CN114558016A - 扎普司特在高尿酸血症及尿酸性肾病中的应用 - Google Patents
扎普司特在高尿酸血症及尿酸性肾病中的应用 Download PDFInfo
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- CN114558016A CN114558016A CN202210222160.5A CN202210222160A CN114558016A CN 114558016 A CN114558016 A CN 114558016A CN 202210222160 A CN202210222160 A CN 202210222160A CN 114558016 A CN114558016 A CN 114558016A
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- Prior art keywords
- uric acid
- zaprinast
- urat1
- hyperuricemia
- nephropathy
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Abstract
本发明提供扎普司特在高尿酸血症及尿酸性肾病中的应用。利用国内外广泛使用的14C尿酸摄取实验来评价扎普司特对URAT1的抑制作用，并构建高尿酸血症小鼠模型评价扎普司特的体内降尿酸效果，构建尿酸性肾病小鼠模型评价扎普司特的肾脏保护作用；从体外发现扎普司特能通过抑制URAT1发挥降尿酸效果从而保护尿酸性肾病，为设计、合成与开发新型的双靶点促尿酸排泄小分子化合物提供设计思路。
Description
技术领域
本发明属于生物医药领域，尤其涉及扎普司特在高尿酸血症及尿酸性肾病中的应用。
背景技术
尿酸为体内嘌呤类物质代谢的最终产物。高尿酸血症(hyperuricemia,HUA)是一种常见的代谢紊乱疾病，其特征是血液中尿酸(uric acid,UA)过多，由尿酸生成过多或排泄不足引起。流行病学研究发现HUA的发病率逐年增加，并呈年轻化趋势。大量研究表明，HUA可以引起痛风、高血压、心血管疾病及肾脏病变等。因此，其预防和治疗具有一定的经济和社会意义。尿酸是人体嘌呤代谢的最终产物，其中70％的尿酸通过肾脏排出，因而肾脏被认为是循环尿酸的重要调节剂。持续的尿酸水平升高容易引发肾小管损伤、间质纤维化、肾小球硬化和尿酸盐结晶沉积，最终导致高尿酸血症性肾病(hyperuricaemic nephropathy,HN)，严重影响疾病预后和患者的生活质量。因此，阐明HUA或者HN的发生机制将有助于提供防治HUA及相关疾病的新策略。
URAT1是近曲肾小管刷状缘侧膜的尿酸-有机阴离子交换蛋白，由有机阴离子编码家族SLC22A12基因编码的一种膜转运蛋白。主要参与尿酸在肾近端小管的重吸收，是维持体内尿酸稳态十分重要的转运体。高尿酸血症动物模型中几乎都能检测到肾脏URAT1表达增强，使用抑制剂降低血尿酸后其表达相应减少，而且当体内尿酸水平升高时，URAT1会由静止状态向激活状态转化。说明尿酸转运体除可通过抑制剂或激动剂改变其功能外，机体存在通过改变转运体表达水平和/或转运状态调节其功能的现象，但是尿酸如何调节尿酸转运体表达和功能目前还不清楚。目前，几乎所有的促尿酸排泄药都集中在URAT1靶点，苯溴马隆和丙磺舒都属于URAT1非选择性抑制剂，只有雷西纳德(Lesinurad)是全球首个上市的特异性URAT1抑制剂。但由于这些药物选择性低，毒副作用大等原因，在一定程度上限制了其临床应用。因此，寻找和开发新的降尿酸药物靶点或者药物显得尤为迫切和重要。
