。***海绵体内的cGMP又被磷酸二酯酶V型失去活性。所以，促使***海棉体平滑肌NO生成增加，或促进鸟苷酸环化酶活性，或抑制磷酸二酯酶的活性的药品，能使cGMP合成或活性增加，促进******故对性功能障碍有治疗作用。利用***海棉体活体组织在体外进行实验(in vitro)，观察药物对其张力的影响，或测定药物对磷酸二酯酶的影响，是研究药物******功能的有效实验方法。2．1．淫羊藿甙对家兔***海面体平滑肌松弛作用：
用雄性家兔(新西兰家兔，体重：2．5-3．0kg)，分离出***海面体平滑肌，在体外进行了淫羊藿甙的药理药效实验。使用的家兔共60只，观察了不同浓度淫羊藿甙对***海面体平滑肌张力的影响，并观察了同浓度淫羊藿甙对腹部大动脉平滑肌张力的影响。为了研究淫羊藿甙对***海面体平滑肌松弛作用的药理机制，观察了已酰胆碱(NANC)能神经阻断剂阿托品，***素E1抑制剂消炎痛，抑制NO生成或NO活性的试剂Nw-nitric-L-精氨酸(L-NNA)和连苯三酚、鸟磷酸环化酶活性抑制剂亚甲兰、1H-[1，2，4]噁二唑并[4，3，-a]喹喔啉-1-酮(ODQ)对淫羊藿甙对***海面体平滑肌松弛作用的影响。实验方法
家兔用戊巴比妥钠(30-50mg／kg)麻醉后切除***和腹部大动脉，在持续供给95％氧气和5％二氧化碳混和气体并盛有Tyrode营养液并保持衡温37．5℃的容器中，将***海绵体分离成2×2×6mm大小的肌条，并将在大动脉中分离出4mm宽的动脉环，分别在盛有Tyrode溶液10ml并持续供给95％氧气和5％二氧化碳混和气体的玻璃器管浴中，一端在底部固定，另一端连接力位移传导器上。***海绵体条和动脉环的紧张度的变化，利用多道记录仪(TSD 105，Biopac Systems，Santa Barbara，CA，USA)测定并记氯，观察了淫羊藿提取物和淫羊藿甙对***海绵体条和大动脉环的紧张度所引起的效应。
为了诱导起初安静状态***海棉体条和动脉环的张力，将***海面体条和动脉环牵拉到2克的张力，效准1．5-2小时。当利用苯副林(PHE；5×10-6M)诱发收缩反应后再用台氏溶液洗去至到回复基线。此法反复三次以上，如三次收缩反应幅度之差在10％以内时，定为效准安静状态***海棉体条和动脉环的张力，进行下一步药效分析。每个平滑肌条或环在实验过程中的先后实验间隔保持30分钟，使其回复到安静状态***海棉体条和动脉环的张力后再进行下一步实验。a．淫羊藿提取物和淫羊藿甙对***海绵体条和大动脉环的紧张度所引起的效应实验
为了观察淫羊藿提取物和淫羊藿甙对***海绵体条和大动脉环的紧张度所引起的效应，将***海绵体条和大动脉环利用苯福林(PHE；5×10-6M)诱发收缩，保持平台时，将淫羊藿提取物和淫羊藿甙以浓度递增的量(淫羊藿提取物1-50mg／ml，淫羊藿甙10-10-104M)依次投入，并观察其个个浓度对平滑肌的松弛效应。每个药物浓度至少观察8只动物肌条或肌环的药物效应并作统计学分析。b．淫羊藿甙对***海绵体条所引起的松弛效应机制实验b-1．观察了已酰胆碱(NANC)能神经阻断剂阿托品(10-6M)对淫羊藿甙对***海绵体条所引起的松弛效应的影响b-2．观察了***素E1抑制剂消炎痛(10-4M)对淫羊藿甙对***海绵体条所引起的松弛效应的影响b-3．观察了抑制NO生成或NO活性的试剂Nw-nitric-L-精氨酸(L-NNA)(10-4M)和连苯三酚(10-4M)对淫羊藿甙对***海绵体条所引起的松弛效应的影响b-4．观察了鸟磷酸环化酶活性抑制剂亚甲兰(10-4M)，1H-[1，2，4]噁二唑并[4，3，-a]喹喔啉-1-酮(ODQ)(10-4M)对淫羊藿甙对***海面体平滑肌松弛作用的影响
