CN115282136B - 丁酸钠在制备预防和/或治疗继发性甲状旁腺功能亢进制剂中的应用 - Google Patents

丁酸钠在制备预防和/或治疗继发性甲状旁腺功能亢进制剂中的应用 Download PDF

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CN115282136B
CN115282136B CN202210948547.9A CN202210948547A CN115282136B CN 115282136 B CN115282136 B CN 115282136B CN 202210948547 A CN202210948547 A CN 202210948547A CN 115282136 B CN115282136 B CN 115282136B
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胡忠良
杜瑶
吴听潮
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Abstract

本发明属于继发性甲状旁腺功能亢进治疗技术领域，具体涉及丁酸钠在制备预防和/或治疗继发性甲状旁腺功能亢进制剂中的应用。本发明可提供一种新的治疗策略：从肠道菌群的效应分子——短链脂肪酸的角度出发，通过补充丁酸钠，预防继发性甲状旁腺功能亢进的发生，从而改善尿毒症患者的预后。

Description

丁酸钠在制备预防和/或治疗继发性甲状旁腺功能亢进制剂 中的应用
技术领域：
本发明属于继发性甲状旁腺功能亢进治疗技术领域，具体涉及丁酸钠在制备预防肾内科尿毒症所引起并发症——继发性甲状旁腺功能亢进的药物中的应用。
背景技术：
继发性甲状旁腺功能亢进(secondary hyperparathyroidism,SHPT)是慢性肾脏疾病(Chronic kidney disease,CKD)中常见的、治疗费用昂贵的并发症，严重影响患者预后。继发性甲状旁腺功能亢进的治疗根据Improving Global Outcomes(KDIGO)2017年慢性肾脏疾病-矿物和骨骼疾病(CKD-MBD)临床实践指南更新提供的建议：对于需要降低甲状旁腺激素治疗的CKD G5D患者，建议钙模拟药物、骨化三醇或维生素D类似物，或钙模拟药物与骨化三醇或维生素D类似物联合使用(4.2.4 2b)，降低血清磷酸盐水平和维持血清钙水平，并将iPTH水平维持在正常上限的大约2-9倍范围内(4.2.3 2c)用以治疗管理CKD-MBD。但由于SHPT现有治疗方案的局限性，仍有相当比例接受慢性替代治疗的患者血清甲状旁腺激素(PTH)、磷酸盐和钙水平远远超过CKD-MBD治疗指南推荐的水平，并且甲状旁腺切除术作为药物治疗失败后的次选手段，目前没有足够的随机临床试验数据提供全面的甲状旁腺切除术风险-收益分析指南：Ketteler M,Block GA,Evenepoel P,Fukagawa M,Herzog CA,McCann L,et al.Diagnosis,Evaluation,Prevention,and Treatment of ChronicKidney Disease-Mineral and Bone Disorder:Synopsis of the Kidney Disease:Improving Global Outcomes 2017Clinical Practice Guideline Update.Annals ofinternal medicine.2018；168(6):422-30.而短链脂肪酸是肠道菌群的效应分子，目前研究表明与糖尿病等代谢性疾病相关。在本发明的研究中SHPT模型大鼠粪便中丁酸钠的水平与正常组相比明显降低。
发明内容
本发明可提供一种新的治疗策略：从肠道菌群的效应分子——短链脂肪酸的角度出发，通过补充丁酸钠，预防继发性甲状旁腺功能亢进的发生，从而改善尿毒症患者的预后。
本发明的首要目的是提供丁酸钠在制备预防和/或治疗继发性甲状旁腺功能亢进制剂中的应用。
进一步地，丁酸钠灌胃浓度为2-5mmol/L；优选丁酸钠灌胃浓度为3mmol/L。
本发明的第二个目的是提供一种预防和/或治疗继发性甲状旁腺功能亢进制剂，包含丁酸钠。
进一步地，丁酸钠灌胃浓度为2-5mmol/L；丁酸钠灌胃浓度为3mmol/L。
本发明的第三个目的是提供检测丁酸钠的试剂在制备继发性甲状旁腺功能亢进诊断制剂中的应用。
进一步地，丁酸钠检测对象包括血液或者粪便。
本发明的第四个目的是提供继发性甲状旁腺功能亢进诊断制剂，包括检测丁酸钠的试剂。
进一步地，丁酸钠检测对象包括血液或者粪便。
本发明优势：
