CN101590037A - 一种穿心莲内酯组合物及其用途 - Google Patents
一种穿心莲内酯组合物及其用途 Download PDFInfo
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- CN101590037A CN101590037A CNA2009100406601A CN200910040660A CN101590037A CN 101590037 A CN101590037 A CN 101590037A CN A2009100406601 A CNA2009100406601 A CN A2009100406601A CN 200910040660 A CN200910040660 A CN 200910040660A CN 101590037 A CN101590037 A CN 101590037A
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- andrographolide
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Abstract
本发明公开了一种穿心莲内酯组合物及其用途。该组合物由摩尔比为1∶10~10∶1的组分I和组分II组成,所述组分I是穿心莲内酯、穿心莲内酯衍生物和穿心莲内酯衍生物在药学上可接受的盐中的至少一种,组分II是硫辛酸和二氢硫辛酸中的至少一种。该组合物可制备成抗癌、抗炎、抗菌、抗病毒或降血糖药物。
Description
技术领域
本发明属于中药领域,特别涉及一种穿心莲内酯组合物及其用途。
背景技术
穿心莲内酯(Andro)是中药穿心莲中的主要有效成分。穿心莲在亚洲国家,包括中国、印度、日本、韩国等广泛用于治疗炎症性疾病,包括风湿性关节炎、咽喉炎、腹泻、细菌和病毒感染。研究表明穿心莲内酯具有广谱的抗癌作用,并且治疗效果良好。近30年来,穿心莲内酯及其3种衍生物穿琥宁、炎琥宁,莲比治已在中国广泛应用于临床,这些药物能够减轻炎症、发热、细菌和病毒感染性疾病的临床症状。因其来源于天然中药且疗效好,这些药物通常称为“绿色抗生素”。临床上应用的穿心莲内酯及其3种衍生物结构图如下:
穿心莲内酯抗菌活性的研究:用穿心莲提取物治疗急性上呼吸道感染合并鼻窦炎,结果穿心莲提取物较安慰剂疗效显著,患者头痛,鼻、咽部和全身不适症状明显改善,治疗组体温温和下降(Caceres et al.,Phytomedicine1997,4,101-104)。在一个有250名受试者的试验中,穿心莲提取物明显降低感冒患者的患病时间和减轻病情(Hancke et al.,Phytother.Res.1995,9,559-5621;Melchior et al.Phytomedicine 1996,3,314-318;Caceres et al.,Phytomedicine 1999,6,217-223)。在107名18岁学生中进行的试验中,每天给予受试者100mg含5.6%穿心莲提取物片剂2片,该剂量远小于临床上用于治疗感冒的穿心莲剂量(每天约1,200到6,000mg)连续三个月,其余53人给予安慰剂治疗。结果,使用穿心莲组只有16人感冒,而安慰剂对照组33人感冒,证明穿心莲减少了患感冒风险(Caceres et al.,Phytomedicine 1997,4,101-104)。
虽然Andro已被广泛用于临床,但试验证明它并无直接杀菌效果(Singhaet al.,Fitoterapia 2003,74,692-694;Li et al.,China J.Chinese Materia Medica2006,12,1015-1017;Xia et al.,J.Immunol.2004,173,4207-4017)。Li发现Andro衍生物(莲必治)虽不能直接抑制绿脓肝菌(PAO1)生长,但能明显抑制它的QS系统(China J.Chinese Materia Medica 2006,12,1015-1017)。莲必治12.5mg/mL(34mM)对培养的PAO1生长无影响,但显著抑制绿脓菌素的产生及蛋白水解酶和弹性蛋白酶的活性。这个新发现的作用机理能够部分的解释其抗菌效果。
金黄色葡萄球菌(Staphylococcus aureus,SA),简称金葡菌,属于革兰氏阳性菌,通常附着在健康人的鼻腔。据统计,全世界大约有十亿人携带不同亚型的金葡菌(Ryan et al.,Sherris Medical Microbiology 2004,4th ed.,McGraw Hill)。金葡菌感染是最常见的皮肤感染疾病之一,在浅脓肿中繁殖可引起严重的感染导致面容毁损和其他危及生命的疾病,如心内膜炎、肺炎、骨髓炎、脓毒性关节炎、脑(脊)膜炎,以及术后伤口感染、败血病、中毒性休克综合征等(Silverstein et al.,Infect.Immun.1994,62,152-161;Dann et al.,Clin.Inf.Dis.1994,18,437-439;Wisplinghoff et al.,Pediatr.Infect.Dis.J.2003,22,686-691;Karlowsky et al.,Ann.Clin.Microbiol Antimicrob.2004,3,7-15)。
随着抗生素的广泛应用,金葡菌的耐药性也越来越严重。MRSA是耐抗生素金葡菌中的一种,它对含β-内酰胺类抗生素耐药,包括甲氧苯青霉素和其他更为常用的抗生素如苯唑西林、盘尼西林和阿莫西林。最近的研究表明,在美国静脉注射感染金葡菌病人中约有20%是MRSA感染(Graham et al.,Ann.Intern.Med.2006,144,318-325)。