为了观察上述各种试剂对淫羊藿甙对***海绵体条松弛效应的影响，将***海绵体条利用苯福林(PHE；5×10-6M)诱发收缩，保持平台时，将各种试剂按照各自的浓度分别投入后，等待20分钟，再将阳藿甙以浓度递增的量(淫羊藿甙10-10-10-4M)依次投入，并观察其个个浓度淫羊藿甙对平滑肌的松弛效应。与透各种试剂前的松弛程度作比较，分析其对淫羊藿甙对***海绵体条松弛效应的影响。每个药物浓度至少观察5只动物肌条或肌环的药物效应并作统计学分析。实验使用溶液
苯福林盐酸盐，氯化乙酰胆碱，硫酸阿托品，连苯三酚，消炎痛，Nω-nitric-L-精氨酸，1H-[1，2，4]噁二唑并[4，3，-a]喹喔啉-1-酮来自Sigma Chemical Co．(St．Louis，MO，USA)产品，亚甲兰来自Mallinckrodt Chemical Co．(St．Louis，MO，USA)产品。Tyrode溶液 的组成(mEq／l)Na+(153．6)，K+(5．3)，Ca++(3．0)，Mg++(1．2)，Cl-(157．2)，H2PO4 -(0．6)，SO4 -(1．2)，HCO3 -(7．1)，葡萄糖(11．4)。统计学分析
数据用计算机分析(Acqkowlege 3．2 program，Biopac systems，USA)且所有松弛反应用最大松弛反应百分比表示，最大松弛指在所有试验中PHE诱导的最大收缩点与曲线中最大向下偏差之间的距离。统计分析用Student’st试验进行。不同药物浓度下的平滑肌张力变化用log衰减分析测定。如p值小于0．05时被认为统计学上有意义。所有值用平均标准误差表示。实验结果c．淫羊藿提取物和淫羊藿甙对***海绵体条和大动脉环的紧张度所引起的效应实验
观察淫羊藿提取物和淫羊藿甙对***海绵体条和大动脉环的紧张度所引起的效应结果，结果见表1和表2。由表l和表2中的数据可看到，淫羊藿提取物和淫羊藿甙对利用苯福林(PHE：5×10-6)诱发收缩的***海绵体条和大动脉环，显示出浓度依存胜的松弛作用(p＜0．001)。淫羊藿甙的半数有效浓度(EC50)在***海绵和动脉环分别为4．67×104M，2．71×103M。这种结果表明淫羊藿甙对***海绵体的松弛作用较对动脉环的松弛作用强5．8倍(p＜0．001)。表1。淫羊藿提取物(IRF)对利用苯福林(PHE：5×10-6M)诱发收缩的***海绵体条和大动脉环表现出浓度依存性的松弛作用。
表2。淫羊藿甙对利用苯福林(PHE：5×10-6M)诱发收缩的***海绵体条和大动脉环表现出浓度依存性的松弛作用。
淫羊藿甙粗品(IRF)和淫羊藿甙的半数有效浓度(EC50)
不同药物浓度下的平滑肌张力变化用log衰减分析结果，淫羊藿甙粗品(IRF)在***海绵体和动脉环的半数有效浓度(EC50)分别为4．08mg／ml，22．4mg／ml。淫羊藿甙在***海绵体和动脉环的半数有效浓度(EC50)分别为4．67×lO-4M，2．83×10-3M。按照淫羊藿甙粗品(IRF)中淫羊藿甙含量8％计算可换算得出淫羊藿甙浓度为4．08×lO4M，2．64×lO-3M，这种结果与淫羊藿甙的半数有效浓度(EC50)4．67×10-4M，2．83×10-3相差无几。说明淫羊藿甙是淫羊藿成分中的主要药效成分，并且对***海绵体的松弛效应较大动脉环强5．5倍以上。淫羊藿甙对***海绵体条所引起的松弛效应机制实验
1．在观察己酰胆碱(NANC)能神经阻断剂阿托品(10-6M)对淫羊藿甙对***海绵体条所引起的松弛效应的影响的结果表明，淫羊藿甙对用阿托品预前处理的***海绵体条所引起的松弛效应较对照组无显著差异(p＞0．05)，这说明这种松弛效应不受阿托品的影响。
2．在观察***素E1抑制剂消炎痛(10-4M)对淫羊藿甙对***海绵体条所引起的松弛效应的影响的结果表明，淫羊藿甙对用消炎痛预前处理的***海绵体条所引起的松弛效应较对照组无显著差异(p＞0．05)，这说明这种松弛效应不受消炎痛的影响。结果见表3。