Zaprinast即扎普司特，是一种新型抗变态反应药物，能稳定肥大细胞和嗜碱粒细胞的细胞膜，阻止脱颗粒，从而抑制组胺和5-羟色胺等过敏反应介质的释放，对支气管哮喘、过敏性鼻炎等有较好的治疗作用。近年来，越来越多研究发现扎普司特新的药理作用，如镇痛、抗炎、抗纤维化、舒张血管、影响能量代谢等作用。有研究发现扎普司特可通过抑制cGMP特异性磷酸二酯酶从而改善肾脏炎症及肾纤维化，从而发挥肾保护作用。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。扎普司特具有明显的降尿酸效果，其作用机制与抑制URAT1的转运功能有关，通过减少对尿酸的重吸收，从而促进尿酸从尿液中排出，减轻尿酸对肾脏的损害作用，发挥肾脏保护作用。
为此，本发明第一个方面提出扎普司特在制备抑制URAT1药物中的应用。
本发明的第二个方面提出扎普司特在制备防治高尿酸血症和/或尿酸性肾病的药物中的应用。
在本发明的一些实施方式中，所述扎普司特抑制URAT1。
在本发明的一些实施方式中，所述药物包括扎普司特作为活性成分和药学上可接受的辅料。
在本发明的一些实施方式中，所述药物是以扎普司特作为活性成分，加入药学上可接受的辅料制成。
在本发明的一些实施方式中，所述扎普司特的剂量为1mg/kg/d～15mg/kg/d。
在本发明的一些优选的实施方式中，所述扎普司特的剂量为2mg/kg/d～10mg/kg/d。
在本发明的一些更优选的实施方式中，所述扎普司特的剂量为2mg/kg/d～7mg/kg/d。
进一步地，所述扎普司特的剂量为2mg/kg/d～5mg/kg/d。
在本发明的一些更优选的实施方式中，所述药物的剂型为口服剂型，或者注射剂型。
在本发明的一些更优选的实施方式中，所述口服剂型为片剂、胶囊剂、口服液体剂、颗粒剂或者散剂。
可以理解的是，为了便于用药，可将活性成分扎普司特与任何一种或者几种药学上可以接受的辅料加工成特定的剂型。这些辅料可以是稀释剂(例如淀粉、预胶化淀粉、糊精、蔗糖、乳糖、甘露醇以及微晶纤维素等)、吸收剂(例如硫酸钙、磷酸氢钙、轻质氧化镁以及碳酸钙等)、润湿剂(例如水以及乙醇等)、粘合剂(例如羟丙甲纤维素、聚维酮、淀粉浆以及糖浆等)、崩解剂(例如干淀粉、羟甲基淀粉钠、低取代羟丙基纤维素、泡腾崩解剂以及交联聚维酮等)、润滑剂(硬脂酸镁、滑石粉、氢化植物油、聚乙二醇以及微粉硅胶等)、着色剂(例如二氧化钛、日落黄、亚甲蓝以及药用氧化铁等)、包衣材料(例如丙烯酸树脂、羟丙甲纤维素以及聚维酮等)、溶剂(例如注射用水、乙醇、丙二醇以及甘油等)、酸碱调节剂(例如盐酸、乳酸、氢氧化钠、酒石酸以及酒石酸钠等)、抗氧剂(例如亚硫酸钠、焦亚硫酸钠以及硫代硫酸钠等)、抑菌剂(例如苯酚、苯甲醇以及硫柳汞等)，也可以是等渗调节剂(例如氯化钠以及葡萄糖等)。
可以理解的是，本发明实施方式所述的口服片剂例包括但不限于肠溶片、包衣片、薄膜衣片、糖衣片、分散片、吸吮片、咀嚼片、泡腾片、划痕片、缓释控释剂型缓释片、缓释包衣片、控释片口腔崩解片、含片、口腔贴片等。
可以理解的是，本发明实施方式所述的口服胶囊剂包括但不限于硬胶囊、软胶囊、肠溶胶囊、缓释胶囊、控释胶囊等。
可以理解的是，本发明实施方式所述的口服液体剂包括但不限于口服混悬剂、口服乳剂、胶浆剂、口服液、口服乳液、乳剂、胶体溶液、合剂、露剂、滴剂、混悬滴剂等。
可以理解的是，本发明实施方式所述的口服颗粒剂包括但不限于肠溶颗粒剂、缓释颗粒剂、细粒剂、茶剂、混悬颗粒剂、泡腾颗粒剂等。
可以理解的是，本发明实施方式所述的口服散剂包括但不限于药粉、粉剂、干混悬剂等。
可以理解的是，本发明实施方式所述的注射药物包括但不限于注射液、注射用溶液剂、静脉滴注用注射液、注射用混悬液、注射用无菌粉末、静脉注射针剂、水针、注射用乳剂、粉针剂、针剂、无菌粉针、冻干粉针等。
本发明的有益效果为：
扎普司特能通过抑制URAT1发挥降尿酸效果从而保护尿酸性肾病，为设计、合成与开发新型的双靶点促尿酸排泄小分子化合物提供了设计思路。
附图说明
下面结合附图和实施例对本发明做进一步的说明，其中：
图1为不同浓度扎普司特(A)和阳性对照雷西纳德(B)对URAT1抑制作用的量效关系曲线及其IC50值。
图2为扎普司特对高尿酸血症小鼠的降尿酸效果图。
图3是扎普司特通过URAT1对尿酸性肾病的保护作用图；A为血尿酸水平，B为血肌酐水平，C为小鼠肾组织URAT1的mRNA相对表达量，D-F分别为空白组、尿酸性肾病模型组和扎普司特给药组的HE病理染色图。
