CN101291680A - 草药提取物的抗氧化和Fe2+螯合特性 - Google Patents
草药提取物的抗氧化和Fe2+螯合特性 Download PDFInfo
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- CN101291680A CN101291680A CNA2006800393127A CN200680039312A CN101291680A CN 101291680 A CN101291680 A CN 101291680A CN A2006800393127 A CNA2006800393127 A CN A2006800393127A CN 200680039312 A CN200680039312 A CN 200680039312A CN 101291680 A CN101291680 A CN 101291680A
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Abstract
本发明涉及抗氧化和抗增殖剂，包括单独或与银杏(Ginkgobiloba，GB)，圣约翰草(Saint John′s Wort，SJW)，银杏内酯，类黄酮，人参皂苷，金丝桃素和/或贯叶金丝桃素组合的西洋参(NorthAmerican ginseng)(专有提取物HT1001)。根据本发明的抗氧化和抗增殖剂显示出对Fe2+催化的脂质过氧化作用及Fe2+螯合活性的显著抑制作用，清除羟基自由基的能力，减少神经母细胞瘤细胞数量的能力和/或促进神经突起生长的能力。这些效应与Fe2+螯合剂的行为一致，并且由化学组分施加的效应的类型和强度的不同提示了协同的作用机制。
Description
发明背景
几百年来，中草医药学利用人参，银杏(Ginkgo biloba，GB)和圣约翰草(Hypericum perforum，SJW)治疗很多种神经系统病症和疾病。尽管强调了需要更大量的临床试验来证明，但近来的荟萃(meta)分析描述了GB提取物对认知，情绪，情感功能和生活质量具有有益作用，用于治疗痴呆无明显不良反应[Birks J，Grimley EV，van DM.用于治疗认知损伤和痴呆的银杏(Ginkgo biloba forcognitive impairment and dementia).Cochrane Database Syst Rev2002；(4)：CD003120]。类似地，西洋参(North American ginseng，Panaxquinquefolius)提取物也被报道能改善记忆[Sloley BD，Pang PK，Huang BH，Ba F，Li FL，Benishin CG，Greenshaw AJ，Shan JJ.(空间学习任务中西洋参提取物减少东莨菪碱诱导的健忘症)American ginseng extract reduces scopolamine-inducedamnesia in a spatial learning task.J Psychiatry Neurosci 1999November；24(5)：442-52]，其成分人参皂苷Rb1和Rg1发挥着神经保护作用[Rudakewich M，Ba F，Benishin CG.人参皂苷Rb(1)和Rg(1)的神经营养和神经保护作用(Neurotrophic and neuroprotective actions of ginsenosides Rb(1)and Rg(1)).Planta Med 2001 August；67(6)：533-7]。人参的有益属性归因于其皂苷组分，达玛烷型三萜葡糖苷的混合物，统称为人参皂苷。目前已分离出一些人参皂苷，并测定了其结构。这些人参皂苷包括Rb1，Rb2，Rc，Rd，Re，Rf和Rg(参见Bombardelli的美国专利No.4,157,894)。在德国被批准用于治疗轻至中度抑郁的SJW在近来的荟萃分析中因更有利的副作用而显示出明显优于合成抗抑郁剂的结果[Roder C，Schaefer M，Leucht S.，用圣约翰草治疗轻至中度抑郁的效力耐受能力的荟萃分析(Meta-analysis of effectiveness and tolerability of treatment of mild to moderatedepression with St.John′s Wort)，Fortschr Neurol Psychiatr 2004July；72(6)：330-43]。
氧化应激与多种神经病理有关，因此，GB，西洋参和SJW提取物的某些作用可以归因于其内在的抗氧化活性。已知为GB和SJW中所含主要生物活性组分的类黄酮显示具有抗氧化活性，包括阻止脂质过氧化作用，清除自由基和Fe2+螯合作用[Rice-Evans CA，Miller NJ，Paganga G.类黄酮和酚醛酸的结构-抗氧化剂活性关系(Structure-antioxidant activity relationships of flavonoids and phenolicacids).Free Radic Biol Med 1996；20(7)：933-56；Sloley BD，Urichuk LJ，Morley P，Durkin J，Shan JJ，Pang PK，Coutts RT.鉴定银杏叶提取物中作为单胺氧化酶抑制剂和潜在神经保护剂的三羟黄酮醇(kaempferol)(Identification of kaempferol as a monoamine oxidase inhibitor andpotential Neuroprotectant in extracts of Ginkgo biloba leaves).J PharmPharmacol 2000 May；52(4)：451-9；Sloley BD，Urichuk LJ，Ling L，Gu LD，Coutts RT，Pang PK，Shan JJ.贯叶金丝桃提取物的化学和药理学评估(Chemical and pharmacological evaluation of Hypericum perforatumextracts).Acta Pharmacol Sin 2000；21(12)：1145-52].
