CN102438625B - 用于患有猝发患者中的神经保护治疗的包含胞磷胆碱和尿酸的药物组合物 - Google Patents
用于患有猝发患者中的神经保护治疗的包含胞磷胆碱和尿酸的药物组合物 Download PDFInfo
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- CN102438625B CN102438625B CN2010800221644A CN201080022164A CN102438625B CN 102438625 B CN102438625 B CN 102438625B CN 2010800221644 A CN2010800221644 A CN 2010800221644A CN 201080022164 A CN201080022164 A CN 201080022164A CN 102438625 B CN102438625 B CN 102438625B
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Abstract
本发明涉及用于患有猝发的患者的神经保护治疗的包含尿酸和胞磷胆碱的药物组合物。
Description
发明领域
本发明涉及生物医学领域并且特别涉及包含尿酸和胞磷胆碱的新药物组合物及其用于患有猝发(ictus)患者的神经保护(neuroprotective)治疗的用途。
发明背景
卒中(stroke)以后的细胞死亡是兴奋性神经毒性、酸中毒、炎症、氧化应激、梗死周围去极化和凋亡的复杂相互作用的结果。
术语凋亡用作程序性细胞死亡(PCD)的同义词;然而,凋亡最初被定义为PCD以后发生的一组形态学改变。在发育的神经元中,这些改变包括染色质的凝聚和切离和所谓凋亡体的形成。这些改变不同于表征由细胞质细胞器的坏死引起的炎症和线粒体和细胞质膜的破裂的形态学改变。
轻微缺血性损伤一般通过类似凋亡的机理而不是通过坏死产生细胞死亡。凋亡激活因子包括氧自由基、连接到死亡受体、DNA损伤、蛋白酶激活和离子平衡失调。数个实验研究已经显示,抑制凋亡降低缺血性损害的严重性。
胱天蛋白酶的激活是线粒体凋亡的结果。线粒体功能异常和线粒体通透性转变通道的开放可以通过细胞色素C排出到细胞质而导致胱天蛋白酶的激活;然而,存在其它不同的机理,通过所述机理,线粒体功能异常可以促进缺血性神经元死亡。严重损伤的线粒体可能不能保持呼吸和葡萄糖氧化所需的电化学梯度。以这种方式,线粒体功能异常可以通过加剧能量失效而恶化缺血性损伤。线粒体功能异常也产生氧自由基,其损害其它细胞细胞器和DNA。因此,预防线粒体功能异常的治疗可以是比胱天蛋白酶抑制更有力的神经保护策略。
高水平的细胞内Ca2+、Na+和ADP使线粒体产生有害水平的氧活性品种。不同于其它器官,脑特别易受氧活性品种攻击,因为神经元具有相对低水平的内源抗氧化剂。氧自由基的丰富引起细胞大分子的破坏并且它们参与产生凋亡性细胞死亡的信号传导机制。缺血激活氧化氮合酶(NOS)并且增加氧化氮(NO)的生成,其与超氧化物结合而产生过氧亚硝酸盐,一种强力氧化剂。也通过聚(ADP-核糖)聚合酶-1(PARP-1),一种用于DNA修复的酶,的过度激活将NO的产生和氧化应激结合。