目前严重感染耐药金葡菌的患者,万古霉素和替考拉宁是目前唯一有效的抗生素,替考拉宁是万古霉素的同源衍生物。万古霉素和替考拉宁口服吸收差,所以,对全身感染必须采用静脉注射。更重要的是现已出现对万古霉素和替考拉宁都耐药的耐药金葡菌(Schito et al.,Clin.Microbiol.Infect.12Suppl.2006,1,3-8)。
绿脓杆菌(铜绿假单胞菌,Pseudomonas aeruginosa,PA)属于革兰氏阴性菌,是一种条件致病菌。绿脓杆菌通常感染肺部,尿道,烧伤等,也会引起血液感染(Stover et al.,Nature 2000,406,959-964;Lyczak et al.,Microbes.Infect.2000,2,1051-1060)。绿脓杆菌也是肺囊性纤维变性患者中引起慢性肺感染的主要病菌(Frederiksen et al.,Pediatr.Pulmonol.1997,23,330-335),近来被认为是引起伤口长期感染的主要病因之一(Bjarnsholt et al.,Anal.Bioanal.Chem.2007,387,409-414)。
细菌黏附在表面并在一个自身产生的多聚体基质中形成社会群落,称之为生物被膜(Costerton et al.,Science 1999,284,1318-1322)。绿脓杆菌常常自身形成生物被膜。在适宜的实验室条件下,绿脓杆菌会形成一个厚达几百毫米的生物被膜,生活在这个生物被膜的细菌对抗生素产生抵抗作用。肺部绿脓杆菌感染的患者中,肺囊性纤维变性患者特别适用于以生物膜为治疗靶点进行治疗。
很多物种通过细胞与细胞之间的信号传导达到一个临界密度,叫群体感应系统(quorum sensing,QS)。细菌细胞通过产生并释放胞外自身诱导分子(autoinducers,Ais)调节基因的表达和细菌群落的排列(生物被膜的形成)(Fuqua et al.,Curr.Opin.Microbiol.1998,1,183-189;Hammer et al.,N.(Engl)J.Med.1996,35,1081-1090)。现认为QS调控系统保证当细菌密度增大到足以压倒寄主时才大量繁殖引起病症出现。
革兰氏阴性菌的酰基高丝氨酸内酯系统(AHLs)是研究最多的QS系统。虽然细菌间的交流是微生物生态学的内容,但现已证明AHLs在植物和动物包括人类疾病中同样重要。这一系统首先在费希尔氏弧菌的生物发光系统中发现(Eberhard et al.,Biochem.1981,20,2444-2449;Nealson et al.,J Bacteriol.1970,104,300-306)。费希尔氏弧菌含有两种蛋白-AI合成酶的Lux I和LuxR,他们都是由AI调节发光操纵子激活的转录调控因子。AHL合成酶产生的AHL分子含有高丝氨酸内酯环(源于S-腺蛋氨酸),伴有可变的酰基链(源于脂类代谢)由酰胺键连接。AHLs为含4-18个碳原子的酰基链,且随其氧化态和不饱和度而变(Fuqua et al.,Curr.Opin.Microbiol.1998,1,183-189)。在绿脓杆菌中已发现两种AHL介导的群体感应途径。Las系统由负责合成3-氧代十二酰基高丝氨酸内酯的AHL合成酶基因lasI和编码LuxR型转录调节子蛋白基因lasR组成(Gambello et al.,J.Bacteriol.1991,173,3000-3009;Zhao etal.,Chin.Med.J.(Engl)1991,104,770-775)。已有研究显示Las系统调节致病因子的表达,包括胞外酶类(LasB elastase,LasA protease,alkaline protease)、次级代谢产物(pyocyanin,hydrogen cyanide,pyoverdin)、毒素(exotoxin A)和lasI自身。在rhl系统中,rhlI基因产物决定丁酰基高丝氨酸内酯(C4-HSL)的合成,它与rhlR基因产物一起激活rhlAB鼠李糖脂生物合成基因的转录。rhl系统同时也调节一些受las系统控制的致病因子的表达。
绿脓杆菌群体感应通用的模型为:当细菌集落密度低时,细菌产生基础水平3-氧代十二酰基高丝氨酸内酯。当细菌密度升高,3-氧代十二酰基高丝氨酸内酯达到临介浓度时,它就与LasR作用形成LasR-3-oxo-C12-HSL复合物,可激活许多基因的转录,这些基因的表达产生胞外酶、次级代谢产物和毒素等致病因子。
在细菌群体行为基因表达调控中,群体感应是广泛认同的一种有效的作用机制。最近二十年关于细菌群体感应的研究表明,细菌群体感应信号途径对新的抗菌药物的研发来说,是十分有前景的方向。
穿心莲内酯及其3种衍生物炎琥宁、穿琥宁、莲比治能够减轻炎症、发热、细菌和病毒感染性疾病的临床症状(Hendrickson et al.,J.Bacteriol.2001,183,7126-7134;Zhang et al.,Clin.Exp.Pharmacol.Physiol.2000,27,358-368;Shen et al.,Br.J.Pharmacol.2002,35,399-406;Gabrielian et al.,Phytomedicine2002,9,589-597)。因其来源于天然中药且疗效好,这些药物通常称为“绿色抗生素”。
穿心莲内酯解热抗炎作用。穿心莲内酯对2,4-二硝基酚或内毒素诱导的发热和蛋清诱导的水肿或巴豆油诱导的炎症模型均有退热、抗炎活性。具有抑制和延缓肺炎双球菌和溶血性乙型链球菌引起的体温升高的作用,对于伤寒、副伤寒菌苗所致的发热家兔或2,4-二硝基苯酚所致发热大鼠有一定的解热作用,对同时感染肺炎双球菌和溶血性链球菌培养物的家兔能延缓体温上升时间,减缓体温上升程度。口服30、100、300mg/kg穿心莲内酯能显著抑制角叉菜藻、高岭土和制霉菌素诱导的大鼠爪脚水肿。而且还显著抑制由棉球诱导的肉芽肿和减轻佐剂诱导的关节炎引起的水肿。穿心莲内酯(300mg/kg)能抑制乙酸诱导的血管通透性试验中染料的漏出(Han et al.,TheChinese J.Modern Applied Pharmacy 2005,22,126-129)。Chiou等(Br.J.Pharmacol.2000,129,1553-1560)研究认为穿心莲内酯(1-100mM)在RAW264.7细胞中通过降低诱导型NO合酶(iNOS)蛋白表达抑制NO合成,且可阻止蛋白从头合成和通过加速降解降低蛋白稳定性。Batkhuu等(Biol.Pharm.Bul.2002,25,1169-1174)结果表明穿心莲内酯抑制NO产生,在0.1-100mM范围内呈浓度依赖性,IC50为7.9mM。
