CN1352563A - 用叶下珠定向刺激免疫系统 - Google Patents
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Abstract
本发明涉及用叶下珠定向刺激免疫系统,最好是刺激肿瘤坏死因子、树状细胞和吞噬细胞。
Description
本发明涉及用叶下珠定向刺激免疫系统，最好是刺激肿瘤坏死因子、树状细胞和吞噬细胞。
叶下珠属包括多种植物，多分布于中印和南印、台湾以及中南美洲。在本发明中，“叶下珠”包括所有代表性品种，例如霸贝菜，amarue叶下珠等。在印度民间医学中，已知可用叶下珠属植物治疗多种疾病。因此，例如“DoctorK.M.Nadarni′s Indian Materia Medica(第3版；A.K.Nadkarni增编)”在第一卷中指出，此类植物具有轻泻、利尿、收敛、清凉的作用。同理，叶下珠属植物配制的组合物据说可用于治疗黄胆、水肿、淋病、经血过多等与泌尿生殖道相关的疾患。还知道，可将取自树干的汁液与油混合，作为眼药或其它制剂用于溃疡、创伤和肿胀等，并可用其叶子治疗瘙痒等皮肤病。
而且，已知可从叶下珠属植物中提取多种活性物质，例如叶下珠脂素、次叶下珠脂素，三十烷醇，三十烷醛，repandusinic酸A(参见JP 03206044 A；AIDS-Res-Hum-逆转录病毒(11/1992)，第8卷(11)，HIV-1逆转录酶……)，phyllanthostatin-1，叶下珠苷，phyllanthocin，phyllanthocin酸(参见，例如EP1734480；美国专利4,388,457)，叶霉素(phyllamycin)A、B和C，反爵床脂素(retroiusticidin)B，爵床脂素(justididin)A和B(参见，例如，AIDS-周刊，25.9.95，AIDS治疗……)，亚油酸，亚麻酸和蓖麻油酸(参见美国油料化学家协会杂志81.06.00，霸贝菜中的蓖麻油酸……)，phyllamyricin D、E和F、phyllamycoside A、B和C(参见J.Nat.Prod.(11/1996)，Vol.59(11)，6(04/1995)，Vol43(4)，Inhibitoryeffects of Egyptian……)，putranjivain A(参见：化学制药通报(东京)，(04/1995)，vol.43(4)，埃及的…抑制作用)，ursulic酸和niruriside(参见J.Nat.Prod.02/96，vol。59(2)，Nimriside，a new HIV……；Recl.Trav.Chim(06/1996)，Synthesisof……)。
迄今已知的治疗作用包括：抗衰老(参见JP08176004)，预防和治疗AIDS等免疫缺陷症，流感，伤风，结核病，肝炎，硬化症(参见US5,529,778；AIDS-Weekly-Plus 05.08.96，抗病毒(药物开发)；Inhibition of HIV……)，抗癌作用(参见US4,388,457)，治疗HIV、HBV和/或HCV感染，尤其是局部治疗Kaposi′s肉瘤(参见EP1734480；US5,466,455)，蛋白酶抑制作用，弹性酶抑制作用和增白作用(参见JP09087136)，镇痛和消炎作用，酪氨酸激酶抑制作用(参见JP08012566)，以及与其它植物提取物联用作为抗感染剂。而且还可用于化妆品。根据以上所述的广泛用途，和可分离得到的多种活性成分可以看出，叶下珠是一类可用于多种病患治疗的药用植物。
免疫系统在维持人体健康及抵抗疾病方面起着重要作用。免疫系统中知悉最多的是介导体液免疫的B细胞(抗体)和介导细胞免疫的T细胞。免疫系统迅速而有效地破坏通过多种渠道(昆虫叮咬、鼻/咽粘膜感染、个体间的非肠胃道传染、母婴间的水平传递)进入机体的细菌、病毒及其它进入体内的异源物质，它们由合适的呈递细胞呈递给免疫系统从而被消灭。
免疫系统中特化的抗原呈递细胞包括例如树状细胞，它们在诱导初次免疫应答中起着重要作用。例如，在树状细胞表面上的病毒表位呈递可引发病毒特异性细胞毒T细胞应答，由此消灭机体内的病毒。
许多现有免疫系统刺激剂的主要缺点在于是来自化学合成而非天然来源。尤其是当前环保意识逐渐增强而且健康越来越受重视时，许多人排斥纯化学合成药而要求医生使用天然药物。
然而，目前还没有可令人满意的药物既可定向刺激免疫系统，同时又具有良好的患者耐受性。
因此，本发明目的就在于提供一种既可定向刺激免疫系统又具有良好耐受性的物质。
本发明涉及用叶下珠定向刺激免疫系统，特别是刺激肿瘤坏死因子(TNF)尤其是TNFα的合成。还包括对树状细胞的刺激。
例如，已经研究发现：作为免疫成分的单核细胞(MNC)或树状细胞可通过改变细胞因子合成对环境改变作出应答。