在再灌注以后,存在超氧化物、NO和过氧亚硝酸盐生产的增加。在血管附近形成这些自由基在由再灌注所引起的损伤中起重要作用。这些自由基激活金属蛋白酶(MMP),其降解基板中的胶原和层粘连蛋白,破坏血管壁中的完整性并且增加血脑屏障(hematoencephalic barrier,HEB)的渗透性。氧化和nitrosilative应激也激活嗜中性粒细胞和其它白细胞向脑血管系统的补充和迁移,这释放额外增加基板中的降解和血管通透性的酶。这些事件可以在脑内部产生实质性出血,血管原性脑水肿和白细胞浸润。
用于与卒中和颅创伤有关的神经病学和认知性病症的预防治疗的胞磷胆碱的用途是已知的。胞磷胆碱刺激神经元膜结构磷脂的生物合成,如用磁共振光谱法进行的研究中所示。通过该作用,胞磷胆碱改善其它膜机制的功能,诸如离子交换泵和其中安置的受体的功能,其调制对于正确的神经传递是必要的。胞磷胆碱由于它的膜稳定化作用而具有有利于脑水肿再吸收的性质。实验研究已经显示,胞磷胆碱抑制某些磷脂酶(A1、A2、C和D)的激活,减少自由基的形成,预防膜体系的破坏并且保持抗氧化剂防御体系,诸如谷胱甘肽。
胞磷胆碱保持神经元能量储备,抑制凋亡并且刺激乙酰胆碱合成。还在实验上证实,胞磷胆碱在病灶性脑缺血模型中具有预防性神经保护效果。临床测定已经显示,胞磷胆碱显著改善患有急性缺血性卒中的患者的功能进化,这与神经成像试验中的脑缺血性损伤的较少生长一致。在患有颅脑创伤的患者中,胞磷胆碱促进这些患者的恢复并且减少震荡后综合征的持续时间和强度。胞磷胆碱改善注意力和意识水平,并且还对于与脑缺血有关的健忘症和认知与神经病学病症具有积极作用。
尿酸是阻断超氧化物阴离子和氧化氮之间反应的有效力的抗氧化剂,其在将蛋白质的甲状腺素残基亚硝基化时破坏细胞。UA血浆浓度几乎是其它抗氧化剂物质诸如维生素C或E的血浆浓度的10倍高,并且它的抗氧化能力更高。此外,UA防止额外的细胞超氧化物歧化酶降解,所述超氧化物歧化酶是用于正常内皮功能化的必要酶。在海马细胞培养中,UA针对由谷氨酸所致的兴奋性神经毒性损伤来保护,这稳定钙体内稳态并且保留线粒体功能。UA也已经显示了Fenton反应的抑制。
在成年大鼠中,在大脑中动脉阻塞以前2小时或在再灌注以后1小时给药UA显著地减少所致的脑梗死形成,抑制ROS积累并且减少脂质过氧化作用。UA给药在大鼠的病灶性脑缺血的血栓栓塞模型中是神经保护性的,并且该神经保护作用对于由rtPA获得的有利效果是协同的。
存在这样的研究,所述研究显示在猝发时血液中更高水平的尿酸和由所述猝发引起的降低的神经病学严重性之间存在的关系。
作为重要研究的结果,在神经病学领域,本发明人已经证实,尿酸和胞磷胆碱的联合给药对于针对与坏死和凋亡有关的细胞死亡的保护具有协同作用。
发明内容
由此,本发明的第一方面指的是包括治疗有效量的尿酸或它的药用盐和胞磷胆碱或它的药用盐的药物组合物,所述药物组合物用于患有猝发的患者的神经保护治疗。
在本发明中,通过“神经保护治疗”,本发明人指的是终止或减缓导致细胞死亡的生物化学和分子事件的顺序的治疗。
在本发明中,通过“患有猝发的患者”,本发明人指的是随着到达脑的血流的突然改变而已经具有卒中的患者。特别地,本发明人指的是已经具有缺血性猝发或脑梗死、血栓形成、栓塞、出血性猝发、动脉瘤或瞬时性缺血性发作的那些患者。
在更具体的方面中,本发明的药物组合物中的治疗有效量的尿酸或它的药用盐的范围在1-4mg/ml之间。
在更具体的方面中,本发明的药物组合物中的治疗有效量的胞磷胆碱或它的药用盐的范围在2-4mg/ml之间。
在更具体的方面中,本发明的药物组合物包括水性载体。更具体而言,所述水性载体是生理血清。更具体而言,所述生理血清包括0.1%碳酸锂和5%甘露醇.