在炎症反应中,粘附分子表达上调及内皮-白细胞粘附增加是炎症反应发展的重要步骤。诱导剂肿瘤坏死因子α(TNF-α)可以通过增加内皮细胞粘附分子(ICAM-1)的表达来增强内皮-白细胞的粘附。当内皮Eahy926细胞与TNF-α(0.5ng/ml)接触培养18h后,其粘附率增加15倍,若同时加入穿心莲内酯(0.6-16.7)mg/ml可减少由TNF-α引起的粘附增加,在研究穿心莲内酯对ICAM-1表达影响的实验中发现穿心莲内酯(0.6-16.7)mg/ml可剂量依赖性抑制由TNF-α引起的ICAM-1表达上调。Shen等(Br.J.Pharmacol.2002,135,399-406)阐明了穿心莲内酯通过鼠嗜中性粒细胞抑制炎症反应的机理是通过调节PKC依赖途径阻止或至少部分阻止活性氧(ROS)的产生,使内酯下调Mac-1高表达。
Tsai等(Euro.J.Pharmacol.2004,498,45-52)评价了穿心莲内酯作用于体外补体5α(C5α)诱导的巨噬细胞补充的抗炎机制。穿心莲内酯呈剂量依赖性抑制细胞分裂,IC50为5.6±0.7μM。胞外信号调节激酶1/2(ERK1/2),P38致分裂原激活的蛋白激酶(P38MAPK)和磷脂酰肌醇-3-激酶(PI3K)是C5α诱导分裂所必需的,而c-Jun N-末端激酶(JNK)是非必需的。穿心莲内酯显著减弱C5α刺激的ERK1/2和其上游激活剂MAP激酶-ERK激酶(MEK1/2)磷酸化作用。在同样条件下,穿心莲内酯不能影响C5α刺激的P38MAPK和JNK磷酸化。穿心莲内酯也显著消除C5α刺激的下游PI3K靶蛋白AKT的磷酸化。因此穿心莲内酯抗炎作用的机理可能是通过掺入ERK1/2和PI3K/Akt信号通路的细胞分裂抑制作用。
Xia等(J.Immunol.2004,173,4207-4217)的研究发现穿心莲内酯抑制细胞核中心转录因子(NF-kappaB)活性。相关机理研究表明,它同p50的还原半胱氨酸(62)形成共价加合物,阻断NF-kappaB寡核苷酸与核酸蛋白的连接。穿心莲内酯能够抑制内皮细胞中NF-kappaB的活化,进而降低细胞粘附分子E选择素(E-selectin)的表达,而且阻止E-selectin介导的白细胞黏附,它也消除细胞因子和内毒素诱导的噬中性白细胞的腹膜沉着,减弱败血症休克,阻止体内变态反应的关节炎。它对IkappaB alpha降解、p50和p65核转位,或细胞生长速率无抑制作用。Hidalgo等(Br.J.Pharmacol.2005,144,680-686)关于穿心莲内酯的抗炎机理研究表明穿心莲内酯抑制某些前炎症蛋白的表达,这些蛋白在基因中起到NF-kappaB连接位点的作用。作者分析了穿心莲内酯在分化成嗜中性粒细胞的HL260中由血小板激活因子(PAF)和N-甲酰-甲硫氨酰-亮氨酰-苯丙氨酸(fMLP)诱导的NF-kappaB激活作用中的作用。发现穿心莲内酯通过抑制NF-kappaB与DNA连接发挥抗炎作用,进而降低前炎症蛋白如COX-2的表达。
穿心莲内酯对心血管系统的影响。Chen等(Biochem.Pharmacol.2004,67,1337-1345)调查了穿心莲内酯保护人脐静脉内皮细胞(HUVES-VCs)免受生长因子(GF)缺乏诱导的凋亡的分子机理和信号通路。结果表明当HUVESVCs缺乏GF 18h后凋亡,但是加入穿心莲内酯可抑制凋亡的发生,且呈剂量依赖性(1-100mM)。穿心莲内酯通过抑制细胞色素C进入细胞质中且消除线粒体势能,导致阻止caspase-3和-9的激活,抑制凋亡的线粒体通路。穿心莲内酯处理内皮细胞诱导一个抗凋亡信号蛋白激酶Akt的活化和一个Akt下游靶BAD的磷酸化。穿心莲内酯在HUVES-VCs中通过激活Akt-BAD通路发挥其抗凋亡作用,因而可作为动脉粥样硬化的候选治疗剂。
穿心莲内酯的保肝作用。在给予半乳糖胺48,24,2h前或给予扑热息痛后1,4,7h,给予不同剂量的(50,100,200,400mg/kg)穿心莲内酯,可使半乳糖胺和扑热息痛引起的天冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)、碱性磷酸酶、胆红素、三酰甘油浓度的增加均受到抑制并恢复到正常水平。穿心莲内酯能对抗四氯化碳所致的大鼠肝损伤。穿心莲内酯(5.0和10mg/kg,p.o.)能抑制大鼠肝微粒体苯胺羟化酶、N-去甲基酶和O-去甲基酶活性,其中对O-去甲基酶最敏感。Visen等(J.Ethnopharmacol.1993.40,131-136)研究表明穿心莲内酯表现出显著的剂量依赖性(0.75-12mg/kg,p.o.)保肝活性,对于扑热息痛诱导的体外分离到的大鼠肝细胞毒性,穿心莲内酯可显著增加肝细胞的存活率,完全对抗扑热息痛对血清中和分离肝细胞中某些酶(GOT,GPT和碱性磷酸酶)的毒性,比水飞蓟素(临床应用的保肝药)更有效。
穿心莲内酯的降血糖作用。糖尿病(Diabetes Mellitus,DM)是一种与遗传因素有关,又与多种环境因素相关的慢性全身性疾病,是由于体内胰岛素的绝对或相对分泌不足而引起的糖、脂肪、蛋白质的代谢紊乱,可分为胰岛素依赖型糖尿病(I型,即IDDM)和非胰岛素依赖型糖尿病(II型,即NIDDM),其中II型患者占糖尿病病例的80%以上。