“细胞因子”是一种细胞分泌的肽，在与特异性受体结合后可影响其它细胞的功能。细胞因子的作用之一是调节免疫细胞间复杂的相互作用。其例子包括干扰素、胆碱刺激因子等。特别重要的是肿瘤坏死因子(TNF)，尤其是TNFα，这是一类内源性蛋白质，接触内毒素后在巨噬细胞内形成单核毒素形式，但由活化肥大细胞体内分泌时仍是三聚体。TNFα既可从组织中分离，也可通过基因工程获得，并具有免疫调节和保护作用。一方面，它可激活免疫系统中的巨噬细胞和白细胞，诱导炎性急相蛋白的合成(触珠蛋白，补体成分C3)，具有抗病毒作用，与γ干扰素具有协同作用，可保护实验动物抵抗疟疾，并能破坏某些肿瘤而不伤及健康组织。另一方面，它也具有某些副作用，例如改变血管内皮细胞的特性，严重减轻体重，发烧和毒性休克等。而且，TNFα与病毒衣壳蛋白非常相似，但氨基酸序列不同。
TNFα由巨噬细胞(特殊的防御细胞)分泌，可抗病毒感染。TNFα参与防御机制中的炎性反应。已知，慢性乙肝和丙肝常与细胞防御衰退有关，因为这些病毒能够绕过宿主的免疫应答(Rosenberg W.(1999)“病毒性肝炎中的免疫逃避机制”，Gut44，759-764)。包括TNFα在内的某些细胞因子能够体外激活“幼稚”T细胞和“记忆”T细胞。因此，慢性病毒性肝炎患者体内富含细胞因子的炎性环境促进T细胞的激活，这对病毒的消除十分重要。因此，这对于即使在无抗原刺激情况下(例如病毒清除后)增强肝内效应T细胞的功能以及维持外周T记忆细胞十分重要。TNFα“路径”是细胞特异性的，但仍是基于丙肝病毒特异性人细胞毒T淋巴细胞(CTL)的“旁观者杀伤机制”。TNFα由CTL分泌，介导所谓“旁观细胞”的破坏，但不发生紧密的细胞与细胞接触。
现在，出人意料地发现，叶下珠提取物能刺激树状细胞并促进TNFα的合成。因此，脂多糖(LPS)刺激的MNC中的TNFα合成显著增强。即使对提取物进行纯化去除其中的内毒素后，在刺激的MNC中仍可看到以上结果。
脂多糖指各种脂类与多肽构成的共轭物。革兰氏阴性菌细胞壁外膜内的LPS主要有三种成分：类脂A，核心寡多糖和O特异性链。类脂A使LPS锚着于细菌膜，并具有免疫激活细菌细胞膜组分的作用。
由于已知叶下珠还具有对其它细胞因子的调节作用，而且，根据不同的研究系统，有时具有消炎作用，有时则具有消灭病毒、抵御病原性物质的促炎作用，因此，叶下珠非常适合用于调节免疫系统，特别是因为，TNFα在细胞因子网络中占据着重要位置。适合接受免疫系统刺激的有免疫缺陷状态、肿瘤形成和感染，但也包括处于一般健康和增强免疫目的的疾病预防。
叶下珠刺激免疫系统的确切机制尚不知道，但一般认为可能是通过粒细胞—巨噬细胞集落—刺激因子(GM-CSF)调节作用导致TNFα的释放(参见，Carreno等(1998)，增刊1，113-115)。GM-CSF是一种糖蛋白性血细胞生长因子，由活化的T淋巴细胞、成纤维细胞和内皮细胞产生，能够增强嗜中性粒细胞、单核细胞和嗜酸性粒细胞的产生，被用于丙肝治疗和化学治疗(Carreno等(1998)，同上)。
在这方面，叶下珠良好的免疫系统刺激效力可能一方面来自其抗氧化作用，另一方面来自其免疫刺激作用，或者两者兼而有之。因此，可以推测，即使目前所有的抗病毒药物也不能消除病毒，而只能抑制病毒。即使病毒在外周血中已消失(低于可测水平)，但仍常会在肝组织中检测到。因此，叶下珠可通过抗氧化作用和免疫刺激作用对消除病毒和抑制慢性炎症作出贡献。
本发明还包括在以上所述路径之一中使用取自叶下珠的分离物。“分离物”在此表示通过层析、蒸馏、沉淀、萃取、过滤等方法从叶下珠中分离得到的叶下珠物质，特别是通过层析、蒸馏、沉淀或萃取得到的萃得物和组分。
本发明的另一种使用方式是，根据以上所述的任一实例使用一种或多种化学物质，尤其是分离自叶下珠的活性物质。这也包括由叶下珠萃得物或其它萃得物即所谓天然分离物分离的单一物质，这些也是现有技术已知的。使用这些分离得到的活性物质的优点在于：与使用全萃得物或片剂相比，这些物质的用量较少，并可获得特异性作用。
本发明用途之一中，所述的叶下珠选自amarus叶下珠，霸贝菜，油柑，刺果叶下珠，myrtofolis Moon叶下珠，maderas patensis叶下珠和/或ussuriensis叶下珠。
在本发明用途中，可以使用叶下珠的叶子、树皮、花、种籽、果实、茎、枝、干、根和/或木质，优选其药用部分(herb)，即植株的全部地上部分。此外，叶下珠材料既可使用其粉碎后形式，也可使用其未加工形式，即完整叶、颗粒、粉末、沉淀物、萃得物、干燥萃得物和/或浸出物，其中优选的是萃得物或干燥萃得物。
用于本发明的叶下珠制剂的制备方法包含：由上述植株部分获得叶下珠材料的粉末或颗粒，先用其它溶剂处理植物萃取物、粉碎后的植物部分、粉末和残留物，然后用己烷、水、甲醇和/或等其它醇进行萃取。其中还包括通过过滤和真空蒸发获得干燥萃得物。另一种方法包括用水溶液和/或醇溶剂和/或极性溶剂进行的多相萃取。另外，常用的还有过滤(例如纤维素滤膜过滤)、沉淀(优选乙醇沉淀)，或超离心分离，以及浸渍。而且，还常提高或降低温度后进行操作。
