CN1235543A - 含有曲格列酮的谷胱甘肽还原酶活性增强剂 - Google Patents
含有曲格列酮的谷胱甘肽还原酶活性增强剂 Download PDFInfo
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- CN1235543A CN1235543A CN97199335A CN97199335A CN1235543A CN 1235543 A CN1235543 A CN 1235543A CN 97199335 A CN97199335 A CN 97199335A CN 97199335 A CN97199335 A CN 97199335A CN 1235543 A CN1235543 A CN 1235543A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
提供一种谷胱甘肽还原酶活性增强剂。解决手段:含有曲格列酮或其可药用盐的谷胱甘肽还原酶活性增强剂。
Description
技术领域
本发明涉及含有曲格列酮(troglitazone)或其可药用盐的优良的谷胱甘肽还原酶活性增强剂。
背景技术
谷胱甘肽在生物体组织内广泛存在,是细胞内主要的还原剂,在氧化还原代谢方面担负着重要的责任。特别是还原型谷胱甘肽(GSH),其分子内存在的巯基对于各种细胞防御及修复机能担负着重要职责。谷胱甘肽过氧化酶是催化GSH引起的过氧化物(过氧化氢和脂过氧化物等)还原反应的酶,是一种对抗氧化物结构很重要的酶。另一方面,谷胱甘肽还原酶是在NADPH存在条件下将被氧化的谷胱甘肽(氧化型谷胱甘肽:GSSG)还原,再生为GSH的酶。
由于含有这些化合物及酶的抗氧化物结构,可以保护细胞免受氧化促进物(例如上述的过氧化物及自由基等)的有害作用。氧化促进物与抗氧化物结构之间的平衡为前者处于优势时,产生氧化应激反应[J.Appl.Physiol.1996 Nov.,81(5),2199-2202页]。其氧化应激反应与各种疾病有关,例如与冠心病,白内障,特发性肺纤维症,慢性肾衰竭,帕金森病、阿尔氏海默病、癫痫、肌肉萎缩性侧索硬化症、脑缺血等包括神经末梢及中枢神经的神经***疾病以及胃溃疡之间的关联均有报告[J.Appl.Physiol.1996 Nov.,81(5),2199-2202页;FreeRadical Biology&Medicine,Vol.21,No.6,845-853页(1996年);Free Radical Biology&Medicine,Vol.20,No.7,925-931页(1996年);Gastoroenterology,112,855-863页(1997年)]。
另外,在WO94/12527中,明确表示促进内因性GSH合成的化合物适于治疗氧化性组织损伤、特别是涉及因过剩自由基损伤引起的疾病等由于谷胱甘肽缺乏而引起的各种疾病,这样的疾病例如,由于过多饮酒、生物体异物、放射线引起的损伤、肝病引起的细胞内氧化状态、药物及化学物质中毒、重金属中毒、脑的生理学老化(丧失记忆及学习能力等帕金森病,它是由于对氧化物质防御机能的变化导致谷胱甘肽浓度减少引起脑的衰退而导致的)、以及急性及慢性神经变性疾病(急性病症如急性缺血状态、特别是大脑发作、低血糖症及癫痫发作;慢性病症如肌肉萎缩性侧索硬化症、阿尔察默病、亨廷顿舞蹈病)、免疫机能异常、特别是癌症的免疫治疗、不育症、特别是***。进一步明确表示其化合物也使用于以自由基为主要原因的缺血状态及器官的持续再灌流。而且,在特开昭64-26516号中,表明能使谷胱甘肽浓度上升的化合物对于以白内障、肝病、肾病为首的各种疾病的治疗及预防都是有作用的。
