CN101654393A - 作为肝脏保护剂的化合物和组合物 - Google Patents
作为肝脏保护剂的化合物和组合物 Download PDFInfo
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- CN101654393A CN101654393A CN200910119936A CN200910119936A CN101654393A CN 101654393 A CN101654393 A CN 101654393A CN 200910119936 A CN200910119936 A CN 200910119936A CN 200910119936 A CN200910119936 A CN 200910119936A CN 101654393 A CN101654393 A CN 101654393A
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Abstract
本发明提供了化合物,包括愈创木烷类化合物、藁本内酯的各种组合物和使用这类化合物治疗、预防与肝损伤、肝纤维化、肝硬化、病原性肝炎相关的疾病或病症的方法。
Description
发明领域
本发明提供了化合物,包括愈创木烷类化合物、藁本内酯的各种组合物和使用这类化合物治疗和预防与肝损伤、肝纤维化、肝硬化、病毒性肝病、酒精肝相关的疾病或病症的方法,涉及化合物在医药和食品中的应用,属于医药和食品领域。
技术背景
肝是人体最重要的代谢、营养器官,肝损伤、肝纤维化、肝硬化是临床常见病和多发病,中国作为一个饮酒大国、肝炎大国、高脂饮食大国以上问题更加多见,亟待研究并发现高效低毒的药物或保健品对抗肝损伤、肝纤维化、肝硬化。肝损伤是肝炎、饮酒、寄生虫导致的常见症状,肝硬化是肝损伤迁延或反复的结果,肝纤维化是肝损伤和肝硬化的桥梁。
肝纤维化是各种病因所致的慢性肝病的共同病理过程是向肝硬化发展的主要中心环节(Arch Pediatr 2002;9:392-405),病因包括酒精、化学物质、病毒、高脂饮食等。近年来随着细胞分子生物学深入研究,认为肝纤维化是慢性肝损伤过程中多种细胞密切联系,并通过多种细胞因子,细胞外基质蛋白等相互作用,相互影响组成的网络来调控。其中肝星状细胞(hepatic stellate cell,HSC)的激活是核心事件(Gut 2002;50:891-896;Am J Pathol2002;160:1705-1715)),并逐渐改变了传统肝纤维化不可逆转的观点,明确提出了肝纤维化完全有可能逆转的观点(World J Gastroenterol,2001;7:42-48),所以阻断肝纤维化的形成和发展对于防治肝硬化具有重要意义。本文主要综述近年来抗肝纤维化在药物治疗、中药有效成分及基因治疗三个方面的研究进展。
各种致病因素的持续存在是肝纤维化形成和发展的原因,故针对原发病的病因治疗,如抗肝炎病毒治疗、治疗血吸虫病、戒酒、祛铁和祛铜等是抗肝纤维化治疗中最重要、最有效的手段。在我国,乙型及丙型肝炎病毒是引起慢性肝病最常见的病因。近几年的临床研究显示干扰素α或核苷(酸)类似物(拉米夫定等)抗病毒治疗,不仅可减轻肝脏炎症坏死,而且肝组织病理学检查可见纤维化甚至肝硬化有所减轻(Liver Int,2006;26:399-405;Gastroenterology,2003;124:105-11)。单磷酸阿糖腺苷治疗CHB,对HBeAg及HBV DNA阴转率可达30%-40%。治疗结束时,III型前胶原肽和透明质酸总有效率分别为75%、80%,对照组为36.4%,40。9%(中华传染病杂志.2000,18(1):70)。目前多数专家已经同意有效抗病毒治疗可以减轻肝纤维化甚至逆转早期肝硬化,但是如何提高疗效和安全性,克服耐药性以取得持久病毒学应答或维持应答,从而提高抗纤维化疗效是值得进一步研究的问题。去除引起肝纤维化病因,绝大多数肝纤维化可以清除或逆转,愈早疗效愈好。