本发明中特别优选的是使用叶下珠水溶液、非极性溶剂或醇溶剂的萃得物，醇性萃得物最好用短链(C1至C4)伯醇(尤其是甲醇或乙醇)或其混合物制取，非极性萃得物用C5-C10分支或不分支烃链或其混合物(尤其是正己烷)制取。
另外适合用作萃取剂的是乙酸乙酯或其它合适的有机溶剂/水混合物，优选甲醇/水混合物或乙醇/水混合物。合适的萃取过程参见，例如美国专利4,673,575或美国专利4,937,074。
本发明用途中，叶下珠的使用形式最好是一种或多种药物产品(参见Rompp，Lexikon Chemie，1.4版)，例如输注液、注射液、片剂、颗粒剂、药膏、药贴、灌肠剂或一种或多种食品/食品补充的形式。这包括通常的药物和治疗应用形式，还特别包括食品补充剂，这使得叶下珠可作为天然无害的食品添加剂用于预防和用作功能性抗氧化剂，并显示前述治疗和预防性功能。
根据本发明，叶下珠制剂可口服、局部和/或肠胃外使用。
在一优选实施例中，除叶下珠物质外还使用了一种或多种活性物质和/或合适添加剂和/或助剂。就本发明而言，“活性物质”指具有治疗活性的物质，例如维生素C或生育酚(特别是α生育酚)，这些是已知的抗氧化剂或可抵抗氧化性应激反应的活性物质，另外例如消炎物质。因此，这也包括与叶下珠制剂组成的混合制剂产品。在这方面需要指出的是，本发明的某一种用途决不仅限于叶下珠或取自所述植物的一种形式、组分或分离得到的活性物质，而是可以就一种用途联合使用多种不同的形式和/或组分和/或分离到的叶下珠活性物质。
助剂和添加剂指已知用于治疗或食物补充以实现或强化效应用途的物质，例如佐剂、崩解剂和润滑剂、膨大剂、缓冲剂、防腐剂、稳定剂等。
以下实施例和附图是用来具体描述本发明而不是限定本发明。
图1是1，1-二苯基-2-苦基偕腙肼(DPPH)和本发明叶下珠萃得物的自由基清除实验结果；
图2是DPPH和维生素C的自由基清除实验结果，用作比较；
图3是DPPH和α-生育酚的自由基清除实验结果，用作比较；
图4是溴化3-[4，5-二甲基噻唑-2-噻唑-2-基]-2，5-二苯基四唑鎓(MTT)和本发明叶下珠萃得物的自由基清除实验结果；
图5是MTT与维生素C的自由基清除实验结果，用作比较；
图6是细胞色素和本发明叶下珠萃得物的自由基清除实验结果，用作比较；
图7是细胞色素与维生素C的自由基清除实验结果，用作比较；
图8是3′[1-[(苯基氨基)-羰基]-3，4-四唑鎓]-二(4-甲氧基-6-硝基)苯磺酸钠水合物/吩嗪硫酸二甲酯(XTT/PMS)和本发明叶下珠萃得物的自由基清除实验结果；
图9是XTT/PMS与维生素C的自由基清除实验结果，用作比较；
图10是叶下珠萃得物对LPS诱导的MNC的作用(萃得物1-4)；
图11是叶下珠萃得物对LPS诱导的MNC的作用(萃得物5-6)；
图12是作为对照的内毒素检测；
图13是叶下珠萃得物对非诱导MNC的作用(萃得物1-4)；
图14是叶下珠萃得物对非诱导的MNC作用(萃得物5-6)；
图15是叶下珠萃得物对树状细胞的作用(LAT NO.00120514)；
图16是叶下珠萃得物对树状细胞的作用(LAT NO.00130514)；
图17是叶下珠萃得物对树状细胞的作用(LAT NO.00140514)；
图18是叶下珠萃得物对树状细胞的作用(LAT NO.00150514)。
实施例1本发明干燥萃得物的制备(组分1；批号：9810H)
由2kg印度Madras Phyllanthus amarus药用部分制取450g粉末。该450g粉末在Soxhlet仪中用3L蒸馏正己烷蒸馏萃取12小时。过滤并真空蒸发后制得25g干燥的正己烷萃得物，其中的主要组分是亲脂性的木酚素、甾醇和色素。该萃得物呈灰棕色糊状，不溶于水和甲醇，可溶于乙酸乙酯。实施例2干燥甲醇萃得物的制备(组分2；批号：9810M)
在Soxhlet仪中，用3L蒸馏甲醇继续萃取实施例1中不溶于正己烷的残留植物残渣12小时。过滤并真空蒸发后得50g干燥的甲醇萃得物。其中的主要组分是类黄酮、寡聚棓单宁和酚羧酸。该深棕色粉末不溶于水，几乎全溶于甲醇。实施例3水性上清液的制备(组分3；批号：9810W)
将甲醇萃取(实施例2)后的不溶性植物残渣(约375g)浸泡在2.5L热蒸馏水中，低温(4℃)浸泡12小时。然后滴加2.5L乙醇(100％(＝1∶1))以沉淀出高分子量的二糖和糖蛋白，然后7500rpm超离心分离。上清液经冷冻干燥得15g干物质。其主要组分是寡聚棓单宁和其它水溶性聚合物。所得是一种红棕色粉末，可溶于水，不溶于有机溶剂。实施例4水沉淀物的制备(组分4：批号9810pp)
