CN100569281C - 治疗和预防坏死的组合物的制备用途 - Google Patents
治疗和预防坏死的组合物的制备用途 Download PDFInfo
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- CN100569281C CN100569281C CNB038119978A CN03811997A CN100569281C CN 100569281 C CN100569281 C CN 100569281C CN B038119978 A CNB038119978 A CN B038119978A CN 03811997 A CN03811997 A CN 03811997A CN 100569281 C CN100569281 C CN 100569281C
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Abstract
一种治疗和/或预防细胞坏死以及相关疾病的方法,包括抑制所述细胞中一种或多种弹性蛋白酶。
Description
技术领域
本发明涉及一种预防和治疗细胞坏死的方法和组合物。更具体的说,本发明的方法和组合物通过抑制正在坏死的细胞中的弹性蛋白酶的活性,来预防和治疗坏死。
背景技术
弹性蛋白酶是一种丝氨酸蛋白酶,可以促进包括弹性蛋白在内的蛋白质的降解,而弹性蛋白是构成哺乳动物结缔组织的主要蛋白。现有技术已经暗示了抑制弹性蛋白酶可能有效治疗多种疾病。
例如,US4683241公开了弹性蛋白酶据信在结缔组织炎症的病因学中起很重要的作用。该专利公开了一类对弹性蛋白酶起抑制作用的酚酯。
US5216022公开了亚苯基二链烷酸的芳族酯作为人中性粒细胞弹性蛋白酶(即白细胞弹性蛋白酶)的抑制剂在治疗许多由中性粒细胞弹性蛋白酶介导的病症中的用途。
US6159938公开了对内源性血管弹性蛋白酶的抑制作用可能在治疗肺部血管疾病以及其他相关疾病中起作用。
坏死,是当细胞环境受到干扰而引起细胞死亡中相对不可控制的步骤,并且最终将导致细胞破裂。坏死可以用高压氧来进行治疗。
发明简述
发明人意外地发现细胞内的弹性蛋白酶与坏死细胞的死亡有关,并且,对受到侵袭的细胞中上述酶的抑制可以作为一个有效的方法用于治疗和/或预防细胞坏死以及与细胞坏死有关的疾病。
本发明提供一种用于治疗和预防细胞坏死以及与细胞坏死有关的疾病的方法,该方法包括抑制所述细胞中一种或多种弹性蛋白酶的活性。
一方面,上述方法包括给患者施用治疗有效量的一种或多种弹性蛋白酶抑制剂,其中所述抑制剂可以抑制被治疗细胞的细胞内弹性蛋白酶的活性。
本发明还包括一种在体外抑制和预防细胞坏死的方法,包括使有效量的一种或多种弹性蛋白酶抑制剂进入被处理细胞。
发明人还意外地发现对受到侵袭细胞中的弹性蛋白酶的抑制,可以使细胞坏死发生转化,至少是部分转化为凋亡性细胞死亡。所以,在优选的实施方案中,本发明提供了一种治疗和预防细胞坏死以及与细胞坏死有关的疾病的方法,该方法包括:抑制所述细胞中弹性蛋白酶的活性;以及抑制凋亡性细胞死亡。
本发明还涉及用于治疗和/或预防细胞坏死以及相关疾病的药物组合物,其中所述组合物包含治疗有效量的一种或多种物质,该物质可以抑制被治疗细胞中一种或多种弹性蛋白酶的活性。所以,上述药物组合物中包含可以进入被治疗细胞的一种或多种弹性蛋白酶抑制剂,以及一种或多种药学上可接受的辅料。
根据本发明的一个优选实施方案,上述药物组合物还进一步包含一种或多种细胞凋亡的抑制剂。
本发明另一方面还提供一种或多种弹性蛋白酶抑制剂在制备治疗和/或预防细胞坏死以及相关疾病的药物中的用途,其中所述弹性蛋白酶抑制剂能够进入所述细胞。
在一个优选的实施方案中,本发明还要求一种或多种弹性蛋白酶抑制剂和一种或多种细胞凋亡抑制剂联合用于制备治疗和/或预防细胞坏死以及相关疾病的药物中的用途,其中所述弹性蛋白酶抑制剂能够进入所述细胞。