肝脏的慢性炎症刺激可持续活化HSC,促进肝纤维化的发生、发展。因此抑制肝脏炎症,保护肝细胞是防治肝纤维化的重要策略之一,许多此类药物已应用于临床,如抗氧化剂谷胱甘肽、维生素E、维生素C、水飞蓟素有效成分西利马林、皮质类固醇、前列腺素E、熊去氧胆酸(UDCA)、S腺苷甲硫酸、秋水仙碱等都可以通过抑制肝脏的炎症反应而起抗肝纤维化的作用。研究证明,UDCA对原发性胆汁性肝纤维化有明显疗效(中华肝脏病杂志,1998,6:193-194)。
细胞因子是抗炎治疗另一策略。细胞因子是机体对微生物或外来抗原引起反应后分泌的多肽,有些细胞因子有较强的抗病毒活性,有的还有增强兔疫作用。细胞因子IL-10作为抗炎因子也具有抗肝纤维化作用(J Biol Chem,1998:273(1):302-308)。IL-12具有促使T0细胞分化T1细胞的作用,并能诱导IL-2和干扰素-γ产生,提示可能具有抗病毒活性和增强对病毒感染的肝细胞兔疫清除作用和抗炎作用。Carreno等报道6例HbeAg阳性慢性乙型肝炎患者接受IL-12治疗12周后H BV DNA水平明显下降,I、III型胶原水平亦明显下降(JHepatol 2000;32:217-324)。
HSC活化是肝纤维化发生发展的中心环节,以HSC激活为核心,导致ECM的降解减少和病理性沉积。研究表明,活化的HSC是肝纤维化新基质的制造者。因此,下调HSC活化,抑制HSC增殖,促进HSC凋亡是抗纤维化的重要措施之一。细胞因子在HSC活化中起了关键的作用,可大致将其分为促进因子和抑制因子,因而分别采取拮抗或增强细胞因子作用的措施。在诸多细胞因子中,TGF-β1是最重要的促纤维化细胞因子。抗纤维化TGF-β的拮抗剂包括:抗TGF-β抗体、TGF-β反义寡核苷酸、可溶性II型TGF-β受体、特异性PDGF受体R亚单位核酶等。目前许多研究观察TGF-β抗体或可溶性受体对肝纤维化的干预效果,动物实验证实这些药物抗肝纤维化效果确切,临床研究中需进一步验证。
目前α和γ干扰素具有明显的抗肝纤维化作用,国外研究其抗纤维化机制为阻止HSC的增殖和活化,减少胶原成分mRNA转录,从而减少ECM的表达(世界华人消化杂志,2000,8(6):684-686)。另外一些保护肝细胞的药物如S腺苷蛋氨酸、前列腺素E2,均有抑制H SC活化的作用。
肝纤维化形成的化学基础是肝脏内细胞外基质(extracellular matrix ECM)合成和降解失衡,表现为ECM大量沉积。胶原是ECM的主要组成成分,因此有效抑制胶原的合成,促进胶原的降解和增加沉积胶原的吸收是预防和治疗肝纤维化的重要途径。
秋水仙碱(Colchicine)抗纤维化作用机制为破坏促进肝前胶原的分泌的微管的聚集,刺激胶原酶的产生而促进胶原的分解,抑制生长细胞因子的释放,如IL-1的分泌。Arrieta等发现秋水仙碱可阻止和延缓肝炎性肝硬化而致的肝癌,这种保护性机制可能与其抗炎有关(Canlcer,2006,107(8):1852-1858)。Poupon等研究发现对PBC患者,秋水仙碱可提高肝脏的生化指标,但对延长生存期、肝移植方面疗效不佳(Hepatoloy,1996,24(5):1098-1103)。鉴于秋水仙碱有微管蛋白毒性,限制了其广泛的临床应用。前列腺素可增加细胞内CAM P水平,减少胶原的产生,抑制磷酸酯酶活性,保持肝细胞膜,改善肝脏微循环,促进肝细胞再生。Zou等都有报道,在慢性肝损伤的纤维化模型中,PGE2可抑制肝内胶原的合成,可能与抑制HSC活化、阻断TGF-R表达有关(Hepatobillary Pancreate Dis Int 2007,6(2):176-181)。