临床常用的治疗糖尿病药物按作用机制主要分为:胰岛素分泌促进剂(如磺酰脲类药物:格列本脲、格列吡嗪等);胰岛素增敏剂(如双胍类药物:苯乙双胍、二甲双胍等);α-葡萄糖苷酶抑制(如阿卡波糖、米格列醇等);以及胰岛素制剂和一些促进葡萄糖代谢、利用的药物。从目前临床所用或即将应用的降糖药物来看,各种西药都有一定的局限性和不良反应,甚至是很严重的不良反应,如导致低血糖、乳酸性酸中毒,长期使用引起并发症等;如磺酰脲类主要副作用为低血糖等,双胍类药可能发生乳酸酸中毒。对于II型糖尿病的治疗,传统的磺酰脲类和双胍类口服降糖药疗效有限,并且无法根本阻止胰岛β细胞的进一步坏死,导致胰岛素依赖。近来研究发现中医药对糖尿病有治疗作用,一些中药除了具备上述西药的降糖机制外,而且对胰岛β细胞有保护作用,并能改善血流动力学,减少糖尿病并发症的发生(李津,刘亚明.山西中医学院学报,2006,7(3):49-51),从而达到标本兼治的目的。
糖尿病发生发展过程中,高糖环境、NF-κB激活、氧化应激、炎症和β细胞凋亡以及糖尿病并发症之间存在错综复杂的联系。
糖尿病的高糖环境激活NF-κB。Sakiko等(Am.J.Physiol.Renal.Physiol.2007,292,1141-1150)发现高糖条件下可促进肾小球内皮细胞ICAM-1表达和激活NF-κB,这种改变可被匹列格酮等一些NF-κB抑制剂所阻断。Pieper等(J.Cardiovasc.Pharmacol.1997,30,528-532)把不同浓度的高糖和血管内皮细胞共孵育,电泳迁移率变动分析法(EMSA)检测出NF-κB的活性升高,加入能抑制NF-κB的抑制物SN250,则可以阻断以上作用。
氧化应激激活NF-κB。对于长期处于高糖环境中的细胞而言,核酸和脂类物质面对被氧化的趋势,其结果是非酶促终末糖基化产物(AGE)的形成,而后者反过来可以和它的受体(RAGE)结合,影响细胞的功能。Mohamed等(Biofactors,1999,10,157-67)的研究发现,AGE可以在体内、体外使细胞内氧化应激增加,进而激活NF-κB。在糖尿病人中,NF-κB的激活与血糖控制的情况相关,并能被抗氧化剂α-硫辛酸所减弱。来自鼠和人类胰岛细胞的资料显示NF-κB激活可促进iNOS的表达,导致胰岛β细胞损害(MohamedA.K,et al.Biofactors,1999,10,157-167)。Hofmann等(Diabetologia.1999,42,222-232)观察43例I型糖尿病人体外分离的末梢血单核细胞中NF-κB的活性,其中10例预先接受抗氧化剂硫辛酸治疗2周。结果显示,糖基化血红蛋白(HbA1c)水平>10%的病人,NF-κB活性明显升高,NF-κB活性的增加与血浆脂质过氧化物的增加相关;用硫辛酸处理的病人NF-κB的结合活性降低。因此认为高血糖可诱导糖尿病患者血液单核细胞的NF-κB活化,而NF-κB的激活至少部分地依赖于氧化应激。
NF-κB调控胰岛β细胞凋亡。NF-κB调节着多种导致胰岛细胞功能损害的促炎症因子基因的表达。例如,NF-κB可通过诱导Fas和iNOS、COX-2的表达促进T细胞介导的杀伤作用和β细胞毒性产生。此外,β细胞内其它的一些促炎症因子,如趋化因子(MCAP-1等)和黏附分子(ICAM-1等)的启动子上有NF-κB的结合序列(May and Ghosh,Immunol.Today 1998,19,80-88)。NF-κB在β细胞炎症反应中的重要作用在一些体外NF-κB抑制模型上也被证实。
抑制NF-κB活性可抑制β细胞死亡。Stephens等(J.Autoimmun.1997,10,293-298)使用TNF刺激NIT-1胰岛β细胞,观察到抑制NF-κB活性可抑制β细胞中免疫介导的几种不同的细胞死亡途径,这种机制在自身免疫性糖尿病中可能作为保护胰岛β细胞的有效策略。
抗氧化剂可保护胰岛β细胞。由诱导型一氧化氮合成酶(iNOS)催化产生的NO是细胞因子介导的β细胞损害及功能异常的潜在的介质。反应性氧化物(ROS)已显示与β细胞的死亡及糖尿病的形成有关。Ho等(Free RadicalBiology Med.2000,28,604-624)使用ROS的清除剂和稳定剂PBN处理alloxan和STZ诱导的糖尿病鼠,结果发现注射alloxan和STZ后30分钟可诱导出胰腺中的NF-κB活性,预先用PBN处理可抑制NF-κB的激活及NO的产生,并有效地降低高血糖。
NF-κB激活与糖尿病并发症。血管病变是糖尿病的主要并发症和患者致残的重要原因,糖基化终末产物(AGEs)促进糖尿病血管并发症的形成已获得共识。Schamidt等(J.Clin.Invest.1995,96,1395-1403)报道从糖尿病患者血清中分离出的AGEs可诱导血管内皮细胞表达粘附分子VCAM-1,诱导机制涉及NF-κB的激活,而AGEs引发的氧化应激亦可激活NF-κB。糖尿病视网膜病变和肾脏病变是当今失明和肾功能衰竭的主要原因。Romeo等(Diabetes.1999,48(Sppl),154)。应用单克隆抗体免疫组化技术比较13例尸检的糖尿病患者和14例年龄、性别配对的非糖尿病人视网膜微血管细胞的凋亡状况和无细胞毛细血管的发生率。结果,糖尿病组具有大量NF-κB激活的外膜细胞,并显示内皮细胞和外膜细胞的凋亡增加,无细胞毛细血管亦增加,提示糖尿病患者视网膜外膜细胞的NF-κB活化可能促进糖尿病视网膜病的早期损害Hofmann等(Diabetologia.1999,42,222-232)。对33例糖尿病患者进行观察,其中21例并发糖尿病肾病。结果,糖尿病肾病患者末梢血单核细胞的NF-κB活性增高,对活化的NF-κB p65的免疫组化染色亦增强,NF-κB的活性与尿微量白蛋白的程度及血浆血栓调节蛋白的浓度呈正相关。
综上所述,糖尿病中的高糖环境和氧化应激状态可激活NF-κB。NF-κB激活所诱导的炎症反应和氧化应激的氧自由基等可引起胰岛β细胞凋亡、坏死,导致糖尿病的发生;此外还发现糖尿病的并发症血管病变、视网膜病变和肾损害程度与NF-κB激活呈正相关。因此,寻找有效的NF-κB抑制剂和抗氧化剂来保护胰岛β细胞和防止糖尿病并发症的发生,从根本上达到治疗糖尿病的目的,这有可能为糖尿病的治疗提供新的策略。
