CN113905726A - 能够激活蛋白质Klotho产生的包含柠檬酸盐和肉碱的组合物 - Google Patents
能够激活蛋白质Klotho产生的包含柠檬酸盐和肉碱的组合物 Download PDFInfo
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- CN113905726A CN113905726A CN202080039556.5A CN202080039556A CN113905726A CN 113905726 A CN113905726 A CN 113905726A CN 202080039556 A CN202080039556 A CN 202080039556A CN 113905726 A CN113905726 A CN 113905726A
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- Prior art keywords
- citrate
- solution
- pharmaceutical composition
- carnitine
- klotho
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Abstract
公开了一种包含柠檬酸盐和肉碱的组合物,其通过保护肾小管细胞激活蛋白质Klotho的产生,从而降低其氧化应激条件,其可用于器官移植的器官的保护、灌注和再灌注。此外,液体和膳食/营养制剂中的组合物可用于减小由含碘造影剂、抗生素、NSAID或诱导氧化应激的剂诱导的肾毒性。
Description
背景技术
本发明涉及药物领域,更具体地,包含柠檬酸盐和肉碱的组合物,其能够激活肾细胞产生蛋白质Klotho(克洛索),因此能够减少由于外源性和内源性原因引起的氧化应激造成的损伤,这会影响肾脏。该制剂可用于降低由含碘造影剂、抗生素或NSAID和由诱导氧化应激的剂诱导的肾毒性。在器官移植领域内,该组合物可以有效地用于移植器官的保存、灌注和再灌注以及用于防止肾早衰
现有技术
Klotho蛋白质以三种不同的异构体存在:α、βeγ。在人类中,Klothoα由基因KL编码,编码属于β-葡萄糖苷酶家族的酶,主要表达于肾脏远端小管但也在脑脉络丛水平,位于甲状旁腺中、膀胱中、骨骼肌中、胎盘中、甲状腺中以及主动脉和肾动脉的内皮细胞中。(Donate-Correa J,Expression of FGF23/KLOTHO system in human vasculartissue.Int J Cardiol.2013;Lim K,Vascular Klotho deficiency potentiates thedevelopment of human artery calcification and mediates resistance tofibroblast growth factor 23.Circulation.2012,Lim K,α-Klotho Expression inHuman Tissues.JClinEndocrinol Metab.2015)。
Klothoα,简称为Klotho(克洛索),是一种对抗衰老和炎症的蛋白质;主要由肾脏释放的其可溶形式被分泌到血液中,并在整个生物体中发挥保护作用,特别是在心血管和中枢神经系统水平。特别是,可溶形式的αKlotho减少了动脉中的钙化,通过抑制平滑肌细胞上的内皮功能障碍和氧化应激(Mencke R,Hillebrands JL;The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology.Ageing ResRev.2017)保护心脏免于肥大(Xie J,Cardioprotection by Klotho throughdownregulation of TRPC6channels in the mouse heart.Nat Commun.2012)(Donate-Correa J,Klotho in cardiovascular disease:Current and futureperspectives.World J Biol Chem.2015)。