也有文献描述了人参皂苷Rb1和Rg3的抗氧化作用[Kim YC，KimSR，Markelonis GJ，Oh TH.人参皂苷Rb1和Rg3保护培养的大鼠皮层细胞防止谷氨酸酯诱导的神经变性(ginsenoside s Rb1 and Rg3 protectcultured rat cortical cells from glutamate-induced neurodegeneration).JNeurosci Res 1998 September 15；53(4)：426-32；Lim JH，Wen TC，Matsuda S，Tanaka J，Maeda N，Peng H，Aburaya J，Ishihara K，SakanakaM.由人参皂苷Rb1，一种人参根的主要成分保护缺血性海马趾神经元(Protection of ischemic hippocampal neurons by ginsenoside Rb1，a mainingredient of ginseng root).Neurosci Res 1997 July；28(3)：191-200]以及SJW提取物[Jang MH，Lee TH，Shin MC，Bahn GH，Kim JW，Shin DH，Kim EH，Kim CJ.在人神经母细胞瘤细胞上贯叶金丝桃Linn(圣约翰草)抗过氧化氢诱导的细胞凋亡的保护效果(Protective effect ofHypericum perforatum Linn(St.John′s wort)against hydrogenperoxide-induced apoptosis on human neuroblastoma cells).Neurosci Lett2002 September 30；329(2)：177-80]。还推测，通过Fe2+螯合作用发挥其抗氧化细胞保护作用的提取物根据病症和所用模型的性质的不同显示出抗增殖/促凋亡活性。由于Fe2+是细胞增殖的关键元素，因此肿瘤细胞对Fe2+的需求增加。临床上也已证实对多种病理的抗癌活性，包括神经母细胞瘤Fe2+螯合剂[Donfrancesco A，Deb G，De SL，Cozza R，Castellano A.去铁胺在肿瘤治疗中的作用(Role of deferoxamine intumor therapy).Acta Haematol 1996；95(1)：66-9]。除了其确定的抗增殖作用[Renton FJ，Jeitner TM.铁螯合剂对人神经肿瘤细胞系的细胞周期依赖的抑制(Cell cycle-dependent inhibition of the proliferation of humanneural tumor cell lines by iron chelators).Biochem Pharmacol 1996 July14；51(11)：1553-61]外，Fe2+螯合剂还可以诱导细胞凋亡[Fan L，Iyer J，Zhu S，Frick KK，Wada RK，Eskenazi AE，Berg PE，Ikegaki N，KennettRH，Frantz CN.在人神经母细胞瘤细胞中由铁螯合作用抑制N-myc以及诱导细胞凋亡(Inhibition of N-myc expression and induction ofapoptosis by iron chelation in human neuroblastoma cells).Cancer Res2001 March 1；61(3)：1073-9]，促进数种肿瘤细胞系，包括胚胎性癌F9的细胞分化[Tanaka T，Muto N，Ido Y，Itoh N，Tanaka K.由去铁胺，一种强效的治疗性铁螯合剂诱导胚胎性癌细胞分化(Induction ofembryonal carcinoma cell differentiation by deferoxamine，a potenttherapeutic iron chelator).Biochim Biophys Acta 1997 July5；1357(1)：91-7]。
近来，对含有已获专利的专有西洋参提取物HT1001和用于治疗注意力缺陷多动障碍(ADHD)的GB的独特提取物组合产物(CVT-E033，AD-
CV Technologies，Edmonton，Alberta)的前瞻研究提示其可以改善ADHD症状，包括认知问题[Lyon MR，Cline JC，Totosy de ZJ，Shan JJ，Pang P，Benishin C.西洋参(Panaxquinquefolium)和银杏(Ginkgo biloba)的草药提取物组合对注意力缺陷多动障碍的作用：一种前瞻研究(Effect of the herbal extractcombination Panax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder：a pilot study).J Psychiatry Neurosci 2001June；26(3)：221-8]。该研究除了报道了西洋参，GB和SJW的神经保护/神经营养及抗氧化作用，还推动了对这些物质及其组合物CVT-E033和CVT-E036(Menta-
GB，西洋参和SJW)的作用机制的研究。
Pang等的美国专利No.5,137,878和6,083,932包括对现有技术的提取物的讨论。美国专利No.5,137,878和美国专利No.6,083,932的全部公开内容因此引入本申请作为参考。美国专利No.5,137,878公开了人参皂苷Rb1和Rg1增强脑皮层和海马区中Ach的利用率，并缓解阿尔茨海默(Alzheimer)型老年痴呆的症状。该专利还公开了分离人参皂苷Rb1的方法。美国专利No.6,083,932公开了衍生自人参的药物组合物和治疗多种脑部病症或疾病及抑郁或改善一般认知功能的方法。
发明简述
本发明人现在发现了西洋参的特定提取物，GB和SJW的提取物及其生物活性组分人参皂苷Rb1，Rg1，Rc，Rd，Re，银杏内酯A和B，类黄酮槲皮素和芦丁，金丝桃素和贯叶金丝桃素具有抗氧化和抗增殖特性。本发明者称之为HT1001的含有约15-50％，优选约25-40％的总人参皂苷(亦称皂苷)的特定人参提取物可以单独或与GB和/或SJW组合作为抗氧化或抗增殖剂给药。
附图说明