穿心莲内酯显著降低糖尿病大鼠的血糖水平。Zhang和Frei(ASEB J.2001,15,2423-2432)在正常和STZ诱导的糖尿病大鼠中研究了穿心莲乙醇提取物的治疗作用,发现口服穿心莲乙醇提取物可呈剂量依赖地降低糖尿病大鼠的血糖水平,当口服剂量达400mg/kg时,降糖效果与二甲双胍(500mg/kg,口服)相当,但对正常大鼠的血糖水平无影响。
在长期实验中,连续给药14天,穿心莲乙醇提取物400mg/kg或二甲双胍500mg/kg,口服,每天两次,发现穿心莲或二甲双胍治疗组糖尿病大鼠较对照组体重明显增加,治疗组进食和饮水量减少,对正常大鼠无影响。糖尿病大鼠间胰岛素水平无明显差异,说明穿心莲的降糖作用与胰岛素无关。穿心莲治疗组肝脏葡萄糖-6-磷酸酶(G-6-Pase)活性明显降低,推测穿心莲降糖作用可能于增加了葡萄糖代谢有关。研究还发现穿心莲乙醇提取物除有降糖作用外,还具有抗氧化应激效应,可增加糖尿病大鼠肝、肾组织中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和还原型谷胱甘肽(GSH)含量,减少了脂质过氧化反应产物(MDA)。氧化应激是糖尿病并发症的重要致病因素,因此推断穿心莲将可降低糖尿病并发症的发生和组织损伤程度。同样,Rao(Iranian J.Pharmacol.Ther.2006,5,47-45)在alloxan诱导的糖尿病大鼠模型中也证实穿心莲氯仿提取物(300mg/kg,口服)具有降血糖作用和肾保护活性,能有效防止蛋白尿、尿毒症的发生。Yu等(Planta Med.2003,69,1075-1079)报道穿心莲内酯(1.5mg/kg,口服)对正常大鼠静脉葡萄糖激发实验和STZ诱导的糖尿病大鼠血糖升高有明显抑制作用。
体外比目鱼肌葡萄糖摄取实验显示穿心莲内酯能增加放射性葡萄糖的摄取,并进一步证实这可能与穿心莲内酯增加了4型葡萄糖转运载体(GLUT4)基因表达有关。葡萄糖转运载体是葡萄糖穿过细胞膜转运的介导者,前期研究已发现,糖尿病患者GLUT4基因表达减少(Sivitz Wi,et al.Nature 1989,340,72-74)。
穿心莲内酯具有抗肿瘤作用。Nanduri等(美国专利US 6486196,2002;Bioorg.Med.Chem.Lett.2004,14,4711-4717)研究表明,8,17-环氧化穿心莲内酯保持了内酯的细胞毒性,在此基础上进一步得到的酯化衍生物使活性有相当大的提高。体外实验IC50范围在5-15μM的穿心莲内酯对多种类型的人肿瘤细胞有活性(Satyanarayana et al.,BMC Cancer 2003,4,26-34)。Rajagopa等(J.Exp.Ther.Oncol.2003,3,147-158)研究表明,穿心莲内酯能抑制多种肿瘤细胞系的增殖。对肿瘤细胞的直接作用是通过诱导周期抑制蛋白P27和降低CDK4的表达使周期阻滞于G0-G1期,通过促进淋巴细胞的增殖和IL-2分泌起免疫刺激作用。穿心莲内酯也增加TNF-α的产生和CD4标志物的表达导致淋巴细胞对肿瘤细胞的毒性,这可能是其抗肿瘤活性的间接原因。
穿心莲内酯使细胞周期停止在G0-G1期,并诱导细胞周期抑制蛋白p27的产生和减少细胞周期依赖的蛋白激酶4(CDK4)的表达。穿心莲内酯治疗对MCF-7细胞细胞周期的影响用流式细胞术和蛋白印迹分析(Rajagopal et al.,J.Exp.Ther.Oncol.2003,3,147-158)。MCF-7细胞用5μM穿心莲内酯处理24和48小时后经分析发现,与用DMSO处理的对照细胞相比,穿心莲内酯处理24小时后G1期细胞增加了10%,伴随S期和G2/M期细胞比例的下降,说明细胞周期停止在G1期。处理48小时后,与对照组相比处于G1期细胞比例下降,而S期和G2-M期细胞数没有变化,然而处于亚G1期的MCF-7细胞数量增加了7%。这就提示在穿心莲处理24小时时,诱导细胞停止在G1期,如果进一步处理,处于G1期的细胞发生凋亡,明显的证据就是反映凋亡特征的亚G1期细胞增加。
体内试验的结果表明,穿心莲内酯具有抗黑色素瘤(B16F0)和结肠癌(HT-29)移植模型的作用(Rajagopal et al.,J.Exp.Ther.Oncol.2003,3,147-158)。Satyanarayana等(Satyanarayana et al.,BMC Cancer 2003,4,26-34)报道了在使用中空纤维系统荷MCF-7乳腺癌小鼠中穿心莲内酯的抗肿瘤活性。在剂量为100mg/kg时,穿心莲内酯可抑制大约50%的肿瘤生长。穿心莲内酯的抗癌活性也在HT-29人结肠癌裸鼠模型和B16F0骨髓瘤小鼠模型中得到了检验。口服剂量为200mg/kg,每天两次,穿心莲内酯对骨髓瘤和结肠癌的生长抑制率分别达到39%和52%。
当MCF-7人乳腺癌小鼠模型用穿心莲内酯治疗,蛋白印迹分析发现,在腹腔或皮下途径接种的肿瘤中100mg/kg穿心莲内酯可明显增加p27的表达(Rajagopal et al.,J.Exp.Ther.Oncol.2003,3,147-158),后者是调节细胞周期G1期的主要CDK抑制剂。细胞周期依赖的蛋白激酶,CDK4水平只是在腹腔注射途径接种的肿瘤中下降,而皮下注射途径没有变化。这些结果显示穿心莲内酯抑制细胞周期的进程是通过调节细胞周期相关蛋白的表达来实现的。
