CN115645405B - 顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用 - Google Patents
顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用 Download PDFInfo
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- CN115645405B CN115645405B CN202211409699.8A CN202211409699A CN115645405B CN 115645405 B CN115645405 B CN 115645405B CN 202211409699 A CN202211409699 A CN 202211409699A CN 115645405 B CN115645405 B CN 115645405B
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- tuberculosis
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Abstract
本发明公开了顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用。本发明还公开了一种抗结核的药物组合物,其原料包括:顺苯磺酸阿曲库铵、抗结核抗生素。本发明首次提出了顺苯磺酸阿曲库铵作为抗生素增效剂,显著促进抗结核一线药物的杀菌活性,保护结核分枝杆菌感染的巨噬细胞活力的效应,直接抑制胞内MTB的存活;本发明有助于开发出新型临床抗结核抗生素疗法辅助用药,应用于临床抗结核抗生素治疗方案,具有重要的社会经济效益。
Description
技术领域
本发明属于医药技术领域,具体涉及顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用。
背景技术
结核病(tuberculosis, TB)是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)引起的慢性致死性传染病。根据世界卫生组织发布的2021年度全球肺结核报告显示,肺结核是全球范围内仅次于COVID-19的第二大死因,在全球范围内严重地危害着人们的生命健康安全,而中国是报告内提出的30个结核病高负担国家之一。尽管抗结核一线药物异烟肼 (INH)、利福平等抗生素展示出有效的抗结核效应,但药物本身副作用大,治疗方案时长至少半年,患者依从性低,导致越来越多的结核患者表现出对传统抗MTB药物的耐药性,这是结核病难治的根本原因。在肺结核高发的经济相对落后地区,人们对疾病的预防和控制意识较差,部分肺结核患者由于未接受规范的抗结核治疗,导致病情的恶化与传播,其体内的MTB也容易产生耐药性。同时,许多MTB检测呈阳性的患者也均表现出了对异烟肼、利福平等抗MTB一线药物的耐药性。因此,随着MTB针对传统药物的耐药性逐渐增强的趋势,目前防治结核病所面临的最大的挑战是药物的创新。
近几年分子生物诊断在耐多药结核病诊断中脱颖而出、发展迅猛;而在治疗结核病方面,尽管有很多缩短疗程的药品,使普通结核病治疗从6~8个月缩短至4个月,但疗程仍不够短,耐多药结核病的治疗更是需要至少两年时间,治疗用药价格昂贵,副作用大。因此,筛查可更有效遏制MTB生长和传播的药物,是当前亟需解决的问题。
目前新药研发难度相对较大,因此老药新用的思路为药物研发提供了重要的手段。顺苯磺酸阿曲库铵(Cisatracurium besylate, CIS)是最新一代肌松剂。该药物自1996年在英国首次上市后,国外已逐渐代替维库溴铵和阿曲库铵,成为临床肌松药的主流。该药物是成熟的临床用药,对机体安全性已经得到充分验证,但其抗结核感染的效应未见报道。
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发明内容