将实施例3中的乙醇沉淀和离心分离所得聚合物溶于热水，冷冻干燥。于是，由450g粗制粉末起始物制得了5g萃得物。其主要组分是高分子量的多糖和糖蛋白。所得产物呈棕色粉末，不溶于水。实施例5无叶绿素甲醇粗提物的制备(组分5：批号9901Mcf；P1159)
在Soxhlet仪中，用500ml蒸馏甲醇12小时萃取100g由药用部分制得的叶下珠粉末。过滤并真空蒸发得15g干燥萃得物，将其溶于300ml热的蒸馏水/甲醇1∶1混合物。在80℃水浴，间或搅拌，将该溶液浓缩至一半体积。通过纤维素纸热(80℃)过滤去除油状沉淀。在滤液中加入热(80℃)蒸馏水至300ml，再过滤。滤液经冷冻干燥得约10g干燥甲醇萃得物，其外观呈棕色糊状，可溶于甲醇。实施例6无叶绿素水萃得物的制备(组分6：批号9901Wcf)
在80-100℃的水浴中，用500ml蒸馏水1小时萃取由药用部分制得的50g叶下珠粉末，间或搅拌。用纤维素纸过滤热溶液。在(约400ml)滤液中加入100ml蒸馏甲醇。在80℃水浴，间或搅拌，将混合物蒸发至一半体积。用纤维素纸趁热(80℃)过滤去除油状沉淀。滤液经冷冻干燥得3g干燥水萃得物。该萃得物为红棕色粉末，可溶于甲醇。实施例7DPPH自由基清除实验
将实施例5制得的本发明萃得物P11599配制成7种不同的浓度，用自由基清除实验研究其捕获自由基的能力。即测定515nm处稳定自由基DPPH(1，1-二苯基-2-苦基偕腙肼)与相应非自由基性1，1-二苯基-2-苦基偕腙肼之间的颜色改变。为此必须将被测物质的DMSO系列稀释液与DPPH的甲醇溶液在37℃保温30分钟，然后测定颜色改变，该实验进行一式两份。根据结果计算SC50，即DPPH的自由基50％被捕获时的样品浓度。用DMSO作为阴性对照，维生素C作为阳性对照，还对α生育酚进行了测定。经测定，P11599的SC50为6.2μg/ml，维生素C的为10μM，α生育酚的为18μM(参见图1-3)。由此可见，作为自由基清除剂，P11599优于α生育酚，与维生素C相当。实施例8MTT自由基清除实验
10.6mM浓度的MTT(溴化3-[4，5-二甲基噻唑-2-噻唑-2-基]-2，5-二苯基四唑鎓)与不同浓度的本发明实施例5萃得物P11599或与作为参照的维生素C在37℃保温1小时，然后用光度法测定因样品作用引起的吸光度改变。结果显示，P11599具有极高的抗氧化能力，接近于较强的还原剂维生素C(参见图4和5)。实施例9细胞色素C自由基清除实验
150μM细胞色素C与不同浓度的本发明实施例5萃得物P11599或与作为参照的维生素C在37℃保温0.5小时，然后用光度法测定因样品作用引起的吸光度改变。结果显示，P11599具有极高的抗氧化能力，接近于较强的还原剂维生素C(参见图6和7)。实施例10XTT/PMS自由基清除实验
500μM/0.21μM的3′[1-[(苯基氨基)-羰基]-3，4-四唑鎓]-二(4-甲氧基-6-硝基)苯磺酸钠水合物/吩嗪硫酸二甲酯(XTT/PMS)与不同浓度的本发明实施例5萃得物P11599或与作为参照的维生素C在37℃保温1小时，然后用光度法测定因样品作用引起的吸光度改变。结果显示，P11599具有极高的抗氧化能力，接近于较强的还原剂维生素C(参见图8和9)。实施例11单核细胞(MNC)的制备
用50ml Perfusor针筒的蝴蝶针抽取空腹健康人的血样，刺人在此前14天中没有用过药，每10ml血样中加入100μl肝素。室温下在Lekosept Bluecaps中加入15ml Ficoll-Hypaque，1000g离心2分钟。Ficoll集于分离盘下。用针筒加入15ml上述肝素化血样，然后加入15ml无菌0.9％NaCl溶液。最后，20℃、2200rpm离心15分钟。于是，从上到下分层如下：血浆/MNC环/Ficoll/分离盘/Ficoll/红细胞等。用移液管吸取MNC环，加入Bluecaps，加NaCl溶液至50ml。然后将此洗涤三次，每次都用等渗盐水重悬细胞沉淀，然后离心。每次倾出上清液。留下的细胞沉淀即MNC，加入MNC培养基。实施例12叶下珠对特异性表面分子表达的刺激
将新鲜分离的MNC培养于培养皿中的营养培养基中。然后用白介素4(500U/ml)和GM-CSF(1000U/ml)刺激，MNC于是进一步发育为树状细胞。培养6天后，细胞表现出典型的树状细胞形态，并表达HLA-DR、CD54(ICAM-1)、CD80(B7.1)和CD86等表面分子(标志)。这些标志是树状细胞的特征。加入TNF等细胞因子可进一步增强树状细胞标志的表达。经如此处理，树状细胞可表达成熟的标志CD83，未受刺激的细胞是不表达该标志的。经一系列实验发现，不同的叶下珠萃得物均能刺激树状细胞标志的表达。以上实验结果可参见图15-18。实施例13对TNFα合成刺激作用的测定
