【摘要】：腎病綜合征(nephrotic syndrome,NS)的臨床表現(xiàn)可以概括為“三高一低”,即高蛋白尿、高血脂、高度水腫、低血蛋白。原發(fā)性的NS以腎小球腎病最為常見,發(fā)生與雙側(cè)腎臟腎小球,病因各不相同。地塞米松(dexamethasone,Dex)為糖皮質(zhì)類激素的代表藥物,具有強(qiáng)大的抗炎、抗毒、抗過敏等作用,臨床應(yīng)用廣泛,同時(shí)對下丘腦-垂體-腎上腺軸(the hypothalamic-pituitary-adrenal axis,HPA)抑制作用較明顯。地塞米松可以抑制腎內(nèi)的炎性反應(yīng),緩解一系列的癥狀,治療方法為開始大劑量靜脈給藥后期口服維持治療。長期使用易產(chǎn)生較嚴(yán)重的毒副作用,治病的同時(shí)也給治療過程中的病人增加痛苦。所以,我們設(shè)想對于腎病的治療,若使藥物在腎臟局部濃度高,而在全身的血藥濃度低,是否不僅可以增加療效,又能減輕毒副作用。故本實(shí)驗(yàn)使用的藥物劑型為地塞米松緩釋劑(sustained-release of dexamethasone,SR Dex),藥物到達(dá)局部后,緩慢釋放,維持時(shí)間長。使用的動物模型為耳緣靜脈注射藏紅花紅O(safranine O)誘導(dǎo)的家兔腎小球腎病,藏紅花紅O能選擇性的引起近端和遠(yuǎn)端腎小管上皮細(xì)胞廣泛壞死,形成的腎病模型與臨床表現(xiàn)較為一致。目的:探討地塞米松緩釋劑對藏紅花紅O腎病家兔的保護(hù)作用、對HPA軸和腎上腺功能的影響及糖皮質(zhì)激素類藥物治療腎病的可能機(jī)制。方法:家兔腎病模型的制備方法為連續(xù)兩次間隔3小時(shí)耳緣靜脈注射臧紅花紅O,每次15mg。地塞米松緩釋劑分別采用手術(shù)腎囊內(nèi)一次性注射給藥(1.48,0.74,0.37 mg/kg),陽性對照組地塞米松灌胃給藥(0.4mg/kg,qd×8w)。每天觀察造模前及造模后家兔一般狀況,每周檢測體重、24h尿蛋白,每周檢測血蛋白(總蛋白、白蛋白)、血脂(總膽固醇)、血腎功能(血肌酐、尿素氮)、血尿酸及血電解質(zhì)(NA+、K+、Cl ),每兩周檢測腎上腺功能指標(biāo)(血液指標(biāo):促腎上腺皮質(zhì)激素、皮質(zhì)酮、尿液指標(biāo):17-羥基皮質(zhì)類固醇)。HE染色觀察腎、腎上腺組織的病理學(xué)變化;PAS染色觀察腎小球系膜(glomerular mesangum,GB)、基底膜(glomerulus basement membrane,GBM)的形態(tài)改變;SR染色觀察腎間質(zhì)膠原纖維的變化;免疫組織化學(xué)法檢測腎組織nephrin、TRPC6蛋白的表達(dá);實(shí)時(shí)熒光定量PCR(real-time PCR)檢測腎組織nephrin、TRPC6 m RNA的表達(dá)量。結(jié)果:地塞米松緩釋劑可顯著降低腎病家兔升高的尿蛋白,改善腎功能(降低血尿素氮和血肌酐),降低血總膽固醇及尿酸水平,升高血總蛋白、白蛋白,改善腎組織病理學(xué)變化。另外,地塞米松緩釋劑對腎病家兔血促腎上腺皮質(zhì)激素和皮質(zhì)酮含量無明顯影響,可不同程度降低尿17-羥基皮質(zhì)類固醇含量,對腎上腺病理組織學(xué)也無明顯影響。結(jié)論:地塞米松緩釋劑腎囊用藥對家兔藏紅花紅O腎病具有較好的保護(hù)作用,其機(jī)制可能與改變TRPC6蛋白通路及nephrin蛋白的表達(dá)與分布,改善腎小球?yàn)V膜的完整性有關(guān)。另外,地塞米松緩釋劑腎囊用藥對HPA軸無明顯抑制,對腎上腺形態(tài)及功能未見明顯影響。
[Abstract]:The clinical manifestations of nephrotic syndrome can be summarized as high proteinuria, hyperlipidemia, high edema and low blood protein. Primary NS, glomerular nephropathy is the most common, and bilateral renal glomeruli, the etiology is different. Dexamethasone Dex is the representative drug of glucocorticoid. It has powerful anti-inflammatory, anti-toxic and anti-allergic effects. It is widely used in clinic and has obvious inhibitory effect on the hypothalamic-pituitary-adrenal axis-adrenal axis. Dexamethasone can inhibit the inflammatory reaction in the kidney and relieve a series of symptoms. Long-term use can lead to severe side effects and increase pain in the course of treatment. Therefore, we imagine that for the treatment of nephropathy, if the drug concentration in the kidney is high, and the blood drug concentration in the whole body is low, it can not only increase the curative effect, but also alleviate the side effects. Therefore, sustained-release of dexamethasone SR Dex), was released slowly and maintained for a long time. The animal model used was rabbit glomerular nephropathy induced by injecting saffron O (safranine O) into ear margin. Saffron O could selectively cause extensive