由于肝纤维化形成机制复杂,具有病因多样性、进展渐变性、病变可逆性、最终难治性等特点而西药治疗往往只针对某一方面或某一环节,难以取得满意的效果。近年来国内学者在中药抗肝纤维化方面取得了可喜的成效,使中药在这一领域的研究与应用倍受青睐和重视。近年来我国肝病学家进行了大量中医中药治疗肝纤维化的研究,结果表明无论采用专方专药、单味药或有效成份均取得了较好疗效,对肝纤维化既有预防作用,又有治疗作用。研究较多的有甘草甜素、氧化苦碱、大黄素等。
甘草甜素是从中药甘草中提取的有效成份。王吉耀等研究发现,甘草酸可明显抑制成纤维细胞I、III型胶原mRNA的表达,使I、III前胶原的合成减少(中华消化杂志.1997,17(1):60)。氧化苦参碱是从中药苦豆子或苦参根中提取的有效成份,具有抗炎、兔疫调节等作用。日乐文等研究表明氧化苦参碱治疗血清ALT,IV-C,HA,TNF-A水平及肝组织内炎症活动度、纤维组织增生程度均低于模型组(第二军医大学学报.1999.20(7):445)。因此氧化苦参碱能减轻肝脏炎症活动度,抑制肝内胶原合成及抗肝纤化作用。王宝恩教授主持研究的复方861中药制剂,已被证明对PDGF诱发的CyclinD水平及细胞外信号调节肽活性均有抑制作用,从而抑制HSC增殖,并能促进HSC凋亡(中华肝脏病杂志.2000,8(4):197-199)。大黄素,具有抗病毒、抑菌、利尿等多种作用。大黄酸除了有保护肝细胞及抑制HSC增殖的作用外,还可通过下调TGF-β1的表达对HSC胶原合成起到抑制作用。大黄素可使CCL4所致的肝纤维化模型大鼠肝功能明显改善,血清透明质酸及层粘蛋白含量显著降低,肝组织胶原蛋白含量明显减少,并呈剂量依赖关系。其机制为保护肝细胞并抑制HSC的激活。
发明内容
本发明提供了化合物,包括愈创木烷类化合物、藁本内酯的各种组合物和使用这类化合物治疗和预防与肝损伤、肝纤维化、肝硬化、病毒性肝病相关的疾病或病症的方法
发明概述
本发明第一方面是根据权利要求第一项和第二项,目的在于保护作为医药和食品产品的藁本内酯、愈创木烷这类化合物可接受的酸、盐和溶剂混合物(例如水合物),其特征在于其选自以下化合物:
1)式(1)化合物:为藁本内酯
式(2)化合物:愈创木烷
式1 式2
本发明第二方面提供了组合物,包括权利要求第一项和第二项提供的藁本内酯混合物或其可接受的盐以及一种或多种赋形剂、原料;或至少包含权利要求1和2中的任一项所述的化合物作为活性物质与另一种治疗或预防上相关活性剂的组合。
本发明第三方面提供了组合物,至少包含权利要求第一项和第二项化合物或其混合物或其可接受的盐与另一种治疗上相关活性剂在制备用于治疗动物疾病中的药物中的用途
本发明第四方面提供了治疗动物疾病的方法,其中抗肝损伤、抗肝纤维化、抗肝硬化活性可以预防、抑制或改善所述疾病的病理学和(或)症状学,该方法包括对所述动物给予治疗量的至少包含一种权利要求第一项和第二项提供的化合物或其可接受的酸、盐或其药物组合物。
本发明第五方面提供了至少包含一种权利要求第一项和第二项提供的化合物或其药学上可接受的盐或其药物组合物在制备用于治疗动物疾病的药物中的用途,其中抗肝损伤、肝纤维化、肝硬化活性对所述疾病的病理学和/或症状学起作用。
因此,本发明所述活性物质用于制备以治疗或预防为目的的产品,所述用途特别是用于病原性肝炎、脂肪肝、肝硬化、肝癌的治疗或预防,这些疾病与肝损伤和肝纤维化关系密切。本发明化合物也可作为活性物质在以预防或治疗以下疾病为目的的产品中使用,所述疾病为病毒性肝炎、肝癌、脂肪肝、肝硬化、肝寄生虫疾病。