将实施例11所得MNC与不同浓度的本发明实施例1-6的样品共培养，用ELISA测定TNFα浓度。48孔培养板的每孔中加200μl MNC悬液，浓度为5×106个细胞/ml MNC培养基(RPMI培养基+1％L-谷氨酰胺+1％AB血清+1％青霉素/链霉素+1％人白蛋白+1％HEPES)，向其中加入100μl LPS溶液(40ng/ml NMC培养基)和100μl叶下珠稀释液。叶下珠稀释液为实施例1-6萃得物的稀释液，稀释度为500、100、10、1和0.1μ/ml，由储备液制得。作为对照，用MNC培养液取代100μl叶下珠稀释液。
48孔培养板在培养箱内37℃培养20小时，然后于-80℃冷冻，经3轮冻融循环后进行TNFα试验。
用ELISA测定所得TNFα浓度，以抗人TNFα作为第一抗体，抗TNF-Bi作为第二抗体，利用450/690nm处的颜色反应。
结果，本发明的某些萃得物显著刺激LPS引起的TNFα合成(图10，11)。
然而，部分萃得物中含有内毒素(Endosafe Inc.USA的LAL测试测得；图12)。所以，作为该试验的继续，在脱毒柱上对萃得物继续纯化。该柱先用5ml 1％脱氧胆酸盐溶液、5ml水和5ml生理盐水洗涤。然后上样，暗培养2小时，然后用生理盐水洗脱。内毒素留在柱上。各活性萃得物4、5和6即使在去除内毒素后仍表现出明显的TNFα合成作用。
若取消LPS刺激仍可获得类似的结果。此时，与以上实验一样，用未纯化的叶下珠稀释液，但用100μl MNC培养基代替100μl LPS溶液(参见图13，14)。
以上结果显示：本发明的萃得物可显著刺激TNFα的合成。
Claims (14)
1.叶下珠用于定向刺激免疫系统的用途。
2.根据权利要求1所述的用途，被刺激的是肿瘤坏死因子TNF，尤其是TNFα的合成。
3.根据权利要求1所述的用途，被刺激的是抗原呈递细胞，尤其是树状细胞。
4.根据权利要求1所述的用途，被刺激的是吞噬细胞，尤其是人吞噬细胞，更好的是粒细胞和单核细胞。
5.根据权利要求1至4中任一项所述的用途，所用的是自中叶下珠分离的组分。
6.根据权利要求1至5中任一项所述的用途，所用的分离自叶下珠的一种或多种化学物质，尤其是活性物质。
7.根据权利要求1至6中任一项所述的用途，所述的叶下珠选自amarus叶下珠，霸贝菜，油柑，刺果叶下珠，myrtofolis Moon叶下珠，maderas patensis叶下珠和/或ussuriensis叶下珠。
8.根据权利要求1至7中任一项所述的用途，所用的是叶子、树皮、花、种籽、果实、茎、枝、干、根和/或木质，优选其药用部分。
9.根据权利要求1至8中任一项所述的用途，所用的是叶下珠的粉碎后或未加工形式，即完整叶、颗粒、粉末、沉淀物、萃得物、干燥萃得物和/或浸出物，优选萃得物或干燥萃得物。
10.根据权利要求9所述的用途，其中使用水性、非极性、C5-10分支或不分支烃链或其混合物，以正己烷为佳，和/或使用醇，以C1-4短链伯醇或其混合物为佳，尤其是甲醇或乙醇。
11.根据权利要求1至10中任一项所述的用途，给药形式是输注液、注射液、片剂、颗粒剂、药膏、灌肠剂、药贴和/或食品补充剂。
12.根据权利要求1至11中任一项所述的用途，通过口服、局部和/或肠胃外给药。
13.根据权利要求1至12中任一项所述的用途，除叶下珠之外还使用了其它活性物质和/或合适的添加剂和/或助剂。
14.根据权利要求13所述的用途，其中使用了维生素C和/或生育酚。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19919585A DE19919585A1 (de) | 1999-04-29 | 1999-04-29 | Verwendung von Phyllanthus zur Behandlung von oxidativem Streß und anderen Symptomen |
| DE19919585.4 | 1999-04-29 |
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| CN00806854A Pending CN1364085A (zh) | 1999-04-29 | 2000-04-28 | 利用叶下珠治疗慢性炎性和纤维化过程 |
| CN00806852A Pending CN1352563A (zh) | 1999-04-29 | 2000-04-28 | 用叶下珠定向刺激免疫系统 |
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| EP (2) | EP1176971B1 (zh) |
| JP (2) | JP2002543140A (zh) |
| CN (2) | CN1364085A (zh) |