因此增强谷胱甘肽还原酶的活性、增加GSH供应量的化合物与促进上述内因性GSH合成的化合物及能使谷胱甘肽浓度上升的化合物具有同样的效果,也就是说可以用于上述疾病的预防或治疗。
因而,如上所述,白内障也是与氧化应激反应有关的疾病,白内障患者晶状体中的GSH急剧减少的事实,以及对老年人的晶状体、X线白内障患者的晶状体、及核白内障患者的晶状体中的蛋白质的巯基高度氧化的事实均有报导[V.N.Reddy,Exp.Eye Res.50,771-778(1990)]。因而可以认为由于氧化应激反应为主要病因的此类白内障,可以通过增强谷胱甘肽还原酶的活性进行预防或治疗。
另一方面,糖尿病性白内障是因糖尿病而引起的白内障,也是糖尿病并发症的一个病症。糖尿病患者的多元醇代谢***亢进,这种现象被看作是糖尿病性自内障等各种糖尿病并发症的原因。在该多元醇代谢***中,在NADPH的存在下,通过醛糖还原酶(AR)的作用将细胞内的葡萄糖被还原成山梨醇的反应是限速反应,因此由于多元醇代谢***的亢进,山梨醇的生成量上升[Satish K.Srivastava et al.,Proc.Natl.Acad.Sci.82,7222-7226(1995)]。由于山梨醇的生物膜通透性低,蓄积在细胞内。山梨醇在晶状体中蓄积的时候,渗透压增高、晶状体膨胀[Kinoshhita et al.,Metabolism 28-4 sup-1,462-469(1979)]、产生浮肿、细胞变性,产生白内障。因此,以通过阻碍AR抑制细胞内山梨醇的蓄积,以能够预防或治疗白内障的假说为基础,研究开发了多种AR抑制剂。
对此,当谷胱甘肽还原酶和AR共存的时候,由于前者优先消耗NADPH,通过增强谷胱甘肽还原酶的活性抑制AR的机能,其结果是抑制了多元醇的蓄积,这个事实也已报道[Yokoyama et al.,Exp.Eye Res.58,207-218(1994)]。
也就是说,能够增强谷胱甘肽还原酶活性的化合物也可以预防或治疗糖尿病性白内障。
已知曲格列酮作为胰岛素非依赖性糖尿病药品在市场上销售,而且被用于其他糖尿病并发症等各种疾病的治疗或预防,但是并不知道其具有增强谷胱甘肽还原酶活性的作用。
发明公开
本发明者就曲格列酮的医药用途进行认真的研究,结果发现曲格列酮具有优良的增强谷胱甘肽还原酶活性的作用,从而完成了本发明。本发明涉及
(1)含有曲格列酮或其可药用盐的谷胱甘肽还原酶活性增强
剂。
优选:
(2)(1)中记载的用于预防或治疗由于缺乏还原型谷胱甘肽
引起的疾病的谷胱甘肽还原酶活性增强剂,
更优选:
(3)(1)中记载的用于预防或治疗因氧化应激反应所引起疾
病的谷胱甘肽还原酶活性增强剂,
进一步更优选:
(4)(1)中记载的用于预防或治疗冠心病的谷胱甘肽还原酶
活性增强剂,
(5)(1)中记载的用于预防或治疗特发性肺纤维化的谷胱甘
肽还原酶活性增强剂,
(6)(1)中记载的用于预防或治疗慢性肾炎的谷胱甘肽还原
酶活性增强剂,
(7)(1)中记载的用于预防或治疗因氧化应激反应引起的神
经***疾病的谷胱甘肽还原酶活性增强剂,
(8)(1)中记载的用于预防或治疗胃溃疡的谷胱甘肽还原酶
活性增强剂,及
(9)用于预防或治疗白内障的(1)中记载的谷胱甘肽还原酶
活性增强剂,
特别是(9)中记载的谷胱甘肽还原酶活性增强剂优选用于:
(10)(9)中记载的谷胱甘肽还原酶活性增强剂,其中白内障
是因晶状体中多元醇的蓄集而引起的白内障、因晶状体中
大分子蛋白质的蓄积而引起的白内障或晶状体中过氧化
物的蓄积而引起的白内障,
更优选:
(11)(9)中记载的谷胱甘肽还原酶活性增强剂,其中自内障
是因晶状体中大分子蛋白质的蓄积而引起的白内障或晶
状体中过氧化物的蓄积而引起的白内障,
进一步更优选:
(12)(9)中记载的谷胱甘肽还原酶活性增强剂,其中白内障
是老年性白内障,
最优选:
(13)(9)中记载的谷胱甘肽还原酶活性增强剂,其中白内障
不是糖尿病性的,而是老年性白内障。
本发明中
所谓‘因还原型谷胱甘肽缺乏引起的疾病’是指由于过多饮酒、生物体异物或放射线引起的损伤;肝病引起的细胞内氧化状态;药物及化学物质中毒;重金属中毒;脑及神经***变性疾病(例如脑血虚、大脑的发作、低血糖症、癫痫、肌肉萎缩性侧索硬化症、阿尔察默病、帕金森病、亨廷顿舞蹈病)类神经***的疾病;免疫机构的机能异常、特别是癌症的免疫治疗;不育症、特别是***;冠心病;白内障;特发性肺纤维症、慢性肾衰竭及胃溃疡类疾病。
所谓‘氧化应激反应引起的疾病’是指上述的‘神经***疾病’、冠心病、白内障、特发性肺纤维症、慢性肾炎、及胃溃疡类疾病、所谓‘氧化应激反应引起的神经***疾病’是指上述的‘神经***疾病’。
所谓‘多元醇’是指糖被醛糖还原酶(AR)还原生成的糖醇,此类糖醇例如山梨糖醇、半乳糖醇。
所谓‘因晶状体中多元醇的蓄积而引起的白内障’特别能举出的例子有糖尿病性白内障、蔗糖白内障及半乳糖白内障。
所谓‘大分子蛋白质’是指分子中至少有一个巯基的多肽或蛋白质,由于它的巯基,通过分子内或分子间形成二硫键从而生成的蛋白质。进一步的说,在‘分子中至少有一个巯基的多肽或蛋白质’包括含有巯基的与阳离子转移和膜透过相关的细胞膜蛋白质。
所谓‘由于大分子量蛋白质蓄积在晶状体中引起的白内障’特别可以举出的例子有老年性白内障、X线白内障、核性白内障。
所谓‘过氧化物’是指超氧离子(O2 -)、羟基自由基(·OH)、单线态氧(·O2)、过氧基、烷氧基等氧化自由基;以及过氧化氢(H2O2)、及过氧化脂肪等能释放氧化自由基的化合物。
所谓‘因晶状体中过氧化物的蓄积而引起的白内障’特别能举出的例子有老年性白内障。
所谓‘不是糖尿病性的、而是老年性白内障’是指由于年龄大而引起的白内障,不是因为糖尿病的原因、也就是说,没得糖尿病的老年人发生的白内障。
另外,上述‘因还原型谷胱甘肽缺乏引起的疾病’,是指一次发病不能完全恢复到正常状态的疾病,所谓此类疾病的‘治疗’是指阻止或延迟病症的发展。
曲格列酮是具有下列化学式(Ⅰ)的化合物:
本发明中的可药用盐是指曲格列酮可以成盐析出称其为它的盐,此类盐中,优选钠盐、钾盐、锂盐等碱金属盐;钙盐等碱土金属盐。
曲格列酮的分子内有2个不对称碳原子,所以存在4种异构体。本发明的化合物中,这些异构体及这些异构体的混合物都用一个化学式、即上述化学式(Ⅰ)表示。因而,本发明包含所有这些异构体及这些异构体的混合物。
可将本发明的曲格列酮放于空气中,或者让其重结晶,这时它可吸收或吸附水分,本发明也包含这些水合物。
本发明的谷胱甘肽还原酶活性增强剂含有曲格列酮或其可药用盐。曲格列酮可以采用特开昭60-51189号记载的方法制造。
曲格列酮或其药理上允许盐的给药形式,可以举出的例子有片剂、胶囊剂、颗粒剂、散剂或糖浆类经口给药,或注射剂或栓剂等非经口给药的形式。这些制剂使用赋形剂、润滑剂、粘合剂、崩解剂、稳定剂、矫味剂等添加剂,采用众所周知的方法制造。
这里的赋形剂可举出的例子有有机赋形剂例如乳糖、蔗糖、葡萄糖、甘露醇、山梨醇等糖衍生物,玉米淀粉、马铃薯淀粉、α-淀粉、糊精、羧甲基淀粉等淀粉衍生物;结晶纤维素等纤维等衍生物;***胶、葡聚糖、Pullulan等,以及无机赋形剂例如轻质硅酸酐、合成硅酸铝、硅酸钙、偏硅酸铝酸镁等硅酸盐衍生物,磷酸氢钙等磷酸盐、碳酸钙等碳酸盐、硫酸钙等硫酸盐等。
润滑剂可以举出的例子有硬脂酸、硬脂酸钙、硬脂酸镁等硬脂酸金属盐,滑石粉,胶体二氧化硅、蜂蜡、鲸蜡等蜡类;硼酸;己二酸;硫酸钠等硫酸盐;乙二醇;富马酸;苯甲酸钠;DL-亮氨酸;十二烷基硫酸钠、十二烷基硫酸镁等十二烷基硫酸盐;无水硅酸、硅酸水和物等硅酸类;以及上述淀粉衍生物。