本发明所应用的弹性蛋白酶活性的抑制剂,用于治疗和预防细胞坏死以及相关疾病,都能够进入靶细胞,以便于所述抑制剂在所述细胞中发挥其抑制作用。
优选地,细胞中的坏死可以根据本发明进行治疗或预防,其中的细胞选自:神经细胞,浦肯耶细胞,海马锥体细胞,神经胶质细胞,造血原细胞(例如淋巴细胞和巨噬细胞),肝细胞,胸腺细胞,成纤维细胞,心肌细胞,上皮细胞,支气管上皮细胞,肾小球,肺上皮细胞,角质细胞,胃肠道细胞,表皮细胞,骨和软骨细胞。
优选地,细胞坏死以及与之相关的疾病可以根据本发明进行治疗或预防,其中的疾病选自:神经变性疾病(neurodegenerative disorders),白血球过多症,淋巴瘤,新生儿呼吸窘迫,窒息,嵌顿性疝,糖尿病,结核病,子宫内膜异位症,血管营养不良,牛皮癣,冻伤,铁负荷并发症(iron-loadcomplications),类固醇治疗的并发症,缺血性心脏病,再灌注损伤,脑血管病或损伤,坏疽,褥疮(pressure sore),胰腺炎,肝炎,血红蛋白尿,细菌性败血症,病毒性败血症,烧伤(burns),体温过高(hyperthermia),克罗恩氏病,腹腔疾病(celiac disease),间隔综合症(compartment syndrome),坏死性直结肠炎(necrotizing procolitis),囊性纤维化,类风湿性关节炎,中毒性肾损害(nephrotoxicity),多重硬化症,脊髓损伤,肾小球肾炎,肌营养不良,退行性关节炎,高酪氨酸血症,遗传性代谢疾病,支原体疾病,炭疽感染(anthraxinfection),其他细菌感染,病毒感染,安德森病(Anderson disease),先天性线粒体病,苯丙酮尿症,胎盘梗塞,梅毒,无菌性坏死,无血管性坏死,酒精中毒以及伴随由于被给予和/或自行服用和/或暴露于,可卡因,药物(例如,对乙酰氨基酚,抗生素,阿霉素,非类固醇抗炎药,环孢霉素),化学毒素比如四氯化碳、氰化物、甲醇、乙二醇和芥子气,农业化学药品例如有机磷酸化合物和百草枯(paraquate),重金属(铅,汞),其他战争用有机磷酸化合物所导致的坏死。
在另一个实施方式中,本发明中的组合物和方法通过抑制一种或多种弹性蛋白酶的活性,尤其是其细胞内的活性,用于治疗和/或预防老化,并且可以任选地与细胞凋亡抑制剂和抗老化剂合用。
附图简述
图1显示分别经和不经寡霉素以及抗Fas抗体处理后,观察到的坏死及凋亡的细胞比例。
图2显示U-937细胞分别经和不经3小时的寡霉素以及抗Fas抗体处理后,细胞裂解产物经含明胶基质的凝胶电泳(gelatin substrate gelelectrophoresis)后的结果。
图3显示U-937细胞分别经和不经3小时的0.5mM KCN处理后,细胞裂解产物经含明胶基质的凝胶电泳后的结果。
图4显示含明胶基质的凝胶电泳的结果,该试验表明用KCN处理细胞裂解产物后,代表蛋白酶活性的谱带(B泳道)出现。而当有200μm弹性蛋白酶抑制剂(C泳道)存在时,再用KCN处理后,上述谱带消失。
图5的结果显示弹性蛋白酶抑制剂III作用于由KCN诱导发生坏死的PC-12细胞,所达到的效果。A部分图表化地表现经处理后的细胞中存活、坏死和凋亡的比例。上述比例的具体数值记载在随图后的表格里。B部分显示当弹性蛋白酶抑制剂III存在或不存在时,PC-12细胞经过KCN处理后的存活率。
图6显示当弹性蛋白酶抑制剂III存在或不存在时,经过KCN处理后,存活、坏死和凋亡的U-937细胞的比例。上述比例的具体数值记载在随图后的表格里。
图7注解弹性蛋白酶抑制剂III(B部分)和elastinal(C部分)作用于由Fas诱导发生凋亡/坏死的U-397细胞所达到的效果。
图8注解PC-12细胞经/不经寡霉素和/或STS处理,检测出的坏死和凋亡细胞的百分数。
图9表示弹性蛋白酶抑制剂作用于经STS诱导发生凋亡的PC-12细胞所达到的效果。
图10注解弹性蛋白酶抑制剂作用于经STS诱导发生坏死的PC-12细胞所达到的效果。