| AT (1) | ATE275411T1 (zh) |
| AU (2) | AU4559300A (zh) |
| BR (2) | BR0010590A (zh) |
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| MX (2) | MXPA01010980A (zh) |
| PT (1) | PT1176971E (zh) |
| WO (2) | WO2000066135A1 (zh) |
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| DE10030139A1 (de) * | 2000-06-20 | 2002-01-10 | Cmi Ag | Verwendung von Phyllanthusbesandteilen zur Behandlung oder Prophylaxe von Infekten durch Flaviviridae |
| ATE275413T1 (de) * | 2000-10-06 | 2004-09-15 | Phytrix Ag | Verfahren zur herstellung von phyllanthusextrakten |
| ES2261507T3 (es) * | 2000-10-06 | 2006-11-16 | Phytrix Inc. | Compuestos derivados de phyllanthus para la prevencion y/o el tratamiento de enfermedades asociadas con un retrovirus. |
| DE10120627A1 (de) * | 2001-04-26 | 2002-10-31 | Cmi Ag | Verwendung von Phyllanthusbestandteilen zur Behandlung oder Prophylaxe von Infekten durch Hepatitis B-Viren |
| US20050064053A1 (en) * | 2002-11-08 | 2005-03-24 | Em Industries | Enriched aqueous components of emblica officinalis |
| WO2004078190A1 (en) | 2003-03-03 | 2004-09-16 | Benny Antony | A process and technique to elevate serum high density liboprotein |
| JP5508656B2 (ja) * | 2004-07-16 | 2014-06-04 | 太陽化学株式会社 | 最終糖化産物生成阻害組成物 |
| TW200607517A (en) * | 2004-08-17 | 2006-03-01 | Hepaguard Biotechnology Int L Co Ltd | Medicinal composition capable of suppressing proliferation or metastasis of tumor cells |
| WO2006131932A1 (en) * | 2005-06-09 | 2006-12-14 | Mmi Corporation | Herbal formulation capable of preventing alcohol-induced hangover, methods of preparing the same and use thereof |
| US7597910B2 (en) * | 2005-08-20 | 2009-10-06 | Slgm Medical Research Institute | Compositions and methods for treating prostate disorders |
| EP2175871B1 (en) * | 2007-07-18 | 2016-08-31 | Council of Scientific & Industrial Research | A synergistic herbal composition for treatment of rheumatic and musculo-skeletal disorders (rmsds) |
