CN1239890A - 17α－二氢马萘雌酮作为医用抗氧化剂的用途 - Google Patents
17α－二氢马萘雌酮作为医用抗氧化剂的用途 Download PDFInfo
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- CN1239890A CN1239890A CN97180446A CN97180446A CN1239890A CN 1239890 A CN1239890 A CN 1239890A CN 97180446 A CN97180446 A CN 97180446A CN 97180446 A CN97180446 A CN 97180446A CN 1239890 A CN1239890 A CN 1239890A
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Abstract
本发明提供了用17α－二氢马萘雌酮或17α－二氢马萘雌酮－3－硫酸酯的药用盐作为抗氧化剂的方法。
Description
发明背景
生物学上生成的自由基与许多疾病均有连带关系，需氧生物在有氧环境中的存活涉及这些极具活性的化学基团的生物生成与生物控制它们的能力之间复杂的相互作用(Del Maestro RF，Acta Phy ScanSuppl.492：153-68(1980))，宿主生物与生物学上生成的自由基之间的这种相互作用导致了以生物细胞的损伤和死亡为终结的深奥的生物化学变化。自由基反应积累的产物导致了许多疾病，这些疾病已被认为部分地起因于增长的细胞内自由基通量而诱发的细胞损伤，这些疾病包括(但不局限于)癌症、心血管疾病、中枢神经系统紊乱、骨疾、衰老、阿尔茨海默氏痴呆、炎症、类风湿性关节炎、自身免疫疾病、呼吸窘迫和肺气肿。
自由基损害与许多疾病的联系被广为报道，包括酶、离子通道、结构蛋白和膜脂质的许多细胞成分均是活性自由基的潜在目标(Rice-Evans C，Mol Aspects of Med 13(1)：1-11(1992))，处于合适位点的抗氧化剂会限制该损害，与这些潜在目标的自由基反应可以影响一系列的细胞功能而导致病变和最终的细胞死亡，处于潜在反应位点的抗氧化剂会限制该损害，抗氧化剂在保护DNA、蛋白质(包括脂蛋白)和膜脂质免于氧化性损害中起着重要的作用。
有强有力的证据证明自由基损害造成许多慢性健康问题，对于大多数人类疾病而言，由内源产生的氧化剂对初期疾病过程是次要的，但氧化性损害加重了初期的损伤，例如，再灌注损伤可以被定义为发生于局部缺血发作之后恢复血流时器官的损害。尽管是必需的，但是氧恢复增加了在损伤的组织中氧化剂的形成并暂时恶化了该损伤(UraizeeA，Circulaton 75(6)：1237-1248(1987))。Guanicri描述了在缺氧心肌中抗氧化剂防御的减少然后随着重新充氧作用而脂质过氧化增加(Biochim-Biophys-ACTA718(2)：157-164(1982))。在再灌注损伤中，局部缺血后由于粘连和激活中性白细胞，在内皮损伤位点处的炎症反应导致产生超氧化物。在许多不同的临床情况中，也增加了肝脏中氧自由基的产生。在病毒性肝炎和慢性活动性肝炎中，肝脏中累积了大量被刺激的巨噬细胞，它们产生自由基，由于肝脏中增加了常由细胞色素P-450介导的自由基的生成，大量有毒的化学物质导致肝中毒性损伤。可以断定从铁蛋白释放出的铁催化羟基的生成是许多肝脏病易发的机理(Lee WM，N Eng J of Med；Review P.1118(1995))。
氧化和抗氧化剂的使用对于许多炎症疾病的治疗也是很重要的，类风湿性关节炎(RA)是最常见的慢性炎性疾病，流行病学研究表明标准和明确的RA流行率在0.3％和1.5％之间。慢性持续性炎性关节疾病伴随有在发炎的类风湿性关节里H2O2的生成，在发炎期间，多形核白细胞(PMN)和巨噬细胞也尤其产生氧自由基。在任何慢性或急性炎症疾病中，PMN和巨噬细胞会产生O2 -和H2O2。结核病、牛皮癣、系统性红斑狼疮、其它自身免疫疾病和成人呼吸窘迫综合症也可以被称为伴随氧化作为主要因素的炎性疾病，许多其它疾病也可以列入该行列中。
在中枢神经系统(CNS)创伤和中风(例如局部缺血)领域中，氧自由基的生成和脂质过氧化过程也已成为研究人员关注的焦点。许多研究提供了大量的证据证明了在损伤或局部缺血的CNS中存在着自由基和脂质过氧化的反应((Hall ED，J-Neurotrauma 9(Suppl.l)：S165-S172(1992))。