图11表示弹性蛋白酶抑制剂作用于经KCN诱导发生坏死的PC-12细胞所达到的效果。
图12注解弹性蛋白酶抑制剂作用于经STS诱导发生坏死的U-937细胞所达到的效果。
优选实施方案详述
本文中术语“坏死”,包括细胞坏死的状态,以及表现出坏死和凋亡特征的中间过渡状态。本文中是术语“弹性蛋白酶”,涉及所述酶的一种或多种形式。
具有抑制弹性蛋白酶特性的化合物,在本文中称作弹性蛋白酶抑制剂,是本领域所公知的,并且被如下述文献所公开:Stein等[Biochemistry 25,p.5414(1986)],Powers等[Biochim.Biophys.Acta.485,p.15(1977)],US4,683,241,US 5,216,022和US 6,159,938.弹性蛋白酶抑制剂可以从例如,Sigma-Aldrich或者Calbiochem-Novabiochem Corpotation购买。
如本发明所述,所用的弹性蛋白酶抑制剂可与一种或多种药学上可接受的载体配制,这些载体是无毒的、惰性的固体、半固体或者液体的充填剂、稀释剂、包封材料或者任何类型的辅助成分。药物组合物可以以任何可接受的方式,优选口服、非肠胃道或者局部地施用于人类和其他哺乳动物。
口服固体剂型包括胶囊剂、片剂、丸剂、粉剂和颗粒剂。这些固体制剂中,活性成分与至少一种惰性的、药学上可接受的辅料或者载体混合,上述辅料或载体例如枸橼酸钠或磷酸二钙,和/或填充剂或增容剂例如淀粉、乳糖、蔗糖、葡萄糖和甘露醇,粘合剂例如羧甲基纤维素和明胶,湿润剂如丙三醇,崩解剂如琼脂、碳酸钙和马铃薯淀粉,吸收剂和润滑剂。该固体制剂可以用本领域公知的方法制备包衣和外壳。
口服液体剂型包括药学上可接受的溶液、乳剂、混悬液和糖浆。该液体制剂中除活性成分外,还含有惰性的稀释剂例如本领域常用的水或者其它溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇和油类。除了惰性稀释剂外,该口服组合物还可以包含辅剂如湿润剂,乳化剂和助悬剂,甜味剂,调味剂和香料。
适合非肠胃道给药的注射制剂可由下列形式提供:药学上可接受的无菌水或者无水溶液剂,分散剂,混悬剂,或者乳剂以及在使用前重新溶解于无菌可注射溶液或分散相的无菌粉末。适合的水的或者非水的载体或者赋形物的例子有水,Ringer’s溶液和等渗的氯化钠溶液。无菌的油类也可以作为合适的分散媒介。注射用配方可以是经灭菌的,例如,经过可以过滤细菌的过滤器,或者在制剂中加入灭菌剂。
如本发明所述,弹性蛋白酶抑制剂的局部或透粘膜剂型可以包括糊剂、乳膏剂、洗剂、凝胶剂、粉剂、溶液和喷雾剂。糊剂、乳膏剂和凝胶剂中除活性成分以外,还可以包含辅料如脂肪、油类、蜡、石蜡、淀粉、纤维素衍生物、聚乙二醇、滑石粉、氧化锌、或者其混合物。粉剂和喷雾剂可以包含辅料如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙以及其混合物。
值得注意的是,弹性蛋白酶抑制剂(并且可选地,抗凋亡剂)局部或透粘膜剂型除了具有医学或药学的作用外,本发明还提供所述组合物作为化妆品试剂的用途。
其他合适的配方可由下列方法制备:将活性成分用脂质体或者生物可降解的聚合基质包裹,或者将活性成分附着在单克隆抗体上。制备脂质体的方法是本领域公知的。
本申请中药物组合物中活性成分的剂量可以变化,只要能为特定的患者提供能足以达到预期治疗目的的量(也就是治疗有效量)的弹性蛋白酶抑制剂。剂型的选择依赖于特定蛋白酶抑制剂的活性、给药的方式、被治疗症状的严重性和患者治疗过程中出现的其他因素。典型的剂量方案为0.1-200mg/kg。