附图标记：★表示有肾小管扩张，→表示有肾小管上皮细胞坏死，**表示与空白组比较P＜0.01，***表示与空白组比较P＜0.001；#表示与模型组比较P＜0.05，##表示与模型组比较P＜0.01。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本发明的目的、特征和效果。显然，所描述的实施例只是本发明的一部分实施例，而不是全部实施例，基于本发明的实施例，本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例，均属于本发明保护的范围。
本发明实施例所用到的试剂材料均为市售可得，也可配制而成。以下实施例中试剂材料的配制或制备如下：
卡那霉素和氨苄西林的配制：溶解1g卡那霉素于足量的ddH2O中，最后定容至20mL，过滤除菌，分装成小份于-20℃贮存，使用时将其稀释1000倍。
感受态细胞制备：全式金Trans1-T1感受态，使用前冰上溶解后备用，用于目的基因转化。
液体大肠杆菌培养基的制备：分别称取5g蛋白胨、5g氯化钠、2.5g酵母提取物至500mL洗净的瓶子中，加入超纯水500mL搅拌均匀，121℃高温灭菌20min。灭菌后降温至37℃，加入500μL的卡那霉素(100μL/100mL)摇匀，4℃保存，备用。
固体大肠杆菌培养基的制备：分别称取3g蛋白胨、3g氯化钠、1.5g酵母提取物、4.5g琼脂至500mL洗净的瓶子中，加入超纯水300mL，121℃高温灭菌20min。灭菌结束后将固体培养基放置于室温，在培养基未凝固时加入300μL卡那霉素(100μL/100mL)，摇匀，倒入无菌的培养皿里，凝固后4℃保存，备用。
在本发明中，扎普司特(Zaprinast)，CAS：37762-06-4；
雷西纳德(Lesinurad)，CAS：878672-00-5；
在本发明中，氧嗪酸钾，CAS：2207-75-2；
次黄嘌呤，CAS：68-94-0；
腺嘌呤，CAS：73-24-5。
试验例1扎普司特对URAT1的体外抑制作用
1)pcDNA3.1(+)-EGFP-URAT1重组质粒的构建
选择pcDNA3.1(+)作为表达载体，目的基因序列活性片段为URAT1全长(Gene ID：116085)。在T4-DNA链接酶的作用下，将目的基因片段克隆至pcDNA3.1(+)-EGFP载体上，将质粒转化到大肠杆菌菌株，将菌液均匀涂布到混有抗生素的固体培养基上，37℃培养16h后，挑取单克隆，筛选出含目的质粒的菌株放置于已经制备好的液体培养液中培养，摇菌16h。摇菌后提取质粒，选取样品送去测序做最终的确认。
2)多聚-D-赖氨酸(PDL)包被96孔板
用0.1mg/ml的多聚-D-赖氨酸铺被96孔板24h，然后将多聚-D-赖氨酸弃去，烘箱37℃干燥12h备用。
3)细胞转染
待人胚胎肾细胞(HEK293T细胞)生长融合至90％时，将HEK293T细胞接种到经PDL包被的96孔板中，置于37℃，含5％CO2培养箱中培养18h～24h后，待细胞融合率约70％～80％，进行DNA-脂质体复合物瞬时转染。
具体转染步骤如下：在两个1.5mL的EP管(1号管和2号管)中分别加入25μL减血清培养基(Opti-MEM)，然后在1号管中加入1)中质粒500ng以及1μL的P3000TM混合均匀；在2号管中加入0.75μL的Lipo 3000TM，将上述样品管涡旋10秒，静置5min；再将两管中液体混匀，涡旋10秒，静置20min，均匀滴入至加入有500μL/孔新培养基的孔中，加入量为10μL/孔，置于37℃，含5％CO2培养箱中培养18h～24h。
其中，Opti-MEM培养基含有：4-羟乙基哌嗪乙磺酸(HEPES)，2400mg/L碳酸氢钠，次黄嘌呤，胸腺嘧啶，丙酮酸钠，L-谷氨酰胺，微量元素，生长因子，以及微量的酚红。
4)14C尿酸摄取实验
(1)制备摄取缓冲液