已建议抗氧化剂可保护性抗乳癌和抗其它癌(包括脑癌和肝癌)，以及保护性抗心血管疾病和骨质疏松((Wiseman H，Free Radical Res21(3)：187-94(1994))。已经证明这些抗氧化剂保护模型和细胞膜(包括核膜)以对抗可能致癌的自由基中间体和脂质过氧化产物。人们已将对于与动脉粥样硬化有关的严重综合症和其通常发病率的注意力集中在能够通过抗氧化剂保护低密度脂蛋白(LDL)免受氧化损伤的能力来预防和治疗该血管疾病上(Steinberg D，N Engl J of Med 14：915-924(1989))。
发明描述
本发明提供了将抗氧化剂量的17α-二氢马萘雌酮或其3-硫酸酯药用盐给入需要的哺乳类动物以治疗或抑制自由基诱导的疾病的方法。依此推论，本发明提供了处理哺乳类动物中自由基与酶、离子通道、结构蛋白和膜脂质反应的方法，该方法包括给入作为牺牲底物的17α-二氢马萘雌酮或其药用硫酸酯盐，其量足以选择性地与同患者的酶、离子通道、结构蛋白和膜脂质反应的自由基反应并抑制自由基与患者的酶、离子通道、结构蛋白和膜脂质的反应，其中确定用抗氧化剂治疗有保证的具体病症是癌症、中枢神经系统紊乱、骨疾、衰老、炎症、末梢血管疾病、类风湿性关节炎、自身免疫疾病、呼吸窘迫、肺气肿、预防重新灌注损伤、病毒性肝炎、慢性活动性肝炎、结核病、牛皮癣、系统性红斑狼疮、成人呼吸窘迫综合症、中枢神经系统创伤和中风。
作为本发明的用途，处理包括已有疾病的治疗、改善疾病或减轻疾病，抑制包括抑制或预防疾病的发展或扩散。
17α-二氢马萘雌酮3-硫酸酯药用盐包括(但不局限于此)碱金属盐、碱土金属盐、铵盐、含有1-6个碳原子的烷基胺盐或在各自的烷基基团中含有1-6个碳原子的二烷基胺盐。
采用标准的药理测试方法确定17α-二氢马萘雌酮抗氧化剂性能，该方法通过TBARS(硫代巴比妥酸活性物质)方法分析游离醛(YagiK.，Biochem Med 15：212-216(1976))测定其对由暴露在Cu++离子或培养的内皮细胞中诱导的氧化变性的低密度脂蛋白(LDL)的形成的抑制能力(Parthasarathy S，Proc Natl Acad Sci USA 86：1046-1050(1989))。
用该标准药理测试方法得到的结果表明17α-二氢马萘雌酮是有效的LDL氧化反应抑制剂，即抑制可达至多100％，在Cu++离子介导的和猪主动脉内皮细胞介导的氧化中分别得到0.17μM和0.065μM的IC50值。由比较，在猪主动脉内皮细胞介导的氧化测试方法中，雌酮所得到的IC50值为0.56μM。用该测试方法也可以证明17α-二氢马萘雌酮是有效的LDL和血浆氧化抑制剂，得到的IC50s值分别为0.065μM和0.07μM。
17α-二氢马萘雌酮抗氧化剂性能还通过它的动力学效果来评价，该动力学效果涉及在Cu++存在下发生的LDL、HDL和血浆的氧化，即已用于诱导LDL变性的标准技术(Esterbauer H，Ann NY Acad Sci1989；570：254-267，Huber LA，Free Rad Res Comms 1990；8：167-173，Vossen Rcrm，Lipids 1993；8：857-861，Jialal I，J Lipid Res1992；33：899-906)。用分光光度法跟踪共轭二烯(主要的初期脂质过氧化物)的形成估计的下列参数为：延迟期或Tmin：氧化开始所用时间；T50：形成50％共轭双二烯所用时间；和Tmax：达到最大氧化所用时间。
浓度为25nM受试的17α-二氢马萘雌酮能够在人类LDL的共轭二烯形成中延长延迟期28％。T50和Tmax分别延长31％和30％。在同样的试验中，25nM的雌酮仅增加所有参数7-10％。25nM的17α-二氢马萘雌酮具有明显抑制人类HDL的共轭二烯形成的效果，它延长延迟期的299％。T50和Tmax分别延长134％和118％。相同浓度的雌酮由延长延迟期20％、T5038％和Tmax46％对HDL共轭二烯的形成起作用。在人类血浆共轭二烯的形成中，25nM的17α-二氢马萘雌酮对延迟期无作用，然而，他的确延长T50和Tmax分别为19％和32％，这就指示了虽然它对氧化初期几乎没有作用，但它降低了它的速率。该体系中的雌酮对延迟期也无作用，对于T50和Tmax的效果仅分别为5％和10％。