另一方面,本发明还涉及通过抑制细胞内弹性蛋白酶的活性,以及,抑制凋亡细胞死亡的方法来治疗或预防细胞坏死。在本发明这一方面的一个优选实施方案中,对凋亡细胞的死亡的抑制是通过对患者给予治疗有效量的抗凋亡剂来实现的。该抗凋亡剂优选自下列物质:[R]-N-[2-庚基]-甲基炔丙基胺(R-2HMP)、维生素E、维生素D、半胱天冬酶抑制剂和亲水的胆汁盐熊脱氧胆酸。其他本领域公知的抑制凋亡的方法,例如,调节促凋亡蛋白和抗凋亡蛋白的表达,也可以运用于本发明中。这些方法在例如Li等[Acta.Anaesthesiol Sin,38(4),p.207-215(2000)]中描述。
实施例
实验方案
1.体外的坏死模型
十字孢碱和抗Fas抗体诱导的坏死
处于对数生长期的人类前单核细胞U-937细胞在4x105/ml的浓度下接种。之后,细胞被清洗两次,再次接种于不含葡萄糖的RPMI-1640培养基(BeitHaemek,Israel)中经一小时,该培养基已补充2mM丙酮酸盐(Beit Haemek,Israel)和10%经透析的FCS(Gibco,BRL)。
大鼠嗜铬细胞瘤PC-12细胞系持续培养于DMEM培养基(Gibco,BRL),该培养基已补充5%经热灭活的小牛血清,10%经热灭活的马血清和2mML-谷氨酰胺。处于对数生长期的PC-12细胞在24孔板(Cellstar)上,以每个孔中含有1.2x105个细胞的浓度接种。然后,这些细胞被清洗两次,保持于不含葡萄糖的RPMI-1640培养基(Beit Haemek,Israel)中一小时,该培养基已补充2mM丙酮酸盐(Beit Haemek,Israel)和10%经透析的FCS。U-937细胞和PC-12细胞加入寡霉素(Sigma)或不加入寡霉素培养45分钟,之后,细胞用或不用1.25μM十字孢碱(STS)(Sigma)处理,U-937细胞需要另外的7小时,PC-125小时。可选择地,细胞可以经相同的时间用或不用100ng/ml抗Fas抗体(Upstate biotechnology,USA)进行处理。
KCN诱导的坏死
在完全RPMI-1640培养基中培养的U-937细胞和PC-12细胞经过清洗,并被接种于不含葡萄糖的RPMI-1640培养基,如前面所述,细胞用或者不用0.5mM的KCN(Merck,Germany)处理,U-937细胞需要7小时,PC-12细胞需要5小时。
2.弹性蛋白酶抑制剂的测试
200μM弹性蛋白酶抑制剂III(MeOSuc-Ala-Ala-Pro-Val-CMK得自Calbiochem)在加入诱导剂30分钟前加入。抑制剂溶解于DMSO中,浓度为100m M。系统中DMSO最终的浓度为0.2%,并且加入到所有的处理过程中。在另一个试验中,200μM弹性蛋白酶抑制剂(CE1037,Cortech Inc.制造)在诱导剂加入前30分钟给药。该抑制剂溶解于PBS。
3.细胞死亡测定
台盼蓝排除
在每个时间点,细胞活性由台盼蓝排除法(Daniel CP,Parreira A.,et al.Leukemia Res.11:191-196(1987)测定。试验一式两份进行。
凋亡和坏死的形态学上的量化
伴随凋亡或者坏死细胞的死亡,细胞经历形态学上的改变,该变化被检测,如McGahon等[Methods Cell Biol,46:p.153-85(1995)]所述。简要地说,1ml细胞被收集并离心。颗粒在稀释20倍的染料混合物(由100μg/ml吖啶橙和100μg/ml溴化乙锭溶于PBS组成)中重新悬浮,放置在载玻片上,用倒置荧光显微镜观察。每份样品最少计数200个细胞。
细胞裂解产物的制备
4x107个U-937细胞,经过各种诱导剂处理,或者不经过处理,培育三小时后被收集起来,用冰冷PBS清洗两次,以108/ml的浓度在冰冷裂解缓冲液(由50nM pH为7.5的三羟甲基氨基甲烷-盐酸,0.1%NP-40,1mMDTT,100μM亮抑酶肽和100μM甲苯磺酰赖氨酸氯甲酮组成)中重新悬浮。细胞通过使用置于冰上的polytron装置进行破碎,碎片在4℃下用超速离心机离心30分钟,转速为120,000xg。上清液用于进一步研究或者在-70℃下储存。每份样品的蛋白质含量用蛋白质测定法(BioRad)进行测定。