配方为：140mM NaCl、5mM KCl、1mM MgCl2、2mM CaCl2、10mM HEPES、10mM D-glucose配制后，使用0.1M的NaOH调pH为7.4左右，然后用0.22μm微孔滤膜过滤后放置4℃保存备用。
(2)制备含药摄取缓冲液：用DMSO溶解扎普司特粉末得到50mM的母液；用摄取缓冲液稀释，获得所需浓度5μM，10μM，20μM，40μM，80μM，100μM。宜现配现用。
(3)制备同时含14C尿酸和扎普司特的摄取溶液：用摄取缓冲液配制浓度为100μM的14C尿酸溶液，再与溶解于(2)摄取缓冲液的不同浓度的扎普司特溶液等体积混匀，最终得到终浓度为50μM的14C尿酸与不同浓度扎普司特的摄取混合溶液。
(4)14C尿酸摄取实验具体步骤：弃去转染URAT1的HEK293T细胞中的培养基，用摄取缓冲液洗细胞3次，每次200μL。分别加入100μL含不同浓度扎普司特(5μM，10μM，20μM，40μM，80μM，100μM)的摄取缓冲液预孵育15min，预孵育结束后，加入同时含药与尿酸的摄取缓冲液，孵育15min后，立即弃去孔中液体，加入冰冷的DPBS缓冲液清洗细胞3次，每次200μL。最后加入40μL 0.1M的NaOH裂解细胞30min，加入0.2mL液体闪烁液，转移至液体闪烁仪中记录加入羧酸与否对放射值CPM值的变化的影响，并通过非线性拟合计算获得羧酸抑制URAT1的半数抑制浓度(IC50值)。其中抑制率计算公式为：(CPM/CPM0)*100％，其中CPM为同时加入含羧酸的尿酸摄取缓冲液时的放射值，CPM0为仅加入尿酸外液时的放射值，雷西纳德按上述同样操作进行。
图1为不同浓度扎普司特(A)和雷西纳德(B)对URAT1抑制作用的量效关系曲线及其IC50值。
如图1所示，扎普司特以浓度依赖性的方式抑制URAT1，其IC50值为12.22±2.70μM(A)，说明扎普司特是URAT1的抑制剂，阳性药雷西纳德的IC50值为10.54±0.62μM(B)，说明扎普司特对URAT1的抑制效应与雷西纳德相当。
试验例2扎普司特体内降尿酸活性测试
1)实验动物分组
选取体重在20±2g左右的SPF级雄性KM小鼠，按平均体重分成4组，并按照下表1进行分组。所有动物饲养温度控制在24℃～26℃，相对湿度控制在40％～60％，每笼8只。实验前将所有动物饲养在IVC笼盒中适应5天后再正式进行实验。
2)高尿酸血症的小鼠模型建立
除空白对照组外，各组小鼠皮下注射400mg/kg的氧嗪酸钾溶液和灌胃给予600mg/kg的次黄嘌呤(溶剂为0.5％CMC-Na)，空白对照组给予同等体积的0.5％CMC-Na，造模结束后，各给药组则灌胃相应的药物，空白对照组与模型组灌胃等量溶剂。
给药结束4小时后，通过眼眶采血采集各组小鼠血样，室温静置40min后，室温3000g离心10min，取上层血清(仔细分离上清)，使用试剂盒分别测定血清中的尿酸水平。
表1扎普司特体内降尿酸活性测试实验小鼠分组及灌胃情况
各组药物配制及浓度分别为：以0.5％羧甲基纤维素钠(CMC-Na)作为药物溶剂，氧嗪酸钾(40mg/mL)、次黄嘌呤(60mg/mL)、扎普司特(0.2mg/mL)和雷西纳德(0.2mg/mL)。注射均以100μL/10g的体积给药。
图2为扎普司特体内的降尿酸效果图，***表示与空白组比较P＜0.001；#表示与模型组比较P＜0.05，##表示与模型组比较P＜0.01。
如图2所示，扎普司特在剂量为2mg/kg下可显著降低高尿酸血症小鼠的血尿酸，其效果比同等剂量特异性URAT1抑制剂雷西纳德更显著。
试验例3扎普司特通过URAT1对尿酸性肾病小鼠的肾脏保护作用
1)实验动物分组
选取体重在20±2g左右SPF级雄性KM小鼠，按平均体重分成3组，并按照下表2进行分组。所有动物饲养温度控制在24℃～26℃，相对湿度控制在40％～60％，每笼6只。实验前将所有动物饲养在IVC笼盒中适应5天后再正式进行实验。
2)尿酸性肾病小鼠模型的建立
