CN117599091A - 牛黄在制备预防或治疗高尿酸血症药物中的应用 - Google Patents
牛黄在制备预防或治疗高尿酸血症药物中的应用 Download PDFInfo
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Abstract
本发明提供了牛黄在制备预防或治疗高尿酸血症药物中的应用，涉及医药技术领域。本发明确定了牛黄具有明显的降尿酸活性，并改善高尿酸导致的肝肾损伤，为促进牛黄的抗高尿酸血症应用提供了新的研究基础，具有潜在的医学价值和经济效益。并且牛黄无明显毒副作用，对肾脏、肝脏功能具有保护作用，且疗效确切，成分清楚，安全可控，用药剂量准确，具有较高的实际应用价值。
Description
技术领域
本发明涉及医药技术领域，尤其涉及牛黄在制备预防或治疗高尿酸血症药物中的应用。
背景技术
痛风(gout)是由沉积于关节和非关节结构中的尿酸单钠晶体诱发先天免疫应答，引起的间歇性发作的疼痛性关节炎。据流行病学分析统计，痛风的患病率在20世纪稳步上升，每年成人痛风的新增发病率为0.6-2.9/1000人，而患病率达到0.68-3.90％。血清尿酸浓度升高是痛风发病机制的核心。据临床研究报道，当血清尿酸水平高于或等于0.42mmol/L(7mg/dL；血清尿酸浓度超过尿酸晶体析出的饱和阈值)时，即可诊断为高尿酸血症(hyperuricemia)。高尿酸血症会导致痛风，并与多种代谢紊乱疾病有关，如糖尿病、高血压和部分肝肾疾病等。
高尿酸血症的发生发展受到遗传变异、环境暴露、基因-环境相互作用和内在风险因素(如年龄、性别和体重)等的影响。尿酸是嘌呤核苷酸降解的最终产物，其主要生成部位是肝脏、肌肉和脂肪组织。高嘌呤饮食(如红肉和海鲜)会增加血清尿酸升高和痛风发生的风险。黄嘌呤氧化酶(xanthine oxidase)是人类嘌呤分解代谢的末端酶和尿酸合成的关键限速酶。
血清尿酸浓度过高主要由肝脏尿酸生成过多和/或肾脏/肠道尿酸排泄不足等因素引起。目前临床治疗药物即是通过作用于上述机制来发挥降尿酸作用，如别嘌呤醇和非布司他等通过抑制肝脏尿酸生成过程中的黄嘌呤氧化酶的活性，减少尿酸的生成；苯溴马隆则通过抑制肾近端小管尿酸阴离子交换蛋白1(URAT1)的功能，抑制尿酸重吸收以促进其尿液排泄。但上述临床常用药物因其多发胃肠道副作用、肝肾毒性或心血管功能异常风险而受到限制。寻找有效且更安全的降尿酸药物是目前研究的主要方向。
发明内容
有鉴于此，本发明提供了一种牛黄在制备预防或治疗高尿酸血症药物中的应用。
牛黄包括天然牛黄以及天然牛黄替代品。其中天然牛黄为括体外培育牛黄。
天然牛黄(Bovis Calculus)是牛科动物黄牛或水牛的胆囊结石，具有镇静、抗惊厥、增强免疫、抗炎、抗氧化、抗心律失常、利胆护肝、抗肿瘤、抗衰老等的功效。因天然牛黄来源匮乏，价格昂贵，研究人员开发了体外培育牛黄作为天然牛黄替代品，以弥补其资源短缺。其中体外培育牛黄(Bovis Calculus Sativus)以牛科动物牛的新鲜胆汁作母液，加入复合胆红素钙、去氧胆酸和胆酸等制成。根据2020年版《中国药典》的规定，按干燥品计，天然牛黄含胆红素(C33H35N4O6)不得少于25.0％，含胆酸(C24H40O5)不得少于4.0％。体外培育牛黄含胆红素(C33H35N4O6)不得少于35.0％，含胆酸(C24H40O5)不得少于6.0％。