图1-草药制剂对SH-SY5Y神经母细胞瘤细胞中由Fe2+催化的脂质过氧化作用的影响。细胞以1×106个细胞/孔的量接种并培养24小时，然后在有或无0.1mM FeSO4的条件下暴露于草药提取物中48小时。然后收集细胞膜，分析脂质过氧化物。脂质过氧化物的存在通过有色MDA产物的形成来指示，结果以相对于对照组的相对值来表示。草药制剂的原始吸光度值与对照组相比具有显著差异(*P＜0.05)。
图2-草药提取物对Fe2+与菲咯嗪的相互作用的阻碍作用。各种草药提取物(图2b)和强效Fe2+螯合剂DFO(图2a)在所示浓度下于无细胞化学测定系统中与0.5mM FeSO4溶液一起孵育，然后与色原菲咯嗪(1mM，终浓度)一起孵育。所示结果为供试样品在562nm处的吸光度相对于适当空白组的相对值。
图3-几种草药提取物的纯化学组分对Fe2+与菲咯嗪的相互作用的阻碍作用。纯化学成分槲皮素，芦丁，银杏内酯A和银杏内酯B(图3a)，人参皂苷Rb1，Rg1，Rc，Rd，Re(图3b)以及金丝桃素和贯叶金丝桃素(图3c)在所示浓度下于无细胞化学测定系统中与0.5mMFeSO4溶液一起孵育，然后与色原菲咯嗪(1mM，终浓度)一起孵育。所示结果为供试样品在562nm处的吸光度相对于适当空白组的相对值。
图4-低和正常血清条件下草药提取物对神经母细胞瘤细胞增殖的影响。50μg/ml的各种草药提取物或仅介质(对照)与培养的SK-N-SH(图4a)，SH-SY5Y(图4b)和N1E 115(图4c)细胞一起在低(2％)或正常(10％)FBS中孵育96小时。对于N1E 115(实心符号)和SH-SY5Y(无阴影符号)细胞，还研究了Fe2+螯合剂DFO对细胞数的影响(图4d)。用WST-1试剂测定活细胞数。与相同血清条件的对照组比较，对细胞数产生了显著抑制(*P＜0.05或**P＜0.001)和显著刺激(#P＜0.05)。
图5-银杏内酯，类黄酮，人参皂苷和贯叶金丝桃素对神经母细胞瘤细胞增殖的影响。银杏内酯A(GA)和B(GB)及类黄酮芦丁和槲皮素(Q)(图5a，b)，或贯叶金丝桃素或人参皂苷Rb1，Rg1，Rc，Rd和Re(图5c，d)，或仅介质(对照)在所示浓度下与培养的N1E115(图5a，c)，SH-SY5Y(图5b，d)细胞一起孵育96小时。用WST-1试剂测定活细胞数。与对照组比较具有显著性(*P＜0.05，**P＜0.001，***P＜0.0001)。
图6-草药提取物对N1E 115神经突起生长的剂量依赖性效应。CVT-E033，HT1001和GB在所示浓度下与培养的N1E 115神经母细胞瘤细胞一起孵育7天，测定神经突起延伸得分。与对照组比较具有显著性(*P＜0.05或**P＜0.01)。
优选实施方案详述
本发明人发现，西洋参的专有提取物(HT1001)单独或与GB和/或SJW组合具有抗氧化和抗癌作用。本发明者还研究并发现了化学成分银杏内酯，类黄酮，人参皂苷，金丝桃素和贯叶金丝桃素具有抗氧化活性。所有供试草药提取物及其组合物通过对Fe2+催化的脂质过氧化作用的显著抑制，在无细胞化学测定系统中螯合Fe2+的能力，以及在GB和CVT-E033(西洋参+GB)的情况下清除自由基而发现具有抗氧化活性。另外，在几种神经母细胞瘤模型中证实了所有草药提取物的抗增殖和/或促分化作用，这与Fe2+螯合剂的行为是一致的。
所有供试草药提取物及其数个化学成分均表现出抗氧化活性。CVT-E033(西洋参+GB)和CVT-E036(西洋参，GB和SJW)显示能减少人神经母细胞瘤细胞系SH-SY5Y中由Fe2+催化的脂质过氧化作用。这可以归因于都独立地抑制Fe2+催化的脂质过氧化作用的HT1001，GB和SJW的贡献。先前已显示GB提取物(Ramassamy C，Girbe F，Christen Y，Costentin J.银杏提取物EGb 761或trolox C阻止抗坏血酸/Fe2+诱导的突触体膜流动性的降低(Ginkgo biloba extract EGb 761 ortrolox C prevent the ascorbic acid/Fe2+induced decrease in synaptosomalmembrane fluidity).Free Radic Res Commun 1993；19(5)：341-50.)，西洋参提取物(Kitts DD，Wijewickreme AN，Hu C.西洋参提取物的抗氧化剂特性(Antioxidant properties of a North American ginseng extract).Mol Cell Biochem 2000February；203(1-2)：1-10)和SJW提取物(Zou Y，Lu Y，Wei D.贯叶金丝桃的富含类黄酮的提取物的体外抗氧化剂活性(Antioxidant activity of a flavonoid-rich extract of Hypericumperforatum L.in vitro).J Agric Food Chem 2004 September11；52(16)：5032-9)以及类黄酮成分(Chen YT，Zheng RL，Jia ZJ，Ju Y.作为超氧化物清除剂和抗氧化剂的类黄酮(Flavonoids as superoxidescavengers and antioxidants).Free Radic Biol Med 1990；9(1)：19-21)可以抑制脂质或脂质体过氧化。Fe2+催化的脂质过氧化作用可以通过清除自由基或螯合Fe2+而被直接拮抗。CVT-E033表现出适中的自由基清除活性；这可能应归功于显示出显著自由基清除活性的GB组分提取物，而不是无可检测活性的人参提取物HT1001。这与其它关于GB提取物清除自由基的报道是一致的(Ramassamy C，Naudin B，Christen Y，Clostre F，Costentin J.由银杏提取物(EGb 761)和trolox C阻止突触体多巴胺的降低以及孵育后血液复合胺摄取的降低(Prevention by Ginkgobiloba extract(EGb 761)and trolox C of the decrease in synaptosomaldopamine or serotonin uptake following incubation).Biochem Pharmacol1992；44(12)：2395-401)。