3．在观察抑制NO生成或NO活性的试剂Nw-nitric-L-精氨酸(L-NNA)(10-4M)和连苯三酚(10-4M)对淫羊藿甙对***海绵体条所引起的松弛效应的影响的结果表明，淫羊藿甙对用Nw-nitric-L-精氨酸(L-NNA)(10-4M)和连苯三酚(10-4M)预前处理的***海绵体条所引起的松弛效应较对照组显著被抑制(p＜0．001)，这说明这种松弛效应与NO生成或NO活化作用有关。结果见表3。
4．在观察鸟磷酸环化酶活性抑制剂亚甲兰(10-4M)，1H-[1，2，4]噁二唑并[4，3，-a]喹喔啉-1-酮(ODQ)(10-4M)对淫羊藿甙对***海面体平滑肌松弛作用的影响的结果表明，淫羊藿甙对用亚甲兰(10-4M)，1H-[1，2，4]噁二唑并[4，3，-a]喹喔啉-1-酮(ODQ)(10-4M)预前处理的***海绵体条所引起的松弛效应比对照组显著被抑制(p＜0．001)，结果见表4。
上述实验结果表明淫羊藿甙对平滑肌的松弛效应与一氧化氮(NO)-鸟磷酸环化酶(GMP)活化作用有关。结果见表3。表3破坏内皮细胞，连苯三酚，亚甲兰，ODQ，阿托品，消炎痛前处理后，淫羊藿甙对利用苯福林(PHE；5×10-6M)诱发收缩的***海绵体条松弛效应的影响。
表4不同浓度ODQ予处理对淫羊藿甙对PHE预接触海绵体肌肉条的松弛作用的反应(PHE；5×10-6M)
实验3淫羊藿甙对磷酸二酯酶活性的影响实验方法
| 淫羊藿甙浓度(M) | 10-6 | 10-5 | 10-4 | P值 |
| 对照组(n=8) | 1．23±0．82 | 4．42±1．08 | 23．12±1．36 | |
| 破坏内皮细胞(n=5) | 0．82±0．58 | 3．23±0．89 | 15．68±1．15 | ＜0．001 |
| 连苯三酚前处理(n=5) | 0．85±0．45 | 3．45±0．73 | 18．12±1．08 | ＜0．01 |
| 亚甲兰前处理(n=5) | 0．52±0．68 | 2．02±0．45 | 13．45±1．12 | ＜0．001 |
| ODQ(n=5) | 0．42±0．48 | 1．85±0．35 | 10．45±1．08 | ＜0．001 |
| 阿托品前处理(n=5) | 1．21±0．58 | 4．11±0．98 | 21．78±1．06 | ＞0．05 |
| 消炎痛前处理(n=5) | 1．18±0．48 | 4．09±1．08 | 20．12±1．14 | ＞0．05 |
| ODQ浓度 | 10-7 | 10-6 | 10-5 | 10-4 | Pvalue |
| 淫羊藿甙松弛作用(％) | 4．33±1．22 | 14．55±2．45 | 48．02±3．78 | 87．76±4．78 | ＜0．001 |
1．人血小板中分离磷酸二酯酶
酸二酯酶V型不仅分布在***海绵体，还分布在血小板。利用血小板分离出磷酸二酯酶V型，分析药物对其活性的影响是一种常规实验方法。其方法是将新鲜人血液(360gm)离心分离(360g)10分钟，得出血小板丰富血浆(PRP)，再将PRP离心分离(1400g)10分钟沉淀血小板。取1ml沉淀的血小板，用冰冷缓冲液(Hepes 20nM，Sucrous 0．25M，EDTA 1mM，苯甲基磺酰氟化物(PMSF)1mM，pH 7．2)混匀漂浮后，用超声波震荡器(Cell distuptor，Burkard Scientific，Uxbridge，Middlesex，UK)破坏细胞膜。细胞溶解物远心分离(799g)10分钟后，在次连续离心分离(165．000g)60分钟，取上层液用Pharmacia FPLC(Pharmacia LTD．，Milton Keynes，UK)将复合酶分离出来备用。