necrosis of proximal and distal renal tubular epithelial cells. Objective: to investigate the protective effect of dexamethasone sustained-release agent on saffron O nephropathy in rabbits, the effects of dexamethasone on HPA axis and adrenal function and the possible mechanism of glucocorticoid in the treatment of nephropathy. Methods: the rabbit model of nephropathy was established by injecting Zang Hua Hong O15 mg every time. Dexamethasone sustained-release agents were injected intraperitoneally into the renal sac for one time (1.48g / kg, 0.37 mg/kg), while those in the positive control group were given dexamethasone (0.4mg / kg / kg QD 脳 8w). The general condition of rabbits before and after modeling was observed every day, the body weight and 24 hours urine protein were measured weekly, the blood protein (total protein, albumin), blood lipid (total cholesterol), blood renal function (serum creatinine) were detected weekly. Urea nitrogen, serum uric acid and serum electrolytes (na) were used to detect adrenal function index (blood index: adrenocorticotropic hormone, corticosterone, urine index: 17 hydroxy corticosteroids). He staining was used to observe the renal function. The pathological changes of adrenal tissue were observed by pas staining, the morphological changes of glomerular Mesangium (GB) and basement membrane (glomerulus basement) were observed by SR staining, and the expression of nephrinTRPC6 protein in renal tissue was detected by immunohistochemistry. The expression of nephrinnin TRPC6 m RNA in renal tissue was detected by real time fluorescence quantitative PCR (real-time PCR). Results: dexamethasone sustained-release agent could significantly reduce the elevated urinary protein, improve renal function (reduce blood urea nitrogen and serum creatinine), decrease serum total cholesterol and uric acid levels, increase serum total protein, albumin, and increase the level of serum total protein and albumin in rabbits with nephropathy. To improve renal histopathological changes. In addition, dexamethasone sustained release had no significant effect on the contents of corticotropin and corticosterone in the blood of nephropathy rabbits, but could decrease the urinary 17-hydroxycorticosteroid content in varying degrees, and had no obvious effect on the histopathology of the adrenal gland. Conclusion: Dexamethasone sustained release agent has a better protective effect on saffron O nephropathy in rabbits. The mechanism may be related to changing the expression and distribution of TRPC6 protein pathway and nephrin protein and improving the integrity of glomerular filter membrane. In addition, Dexamethasone sustained release agent did not inhibit the HPA axis, but had no obvious effect on the morphology and function of adrenal gland.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R965