在更具体的方面中,本发明的药物组合物是通过肠胃外给药施用的,更特别地,本发明的药物组合物是静脉内给药的。
在第二方面中,本发明指的是尿酸或它的药用盐和胞磷胆碱或它的药用盐的协同组合,其用于在患有猝发患者的神经保护治疗的组合疗法中使用。
在更具体的方面中,通过同时给药尿酸或它的药用盐和胞磷胆碱或它的药用盐进行所述组合疗法,在更具体的方面中,通过尿酸和胞磷胆碱的顺序给药进行所述组合疗法。
在本发明中,通过“同时给药”,本发明人指的是在与胞磷胆碱给药的同时进行尿酸的给药。
在本发明中,通过“顺序给药”,本发明人指的是,尿酸的给药在即将给药胞磷胆碱之前,或胞磷胆碱的给药在即将给药尿酸之前。
在更具体的方面中,以溶解在包含0.1%碳酸锂和5%甘露醇的生理血清中在1-4mg/ml之间包含的量进行尿酸或它的药用盐的给药。在更具体的方面中,尿酸是通过肠胃外给药施用的,更特别地,它是静脉内给药的。
在更具体的方面中,以500-2000mg之间包含的量进行胞磷胆碱或它的药用盐的给药。在更具体的方面中,胞磷胆碱是通过肠胃外给药施用的,更特别地,它是静脉内给药的。
在更具体的方面中,通过尿酸和胞磷胆碱的联合给药进行所述组合疗法。
在本发明中,通过“联合给药”,本发明人指的是将尿酸与胞磷胆碱混合。
在更具体的方面中,以本发明药物组合物的形式进行胞磷胆碱或它的药用盐和胞磷胆碱或它的药用盐的联合给药。
附图说明
图1描述尿酸和胞磷胆碱对于由缺糖缺氧(OGD)产生的细胞死亡的影响。所述值是中值+/-SEM(n=4)。显著性:*对比对照,$对比OGD。(C:对照;UA:尿酸;Cit:胞磷胆碱;UA+Cit:尿酸+胞磷胆碱;OGD:缺糖缺氧。
图2显示尿酸和胞磷胆碱对于由OGD诱导的染色质凝聚的影响,(Hoechst染色)。所述值是中值+/-SEM(n=6)。
图3显示胱天蛋白酶-3在OGD以后24小时的活性。所述值是中值+/-SEM(n=2-3)。
发明详述
如Petegnief,V.Saura,J.De Gregorio-Rocasolano,N.,和Paul,S.M.(2001)神经科学(Neuroscience)104,223-234中所描述制备18-天大鼠胎儿胚胎Sprague-Dawley的神经元/神经胶质的混合培养。将细胞悬浮在用10%胎牛血清和100μg/ml庆大霉素补充的极限必需培养基(MEM)中,并放在预先用聚-L-赖氨酸(5μg/ml)(Nunc,Roskilde,丹麦)覆盖的24-孔板上,密度为0.6×106细胞/孔并在含有95%大气/5%CO2的培养箱中在37℃培养。在第4、7和10天(DIV),将体外培养基用补充有B27的MEM部分改变。在11/13DIV中使用培养物。在1.35mM碳酸锂和5%甘露醇中制备11.9mM尿酸。在用OGD(缺糖缺氧)的处理以前60分钟,以100μM的浓度将尿酸添加到培养基,并且它在OGD或常氧(normoxia)期间或以后也存在于相应的HEPES缓冲剂和培养基中。在OGD或常氧以前60分钟、期间和以后,以100μM的浓度添加胞磷胆碱。将培养物单独用尿酸、单独用胞磷胆碱或用这两种药物的组合来处理。将兄弟培养物(Brothercultures)用载体:1.35mM碳酸锂和5%甘露醇处理。
对于用缺糖缺氧(oxygen and glucose deprivation)(OGD)的处理,在含有5%CO2/0.6%O2的缺氧培养箱中在90分钟期间将细胞培养物温育在无葡萄糖的HEPES缓冲剂(10Mm HEPES,pH 7.4,135nM NaCl,5mM KCl,1.8CaCl2,0.62Mm MgSO4)中。在含有95%大气/5%CO2的培养箱中,将对照培养物温育在含有5.5mM D-葡萄糖的相同培养箱中的常氧中。在缺氧或常氧期间结束时,将缓冲剂用没有抗氧化剂的MEM+B27替换,并将细胞返回到含有95%大气/5%CO2的培养箱。
对于乳酸脱氢酶活性测定,在OGD以后3小时30分钟估计细胞死亡,并且接着根据(Wroblewski和LaDue,1995)的方法的修改来测量培养基中释放的乳酸脱氢酶(LDH)活性。在340nm处的0.75NADH中的吸光度减少在存在4.2mM丙酮酸作为底物条件下在磷酸盐缓冲液(50nM,pH7.4)中测量。
对于Hoechst染色,将培养物用PBS洗涤,在4℃在20分钟期间将它们固定在4%低聚甲醛中并用PBS洗涤。随后将细胞用0.1μg/ml浓度的核着色剂Hoechst 33258在30分钟期间温育。在洗涤以后,在紫外线下在荧光显微镜中检验细胞。用analySIS软件进行凋亡核的半定量分析。选择阈值以在凝聚的凋亡核中的光亮着色和健康细胞中的正常核着色之间区别。将对应于凝聚染色质着色(明亮着色)的面积作为每个视野(field)总面积的百分比来计算。结果表示为对照百分比。
