本文選題：貝伐單抗 + 膜聯(lián)蛋白A5脂質(zhì)體　； 參考：《新鄉(xiāng)醫(yī)學(xué)院》2017年碩士論文

【摘要】：背景目前,新生血管性眼病的發(fā)病率不斷上升。貝伐單抗是一種治療新生血管性眼病的單克隆抗體藥物。由于各種眼部屏障的存在,局部點(diǎn)眼治療無(wú)法在眼內(nèi)到達(dá)有效濃度。目前臨床上采用玻璃體注射此類藥物來(lái)治療眼內(nèi)新生血管性疾病。但多次玻璃體注射可能產(chǎn)生一些嚴(yán)重并發(fā)癥。近來(lái)研究發(fā)現(xiàn),采用膜聯(lián)蛋白A5脂質(zhì)體作為載體可以使貝伐單抗穿過(guò)角膜的能力有較大的提高,具有成為對(duì)眼內(nèi)新生血管性疾病進(jìn)行無(wú)創(chuàng)性治療方法的潛力。因此,對(duì)貝伐單抗膜聯(lián)蛋白A5脂質(zhì)體滴眼液在兔眼的藥物代謝動(dòng)力學(xué)進(jìn)行研究將會(huì)對(duì)臨床治療眼內(nèi)新生血管性疾病能夠提供幫助。目的為減少眼部并發(fā)癥,提高藥物局部應(yīng)用的眼內(nèi)通透性,本研究通過(guò)制備一種新型貝伐單抗膜聯(lián)蛋白A5脂質(zhì)體滴眼液,通過(guò)對(duì)實(shí)驗(yàn)動(dòng)物進(jìn)行局部點(diǎn)眼,對(duì)其眼部藥動(dòng)學(xué)進(jìn)行研究,為臨床治療視網(wǎng)膜脈絡(luò)新生血管性疾病提供實(shí)驗(yàn)基礎(chǔ)與理論依據(jù)。方法1.制備藥品:貝伐單抗來(lái)自購(gòu)買(mǎi)的成品。貝伐單抗脂質(zhì)體由脂質(zhì)體微泡和貝伐單抗采用雙水化法制成。貝伐單抗膜聯(lián)蛋白A5脂質(zhì)體由貝伐單抗脂質(zhì)體加酶聯(lián)蛋白A5于攪拌器上低速旋轉(zhuǎn)制成。2.實(shí)驗(yàn)動(dòng)物分組:105只健康無(wú)眼病的新西蘭大白兔,不分雌雄,隨機(jī)數(shù)字表法分為實(shí)驗(yàn)組、對(duì)照組1、對(duì)照組2,每組35只,每組再隨機(jī)分為7個(gè)亞組,每個(gè)亞組5只,分別對(duì)應(yīng)給藥后的7個(gè)時(shí)間點(diǎn)(5min、15min、30min、1h、2h、4h、8h)。3.給藥及樣品采集:實(shí)驗(yàn)組新西蘭大白兔單眼接受貝伐單抗膜聯(lián)蛋白A5脂質(zhì)體局部點(diǎn)眼50μL;對(duì)照組1新西蘭大白兔單眼接受貝伐單抗脂質(zhì)體局部點(diǎn)眼50μL;對(duì)照組2新西蘭大白兔單眼接受貝伐單抗局部點(diǎn)眼50μL。各組分別在給藥后預(yù)定時(shí)間點(diǎn)處死動(dòng)物,摘取眼球,取房水及玻璃體、視網(wǎng)膜脈絡(luò)膜標(biāo)本,備用。4.獲取藥代動(dòng)力學(xué)參數(shù)及統(tǒng)計(jì)學(xué)分析:酶聯(lián)免疫吸附法計(jì)算各樣本濃度值。應(yīng)用DAS 2.1.1軟件計(jì)算各個(gè)藥物代謝動(dòng)力學(xué)參數(shù),擬合曲線。應(yīng)用SPSS 19.0軟件進(jìn)行統(tǒng)計(jì)分析,采用方差分析和LSD檢驗(yàn)對(duì)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果1.各組實(shí)驗(yàn)數(shù)據(jù)證明貝伐單抗膜聯(lián)蛋白A5脂質(zhì)體在各個(gè)已測(cè)時(shí)間點(diǎn)的濃度明顯高于對(duì)照組1和對(duì)照組2(P0.05)。2.實(shí)驗(yàn)組視網(wǎng)膜脈絡(luò)膜組織中的貝伐單抗?jié)舛雀哂隗w外貝伐單抗對(duì)hVEGF的IC50。結(jié)論貝伐單抗膜聯(lián)蛋白A5脂質(zhì)體有望成為治療新生血管性眼病的新劑型,通過(guò)局部點(diǎn)眼的方式給藥從而避免眼內(nèi)注射,減少并發(fā)癥。
[Abstract]:Background at present, the incidence of neovascular ophthalmopathy is increasing. Bevacizumab is a monoclonal antibody drug for the treatment of neovascular ophthalmopathy. Due to the presence of various eye barriers, local eye therapy cannot reach the effective concentration in the eye. At present, vitreous injection is used to treat intraocular neovascularization. But multiple vitreous injections can lead to serious complications. Recently, it has been found that the ability of bevacizumab to penetrate the cornea can be improved by using A5 liposome as carrier, and it has the potential to be a non-invasive therapy for intraocular neovascularization. Therefore, the study of pharmacokinetics of bevacizumab A5 liposome eye drops in rabbit eyes will be helpful for the clinical treatment of intraocular neovascularization. Objective to reduce the ocular complications and