在中枢神经系统水平,αKlotho在促进认知能力以及在对比神经和精神疾患方面发挥着重要作用(Vo HT,.Klotho,the Key to Healthy Brain Aging?BrainPlast.2018)。在动物模型中,这种蛋白质表达的增加已经显示出认知改善和对阿尔茨海默相关神经变性的更大抵抗力。此外,在体外细胞培养物中,已经观察到蛋白质Klotho诱导对氧化应激的更大抵抗力和显著保护免受由蛋白质A13和由与阿尔茨海默病相关的谷氨酸盐诱导的细胞毒性(Cararo-Lopes MM,The relevance ofα-KLOTHO to the centralnervous system:Some key questions.Ageing Res Rev.2017)。
作为FGF23(成纤维细胞生长因子-23)的共同受体,αKlotho的跨膜形式由130kDa组成,而在血清、尿和脑脊液中可以检测到的分泌形式可以由于跨膜蛋白质的裂解和由于可变剪接(形成70kDa的异构体)二者而形成。在肾小管中,膜蛋白质Klotho调节磷酸盐的重吸收并控制维生素D的代谢,参与钙的稳态。相反,分泌形式独立于FGF23受体发挥作用,并通过激素作用沿着血流扩散,调节胰岛素信号的转导(SchmidC,.Growth hormone andKlotho.J Endocrinol.2013)以及具有抗氧化和抗衰老作用的Wnt的转导途径。
没有Klotho的转基因小鼠会出现类似于加速衰老的综合征,伴随过早死亡、骨质疏松、失明、动脉硬化和血管钙化,特别是它们在内皮依赖性血管扩张和血管生成方面表现出缺陷。心血管系统的蛋白质Klotho的保护是通过控制一氧化氮的释放来实现的,一氧化氮是一种已知的抗氧化分子,其对抗血管收缩和内皮功能障碍。与基因敲除小鼠不同,高表达Klotho的小鼠比正常小鼠活得更长。
关于βKlotho,已知它控制脂质代谢、葡萄糖的稳态和胆汁的释放(XuY.Molecular basis of Klotho:from gene to function in aging.Endocr Rev.2015;Yamamoto M,等人Regulation of oxidative stress by the anti-aging hormoneklotho.JBiolChem 2005;Ito S,.Impaired negative feedback suppression of bileacid synthesis in mice lacking beta Klotho.JClin Invest 2005;.Razzaque MS.Therole of Klotho in energy metabolism.Nat Rev Endocrinol 2012)。β的失调与脂肪组织的改变有关(Nies VJ,Fibroblast Growth Factor Signaling in MetabolicRegulation.FrontEndocrinol(Lausanne).2016)诸如肥胖。已经注意到由βKlotho调节的棕色脂肪组织、肝脏和肠道微生物群之间存在相互作用(交互作用)(E.Somm等人,β-Klothodeficiency protects against obesity through a crosstalk between liver,microbiota,and brown adipose tissue,JCI Insight.2017)。γKlotho的功能不是很为人知,也有很多争论(Kim JH,.Biological role of anti-aging protein Klotho.JLifestyle Med 2015)。众所周知,在健康个体中,Klotho的平均血清值为约472pg/ml(Pedersen L,Soluble serum Klotho levels in healthy subjects.ClinBiochem.2013),而随着年龄的增长,在慢性肾病患者中、心血管疾病或糖尿病受试者中该值大幅下降。特别是,已经观察到可溶Klotho的水平与血清肌酐呈负相关。关于女性/男性对血浆Klotho正常水平的影响仍有很多争论(Yamazaki Y,Establishment of sandwichELISA for soluble alpha-Klotho measurement:Age-dependent change of solublealpha-Klotho levels in healthy subjects.BiochemBiophys Res Commun.2010)。