实验过程中小鼠均正常进食与饮水。给药组小鼠每天9:00灌胃给药给予扎普司特5mg/kg，空白对照组与模型组灌胃同等体积的0.5％羧甲基纤维素钠，1小时后(10:00)，除空白对照组外，其余各组小鼠腹腔注射350mg/kg氧嗪酸钾和给予腺嘌呤70mg/kg(溶剂均为0.5％羧甲基纤维素钠)灌胃，空白对照组给予注射同等体积的0.5％羧甲基纤维素钠。本实验一共持续14天，于第14天给药结束后取血并处死小鼠。处死时留取肾脏组织样品一部分浸泡于福尔马林溶液固定，一部分于-80℃保存。
表2扎普司特对尿酸性肾病小鼠的肾脏保护作用测试小鼠分组及灌胃情况
各组药物配制及浓度分别为：以0.5％羧甲基纤维素钠作为药物溶剂，氧嗪酸钾(35mg/mL)、腺嘌呤(7mg/mL)、扎普司特(0.5mg/mL)。注射均以100μL/10g的体积给药。
3)样品处理与测定
血液：将约200μL的血液室温静置40min后，室温3000g离心10min，取上清(仔细分离上清)，于-20℃保存。使用试剂盒测定血清中的尿酸(UA)和肌酐(CR)水平。
肾脏：处死小鼠后，快速分离肾脏组织，并剥去肾膜，右肾置于福尔马林保存用于HE染色，左肾置于-80℃用于测定URAT1基因的表达量。
4)实时荧光PCR法检测肾脏URAT1的表达
通过RT-qPCR法检测小鼠肾脏的URAT1相对表达，其具体步骤如下：称取20mg肾脏组织加入裂解液，剪碎后使用冰浴匀浆机充分匀浆，以12000rpm/min转速离心2min后收集上清液。按照动物RNA提取试剂盒提取RNA，并逆转录成cDNA。按照试剂盒说明书，加入各反应试剂，使用Roche LightCycle480高通量实时荧光PCR仪按qPCR反应程序测定Ct值，使用β-actin作为内参，结果以2-△△Ct计算mRNA的相对表达量。其中URAT1的引物序列URAT1-F:AGCTCTTGGACCCCAATGC,URAT1-R:CTTCAGAGCGTGAGAGTCACACA；β-actin-F:CCCATCTATGAGGGTTACGC,β-actin-R:TTTAATGTCACGCACGATTT。
图3是扎普司特通过URAT1对尿酸性肾病的保护作用图；A为血尿酸水平，B为血肌酐水平，C为小鼠肾组织URAT1的mRNA相对表达量，D-F分别为空白组、尿酸性肾病模型组和扎普司特给药组的HE病理染色图。
图中**表示与空白组比较P＜0.01，***表示与空白组比较P＜0.001；#表示与模型组比较P＜0.05，##表示与模型组比较P＜0.01；★表示有肾小管扩张，→表示有肾小管上皮细胞坏死。
如图3所示，扎普司特可显著降低尿酸性肾病小鼠模型的血尿酸水平(A)及血肌酐水平(B)，HE染色图(D-F)也表明，尿酸性肾病模型(E)可引起小鼠肾脏的肾小管扩张(★标记处)，肾小管上皮细胞坏死(→标记处)，而扎普司特给药(F)可改善肾小管扩张的损害作用，同时扎普司特给药也减少了肾脏中URAT1(C)的mRNA表达水平，说明扎普司特可以通过抑制URAT1的表达促进尿酸排泄，从而减小尿酸对肾脏的损害作用。
上面对本发明实施例作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。
Claims (8)
1.扎普司特在制备抑制URAT1药物中的应用。
2.扎普司特在制备防治高尿酸血症和/或尿酸性肾病的药物中的应用。
3.根据权利要求2所述的应用，其特征在于，所述扎普司特抑制URAT1。
4.根据权利要求1～3任一项所述的应用，其特征在于，所述药物包括扎普司特作为活性成分和药学上可接受的辅料。
5.根据权利要求1～3任一项所述的应用，其特征在于，所述药物中，所述扎普司特的剂量为1mg/kg/d～15mg/kg/d。
6.根据权利要求5所述的应用，其特征在于，所述药物中，所述扎普司特的剂量为2mg/kg/d～10mg/kg/d。
7.根据权利要求5所述的应用，其特征在于，所述药物的剂型为口服剂型，或者注射剂型。
8.根据权利要求7所述的应用，其特征在于，所述口服剂型为片剂、胶囊剂、口服液体剂、颗粒剂或者散剂。
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