本发明的目的在于克服现有技术的至少一个不足,提供顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用。
本发明所采取的技术方案是:
本发明的第一个方面,提供:
顺苯磺酸阿曲库铵在制备抗结核抗生素治疗方案增效剂中的应用。
在一些实例中,所述增效剂还包括药学上可接受的载体,这些载体选自填充剂、崩解剂、润滑剂、助悬剂、粘合剂中的任意一种或多种组合。
在一些实例中,所述的填充剂选自淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖任意一种或多种组合。
在一些实例中,所述的崩解剂选自淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素钠任意一种或多种组合。
在一些实例中,所述的润滑剂选自硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅任意一种或多种组合。
在一些实例中,所述的助悬剂选自聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素任意一种或多种组合。
在一些实例中,所述的粘合剂选自淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素任意一种或多种组合。
在一些实例中,所述增效剂可以制成药剂学可接受的各种液体剂型或固体剂型。
在一些实例中,所述的药剂学可接受的液体剂型为糖浆剂、注射溶液、非水溶液、悬浮液或乳剂;所述的固体剂型为片剂、锭剂、胶囊、滴丸、丸剂、粒剂、粉剂或霜剂。
在一些实例中,所述抗生素选自异烟肼、利福平、乙胺丁醇或吡嗪酰胺任意一种或多种组合。
本发明的第二个方面,提供:
一种治疗耐药性结核的组合物,包含抗结核抗生素和增效剂。
在一些组合物的实例中,所述抗结核抗生素选自异烟肼、利福平、乙胺丁醇或吡嗪酰胺中的任意一种或者多种。
本发明的有益效果是:顺苯磺酸阿曲库铵为FDA通过认证的临床用药,具有良好的案例性。研究显示顺苯磺酸阿曲库铵对MTB感染的巨噬细胞活性具有显著保护效应,减少被感染细胞的坏死性凋亡水平,使巨噬细胞可继续发挥抑制胞内MTB活性的免疫应答效应,机体内该效应将减少被感染组织损伤。
顺苯磺酸阿曲库铵同时可直接发挥抑制巨噬细胞胞内MTB存活的活性,并显著促进抗结核一线药物异烟肼的杀菌活性。因此,顺苯磺酸阿曲库铵有望快速研发,作为辅助药物,应用于临床抗结核抗生素治疗方案,预期将减少抗生素治疗时长,减少耐药结核的发生。
附图说明
图1是保护性药物筛选流程及部分筛选结果。
图2是CIS初筛及时间剂量效应验证结果。
图3是探讨CIS调节的细胞死亡方式—之一。
图4是探讨CIS调节的细胞死亡方式—之二。
图5是H37Rv感染BMDM细胞不同处理后的扫描电镜(SEM)结果。
图6是CIS抑制H37Rv感染引起的坏死性凋亡坏死的结果。
图7是CIS对坏死性凋亡的调控结果。
图8是CIS处理对MLKL和RIPK3的影响。
图9是CIS阻断RIPK3的激酶结构域RHIM与MLKL的PsKD结构域之间相互作用的结果。
图10是不同处理的菌落形成实验结果。
图11是不同处理对H37Rv感染的小鼠的影响。
图12是不同处理H37Rv感染后小鼠肺部组织的苏木精-伊红(HE)染色结果。
图13是不同处理H37Rv感染后小鼠的免疫组化(IHC)检测结果。显示,感染了H37Rv的小鼠其肺部MLKL磷酸化水平显著升高。CIS单独治疗或与INH联合治疗可显著抑制MLKL磷酸化,提示CIS通过抑制坏死性凋亡水平而对组织发挥保护作用。
具体实施方式
下面结合实验,进一步说明本发明的技术方案。
实验流程:
1.CIS作用的发现
图1是保护性药物筛选流程及部分筛选结果。采用CCK-8法,筛查了FDA批准的小分子药物库中1411种药物对卡介苗(BCG)感染的THP-1来源巨噬细胞(THP-1-Mφ)活力的保护效应。结果显示,大多数药物未表现出对被感染细胞活力的保护性作用,部分药物甚至加剧了菌感染诱导的细胞活力的降低。上述已筛选药物中,顺苯磺酸阿曲库铵(CIS)表现出显著且较稳定的、对MTB感染后Mφ活力的保护性作用。