不同的研究已经测试了可以增加Klotho释放的因素,并导致确定要采用的药物、天然化合物或生活方式。这些包括例如在糖尿病或糖尿病肾病的动物模型中静脉内给药的ACE抑制剂(雷米普利)(Zanchi C,Renal expression of FGF23 in progressive renaldisease of diabetes and the effect of ACE inhibitor.PLoS One.2013)(EltablawyN,Vitamin D protection from rat diabetic nephropathy is partly mediatedthrough Klotho expression and renin-angiotensin inhibition.ArchPhysiolBiochem.2018)、益生菌因子诸如在衰老小鼠模型中作为膳食补充剂进行评估的嗜酸乳杆菌或两歧双歧杆菌(Kaushal D,Probiotic Dahi containing Lactobacillusacidophilus and Bifidobacteriumbifidum alleviates age-inflicted oxidativestress and improves expression of biomarkers of ageing in mice.MolBiolRep.2012)、胰岛素(Chen CD,Insulin stimulates the cleavage and release of theextracellular domain of Klotho by ADAM10 and ADAM17.Proc Natl AcadSci U SA.2007)其对在猴肾细胞的效果在体外分析。
一些化合物,诸如活性炭,能够通过螯合尿毒症毒素(诸如例如硫酸吲哚酚)来起作用,其减少klotho的释放,这在不同的研究中已经证明是有效的(Lekawanvijit S,Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducingcirculating levels of a non-dialysable uremic toxin,indoxylsulphate.PLoSOne.2012)。
最后,通过膳食补充维生素D获得了对比结果,尤其是在透析患者中(PriéD,Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involvingthe FGF23/Klotho system.Clin J Am Soc Nephrol.2010;Seibert E,Influence ofcholecalciferol supplementation in hemodialysis patients on monocyte subsets:a randomized,double-blind,placebo-controlled clinical trial.NephronClinPract.2013)。
体育锻炼被示出是能够稳定增加循环Klotho水平的主要因素之一(Avin KG,Skeletal muscle as a regulator of the longevity protein,Klotho.FrontPhysiol.2014)。
国际专利申请no.WO2018098375公开了klotho重组蛋白。
韩国专利申请no.KR20170111384公开了包含klotho的组合物,用于降低药物他克莫司诱导的肾水平毒性。
中国专利申请no.CN107438423公开了含有klotho的组合物,用于激活长寿基因。
加拿大专利申请no.CA3025461公开了蛋白质klotho的各种治疗应用。
美国专利申请no.US2018289306公开了klotho作为肾损伤的生物标志物的用途。
美国专利申请no.US2018037868公开了表达klotho的转基因间充质干细胞。
中国专利申请no.CN105838661公开了该基因的遗传修饰用于肾脏异源移植的用途。
以色列专利申请no.IL201880和美国专利申请no.US2012172314和US2012232024公开了用于治疗癌症的含有klotho的药物制剂。
日本专利申请no.JP2001072607公开了一种包含载体的药物组合物,该载体含有编码蛋白质αklotho的基因KL,其可以保护内皮免受高血压和动脉粥样硬化。
中国专利no.CN104826164公开了一种含有蛋白质Klotho或GDNF的人造血管。