| DE102007044487A1 (de) * | 2007-09-18 | 2009-04-02 | Universität Leipzig | Verwendung des umgekehrten Zelldifferenzierungsprogramms (OCDP) zur Behandlung degenerierter, im pathologischen Zustand befindlicher Organe |
| US20110009692A1 (en) * | 2007-12-26 | 2011-01-13 | Yossi Gross | Nitric oxide generation to treat female sexual dysfunction |
| US20090198271A1 (en) * | 2008-01-31 | 2009-08-06 | Rainbow Medical Ltd. | Electrode based filter |
| US7749284B2 (en) * | 2008-04-28 | 2010-07-06 | Aveda Corporation | Oxidative hair dye compositions, methods and products |
| EP2116253A1 (en) * | 2008-05-07 | 2009-11-11 | Phytrix JV, LLC | Novel phyllanthus extract |
| US8916209B2 (en) * | 2009-10-02 | 2014-12-23 | Johnson & Johnson Consumer Companies, Inc. | Extracts of Phyllanthus niruri |
| US20110202108A1 (en) * | 2010-02-18 | 2011-08-18 | Rainbow Medical Ltd. | Electrical menorrhagia treatment |
| US20130064912A1 (en) * | 2011-09-09 | 2013-03-14 | Jon Barron | Formulation for alleviation of kidney stone and gallstone symptoms |
| US8980340B1 (en) | 2013-10-08 | 2015-03-17 | Benny Antony | Medicinal composition of extract of seed of emblica officinalis and method of preparing the same |
| US10286022B2 (en) | 2013-10-08 | 2019-05-14 | Benny Antony | Medicinal composition of extract of seed of emblica officinalis and method of preparing the same |
| IN2013CH04565A (zh) | 2013-10-08 | 2015-09-25 | Benny Antony | |
| CN105168314A (zh) * | 2015-09-10 | 2015-12-23 | 福建农林大学 | 一种复方叶下珠制剂及其在犬日粮上的应用 |
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| US4388457A (en) | 1982-02-11 | 1983-06-14 | University Patents, Inc. | Phyllanthostatin compounds |
| US4673575A (en) | 1985-04-26 | 1987-06-16 | Fox Chase Cancer Center | Composition, pharmaceutical preparation and method for treating viral hepatitus |
| US4937074A (en) | 1988-03-29 | 1990-06-26 | Fox Chase Cancer Center | Method of treating retrovirus infection |
| US5854233A (en) * | 1993-09-08 | 1998-12-29 | Pharmacy And Therapeutic Advisory Consultancy Ltd. | Method of treating liver disease and like indications with vasodilating agents |