发明详述
药理学和应用
本发明所述活性物质用于制备以治疗或预防为目的的产品,所述用途特别是用于病原性肝炎、脂肪肝、肝硬化、肝癌的治疗或预防,这些疾病与肝损伤、肝纤维化关系密切。本发明化合物也可作为活性物质在以预防或治疗以下疾病为目的的产品中使用,所述疾病为病毒性肝炎、肝癌、脂肪肝、肝硬化、肝寄生虫疾病。
按照上述描述,本发明进一步提供了在需要这类治疗的受试者预防或治疗上述任意疾病或病症的方法。该方法包括对所述受试者给予治疗有效量的(参见下文中的“给药和药物组合物”部分)本发明的权利要求1和2中化合物中的至少一种化合物或其上可接受的盐或其药物组合物。对任意上述用途而言,所需的剂量随给药方式、所治疗的特定疾病和所需作用而异。
给药和药物组合物
一般而言,本发明化合物以治疗有效量、经由本领域中已知的任意常用和可接受的方式单独或与一种或多种治疗剂组合给予。治疗有效量可以随疾病的严重程度、受试者年龄和相对健康情况、所用化合物的功效和其他因素而宽泛变化。一般而言,在约50-200mg/kg体重的每日剂量下获得令人满意的全身效果。在较大哺乳动物例如人中的适用每日剂量在约10mg-2000mg范围内。
本发明的化合物可以通过任意常规的途径作为药物组合物给药,特别是通过胃肠,例如口服,例如为片剂或胶囊形式;或通过胃肠外,例如为可注射溶液或混悬液形式;局部,例如为洗剂,凝胶、软膏剂或霜剂或以鼻用或栓剂形式。包括游离形式或药学上可接受的盐、酸、酯形式的本发明化合物与至少一种药学上可接受的载体或稀释剂的药物组合物可以通过常规方式,经混合、制粒或包衣方法制备。例如,口服组合物可以为片剂或胶囊,它们包含活性组分以及:1)稀释剂,例如乳糖、葡萄糖、蔗糖、肝糖露醇、山梨醇、纤维素和/或甘氨酸;2)润滑剂,例如二氧化硅、滑石粉、硬脂酸、其镁或钙盐和/或聚乙二醇;就片剂愕然还包括3)粘合剂,例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如需要,还有4)崩解剂,例如淀粉、琼脂、藻酸或其钠盐或泡腾混合物;和/或5)吸收剂、着色剂、矫味剂和增甜剂,可注射组合物可以为水性等渗溶液或混悬液,且栓剂可以由脂肪乳剂或混悬液制备。这些组合物可以为无菌的和/或含有佐剂,如防腐剂、稳定剂、湿润剂、或乳化剂、溶解促进剂、用于调节渗透压的盐和/或缓冲剂。此外,它们还含有其它治疗上有价值的物质。用于透皮应用的合适的制剂包括有效量的本发明化合物与载体,载体可以包括可吸收的药学上可接受的溶剂以帮助宿主皮肤,例如,透皮装置为绷带形式,包括裱褙部件(backing member),含有可选的混有载体的化合物的储器、可选的速率控制屏障一再延长时间期限内以受控和预定速率将化合物递送至宿主皮肤和使装置与皮肤固定的用具。还可以使用基质透皮制剂。用于局部,例如施用在皮肤和眼部的合适的制剂优选为本领域众所周知的水溶剂、软膏剂、霜剂或凝胶。这类制剂可以含有增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。
本发明的化合物可以以治疗有效量与一种或多种治疗即共同给药(药物组合)。例如根据有待治疗的病理,结合使用其它用于治疗肝损伤、肝纤维化、肝硬化、肝毒性、肝炎、肝癌的物质可以发生协同作用。这类化合物的实例包括治疗药物如干扰素、单磷酸阿糖腺苷、膦甲酸钠、阿昔洛韦、拉米夫定、阿德福韦、恩替卡韦、替比夫定、抗癌药物。如果将本发明的化合物与其他疗法共同给予,那么共同给予的化合物的剂量当然随共同使用的药物的类型,所用的具体药物、所治疗的疾病等而异。
本发明还提供了药物组合,例如药盒,包括1)为本文所述的本发明化合物的第一种活性剂,它为游离形式或药学上可接受的盐形式;2)至少一种共同使用的活性剂(co-agent)。该药盒包括其包括其给药说明书。