improve the intraocular permeability of the drug, we prepared a new type of bevacizumab membrane binding protein A 5 liposome eye drops, and made a local eye spot on the experimental animals by the preparation of a new type of bevacizumab A5 liposome eye drops. The study of ocular pharmacokinetics provides experimental and theoretical basis for the clinical treatment of retinal choroidal neovascularization. Method 1. Preparation of drugs: bevacizumab comes from the finished product purchased. The bevacizumab liposome was prepared by double hydration of liposome microbubbles and bevacizumab. The bevacizumab membrane linked protein A5 liposome was prepared from bevacizumab liposome and enzyme linked protein A5 by rotating at low speed on the agitator. The experimental animals were divided into 10 groups: 105 healthy New Zealand white rabbits without eye disease, male and female, randomly divided into experimental group, control group 1, control group 2, each group 35. Each group was randomly divided into 7 subgroups, 5 in each subgroup. The results showed that 7 time points after administration were 5 min ~ 15 min ~ 30 min ~ (-1) ~ 1 h ~ (-1) ~ 2 h ~ (-1) ~ 4 h ~ (8) h ~ (-1) ~ 8 h ~ (-1) ~ (3). Administration and sample collection: the experimental group New Zealand white rabbits received bevacizumab A5 liposome 50 渭 L locally; the control group 1 New Zealand white rabbit single eye received bevacizumab liposome 50 渭 L; control group 2 The local point of bevacizumab was 50 渭 L in single eye of blue white rabbit. The animals in each group were killed at a predetermined time point after administration, eyeball was removed, aqueous humor and vitreous body, retinal choroid specimen were taken, reserve. 4. The pharmacokinetic parameters and statistical analysis were obtained: enzyme linked immunosorbent assay (Elisa) was used to calculate the concentration of each sample. DAS 2.1.1 software was used to calculate the pharmacokinetic parameters and fit the curve. SPSS 19.0 software was used for statistical analysis, and ANOVA and LSD test were used for statistical analysis. Result 1. The experimental data showed that the concentration of bevacizumab A5 liposome at each time point was significantly higher than that of control group 1 and control group 2 (P0.05 路2). The concentration of bevacizumab in retinal choroid tissue of experimental group was higher than that of in vitro bevacizumab on hVEGF. Conclusion the bevacizumab A5 liposome is expected to be a new dosage form for the treatment of neovascular ophthalmopathy, which can avoid intraocular injection and reduce complications.
【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R77

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