为进一步证明17α-二氢马萘雌酮的抗氧化性能，用培养的细胞进行两个附加标准药理学测试步骤。在第一个测试步骤中，在17α-二氢马萘雌酮存在或不存在的情况下，将放射性同位素标记的LDL(125I-LDL)(McFarlane AS，In：Munro HN，Allison JB，eds.MammalianProtein Metabolism.Vol.l.New York：Academic Press297-341(1964))置于Cu++中变性。下一步，将表达结合氧化变性LDL的清除剂脂蛋白受体的J774巨噬细胞置于处理的125I-LDL中。该试验结果表明：在17α-二氢马萘雌酮存在下，氧化的Cu++-处理的LDL的结合减少70％和41％(分别是2.5和0.25μM17α-二氢马萘雌酮)，通过比较，相同浓度的雌酮分别减少39％和0％的氧化LDL的结合。因为氧化的LDL由巨噬细胞结合和代谢被认为极强地促成了海绵状细胞和动脉粥样硬化斑的生长，因此，该减少LDL氧化和随后结合到清除剂受体上的效果被认为是非常有益的。
在第二个测试步骤中，将猪主动脉内皮细胞(PAEC)置于LDL中，该LDL已如上述通过置于有或没有17α-二氢马萘雌酮情况下的Cu++中而变性。已证明氧化的LDL对内皮细胞具有细胞毒性并且该过程与动脉粥样硬化有很强的连带关系。用处理的LDL孵育细胞24小时之后，进行MTT试验以评价细胞毒性(Hansen MB，.J Immu Methods 119：203-210(1989))。该测定方法对所给试验中活细胞的百分率作出评价。在该试验中，将细胞置于无化合物存在时氧化的25μg/ml LDL中，之后仅2％的细胞存活下来。与之对照，随后将细胞置于在17a-二氢马萘雌酮(0.25μM)存在下的Cu++处理的LDL中，存活细胞的百分率是45％或更多。在相同试验中测试的其它化合物对PACE的保护影响最小(17β-雌二醇＝11％存活；马烯雌酮＝4％存活；雌酮＝37％存活)。该测试方法的结果证明：17a-二氢马萘雌酮存在下改性的LDL无细胞毒性，因此，该数据与上述由TBARS方法证明的由17α-二氢马萘雌酮抑制氧化变性相一致。
基于这些测试方法得到的结果，17α-二氢马萘雌酮和其硫酸酯的药用盐作为抗氧化剂可用于治疗或抑制自由基诱导的疾病，所述药用盐如碱金属盐、碱土金属盐、铵盐、含有1-6个碳原子的烷基胺盐或在各自的烷基基团中含有1-6个碳原子的二烷基胺盐。
本发明抗氧化剂可配制成纯品给药或与药用载体一起配制给药，通过化合物的溶解度和化学性质、选择的给药途径和标准药理学实践来确定载体的比例。药用载体可以是固体或液体。
固体载体可以包括一种或多种物质，该物质也可以起矫味剂、润滑剂、增溶剂、悬浮剂、填充剂、助流剂、压缩助剂、粘合剂或片剂崩解剂的作用；固体载体也可以是包胶物质。在粉剂中，载体是细分的固体，该固体与细分的活性成分混合。在片剂中，活性成分与具有所需压缩性质的载体以合适的比例混合并被压成所需的形状和大小。优选粉剂和片剂含有至多达99％的活性成分。合适的固体载体包括磷酸钙、硬脂酸镁、滑石、蔗糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。
液体载体用于制备溶液、悬浮液、乳剂、糖浆、酏剂和加压组合物。活性成分能被溶解于或悬浮于药用液体载体，如水、有机溶剂、两者的混合物或药用油或脂肪中，液体载体能够含有其它合适的药用添加剂，如增溶剂、乳化剂、缓冲液、防腐剂、甜味剂、矫味剂、悬浮剂、增稠剂、色素、黏度调节剂、稳定剂或渗透调节剂。口服和肠胃外给药的液体载体合适的实例包括水(部分地含有如上的添加剂，如纤维素衍生物，优选羧甲基纤维素钠溶液)、醇(包括一羟基醇和多羟基醇，如乙二醇)和它们的衍生物、lethicins和油(如精馏的椰子油和花生油)。对于肠胃外给药，载体也可以是油脂，如油酸乙酯和肉豆蔻异丙酸酯。无菌液载体用于肠胃外给药的无菌液形式的组合物中，对于加压组合物的液体载体能够是卤化的烃或其它药用推进剂。
无菌溶液或悬浮液的液体药物组合物可以通过例如肌内、腹膜内或皮下注射使用。无菌溶液也能够静脉给药，本发明的化合物也能够以液体或固体组合物的形式口服给药。
