本文選題：雷珠單抗 + 滲出型年齡相關(guān)性黃斑變性　； 參考：《北京中醫(yī)藥大學(xué)》2017年博士論文

【摘要】：(一)黃斑變性1號方治療滲出型年齡相關(guān)性黃斑變性的臨床觀察研究目的:觀察黃斑變性1號方(Huangban Bianxing One Decoction,HBOD)聯(lián)合雷珠單抗治療滲出型年齡相關(guān)性黃斑變性(aged-related macular degeneration,AMD)患者的有效性和安全性。方法:從2014年7月至2016年2月,共75例符合納入標(biāo)準(zhǔn)和排除標(biāo)準(zhǔn)的滲出型AMD患者(75只眼)入選本次研究,隨機(jī)分為治療組和對照組,兩組均在入組后給予雷珠單抗治療1次。在此基礎(chǔ)上,治療組每天口服HB0D水煎劑,1天2次,每次100mL,療程持續(xù)6個月。作為主要結(jié)果,評估治療前后的早期治療糖尿病視網(wǎng)膜病變研究(early treatment diabetic retinopathy study,ETDRS)字母數(shù)的最佳矯正視力、黃斑中心凹厚度(center macular thickness,CMT)、病變高度、眼底出血面積、眼底熒光滲漏面積。結(jié)果:經(jīng)過3個月的治療,兩組的ETDRS字母數(shù)都獲得了較大改善(P0.05)。治療6個月后,治療組的ETDRS字母數(shù)明顯提高(P0.01),且明顯優(yōu)于對照組(P0.05)。治療3個月后,兩組相比于治療前CMT和病變高度也明顯降低(P0.01或P0.05),治療6個月后,治療組相比治療前CMT和病變高度也明顯降低(P0.01)。治療6個月后,出血面積和熒光素滲漏面積也明顯縮小(P0.01或P0.05),且與對照組比較,治療后的出血面積和熒光滲漏面積減小明顯優(yōu)于對照組(P0.01或P0.05)。治療期間,也未有明確與治療有關(guān)的重大不良事件。結(jié)論:滲出型AMD屬于新生血管性視網(wǎng)膜病變,是世界老年人口失明的主要原因之一。在本研究結(jié)果的基礎(chǔ)上,HBOD可以輔助改善視力,并減少滲出型AMD患者的出血和熒光素滲漏,減少抗VEGF藥物注射次數(shù),這可能是滲出型AMD有效的輔助和安全治療方法。(二)黃斑變性1號方治療滲出型年齡相關(guān)性黃斑變性的機(jī)制研究目的:圍繞白細(xì)胞介素(interleukin,IL)-17信號調(diào)控通路,探討中藥復(fù)方HBOD對滲出型AMD患者血漿中IL-17、血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)-A表達(dá)水平的影響。方法:2014年7月至2016年2月,納入臨床觀察研究中治療組的38例滲出型AMD患者。治療前和服用中藥復(fù)方HBOD 6個月后患者于清晨空腹抽取靜脈血,分別作為AMD組和治療組,并招募20例健康者作為對照組。并用酶聯(lián)免疫吸附測定法測定血漿中IL-17A、VEGF-A 表達(dá)水平。結(jié)果:本次研究中,IL-17A在對照組中僅有1例可測出,AMD組中有6例,治療組中有3例,因而無法做統(tǒng)計(jì)學(xué)差異比較。AMD組血漿中的VEGF-A水平明顯高于治療組和對照組(P＜0.01或P0.05),治療后與對照組比較無顯著性差異(P0.05)。結(jié)論:HB0D可以調(diào)節(jié)滲出型AMD患者血漿中的VEGF-A的水平,但HBOD是否能影響IL-17A的水平還有待進(jìn)一步研究。(三)黃斑變性1號方治療滲出型年齡相關(guān)性黃斑變性的血漿代謝組學(xué)研究目的:AMD是具有高發(fā)病率和復(fù)雜發(fā)病機(jī)制的主要失明疾病。我們的目的是研究中藥復(fù)方HBOD治療滲出型AMD患者血漿代謝組學(xué)特征。方法:這項(xiàng)代謝組學(xué)研究是通過分析20例健康對照者和20例滲出型AMD患者接受HBOD治療前與治療6個月后的的血漿進(jìn)行的。我們使用超高壓液相色譜和四極桿飛行時間質(zhì)譜法進(jìn)行分析。這些差異與AMD病理生理和治療的關(guān)系也得到了確定。剩余數(shù)據(jù)通過Pareto scaling進(jìn)行歸一化,然后通過使用MetaboAnalysis軟件的多變量數(shù)據(jù)分析處理有效數(shù)據(jù),包括無監(jiān)督主成分分析(principal component analysis,PCA)和監(jiān)督偏最小二乘法分析(partial least squares-discriminate analysis,PLS-DA)。目的是確定分析的重要代謝物。進(jìn)行分層聚類,以區(qū)分組間的代謝物。然后使用建立的數(shù)據(jù)庫鑒定重要的代謝物,并將其進(jìn)行京都基因和基因組百科全書(Kyoto Encyclopedia of Genes and Genomes,KEGG)代謝通路分析。結(jié)果:PCA、PLS-DA和分層聚類結(jié)果分析顯示,滲出型AMD治療前后血漿代謝狀態(tài)無明顯變化。在正離子模式下,檢測到總共5443個離子峰,其中包括一些氨基酸、異麥芽糖、氫化可的松和膽紅素10種代謝物在滲出型AMD和健康對照之間有顯著不同。氨基酸生物合成的代謝通路在滲出型AMD患者和對照者間有顯著差異。結(jié)論:這些研究結(jié)果表明,滲出型AMD和對照之間的代謝特征不同,并且可能為AMD指導(dǎo)的治療和診斷提供有希望的新目標(biāo)。同時,因建立的模型可靠性較差,尚未發(fā)現(xiàn)HBOD可以顯著調(diào)節(jié)滲出型AMD患者的代謝狀態(tài)。(四)黃斑變性1號方及其主要成分干預(yù)IL-17A刺激ARPE-19細(xì)胞分泌促炎因子研究目的:本研究旨在探討中藥復(fù)方HBOD及其主要成分對IL-17A在人視網(wǎng)膜上皮細(xì)胞ARPE-19細(xì)胞中誘導(dǎo)促炎細(xì)胞因子產(chǎn)生的影響。方法：將 ARPE-19 細(xì)胞與 100ng/mL IL-17A 孵育 6、12、24 或 36h,以及與 10、20、50、100或200ng/mL IL-17A孵育6h,通過定量實(shí)時聚合酶鏈反應(yīng)(quantitative real-time polymerase chain reaction,qRT-PCR)以測定IL-1 β、IL-6、IL-8、趨化因子(C-C 形)配體(chemokine(C-Cmotif)ligands,CCLs)CCL2 和 CCL20mRNA 的表達(dá)。進(jìn)行細(xì)胞增殖-毒性檢測試劑盒(Cell Counting Kit,CCK-8)測定以確定HB0D、黃芪多糖(astragalus polysacharin,APS),三七總皂甙(panax notoginseng saponins,PNS)和貝母素甲(peimine,PE)的細(xì)胞毒性。ARPE-19細(xì)胞用非細(xì)胞毒性藥物溶液預(yù)處理2h,然后給與或不與人重組IL-17A孵育6h或24h。分別通過qRT-PCR和酶聯(lián)免疫吸附測定法測定所得的促炎細(xì)胞因子mRNA和蛋白表達(dá)水平。結(jié)果:IL-17A 可顯著增加 ARPE-19 細(xì)胞中的 IL-1 β、IL-6、IL-8、CCL2 和 CCL20mRNA和蛋白表達(dá)(P0.01)。HB0D可以抑制上述促炎細(xì)胞因子mRNA和蛋白表達(dá)水平(P0.01或P0.05)。作為主要成分,APS、PNS和PE能部分或全部抑制這些促炎細(xì)胞因子mRNA和蛋白表達(dá)水平(P0.01)。且PE對CCL20表達(dá)有很強(qiáng)的抑制作用,其抗炎作用更廣泛。我們的研究結(jié)果表明,HB0D及其主要成分可能通過部分抑制由IL-17A誘導(dǎo)的視網(wǎng)膜色素上皮細(xì)胞的炎癥反應(yīng)來治療AMD。結(jié)論:對IL-17A誘導(dǎo)的促炎細(xì)胞因子產(chǎn)生的抑制作用可能解釋了 HB0D治療AMD的有效機(jī)制。