硫辛酸:Alpha-硫辛酸(LA)存在于各种原核和真核细胞。在人体中,它是许多参与能量形成的2-含氧酸脱氢酶的一部分,并且是一些多酶复合体的辅助因子(Biewenga et al.,Drug Metab.Rev.1997,29,1025-1054)。硫辛酸及其还原形式脱氢硫辛酸(DHLA),作为氧化还原作用物质,从脱氢酶底物转运电子给NAD+。实际上,脱氢硫辛酸比硫辛酸具有更强的抗氧化特性。除了充当酶的角色,体内外研究表明硫辛酸还可作为强大的微量营养物质,具有多种药理学和抗氧化特征。药理学上,硫辛酸可改善肝抗胰岛素物质的控制,糖尿病引起的多神经病变,可有效减轻重金属中毒。作为抗氧化剂,硫辛酸直接清除自由基,鳌合过渡金属离子,例如铁和铜,增加胞浆中谷胱苷肽和维他命C的水平,并阻止它们丢失引起的毒性。这些不同的功能暗示硫辛酸通过多种生理学和药理学机制来发挥作用(Smith et al.,Curr.Med.Chem.2004,11,1135-1146)。由于以上原因,硫辛酸是应用最广泛的保健补充剂之一,在德国,硫辛酸被批准用于治疗糖尿病引起的症状性神经病已有20余年的历史。硫辛酸的结构如下:
硫辛酸是一种很强的抗氧化剂。Lester Packer(Free Radic.Biol.Med.1995,19,227-250)认为硫辛酸是最强的生物抗氧化剂。这一观点来源于很多的研究资料。首先,LA/DHLA能直接清除自由基,包括羟基、过氧化氢、次氯酸和纯态氧(Packer et al.,Free Radic.Biol.Med.1995,19,227-250;Matsugo et al.,Biochem.Biophys.Res.Commun.1996,227,216-220)。其次,它们鳌合过渡金属离子,具有改变相对弱的氧化剂(例如超氧阴离子和过氧化氢)向有害的羟基活性物质转化的益处(Matsugo et al.,Biochem.Biophys.Res.Commun.1996,227,216-220)。最后,它们再生其它的抗氧化剂。氧化还原作用抗氧化剂的有效功能需要氧化形式的抗氧化剂向有效的还原新式再循环。DHLA是一种强还原剂,因此它能够使氧化型抗氧化剂再循环(Matsugo et al.,Biochem.Biophys.Res.Commun.1996,227,216-220)。DHLA可从它们各自的氧化形式直接再生抗坏血栓盐和间接再生维他命E,并能够使氧化型谷胱苷肽还原成还原形式(Jocelyn,P.C.Eur.J.Biochem.1967,2,327-331)。实际上,体内外实验中,硫辛酸已被发现可增加细胞内谷胱苷肽的含量(Busse et al.,Arzn.Forsch.1992,42,829-831)。给注射动物抗氧化剂硫辛酸,发现谷胱苷肽水平增加了30%-70%,特别是在肺、肝和肾脏细胞中。
Zhang et al.(FASEB J.2001,15,2423-2432)以人大动脉内皮细胞(HAEC)为模型,研究了LA以及谷胱苷肽和维他命C在TNF-α诱导黏附分子表达和NF-kappa B信号传导中的作用。用硫辛酸(0.05-1mmol)预处理HAEC 48小时可呈剂量依赖性地抑制TNF-α(10U/ml)诱导的NF-kappaB结合活性。当硫辛酸为0.5mmol/l,TNF-α诱导的NF-kappa B活性被抑制81%。硫辛酸对TNF-α诱导内皮细胞活化的这种抑制效应提示是金属鳌合作用,而非普通的抗氧化剂效应。这也可能解释了需预处理HAEC48小时后硫辛酸才能发挥最大的抑制效应,因为细胞内金属离子鳌合作用和从细胞内排除是一个缓慢的过程。
De Mark et al.(J.Cell Physiol.2003,194,325-340)报道硫辛酸在体内诱导组蛋白高度乙酰化,且对正常细胞和变化了的细胞系的生长和生存能力有不同的效应。人肿瘤细胞系FaDu和Jurkat,以及Ki-v-Ras-改造了的Balb/c-3T3鼠间间质细胞系,经硫辛酸处理后都发生凋亡。相应地,硫辛酸处理的未改变细胞系只是细胞周期被可逆地阻滞在G0/G1期。硫辛酸导致细胞周期依赖性蛋白激酶的抑制剂水平翻译后升高。动物实验表明,硫辛酸减少了环磷酰氨和长春新碱引起的副作用,但没有降低药效(Berger et al.,Arzneimittelforschung 1983,33,1286-1288)。最近,Dovinova,et al.(Neoplasma,1999,46,237-241)提出联合应用硫辛酸(16mg/kg)和阿霉素(5mg/kg)可使L 1210白血病小鼠成活率增加67%。而硫辛酸经腹腔给药的LD50达160mg/kg,说明上述结果很不平常。
尽管硫辛酸在体外、实验动物肿瘤模型和人体内都已被证实具有抗肿瘤活性,但作用机理还不明确。如前所述,硫辛酸可清除自由基,抑制NF-κB活化,增加p27表达等等。然而,没有单一机制足以解释其抗肿瘤活性,也许它们中的每一种机制各自发挥一种作用。
药理学上,硫辛酸可改善肝抗胰岛素物质,糖尿病引起的多神经病变,可有效减轻重金属中毒。作为抗氧化剂,硫辛酸直接清除活性氧和自由基,鳌合过渡金属离子,例如铁和铜,增加胞浆中谷胱苷肽和维他命C的水平,并阻止它们丢失引起的毒性。这些不同的功能暗示硫辛酸通过多种生理学和药理学机制来发挥作用(Smith et al.,Curr.Med.Chem.2004,11,1135-1146)。
硫辛酸被用来治疗糖尿病及其并发症。近年来的研究发现,线粒体电子传递呼吸链超氧化物产生过多是高糖介导组织损伤的主要途径激活的原因,认为氧化应激状态是糖尿病慢性并发症发生发展的共同因素(Brown,L.Nature 2001,414,813-820),改善氧化应激状态可能成为防治糖尿病慢性并发症的有效措施。Yorek等(Yorek,M.A.Exp.Diabetes Res.,2004,5,123-135)报道硫辛酸确能改善糖尿病血管内皮的功能。临床研究提示抗氧化剂能改善糖尿病患者的自主神经症状(Ziegler D,et al.,Diabetologia,1995,38,1425-1433)。短期口服α-硫辛酸能增加II型糖尿病患者外周胰岛素敏感性,从而降低血糖和减少心血管并发症(Kamenova P.Hormones(Athens),2006,5,251-258)。
综上所述,天然产物穿心莲内酯的应用已有很长的历史,具有良好的安全性。尤为重要的是,研究表明它可通过独特的作用机理发挥抗肿瘤、免疫调节、抗感染、抗炎、护肝利胆、降血糖等多种功效。但将穿心莲内酯和硫辛酸结合使用在国内外还没有文献报道。
