CN117530944A - 衣康酸四辛酯在制备防治放射性肠损伤药物中的应用 - Google Patents
衣康酸四辛酯在制备防治放射性肠损伤药物中的应用 Download PDFInfo
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Abstract
本发明公开了衣康酸四辛酯在制备预防或治疗辐射诱导肠道损伤药物的应用,申请人发现,其对辐射诱导的肠道损伤具有突出的保护作用,可用于制备防治辐射诱导肠损伤,可以作为放射性物质辐射、核电站泄漏、空间电离辐射以及肿瘤放疗引起的生命体损伤防护方面的药物。
Description
技术领域
本发明属于核医药学领域,涉及一种衣康酸四辛酯在药学领域中的应用,更具体地说是衣康酸四辛酯在制备防治电离辐射诱导的放射性肠损伤药物中的应用。
背景技术
电离辐射的研究发展使得人类将其能够应用于生活中的各个领域,其体量尤以工业和医疗显著,但核工业的意外暴露和放射治疗的副作用严重危害着暴露人群或放疗患者的生命健康。肠道在机体内承担着吸收、消化、***以及免疫调节的重要作用,肠道上皮对于肠道功能的发挥又有着关键不可替代的作用。人体的肠道上皮平均每3-5天更新一次,承担着抵御外界病原体和异物的屏障作用,吸收肠道营养物质的吸收作用,免疫调节作用以及分泌消化酶和粘液的分泌作用。承担着肠道组织更新作用的肠道干细胞对辐射高度敏感,尤其是隐窝基底部的肠道干细胞-隐窝柱状细胞(crypt-based columnar cell,CBC)。电离辐射暴露会导致肠道绒毛的破坏、肠道干细胞的大量丢失以及肠道炎性因子水平的迅速升高,进而导致肠上皮更新的严重抑制和放射性肠炎的发生。因此,伴随着呕吐、腹泻、出血、感染、肠穿孔甚至是死亡的放射性肠炎在辐射暴露后常见且致命。但目前临床上针对放射性肠炎的药物都只停留在“治标”上,例如抗炎的肾上腺皮质激素药物***、缓解腹泻症状的***类药物以及减轻肠道蠕动的多巴胺受体拮抗剂。因此,迫切需要开发一种针对放射性肠炎的药物来改善临床用药高局限性的现状。
衣康酸(Itaconate)是一种可由内源性葡萄糖代谢生成的小分子,通常在线粒体内由免疫应答基因1(Immune responsive gene 1,IRG1)表达产物蛋白催化其前体顺乌头素酸生成。IRG1编码的ITAC酶可以将衣康酸转化为辅酶A内酯,从而进入三羧酸循环。这个代谢途径被称为衣康酸代谢通路,可以调节葡萄糖代谢、氧化磷酸化和胆固醇代谢等过程,并且在免疫应答中也发挥一定的调节作用。
衣康酸在细胞内的生物学功能目前已知的可通过催化KEAP1烷基化释放与其结合的Nrf2,促使胞内Nrf2水平升高,并激活下游通路发挥抗炎功效。此外,农康酸对于NLRP3炎症小体的聚合也有抑制作用,进而抑制下游铁死亡的发生,减轻如在感染条件下的宿主炎症损伤。衣康酸已被发现可以减轻多种模型,如缺血再灌注模型、过氧化氢诱导的神经元损伤模型、UVB诱导的皮肤损伤模型的损伤程度。
在肠道损伤方面,衣康酸的研究现主要集中于一般肠道性炎症(IBD)。在炎症性肠病IBD模型中,衣康酸可以调节肠道炎症反应,并通过保护肠道粘膜完整性发挥作用,其相关机制包括抑制炎症因子的产生,调节TNF信号通路,抑制NLRP3炎症小体的活化等起到抗炎作用、促进巨噬细胞M2型极化和抑制T细胞活化发挥抗炎作用。
