CN116869982A - 羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用 - Google Patents
羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用 Download PDFInfo
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Abstract
本发明公开了羟基‑α‑山椒素在制备预防、治疗心力衰竭药物的应用，涉及药物制备技术领域，其技术方案要点是：所述羟基‑α‑山椒素可降低天乳酸脱氢酶、肌酸激酶、冬氨酸氨基转移酶和心肌肌钙蛋白T的活性，因此羟基‑α‑山椒素可用于制备预防、治疗心力衰竭的药物，能够为该药物的制备提供了物质基础，可推进相关药物体系的建立。
Description
技术领域
本发明涉及药物制备技术领域，更具体地说，它涉及羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用。
背景技术
心肌炎在临床及病理学上被定义为病变范围主要限于心肌的炎症性疾病，由多种病原体、过敏或自身免疫疾病等引起。心肌炎的临床表现差异很大，部分患者无明显症状或有轻微临床症状，严重者常表现为心力衰竭、顽固性心律失常、休克，甚至心源性猝死。心肌炎的全球发病率估计每年有22/10万。1997至2002年及2006至2011年日本2次全国临床调查资料显示，儿童心肌炎年发病率分别为0.26/100000及0.3/100000。中华医学会儿科学分会曾调查了国内33家医院2006年7月至2018年12月4981例心肌病住院患儿，发现儿童心肌病占同期儿科住院患儿的0.079％，且年度住院人数整体呈逐年增多趋势，总体病死率为7.31％。心肌病治疗的药物非常有限，副作用明显，HAS作为一个有前途的创新药，其在心肌细胞保护方面的药效及作用机制目前还未见报道。
羟基-α-山椒素(Hydroxy-α-sanshool,HAS)是花椒果皮中提取得到一种酰胺类生物碱。HAS能与多种离子通道和受体结合，具有广泛的药理作用。HAS具有调节脂质代谢和抗动脉粥样硬化作用，其作用机制可能与抗炎、抗氧化应激以及通过PPARγ-LXRα-ABCA1通路上调ABCA1蛋白表达和促进胆固醇逆向转运有关。口服HAS能改善东莨菪碱引起的认知能力障碍、保护海马神经元细胞和上调BDNF和CREB；HAS通过上调PI3K/Akt信号抑制H2O2诱导的PC12细胞氧化应激水平和细胞凋亡。花椒酰胺类物质喂养20天能显著改善糖尿病模型鼠血糖、血脂紊乱，修复胰岛β细胞，下调CB1受体和上调TRPV1的表达；HAS干预还可以通过调节Ins/IGF1-PI3K/Akt-mTOR信号，提高葡萄糖转运速率，通过UPP途径增加蛋白质合成，降低骨骼肌的蛋白质分解代谢。此外，HAS还具有局部止痛，防治术后肠梗阻和缓解腹胀腹痛等作用。HAS口服后能经胃肠道迅速吸收，起效迅速，全身分布，经肾脏排泄，在血浆中形成糖苷酸结合物，生物利用度高，具有良好的成药性。目前用于心肌病治疗的药物非常有限，副作用明显，如能开发更多有效保护心肌细胞的药物，在治疗儿童心肌炎，减少重症发生率等方面具有重要意义。
发明内容
本发明的目的是提供羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用，羟基-α-山椒素可用于制备预防、治疗心力衰竭药物，为该药物的制备提供了物质基础，可推进相关药物体系的建立。
本发明的上述技术目的是通过以下技术方案得以实现的：羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用，所述羟基-α-山椒素可用于制备预防、治疗心力衰竭的药物。
本发明进一步设置为：所述羟基-α-山椒素可降低天乳酸脱氢酶、肌酸激酶、冬氨酸氨基转移酶和心肌肌钙蛋白T的活性。
本发明进一步设置为：所述羟基-α-山椒素有效的浓度范围为5-20mg·Kg-1(大鼠剂量)。