为了确定胱天蛋白酶-3活性,根据Valencia,A.和Moran,J.(2001)神经科学研究杂志(J.Neurosci.Res.)64,284-297 Wrobleswski,F.,和LaDue,J.S.(1955)实验生物医学学会志(Proc.Soc.Exp.Biol.Med.)90,210-213,使用100μg蛋白质和25μM Ac-DEVD-AMC作为底物进行测定。在GeminiXS微板分光荧光计(分子探针(Molecular Probles))中,在30分钟期间每2分钟监控由Ac-DEVD-AMC(激发/发射380/460nm)的分裂(split)生成的AMC的荧光。将酶活性作为荧光/mg蛋白质/分钟的三角关系(triangle)来计算。
用后hoc Bonferroni测试进行方差的单向统计分析(ANOVA)以确定所述组是否显著不同。显著性:***P<0.001,**P<0.01,*P<0.05相对对照.$$P<0.01相对OGD。
实施例
实施例1:尿酸和胞磷胆碱对于用OGD诱导的死亡的影响
缺血性损伤诱导显著的细胞死亡。实际上,对于3小时30分钟的再氧合(reoxigenation),当与常氧条件相比较时,它的乳酸脱氢酶活性增加288%(P<0.001)。如图1中所示,单独用尿酸或单独用胞磷胆碱处理没有增加缺血性条件中的细胞生存力。然而,两种处理的组合容许细胞死亡的显著减少(当与OGD相比时,38%,P<0.01)。这显示用两种化合物一起处理的协同效果。
实施例2:用尿酸/胞磷胆碱的联合处理减少OGD-诱导的染色质凝聚。
因为染色质浓度是凋亡的指标,所以本发明人在缺血性损害以后48小时测量该参数。当相比于常氧时,用OGD处理增加凋亡核的数目。如图2中所示,在存在用尿酸+胞磷胆碱的联合处理时,凋亡核的数目显著减少(P<0.01对比OGD),这显示当它们联合给药时两种化合物的协同作用。
实施例3:用尿酸/胞磷胆碱的联合处理抑制OGD-诱导的胱天蛋白酶-3活性。
因为胱天蛋白酶-3活性可以促进凋亡性死亡,本发明人在我们的模型中在OGD以后24小时测量该蛋白酶的酶活性。初步数据显示,缺血性损伤增加胱天蛋白酶-3活性40%并且用尿酸/胞磷胆碱的联合处理消除该效果,图3显示两种化合物的协同作用。
实施例4:尿酸和胞磷胆碱的药物组合物
Claims (14)
1.治疗有效量的尿酸或它的药用盐和胞磷胆碱或它的药用盐用于制备药物组合物的用途,所述药物组合物用于患有猝发的患者的神经保护治疗。
2.根据权利要求1的用途,其特征在于所述治疗有效量的尿酸或它的药用盐的范围在1-4mg/ml之间。
3.根据权利要求1-2的任一项的用途,其特征在于所述治疗有效量的胞磷胆碱或它的药用盐的范围在2-4mg/ml之间。
4.根据权利要求1-2的任一项的用途,其特征在于所述药物组合物包含水性载体。
5.根据权利要求4的用途,其特征在于所述水性载体是生理血清。
6.根据权利要求5的用途,其特征在于所述生理血清包含碳酸锂和甘露醇。
7.根据权利要求1-2的任一项的用途,其特征在于所述药物组合物是通过肠胃外给药施用的。
8.根据权利要求1-2的任一项的用途,其特征在于所述药物组合物是静脉内给药的。
9.组合疗法中的尿酸或它的药用盐和胞磷胆碱或它的药用盐的协同组合用于制备药物组合物的用途,所述药物组合物用于患有猝发的患者的神经保护治疗。
10.根据权利要求9的用途,其特征在于通过尿酸和胞磷胆碱的同时或顺序给药进行所述组合疗法。
11.根据权利要求9-10任一项的用途,其特征在于以溶解在含有碳酸锂和甘露醇的生理血清中范围在1-4mg/ml之间的量进行所述尿酸给药。
12.根据权利要求9-10任一项的用途,其特征在于以范围在500-2000mg之间的量进行所述胞磷胆碱给药。
13.根据权利要求9-10任一项的用途,其特征在于所述协同组合是经由肠胃外给药而给药的。
14.根据权利要求9-10任一项的用途,其特征在于所述协同组合是静脉内给药的。
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NZ707081A (en) * | 2012-10-30 | 2019-03-29 | Kyowa Hakko Bio Co Ltd | Agent for preventing or improving decline in brain function |
US10709710B2 (en) | 2017-05-09 | 2020-07-14 | Hospital Clinic De Barcelona | Composition comprising uric acid for the treatment treated with mechanical thrombectomy |
EP4173616A1 (en) | 2021-10-29 | 2023-05-03 | Hospital Clínic de Barcelona | Uric acid liposomes |