本文所用的术语“共同给药”或“联合给药”值得是包括对单一患者给予所选择的治疗剂并且用以包括其中活性剂不一定通过相同给药途径或同时给予的治疗方案。
本文所述的术语“药物组合”指的是混合或合并一种以上活性组分而产生并且包括固定和非固定活性组分组合的医药产品。术语“固定组合”指的是以单一实体或剂量同时对患者给予活性成分,如时1-2中的化合物和共同使用的活性剂。术语“非固定组合”指的是活性成分、例如式1-2化合物和共同使用的活性剂作为单独实体的同时,伴随或没有具体时间显示依次对患者给予,其中这类给药在患者体内提供了有效水平的2种化合物,后者还可应用于鸡尾酒疗法,例如给予3种或3种以上活性成分。
制备本发明化合物的方法
制备本发明权利要求1和2化合物(式1-2化合物)的方法及其理化性质参见以下文献中所述,其中式1化合物名称为藁本内酯;式2化合物名称为愈创木烷(藁苯内酯的文献:中国中药杂志2003,28(5):423-425;愈创木烷文献:沈阳药科大学学报2008,25(3):188-190)。
附图说明
图一愈创木烷、藁本内酯对大鼠肝脏纤维化和硬化的影响的病理表现
具体实施方式
优选实施方案的描述
下文的实施例和实施方案详细描述了化合物的活性,通过下文实施例进一步说明本发明但不起限定作用,这些实施例和实施方案仅用于解释目的,本领域工作人员将可以想到依据其进行各种修改或改变,这些修改或改变也包括在本申请的实质和范围和所附权利要求范围内。本文引述的所有公开文献、专利和专利申请为所有目的引入本文作为参考。
实施例一:愈创木烷对四氯化碳肝损伤和肝硬化模型的影响
采用氨基半乳糖腹腔注射致肝损伤模型,愈创木烷(Gua)溶液分别灌胃治疗。Wistar大鼠36只,SPF级,随机分为:Nor组(正常对照组,等量溶媒)、Mod组(模型组,等量溶媒);双环醇组(Bicyclol,0.2mg/kg.d),L组(低剂量组,5mg/kg.d),M组(中剂量组,15mg/kg.d),H组(高剂量组,45mg/kg.d)。除Nor组外,各组以氨基半乳糖溶液造模,8.5%腹腔注射,1ml/100g,每周2次;同时50%酒精灌胃,5ml/kg,每周2次。造模后次日给药,连续7天。四周后以戊巴比妥钠腹腔麻醉取材,腹主动脉取血检测血清ALT(丙氨酸氨基转移酶)、血清AST(天冬氨酸氨基转移酶)、MDA(丙二醛)。给药4周后以戊巴比妥钠腹腔麻醉取材,拍摄肝脏外观;腹主动脉取血检测血清ALT(丙氨酸氨基转移酶)、血清AST(天冬氨酸氨基转移酶)、MDA(丙二醛);肝左下叶进行HE、Masson染色观察病理改变并评分,所有实验数据用均数±标准差(x±s)表示,用SPSS11.0软件进行单因素方差分析。
Group | Dose(mg/kg.d) | ALT(U/L) | AST(U/L) | MDA(nmol.mg/g.pro) |
Normal | 68.9±20.9 | 73.5±8.3 | 8.9±1.1 | |
Model | 345.7±56## | 395.3±63## | 11.9±2.8## | |
Bicyclol | 0.2 | 197.8±70** | 291.4±76** | 10.1±1.1* |
Gua | 5 | 266.8±65* | 321.5±74* | 9.5±1.7* |
Gua | 15 | 212.6±83** | 293.6±80** | 9.4±1.4** |
Gua | 45 | 190.7±56** | 269.6±75** | 9.1±1.9** |
#P<0.05,##P<0.01 vs normal group,*P<0.05,**P<0.01 vs model group