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 郁世芳,袁冬明,張國江;聚氯乙稀藥物緩釋劑殺滅蒼蠅的效果觀察[J];中國公共衛(wèi)生;1985年06期

2 張雪娟;李國勤;孫仁寅;袁國華;方蘭勇;馮尚連;徐海風(fēng);;皮復(fù)康緩釋劑研究與應(yīng)用[J];合作經(jīng)濟(jì)與科技;2002年06期

3 王洪權(quán),劉克福,張輝,張英峰,王硯英;緩釋劑滅蛆效果觀察[J];中國媒介生物學(xué)及控制雜志;1992年06期

4 韓詠霞;;緩釋劑的合理應(yīng)用[J];藥物與人;2002年01期

5 沙懷，，胡家銀;阿斯匹林緩釋劑的制備[J];中國藥房;1995年02期

6 劉娟;肖麗英;李偉;丁一;肖曉蓉;袁明龍;;替硝唑緩釋劑治療牙周炎的動物實(shí)驗(yàn)研究[J];牙體牙髓牙周病學(xué)雜志;2008年09期

7 曾小鴻,張勇;口服控釋/緩釋劑的應(yīng)用特點(diǎn)及注意事項(xiàng)[J];中國醫(yī)院藥學(xué)雜志;1999年09期

8 王皓,段亞東,秦迎新;緩釋劑在眼科的應(yīng)用[J];第四軍醫(yī)大學(xué)吉林軍醫(yī)學(xué)院學(xué)報(bào);2003年01期

9 張世聯(lián),王薇,劉京生,余素清;白細(xì)胞介素-2緩釋劑的研制[J];中國生化藥物雜志;1996年03期

10 張中原 ,陳桂蘭;腦血管疾病長期應(yīng)用海得琴緩釋劑的臨床療效[J];新醫(yī)學(xué);1990年06期

相關(guān)會議論文 前2條

1 杜衛(wèi)東;袁祖榮;倪泉興;華魯純;沈達(dá)明;唐健雄;張群華;竺越;;5-氟尿嘧啶緩釋劑瘤內(nèi)注射治療胰腺癌的實(shí)驗(yàn)研究和臨床研究[A];中華醫(yī)學(xué)會第10屆全國胰腺外科學(xué)術(shù)研討會論文匯編[C];2004年

2 張世璉;譚效松;梅嘉;羅建林;陳愛;;高分子復(fù)合型緩釋劑農(nóng)藥的研究[A];中國化工學(xué)會農(nóng)藥專業(yè)委員會第八屆年會論文集[C];1996年

相關(guān)重要報(bào)紙文章 前5條

1 方海　編譯;丹麥開發(fā)出磷肥緩釋劑[N];中國花卉報(bào);2005年

2 浙江省農(nóng)業(yè)科學(xué)院 張雪娟;新型抗蟲抗菌聯(lián)合緩釋劑防治技術(shù)[N];中國畜牧報(bào);2004年

3 蘇海;緩釋劑和控釋劑——談?wù)劷祲核?3)[N];家庭醫(yī)生報(bào);2006年

4 ;凌昌全：抗癌中藥緩釋劑局部注射治療肝癌[N];中國中醫(yī)藥報(bào);2003年

5 錢蘇寧;聯(lián)合使用煙酸緩釋劑可有效治療脂類代謝障礙[N];中國醫(yī)藥報(bào);2008年

相關(guān)碩士學(xué)位論文 前6條

1 唐欣影;ClO_2緩釋劑結(jié)合1-MCP處理對西蘭花常溫貨架期保鮮作用的研究[D];沈陽農(nóng)業(yè)大學(xué);2017年

2 王艷龍;高錳酸鉀緩釋劑處理地下水中苯酚的研究[D];吉林大學(xué);2014年

3 張小娟;Bt高抗紫外突變株的篩選及其漂浮緩釋劑分析優(yōu)化[D];福建農(nóng)林大學(xué);2014年

4 江熠輝;多孔材料負(fù)載農(nóng)藥緩釋劑的制備及緩釋性能的研究[D];北京化工大學(xué);2011年

5 梁旭東;多孔二氧化硅材料負(fù)載農(nóng)藥可控緩釋劑的制備及性能研究[D];北京化工大學(xué);2008年

6 張娟;光動力學(xué)聯(lián)合5-FU緩釋劑治療兔口腔Vx-2腫瘤的實(shí)驗(yàn)研究[D];安徽醫(yī)科大學(xué);2008年

本文編號：2171434