为了利用Mono-Q离子交换色谱法提纯磷酸二酯酶，利用Mono-Q柱(5ml×50mm)，缓冲液A 5ml和缓冲液B 10ml反复冲洗后，远心分离(165．000g)得到的上清液10ml，放入Mono-Q柱，流速定为1ml／min。再让复合酶的活性成分以1ml／分钟的流速通过线性梯度盐(lineargradient salt)(0-0．5M NaCl)分析各种酶成分。在所得到的各种酶成分分别测定其活性，收集对活性酶成分，放入液氮瓶备用。
2．筛选抑制酶活性物质
磷酸二酯酶的活性分析在最终反应容量0．5ml进行，而且从加入酶到反应开始的操作在冰上做准备。分析用缓冲液(Tris 40mM pH8．0，MgCl210mM，BSA 0．125mg／ml，2-巯基乙醇3．75mM)每次使用新鲜配制的缓冲液，被酶作用物[2H]cGMP(ca．28 ci／mmol；ca．100，000cpm／100μL)是事前用分析用缓冲液做好准备备用。PDE V型的活性检测方法是利用[3H]cGMP标记的同位素两步分析法。测定时将[3H]cGMP 200μL加入试管内，再加入被试物质(淫羊藿甙10-10M-10-4M)或对照物用同量DMSO)100μL和提纯的磷酸二酯酶100μL，再加入缓冲液到0．5ml，在30℃衡温下反应20分钟后，将试管浸入开水中以终止反应。反应终了后试管内加入蛇毒(Ophiophagus Hannah；Sigma Chemical Co)100μL(1mg／ml)，30℃衡温下孵化10分钟，将[3H]5-GMP转化成[3H]鸟苷。被转换的[3H]鸟苷在AG1-X2 resion(Bio-Rad)反应器中，利用NaOH(0．1N)在离子交换柱型色谱分析洗脱后得到的样品，测定其放射性来分析磷酸二酯酶V的活性，
3．实验结果
本实验结果淫羊藿甙对磷酸二酯酶V活性有浓度依赖性抑制作用(10-8M，0．06％；10-7M，32．7％；10-6M，56．2％；10-5M，83．7％；10-4M，99．9％)，EC50为0．43μM。见下表。表5。淫羊藿甙对磷酸二酯酶V活性的抑制作用(％)。
| 浓度 | 10-4M | 10-5M | 10-6M | 10-7M | 10-8M | 10-9M |
| 淫羊藿甙 | 99．7 | 87．9 | 63．2 | 42 | 2 | 0 |
通过实验证明，淫羊藿甙对***海绵体比对大动脉环有强大的松弛作用，而且淫羊藿甙的***海绵体平滑肌的松弛作用的机制是，通过增加NO的生成和鸟磷酸环化酶活化作用，并抑制磷酸二酯酶的活性来阻止cGMP的灭活，使***海绵体平滑肌内cGMP浓度增加而松驰***海绵体，诱发******。实验4。临床效果
为了了解淫羊藿甙的临床效果，在56名性功能障碍为主述并自愿受试者为对象利用国际性功能评价询问表(International Index forSexual Function．IIEF-V)进行了安慰剂对照，二重双盲预备临床实验。被试者平均年龄为39±6．1岁，发病期间为5．4±3．7年。其中患糖尿病17例，高血压病9例，心脏病8例。
实验药品(含淫羊藿甙50mg／片)和安慰剂包装相同，透药者和服药者均不知道药品情报的条件下进行实验。被选的自愿者不随机的分成两组，投用安慰剂或实验药品(2片／次，3次／日)，口服1个月。患者在投药前和服药完了后分别添写性功能评价询问表(共5项，各项5度评分)，比较用药前后的性功能变化通过Student t test分析来评价药效。