CCK-8实验检测细胞活性的具体操作如下:
a)接种细胞:小鼠原代巨噬细胞,接种2 × 105/孔于24孔板;
b)对细胞进行相应实验需要所做的处理;
c)MOI = 2 / 5感染MTB标准毒株H37Rv;
d)培养至实验观察时间点,吸取细胞上清,PBS洗涤两次,向培养板中加入20 μL的CCK-8和180 μL的DMEM完全培养基;
e)细胞在培养箱中培养2-4 h;
f)检测:使用酶标仪在450 nm,参考波长630 nm条件下检测每孔OD值。
图2是CIS初筛及时间剂量效应验证结果。左图—初筛:采用FDA批准药物库中的小分子药物CIS(10 μM)处理THP-1-Mφ细胞后,感染卡介苗(BCG),24 h后采用CCK-8法检测细胞活力。结果显示,CIS表现出对被感染细胞活力的保护作用。中图—根据初筛结果,将药物以系列剂量处理THP-1-Mφ细胞后,感染BCG,CCK-8法检测细胞活力,探讨药物发挥保护效应的有效作用浓度。结果显示,CIS的最佳保护作用浓度为10 μM。右图—在MTB标准毒株H37Rv感染的小鼠骨髓来源的原代巨噬细胞(BMDM)中,重复验证CIS对细胞活力保护作用的时间、剂量效应,结果显示CIS在10 μM具有较为稳定的保护作用,并可持续至感染后较长时间。
2.结合Western blot、免疫荧光染色与扫描电镜等形态学指标检测及验证顺苯磺酸阿曲库铵所调节的细胞死亡信号通路,确定顺苯磺酸阿曲库铵调节的细胞死亡类型(图3~6)。
采用CIS处理BMDM后感染H37Rv,Western blot检测结果表明,CIS显著抑制了由MTB感染所激活的坏死性凋亡标志性分子MLKL的磷酸化,提示CIS参与调控坏死性凋亡的发生(图3)。
采用CIS处理BMDM后感染H37Rv,Western blot检测LC3转变(自噬标志)、PARP切割(凋亡标志)或GSDMD切割(焦亡标志)、GPX4和 SLC7A11表达(铁死亡标志),结果显示上述指标均无明显变化。提示CIS不参与调控自噬、凋亡、焦亡或铁死亡(图4)。
扫描电镜(SEM)观测到H37Rv感染后发生坏死性凋亡的BMDM细胞比例显著增加,主要表现为细胞体积扩张、细胞器肿胀和质膜破裂;CIS处理显著抑制了发生坏死性凋亡细胞的比率(图5)。
采用免疫荧光(IF)染色技术检测MLKL(红色荧光)向鬼笔环肽标记的质膜(绿色荧光)的转位及二者的共定位(黄色荧光),结果显示H37Rv感染后可诱导MLKL发生膜转位,该过程可被CIS处理显著抑制,表明CIS可抑制H37Rv感染引起的坏死性凋亡(图6)。
3.进一步深入研究顺苯磺酸阿曲库铵发挥作用的具体机制。通过免疫共沉淀实验发现该化合物通过抑制RIPK3蛋白的Kinase结构域与MLKL蛋白的PsKD结构域之间的相互作用,从而抑制MTB感染引起的坏死性凋亡(图7~9)。
因TNF-α可诱导细胞凋亡和坏死性凋亡,zVAD抑制细胞凋亡,而L929细胞为坏死性凋亡敏感细胞,因此采用TNF-α和zVAD共同处理L929细胞,建立坏死性凋亡经典细胞模型,验证CIS对坏死性凋亡的调控。左图—Western blot检测显示,在L929细胞坏死性凋亡模型中,CIS能够抑制TNF-α和zVAD激活的坏死性凋亡蛋白复合体(由RIPK1、RIPK3和MLKL蛋白构成)。右图--采用非变性聚丙烯酰胺凝胶电泳(Native PAGE)检测细胞膜及细胞质中MLKL分子寡聚化的水平,以指示其在质膜上寡聚化打孔造成坏死性凋亡的水平。结果显示,TNF-α合并zVAD可诱导胞膜上MLKL寡聚化水平增强,而CIS处理则显著抑制这一现象(图7)。
坏死性凋亡蛋白复合体中,MLKL在其上游RIPK3作用下发生磷酸化而活化。免疫共沉淀(Co-IP)实验表明,CIS处理显著抑制MLKL和RIPK3之间的结合,从而抑制了RIPK3对MLKL磷酸化的激活(图8)。
通过构建RIPK3与MLKL截短体真核表达质粒并转染细胞,采用Co-IP实验检测,进一步确定CIS可阻断RIPK3的激酶结构域RHIM与MLKL的PsKD结构域之间的相互作用,由此抑制了RIPK3对下游MLKL的磷酸化,阻遏坏死性凋亡的发生(图9)。
