CN1206206C - 肝脏储备功能检测试剂碳核素标记的利多卡因 - Google Patents
肝脏储备功能检测试剂碳核素标记的利多卡因 Download PDFInfo
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Abstract
本发明涉及医药技术领域，是一种用于检测肝脏储备功能的试剂碳核素标记的利多卡因。本发明利用利多卡因在肝内代谢过程中产生CO2通过呼吸排出这一现象，采用核素13C或14C取代基团上的任一碳原子，最终4个碳原子均生成CO2通过呼吸排出体外，检测13CO2或14CO2的量以确定脱乙基量，从而判断具有正常代谢功能的肝细胞数量，亦即肝脏的储备功能。用本发明碳核素标记的利多卡因检测肝储备功能，方法简单，价格低廉，灵敏度高，不受病人黄疸的干扰。
Description
技术领域：本发明涉及医药技术领域，是用于检测肝脏储备功能的试剂13C或14C标记的利多卡因。
背景技术：利多卡因是临床上常用的药物，主要用以局部麻醉、浸润麻醉及抗心律失常，近年来被作为试剂用于肝脏外科、肝移植及肝病学等领域的肝脏储备功能的检测。其原理是根据利多卡因在肝内的代谢过程中生成产物单乙基甘氨酰二甲苯胺(MEGX)，用荧光偏振免疫法检测血液中的MEGX的含量来确定具有正常代谢功能的肝细胞的数量，从而反映出肝脏的储备功能。(M Oellerich，et al.Monoethyglycinexylidide formationRinetics：A novel approach to assessment of liver function.Journd of clinicalchemestry and clinical biochemistry，1987：25(12)：845-853)
利多卡因在肝脏内的代谢途径为：
利用代谢产物MEGX检测肝储备功能对肝硬化诊断、肝脏大范围手术后并发症的预测等均优于常规肝功能试验，但其不足之处为：1、必须抽血检测，标本要处理，必须使用进口试剂盒及进口的专用检测设备，故价格昂贵；2、由于使用荧光法检测，因此易受肝病病人常见的胆红素异常的干扰而影响结果的准确性。
发明内容：本发明根据利多卡因在肝内代谢过程中脱下乙基生成乙醛，最终四个碳原子经代谢均生成CO2并通过呼吸排出体外这一现象，采用核素14C或13C取代基团上乙基的任一碳原子，定时定量检测呼出气体中核素标记的14CO2或13CO2的量即可判断肝脏的储备功能。
本发明的优点和积极效果为：
采用本发明试剂检测，方法简单不必抽血，无需进口试剂及设备，费用较低，检测结果不受血胆红素异常的影响，灵敏度高。
具体实施方式：
实施例1：14C标记利多卡因的制备
试剂与材料：
放射性试剂 购自英国Amersh公司
其余普通试剂 购自上海化学试剂公司
步骤：
1、14C-KCN的合成
以Ba14CO3为初始原料，制备K14CN：Ba14CO3 18mg(0.09mmol)，比活度为2146MBq/mmol，加BaCO3 150mg(0.757mmol)、NaN3 700mg(10.7mmol)，再加5倍体积的石英砂，在玛瑙研钵中研细混和后移入石英玻璃管，上面覆盖一层石英砂，再将玻璃管放入不锈钢套管中抽真空，加热至700℃，保温半小时；冷却，用0.1M磷酸将PH调至5，用KOH溶液吸收，得到14C-KCN。
2、CH3 14CN的制备
将分析纯碘甲烷(CH3I)0.4ml加入到盛有以上所得14C-KCN的蛋形瓶中，电磁搅拌反应，过夜；反应结束后，进行高真空转移除盐，得CH3 14CN。
3、14C-二乙胺的合成
在氢化蛋形瓶中放入催化剂PtO2 61mg，加入上述所得的CH3 14CN反应液，在乙醇∶醋酸＝2∶1(V/V)、总体积3ml、温度30℃条件下氢化反应23小时；反应完毕后离心分离催化剂PtO2，经真空转移浓缩，得14C-二乙胺。
4、14C-利多卡因的合成
取上述所得14C-二乙胺加无水乙醇5ml，再加碳酸钠930mg和w-氯乙酰-2，6-二甲苯胺，搅拌反应96小时后用HCl调至PH5，用3×10ml氯仿萃取；弃有机相，水相用NaOH调至PH8.0，10ml氯仿萃取，得MEGX和利多卡因混合物；用硅胶G板层析分离，溶剂系统为正丁醇∶醋酸∶水＝4∶1∶1(V/V)；与标准品对照，在相应部位挖取放射性标记物，以注射用水浸取，即得14C-利多卡因纯品。
实施例2 13C标记的利多卡因的制备
具体操作为：
1、制备氯化乙酰
氯化亚砜6ml滴加于13C标记的醋酸钠中，加热回流，蒸馏收集沸程为48-51℃得1.5mlCH3COCl，化学产率30％。
2、制备N-乙基乙酰胺
6ml 13C标记氯化乙酰溶于6ml无水乙醚，滴加20ml无水乙胺醚溶液搅拌反应，过滤沉淀得产品6.5g(理论计算值为7.34g)化学产率88％。
3、制备二乙胺
上述所得N-乙基乙酰胺醚溶液滴加LiALH4醚溶液，室温还原反应约16小时，加热回流3小时，用饱和Na2CO3水溶液水解进行蒸馏，收集沸点58℃左右得到0.5ml二乙胺，化学产率16.7％。
4、合成利多卡因前体1.4ω-氯代乙酰-2，6-二甲基苯胺。0.02M2.6-二甲基苯胺溶于醋酸，滴加氯乙酰氯(0.022M)搅拌反应5小时，有固体生成，反应完毕，滤出固体，水洗至无酸味即可。
5、合成利多卡因(二乙基甘氨酰二甲苯胺)
将以上所得的二乙胺醇溶液加碳酸钠及所得1.4ω-氯代乙酰-2，6-二甲基苯胺，回流反应6小时，去除醇，加水酸化，过滤沉淀，去除未反应前体，再用丙酮重结晶。即得13C标记的利多卡因。
实施例3：动物实验14C标记利多卡因呼出14CO2的检测：
将小鼠用乙醚麻醉法麻醉后，抽取0.2ml(0.2微居)利多卡因注入小鼠腹腔内，将小鼠放入经典的密封气体收集循环系统中，启动循环泵，调整开关，达到流量为180ml/min，气体进入海胺溶液时，小鼠呼出的14CO2被海胺溶液吸收，海胺溶液中加入酚酞指示剂，当海胺吸收14CO2饱和后，PH改变，指示剂变色，即更换新的溶液。将吸收14CO2的海胺溶液装入液闪瓶中检测。分别在注药后45min、90min、135min、180min、225min、270min、315min、360min、405min取样检测，发现正常小鼠从90min到135min出现峰值，至360min、405min已基本降至注药后45min时浓度。而肝脏受损害或被切除肝叶的小鼠试验可发现峰值延后及峰值降低，从而反映出了肝储备功能受损的小鼠的肝功真实情况。
Claims (1)
1.肝脏储备功能检测试剂碳核素标记的利多卡因，分子结构如下：
其特征在于*C表示的碳核素为13C。
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| CN112521315B (zh) * | 2019-09-17 | 2023-04-07 | 鲁南制药集团股份有限公司 | 一种利多卡因降解杂质的制备方法 |
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