本文選題：西夫韋肽 + 臨床藥代動(dòng)力學(xué)��； 參考：《北京理工大學(xué)》2014年博士論文

【摘要】：西夫韋肽是基于HIV-1膜融合蛋白gp41的核心構(gòu)象的三維結(jié)構(gòu)全新設(shè)計(jì)開發(fā)的新一代HIV融合抑制劑,具有良好的抗HIV藥物開發(fā)前景。為了對(duì)一類新抗HIV藥物西夫韋肽的臨床藥代動(dòng)力學(xué)、分子水平的藥理機(jī)制做出全面深入評(píng)價(jià)與研究,本文首先建立了HIV感染者體內(nèi)西夫韋肽的液質(zhì)聯(lián)用定量方法,并對(duì)方法進(jìn)行了完整詳細(xì)的確證性考察,結(jié)果表明液質(zhì)聯(lián)用定量方法靈敏度高達(dá)9.75 ng/mL;批內(nèi)(間)準(zhǔn)確度在-8.37~2.53%之間,精密度CV在2.74~7.57%之間;回收率在75.60~80.35%之間;血漿樣品在各種不同貯存條件下,準(zhǔn)確度在-6.56~4.51%之間,精密度CV在3.86~10.41%之間,表明各項(xiàng)方法學(xué)指標(biāo)考察結(jié)果均符合新藥臨床藥代動(dòng)力學(xué)研究要求,適用于HIV感染者血漿中西夫韋肽的含量測(cè)定。本文利用所建方法對(duì)IIa臨床試驗(yàn)兩個(gè)劑量組(10 mg、20 mg)共19名無(wú)治療經(jīng)驗(yàn)的HIV感染者每天一次皮下注射西夫韋肽連續(xù)給藥28天的藥代動(dòng)力學(xué)進(jìn)行了研究。結(jié)果表明在兩個(gè)劑量組(10 mg、20 mg)的病人體內(nèi),西夫韋肽被迅速吸收,達(dá)峰時(shí)間短,表觀分布較廣,半衰期長(zhǎng),表現(xiàn)出良好的藥代動(dòng)力學(xué)行為。連續(xù)28天多次給藥兩個(gè)劑量組病人血藥濃度平穩(wěn);累積比達(dá)到1.7和1.3,表現(xiàn)體內(nèi)有一定蓄積現(xiàn)象。在IIb臨床試驗(yàn)中,對(duì)8名有治療經(jīng)歷的HIV感染者皮下注射西夫韋肽聯(lián)合口服HAART(HighActiveAnti-Retrovirul Therapy)藥物連續(xù)治療168天的藥代動(dòng)力學(xué)進(jìn)行了研究。結(jié)果顯示HIV感染者連續(xù)128天給予20 mg西夫韋肽聯(lián)合HAART治療的藥時(shí)曲線表明平均波谷濃度Cmin均遠(yuǎn)大于體外藥效試驗(yàn)EC50;首次給藥后及末次給藥后各藥代動(dòng)力學(xué)參數(shù)均無(wú)顯著統(tǒng)計(jì)意義差異(P0.05),說(shuō)明168次連續(xù)給藥后,首末次給藥的藥代動(dòng)力學(xué)情況無(wú)顯著變化;聯(lián)合用藥病人代謝明顯加快,表現(xiàn)為清除速率加快,消除半衰期變短,西夫韋肽的藥代動(dòng)力學(xué)可能受到與HAART藥物合用的影響。本文第二部分首先建立了基于表面等離子體共振(SPR)的多肽-單雙層生物膜相互作用研究系統(tǒng),通過(guò)數(shù)據(jù)擬和結(jié)合模型分析,研究西夫韋肽(及恩夫韋肽)與生物膜親和常數(shù)的定量信息、多肽與生物膜結(jié)合的相互作用力的性質(zhì)(疏水作用及靜電作用)、多肽與生物膜結(jié)合方式(表面接合及插膜、孔道)的定性信息,以及動(dòng)力學(xué)過(guò)程信息(一步結(jié)合、兩步法反應(yīng)結(jié)合),從分子水平完善了西夫韋肽融合抑制的藥理機(jī)制。結(jié)果表明西夫韋肽首先在疏水相互作用或靜電吸附的驅(qū)動(dòng)下,以兩步反應(yīng)的方式,選擇性吸附和富集在生物膜受體豐富的剛性區(qū)域,只是膜表面結(jié)合,未能插膜或形成孔道,再與gp41結(jié)合發(fā)揮融合抑制藥效。而恩夫韋肽對(duì)所有磷脂膜均有一定程度的結(jié)合,并不特異選擇性吸附于飽和程度較高的磷脂構(gòu)成的單(雙)層生物膜,表明恩夫韋肽的磷脂膜普遍結(jié)合能力是其發(fā)揮融合抑制藥效的途徑。兩者對(duì)于生物膜選擇性的不同既表明兩者分子水平上不同的藥理機(jī)制,也解釋了西夫韋肽藥效強(qiáng)于恩夫韋肽的原因。本研究首次對(duì)無(wú)治療經(jīng)歷以及有HAART治療經(jīng)歷的HIV感染者中注射用西夫韋肽藥代動(dòng)力學(xué)以及安全性、療效等的長(zhǎng)期跟蹤和完整評(píng)價(jià)報(bào)道,直接為西夫韋肽的藥物上市審批提供第一手的臨床依據(jù),為不同治療經(jīng)歷的HIV感染者西夫韋肽的單用和與HAART藥物聯(lián)用的臨床給藥方案的完善提供了依據(jù)。第二部分的創(chuàng)新性在于建立了新型基于SPR的多肽-單雙層生物膜相互作用研究系統(tǒng),并首次應(yīng)用于多肽類融合抑制劑-生物膜相互作用研究,克服了目前其他方法不能解析多肽生物膜相互作用實(shí)時(shí)信息的缺陷,首次完整闡明了西夫韋肽和恩夫韋肽分子水平上與生物膜相互作用的膜向性、作用力分析、動(dòng)力學(xué)過(guò)程,并對(duì)西夫韋肽、恩夫韋肽已知融合抑制的藥理機(jī)制做出了進(jìn)一步完善,對(duì)西夫韋肽藥效遠(yuǎn)好于恩夫韋肽做出了合理解釋,為今后多肽類藥物與生物膜相互作用研究提供了新的方法選擇,也為HIV融合抑制劑篩選靶標(biāo)提供了新的思路。
[Abstract]:Siv Vee is a new generation of HIV fusion inhibitor based on the core conformation of the core conformation of HIV-1 membrane fusion protein gp41. It has a good prospect of anti HIV drug development. In order to make a comprehensive evaluation and Research on the clinical pharmacokinetics and molecular mechanism of a class of new anti HIV drugs, the molecular level mechanism of molecular level is thoroughly evaluated and studied. First, a quantitative method of liquid mass combined with SF in HIV infected people was established and a complete and detailed investigation was carried out. The results showed that the sensitivity of the quantitative method was up to 9.75 ng/mL; the intra (inter) accuracy was between -8.37~2.53% and CV in 2.74~7.57%; the recovery rate was between 75.60~80.35% and plasma samples. Under various storage conditions, the accuracy is between -6.56~4.51% and the precision of CV is between 3.86~10.41%. It shows that all the results of the methodology are in line with the requirements of the study of the pharmacokinetics of the new drug. It is suitable for the determination of the content of the plasma in the plasma of the HIV infected people. We use the method built for the two dose groups of the IIa clinical trial. (10 mg, 20 mg) a total of 19 HIV infected people with no therapeutic experience were studied for 28 days by subcutaneous injection of the subcutaneous injection of Western Fu. The results showed that in two dose groups (10 mg, 20 mg), Western FV was quickly absorbed, the peak time was short, the apparent distribution was wide, the half-life was long, and a good drug generation was shown. Dynamic behavior. The blood concentration of patients with two doses of medication for 28 consecutive days for 