中国专利申请no.CN102961739、CN107148215、CN107148215、CN106342787、CN106035316,以及美国专利申请no.US2018070582、US2017265456、US2017265456、US2016302406、US2017265456;新加坡专利申请no.SG10201709595和SG10201709595,以及日本专利申请JP2017186295、JP2017061531、JP2017057184、JP2017186295,国际专利申请no.WO2015152429公开了用于移植器官保存的溶液。
国际专利申请公开no.WO02/102149公开了一种用于等待移植器官的保存、维护和灌注的溶液,包括:钾、一酸磷酸盐、二酸磷酸盐、离子、氯化物、钠和碳酸氢盐的平衡等张溶液;50-250mM的葡萄糖;0.2-20mM的烷酰基L-肉碱或其生理学上可接受的盐;1-100mM的L-肉碱或其生理学上可接受的盐;以及(e)水,其中肉碱优选作为柠檬酸盐存在。该溶液还可含有抗氧化剂,诸如甘露醇。
美国专利申请公开no.US2018070582公开了一种用于器官保存的溶液,包括:胶体,诸如葡聚糖或聚乙二醇;具有pH缓冲特性的缓冲化合物诸如柠檬酸钠,具有防水特性的组分诸如甘露醇,至少一种维生素,至少一种电解质,能量供应系统的至少一种组分,用于形成抗氧化剂的至少一种底物,一种或多种氨基酸诸如肉碱。特别地,它公开了两种标准的HTK保存组合物,其包含甘露醇和ES2,其包含柠檬酸钠、肉碱和防水剂,所述防水剂选自棉子糖、海藻糖和乳糖酸。
科学出版社Mark D Kay等人,“NormothermicHypothermicFlush Using a NovelPhosphate-Free Preservation Solution(AQIX)in Porcine Kidneys”,外科研究杂志,171(1)275-282,公开了称为AQIX、高渗柠檬酸盐(HOC)和威斯康星大学(UW)的器官溶液。
科学出版社Ren Hany Tolba,“Improved Preservation of Warm Ischemia-Damaged Porcine Kidneys after Cold Storage in Ecosol,a Novel PreservationSolution”,移植年鉴,20,233-242,比较了两种保存溶液:包含柠檬酸肉碱的Ecosol和包含甘露醇的HTK。
中国专利no.CN 109 549 032公开了一种功能性减肥饮料,其包括孔雀石茶16-20%、L-肉碱8-20%、抗性糊精1-3%、甜味剂8-10%、浓缩甜橙汁3-5%、柠檬酸0.02-0.04%、苹果酸0.02-0.04%、复合维生素,其中B1为0.002-0.004%0,B6为0.0008%0-0.0016%0以及B12为0.00008%0-0.0002%0,其中甜味剂为多元醇诸如木糖醇、麦芽糖醇、山梨糖醇、甘露醇和乳糖醇。
技术问题
肾小管细胞是释放Klotho的主要来源,其对不同的身体部位具有多种有益的抗衰老、抗纤维化和抗炎作用。
在损伤或细胞衰老的情况下,肾小管会显著减少Klotho的产生,其无法再发挥其基本的抗衰老功能。
由于其作为血液过滤器的功能,肾脏构成了指定用于净化生物体的器官,因此会由于穿过它的物质而受到潜在损伤。在对肾脏生理最有害的外源性物质中,有一些药物和/或其代谢物、放射学中使用的造影剂和抗生素。
本发明的发明人已经鉴定并测试了能够保护肾脏上皮细胞中蛋白质Klotho的产生,防止其合成和释放受到抑制的物质;这种保护作用于不同的有毒小管物质,诸如肾毒性物质、引起氧化应激的剂和含碘造影剂。
其他情况,诸如脓毒症或外科手术诸如肾移植,会急剧地并突然地降低肾功能,导致与高死亡率相关的严重病理状况,定义为急性肾损伤。
脓毒症是一种临床综合征,其特征是由于机体的异常免疫响应引起的全身性炎症,可演变为急性肾损伤。已经证明,在脓毒症过程中Klotho的急剧失调决定了多器官功能障碍的发生率和死亡率的增加(Jorge LB,Klotho deficiency aggravates sepsis-related multiple organ dysfunction.Am J Physiol Renal Physiol.2019;Jou-Valencia D,Renal Klotho is Reduced in Septic Patients and Pretreatment WithRecombinant Klotho Attenuates Organ Injury in Lipopolysaccharide-ChallengedMice.Crit Care Med.2018)。
迄今为止,肾移植代表了晚期肾病患者的首选治疗策略,在透析方面提供更好的生活质量。然而,仍然有许多晚期移植失败的病例,主要是由于捐赠和移植过程中不可避免的事件,诸如缺血性损伤/再灌注,以及由于所用器官的质量差。