5.电泳
以明胶为基质的电泳根据以往的记载(Distefano J.F.,Cotto C.A.,等Cancer invest.6,487-498,(1988))来进行操作。将100μl等份内含200μg蛋白质的细胞裂解物,加入50μl的0.625M,pH为6.8的三羟甲基氨基甲烷-盐酸缓冲液后,蛋白酶发生可逆性失活,其中该缓冲液还含有2.5%SDS,10%蔗糖和0.03%酚磺酞。然后样品在11%聚丙烯酰胺凝胶中用0.1%共聚明胶进行电泳。电泳后,将凝胶重复三次浸入pH为7.0的、包含2.5%(V/V)Triton X-100的0.1M三羟甲基氨基甲烷-盐酸缓冲液,去除SDS,并使蛋白酶再活化。凝胶被切片,在37℃下在0.1M甘氨酸-氢氧化钠缓冲液中培养过夜,该缓冲液的pH为7.0,其中含有或者不含有100μM TPCK(糜蛋白酶样丝氨酸蛋白酶抑制剂)和100μM elastinal(弹性蛋白酶样丝氨酸蛋白酶抑制剂)。蛋白酶的活性的谱带用品红染色后显影。
结果
1.抗Fas抗体诱导的U-937细胞的凋亡/坏死
图1显示与对照组相比,用抗Fas抗体处理诱导大约60%的凋亡。寡霉素本身是非活性的(inactive),但是加入100ng/ml抗Fas抗体到寡霉素,使凋亡细胞死亡转化为坏死细胞死亡。在这些状况下,大约70%的坏死发生,并且凋亡转回到对照水平。细胞核用吖啶橙和溴化乙锭双重染色后,用荧光显微镜测定分析其形态学。
2.寡霉素存在下由抗Fas抗体诱导的坏死细胞死亡过程中蛋白酶样活 性的诱导作用
U-937细胞保存于不含葡萄糖的基质中,用或不用1μM寡霉素预培养45分钟,经过或不经过100ng/ml抗Fas抗体处理三小时。之后,细胞裂解产物用“试验方案”中描述的方法制备,并且用于以明胶为基质的电泳。图2显示的结果表明,经过抗Fas抗体和寡霉素的处理,导致一条蛋白酶活性谱带(泳道D)的出现。该谱带在未被处理的对照组细胞(泳道A)、用抗Fas抗体处理的细胞(泳道B)或者用寡霉素处理的细胞(泳道C)中都没有发现。当有100μM elastinal(泳道D)存在时该谱带消失,当有100μM TPCK时(泳道D)该谱带不消失。上述现象表明用抗Fas抗体和寡霉素处理时,可诱导弹性蛋白酶样活性,而不诱导糜蛋白酶样活性。
3.由KCN诱导的坏死细胞死亡过程中弹性蛋白酶样活性的诱导
U-937细胞经过0.5mM KCN处理三小时或不经处理后,细胞裂解产物用“试验方案”中描述的方法制备,并且用于以明胶为基质的电泳。图3显示的结果表明,用KCN处理后,导致一条蛋白酶活性谱带(泳道B)出现,该谱带在未经过处理的对照组细胞(泳道A)中未发现。当有100μM的elastinal(泳道B)存在时,该谱带消失,而当有100μM的TPCK(泳道B)时则不消失。上述现象表明用KCN处理时,可诱导弹性蛋白酶样活性,而不诱导糜蛋白酶样活性。
4.弹性蛋白酶抑制剂在坏死细胞死亡过程中对弹性蛋白酶样活性的诱 导所起的作用
U-937细胞经过5mM的KCN处理,或不经过处理。加入200μM的弹性蛋白酶抑制剂(Cortech)并保持3小时,之后,细胞裂解产物用“试验方案”中描述的方法制备,并且用于以明胶为基质的电泳。图4显示的结果表明用KCN处理后,导致一条蛋白酶活性谱带(泳道B)出现,该谱带在未经处理的对照组细胞(泳道A)中未发现。当有200μM的弹性蛋白酶抑制剂存在下给予KCN时(泳道C),该谱带消失。
5.弹性蛋白酶抑制剂III对由KCN诱导的PC-12细胞坏死的预防作用
PC-12细胞暴露于0.5mM的KCN中,与对照组相比,诱导大量坏死细胞死亡。虽然弹性蛋白酶抑制剂III本身是非活性的(inactive),然而加入后,可以显著抑制由KCN诱导的坏死(图5,B)。用台盼蓝排除法测定出相同状况下存活的细胞,可以看出弹性蛋白酶抑制剂III对细胞的保护作用(图5,A)。
6.弹性蛋白酶抑制剂III对KCN诱导的U-937细胞坏死的抑制作用
