CN116672437A - TNF-α在制备缓解顺铂肾毒性及其所致急性肾损伤的药物中的用途 - Google Patents
TNF-α在制备缓解顺铂肾毒性及其所致急性肾损伤的药物中的用途 Download PDFInfo
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Abstract
本发明提供了一种TNF‑α在制备缓解顺铂肾毒性及其诱导的急性肾损伤的药物中的用途。本发明首次证实使用低剂量的TNF‑α进行预处理后，能够显著缓解顺铂的肾毒性，有效减轻顺铂诱导的肾损伤，对于急性肾损伤或肿瘤化疗临床治疗干预措施具有指导作用。
Description
技术领域
本发明属于生物医药领域，具体涉及TNF-α在制备缓解顺铂肾毒性及其所致急性肾损伤的药物中的用途。
背景技术
顺铂是当前临床最有效和最常用的抗肿瘤药物之一，广泛用于膀胱癌、卵巢癌、头颈部鳞癌、睾丸癌、非小细胞肺癌等多种实体肿瘤。然而，顺铂化疗却往往会导致严重的不良反应，包括肾毒性、耳毒性、神经毒性、呕吐等。其中，顺铂肾毒性是限制顺铂在化疗中应用的最主要的因素，即便采用了水合疗法等防护措施，但临床上由于顺铂诱导的肾损伤发生率依然较高。顺铂的疗效与用药剂量成正比，但同时顺铂引起的肾毒性也呈剂量依赖性，因此，顺铂肾毒性限制了顺铂的临床用量和疗效。所以，如何减轻顺铂的肾毒性，预防、缓解其引起的急性肾损伤，更好地发挥顺铂抗肿瘤作用，提高患者化疗质量，是本领域亟待解决的问题。
目前临床上对于顺铂肾毒性的主要防护措施是水化利尿，并以血肌酐、尿素氮等作为顺铂肾毒性的监测指标，在肾功能改变时降低顺铂剂量或者停药。但这种方式相对比较被动，由于肾脏本身的储备力和代偿力，肾功能轻度或早期受损时，血肌酐、尿素氮通常没有变化，当期高于正常值时，说明有效肾单位的60～70％已受到损害(万婷,李连宏.顺铂肾毒性机制及其防护的研究进展[J].中华临床医师杂志(电子版),2013(14):6623-6625.DOI:10.3969/cma.j.issn.1674-0785.2013.14.098.)。因此，采用更加主动的手段来预先保护肾脏，提前预防顺铂带来的肾毒性和肾损伤，具有更加重要的意义。
TNF-α即肿瘤坏死因子，是TNF超家族的配体。它是一种多效细胞分子，在炎症、细胞凋亡和免疫系统发育中起着核心作用。TNF-α由巨噬细胞、单核细胞、中性粒细胞、CD4+T细胞、NK细胞等分泌，属于促炎细胞因子，参与正常炎症反应和免疫反应，可以协同调节其它细胞因子的产生、细胞存活和死亡来协调组织的稳态。
研究发现，顺铂肾毒性与炎症反应有所关联，在顺铂肾毒性小鼠模型中，肾脏的TNF-α表达量增加，并且在使用TNF-α抑制剂或敲除TNF-α基因后，能够显著降低顺铂引发的肾功能不全和组织学损伤。然而，TNF-α对于顺铂的肾毒性会带来何种影响，至今尚未见报道。
发明内容
本发明的目的在于提供TNF-α的一种新用途。
本发明提供了TNF-α在制备缓解肾损伤的药物中的用途。
述肾损伤是药物性肾损伤。
进一步地，上述药物性肾损伤是抗生素类药物、非甾体类抗炎药物、抗肿瘤药物、中药药物、造影剂或利尿剂诱导的肾损伤；
优选地，所述抗生素类药物包括新霉素、卡那霉素，庆大霉素、青霉素、头孢霉素、多粘菌素；
所述非甾体类抗炎药物包括阿司匹林、布洛芬、保泰松、萘普生、吲哚美辛、吡罗昔康、喜乐宝；
所述抗肿瘤药物包括顺铂、氨甲蝶呤、链氨霉素、卡莫司汀氯乙环、己硝脲；
所属中药药物主要包括含有马兜铃酸和/或其衍生物的中药药物，所述含有马兜铃酸和/或其衍生物的中药药物包括关木通、马兜铃、天仙藤；
所述造影剂包括含碘造影剂；所述利尿剂包括渗透性利尿剂、呋塞米。
更进一步地，上述药物是缓解顺铂诱导的急性肾损伤的药物。
更进一步地，上述药物是减轻肾组织损伤的药物。
本发明还提供了TNF-α在制备缓解顺铂肾毒性的药物中的用途。
进一步地，上述药物是降低血清肌酐水平的药物。
本发明还提供了一种缓解肾损伤的药物，它是以TNF-α为唯一活性成分，加上药学上可接受的辅料制备而成的制剂。
进一步地，上述制剂是注射剂；优选地，所述药学上可接受的辅料是PBS溶液。
更进一步地，上述注射剂每单位制剂含有550～770μg的TNF-α，优选为660μg的TNF-α。
本发明的有益效果：本发明首次发现，使用低剂量的TNF-α进行预处理后，能够显著缓解顺铂的肾毒性，有效减轻顺铂诱导的肾损伤，对于急性肾损伤或肿瘤化疗临床治疗干预措施具有指导作用。