另外，所有提取物都在化学模型中表现出相似程度的Fe2+螯合作用。对这些提取物的某些纯化学组分的研究表明，槲皮素(先前在Sestili P，Guidarelli A，Dacha M，Cantoni O.槲皮素阻止DNA单链破裂以及由4-丁基过氧化氢导致的细胞毒性：自由基清除与铁鳌合机制的对比(Quercetin prevents DNA single strand breakage andcytotoxicity caused by tert-butylhydroperoxide：free radical scavengingversus iron chelating mechanism).Free Radic Biol Med 1998 August15；25(2)：196-200中报道)，金丝桃素和20-(s)-原人参二醇型人参皂苷Rb1，Rc及Rd显示了Fe2+螯合活性，但值得注意的是，20-(s)-原人参三醇型人参皂苷Rg1和Re未显示该活性，这表明了独特的构效关系。以下实施例中所示数据提示，CVT-E033，GB，HT1001，SJW和CVT-E036具有不同的可以起Fe2+螯合剂作用的化学组分，然而，当各组分以反映其在草药提取物中的含量的浓度进行研究时，却显示出非常小的活性，提示提取物的各组分协同促成或提供了结合Fe2+的累加效应。
在多种神经母细胞瘤细胞系中，所有提取物均被观察到了抗增殖和/或促分化作用。鉴于所有草药制剂均表现为Fe2+螯合剂--已显示在神经母细胞瘤中具有抗癌和抗增殖特性的物质的研究结果，这并不令人惊讶(Donfrancesco A，Deb G，De SL，Cozza R，Castellano A.去铁胺在肿瘤治疗中的作用(Role of deferoxamine in tumor therapy).ActaHaematol 1996；95(1)：66-9)。在本研究所用神经母细胞瘤培养模型中，Fe2+螯合相关神经保护(即，促存活)活性(在血清剥夺模型中测试)与抗增殖/促分化活性间的平衡似乎向后者的方向迁移。在所考察的所有化学成分中，仅槲皮素和贯叶金丝桃素显示出对神经母细胞瘤细胞数的抑制作用。贯叶金丝桃素(Dona M，Dell′Aica I，Pezzato E，Sartor L，Calabrese F，Della BM，Donella-Deana A，Appendino G，Borsarini A，Caniato R，Garbisa S.贯叶金丝桃素抑制癌症浸润合转移(Hyperforininhibits cancer invasion and metastasis).Cancer Res 2004 October1；64(17)：6225-32)，GB和某些类黄酮显示在其它肿瘤模型中发挥抗增殖/促凋亡作用(Huang YT，Hwang JJ，Lee PP，Ke FC，Huang JH，HuangCJ，Kandaswami C，Middleton E Jr，Lee MT.地毛黄黄酮和槲皮素，酪氨酸激酶的抑制剂对过表达表皮生长因子受体的A431细胞中细胞生长和转移相关特性的影响(Effects of luteolin and quercetin，inhibitors oftyrosine kinase，on cell growth and metastasis-associated properties inA431 cells overexpressing epidermal growth factor receptor).Br JPharmacol 1999 December；128(5)：999-1010)。尽管明显不是本研究期间所考察的人参皂苷(Rb1，Rg1，Rc，Rd和Re)，但某些特定人参皂苷也显示在多种肿瘤模型，包括人白血病(THP-1)细胞中发挥抗增殖和促凋亡作用(Popovich DG，Kitts DD.在人白血病(THP-1)细胞系中减少细胞增殖和诱导细胞凋亡中人参皂苷存在构效关系(Structure-function relationship exists for ginsenosides in reducing cellproliferation and inducing apoptosis in the human leukemia(THP-1)cellline).Arch Biochem Biophys 2002 November 1；406(1)：1-8)，这与本文所述结果一致。这也与单独的西洋参提取物HT1001与对神经母细胞瘤细胞数的抑制作用无关的研究结果是一致的。在HT1001和GB之间观察到了协同效应。与单个成分相比较，CVT-E033和CVT-E036在低血清条件(应激)下都减少细胞数。CVT-E033在非应激条件下也可以减少细胞数。本发明者发现，当组分以反映其在提取物的组合物中的比例的浓度进行分析时，未观察到对细胞数的明显作用(图4c)，因此，各组分间似乎为协同作用。
除了其抗增殖/促凋亡作用外，Fe2+螯合剂还显示能诱导细胞分化(Tanaka T，Muto N，Itoh N，Dota A，Nishina Y，Inada A，Tanaka K.由铁鳌合剂诱导胚胎性癌F9细胞的分化(Induction of differentiation ofembryonal carcinoma F9 cells by iron chelators).Res Commun MolPathol Pharmacol 1995 December；90(2)：211-20)。在本研究中，神经突起生长的程度被定量化，以提供神经母细胞瘤分化的指征。在N1E 115细胞中，发现CVT-E033，GB和HT1001都能以相似的程度诱导显著的神经突起生长。GB提取物被观察到诱导高比例的培养的神经母细胞死亡，但存活的神经母细胞表现出非常高度的神经突起延伸。由于HT1001不抑制神经母细胞瘤细胞数，甚至在SH-SY5Y细胞中还轻微地增加细胞数，因此西洋参提取物可能通过经未知机制增强细胞存活和诱导分化来起作用。先前已显示几种粗制的人参提取物及人参皂苷Rb1和Rg1在N1E 115细胞中能直接促进神经突起生长，或增强神经生长因子(NGF)对神经突起生长的刺激作用(Rudakewich M，Ba F，Benishin CG.人参皂苷Rb(1)和Rg(1)的神经营养和神经保护作用(Neurotrophic and neuroprotective actions of ginsenosides Rb(1)andRg(1)).Planta Med 2001 August；67(6)：533-7)。此外，人参皂苷Rb1和Rb3以及三七皂苷R4，6和Fa7在SK-N-SH细胞中也表现出促进神经突起生长的能力(Zou K，Zhu S，Meselhy MR，Tohda C，Cai S，Komatsu K.来自三七的达玛烷-型皂苷及其在SK-N-SH细胞中的神经突触生长活性(Dammarane-type Saponins from Panax japonicus and theirneurite outgrowth activity in SK-N-SH cells).J Nat Prod 2002October；65(9)：1288-92)。