发明内容
为解决现有技术存在的不足之处,本发明的首要目的在于提供一种具有协同作用的穿心莲内酯组合物,该组合物的作用强于其中任何一种组分单独使用的作用。
本发明的另一目的在于提供上述穿心莲内酯组合物的用途。
本发明的目的通过下述技术方案实现:一种穿心莲内酯组合物,该组合物由摩尔比为1∶10~10∶1的组分I和组分II组成,所述组分I是穿心莲内酯、穿心莲内酯衍生物和穿心莲内酯衍生物在药学上可接受的盐中的至少一种,组分II是硫辛酸和二氢硫辛酸中的至少一种。
所述穿心莲内酯衍生物是穿心莲内酯的有机酸根取代物、无机酸根取代物、烷基取代物、芳基取代物或杂芳基取代物;所述有机酸根是乙酸根、丙酸根、丁酸根、丙二酸根、丙酮酸根、肉桂酸根、琥珀酸根、柠檬酸根、乳酸根、葡萄糖酸根、硫辛酸根、N-乙酰半胱氨酸、氨基酸根、苯甲酸根;所述无机酸根是硫酸根、硝酸根、磷酸根;
所述硫辛酸是R-α-硫辛酸和/或S-α-硫辛酸;所述二氢硫辛酸是R-α-二氢硫辛酸和/或S-α-二氢硫辛酸。
所述组分I和组分II的摩尔比为1∶2~2∶1。
所述组分I和组分II的摩尔比为1∶1。
上述穿心莲内酯组合物作为制备抗癌药物的用途。
上述穿心莲内酯组合物作为制备抗炎药物的用途。
上述穿心莲内酯组合物作为制备抗菌药物和抗病毒药物的用途。
上述的穿心莲内酯组合物作为制备降血糖药物的用途。
所述药物含有治疗有效量的穿心莲内酯组合物和药学上可接受的载体。
所述药物制剂为片剂、胶囊剂、颗粒剂、细粒剂、粉剂、丸剂、贴剂、口服液或注射剂。
“药学上可接受的”指的是在化合物如盐或赋形剂中不具有不能接受的毒性。药学上可接受的盐包括无机阴离子,例如氯离子、溴离子、碘离子、硫酸根、亚硫酸根、硝酸根、亚硝酸根、磷酸根等。有机阴离子包括乙酸根、丙酮酸根、丙酸根、肉桂酸根、甲苯磺酸根、柠檬酸根、乳酸根、葡萄糖酸根等。药学上可接受的赋形剂参见E.W.Martin,in Remington’sPharmaceutical Sciences Mack Publishing Company(1995),Philadelphia,PA,19th ed中。
本发明穿心莲内酯组合物的治疗有效量根据正在治疗的患者是变化的,但最适剂量位于1mg/kg体重~1g/kg体重之间。
本发明的原理是:穿心莲内酯可抑制NF-κB,而NF-κB在肿瘤的发生、发展、血管形成以及转移等过程发挥重要作用,肿瘤微环境诱导NF-κB的表达,在很多癌症中高表达NF-κB,从而诱导癌症耐药性的产生;穿心莲内酯也用于抗细菌与病毒感染,抗炎,治疗糖尿病等。硫辛酸是一种有效的抗氧化剂,具有对多种疾病的治疗作用,例如抗细菌与病毒感染,抗炎,治疗糖尿病及其并发症;本发明提供的化合物是穿心莲内酯及其衍生物与抗氧化剂如Alpha-硫辛酸的组合物,具有多重作用机理和对多种疾病的治疗作用;因此,本发明提供的穿心莲内酯衍生物与硫辛酸组合物不同于,而且优于现有的穿心莲内酯衍生物或优于硫辛酸。
本发明与现有的技术相比,有以下优点:本发明穿心莲内酯组合物适用于作为抗癌药物或治疗具有耐药性的肿瘤;作为抗微生物药物,包括细菌和病毒感染药物,能直接杀灭革兰氏阳性菌金黄色葡萄球菌和耐药菌MRSA5676和MRSA5677,还能抑制革兰氏阴性菌绿脓杆菌的QS系统,同时抑制和破坏绿脓杆菌生物被膜的形成;作为抗糖尿病药物;由于穿心莲内酯及其衍生物和硫辛酸独特的结构特征,本发明组合物具有多种治疗功效,不仅仅包括抗菌、抗病毒、抗炎、抗肿瘤和抗糖尿病作用。
附图说明
图1为本发明组合物抑制H2O2诱导的RIN-m细胞凋亡实验结果图。
图2为本发明组合物抑制活性氧产生实验结果图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
将穿心莲内酯(350g,1mol)加入到R-α-硫辛酸的(2063g,10mol)中,充分混合均匀,加药用淀粉800.0g等,压制成5000片,即得穿心莲内酯组合物片剂。
实施例2:
将穿心莲内酯(350g,1mol)加入到S-α-硫辛酸的(412g,2mol)中,充分混合均匀,加入200g蒸馏水和400g蔗糖粉与糊精的混合物(蔗糖∶糊精=3∶1),拌合成软材,挤压过筛(12目~14目)制颗粒,60℃干燥,整粒,按每袋相当于穿心莲内酯组合物4.0g分装于塑料袋中,密封,即得穿心莲内酯组合物颗粒剂。
实施例3:
将14-去氧穿心莲内酯(350g,1mol)加入到R-α-二氢硫辛酸的(206g,1mol)中,充分混合均匀,过80目筛,与淀粉150g混匀,加入10%淀粉浆100mL,拌和制成软材,压过80~100目筛制粒,于60℃~70℃干燥,整粒,加入硬脂酸镁0.2g,混合均匀,装胶囊1000个,即得穿心莲内酯组合物胶囊剂。口服,一次1~3粒,一日3次。
实施例4:
将穿心莲内酯琥珀酸半酯钠钾盐(800g,2mol)加入到S-α-二氢硫辛酸的(206g,1mol)中,充分混合均匀,用1000ml无菌蒸馏水溶解,加无菌蒸馏水至2000ml,灌封,包装,即得每支10ml的穿心莲内酯组合物口服液200支。
实施例5:
将穿心莲内酯三马来酸半酯钠盐(4000g,10mol)加入到α-硫辛酸的((206g,1mol)中,过滤,灌封,在100℃下流动蒸汽灭菌30分钟,质量检查,包装,即得穿心莲内酯组合物注射液。
实施例6:体外对L1210白血病细胞的抗肿瘤活性实验
以实施例1所得穿心莲内酯组合物片剂进行体外对L1210白血病细胞的抗肿瘤活性实验:将小鼠白血病细胞株L1210细胞(1.5-2.0×105cells/mL)分别接种于96孔培养板中(90μL/孔),加入含梯度稀释浓度的穿心莲内酯组合物(Andro+LA)及阳性对照药物盐酸阿霉素(Dox,10μL/孔)。置于37℃,在5%CO2和饱和湿度的培养箱中培养48h。加入5mg/mL的MTT(20μL/孔)培养基中,同样条件培养4h,加入二甲基亚砜(DMSO,150μL/孔),溶解紫蓝色结晶,用酶标仪测定(570/630nm)吸光度(A值)。
