新药左旋班布特罗的降胆固醇效果及其机理的初步研究

发布时间：2018-03-17 23:27

本文选题：左旋班布特罗　切入点：高血脂症　出处：《华南理工大学》2016年硕士论文　论文类型：学位论文

【摘要】：高血脂症能够导致各种心脑血管疾病,是严重威胁人类健康的一种疾病。班布特罗是一种治疗哮喘的药物,左旋班布特罗(R-bambuterol,R-BMB)是班布特罗的左旋异构体,具有比消旋班布特罗更好的安全性以及治疗效果。通过临床一期实验证明其存在着有效地降脂的作用,但是其具体的降脂机理却需要进一步的研究。本研究的主要内容是:1)临床数据分析显示R-BMB能够有效地降低血脂总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)的浓度,对高血脂病症体现出良好的治疗效果。对给药后24 h的血脂分析发现R-BMB可能是通过降低小而密低密度脂蛋白胆固醇(sd-LDL-C)的方式来实现降低LDL-C;研究中发现R-BMB能够有效地抑制丁酰胆碱酯酶(BuChE)活性,且BuChE活性的变化程度与ApoB、sd-LDL的变化程度存在一定的相关性。2)采用含有1%胆固醇的高脂饲料能够在3周的时间内建立稳定的新西兰大白兔高脂模型;高剂量的R-BMB能够有效地降低高血脂家兔的血脂TC和LDL-C的浓度,和阿托伐他汀一样对高血脂症能起到良好的治疗作用,且R-BMB降低高血脂的作用呈现出剂量相关性;相比模型组,单独给予BuChE抑制剂ISO-OMPA能有效降低血脂TC和LDL-C浓度;而R-BMB的原型药左旋特布他林(R-TBT),它能发挥β2受体激动的作用却对血脂没有作用,可知R-BMB降低血脂的主要原因是抑制了BuChE的活性而导致。3)通过对空白组、模型组、R-BMB高剂量组和ISO-OMPA组的血浆BuChE的活性的测定,发现R-BMB高剂量组和ISO-OMPA组血浆中BuChE活性被明显的抑制,且BuChE活性的抑制程度与R-BMB血药浓度有严格的相关性,进一步表明血脂的降低与BuChE存在着一定的关联;对肝脏、心脏以及脂肪等器官中BuChE活性分析发现,与模型组相比R-BMB和ISO-OMPA均能够有效地降低肝脏和心脏中游离的以及与膜紧密结合的BuChE活性;对血浆中谷丙转氨酶(ALT)和天冬氨酸转移酶(AST)的浓度进行测定,发现R-BMB不会升高ALT和AST的浓度,而阿托伐他汀会导致ALT浓度的升高;对血糖血钾的研究发现,R-BMB能降低血糖的浓度,而对血钾没有影响;最后对空白组、模型组、R-BMB高剂量组和阿托伐他汀组的肝脏、心脏的HE染色切片发现,各组之间心脏切片没有明显的变化,而在肝脏中可以观察发现,对比模型组R-BMB对脂肪肝会有改善作用,结合上述R-BMB对转氨酶的影响可知,R-BMB对肝脏存在着保护作用。
[Abstract]:Hyperlipidemia can cause various cardiovascular and cerebrovascular diseases, is a serious threat to human health. Bambuterol is a medicine for treating asthma, bambuterol (R-bambuterol, R-BMB) - is levoisomer bambuterol, has better security than racemic bambuterol and therapeutic effect. Through clinical experiments to prove its existence period effective lipid-lowering effect, but the specific lipid-lowering mechanism is the need for further research. The main contents of this study are: 1) the clinical data analysis showed that R-BMB can effectively reduce the blood total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) concentrations, showed good therapeutic effect on high blood lipid disorders. On blood lipid analysis of 24 h after administration of R-BMB may be through the reduction of low density lipoprotein cholesterol (sd-LDL-C) method to reduce the R-B of LDL-C; MB can effectively inhibit the butyrylcholinesterase (BuChE) activity, and the change degree of the activity of BuChE and ApoB, the changes of sd-LDL.2 exist certain correlation) with high fat diet containing 1% cholesterol to New Zealand white rabbits with high fat model is stable over a period of 3 weeks; the high dose of R-BMB can effectively to reduce the concentration of hyperlipidemia rabbits serum lipids in TC and LDL-C, and atorvastatin for hyperlipidemia can play a good therapeutic effect, and reduce the R-BMB effect of high blood cholesterol showed dose dependence; compared to model group, separately given BuChE inhibitor ISO-OMPA can effectively reduce the blood TC and LDL-C concentration; and the drug prototype L R-BMB terbutaline (R-TBT), it can play the role of the beta 2 receptor had no effect on blood lipids, the main reason is the decrease of R-BMB lipids inhibited the activity of BuChE and.3) of the blank group by lead, The model group, plasma BuChE high dose of R-BMB group and ISO-OMPA group activity, BuChE activity in high dose of R-BMB group and ISO-OMPA group in plasma were obviously inhibited, and the inhibition of BuChE activity and R-BMB blood concentration has a strict correlation, further shows that reducing blood lipids have a certain relevance with BuChE; the analysis shows that the activity of BuChE on the liver, heart and other organs in fat, R-BMB and ISO-OMPA could effectively reduce the liver and heart free and combined with membrane BuChE activity compared with the model group; the plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations were measured and found the concentration of R-BMB and AST ALT will not increase, and atorvastatin can lead to the increase of ALT concentration; Study on serum glucose and potassium found that R-BMB can reduce the blood glucose concentration of blood potassium did not influence; at the end of the blank group, The model group, R-BMB high dose group and atorvastatin group in the liver and heart HE staining were found between cardiac sections did not change obviously, while in the liver can be observed, compared with the model group R-BMB will improve effect on fatty liver, with the effect of R-BMB on transaminase shows that the existence of R-BMB a protective effect on the liver.

【学位授予单位】：华南理工大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R589.2

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