| US5529778A (en) * | 1994-09-13 | 1996-06-25 | Rohatgi; Surendra | Ayurvedic composition for the prophylaxis and treatment of AIDS, flu, TB and other immuno-deficiencies and the process for preparing the same |
| US5571441A (en) | 1994-11-01 | 1996-11-05 | The Procter & Gamble Company | Nutrient supplement compositions providing physiologic feedback |
| US5648089A (en) * | 1995-07-03 | 1997-07-15 | Shawkat; Tarek | Extract solution and herbal mixture for treatment of hepatitis |
| US6136316A (en) | 1996-04-17 | 2000-10-24 | Dabur Research Foundation | Hepatoprotective compositions and composition for treatment of conditions related to hepatitis B and E infection |
| US6747136B2 (en) | 1996-04-19 | 2004-06-08 | Karolinska Innovations Ab | Human monoclonal antibodies specific for hepatitis C virus (HCV) E2 antigen |
| EP1136075B1 (en) | 1997-09-21 | 2003-01-15 | Schering Corporation | Combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection |
| CA2334754A1 (en) | 1999-04-12 | 2000-10-19 | University Of Madras | A pharmaceutical formulation useful for the treatment of hepatitis b, hepatitis c and other viral infections of the liver and a process for its preparation |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU4559200A (en) | 2000-11-17 |
| AU4559300A (en) | 2000-11-17 |
| EP1176971B1 (de) | 2004-09-08 |
| EP1176971A1 (de) | 2002-02-06 |
| US6586015B1 (en) | 2003-07-01 |
| BR0010604A (pt) | 2002-02-05 |
| DE19919585A1 (de) | 2000-12-07 |
| MXPA01010980A (es) | 2003-06-30 |
| JP2002543140A (ja) | 2002-12-17 |
| CA2372220A1 (en) | 2000-11-09 |
| CA2372223A1 (en) | 2000-11-09 |
| EP1176972A1 (de) | 2002-02-06 |
| DE50007689D1 (de) | 2004-10-14 |
| WO2000066134A1 (de) | 2000-11-09 |
| PT1176971E (pt) | 2005-01-31 |
| ES2226831T3 (es) | 2005-04-01 |
| ATE275411T1 (de) | 2004-09-15 |
| MXPA01010982A (es) | 2003-07-21 |
| CN1364085A (zh) | 2002-08-14 |
| JP2002543139A (ja) | 2002-12-17 |
| BR0010590A (pt) | 2003-07-22 |
| WO2000066135A1 (de) | 2000-11-09 |
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