粘合剂可以举出的例子有羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇及与上述赋形剂相同的化合物。
崩解剂可以举出的例子有低取代度的羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、内部桥联交叉羧甲基纤维素钠等纤维素衍生物;羧甲基淀粉钠、桥联聚乙烯吡咯烷酮等经化学修饰的淀粉·纤维素类。
稳定剂可以举出的例子有对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等对羟基苯甲酸酯类;氯丁醇、苯甲醇、苯乙醇等醇类;氯代新洁尔灭、苯酚、甲酚等苯酚类;硫柳撒、脱水醋酸及山梨酸。
矫味剂可以举出的例子有通常使用的甜味剂、酸味剂、香料等。
同时,含有本发明曲格列酮的谷胱甘肽还原酶活性增强剂可以在眼部局部给药。适于眼部局部给药的剂型是给药后几乎完全残留的固形***剂、或溶解于泪液或用其它方法崩解的崩解性***剂,可以举出的例子有溶液、悬浊液、凝胶、眼用软膏及固形***剂等。
这些眼科用的组合物处方中,曲格列酮或其可药用盐的含量的下限是0.01%,优选0.1%,上限是10%,优选5%。
眼科用的组成物中可以含有无毒的眼科用无机或有机载体,典型的眼科用组合物的载体如水、低级链烷醇或芳烷醇可以与水混合的溶剂与水的混合物、植物油、聚亚烷基二醇、以石油为基质的冻胶、乙基纤维素、油酸乙酯、羧甲基纤维素、聚乙烯吡咯烷酮、肉豆蔻酸异丙酯及其它通常使用的可接受的载体。另外,眼科用组合物可以含有乳化剂、防腐剂、润湿剂、赋形剂等无毒的添加剂,例如聚乙二醇200、300、400及600,碳蜡1000、1500、4000、6000及10000,对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等对羟基苯甲酸酯,已知具有低温杀菌性且使用的无毒的季铵盐化合物(例如氯化苄甲乙氧铵、氯化苄胺)、苯酚汞盐等抗菌剂、硫柳撒、对羟基苯甲酸甲酯及丙酯、苯甲醇、苯乙醇、食盐、硼酸钠、醋酸钠等缓冲剂成分、葡萄糖酸缓冲剂及脱水山梨糖醇单月桂酸酯、三乙醇胺、聚氧乙烯脱水山梨糖醇软脂酸酯、二辛基钠磺化琥珀酸酯、单硫代甘油、硫代山梨醇、乙二胺四乙酸。
进一步的说,可以使用适当的眼科用赋形剂,其中包括常用的磷酸缓冲赋形剂(例如磷酸钠缓冲液、磷酸钾缓冲液)、等渗硼酸赋形剂、等渗食盐赋形剂、等渗硼酸钠赋形剂等。
本发明中,曲格列酮或其可药用盐的给药量根据症状、年龄、给药方法等有所不同,例如口服给药的时候,成人可以对应症状每日1次或分数次给药,下限是0.1mg(优选1mg)、上限是1000mg(优选500mg)。静脉给药的时候,成人可以对应症状每日1次或分数次给药,下限是0.01mg(优选0.1mg)、上限是500mg(优选200mg)。
含有曲格列酮或其药理上允许盐的制剂可以用如下方法制造。
制剂例1 散剂
曲格列酮5g、乳糖895g及玉米淀粉100g用混合机混合,得到散剂。
制剂例2 颗粒剂
将曲格列酮5g、乳糖895g及低取代羟丙基纤维素100g混合后,加入10%羟丙基纤维素水溶液300g混合。将其挤出后使用造粒机造粒、干燥,从而得到颗粒剂。
制剂例3 胶囊剂
使用V型混合机将曲格列酮5g、乳糖115g、玉米淀粉58g及硬脂酸镁2g混合后,于每粒3号胶囊中充填180mg,从而得到胶囊剂。
制剂例4 片剂
曲格列酮5g、乳糖90g、玉米淀粉34g、结晶纤维素20g及硬脂酸镁1g用混合机混合后,使用打片机打片,从而得到片剂。
制剂例5 滴眼剂
曲格列Ⅰ酮 2.0g
磷酸氢二钠 0.716g
磷酸二氢钠 0.728g
氯化钠 0.400g
对羟基苯甲酸甲酯 0.026g
对羟基苯甲酸丙酯 0.014g
灭菌蒸馏水 适量
氢氧化钠 适量
余量 100ml