[Abstract]:(1) a clinical study of macular degeneration 1 in the treatment of exudative age-related macular degeneration. Objective: To observe the efficacy and safety of Huangban Bianxing One Decoction (HBOD) combined with lezumab in the treatment of exudative age-related macular degeneration (aged-related macular degeneration, AMD). Methods: from 20 From July to February 2016 14 years, 75 cases of exudative AMD patients (75 eyes) were enrolled in this study. They were randomly divided into treatment group and control group. The two groups were treated with leuzumab for 1 times after entering group. On this basis, the treatment group took HB0D Decoction every day, 1 days 2 times, each time lasted for 6 months. The main results were to evaluate the best corrected visual acuity of the early treatment of diabetic retinopathy (early treatment diabetic retinopathy study, ETDRS), the thickness of the macular fovea (center macular thickness, CMT), the height of the lesion, the area of the fundus hemorrhage, and the fluorescent leakage area of the fundus. Results: after 3 months of treatment, two The number of ETDRS letters in the group was greatly improved (P0.05). After 6 months of treatment, the number of ETDRS letters in the treatment group was significantly increased (P0.01), and obviously superior to the control group (P0.05). After 3 months of treatment, the two groups were also significantly lower (P0.01 or P0.05) than before the treatment and the height of the lesion (P0.01 or P0.05). After 6 months of treatment, the treatment group compared with the pre treatment CMT and the height of the lesion. Obviously decreased (P0.01). After 6 months of treatment, the area of hemorrhage and the area of fluorescein leakage were also significantly reduced (P0.01 or P0.05), and compared with the control group, the area of hemorrhage and the area of fluorescent leakage were significantly lower than those of the control group (P0.01 or P0.05). During the treatment, there were no significant adverse events related to the treatment. Conclusion: exudative AMD Neovascular retinopathy is one of the main causes of blindness in the aged in the world. On the basis of this study, HBOD can help improve vision, reduce bleeding and fluorescein leakage in exudative AMD patients, and reduce the number of anti VEGF drug injections. This may be an effective adjuvant and safe treatment for exudative AMD. (two) Study on the mechanism of macular degeneration 1 in the treatment of exudative age-related macular degeneration. Objective: To explore the effect of traditional Chinese medicine compound HBOD on the level of IL-17, vascular endothelial growth factor (vascular endothelial growth factor, VEGF) -A expression in plasma of exudative AMD patients by interleukin (IL) -17 signal regulation pathway. Method: 201 From July to February 2016 4 years, 38 cases of exudative AMD patients in the clinical observation group were included in the treatment group. Before and 6 months after the treatment of the compound HBOD, the patients were selected as the AMD group and the treatment group, and 20 healthy persons were recruited as the control group, and the plasma IL-17A, VEGF-A was measured by the enzyme immunoadsorption assay. Results: in this study, there were only 1 cases of IL-17A in the control group, 6 in group AMD and 3 in the treatment group, and there were 3 cases in the treatment group, so the VEGF-A level in the plasma of.AMD group was significantly higher than that in the treatment group and the control group (P < 0.01 or P0.05). There was no significant difference between the control group and the control group (P0.05). Conclusion HB0D The level of VEGF-A in plasma of exudative AMD patients can be regulated, but whether HBOD can affect the level of IL-17A remains to be further studied. (three) the objective of plasma metabonomics for the treatment of exudative age related macular degeneration by macular degeneration 1 Prescription: AMD is a major blindness disease with high incidence and complex pathogenesis. Our objective We studied the plasma metabolic characteristics of the HBOD