区别于一般肠道性炎症,其主要表现为溃疡性结肠炎,很少涉及小肠及直肠。放射性肠损伤(RIII,radiation-induced intestinal injury),是临床盆腔,腹腔,腹膜后恶性肿瘤患者接受放射治疗过程中或结束后常见的并发症之一,可累及小肠,结肠以及直肠等整个肠道组织。自1896年首次发现以来,关于RIII的发病机制仍然不完全清楚,仍没有好的药物治疗手段。目前临床仅采用手术治疗或营养支持的手段,患者的生理机能以及躯体疼痛等放疗后的生活质量得不到有效改善。
在核医学、核能利用等领域,衣康酸四辛酯(40I)为衣康酸的衍生物,对放射性肠损伤(radiation-induced intestinal injury,RIII)是否有救治效果、以及具体机制方面还处于研究空白。针对目前临床上关于放射性肠损伤治疗药物局限性较大的现状,本发明人开展了衣康酸四辛酯在肠道辐射损伤防护方面的研究,并在研究过程中首次发现了衣康酸四辛酯对电离辐射诱导的肠损伤有明确的治疗作用,基于此,本发明人进行了更进一步的实验并完成了本发明。
发明内容
本发明旨在提供一种新的能够预防/治疗电离辐射损伤的药物,用于核医学领域,特别是核辐射损伤病人用药。
本发明的目的,一方面在于提供衣康酸四辛酯在制备预防或治疗电离辐射肠损伤药物中的应用,另一方面在于提供衣康酸四辛酯在放疗防护中应用,具体与营养物质、和/或维持肠道结构和功能药物、和/或抑制放射性肠炎的药物组合,降低放疗所带来的毒副作用。
为实现上述发明目的,设计了如下的技术方案:
一种衣康酸四辛酯在制备预防/治疗电离辐射诱导的放射性肠损伤药物中的应用。
其中,所述的电离辐射诱导的肠损伤,其病患人群但不限于:辐射暴露的工作人员、意外辐射性同位素暴露的人员、接受放射治疗的肿瘤患者。
其中,所述的放射性肠损伤,包括整体肠道尤其是小肠绒毛结构破坏、肠道炎症加重、呕吐腹泻、出血感染、死亡。
本发明公开了衣康酸四辛酯与其他营养物质、和/或、和/或减轻放射性肠炎症状药物(维持肠道结构和功能药物、抑制放射性肠炎药物,等)组合,用于制备临床各种剂型的治疗药物、预防药物及保健食品等。本发明所述的营养物质包括:氨基酸营养液、维生素、葡萄糖、脂肪乳、离子等。
本发明公开了其特征在于可以将衣康酸四辛酯与抗肿瘤药物组合,用于制备肿瘤辅助药物。本发明所述抗肿瘤药物,例如:各种中药制剂如多糖类(枸杞、银耳、党参、黄芪、人参多糖等)、生物碱类(小檗碱、苦参总碱等)、皂甙类(人参皂甙、黄芪甙等)及其他如六味地黄口服液等升白中药制剂;人粒细胞巨噬细胞集落刺激因子(rHuGM-CSF)、升白欣、肌苷、左旋咪唑、三株口服液、康力龙等。
本发明所述的衣康酸四辛酯与其他营养物质、减轻放射性肠炎症状药物混合制成药物组合物,或衣康酸四辛酯作为支持药物与抗肿瘤药物配合使用。一般使用常规的技术,与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质,其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉针剂等等。
本发明公开了将治疗有效量的衣康酸四辛酯与药学上可接受的药用辅料混合,用于制备人用制剂;用于制备固体制剂、液体制剂,包括片剂、胶囊剂、颗粒剂、丸剂、滴丸剂、预乳剂、混悬剂、糖浆剂、各种肠溶制剂或注射剂。各制剂可以根据常规的工艺制备而成。在制备成药剂时可以加入药学上可接受的辅料,所述的药学上可接受的辅料,包括制剂中常规的稀释剂、填充剂(如甘露醇、乳糖、聚乙二醇),粘合剂(淀粉、微晶纤维素),崩解剂(如羧甲基纤维素、低取代的羟丙基纤维素),润滑剂(如滑石粉、硬脂酸镁),湿润剂(如丙二醇、乙醇),稳定剂(EDTA-2Na、硫代硫酸钠、焦亚硫酸钠、亚硫酸钠、乙醇胺、碳酸氢钠)等等。