本发明“每单位制剂”的含义即：适于作为用于人类受试者的单位剂量的物理离散单位，每个单位含有经计算产生所需治疗效果的预定量的活性物质以及合适的药物辅料。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为TNF-α预处理降低顺铂导致AKI小鼠模型血清肌酐水平。
图2为TNF-α预处理改善顺铂导致AKI小鼠模型肾组织损伤(n＝10)。实验独立重复两次。
图3为TNF-α预处理改善顺铂导致AKI小鼠模型生存期。实验独立重复两次(n＝10)。
具体实施方式
本发明TNF-α购买自Peprotech,Cat#315-01A，以PBS稀释备用。本发明小鼠为从维通利华公司购买的6-8周C57/BL6小鼠，适应约一周后进行实验。
除另有说明外，本发明所用其他原料与设备均为已知产品，通过购买市售产品所得。
实施例1、低剂量TNF-α预处理缓解顺铂肾毒性及其所致急性肾损伤
1、实验方法
小鼠随机分为PBS组、顺铂组、TNF-α+顺铂组共3组，每组10只。
(1)PBS组(NS)：于小鼠腹腔注射PBS溶液，不进行小鼠急性肾损伤(AKI)建模。
(2)顺铂组(Cis)：于小鼠腹腔注射PBS溶液，24小时后，使用顺铂进行小鼠急性肾损伤(AKI)建模。
(3)TNF-α+顺铂组(TNF-α+Cis)：于小鼠腹腔注射TNF-α，剂量2μg/只(100μg/kg)，24小时后，使用顺铂进行小鼠急性肾损伤(AKI)建模。
于建模24h后收取标本，通过血肌酐和组织HE染色对AKI的进展进行评价。且每隔6-12小时观察一次小鼠生存状况并记录数据。
AKI建模方法：使用顺铂(Chemlin公司)，剂量为25mg/kg，对小鼠腹腔一次性注射。该方法事先通过了验证：选用6-8周C57/BL6雌鼠腹腔一次性注射(剂量25mg/kg)，24小时后收取标本(血清和肾组织)。分别通过血清肌酐和肾脏组织HE染色，确定AKI建模成功。
2、实验结果
如图1所示，可见，使用TNF-α预处理后，可以显著降低顺铂诱导后的小鼠模型血清肌酐水平，说明TNF-α对顺铂肾毒性有显著缓解作用。
如图2所示，从HE染色结果可以看出，TNF-α预处理能够显著改善AKI小鼠模型肾组织损伤的情况，对肾组织有保护作用。
如图3所示，TNF-α预处理还能够显著延长AKI小鼠模型的生存期。
以上结果说明，使用TNF-α进行预处理后，能够显著缓解顺铂的肾毒性，有效减轻顺铂诱导的肾损伤；小鼠所注射的TNF-α剂量为100μg/kg，按照成年人平均体重换算，人用剂量只需660μg/kg左右，剂量低，安全性高，对于急性肾损伤或肿瘤化疗临床治疗干预措施具有指导作用。
Claims (10)
1.TNF-α在制备缓解肾损伤的药物中的用途。
2.如权利要求1所述的用途，其特征在于，所述肾损伤是药物性肾损伤。
3.如权利要求2所述的用途，其特征在于，所述药物性肾损伤是抗生素类药物、非甾体类抗炎药物、抗肿瘤药物、中药药物、造影剂或利尿剂诱导的肾损伤；
优选地，所述抗生素类药物包括新霉素、卡那霉素，庆大霉素、青霉素、头孢霉素、多粘菌素；
所述非甾体类抗炎药物包括阿司匹林、布洛芬、保泰松、萘普生、吲哚美辛、吡罗昔康、喜乐宝；
所述抗肿瘤药物包括顺铂、氨甲蝶呤、链氨霉素、卡莫司汀氯乙环、己硝脲；
所属中药药物包括含有马兜铃酸和/或其衍生物的中药药物，所述含有马兜铃酸和/或其衍生物的中药药物包括关木通、马兜铃、天仙藤；
所述造影剂包括含碘造影剂；所述利尿剂包括渗透性利尿剂、呋塞米。
4.如权利要求3所述的用途，其特征在于，所述药物是缓解顺铂诱导的急性肾损伤的药物。
5.如权利要求4所述的用途，其特征在于，所述药物是减轻肾组织损伤的药物。
6.TNF-α在制备缓解顺铂肾毒性的药物中的用途。
7.如权利要求6所述的用途，其特征在于，所述药物是降低血清肌酐水平的药物。
8.一种缓解肾损伤的药物，其特征在于，它是以TNF-α为唯一活性成分，加上药学上可接受的辅料制备而成的制剂。
9.如权利要求8所述的药物，其特征在于，所述制剂是注射剂；优选地，所述药学上可接受的辅料是PBS溶液。
10.如权利要求9所述的药物，其特征在于，所述注射剂每单位制剂含有550～770μg的TNF-α。
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