表1是体外对L1210白血病细胞的抗肿瘤活性的结果,表1的数据表明本发明穿心莲内酯组合物具有比穿心莲内酯及其临床上常用的穿琥宁,炎琥宁及莲必治更强的抗肿瘤活性。
表1 体外对L1210白血病细胞的抗肿瘤活性
实施例7:抑制H2O2诱导的RIN-m细胞凋亡实验
以实施例2所得穿心莲内酯组合物胶囊剂进行抑制H2O2诱导的RIN-m细胞凋亡实验:四氧嘧啶(alloxan)产生ROS引起胰岛β-细胞的损伤而产生糖尿病。为进一步确证组合物的β-细胞保护作用,我们在体外RIN-m细胞中考察了本发明穿心莲内酯组合物(Andro+LA)的抑制凋亡作用。用500μMH2O2培养24小时,RIN-m细胞活性减低到42.7±11.1%(如图1所示)。在用H2O2处理60min前,先用穿心莲内酯(Andro)、α-硫辛酸(LA)、穿心莲内酯组合物(Andro+LA),浓度分别为0.01,0.1和1μM分别预保护RIN-m细胞30min,显示有明显保护作用,其中1μM浓度下经24h培养后细胞活性情况为穿心莲内酯(Andro)59.7±5.9%、α-硫辛酸(LA)59.7±4.4%、穿心莲内酯组合物(Andro+LA)62.2±10.6%。
实施例8:抑制和消除由高血糖和格列苯脲引起的活性氧(ROS)产生
以实施例3所得穿心莲内酯组合物颗粒剂进行抑制和消除由高血糖和格列苯脲引起的活性氧(ROS)产生的实验:将RIN-m细胞暴露于高糖中(100~450mg/dl)2h,依剂量而增加ROS的产生。用1μM Andro、LA可有效抑止增加ROS的产生,结果如图2所示。
格列苯脲虽然降糖和保护β-细胞使其数量不明显损失,但格列苯脲作用过的β-细胞产生胰岛素却减少。用RIN-m细胞研究发现,在格列苯脲浓度0.1-100μM实验中,其呈剂量依赖地引起ROS的产生和RIN-m细胞活性下降。1μM的穿心莲内酯组合物(Andro+LA)能明显地降低格列苯脲(1μM)引起的ROS的产生(从图2B中可以看出)。
实施例9:对链尿佐菌素(STZ)诱导糖尿病大鼠的血糖的调节作用。
SD远交群大鼠每组4只,体重180~220g,禁食16hrs后腹腔注射链尿佐菌素(STZ,购自sigma公司)60mg/kg。72hrs后剪尾采血,采血之前禁食16hrs,用血糖仪(强生公司)测定血糖;实验组动物根据分组分别给予Andro,Andro+LA和格列苯脲治疗,以1μmol/kg的剂量灌胃,每天1次,连续7天,7天后称重、采血,采血之前禁食16hrs,用血糖仪测各组动物血糖值。结果如表2所示,可见本发明穿心莲内酯组合物(Andro+LA),相比穿心莲内酯(Andro)和格列苯脲具有显著的降糖作用。
表2 本发明组合物对STZ诱导糖尿病大鼠的血糖的调节作用
实施例10:本发明穿心莲内酯组合物与抗生素联合用药实验
临床上红霉素(Erythromycin)和环丙沙星(Ciprofloxacin)是治疗绿脓杆菌感染较为有效的药物。前已叙述,天然Andro和红霉素类药物及环丙沙星有协同作用。因此,我们对悬浮的绿脓杆菌用本发明穿心莲内酯组合物Andro+LA和红霉素及环丙沙星进行了联合抗菌实验。结果如表3所示:Andro+LA与环丙沙星和红霉素合用时的效果明显强于穿心莲内酯Andro与环丙沙星和红霉素合用;再次证明了Andro+LA的疗效强于临床应用的Andro。LA无抗菌活性。
表3 本发明组合物与抗生素联合用药实验
注:Andro和Andro+LA的摩尔浓度相同,即1mol/mL.用药后的绿脓杆菌,经15h培养,OD600测A值。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1、一种穿心莲内酯组合物,其特征在于:该组合物由摩尔比为1∶10~10∶1的组分I和组分II组成,所述组分I是穿心莲内酯、穿心莲内酯衍生物和穿心莲内酯衍生物在药学上可接受的盐中的至少一种,组分II是硫辛酸和二氢硫辛酸中的至少一种。
2、根据权利要求1所述的一种穿心莲内酯组合物,其特征在于:所述穿心莲内酯衍生物是穿心莲内酯的有机酸根取代物、无机酸根取代物、烷基取代物、芳基取代物或杂芳基取代物;所述有机酸根是乙酸根、丙酸根、丁酸根、丙二酸根、丙酮酸根、肉桂酸根、琥珀酸根、柠檬酸根、乳酸根、葡萄糖酸根、硫辛酸根、N-乙酰半胱氨酸、氨基酸根、苯甲酸根;所述无机酸根是硫酸根、硝酸根、磷酸根;
所述硫辛酸是R-α-硫辛酸和/或S-α-硫辛酸;所述二氢硫辛酸是R-α-二氢硫辛酸和/或S-α-二氢硫辛酸。
3、根据权利要求1所述的一种穿心莲内酯组合物,其特征在于:所述组分I和组分II的摩尔比为1∶2~2∶1。
4、根据权利要求1所述的一种穿心莲内酯组合物,其特征在于:所述组分I和组分II的摩尔比为1∶1。
5、根据权利要求1~4任一项所述的穿心莲内酯组合物作为制备抗癌药物的用途。
6、根据权利要求1~4任一项所述的穿心莲内酯组合物作为制备抗炎药物的用途。
7、根据权利要求1~4任一项所述的穿心莲内酯组合物作为制备抗菌药物和抗病毒药物的用途。
8、根据权利要求1~4任一项所述的穿心莲内酯组合物作为制备降血糖药物的用途。
9、根据权利要求1~4任一项所述的穿心莲内酯组合物,其特征在于:所述穿心莲内酯组合物在治疗有效量的剂量下和药学上可接受的载体制备成药物制剂。
10、根据权利要求9所述的穿心莲内酯组合物,其特征在于:所述药物制剂为片剂、胶囊剂、颗粒剂、细粒剂、粉剂、丸剂、贴剂、口服液或注射剂。
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CN107417748A (zh) * | 2017-09-13 | 2017-12-01 | 兰州大学 | 一种抗癌前药分子及其制备方法与靶向化合物 |
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