当衣康酸四辛酯与药学上可接受的药用辅料混合组成药物组合物时,组合物中含有的活性成分衣康酸四辛酯的量可以根据患者的病情、医生诊断的情况特定的加以应用,所用衣康酸四辛酯的量或浓度在一个较宽的范围内调节,通常衣康酸四辛酯的量范围为组合物的0.5%~90%(重量)。另一优选的范围为0.5%-70%。再一优选的范围为3%-50%。
本发明公开了衣康酸四辛酯在制备预防/治疗辐射诱导肠道损伤药物的应用,申请人发现,其对辐射诱导的肠道损伤具有突出的保护作用,主要包括以下几个方而:
1.衣康酸四辛酯正常状态HIEC6细胞无毒性作用,且能够缓解HIEC6细胞电离辐射照射后导致的细胞活力降低;
2.衣康酸四辛酯降低了电离辐射导致的HIEC6细胞的ROS水平;
3.衣康酸四辛酯降低了电离辐射导致的HIEC6细胞凋亡水平;
4.衣康酸四辛酯能够延长全身9Gy电离辐射暴露小鼠的生存时间,并减轻体重降低;
5.衣康酸四辛酯能够缓解9Gy电离辐射暴露小鼠造成的小肠结构破坏。
本发明可以作为制备放射性物质辐射、核电站泄漏、空间电离辐射以及肿瘤放疗引起的生命体损伤防护方面的药物,解决放射性肠炎(RIII)长期以来缺乏特异性治疗药物的问题。
附图说明
图1衣康酸四辛酯小鼠生存时间图:衣康酸四辛酯能够延长全身9Gy电离辐射暴露小鼠的生存时间;
图2衣康酸四辛酯小鼠体重图:衣康酸四辛酯能够减轻全身9Gy电离辐射暴露小鼠的体重降低程度;
图3衣康酸四辛酯肠道结构HE染色图:衣康酸四辛酯能够缓解9Gy电离辐射暴露小鼠造成的小肠结构破坏;
图4衣康酸四辛酯细胞活力测定图:衣康酸四辛酯对HIEC6细胞无毒性作用,且能够缓解HIEC6细胞电离辐射照射后导致的细胞活力降低;
图5衣康酸四辛酯细胞活性氧测定图:衣康酸四辛酯降低电离辐射导致的HIEC6细胞的ROS水平;
图6衣康酸四辛酯细胞凋亡检测图。衣康酸四辛酯降低电离辐射导致的HIEC6细胞凋亡水平;
具体实施方式
为了更充分的解释本发明的实施,提供下述制剂实施例。这些实施例仅仅是解释、而不是限制本发明的范围。
实施例1全身照射小鼠生存率实验
C57BL/6小鼠随机分组,5只/组,衣康酸四辛酯在小鼠照射前1h灌胃给药(15mg/kg/d),全身照射9Gy后,持续两日灌胃给药,观察生存时间并在前期记录体重变化。
结果如图1和2所示。结果表明,衣康酸四辛酯能够延长全身9Gy电离辐射暴露小鼠的生存时间,并减轻体重降低程度。
实施例2肠道结构HE染色
C57BL/6小鼠随机分组,5只/组,衣康酸四辛酯在小鼠照射前1h灌胃给药(15mg/kg/d),全身照射9Gy后,持续两日灌胃给药,照射后第三天取小肠固定,组织脱水、石蜡包埋、切片后进行HE染色,步骤包括石蜡切片脱蜡水化,苏木素染细胞核并进行分化反蓝,伊红染细胞质,最后脱水有机化历中性树胶封片观察并记录。
结果如图3所示。结果表明,衣康酸四辛酯能够缓解9Gy电离辐射暴露小鼠造成的小肠结构破坏。
实施例3细胞活力测定
HIEC6细胞培养于96孔板中,每孔加入100μl单个核细胞悬液,按设计加入处理药物100μl,照射9Gy后37℃培养箱孵育18h。取出培养板,放置室温,CCK8细胞活力检测实验检测细胞活力变化。