现在已有很多关于西洋参，GB和SJW提取物的体外及体内神经营养和神经保护作用的报道。尽管这些作用多数都归因于对神经递质系统的特定作用，但抗氧化活性也是其重要因素。本发明首次提供了关于5种标准化草药及西洋参，GB和SJW的组合提取物在神经母细胞瘤中的抗氧化，铁螯合和抗增殖/促分化作用的说明。本发明还首次提供了人参皂苷(20-(s)-原人参二醇型人参皂苷)和SJW提取物成分金丝桃素的Fe2+螯合活性的证据，并阐明了独特的构效关系。所考察提取物及其某些纯生物活性化学成分的Fe2+螯合活性至少部分地为在神经母细胞瘤恶性细胞系中观察到的抗增殖和促分化作用负责。
HT1001的优选提取工艺在美国专利No.6,083,932中描述。在该工艺中，用300kg干燥碾碎的人参粉末作为起始原料。如果需要，可以将人参置于Fitz碾磨机中，碾磨至约80目。然后用乙醇提取人参。虽然在本领域工作者的普通技术范围内，改变是可取的，但优选使用85％的乙醇。约1∶5至1∶10的固体∶溶剂比是适宜的，但优选1∶8。必要时，提取可以进行约1至5小时。优选提取时间为3小时。提取温度可以在80-105℃的范围内，但优选90-95℃。推荐搅拌。固相和液相优选用沉降式离心机以约4200rpm的速度用25μm在线筒式滤器在输出线上分离。
当许多提取物分离后，将上清液集中起来。无论如何，使上清液进入浓缩步骤，以回收乙醇。优选真空蒸馏工艺。目标固体内容物为约10-12°(Brix)。温度优选为50℃，15″Hg，补料速率为220-225kg/h。为避免稠化，可能必须加水。
浓缩后的提取物可以冷冻，烘干或滚筒干燥，但优选在约42-58℃的补料温度和约20kg/h的补料速率下喷雾干燥。入口温度优选为约150-175℃，出口温度优选为约70-90℃。一旦干燥，便将提取物研细，需要时除去存在的任何团块。优选使用装配有0.065″筛网的Fitz碾磨机。然后提取物优选进行掺和，得到约20％的收率。
银杏提取物可以获自商业来源，如Acta Pharmacal(Sunnyvale，CA)。如Sloley BD，Urichuk LJ，Morley P，Durkin J，Shan JJ，Pang PK，Coutts RT.鉴定银杏叶提取物中作为单胺氧化酶抑制剂和潜在神经保护剂的三羟黄酮醇(Identification of kaempferol as a monoamine oxidaseinhibitor and potential Neuroprotectant in extracts of Ginkgo bilobaleaves)(J Pharm Pharmacol 2000 May；52(4)：451-9)中所述，银杏叶的标准化提取物含有约24％的银杏类黄酮苷和约6％的萜内酯。
如Sloley BD，Urichuk LJ，Ling L，Gu LD，Coutts RT，Pang PK，ShanJJ.，贯叶金丝桃提取物的化学和药理学评估(Chemical andpharmacological evaluation of Hypericum perforatum extracts)(ActaPharmacol Sin 2000；21(12)：1145-52.)中所述，圣约翰草提取物可以获自商业来源，并通常被标准化为0.3％的金丝桃素含量。
含有约15-50％，优选约25-0％的总人参皂苷(亦称皂苷)的特定人参提取物HT1001可以单独或与GB，SJW，银杏内酯，类黄酮，人参皂苷，金丝桃素和/或贯叶金丝桃素组合作为抗氧化剂或抗增殖剂给药。
根据本发明的抗氧化剂或抗增殖剂可以通过任何适宜的途径，包括经口服，气雾剂或其它用于递送至肺的装置，鼻喷雾，静脉内，肌内，腹膜内，阴道，直肠和局部或透皮给药。可以用作递送抗氧化剂或抗增殖剂的介质的赋形剂对于本领域技术人员是显而易见的。例如，抗氧化剂或抗增殖剂可以为干燥的形式，在临静脉注射给药前溶解。优选单独或与BB，SJW和/或其活性组分组合的HT1001为口服或静脉内给药。如果计划口服给药，则HT1001优选制成100mg的胶囊。HT1001和GB的组合物CVT-E033优选制成125mg的胶囊。HT1001和GB的组合物CVT-E036优选制成325mg的胶囊(SJW∶HT1001∶GB，200mg∶100mg∶25mg)。
适宜的载体，稀释剂或赋形剂为本领域用于制备药物组合物的已知的载体，稀释剂或赋形剂。这些适宜的稀释剂或赋形剂包括但不限于水，盐溶液，醇，阿拉伯胶，植物油，聚乙二醇，明胶，乳糖，直链淀粉，硬脂酸镁，滑石粉，淀粉，如玉米淀粉或土豆淀粉，硅酸，粘性石蜡，脂肪酸甘油一酯和甘油二酯，季戊四醇脂肪酸酯，羟甲基纤维素，聚乙烯吡咯烷酮等。药物组合物可以灭菌，需要时与助剂，如润滑剂，防腐剂，稳定剂，润湿剂，乳化剂，用于影响渗透压的盐，缓冲剂，着色剂，香精和/或芳香物质混合。如果单独给药，优选HT1001对75kg的个体以10-1000mg活性剂/天的剂量范围给药。更优选采用75-500mg/天的剂量，最优选采用100-200mg/天的剂量。
本文所用短语“有效量”包括HT1001单独或与GB，SJW，银杏内酯，类黄酮，人参皂苷，金丝桃素和/或贯叶金丝桃素组合时的给药。当HT1001与另一抗氧化或抗增殖剂同时给药时，可以减少HT1001的通常情况下的有效量。因此，术语“有效量”意欲包括HT1001与其它活性成分组合时的使用，由此，各成分的组合物有效，并且每种成分的剂量可以按比例地减少。例如，如果HT1001通常以100mg/个体/天的量给药时有效，并且银杏通常以100mg/个体/天的量给药时有效，则使用这两种成分的组合物时可以各自以50mg/个体/天的量给药。当另一种活性成分(除HT1001之外)较昂贵时(这是许多药物常有的情况)，这种组合使用对于消费者而言是更具有成本效益的。