28 consecutive days was stable; the cumulative ratio reached 1.7 and 1.3, showing a certain accumulation in the body. In the IIb clinical trial, 8 patients with therapeutic HIV infection were subcutaneously injected with Western Fu Wei peptide combined with oral HAART (HighActiveAnti-Retrovirul Therapy) for 168 days. The results of pharmacokinetics were studied. The results showed that the curves of HIV infected people with 20 mg and HAART for 128 days showed that the average trough concentration Cmin was far greater than that of EC50 in vitro, and there was no statistically significant difference in the pharmacokinetic parameters after and after the first administration (P0.05), indicating 168 consecutive times. In the second part, the second part first established a surface plasmon resonance (SPR). The second part of the article first established a surface plasmon resonance (SPR). The research system of the interaction of polypeptides and double layers biofilm. Through the analysis of data quasi and binding models, the quantitative information of the affinity constants of the peptide and the biofilm, the properties of the interaction between the peptide and the biofilm (hydrophobic interaction and electrostatic action), the binding of the peptide and the biofilm (surface conjugation and intercalation, hole) The qualitative information of the road, as well as the dynamic process information (one step combined with the combination of the two step method), improved the pharmacological mechanism of the fusion inhibition from the molecular level. The results showed that the SFG first was selectively adsorbed and enriched in the biofilm receptor, driven by hydrophobic interaction or electrostatic adsorption. The rich rigid area is only the membrane surface binding, failure to insert the membrane or form the channel, and then combine with the gp41 to inhibit the efficacy of fusion, while Don J Vee has a certain combination of all phospholipid membranes, which is not selectively adsorbed on the single (double) layer of high saturated phospholipids, indicating that the phospholipid membrane of the peptide is generally nodding. Combining ability is the way to play the inhibitory effect of fusion. The difference in selectivity to the biofilm shows both the different pharmacological mechanisms at the molecular level and the reason for the stronger efficacy of the drug than emweinin. This study was the first time for the non treatment experience and the injection of the Western Fu Wei peptide drug in the patients with HIV infection with HAART therapy. The long-term tracking and complete evaluation of the pharmacokinetics, safety, efficacy, and so on provide the first hand clinical basis for the approval of the drug listing for the drugs of the HIV, which provides the basis for the improvement of the single use of the HIV infected people with different treatment experiences and the clinical drug delivery scheme combined with HAART drugs. The second part is innovative. A new SPR based polypeptides single layer biomembrane interaction study system was established, and it was first applied to the study of polypeptides fusion inhibitors biological membrane interaction, which overcome the shortcomings of other methods that can not analyze the real-time information of the interaction of polypeptides, and first fully elucidated the water of Siv Vee and Don J Vee molecules. The film direction, force analysis and kinetic process of the interaction with the biofilm have been further improved, and the pharmacological mechanism of the known fusion inhibition of Siv Vee and En Fuwei peptide has been further perfected, and a reasonable explanation for the efficacy of the Western husband peptide is better than that of the weilweir peptide, which provides a new study for the study of the interaction of polypeptide drugs and biofilm in the future. The method also provides a new idea for screening targets of HIV fusion inhibitors.
【學(xué)位授予單位】：北京理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R969.1

【共引文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前1條

1 譚娟;HIV患者腦脊液蛋白質(zhì)組學(xué)的研究[D];華東師范大學(xué);2013年

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本文編號(hào)：2069754