经KCN处理后的坏死率达到95%,而与之相比,对照组仅为10%。在KCN中加入弹性蛋白酶抑制剂III,显著将坏死率降低至21%,并且使坏死细胞死亡中的22%转化为细胞凋亡。52%的细胞由于该抑制剂的保护而避免了坏死细胞死亡。弹性蛋白酶抑制剂III不会导致任何细胞损伤(图6)。
7.可渗透的与不可渗透的弹性蛋白酶抑制剂对由抗Fas抗体诱导的坏 死的抑制作用的比较
图7A显示的是由抗Fas抗体诱导的凋亡/坏死。在这些状况下,细胞暴露于一种可渗透的弹性蛋白酶抑制剂(Cortech Inc.)。该暴露过程使凋亡和坏死细胞死亡完全消除(图7B)。而不可渗透弹性蛋白酶抑制剂-elastinal则在该系统中没有这样的作用(图7,C)。
8.PC-12细胞中由STS诱导的凋亡/坏死
图8显示与对照组相比,用1.25μM的STS处理诱导约73%的凋亡。寡霉素本身是非活性的(inactive),但是将STS加入寡霉素,使凋亡细胞死亡转化为坏死细胞死亡。在这些状况下,大约70%的坏死发生,而凋亡则回到对照水平。细胞核用吖啶橙和溴化乙锭双重染色后,用荧光显微镜测定分析其形态学。
9.PC-12细胞中弹性蛋白酶抑制剂对STS诱导的凋亡的抑制作用
PC-12细胞暴露于1.25μM的STS中,与对照组相比,诱导大量的凋亡细胞死亡。加入200μM本身是非活性的弹性蛋白酶抑制剂(Cortech,Inc.)后,可以显著地抑制由STS诱导的凋亡(图9)。
10.PC-12细胞中弹性蛋白酶抑制剂对STS诱导的坏死的预防作用
如图10A所示,1.25μM的STS和1μM的寡霉素共同诱导大约70%的坏死。200μM弹性蛋白酶抑制剂本身是非活性的(inactive),然而能完全消除由STS诱导的坏死。在同样的状况下,100μM的弹性蛋白酶抑制剂能显著地将坏死细胞死亡降低至9%,并且使坏死细胞死亡的39%转化为凋亡细胞死亡(图10B)。
11.PC-12细胞中弹性蛋白酶抑制剂对KCN诱导的坏死的抑制作用
PC-12细胞暴露于0.5mM的KCN中,与对照组相比,诱导大量的坏死细胞死亡。加入200μM的本身无活性的弹性蛋白酶抑制剂,可以显著的抑制由KCN诱导的坏死(图11)。
12.U-937细胞中弹性蛋白酶抑制剂对STS诱导的坏死的作用
如图12所示,在寡霉素存在下,用STS处理后,与对照组相比,细胞的存活显著地降低。弹性蛋白酶抑制剂自身有轻微的效果,但是能显著抑制由STS和寡霉素诱导的细胞杀伤。该抑制效果在延长培养的48小时中可以被测定。细胞的生存能力可以用台盼蓝排除法来测定。同样的结果也可以从细胞凋亡中得到(数据未显示)。
Claims (9)
1.一种或多种能够进入被治疗细胞并能抑制所述被治疗细胞中细胞内弹性蛋白酶的酶活性的弹性蛋白酶抑制剂在制备治疗和/或预防细胞坏死以及与其相关的疾病的药物中的用途。
2.根据权利要求1的用途,其中所述一种或多种弹性蛋白酶抑制剂的药物联合一种或多种凋亡抑制剂使用。
3.根据权利要求1和2中任一项的用途,其中所述被治疗的细胞选自下列:神经细胞,神经胶质细胞,造血细胞,淋巴细胞,巨噬细胞,肝细胞,胸腺细胞,肌肉细胞,成纤维细胞,心肌细胞,上皮细胞,肾小球,角质细胞,胃肠道细胞,表皮细胞,骨和软骨细胞。
4.根据权利要求1和2中任一项的用途,其中与细胞坏死相关的疾病选自下列:神经变性疾病,白血球过多症,淋巴瘤,新生儿呼吸窘迫,窒息,嵌顿性疝,糖尿病,结核病,子宫内膜异位症,牛皮癣,冻伤,铁负荷并发症,类固醇治疗的并发症,缺血性心脏病,再灌注损伤,脑血管病或损伤,坏疽,褥疮,胰腺炎,肝炎,血红蛋白尿,细菌性败血症,病毒性败血症,烧伤,体温过高,克罗恩氏病,腹腔疾病,间隔综合症,坏死性直结肠炎,囊性纤维化,类风湿性关节炎,中毒性肾损害,多重硬化症,脊髓损伤,肾小球肾炎,肌营养不良,退行性关节炎,高酪氨酸血症,遗传性代谢疾病,支原体疾病,细菌感染,病毒感染,安德森病,先天性线粒体病,苯丙酮尿症,胎盘梗塞,梅毒,无菌性坏死,无血管性坏死,酒精中毒以及伴随由于被给予和/或自行服用和/或暴露于药物,化学毒素和重金属而致的坏死。