根据本发明的组合物可以用于治疗氧化应激，铁超负荷和/或促进神经突起生长。氧化应激和铁超负荷是由许多病症或疾病，包括但不限于癌症，阿尔茨海默氏病，结核病，帕金森氏病，镰状细胞病，肝豆状核变性，肝损伤，β-地中海贫血，心脏病，多发性硬化症，炎性肠病(克隆氏病和溃疡性结肠炎)，感染，肿瘤，心肌病和/或关节病引起的。特定组织中的铁负荷与增加的疾病风险相关(Eugene D.Weinberg，铁负荷和疾病监视(Iron Loading and Disease Surveillance)，EmergingInfectious Diseases，Vol.5，No.3，May-June 1999346-352)。铁起到促氧化剂的作用，刺激被称作自由基的物质在机体内的损害效应。下表1显示了与不同组织中铁超负荷相关的疾病。
表1
T组织类型 疾病
肺泡巨噬细胞 肺部肿瘤和感染
垂体前叶 性腺和生长功能障碍
主动脉；颈动脉和冠状动脉 动脉粥样硬化
结直肠粘膜 腺瘤，癌
心脏 心律失常，心肌病
婴儿肠 肉毒中毒，沙门氏菌病，猝死
关节 关节病
肝 病毒性肝炎，肝硬化，癌
巨噬细胞 细胞内感染
胰 腺泡和β细胞坏死，癌
血浆和淋巴 细胞外感染
骨骼系统 骨质疏松症
皮肤 麻风病，黑色素瘤
软组织 肉瘤
黑质 帕金森氏病
实施例
材料
菲咯嗪，去铁敏(DFO)，槲皮素，芦丁，银杏内酯A和银杏内酯B获自Sigma。所有提取物(HT1001，GB，SJW，CVT-E033和CVT-E036)及化学组分人参皂苷(Rb1，Rg1，Rc，Rd和Re)均由CV Technologies(Edmonton，Alberta，Canada)制备和纯化。先前已描述了西洋参提取物HT1001(REMEMBER-
)(Sloley BD，Pang PK，Huang BH，Ba F，Li FL，Benishin CG，Greenshaw AJ，Shan JJ.空间学习任务中西洋参提取物减少东莨菪碱诱导的健忘症(American ginsengextract reduces scopolamine-induced amnesia in a spatial learning task).JPsychiatry Neurosci 1999November；24(5)：442-52)，GB提取物(SloleyBD，Urichuk LJ，Morley P，Durkin J，Shan JJ，Pang PK，Coutts RT.鉴定银杏叶提取物中作为单胺氧化酶抑制剂和潜在神经保护剂的三羟黄酮醇(Identification of kaempferol as a monoamine oxidase inhibitor andpotential Neuroprotectant in extracts of Ginkgo biloba leaves).J PharmPharmacol 2000 May；52(4)：451-9)和SJW(Sloley BD，Urichuk LJ，LingL，Gu LD，Coutts RT，Pang PK，Shan JJ.，贯叶金丝桃提取物的化学和药理学评估(Chemical and pharmacological evaluation of Hypericumperforatum extracts).Acta Pharmacol Sin 2000；21(12)：1145-52)的化学特征。CVT-E033(AD-
4∶1的HT1001∶GB提取物(w/w))和CVT-E036(MENTA-
8∶4∶1的标准化SJW提取物∶HT1001∶GB提取物(w/w))是经ChemBioPrintTM标准化的专有组合产物，购自CVTechnologies。WST-1细胞增殖试剂购自F.Hoffmann-La Roche Ltd.(Postfach，Switzerland)。细胞培养试剂购自Gibco Life TechnologiesCanada(Burlington，ON，Canada)。所有其它化学试剂均购自Sigma-Aldrich Chemical Co.(Oakville，Ontario，Canada)或FisherChemical Co.(Edmonton，Alberta，Canada)。所有样品，除水溶性人参皂苷外，均先溶解在DMSO中，然后用水稀释以供实验用。
脂质过氧化测定
用Ohkawa等人建立的硫代巴比妥酸测定法(Ohkawa H，Ohishi N，Yagi K.通过硫代巴比妥酸反应分析动物组织中的脂质过氧化物(Assay for lipid peroxides in animal tissues by thiobarbituric acidreaction).Anal Biochem 1979 July；95(2)：351-8)和儿茶酚胺能神经母细胞瘤细胞系SH-SY5Y(来自University of Saskatchewan的Peter Yu博士的慷慨礼物)评价草药提取物抑制脂质过氧化作用的能力。细胞在补充有10％胎牛血清(FBS)(v/v)和1％抗生素混合物(青霉素50μg/ml，链霉素50μg/ml，100μg/ml；PSN)的Dulbecco改良Eagle培养基(DMEM)中保持至约90-100％铺满。然后将其以1×106个细胞/孔的量接种在6孔Nunclon组织培养板中，培养24小时，接着在有或无0.1mM硫酸亚铁(FeSO4)存在下暴露于草药提取物中48小时。然后收集细胞，置于一次性玻璃培养管中，离心，所得团块重新悬浮在0.4ml 1.15％的氯化钾中，用超声波破碎仪匀浆化。然后取300μl样品，用Ohkawa等人的方法以四乙氧基丙烷为参比标准测定脂质过氧化物。用Lowry的方法测定剩余材料的蛋白质含量。
草药提取物在有或无0.1mM Fe2+存在的条件下对脂质过氧化作用的影响见图1。所有样品均只在Fe2+存在下显著(P＜0.05)抑制脂质过氧化作用，在无Fe2+存在时对脂质过氧化作用无影响(数据未显示)。效价顺序为GB＞SJW＞CVT-E033＝CVT-E036＞HT1001。
清除自由基