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CN1181015A (zh) * | 1995-03-06 | 1998-05-06 | 英特纽隆制剂药有限公司 | 使用胞磷胆碱减少梗塞面积 |
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US5827832A (en) * | 1995-03-06 | 1998-10-27 | Interneuron Pharmaceuticals, Inc. | Method of protecting brain tissue from cerebral infarction subsequent to ischemia |
US20060264357A1 (en) * | 1997-04-22 | 2006-11-23 | Zikria Bashir A | Capillary membrane stabilization and reduction of tissue injury through use of biodegradable macromolecules with antioxidants and/or other chemicals |
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2009
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- 2010-03-01 JP JP2012502476A patent/JP5692871B2/ja not_active Expired - Fee Related
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- 2010-03-01 EP EP20100708493 patent/EP2413939B1/en active Active
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CN1181015A (zh) * | 1995-03-06 | 1998-05-06 | 英特纽隆制剂药有限公司 | 使用胞磷胆碱减少梗塞面积 |
Non-Patent Citations (4)
Title |
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Angel Chamorro, et al..uric acid administration for neuroprotection in patients with acute brain ischemia.《medical hypotheses》.2004,第62卷(第2期),摘要. * |
Eduardo Romanos, et al..uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke.《journal of cerebral blood flow & metabolism》.2007,第27卷(第1期),摘要,第17页图1. |
Eduardo Romanos, et al..uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke.《journal of cerebral blood flow & * |
metabolism》.2007,第27卷(第1期),摘要,第17页图1. * |
Also Published As
Publication number | Publication date |
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JP5692871B2 (ja) | 2015-04-01 |
WO2010112113A1 (en) | 2010-10-07 |
CA2757222A1 (en) | 2010-10-07 |
CN102438625A (zh) | 2012-05-02 |
ES2345802B1 (es) | 2011-09-08 |
ES2345802A1 (es) | 2010-10-01 |
US20120108532A1 (en) | 2012-05-03 |
CA2757222C (en) | 2016-08-16 |
EP2413939B1 (en) | 2015-04-22 |
EP2413939A1 (en) | 2012-02-08 |
JP2012522025A (ja) | 2012-09-20 |
ES2543215T3 (es) | 2015-08-17 |
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