patients with exudative AMD. Methods: This metabonomics study was conducted by analyzing 20 healthy controls and 20 cases of exudative AMD patients before and after 6 months of treatment with HBOD. We used high pressure liquid chromatography and quadrupole time of flight mass spectrometry. The relationship between these differences and the pathophysiology and treatment of AMD is also determined. The remaining data are normalized by Pareto scaling, and then the effective data are processed by multivariable data analysis using MetaboAnalysis software, including unsupervised principal component analysis (principal component analysis, PCA), and supervised partial least square method. Analysis (partial least squares-discriminate analysis, PLS-DA). The purpose is to determine the important metabolites of the analysis. Stratify clustering to distinguish between groups of metabolites. Then use the established database to identify important metabolites and carry out the Kyoto gene and genome 100 family (Kyoto Encyclopedia of Genes and Genomes, KEGG). Results of metabolic pathway analysis. Results: PCA, PLS-DA and stratified cluster analysis showed that there was no significant change in plasma metabolic state before and after the exudative AMD treatment. In the positive ion mode, a total of 5443 ion peaks were detected, including some amino acids, ISO maltose, hydrocortisone and bilirubin 10 metabolites in the exudative AMD and health control There were significant differences between the metabolic pathways of the amino acid biosynthesis in the exudative AMD patients and the controls. Conclusions: These findings suggest that the metabolic characteristics between the exudative AMD and the control are different, and may provide promising new targets for the treatment and diagnosis of AMD guidance. It is not found that HBOD can significantly regulate the metabolic state of exudative AMD patients. (four) macular degeneration No. 1 and its main components interfere with IL-17A stimulation of ARPE-19 cells to secrete proinflammatory cytokines. The purpose of this study was to explore the effect of HBOD and its main components on the induction of proinflammatory cells in the ARPE-19 cells of human retina membrane epithelial cells. Methods: to incubate ARPE-19 cells with 100ng/mL IL-17A for 6,12,24 or 36h, and to incubate 6h with 10,20,50100 or 200ng/mL IL-17A, by quantitative real-time polymerase chain reaction (quantitative real-time polymerase) (C-Cmotif) ligands, CCLs) expression of CCL2 and CCL20mRNA. Cell proliferation toxicity detection kit (Cell Counting Kit, CCK-8) was used to determine HB0D, astragalus polysaccharide (Astragalus Polysacharin,), 37 total saponins and fritillin a cytotoxic cells used for non cytotoxicity. Pretreated 2h, and then incubated with or without human recombinant IL-17A to incubate 6h or 24h. by qRT-PCR and enzyme linked immunosorbent assay to determine the level of proinflammatory cytokines mRNA and protein expression. Results: IL-17A can significantly increase IL-1 beta, IL-6, IL-8, CCL2, CCL2 and protein expression in ARPE-19 cells. D can inhibit the above proinflammatory cytokine mRNA and protein expression level (P0.01 or P0.05). As a major component, APS, PNS and PE can partially or completely inhibit the level of mRNA and protein expression (P0.01) of these proinflammatory cytokines. And PE has a strong inhibitory effect on CCL20 expression, and its anti-inflammatory effect is more extensive. Our results showed that HB0D and The main components may be treated by partially inhibiting the inflammatory response of IL-17A induced retinal pigment epithelial cells to treat the AMD. conclusion: the inhibitory effect of IL-17A induced proinflammatory cytokines may explain the effective mechanism of HB0D for the treatment of AMD.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R774.5