本发明抗氧化剂可以常规栓剂的形式经直肠给入，为了由鼻内或支气管内吸入或吹入给药，可以将本发明抗氧化剂配制成水溶液或部分水溶液，然后使其能够以气雾剂的形式使用，本发明化合物也可以通过含有活性化合物和载体的透皮片经皮给入，所述载体对于活性化合物是惰性的、对于皮肤是无毒的、并可通过皮肤使传输的药剂全身性吸附到血流中。载体可采取多种形式，如霜剂和软膏剂、糊剂、凝胶和闭合装置。霜剂和软膏剂可以是水包油型或油包水型的粘稠液体或半固态乳剂，在含有活性成分的石油或亲水石油中分散的吸附性粉末组成的糊剂也是适用的。也可以利用多种闭合装置将活性成分释放到血流中，如覆盖含有活性成分、有或无载体的储层的半透膜或含有活性成分的基质，其它闭合装置见于文献中。
此外，通过与药用赋形剂配制成含有0.1-5％(优选2％)活性化合物的制剂，本发明抗氧化剂可以作为溶液、霜剂或洗液使用施于真菌作用的区域。
所需剂量随所用具体组合物、给药途径、呈现症状的严重性和被治疗的具体客体而变化，基于标准药理测试方法得到的结果，设计的活性化合物的日剂量应为0.02μg/kg-500μg/kg，通过用少于化合物的最佳剂量的小剂量开始治疗。然后，增加剂量至达到治疗环境下的最佳效果；药剂师会根据治疗各客体的经验确定口服、肠胃外、鼻内或腹膜内给药的精确剂量，优选药物组合物是单位剂量形式，例如，片剂或胶囊，在该形式中，组合物被再分为含有合适量活性成分的单位剂量；单位剂量形式可以是被包装的组合物，例如，是被包装的粉剂，可以是药瓶、安瓿、预填充注射器或含液体的sachets。单位剂量形式可以是例如胶囊或片剂本身，或可以是包装形式下合适数量的任何所述组合物。
Claims (4)
1.抑制或治疗自由基诱导的疾病的方法，该方法为将抗氧化剂量的17α-二氢马萘雌酮或17α-二氢马萘雌酮-3-硫酸酯的药用盐用于需要的哺乳类动物。
2.权利要求1的方法，其中3-硫酸酯的药用盐是碱金属盐、碱土金属盐、铵盐、含有1-6个碳原子的烷基胺盐或在各烷基基团中含有1-6个碳原子的二烷基胺盐。
3.抑制需要相应治疗的哺乳类动物中自由基与酶、离子通道、结构蛋白和膜脂质反应的方法，该方法包括使用作为牺牲底物的17α-二氢马萘雌酮或17α-二氢马萘雌酮-3-硫酸酯的药用盐，其量足以选择性地与同所述哺乳类动物的酶、离子通道、结构蛋白和膜脂质反应的自由基反应并抑制自由基与所述哺乳类动物的酶、离子通道、结构蛋白和膜脂质的反应。
4.抑制与下列疾病的发展有关的内源性自由基的方法，所述疾病为癌症、中枢神经系统紊乱、阿尔茨海默氏病、骨疾、衰老、炎症、末梢血管疾病、类风湿性关节炎、自身免疫疾病、呼吸窘迫、肺气肿、预防重新灌注损伤、病毒性肝炎、慢性活动性肝炎、结核病、牛皮癣、系统性红斑狼疮、成人呼吸窘迫综合症、中枢神经系统创伤和中风，或在重新灌注过程中的损伤，该方法包括使用17α-二氢马萘雌酮或17α-二氢马萘雌酮-3-硫酸酯的药用盐。
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97180446A Pending CN1239890A (zh) | 1996-12-09 | 1997-12-05 | 17α－二氢马萘雌酮作为医用抗氧化剂的用途 |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0946182A1 (zh) |
| JP (1) | JP2001506629A (zh) |
| KR (1) | KR20000069346A (zh) |
| CN (1) | CN1239890A (zh) |
| AR (1) | AR010336A1 (zh) |
| AU (1) | AU743519B2 (zh) |
| BR (1) | BR9714382A (zh) |
| CA (1) | CA2272089A1 (zh) |
| HU (1) | HUP0000570A3 (zh) |
| IL (1) | IL130069A0 (zh) |
| NZ (1) | NZ336341A (zh) |
| WO (1) | WO1998025627A1 (zh) |
| ZA (1) | ZA9711053B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6271221B1 (en) * | 1996-12-10 | 2001-08-07 | American Home Products Corporation | Use of equilenin as an antioxidant |