结果表明,和模型组相比,愈创木烷可显著降低给药组大鼠血清ALT、AST、MDA,高剂量组效果最明显;以上作用有剂量依赖性。模型组肝脏颜色灰黄、表面颗粒密布,而给药组肝脏颜色发红,表面光滑,色泽发亮,高剂量组最明显。病理结果可见,模型组肝硬化明显,胶原纤维明显增生,出现假小叶,腹水现象严重,愈创木烷组大鼠肝纤维化程度明显改善,无肝萎缩和腹水现象,表明愈创木烷具有抗损伤、抗肝硬化,逆转肝纤维化作用。
实施例二:藁本内酯对氨基半乳糖肝损伤模型的影响
采用四氯化碳制备肝损伤和模型,藁本内酯溶液分别灌胃治疗。Wistar大鼠36只,SPF级,随机分为:Nor组(正常对照组,等量溶媒)、Mod组(模型组,等量溶媒),Bicyclol组(秋水仙碱组,0.2mg/kg.d),L组(低剂量组,5mg/kg.d),M组(中剂量组,15mg/kg.d),H组(高剂量组,45mg/kg.d)。除Nor组外,各组以50%CCl4花生油灌胃造模,2ml/kg,同时10%酒精灌胃,5ml/kg,每周2次,造模4周后给药。给药4周后以戊巴比妥钠腹腔麻醉取材,拍摄肝脏外观;腹主动脉取血检测血清ALT(丙氨酸氨基转移酶)、血清AST(天冬氨酸氨基转移酶)、MDA(丙二醛);肝左下叶进行HE、Masson染色观察病理改变并评分,所有实验数据用均数±标准差(x±s)表示,用SPSS11.0软件进行单因素方差分析。
结果表明,和模型组相比,藁本内酯可显著降低给药组大鼠血清ALT、AST、MDA,藁本内酯组大鼠肝纤维化程度明显改善,肝纤维化计分明显降低,以上作用有剂量依赖性。模型组肝脏颜色灰黄、表面颗粒密布,而给药组肝脏颜色发红,表面光滑,色泽发亮,高剂量组最明显。病理结果可见,模型组肝硬化明显,胶原纤维明显增生,出现假小叶,有肝萎缩和腹水现象,愈创木烷组大鼠肝纤维化程度明显改善。
Group | Dose(mg/kg.d) | ALT(U/L) | AST(U/L) | MDA(nmol.mg/g.pro) |
Normal | 67.7±18.6 | 70.3±7.9 | 9.1±1.0 | |
Model | 333.7±51## | 377.8±68## | 12.3±2.6## | |
Bicyclol | 0.2 | 188.8±79** | 298.6±79** | 12.2±1.3* |
Gua | 5 | 256.8±75* | 321.5±74* | 9.5±1.4* |
Gua | 15 | 248.4±88* | 313.6±80* | 9.1±1.2** |
Gua | 45 | 242.8±69* | 298.6±75* | 11±1.2** |
#P<0.05,##P<0.01 vs normal group,*P<0.05,**P<0.01 vs model group
Claims (6)
1、式1化合物及其药学、食品领域可接受的盐、酸、酯、萜、水合物、溶剂合物,其特征在于愈创木烷。
2、式2化合物及其药学、食品领域可接受的盐、酸、酯、萜、水合物、溶剂合物,其特征为藁本内酯。
3、权利要求1和2中的任一项所述的化合物的用途,所述用途是制备用于治疗和预防肝损伤、肝纤维化、肝硬化、病毒性肝病、酒精性肝病、饮食性肝病为目的的产品。
4、组合物,其特征在于,所述组合物包含至少一种治疗有效量的根据权利要求1和2中任一项所述的化合物与可接受的赋形剂、添加剂。
5、组合物,其特征在于,所述组合物至少包含权利要求1和2中的任一项所述的化合物作为活性物质与另一种治疗上相关活性剂的组合。
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