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 Xunxian Liu;Zemin Yao;;Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients[J];The Journal of Biomedical Research;2017年03期

2 臧凱宏;吳建軍;秦紅巖;吳國泰;段海婧;任遠(yuǎn);;黃芪多糖對潰瘍性結(jié)腸炎大鼠腸道黏膜屏障的影響[J];中藥材;2017年01期

3 王芝艷;高景成;;復(fù)方樟柳堿注射液聯(lián)合杞菊地黃丸治療老年性黃斑變性的臨床研究[J];中國臨床藥理學(xué)雜志;2016年22期

4 閆平;;中西醫(yī)結(jié)合治療濕性年齡相關(guān)性黃斑變性效果觀察[J];河南醫(yī)學(xué)研究;2016年10期

5 歸改霞;;貝母素甲對急性肺損傷小鼠保護(hù)作用的實(shí)驗(yàn)研究[J];中醫(yī)臨床研究;2016年26期

6 王鑫;;益氣活血法在老年性黃斑變性治療中的應(yīng)用觀察[J];中國社區(qū)醫(yī)師;2016年25期

7 鐘玲;;散血明目丸聯(lián)合抗血管內(nèi)皮生長因子治療年齡相關(guān)性黃斑變性的臨床研究[J];現(xiàn)代中西醫(yī)結(jié)合雜志;2016年24期

8 陳冬雪;;歸芍地黃湯聯(lián)合經(jīng)瞳孔溫?zé)岑煼ㄖ委煗B出型年齡相關(guān)性黃斑變性的療效觀察[J];臨床醫(yī)藥文獻(xiàn)電子雜志;2016年26期

9 張敏;寧學(xué)玲;寧學(xué)洪;;西藥聯(lián)合駐景丸加減方治療年齡相關(guān)性黃斑變性的臨床觀察[J];廣東醫(yī)學(xué)院學(xué)報;2016年03期

10 Yao Tong;Ke-Ke Zhao;Dong Feng;Manas Biswal;Pei-Quan Zhao;Zhao-Yang Wang;Yun Zhang;;Comparison of the efficacy of anti-VEGF monotherapy versus PDT and intravitreal anti-VEGF combination treatment in AMD: a Meta-analysis and systematic review[J];International Journal of Ophthalmology;2016年07期

，

本文編號：1844653