事实上,活体捐赠的短缺迫使移植界将脑死亡或心脏死亡后的移植供体视为潜在的候选者,最近又扩大了纳入标准,同时考虑了边缘供体(扩展标准供体):患有高血压、心血管并发症或血清肌酐大于1.5mg/ml)的那些老年人。
面对这些病症,其特征在于包括血流动力学改变、促炎响应和氧化应激的复杂生理病理学,本发明提供了能够增加Klotho肾脏产生的化合物,这导致肾功能参数或要移植的器官质量的改善。
上述技术问题是通过提供一种由生物体内源性产生并参与正常细胞代谢的天然物质组成的组合物来解决的。
本发明的发明人还对包括现有技术中所有那些可获得的单个组分的浓度区间进行了有目的的选择,以验证并获得这些组分组合的出乎意料的和令人惊讶的协同效应,其中相对于单个组分所产生的叠加效应,这些组分的组合显示出更大的协同效应。
发明目的
通过提供一种药物组合物来解决上述技术问题,该药物组合物包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合。
本发明的另一目的是一种药物组合物,其包含作为活性成分的柠檬酸盐、肉碱以及任选地和另外的至少一种多元醇和合适的药理学上可接受的赋形剂的组合。
本发明的另一目的是液体形式的药物组合物,其包含作为活性成分的柠檬酸盐和肉碱以及任选地和另外的至少一种多元醇的组合,所述多元醇添加到用于移植器官的保存和/或保护溶液和/或用于移植器官的灌注和/或再灌注溶液中。
本发明的目的是用于减小肾毒性物质诱导的肾损伤的用途的上述组合物。
本发明的目的是液体形式的上述组合物,其用作用于预防和/或减少肾毒性物质诱导的肾损伤的输注溶液的用途。
本发明的目的是液体形式的所述组合物,其用作移植器官的保存和/或保护溶液的用途和用作移植器官的灌注和/或再灌注溶液的用途。
另一目的是固体形式的所述组合物,其构成用于预防和/或减少肾毒性物质诱导的肾损伤的膳食/营养产品。
参考附图和所提供的实验数据,本发明的其他特征将从以下详细描述中变得清楚。
附图说明
图1示出了体外培养模型以及用于测试化合物以及柠檬酸盐和肉碱浓度的条件,能够在生理基础条件和肾毒性损伤后增加RPTEC(肾小管细胞)上清液中Klotho的水平。
图2示出了在用柠檬酸盐和/或肉碱预处理12小时后,通过用H2O2刺激暴露于氧化应激6小时后,原代小管细胞上清液中αKlotho的释放结果。
图3示出了在用柠檬酸盐和/或肉碱预处理12小时后,暴露于碘克沙醇(商品名威视派克,一种含碘造影剂)6小时后,原代小管细胞上清液中αKlotho的释放结果。
图4示出了在用柠檬酸盐和/或肉碱预处理12h后,暴露于硫酸庆大霉素(抗生素)诱导的小管损伤6h后,原代小管细胞培养物上清液中αKlotho的释放结果。
图5示出了对源自脐带的原代内皮细胞(HUVEC)培养物进行的用于KL基因转录(α-Klotho蛋白质)的实时PCR的结果。
图6示出了MTT测试的结果,在用5mM浓度的柠檬酸盐和/或肉碱预处理12小时后,在原代肾小管细胞培养物中观察到的细胞增殖增加。
具体实施方式
本发明涉及一种药物组合物,包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合。
或者,包含作为活性成分的肉碱以及合适的药理学上可接受的赋形剂的组合的药物组合物可进一步包含至少一种多元醇。
优选地,多元醇选自由以下组成的组:赤藓糖醇、山梨糖醇、甘露醇、麦芽糖醇、异麦芽酮糖醇、乳糖醇、聚葡萄糖醇、木糖醇。
药物组合物可根据应用配制成液体或固体形式。
固体形式可以是片剂、丸剂、硬胶囊、粉末、颗粒、栓剂。
本发明涉及一种能够刺激肾小管和内皮细胞产生蛋白质Klotho的药物组合物,包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合。
优选地,肾细胞是小管细胞和/或内皮细胞。
本发明涉及一种药物组合物,包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合,用于减小肾毒性物质诱导的肾损伤。
本发明的另一目的是液体形式的组合物,该组合物包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合,用作移植器官的保存和/或保护溶液的用途。
本发明的另一目的是液体形式的组合物,该组合物包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合,用作移植器官的灌注和/或再灌注溶液的用途。