5.一种在体外抑制和预防细胞坏死的方法,包括使有效量的一种或多种能够进入被治疗细胞并能抑制所述被治疗细胞中细胞内弹性蛋白酶的酶活性的弹性蛋白酶抑制剂进入被治疗细胞。
6.一种或多种能够进入被治疗细胞并能抑制所述被治疗细胞中细胞内弹性蛋白酶的酶活性的弹性蛋白酶抑制剂在制备治疗和/或预防老化的药物中的用途。
7.根据权利要求6的用途,其中一种或多种弹性蛋白酶抑制剂的药物还联合一种或多种凋亡抑制剂使用。
8.一种用于治疗和/或预防老化的药物组合物,其中所述组合物包含治疗有效量的一种或多种能够进入被治疗细胞并能抑制所述被治疗细胞中细胞内弹性蛋白酶的酶活性的弹性蛋白酶抑制剂,和药学上可接受的辅料。
9.根据权利要求8的用于治疗和/或预防老化的药物组合物,其还包括凋亡抑制剂和抗老化剂。
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- 2003-03-26 AU AU2003227309A patent/AU2003227309B2/en not_active Ceased
- 2003-03-26 EP EP03744970.9A patent/EP1494698B1/en not_active Expired - Lifetime
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107690429A (zh) * | 2015-04-07 | 2018-02-13 | Ela制药有限公司 | 用于治疗和/或预防细胞或组织坏死的组合物,其特异性靶向组织蛋白酶c和/或cela1和/或cela3a和/或与其结构相关的酶 |
CN107690429B (zh) * | 2015-04-07 | 2022-02-25 | Ela制药有限公司 | 用于治疗和/或预防细胞或组织坏死的组合物,其特异性靶向组织蛋白酶c和/或cela1和/或cela3a和/或与其结构相关的酶 |
Also Published As
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IL148924A0 (en) | 2002-09-12 |
AU2003227309B2 (en) | 2008-09-18 |
ES2443990T3 (es) | 2014-02-21 |
KR20050058283A (ko) | 2005-06-16 |
WO2003079969A2 (en) | 2003-10-02 |
EP1494698A2 (en) | 2005-01-12 |
JP2005526779A (ja) | 2005-09-08 |
US20050288368A1 (en) | 2005-12-29 |
IL148924A (en) | 2015-06-30 |
JP5427336B2 (ja) | 2014-02-26 |
CA2480302C (en) | 2020-05-19 |
JP2010189438A (ja) | 2010-09-02 |
CN1655809A (zh) | 2005-08-17 |
EP1494698B1 (en) | 2013-11-06 |
AU2003227309A1 (en) | 2003-10-08 |
US20120289452A1 (en) | 2012-11-15 |
CA2480302A1 (en) | 2003-10-02 |
WO2003079969A3 (en) | 2004-01-15 |
EP1494698A4 (en) | 2007-12-26 |
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