4.菌落形成实验(CFU)检测顺苯磺酸阿曲库铵是否调节巨噬细胞对MTB的杀伤作用,探讨药物的保护性作用的方向;以及顺苯磺酸阿曲库铵与异烟肼联用后检测细胞活性与对MTB的杀伤作用(图10)。
图10是不同处理的菌落形成实验结果。左图--菌落形成实验(CFU)检测CIS处理后的BMDM感染H37Rv后胞内菌增殖活性,结果显示,CIS显著抑制BMDM中胞内H37Rv的增殖。右图—CFU实验检测结果显示,与单独INH治疗组相比,异烟肼(INH)与CIS联合处理H37Rv感染的BMDM,显著减少了胞内H37Rv的扩增,表明CIS可有效辅助一线抗结核药物对抗MTB感染。
5.动物实验验证顺苯磺酸阿曲库铵和(或)异烟肼治疗MTB感染小鼠的荷菌情况及组织损伤、炎性浸润、坏死性凋亡发生的情况(图11~13)。
采用CIS 单独治疗或与INH联合治疗H37Rv感染的小鼠,试验结果(图11)显示,CIS显著抑制肺、脾组织中H37Rv的增殖,INH和CIS的联合治疗效果显著优于INH单独治疗效果。
图12是不同处理H37Rv感染后小鼠肺部组织的苏木精-伊红(HE)染色结果。显示H37Rv感染后小鼠肺部组织损伤严重,而CIS单独治疗或与INH联合治疗均可显著减少其肺部组织损伤。
图13是不同处理H37Rv感染后小鼠的免疫组化(IHC)检测结果。显示感染了H37Rv的小鼠其肺部MLKL磷酸化水平显著升高。CIS单独治疗或与INH联合治疗可显著抑制MLKL磷酸化,提示CIS通过抑制坏死性凋亡水平而对组织发挥保护作用。
从上述实验可以看出,顺苯磺酸阿曲库铵对MTB感染的巨噬细胞发挥显著的维持细胞活性的作用,由此将维持巨噬细胞的抗结核免疫应答,体内将减少组织损伤,对机体具有重要的保护作用。同时该化合物具有直接抑制胞内MTB存活的效应,并显著促进抗结核一线药物异烟肼的杀菌效应。
以上是对本发明所作的进一步详细说明,不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的简单推演或替换,都在本发明的保护范围之内。
Claims (9)
1.顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用。
2.根据权利要求1所述的应用,其特征在于,所述增效剂还包括药学上可接受的载体。
3.根据权利要求1所述的应用,其特征在于,所述的药学上可接受的载体为填充剂、崩解剂、润滑剂、助悬剂、粘合剂中的任意一种或多种组合。
4.根据权利要求3所述的应用,其特征在于,所述的填充剂选自淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖中的至少一种;
所述的崩解剂选自淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素钠的至少一种;
所述的润滑剂选自硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅的至少一种;
所述的助悬剂选自聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素的至少一种;
所述的粘合剂选自淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素的至少一种。
5.根据权利要求1所述的应用,其特征在于,所述增效剂为液体制剂或固体制剂。
6.根据权利要求5所述的应用,其特征在于,所述的液体制剂为糖浆剂、注射溶液、非水溶液、悬浮液或乳剂;所述的固体制剂为片剂、锭剂、胶囊、滴丸、丸剂、粒剂、粉剂或霜剂。
7.根据权利要求1~6任一项所述的应用,其特征在于,所述的抗结核抗生素选自异烟肼、利福平、乙胺丁醇或吡嗪酰胺中的至少一种。
8.一种治疗耐药性结核的组合物,包含抗结核抗生素和增效剂,所述增效剂为顺苯磺酸阿曲库铵,所述的抗结核抗生素选自异烟肼、利福平、乙胺丁醇或吡嗪酰胺中的至少一种。
9.根据权利要求8所述的组合物,其特征在于,所述的组合物为口服制剂或注射剂。
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