本发明的另一目的是液体形式的组合物,该组合物包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合,用于预防和/或减少肾毒性物质诱导的肾损伤。
本发明的另一目的是固体形式的组合物,该组合物包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合,用于构成预防和/或减少肾毒性物质诱导的肾损伤的膳食/营养产品。
肾毒性物质选自由以下组成的组:含碘造影剂、肾毒性抗生素、抗炎NSAID和诱导氧化应激的剂。
固体形式可优选为片剂、丸剂、硬胶囊、粉末、颗粒、栓剂。
诱导氧化应激的剂选自由以下组成的组:氧自由基、过氧化氢(H2O2)、活性氮。
氧自由基(活性氧,ROS)是指伴随之后的单电子还原导致分子氧转化为水的所有中间分子。例如,超氧阴离子(O2·-)的形成导致H2O2的释放;例如羟基自由基(HO-)是一种高反应性分子,它是从具有强氧化能力的H2O2开始形成的,并构成主要负责组织中过氧化过程初始阶段的剂。
优选地,活性氧选自由以下组成的组:超氧阴离子、羟基自由基。
当细胞内高水平的超氧阴离子和H2O与一氧化氮反应时形成活性氮(RNS)。
优选地,活性氮选自由以下组成的组:一氧化氮、过氧化亚硝酸盐、二氧化氮、三氧化氮。
例如,膳食/营养产品可以在放射学研究诸如例如CT扫描之前给药以减小含碘造影剂的肾毒性作用,设想CT扫描使用含碘造影剂,众所周知含碘造影剂具有肾毒性。
例如,膳食/营养品可以与肾毒性抗生素或抗炎NSAID联合给药以减小其肾毒性作用。
组合物的液体形式可以在放射学研究诸如例如CT扫描之前给药以减小含碘造影剂的肾毒性作用,设想CT扫描使用含碘造影剂,众所周知含碘造影剂具有肾毒性。
组合物的液体形式可以与肾毒性抗生素或抗炎NSAID联合给药以减小其肾毒性作用。组合物的液体形式可以用作移植器官的保存和/或保护溶液。
组合物的液体形式可以用作移植器官的灌注和/或再灌注溶液。
组合物的液体形式也可以用于静脉或动脉输注的器官预采集步骤。
根据本发明的液体形式的组合物可以用作在灌注机器内移植器官的灌注溶液。
柠檬酸钠优选以以下的形式使用:柠檬酸二钠、柠檬酸一钠和柠檬酸三钠盐。
柠檬酸盐的浓度优选包括在0.25和10mM之间。
柠檬酸盐的浓度优选包括在2.5mM和5mM之间。
更优选地,柠檬酸盐的浓度等于2.5mM。
更优选地,柠檬酸盐的浓度等于5mM。
L-肉碱的浓度优选包括在2.5mM和5mM之间。
更优选地,L-肉碱的浓度等于2.5mM。更优选地,肉碱的浓度等于5mM。
甚至更优选地,包含浓度等于5mM的柠檬酸盐和浓度等于5mM的肉碱的药物组合物。
根据本发明的组合物含有与活性成分一起的至少一种合适的载体或药理学上可接受的赋形剂,其根据要获得的制剂和形状可以是佐剂,其可以由本领域技术人员基于他们的平均知识来选择。
可以将液体形式的组合物添加到现有技术已知的用于移植器官的保存和/或保护和/或灌注和/或再灌注溶液中,这可以由本领域技术人员基于要保存、保护、灌注或再灌注的器官来合适地选择。
所述溶液的实例描述于Guibert EE等人,2011,Organ Preservation:CurrentConcepts and New Strategies for the Next Decade,Transfus Med Hemother,38(2):125–142和O'Callaghan J,Leuvenink H,Friend P,Ploeg R.Kidney Preservation,Chapter 9in:Kidney Transplantation,Principles and Practice 7thEdition.Saunders.Eds Peter J Morris and Stuart J Knechtle.p130-141。
或者,例如,含有碳酸氢钠、磷酸二氢钾、磷酸氢二钾三水合物、氯化钾的溶液,称为Eurocollins(欧洲柯林)溶液。
或者,例如,含有钠、钾、镁、钙、酮戊二酸/谷氨酸、组氨酸、甘露醇和色氨酸的溶液,称为组氨酸-色氨酸-酮戊二酸HTK溶液。
或者,例如,含有钾、钠镁、柠檬酸盐或HEPES的溶液,称为马歇尔(Marshall)溶液或HOC溶液。
或者,例如,含有谷胱甘肽、甘露醇、乳糖酸、谷氨酸、氢氧化钠、氯化钙二水合物、氯化钾、氯化镁六水合物、组氨酸的溶液,称为施尔生溶液。
或者,例如,含有钾离子、钠离子、镁离子、硫酸根离子、二磷酸盐、棉子糖、乳糖酸、聚乙二醇、谷胱甘肽、别嘌呤醇、腺苷的溶液,称为Institute Georges Lopez溶液或IGL溶液。
实施例
