發(fā)布時間：2018-02-22 02:52

  本文關(guān)鍵詞： 丹參素 冰片 前藥 腦靶向 P-糖蛋白　出處：《合肥工業(yè)大學》2017年碩士論文　論文類型：學位論文

【摘要】：丹參素(Danshensu,DSS)具有治療缺血性心腦血管疾病的藥理活性,但其易氧化、化學性質(zhì)不穩(wěn)定、體內(nèi)半衰期短、腦部靶向性也有待加強。血腦屏障通透性增加及P-糖蛋白(P-gp)外排功能抑制均有助于提高藥物腦靶向性。已有研究報道,丹參-冰片合用,能提高丹參素的腦部分布。為此,本文將具有血腦屏障促透及P-gp抑制作用的冰片作為載體引入丹參素,設(shè)計了一系列丹參素-冰片酯類前藥,通過對這些分子腦靶向相關(guān)參數(shù)預測、篩選,確定了目標分子,并進行目標分子及丹參素-冰片聯(lián)合用藥腦靶向作用研究,研究結(jié)果如下:(1)采用計算軟件對丹參素-冰片酯類分子的篩選結(jié)果表明:丹參素冰片酯(Danshensu Broneol ester,DBE)可能具有潛在腦靶向作用。對設(shè)計的6個丹參素-冰片酯類分子(DB1-DB6)進行了脂水分配系數(shù)(logP)、腦血濃度比(BB)預測及P-gp親和力,并結(jié)合合成難易分析,我們選擇DBE(代號DB1)作為目標分子進行合成及后續(xù)體內(nèi)靶向性評價。(2)前藥DBE及丹參素鈉-冰片(Sodium Danshensu-borneol,SDSS-B)聯(lián)合用藥均表現(xiàn)出明顯的腦靶向作用,DBE治療有效指數(shù)(therapeutic availability,TA)和腦靶向指數(shù)(drug targeting index,DTI)優(yōu)于聯(lián)合用藥。建立了DSS在大鼠血漿和腦勻漿的HPLC定量檢測方法,采用該方法研究了大鼠尾靜脈注射SDSS、DBE及SDSS-B藥代動力學。DBE在大鼠血漿中藥代動力學參數(shù)得以改善,其分解得到DSS的t1/2、MRT0-∞相比SDSS分別增加了1.76、1.71倍。同時,DBE及SDSS-B在大鼠腦內(nèi)檢測到DSS的腦部吸收量明顯增加;MRT0-∞分別為直接注射SDSS的2.71倍和1.42倍,DBE相比SDSS-B更能顯示出長效緩釋特性。SDSS-B和DBE的TA分別為3.39和4.15;DTI分別為3.63和9.93。(3)DBE腦靶向性強于SDSS-B,這與其有效抑制P-gp表達和外排轉(zhuǎn)運功能有關(guān)。通過大鼠給藥后腦組織海馬區(qū)P-gp的蛋白免疫印跡檢測結(jié)果表明:與溶媒控制組相比,SDSS僅在30min時對P-gp表達有抑制作用;DBE和SDSS-B除給藥5 min外,在其它給藥間隔均可顯著降低大鼠海馬組織中P-gp表達量(P0.01)。在給藥45 min時,DBE及SDSS-B組的P-gp表達量均處于最低水平,分別達到47.58%和46.54%;隨著給藥時間延長至60 min,DBE對P-gp表達的抑制作用強于SDSS-B(85.04%vs.95.29%)。以羅丹明123作為底物對大鼠給予SDSS、DBE、SDSS-B的P-gp外排功能檢測結(jié)果表明:與SDSS給藥相比,SDSS-B聯(lián)合給藥和DBE前藥在給藥后各時間的腦組織中Rho123濃度均呈現(xiàn)增加趨勢,對應的Kp值也分別增至1.26~4倍和1.38~5.4倍。在四個給藥時刻,SDSS-B及DBE均能抑制大鼠腦部P-gp外排功能,以DBE的抑制作用更強。
[Abstract]:Danshensuang DSSs has pharmacological activity in treating ischemic cardiovascular and cerebrovascular diseases, but it is easy to be oxidized, unstable in chemical properties, and has a short half-life in vivo. The enhancement of blood-brain barrier permeability and the inhibition of P-gp efflux function can improve the drug's brain targeting. It has been reported that the combination of Danshen and Borneol can improve the brain distribution of Danshensu. In this paper, borneol with blood-brain barrier penetration and P-gp inhibition was introduced into Danshensu. A series of Danshensin-borneol prodrugs were designed. The target molecules and the brain targeting effect of Danshensu combined with borneol were studied. The results are as follows: (1) the screening results of Danshensu borneol ester molecules by computer software show that Danshensu Broneol estersterol DBE) may have a potential brain targeting effect on the design of six Danshensin-borneol ester molecules (danshensu Broneol ester-DB6). The prediction of lipid water partition coefficient (log P), brain blood concentration ratio (BBB) and P-gp affinity were carried out. And combined with the difficult and easy analysis of synthesis, We selected DBE (code name DB1) as target molecule to synthesize and evaluate in vivo targeting ability of DBE) prodrug DBE and sodium Danshensu-borneoln SDSS-B both showed obvious brain targeting effect and DBE showed significant therapeutic effect on efficacy index of therapeutic efficacy and availability of brain target TA) and brain target drugs such as Danshensu-borneolium SDSS-B). The index drug targeting index (DTI) was superior to that of combined drug therapy. A HPLC quantitative method for the detection of DSS in plasma and brain homogenate of rats was established. This method was used to study the improvement of plasma pharmacokinetic parameters of SDSS-dae and SDSS-B pharmacokinetics in rats. Compared with SDSS, the t 1 / 2% MRT0- 鈭，

本文編號：1523470