将PH调节为7.0,采用常用方法制造滴眼剂。
以下结合实施例更详细的说明本发明,但本发明并不限于此。
实施例1 还原酶活性增强剂
(1)晶状体器官的培养
6至8周的SD系雄性大鼠(日本SLC)吸入二氧化碳使其窒息死亡后,摘除两眼球。切开眼球后部的巩膜,除去玻璃体及虹膜-睫状体、取出品状体。
将所得的各种晶状体在6孔组织培养板(FALCON)中用后述的任一种培养液3ml浸润,培养。5%的二氧化碳(空气中)存在、湿度为100%、37℃的条件下,在二氧化碳气体保温箱中放置48小时。
阴性对照用的培养液使用含有青霉素(20单位/ml)及链霉素(20μg/ml)的培养基199(GIBCO)。
正对照用的培养液使用的是将半乳糖(D-galactose)溶于上述阴性对照培养液和纯化水的混合液(85∶15)制成的浓度为30mM的半乳糖溶液。
试验用的培养液使用的是用10%丙酮水溶液使曲格列酮溶解或悬浊,并按照1%的比例添加到上述阳性对照用的培养液中所得到的物质。该试验用的培养液使用曲格列酮的浓度分别为0.2μM、2μM及20μM的溶液。
另外,冷冻保存培养的晶状体。
这里在阴性对照用培养液中培养的晶状体相当于正常状态下的晶状体,在阳性对照用培养液中培养的晶状体相当于受半乳糖负荷的晶状体,在试验用培养液中培养的晶状体相当于受半乳糖负荷且投给曲格列酮的晶状体。
(2)谷胱甘肽还原酶活性的测定
使用(1)培养的晶状体,配制谷胱甘肽还原酶溶液,测定其酶的样品。
也就是说,在2ml蒸馏水中将冷冻的大白鼠的晶状体匀浆后,进行离心分离(10000g、20分钟),将得到的上清液作为酶样品。
向含有lmM氧化型谷胱甘肽(GSSG)及100μM NADPH的磷酸缓冲液0.6ml中加入酶样品400μl,25℃下进行反应6分钟。测定未消耗的反应液中剩余的NADPH的吸光度(340nm∶OD340nm),以反应前的OD340nm和反应后的OD340nm的差(ΔOD340nm)作为NADPH的消耗量,作为谷胱甘肽还原酶活性的指标。结果(ΔOD340nm/分/晶状体)如表1所示。
表1
对照组 | 添加曲格列酮组 | ||
负对照(-半乳糖) | 正对照(+半乳糖) | 2μM | 20μM |
0.027±0.001 | 0.026±0.001 | 0.031±0.000 | 0.031±0.001 |
从表1可以看出,添加曲格列酮组的ΔOD340nm比阴性、阳性对照试验d大,消耗NADPH的多。也就是说,由于添加了曲格列酮,谷胱甘肽还原酶的活性被增强。
实施例2对醛糖还原酶(AR)的抑制作用
采用与实施例1(1)相同的方法培养的晶状体作为酶的来源,按照Hayman and Kinos hita等的方法(J.Biol.Chem.240,877-882(1965))测定AR活性。
也就是说,用与实施例1(1)相同的方法培养的大白鼠晶状体用生理盐水洗净,在0.05mM EDTA中匀浆。对其进行离心分离(1000g、15分钟),得到的上清液用作酶的标本。将该酶溶液加入到含有0.5mMDL-甘油醛、0.4M硫酸锂、0.05mM NADPH、67mM磷酸氢二钠及1mMEDTA的蒸馏水溶液中,开始进行酶反应。室温下,反应进行7分钟后,测定未消耗的反应液中剩余的NADPH的吸光度(340nm:OD340nm)。以反应开始前的吸光度和反应的吸光度的差作为NADPH的消耗量,作为AR活性的指标。
在曲格列酮的浓度为2μM、20μM时,不显示AR的抑制作用。
实施例3 晶状体内多元醇集聚的抑制作用
测定在晶状体内半乳糖参加AR引起的还原反应所生成多元醇即半乳糖的量。