在体外模型中,肾原代小管上皮细胞(RPTEC)被置于培养物中,并经受暴露于含有柠檬酸钠盐(柠檬酸三钠)和L-肉碱的不同溶液中。测试的浓度区间为:0.1-50mM的柠檬酸钠和0.1-20mM的L-肉碱。
图1中示意性地示出了体外模型,该模型能够测试化合物以及柠檬酸盐和肉碱的浓度,能够在生理基础条件和肾毒性损伤后增加RPTEC上清液中Klotho的水平。
结果表明,在5mM浓度的柠檬酸钠和L-肉碱下暴露12小时后,原代小管细胞培养物上清液中αKlotho的释放增加,如图2中所示。
然后验证了这种增加在以下不同的肾毒性损伤后是否也保持不变:诸如H2O2诱导的氧化应激,如图2中所示;暴露于含碘造影剂,如图3中所示;暴露于肾毒性抗生素,诸如硫酸庆大霉素,如图4中所示。
图2示出了在用柠檬酸盐和/或肉碱预处理12小时后,通过用H2O2刺激暴露于氧化应激6小时后,原代小管细胞培养物上清液中αKlotho的释放增加的图表,所述H2O2处于0.1mM的浓度,即能够诱导Klotho统计学显著减少的最低浓度。还测试了等于0.1、0.2、0.5至1mM的H2O2浓度。
5次独立实验的P-值通过t-检验(未配对)计算,P值<0.05和**P值<0.01是相对于H2O2的条件计算的,如图中虚线所指示。按照制造商的说明,使用商业测试ELISA Ibl代码277789进行可溶性aKlotho分析。
所指示的相关条件的Klotho值(pg/ml)如下表1中示出:
表1
同时暴露于柠檬酸盐和肉碱导致协同效应,即这两种物质的组合效应大于单独考虑的柠檬酸盐或肉碱增加的总和,如表1中的数值所示。
图3示出了在用柠檬酸盐和/或肉碱预处理12小时后,暴露于含碘造影剂碘克沙醇(商品名威视派克)6小时后,原代小管细胞上清液中αKlotho的释放结果。
所用造影剂的浓度为50和100mg/ml;该图示出了与比100mg/ml更高浓度相关的数据。*P值<0.05;**P值<0.01,与仅使用碘克沙醇造影剂的条件相比,如虚线所指示。与基础条件相比,碘克沙醇诱导Klotho的急剧减少。
相关条件的Klotho值(pg/ml)如下表2中示出:
表2
在碘克沙醇的存在下,同时暴露于柠檬酸盐和肉碱产生协同效应,即这两种物质的组合效应大于单独考虑的柠檬酸盐或肉碱增加的总和,如表2中的数值所示。
图4示出了在用柠檬酸盐和/或肉碱预处理12小时后,暴露于肾毒性抗生素硫酸庆大霉素6小时后,原代小管细胞上清液中αKlotho的释放结果。
测试浓度为0.1-1-10mM,图表中指示了10mM的浓度。*P值<0.05;**P值<0.01,与仅使用硫酸庆大霉素的条件相比,如虚线所指示。通过柠檬酸盐和肉碱的共同孵育获得的Klotho水平的增加是协同的,如下表3的数值所示。
表3
使用ELISA Ibl测试进行可溶性αKlotho分析。
肾脏是人体血管最丰富的器官之一;因此测试了该化合物对人内皮细胞的影响。图5示出了在暴露于含有柠檬酸盐和/或肉碱的制剂24小时后,通过原代内皮细胞培养物(HUVEC,人脐静脉内皮细胞)增加KL(编码蛋白质αKlotho)的基因表达水平的图表。因此,该化合物对内皮细胞没有毒性作用,并表现出与在小管细胞中发生的相同的诱导Klotho基因转录的能力。
3次独立实验的P-值通过t-检验(未配对)计算,P值(*p<0.05)是相对于基础条件计算的。αKlotho的转录的基因表达的分析是通过实时PCR进行的,特别是SYBR green测定(使用SsoAdvancedTMUniversalGreen Supermix),量化是通过软件Light Cycler96(Roche)进行的,用方法2-DDCT将值1分配给基础条件。
图6示出了在用5mM浓度的柠檬酸盐和/或肉碱预处理12小时后,在原代肾小管细胞培养物中观察到的细胞增殖增加(白色背景条)。该图表还示出了在将小管细胞暴露于0.5mM的H2O2细胞毒性浓度后观察到的细胞活力显著降低(灰色背景条)。只有同时暴露于柠檬酸盐和肉碱,才能提供从H2O2诱导的氧化损伤中恢复细胞活力的协同效应,即这两种物质的组合效应大于单独考虑的柠檬酸盐或肉碱增加的总和。因此,示出了在5mM的浓度下,这两种物质同时存在且不单独存在,在基础条件下和氧化应激后均能显著增加细胞活力(MTT测试)。
Claims (17)
1.药物组合物,包含作为活性成分的柠檬酸盐和肉碱以及合适的药理学上可接受的赋形剂的组合,其中所述柠檬酸盐以包含在0.25和10mM之间的浓度存在并且肉碱以包含在2.5mM和5mM之间的浓度存在。
2.根据权利要求1所述的药物组合物,其中,所述柠檬酸盐的浓度等于2.5mM或5mM。