与现有技术相比，本发明具有以下有益效果：
本发明通过研究确定了牛黄具有明显的降尿酸活性，并改善高尿酸导致的肝肾损伤，为促进牛黄的抗高尿酸血症应用提供了新的研究基础，具有潜在的医学价值和经济效益。
并且牛黄无明显毒副作用，对肾脏、肝脏功能具有保护作用，且疗效确切，成分清楚，安全可控，用药剂量准确，具有较高的实际应用价值。
附图说明
图1为天然牛黄对尿酸酶抑制剂诱导的高尿酸血症小鼠尿酸水平及肾损伤的影响；
图2为体外培育牛黄对尿酸酶抑制剂诱导的高尿酸血症小鼠尿酸水平及肾损伤的影响；
图3为天然牛黄和体外培育牛黄通过降低肝脏尿酸合成酶改善高尿酸血症诱导小鼠的效果。
具体实施方式
下面对本发明利用牛黄作为预防或治疗高尿酸血症药物进行具体实验说明。
实施例1天然牛黄改善尿酸酶抑制剂诱导高尿酸血症小鼠
1.1药品来源
天然牛黄(BC)购自杭州华东中药饮片有限公司(胡庆余堂)。生产批号为200527。
1.2动物分组及造模给药
天然牛黄(BC)降尿酸作用研究：C57/BL雄性8周龄小鼠35只，正式实验前进行适应性饲养一周，饲养期间小鼠可自由进食和饮水，饲养环境控制合适的温度(20-25℃)和湿度(50-60％)，12h昼夜循环。实验前将小鼠随机分为5组：溶剂对照组、模型组(氧嗪酸钾PO250mg/kg+次黄嘌呤250mg/kg)、和天然牛黄低(12.5mg/kg)、中(25mg/kg)、高(50mg/kg)剂量组，每组7只。溶剂对照组每天灌胃给予0.5％ CMC-Na溶液，模型组动物每天灌胃氧嗪酸钾和次黄嘌呤建立高尿酸血症小鼠模型，天然牛黄组每天除灌胃氧嗪酸钾和次黄嘌呤外，按低、中、高剂量同时灌胃天然牛黄。给药体积为10ml/kg，按上述方式连续给药14天，每天记录小鼠体重，给药前后观察小鼠毛发和状态变化情况。
1.3样品收集
末次给药后1h，小鼠麻醉后眼眶取血，肝素钠抗凝，离心分离血浆。小鼠取血后脱颈处死，迅速分离肝、肾组织，移至液氮速冻，随后置-80℃储存备用。杀鼠前12h禁食不禁水。
1.4生化指标测定
采用HPLC-MS/MS法测定小鼠血浆尿酸(UA)浓度；血浆尿素氮水平按试剂盒方法测定。
1.5Western Blot实验
提取小鼠肾脏和肝脏蛋白，以Western Blot法测定小鼠肾脏纤维化蛋白表达水平变化。
1.6结果分析
如图1A所示，尿酸酶抑制剂(PO)诱导的高尿酸血症模型组小鼠，血浆尿酸(UA)水平显著高于溶剂对照组(CON)。低、中、高剂量的天然牛黄(12.5，25和50mg/kg)剂量依赖性地降低PO诱导的血浆尿酸(图1A)水平的升高。提示低、中、高剂量的天然牛黄均有明显的降尿酸作用。
尿素氮水平是评价肾脏功能的经典指标，PO诱导的高尿酸血症模型小鼠血浆尿素氮水平显著高于溶剂对照组，低、中、高剂量的天然牛黄均能显著降低PO模型小鼠的血浆尿素氮水平(图1B)。Western Blot结果进一步显示(图1C)，高尿酸血症模型小鼠肾脏中，与肾纤维化相关的钙粘蛋白(E-CAD)表达降低、转化生长因子β1(TGFβ1)表达增加，而低、中、高剂量的天然牛黄能够显著缓解上述表达改变。
上述结果说明，天然牛黄在PO诱导高尿酸血症小鼠模型中有显著的降尿酸作用，且能够明显改善高尿酸血症引起的肾脏损伤。
实施例2牛黄替代品(体外培育牛黄)改善尿酸酶抑制剂诱导高尿酸血症小鼠
为阐明牛黄替代品是否具有降低血尿酸、改善高尿酸血症引起的肾损伤作用，本发明以体外培育牛黄为代表进行了相关研究。