也就是说,按照实施例(1)培养,在1ml 0.6mM二甲基巯基葡萄糖(内标物)的蒸馏水溶液中将冷冻的大白鼠的晶状体匀浆,再向其中加入冷却的乙醇2.4ml,放置5分钟,将其离心分离(1000g、5分钟),得到的上清液25μl放入螺口小玻璃瓶中,冷冻干燥。再向其中添加70μl吡啶及20μl苯基异氰酸酯后,在55℃下,恒温5分钟。进一步添加20μl甲醇,55℃下恒温1小时。向其中加入90μl吡啶,以此为检测溶液,注入高效液相色谱分析仪(流动相;乙腈∶乙醇∶水(=5∶2∶3)混合液、流速:1ml/分),用分光光度计测定吸光度(240nm),计算出1个晶状体中含半乳糖醇的量。以正对照组半乳糖醇的量为100时,添加曲格列酮组的半乳糖醇的量如表2所示。
表2
曲格列酮的添加浓度 | 0μm(正对照) | 2μm | 20μm |
半乳糖醇的量 | 100 | 65±8 | 47±6 |
从表2中可以看出,曲格列酮根据浓度可以抑制晶状体中半乳糖醇的蓄积。
实施例4 降低过氧化脂肪的作用
测定按照实施例1(1)培养的大鼠晶状体中过氧化脂肪的量。
也就是说,测定晶状体的湿重后,在含有1mM EDTA的50mM tris盐酸缓冲液(PH7.6)0.5ml中匀浆。进行离心分离(2500g、30分钟),测定得到的上清液中含有的过氧化脂肪,测定时使用过氧化脂肪测定工具(LPO-585,BIOXY TWCHS.A.公司),以丙二醛和羟基アルクナ-ル作为过氧化脂肪的指标,比色定量过氧化脂肪。得到的结果(晶状体中过氧化脂肪量:nmol/g)如表3所示。
表3
对照组 | 曲格列酮添加组 | ||
阴性对照-半乳糖) | 阳性对照(+半乳糖) | 2μM | 20μM |
0.68±0.28 | 5.17±1.09 | 4.52±0.19 | 1.25±0.92 |
从表3中可以看出,由于负荷了半乳糖,晶状体中脂肪过氧化物浓度上升,但其上升的程度可以根据添加的曲格列酮的浓度而被抑制。
如实施例1所示,曲格列酮具有增强谷胱甘肽还原酶活性的作用能够增加生物体内GSH的供应量,因此可以用于预防或治疗还原型谷胱甘肽缺乏引起的疾病。进一步的说,如实施例4所示,曲格列酮可以降低脂过氧化物,所以能够用于预防或治疗氧化应激反应引起的疾病(特别是晶状体氧化应激反应引起的白内障)。
另外,实施例1、2及3的结果表明,即使在曲格列酮不显示抑制AR活性的浓度(2μM)下,也能显示增强谷胱甘肽还原酶活性的作用及抑制多元醇的蓄积作用。也就是说,曲格列酮通过增强谷胱甘肽还原酶活性抑制多元醇代谢***,抑制了多元醇的蓄积。因此,含有曲格列酮的谷胱甘肽还原酶活性增强剂可用于预防或治疗糖尿病性白内障等由于细胞内多元醇的蓄积而引起的疾病。
Claims (13)
1、谷胱甘肽还原酶活性增强剂,含有曲格列酮及其可药用盐的。
2、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗由于缺乏还原型谷胱甘肽而引起的疾病。
3、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗因氧化应激反应所引起的疾病。
4、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗冠心病。
5、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗特发性肺纤维化。
6、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗慢性肾功能衰竭。
7、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗因氧化应激反应引起的神经***疾病。
8、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗胃溃疡。
9、如权利要求1所述的谷胱甘肽还原酶活性增强剂,用于预防或治疗白内障。