3.根据权利要求1所述的药物组合物,其中,所述肉碱的浓度等于2.5mM或5mM。
4.根据权利要求1所述的药物组合物,其中,所述柠檬酸盐的浓度等于5mM并且所述肉碱的浓度等于5mM。
5.根据权利要求1所述的药物组合物,还包含至少一种多元醇。
6.根据权利要求5所述的药物组合物,其中,所述多元醇选自由以下组成的组:赤藓糖醇、山梨糖醇、木糖醇、甘露醇、麦芽糖醇、异麦芽酮糖醇、乳糖醇、聚葡萄糖醇。
7.根据权利要求1所述的药物组合物,其中,所述柠檬酸钠是以下的钠盐的形式:柠檬酸二钠、柠檬酸一钠和柠檬酸三钠。
8.根据权利要求1-7所述的药物组合物,配制成液体或固体形式。
9.根据权利要求1所述的药物组合物,其中,所述固体形式选自由以下组成的组:片剂、丸剂、硬胶囊、粉末、颗粒、栓剂。
10.根据权利要求8所述的液体形式的药物组合物,添加到用于移植器官的保存和/或保护和/或灌注和/或再灌注溶液中。
11.根据权利要求10所述的液体形式的药物组合物,其中,所述用于移植器官的保存和/或保护和/或灌注和/或再灌注溶液选自由以下组成的组:Steen溶液、Eurocollins溶液、威斯康星大学溶液、组氨酸-色氨酸-酮戊二酸溶液、马歇尔溶液、施尔生溶液、Institute Georges Lopez溶液。
12.根据权利要求8、10-11所述的液体形式的组合物,用作移植器官的保存和/或保护溶液的用途。
13.根据权利要求8、10-11所述的液体形式的组合物,用作移植器官的灌注和/或再灌注溶液的用途。
14.根据权利要求1-9中任一项所述的药物组合物,用于预防和/或减少肾毒性物质诱导的肾损伤的用途。
15.根据权利要求14所述用途的组合物,其中,所述肾毒性物质选自由以下组成的组:含碘造影剂、肾毒性抗生素、抗炎NSAID和诱导氧化应激的剂。
16.根据权利要求15所述用途的组合物,其中,所述诱导氧化应激的剂选自由以下组成的组:活性氧、过氧化氢、活性氮。
17.根据权利要求10-11所述的液体形式的组合物,用作在灌注机器内移植器官的灌注溶液的用途。
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US (1) | US20220241235A1 (zh) |
EP (1) | EP3976006A1 (zh) |
JP (1) | JP2022535801A (zh) |
KR (1) | KR20220015428A (zh) |
CN (1) | CN113905726A (zh) |
AU (1) | AU2020281493A1 (zh) |
CA (1) | CA3141666A1 (zh) |
IT (1) | IT201900007446A1 (zh) |
WO (1) | WO2020239459A1 (zh) |
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- 2020-05-14 JP JP2021571471A patent/JP2022535801A/ja active Pending
- 2020-05-14 CA CA3141666A patent/CA3141666A1/en active Pending
- 2020-05-14 EP EP20724851.9A patent/EP3976006A1/en active Pending
- 2020-05-14 US US17/613,390 patent/US20220241235A1/en active Pending
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Also Published As
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WO2020239459A1 (en) | 2020-12-03 |
KR20220015428A (ko) | 2022-02-08 |
EP3976006A1 (en) | 2022-04-06 |
JP2022535801A (ja) | 2022-08-10 |
US20220241235A1 (en) | 2022-08-04 |
AU2020281493A1 (en) | 2021-12-02 |
IT201900007446A1 (it) | 2020-11-29 |
CA3141666A1 (en) | 2020-12-03 |
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