通过Arnao等人(Arnao MB，Cano A，Hernandez-Ruiz J，Garcia-Canovas F，Acosta M.通过L-抗坏血酸和其他抗氧化剂抑制由过氧化物酶催化的2.2′-连氮基-双(乙基苯并噻唑啉-6-磺酸)氧化：确定食物的总抗氧化剂状况的新方法(Inhibition by L-ascorbic acid and otherantioxidants of the 2.2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)oxidation catalyzed by peroxidase：a new approach for determining totalantioxidant status of foods).Anal Biochem 1996 June 1；236(2)：255-61)开发的动态法的改良法评价草药提取物和纯化学组分的羟基自由基清除能力。简而言之，草药提取物与过氧化氢和2，2′-连氮基-双(3-乙基苯并噻唑啉-6-磺酸)(ABTS)在50mM的Tris-HCl缓冲液(pH 7.2)中混合，加入2nM辣根过氧化物酶启动反应。样品的羟基清除活性通过阻止有色ABTS自由基形成的能力(在405nm处的吸收度)来推断。将各样品的自由基清除活性与由抗坏血酸产生的标准曲线进行比较。
提取物GB，HT1001和CVT-E033的自由基清除能力见下表2。由阻止过氧化物酶催化的ABTS自由基形成的能力推断羟基清除活性。CVT-E033，直至更高水平的GB显示出显著的羟基清除活性，而HT1001则未检出活性。
表2
表2.西洋参提取物HT1001，GB提取物和组合物CVT-E033(HT1001+GB)的自由基清除作用。草药提取物与过氧化氢和ABTS一起孵育，加入辣根过氧化物酶启动反应。样品的羟基清除活性通过阻止有色ABTS自由基形成的能力(在405nm处的吸收度)来推断。将各样品的自由基清除活性与由抗坏血酸产生的标准曲线进行比较，并表示为以重量计的％抗坏血酸。
Fe2+螯合作用测定
草药提取物或纯化学组分在无细胞测定系统中螯合Fe2+的能力通过孵育FeSO4和Fe螯合色原菲咯嗪后对有色Fe(菲咯嗪)3 2+络合物形成的抑制作用来评价。菲咯嗪先前已被用于测量从铁蛋白释放的游离Fe2+。所有供试草药提取物和纯化学成分都在4％DMSO水溶液中分别以5和0.2mg/ml的浓度制备。50μl等分样品与50μl 1mM的FeSO4溶液在96孔微量滴定板(MTP)中室温孵育30min。然后将所得50μl等分溶液转移至新的96孔MTP中，与50μl 2mM(饱和浓度)的菲咯嗪溶液合并。HT1001，GB，SJW，CVT-E033和CVT-E036在1.25mg/ml的浓度下测试，纯化学组分在50μg/ml(终浓度)的浓度下测试。立即显色，在562nm处读取吸光度。结果以相对于空白组的相对值来表示，并将样品的活性与已知Fe2+螯合剂DFO的活性进行比较。DMSO能抑制Fe(菲咯嗪)3 2+络合物的形成，因此供试提取物和化学组分与相同百分比的DMSO空白进行比较。
测定所有草药提取物和纯化学组分银杏内酯A和B，类黄酮槲皮素和芦丁，贯叶金丝桃素，金丝桃素及5种人参皂苷Rb1，Rg1，Rc，Rd和Re在无细胞化学测定系统中抑制Fe2+与菲咯嗪结合的能力。为获得足够的Fe(菲咯嗪)3 2+络合物的吸光度信号，选择了非生理浓度的Fe2+与菲咯嗪反应。这要求高浓度的潜在螯合Fe2+的草药提取物和组分。CVT-E033，GB，HT1001，SJW和CVT-E036(图2b)均观察到了相似强度的对Fe(菲咯嗪)3 2+络合物形成的剂量依赖性抑制作用。已知Fe2+螯合剂DFO的剂量效应曲线见2a，其显示了在本测定系统中，DFO能阻止Fe(菲咯嗪)3 2+络合物的形成。银杏内酯A和B以及类黄酮芦丁的滴定曲线显示无活性，而类黄酮槲皮素能抑制Fe(菲咯嗪)3 2+络合物的形成(图3a)。20-(s)-人参二醇型人参皂苷Rb1，Rc和Rd，而不是20-(s)-原人参三醇型人参皂苷Rg1和Re，也证明了抑制Fe2+与菲咯嗪相互作用的能力(图3b)。对SJW的主要已知生物活性组分的分析显示，金丝桃素，而不是贯叶金丝桃素，能抑制Fe(菲咯嗪)3 2+络合物的形成(图3c)。这些数据结合起来，提示CVT-E033，GB，HT1001，SJW和CVT-E036具有不同的起Fe2+螯合剂作用的化学组分。然而，当各个组分以反映其在草药提取物中的含量的浓度进行研究时却显示出非常小的活性，提示提取物的各个组分协同促成或提供了结合Fe2+的累加效应。
神经母细胞瘤细胞存活率测定
SH-SY5Y，N1E 115和SK-N-SH(ATCC，Rockville，MD，USA)神经母细胞瘤细胞通过在补充有10％FBS(v/v)，1mM丙酮酸钠，2mML-谷氨酰胺和MEM非必需氨基酸混合物的最小必需培养基(MEM)中于37℃，5％CO2，95％空气的条件下传代培养来维持。在约80％铺满时，收集细胞，并以1×104个细胞/孔的量接种于含有草药提取物或化学组分和不同量FBS的96孔培养板中。DMSO的终浓度不得超过0.05％。96小时后，照制造商的说明书向各样品孔中加入WST-1细胞增殖试剂，评价对细胞数的影响。采用前述细胞增殖试剂WST-1测定法测定细胞数(Ba F，Pang PK，Benishin CG.用SK-N-SH神经母细胞瘤细胞培养物建立可靠的细胞毒系统(The establishment of a reliablecytotoxic system with SK-N-SH neuroblastoma cell culture).J NeurosciMethods 2003 March 15；123(1)：11-22)。与细胞计数的传统台盼蓝拒染法相比，WST-1法的准确度显示了两种技术间的强相关。结果以相对于对照组的相对值表示。
比较所有提取物在浓度为50μg/ml时，于正常(10％)和低(2％)血清条件下在3种神经母细胞瘤细胞系中的作用。结果见图4。含银杏的提取物GB，CVT-E033和CVT-E036是最常显示对细胞数具有抑制作用的提取物。具体地，GB在人神经母细胞瘤细胞系SK-N-SH细胞(低和正常血清)及SH-SY5Y(低血清)中抑制细胞数。相比之下，CVT-E033在SH-SY5Y(低血清)和鼠神经母细胞瘤细胞系N1E 115(低和正常血清)中显著抑制细胞数，CVT-E036在低血清条件下抑制所有3种细胞系的细胞数，另外还在正常血清条件下抑制N1E 115的细胞数。SJW提取物也在低血清条件下抑制SH-SY5Y和N1E 115细胞的细胞数。HT1001对细胞数无抑制作用，并在高血清条件下对SH-SY5Y细胞的细胞数产生了微弱的刺激作用。Fe2+螯合剂DFO在N1E 115细胞中也显示能抑制神经母细胞瘤细胞数(图4d)，但在SH-SY5Y细胞中却产生了双相作用。