10、如权利要求9所述的谷胱甘肽还原酶活性增强剂,其中白内障是指由于晶状体中多元醇蓄积而引起的白内障、由于晶状体中大分子量蛋白质蓄积而引起的白内障或晶状体中过氧化物蓄积而引起的白内障。
11、如权利要求9所述的谷胱甘肽还原酶活性增强剂,其中白内障是指由于晶状体中大分子蛋白质的蓄积而引起的白内障或晶状体中过氧化物的蓄积而引起的白内障。
12、如权利要求9所述的谷胱甘肽还原酶活性增强剂,其中白内障是老年性白内障。
13、如权利要求9所述的谷胱甘肽还原酶活性增强剂,其中白内障不是糖尿病性的,而是老年性白内障。
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AP2001002036A0 (en) * | 1998-07-21 | 2001-03-31 | Smithkline Beecham Plc | Use of glucose uptake enhancer for reducing apoptosis. |
MA26662A1 (fr) * | 1998-07-21 | 2004-12-20 | Smithkline Beecham Plc | Derives de thiazolidinedione, compositions pharmaceutiques les contenant et leur utilisation |
WO2000007582A2 (en) * | 1998-08-06 | 2000-02-17 | Warner-Lambert Company | Use of thiazolidinedione derivatives for the treatment or prevention of cataracts |
US6379664B1 (en) | 1998-09-29 | 2002-04-30 | Board Of Regents University Of Nebraska-Lincoln | Composition and method for the prevention and treatment of oxidative damage in ocular tissues |
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JPS6136284A (ja) * | 1984-07-27 | 1986-02-20 | Sankyo Co Ltd | チアゾリジン誘導体およびその製造方法 |
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JPS62234085A (ja) * | 1985-12-18 | 1987-10-14 | Sankyo Co Ltd | チアゾリジン誘導体を有効成分とする糖尿病性合併症治療剤 |
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ID21778A (id) | 1999-07-22 |
AU723354B2 (en) | 2000-08-24 |
NZ334577A (en) | 2001-03-30 |
KR20000036035A (ko) | 2000-06-26 |
AU4219597A (en) | 1998-04-02 |
WO1998010760A1 (fr) | 1998-03-19 |
HUP0002941A2 (hu) | 2001-08-28 |
CA2265656A1 (en) | 1998-03-19 |
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