结果如图4所示。结果表明,衣康酸四辛酯对HIEC6细胞无毒性作用,且能够缓解HIEC6细胞电离辐射照射后导致的细胞活力降低。
实施例4细胞活性氧测定
HIEC6细胞培养于96孔板中,每孔加入100μl单个核细胞悬液,按设计加入处理药物100μl,照射1Gy后37℃培养箱孵育18h。取出培养板,放置室温,加入配置好的DFCH试剂(500μl/样)。PBS洗涤后重悬细胞,通过流式细胞术检测细胞活性氧水平。
结果如图5所示。结果表明,衣康酸四辛酯降低了电离辐射导致的HIEC6细胞内升高的ROS水平。
实施例5细胞凋亡检测
HIEC6细胞培养于96孔板中,每孔加入100μl单个核细胞悬液,按设计加入处理药物100μl,照射1Gy后37℃培养箱孵育18h。取出培养板,放置室温,加入Annexin V/PI凋亡检测试剂盒binding buffer(200μl/管),混匀,再依次加入1μl Annexin V-FITC,2μl PI每孔,室温避光孵育15min。随后流式细胞术检测细胞凋亡水平。
结果如图6所示。结果表明,衣康酸四辛酯降低了电离辐射导致的HIEC6细胞凋亡水平。
实施例6衣康酸四辛酯片剂
衣康酸四辛酯100mg,乳糖50mg,微晶纤维素80mg,淀粉50mg,羟甲纤维素40mg,硬脂酸镁5mg。将活性成分,乳糖、淀粉、微晶纤维素过100目筛,并充分混匀,将2%羟甲纤维素水溶液加入到上述混合粉末中混合,过20目筛制软材,制得湿颗粒于45-55℃干燥,将羧甲淀粉钠、硬脂酸镁加入到上述的干燥颗粒中压片。
实施例7衣康酸四辛酯片剂
衣康酸四辛酯100mg,升白新500mg,加4g(乳糖-微晶纤维5∶1)、硬脂酸镁1%,用70%乙醇制粒、压片即得。
实施例8农康酸四辛酯注射用冻干粉针
衣康酸四辛酯10g,甘露醇60g,加1000ml注射用水溶解,补足注射用水至2000ml,加适量活性炭除热源,0.2um微孔滤膜滤过,灌装,冷冻干燥,制得2000支冻干粉针。规格:70mg/支,供静脉注射用。
实施例9衣康酸四辛酯胶囊剂
衣康酸四辛酯10g,加糊精10g、乳糖30g用60%乙醇制粒、干燥、装胶囊,制得1000粒胶囊剂。规格:50mg/粒。
综上所述,本发明的内容并不局限在的实施例中,相同领域内的有识之士可以在本发明的技术指导思想之内可以轻易提出其他的实施例,但这种实施例都包括在本发明的范围之内。
Claims (7)
1.衣康酸四辛酯在制备预防/治疗电离辐射诱导的放射性肠损伤药物中的应用。
2.权利要求1所述的应用.其中所述电离辐射诱导的放射性肠损伤,其人群包括辐射暴露的工作人员、意外辐射性同位素暴露的人员、接受放射治疗的肿瘤患者。
3.权利要求1所述的应用,其特征在于所述的放射性肠损伤,包括肠道绒毛结构破坏、肠道炎症加重、呕吐腹泻、出血感染、死亡。
4.权利要求1-3任一项所述的应用,其特征在于将它是将农康酸四辛酯与营养物质、维持肠道结构和功能药物组合。
5.权利要求1-3任一项所述的应用,其特征在于将农康酸四辛酯与抗肿瘤药物组合。
6.权利要求1-3任一项所述的应用,其特征在于将治疗有效量的衣康酸四辛酯与药学上可接受的药用辅料组合。
7.权利要求6任一项所述的应用,其特征在于所述的组合物是片剂、胶囊剂、颗粒剂、丸剂、滴丸剂、预乳剂、混悬剂、糖浆剂、各种肠溶制剂或注射剂。
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