当单个组分以反映其在提取物中的比例的浓度进行分析时，在任何细胞系中均未观察到对细胞数的显著影响。由于怀疑部分化合物在过滤的过程中损失了，因此对所有组分建立了在鼠模型(N1E 115)和人神经母细胞瘤模型(SH-SY5Y)中的剂量效应曲线。在GB提取物和CVT-E033及CVT-E036中发现的银杏内酯(A和B)以及在SJW提取物中发现的类黄酮(槲皮素和芦丁)的剂量效应曲线见图5a(N1E115细胞)和图5b(SH-SY5Y)。仅槲皮素在人SH-SY5Y和小鼠N1E115细胞系中显示出了对细胞数的显著抑制作用，显著性(P＜0.05)首先出现在5μg/ml时。人参皂苷和贯叶金丝桃素的结果见图5c(N1E115细胞)和图5d(SH-SY5Y细胞)，结果表明，仅贯叶金丝桃素在两种细胞系中显示出了对细胞数显著且剂量依赖性的抑制作用。
神经突起生长
用鼠神经母细胞瘤细胞系N1E 115研究草药提取物HT1001，GB和CVT-E033对神经突起生长的影响。将N1E 115细胞接种于100cm2的组织培养皿中，在37℃下，于添加有10％FBS和1％PSN抗生素(v/v)的DMEM中维持。然后机械移出细胞，以2×104个细胞/皿的密度平板接种于35mm的胶原涂敷组织培养皿中。与草药提取物一起培养7或14天后，对代表性细胞区域的神经突起生长进行定量。每个处理培养皿对两个细胞区域拍照，神经突起延伸的程度记分如下：S1＝细胞延长或非常小的神经突起生长；S2＝两个以上从细胞体延伸的小神经突起；S3＝一个或两个生长细胞体直径的至少两倍的神经突起；S4＝两个以上长神经突起。如下计算神经突起指数：
神经突起指数(In)＝总神经突起得分(∑S)/总细胞数∑N；
其中∑S＝S1*N+S2*N+S3*N+S4*N，N是每个细胞区域的细胞数。
CVT-E033，HT1001和GB对神经突起延伸的影响概述于图6。所有供试草药提取物均从50μg/ml开始显示出相似程度的诱导N1E 115神经母细胞瘤细胞神经突起生长的能力。GB和HT1001的作用是剂量依赖性的。GB被观察到诱导细胞死亡(得到了上述对细胞数的研究的支持)，但却刺激剩余细胞的神经突起生长。
统计分析
除非另有说明，采用单向方差分析法(ANOVA)(Student-Newman-Keuls检验)确定显著性差异，显著性水平设置为0.05。所有结果以平均值±平均值的标准误差(SEM)的形式表示。统计分析采用GraphPad Prism或SigmaStat绘图和统计软件进行。
Claims (9)
1.一种药物组合物，包括与至少一种选自银杏(Ginkgo biloba)，圣约翰草(Saint John′s Wort)，银杏内酯，类黄酮，人参皂苷，金丝桃素和贯叶金丝桃素的药剂组合的HT1001。
2.根据权利要求1的药物组合物，其中所述HT1001的总人参皂苷含量以人参提取物的重量计为约15-50％。
3.根据权利要求1的药物组合物，其中所述药剂是银杏。
4.根据权利要求1的药物组合物，其中所述药剂是圣约翰草。
5.一种治疗氧化应激的方法，包括向需要这种治疗的患者施予有效减少氧化应激的量的药物组合物，所述组合物包括单独或与至少一种选自银杏，圣约翰草，银杏内酯，类黄酮，人参皂苷，金丝桃素和贯叶金丝桃素的药剂组合的HT1001。
6.根据权利要求5的方法，其中所述氧化应激是由癌症引起的。
7.一种治疗铁超负荷的方法，包括向需要这种治疗的患者施予有效减少铁超负荷的量的药物组合物，所述组合物包括与至少一种选自银杏，圣约翰草，银杏内酯，类黄酮，人参皂苷，金丝桃素和贯叶金丝桃素的药剂组合的HT1001。
8.根据权利要求7的方法，其中所述铁超负荷是由癌症，阿尔茨海默氏病，结核病，帕金森氏病，镰状细胞病，肝豆状核变性，肝损伤，β-地中海贫血，心脏病，多发性硬化症，炎性肠病(克隆氏病和溃疡性结肠炎)，感染，肿瘤，心肌病或关节病等引起的。
9.一种促进神经突起生长的方法，包括向需要这种治疗的患者施予促进神经突起生长的量的药物组合物，所述组合物包括与至少一种选自银杏，圣约翰草，银杏内酯，类黄酮，人参皂苷，金丝桃素和贯叶金丝桃素的药剂组合的HT1001。
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| US72874705P | 2005-10-21 | 2005-10-21 | |
| US60/728,747 | 2005-10-21 |
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| JP (1) | JP2009512675A (zh) |
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| CN (1) | CN101291680A (zh) |
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| CN101474243A (zh) * | 2008-11-14 | 2009-07-08 | 杜志政 | 具有血管清道夫功能的植物提取物组合物及其制备方法 |
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| CA2625204A1 (en) | 2007-04-26 |
| JP2009512675A (ja) | 2009-03-26 |
| KR20080064174A (ko) | 2008-07-08 |
| WO2007045959A8 (en) | 2008-05-15 |
| WO2007045959A2 (en) | 2007-04-26 |
| AU2006305682A1 (en) | 2007-04-26 |
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