2.1药品来源
体外培育牛黄(BCS)由武汉健民大鹏药业有限公司生产。
2.2动物分组及造模给药
体外培育牛黄(BCS)降尿酸作用实验：C57/BL雄性8周龄小鼠35只，饲养环境和给药方式如1.2。随机分为5组：溶剂对照组、模型组(氧嗪酸钾PO 250mg/kg+次黄嘌呤250mg/kg)、体外培育牛黄低(6.25mg/kg)、中(12.5mg/kg)和高(25mg/kg)剂量组，每组7只。
2.3样品收集
如1.3。
2.4生化指标测定和Western Blot实验
如1.4-1.5。
2.5结果分析
如图2所示，低、中、高剂量的体外培育牛黄(6.25，12.5和25mg/kg)均能显著降低PO模型小鼠的血浆尿酸(UA；图2A)和尿素氮(图2B)水平。Western Blot结果(图2C)表明，低、中、高剂量的体外培育牛黄均能有效恢复PO模型小鼠的肾脏促纤维化因子α平滑肌肌动蛋白(α-SMA)和转化生长因子β1(TGFβ1)等的表达。上述结果说明，体外培育牛黄在PO诱导高尿酸血症小鼠模型中有一致的降尿酸和肾脏保护作用。
实施例3天然牛黄和体外培育牛黄降低肝脏黄嘌呤氧化酶(xanthine oxidase，XO)和酮己糖激酶(ketohexokinase，KHK)的蛋白水平
黄嘌呤氧化酶(xanthine oxidase，XO)是人类嘌呤分解代谢的末端酶和尿酸合成的关键限速酶。果糖在肝脏中由酮己糖激酶(ketohexokinase，KHK)迅速代谢为果糖-1-磷酸，导致腺嘌呤核苷三磷酸(ATP)和磷酸化水平急剧下降，诱发不良代谢反应。在细胞内低水平磷酸盐作用下，腺苷单磷酸(AMP)脱氨酶活性增强，将AMP转化为肌苷-5'-单磷酸(IMP)，促进后续次黄嘌呤和黄嘌呤的累积。随后这些嘌呤前体在限速酶黄嘌呤氧化酶(XO)的催化作用下产生尿酸。因此肝脏黄嘌呤氧化酶(XO)和酮己糖激酶(KHK)是参与肝脏尿酸生成和促进高尿酸疾病进展的关键酶。
3.1牛黄降低肝脏黄嘌呤氧化酶的表达
提取实施例1-2中的小鼠肝脏蛋白，通过Western Blot测定黄嘌呤氧化酶(XO)蛋白表达变化。
5.2牛黄降低肝脏酮己糖激酶的表达
提取实施例1-2小鼠肝脏蛋白，通过Western Blot测定酮己糖激酶(KHK)蛋白表达变化。
3.3结果分析
如图3所示，实施例1-2中PO和HF诱导的高尿酸血症模型小鼠肝脏尿酸合成关键酶黄嘌呤氧化酶(XO)和酮己糖激酶(KHK)的蛋白表达上升。低、中、高剂量的天然牛黄(图3A)和体外培育牛黄(图3B)均能显著(P<0.05)降低PO模型小鼠肝脏黄嘌呤氧化酶(XO)和酮己糖激酶(KHK)的蛋白表达水平。
上述结果表明牛黄通过降低肝脏尿酸合成关键酶-黄嘌呤氧化酶和酮己糖激酶的蛋白表达水平，减少肝脏尿酸生成，从而发挥降尿酸作用，维持血尿酸稳态。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (3)
1.牛黄在制备预防或治疗高尿酸血症药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述牛黄为天然牛黄以及天然牛黄替代品。
3.如权利要求2所述的应用，其特征在于，所述天然牛黄替代品为体外培育牛黄。
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