本发明在现有药物治疗或手术切除治疗方案无法达到预期疗效的前提下，通过从补充相关低浓度短链脂肪酸的角度，加深对继发性甲状旁腺功能亢进这种疾病的理解，并为终末期肾脏病病人预防SHPT发生发展提供新的治疗思路。并且短链脂肪酸作为肠道菌群的效应分子，存在于人体的内环境中发挥作用。从这一方面着手，更利于从发病根源上更加温和高效的控制疾病的发展。
附图说明
图1为实施例1中慢性肾衰竭模型组(HP组)和空白对照组(NC组)中的血清肌酐(a)和尿素氮(b)水平。
图2为实施例1中慢性肾衰竭模型组(HP组)和空白对照组(NC组)中的血清iPTH水平。
图3为实施例1中慢性肾衰竭模型组(HP组)和空白对照组(NC组)粪便中丁酸钠水平；其中QC是质控的标记。
图4为实施例2中HP组、BNA组和NC组的ALP水平(辅助SHPT诊断)。
图5为实施例2中HP组、BNA组和NC组血清甲状旁腺激素水平；((*P<0.05**P<0.01***P<0.001,非参数T检验)。
图6为实施例2中收集粪便进行靶向代谢组学检测观察短链脂肪酸含量。
具体实施方式
以下结合实施例旨在进一步说明本发明，而非限制本发明。
实施例1：
选取重量基本相当的SD大鼠(150-250g)
一期实验：
(1)实验分组：①空白对照组(NC组)②5/6肾切除+高磷饮食8周诱导继发性甲状旁腺功能亢进(HP组)确定造模成功后，收集8周后两组大鼠粪便进行靶向代谢组学(短链脂肪酸)检测，发现丁酸钠在HP(疾病组)中含量降低；
(2)尿毒症继发甲状旁腺功能亢进大鼠造模方法：在全身麻醉(腹腔注射戊巴比妥钠0.2g/ml)下手术切除左肾上、下极，左肾仅留1/3。7天后切除右肾，最终完成5/6肾切除。严格结扎止血，无菌操作。观察一天后采用高磷饮食喂养八周。在手术前既0周，术后4周，术后8周取血。8500r/min离心10分钟后取上清，既血清，保存至-80℃冰箱中。血生化检测肌酐和尿素氮水平(见图1)，观察到在4周和8周时，HP组的血清肌酐以及尿素氮水平与未处理(0周)时相比，明显升高；而NC组指标无统计学差异，代表大鼠慢性肾衰竭造模成功；同时，RatiPTH ELISA试剂盒检测血清中iPTH水平(见图2)，可见4周和8周时，HP组大鼠血清iPTH水平与0周相比明显上升，而NC组大鼠0周，4周，8周血清iPTH水平无明显差异，由此判断大鼠继发性甲状旁腺功能亢进造模成功；取粪便进行靶向代谢组学检测其短链脂肪酸水平，发现丁酸水平在疾病组中下降明显(见图3)；粪便中检测的短链脂肪酸丁酸在肠腔吸收时是以丁酸钠的形式，故探究短链脂肪酸影响可用丁酸进行表征。SHPT大鼠造模方法：5/6肾切除+术后8周高磷饮食喂养(造模方法参考文献Vaziri ND,Wong J,Pahl M,Piceno YM,Yuan J,DeSantis TZ,Ni Z,Nguyen TH,Andersen GL.Chronic kidney disease altersintestinal microbial flora.Kidney Int.2013Feb；83(2):308-15.)
实施例2
选取重量基本相当的SD大鼠(150-250g)
二期实验：
(1)实验分组①空白对照组(NC组)②5/6肾切除+高磷饮食8周诱导继发性甲状旁腺功能亢进(HP组)③5/6肾切除+高磷饮食8周+3mmol/L丁酸钠灌胃8周(BNA组)
(2)BNA组大鼠肾脏手术后即给予丁酸钠灌胃并给予高磷饮食喂养。取0周、4周、8周血样同HP组和NC组比对，检测血生化指标碱性磷酸酶和尿素氮；ELISA试剂盒检测大鼠全波段甲状旁腺激素(iPTH)，确定造模成功的同时观察治疗效果。方法同一期实验，结果见图4和5，以及表1和表2。由图4可知8周时造模组ALP水平明显升高，灌胃降低了ALP水平；图5可知用丁酸钠灌胃处理后的大鼠与造模组对比，4周和8周的血清iPTH水平明显降低，甲状旁腺功能亢进的疾病状态明显改善。
图4和5的结果能够证明，丁酸钠灌胃能够预防或者治疗继发性甲状旁腺功能亢进。
同时收集粪便进行靶向代谢组学检测观察短链脂肪酸含量，排除其他干扰因素。图6的结果可知仅丁酸水平在灌胃后增高，并具有统计学意义。粪便中检测的短链脂肪酸丁酸在肠腔吸收时是以丁酸钠的形式，故探究短链脂肪酸影响可用丁酸进行表征。
表1
表2iPTH水平(ELISA)(pg/ml)

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1.丁酸钠在制备预防和/或治疗尿毒症引起的继发性甲状旁腺功能亢进制剂中的应用。
CN202210948547.9A 2022-08-09 2022-08-09 丁酸钠在制备预防和/或治疗继发性甲状旁腺功能亢进制剂中的应用 Active CN115282136B (zh)

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