实验结果，在治疗前受试者性功能评价分数分别为，对***和***的维持功能的自信感评分为1．82±0．54，***可******的***频度评分为1．89±0．67，***时*********并维持***的频度评分为1．82±0．65，***时******和***维持困难评分为1．89±0．61，对性生活的满足度评分为1．79±0．62。治疗后性功能评分分别为，对***和***的维持功能的自信感评分中淫羊藿甙组为3．32±0．39，安慰剂为2．04±0．63，***可******的***频度评中淫羊藿甙组为3．11±0．32，安慰剂为2．07±0．88，***时*********并维持***的频度评分中淫羊藿甙组为3．18±0．47，安慰剂为2．17±0．97，***时******和***维持困难评分中淫羊藿甙组为3．25±0．43，安慰剂为2．18±0．92，对性生活的满足度评分中淫羊藿甙组为3．36±0．47，安慰剂为2．14±0．95，服用淫羊藿甙片组的评分比较安慰剂显著增高(p＜0．01)。总体临床效果淫羊藿甙片组和安慰剂分别为75．4％和35．4％。除4名患者有轻微的胃肠道反应外未发现明显的副作用。患糖尿病，高血压和心脏病患者在临床效果和副作用方面无显著差异。结果见下表。
表5。淫羊藿甙对性功能障碍治疗效果的IIEF评分表
Claims (5)
1．淫羊藿甙在制备用于预防或治疗性功能障碍和血管收缩有关疾病药物中的用途。
2．用于预防或治疗性功能障碍和血管收缩有关疾病的药物组合物，其包括作为活性成分的淫羊藿甙及要用载体和赋形剂。
3．根据权利要求1的用途或权利要求2的药物组合物，其中所述的药物或药物组合物含10-500毫克的淫羊藿甙。
4．根据权利要求1-3的用途或药物组合物其中所述的药物或药物组合物是以片剂，丸剂，胶囊，悬浮液，溶液，注射剂，霜剂，软膏，喷雾剂，口嚼剂，贴剂形式使用。
5．根据权利要求1-3的用途或药物组合物，其中所述的药物给药途经可以为口服，舌下，经皮，经肌肉或皮下，皮肤粘膜，尿道，***，或静脉。
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| ITMI20020994A1 (it) * | 2002-05-10 | 2003-11-10 | Indena Spa | Formulazioni utili nel trattamento dell'impotenza maschile e femminile |
| ITMI20031427A1 (it) * | 2003-07-11 | 2005-01-12 | Indena Spa | Combinazioni di agenti vasoattivi, loro uso in campo farmaceutico e cosmetico e formulazioni che li contengono |
| KR100821683B1 (ko) * | 2006-11-01 | 2008-04-15 | 우석대학교 산학협력단 | 이카리사이드 Ⅱ (ｉｃａｒｉｓｉｄｅ Ⅱ)를 유효성분으로 하는 혈관 형성 장애 관련 질환의 예방 및 치료용 조성물 |
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| WO2009149621A1 (zh) * | 2008-06-13 | 2009-12-17 | 北京东方百奥医药开发有限公司 | 淫羊藿次苷在制备用于预防或治疗男性或女性性功能障碍的产品中用途 |
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| AU5386700A (en) | 2001-01-09 |
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