综上所述，本发明具有以下有益效果：本发明提供了羟基-α-山椒素的新用途，将其用于制备预防、治疗心力衰竭药物，为该药物的制备提供了物质基础，可推进相关药物体系的建立。基于本发明所提供的物质基础能开发更多有效保护心肌细胞的药物，在治疗儿童心肌炎、减少重症发生率等方面具有重要意义。
附图说明
图1是本发明对大鼠做的心电图；
图2是本发明HAS对心肌缺血大鼠血清LDH酶的影响.**P<0.01,vs.Model；
图3是本发明HAS对心肌缺血大鼠血清CK酶的影响.**P<0.01,vs.Model；
图4是本发明HAS对心肌缺血大鼠血清AST的影响.**P<0.01,vs.Model；
图5是本发明HAS对心肌缺血大鼠血清cTnT的影响.**P<0.01,vs.Model。
具体实施方式
以下结合附图1-5对本发明作进一步详细说明。
实施例1：心肌梗死(MI)模型的构建
选取50只健康SD大鼠进行适应性喂养，喂养一周后，随机选取10只大鼠做空白对照组，剩余40只大鼠采用ISO模型进行造模。将40只大鼠随机分为四组，每组10只，分别是模型组、HAS低剂量组、HAS中剂量组、HAS高剂量组。
实验持续时间共14天。
模型组每天腹腔注射40mg/kg盐酸异丙肾上腺素(ISO)建立心肌梗死(MI)模型，实验期间使其自由进食饮水。
HAS低剂量组每天灌胃5mg/Kg羟基-α-山椒素，第13天和第14天的末次给药1h后，腹腔注射40mg/kg盐酸异丙肾上腺素(ISO)建立心肌梗死(MI)模型，实验期间使其自由进食饮水。
HAS中剂量组每天灌胃10mg/Kg羟基-α-山椒素，第13天和第14天的末次给药1h后，腹腔注射40mg/kg盐酸异丙肾上腺素(ISO)建立心肌梗死(MI)模型，实验期间使其自由进食饮水。
HAS高剂量组每天灌胃20mg/Kg羟基-α-山椒素，第13天和第14天的末次给药1h后，腹腔注射40mg/kg盐酸异丙肾上腺素(ISO)建立心肌梗死(MI)模型，实验期间使其自由进食饮水。
空白对照组不做任何处理，使其自由进食饮水即可。
与空白对照组相比，模型组S-T段抬高显著；与模型组相比，HAS给药组S-T段显著降低。模型组LDH、CK、AST、cTnT含量显著升高(P<0.01)，HAS中剂量组MDA、cTnl、LDH、CK-MB含量较模型组显著降低(P<0.01)。
实施例2：大鼠身体表征
(1)心电图测试
对空白组、HAS中剂量组和模型组的大鼠做心电图测试，其测试结果如图1所示，从心电图测试结果可以看出HAS对心肌缺血大鼠心电图有保护作用。
(2)血清LDH、CK、AST、cTnT含量测定
分别取空白组、HAS中剂量组和模型组大鼠的血液，将血液在4℃下静置30min，离心(3500r/min，4℃，10min)，取上清，于-80℃保存备用。按照试剂盒说明书检测各组血清样本中天乳酸脱氢酶(LDH)、肌酸激酶(CK)、冬氨酸氨基转移酶(AST)、心肌肌钙蛋白T(cTnT)活性。检测结果如图2-5所示，根据图中可以看出HAS能够有效降低天乳酸脱氢酶(LDH)、肌酸激酶(CK)、冬氨酸氨基转移酶(AST)和心肌肌钙蛋白T(cTnT)的活性。
本具体实施例仅仅是对本发明的解释，其并不是对本发明的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本发明的权利要求范围内都受到专利法的保护。
Claims (3)
1.羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用，其特征是：所述羟基-α-山椒素可用于制备预防、治疗心力衰竭的药物。
2.根据权利要求1所述的羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用，其特征是：所述羟基-α-山椒素可降低天乳酸脱氢酶、肌酸激酶、冬氨酸氨基转移酶和心肌肌钙蛋白T的活性。
3.根据权利要求1所述的羟基-α-山椒素在制备预防、治疗心力衰竭药物的应用，其特征是：所述羟基-α-山椒素有效的浓度范围为5-20mg·Kg-1。
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