| DE10154221A1 (de) * | 2001-11-07 | 2003-05-15 | Max Delbrueck Centrum | Mittel zur Behandlung von Läsionen des Nervensystems |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4338314C1 (de) * | 1993-11-10 | 1995-03-30 | Jenapharm Gmbh | Pharmazeutische Präparate zur Prophylaxe und Therapie radikalvermittelter Zellschädigungen |
-
1997
- 1997-12-05 BR BR9714382-0A patent/BR9714382A/pt not_active IP Right Cessation
- 1997-12-05 HU HU0000570A patent/HUP0000570A3/hu unknown
- 1997-12-05 WO PCT/US1997/022155 patent/WO1998025627A1/en not_active Application Discontinuation
- 1997-12-05 IL IL13006997A patent/IL130069A0/xx unknown
- 1997-12-05 KR KR1019997005048A patent/KR20000069346A/ko not_active Application Discontinuation
- 1997-12-05 AR ARP970105739A patent/AR010336A1/es unknown
- 1997-12-05 JP JP52680598A patent/JP2001506629A/ja active Pending
- 1997-12-05 CA CA002272089A patent/CA2272089A1/en not_active Abandoned
- 1997-12-05 CN CN97180446A patent/CN1239890A/zh active Pending
- 1997-12-05 EP EP97948610A patent/EP0946182A1/en not_active Ceased
- 1997-12-05 AU AU54644/98A patent/AU743519B2/en not_active Ceased
- 1997-12-05 NZ NZ336341A patent/NZ336341A/en unknown
- 1997-12-09 ZA ZA9711053A patent/ZA9711053B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU5464498A (en) | 1998-07-03 |
| HUP0000570A2 (hu) | 2000-10-28 |
| KR20000069346A (ko) | 2000-11-25 |
| ZA9711053B (en) | 1999-06-09 |
| AU743519B2 (en) | 2002-01-31 |
| NZ336341A (en) | 2002-02-01 |
| BR9714382A (pt) | 2000-05-16 |
| EP0946182A1 (en) | 1999-10-06 |
| WO1998025627A1 (en) | 1998-06-18 |
| CA2272089A1 (en) | 1998-06-18 |
| IL130069A0 (en) | 2000-02-29 |
| JP2001506629A (ja) | 2001-05-22 |
| HUP0000570A3 (en) | 2000-12-28 |
| AR010336A1 (es) | 2000-06-07 |
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Legal Events
| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |