【摘要】：背景:高血脂癥的發(fā)病率很高,可導(dǎo)致多種心腦血管疾病,而目前臨床上的降脂藥物仍無法達到預(yù)期治療目標,研究新的降脂藥物對于控制高血脂癥十分有必要。左旋班布特羅(R-bambuterol,R-BMB)是班布特羅(bambuterol,BMB)的左旋異構(gòu)體,具有比BMB更好的成藥性且安全性十分良好,而BMB具有改善血脂的功效。因此,考察R-BMB是否具有更好的降血脂效果十分有意義。由此,我們對R-BMB在小鼠、家兔和人體內(nèi)降血脂的效果進行了評價,為R-BMB作為一種降脂藥提供實驗基礎(chǔ)。目的:考察R-BMB在動物體和人體內(nèi)降脂效果,初步推測R-BMB降血脂的作用過程和可能的機制。方法:(1)建立Apo E-/-小鼠高血脂模型,灌胃給予R-BMB,測定小鼠不同時間點血脂水平。(2)通過高膽固醇喂養(yǎng),建立家兔高血脂模型,給予R-BMB并測定家兔在不同時間點血脂的水平。(3)在隨機開放的I期臨床實驗中,測定血漿中膽固醇及相關(guān)脂蛋白的水平,結(jié)合關(guān)鍵藥代動力學參數(shù),分析健康受試者口服不同劑量R-BMB后血脂下降情況。結(jié)果:(1)在給予R-BMB后,Apo E-/-小鼠體內(nèi)血脂無顯著性變化;(2)在進行高脂喂養(yǎng)后,家兔體內(nèi)血脂水平(TC、LDL-C、HDL-C)顯著升高,成功建立高血脂家兔模型。在給予R-BMB后,高血脂模型家兔血漿TC和LDL-C顯著性下降(P0.05),而TG和HDL-C水平無顯著性變化(P0.05)。(3)口服不同劑量R-BMB后,臨床受試者LDL-C和TC水平顯著性下降(P0.05),且具有劑量相關(guān)性,HDL-C在短期出現(xiàn)下降,但多次給藥后恢復(fù)到給藥前的水平。R-BMB對血脂的降低效果高于BMB。結(jié)論:在Apo E-/-小鼠內(nèi),R-BMB無明顯降脂效果。而在家兔體內(nèi),R-BMB可顯著降低LDL-C和TC水平。在人體內(nèi),R-BMB可降低血漿LDL-C和TC水平,其中對LDL-C的降低效果最為明顯,且具有劑量相關(guān)性。本試驗中,R-BMB對TG水平無顯著性影響。R-BMB具有比Rac-BMB更好的降脂前景。
[Abstract]:Background: the incidence of hyperlipidemia is very high, which can lead to a variety of cardiovascular and cerebrovascular diseases. R-BMB is a levoisomer of bambuterolol (BMB), which has better drug formation and better safety than BMB, while BMB has the effect of improving blood lipid. Therefore, it is very meaningful to investigate whether R-BMB has better effect of lowering blood lipid. Therefore, we evaluated the effect of R-BMB on blood lipids in mice, rabbits and human beings, and provided the experimental basis for R-BMB as a lipid lowering drug. Aim: to investigate the effect of R-BMB on lowering blood lipid in animals and human body, and to speculate the mechanism and mechanism of R-BMB. Methods: (1) the hyperlipidemia model of Apo E-r-mice was established, and R-BMBs were administered intragastrically. (2) the hyperlipidemia model of rabbits was established by high cholesterol feeding. R-BMB was given to rabbits and blood lipids were measured at different time points. (3) in a randomized phase I clinical trial, the plasma cholesterol and related lipoproteins were measured, and the key pharmacokinetic parameters were combined. To analyze the decline of blood lipids in healthy subjects after oral administration of different doses of R-BMB. Results: (1) there was no significant change of blood lipid in Apo E-r-mice after R-BMB administration, and (2) after hyperlipidemia feeding, the level of serum lipids (TCU LDL-C) in rabbits was significantly increased, and the hyperlipidemia rabbit model was successfully established. After administration of R-BMB, plasma TC and LDL-C decreased significantly in hyperlipidemia model rabbits (P0.05), while TG and HDL-C levels did not change significantly (P0.05). (3) after taking different doses of R-BMB. The levels of LDL-C and TC decreased significantly in clinical subjects (P0.05), and HDL-C decreased in a short period of time, but returned to the level before administration. R-BMB was more effective than BMB in reducing blood lipids. Conclusion: R-BMB has no effect on lipid reduction in Apo-E-r-mice. However, R-BMB significantly decreased the levels of LDL-C and TC in rabbits. R-BMB can reduce plasma LDL-C and TC levels in human body. The effect of R-BMB on the decrease of LDL-C is the most obvious, and it has a dose-dependent effect. In this experiment, R-BMB has no significant effect on TG level. R-BMB has a better lipid lowering prospect than Rac-BMB.
【學位授予單位】：華南理工大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R589.2

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