本文選題：四神丸　切入點(diǎn)：伊立替康　出處：《南京中醫(yī)藥大學(xué)》2017年碩士論文

【摘要】：目的:遲發(fā)性腹瀉為伊立替康(Irinotecan,CPT-11)主要?jiǎng)┝肯拗菩远拘?嚴(yán)重影響患者的生活質(zhì)量,甚至導(dǎo)致治療中斷,影響患者的療效。目前依然缺乏較滿意的防治方法。在本項(xiàng)研究中,建立小鼠CPT-11所致遲發(fā)性腹瀉模型,研究四神丸各劑量組對(duì)CPT-11引起的遲發(fā)性腹瀉的防治作用,并探討其可能的機(jī)制。方法:1)遲發(fā)性腹瀉模型的建立、分組50只健康雄性ICR小鼠被隨機(jī)分為5組:腹瀉模型組、四神丸低(0.6g·kg-1)、中(1.2g·kg-1)、高(2.4g·kg-1)劑量組、正常對(duì)照組,每組10只。腹瀉模型組及四神丸各劑量組均尾靜脈注射CPT-11(35mg·kg-1·d-1),每日1次,連續(xù)4日;正常對(duì)照組小鼠尾靜脈被注射同等體積生理鹽水。四神丸各劑量組于造模前一天灌胃給藥,每日1次,連續(xù)7日,腹瀉模型組及正常對(duì)照組小鼠被給予同等體積雙蒸水灌胃。2)每日觀察、記錄小鼠遲發(fā)性腹瀉發(fā)生的情況、飲食及精神活動(dòng)狀態(tài)等。3)樣本采集小鼠末次灌胃給藥24h后,腹腔注射水合氯醛麻醉,腹主動(dòng)脈取血;斷頸后處死,取結(jié)腸組織及盲腸內(nèi)容物。4)樣本的檢測(cè)通過酶聯(lián)免疫吸附法(enzyme-linked immunosorbent assay,ELISA)檢測(cè)小鼠血樣中的白介素 1β(Interleukin-1β,IL-1β)、腫瘤壞死因子 α(tumor necrosis factor-α,TNF-α)的含量;比色法檢測(cè)盲腸內(nèi)容物β-葡萄糖醛酸苷酶(β-glucuronidase,β-G)的表達(dá)水平;盲腸內(nèi)容物大腸桿菌培養(yǎng),計(jì)數(shù)菌落數(shù);結(jié)腸組織被固定、切片、HE染色后,于顯微鏡下觀察結(jié)腸粘膜的結(jié)構(gòu)和形態(tài)。結(jié)果:1)遲發(fā)性腹瀉的發(fā)生情況:小鼠尾靜脈注射CPT-11后,于24h后出現(xiàn)遲發(fā)性腹瀉,腹瀉模型組小鼠發(fā)生遲發(fā)性腹瀉率為100%,其中重度腹瀉發(fā)生率為80%;四神丸中、高劑量組重度腹瀉發(fā)生率分別為40%;與腹瀉模型組比較:四神丸中、高劑量組腹瀉程度明顯減輕(P=0.021,P=0.019)。2)結(jié)腸粘膜的損傷情況腹瀉模型組小鼠5-6級(jí)粘膜損傷發(fā)生率為70%,而四神丸中、高劑量組均為30%,與腹瀉模型組比較,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。3)小鼠血清IL-1β的變化情況四神丸中高劑量組血清IL-1β分別為:(72.61 土 10.15)/g·L-1,(71.86 土 8.78)/g·L-1較腹瀉模型組(116.57 土 17.16)/g·L-1的水平顯著降低(P0.01)。4)小鼠血清TNF-α的變化情況四神丸中高劑量組血清TNF-α分別為:(71.50 土 3.39)/g·L-1,(69.43 土 6.23)/g·L-1較腹瀉模型組(109.50 土 4.21)/g·L-1的水平顯著降低(P0.01)。5)小鼠腸道β-G的表達(dá)水平四神丸中、高劑量組腸道β-G分別為:(1.109 土 0.055)U,(1.100 土 0.063)U;較腹瀉模型組(1.438 土 0.022)U的表達(dá)顯著降低(P0.01)。6)小鼠盲腸內(nèi)大腸桿菌菌落數(shù):四神丸低中高劑量組分別為(29.5 土 2.2)×1013/g,(30.4 土 3.5)×1013/g,(31.4 土2.7)×1013/g;腹瀉模型組(31.4 土 3.2)×1013/g;正常對(duì)照組(31.2 土 2.9)×1013/g。各組之間比較,菌落數(shù)無明顯差異(P0.05)。結(jié)論:四神丸對(duì)CPT-11所致小鼠遲發(fā)性腹瀉有一定的預(yù)防和減緩作用,其機(jī)制可能與減少腸道β-G的含量,并降低血清中IL-1β、TNF-α的水平,從而減輕CPT-11對(duì)腸道黏膜的損傷有關(guān)。
[Abstract]:Objective: delayed diarrhea for irinotecan (Irinotecan, CPT-11) the main dose limiting toxicity, seriously affect the patient's quality of life, and even lead to the interruption of treatment, therapeutic efficacy. There is currently no satisfactory treatment method. In this study, mice CPT-11 induced delayed diarrhea model, prevention and control to study the effect of Sishen pill each dose group of CPT-11 induced delayed diarrhea, and to explore its possible mechanism. Methods: 1) the establishment of delayed diarrhea model group, 50 healthy male ICR mice were randomly divided into 5 groups: diarrhea model group, Sishen pill low (0.6g - kg-1), in (1.2g - kg-1) (2.4G, kg-1), high dose group, normal control group, 10 rats in each group. The diarrhea model group and Sishen pill groups were intravenous injection of CPT-11 (35mg kg-1 D-1), 1 times a day for 4 days; the normal control group by tail vein of mice injected with the same volume of physiological four saline. God pill groups one day before the rats administered orally, 1 times daily for 7 consecutive days, diarrhea model group and normal control group mice were given the same volume of double distilled water.2) observed daily, delayed diarrhea cases were recorded, diet and mental activity status like.3) the last acquisition of mice administered 24h after intraperitoneal injection of chloral hydrate anesthesia, abdominal aortic blood; broken neck after death, the colon and cecum.4) samples was detected by enzyme-linked immunosorbent assay (enzyme-linked immunosorbent assay, ELISA) were detected in blood interleukin 1 beta (Interleukin-1 beta, beta IL-1), tumor necrosis factor alpha (tumor alpha factor- alpha necrosis, TNF-) content; detection of cecal contents of beta glucuronidase assay (beta -glucuronidase and beta -G) expression level; cecal contents of Escherichia coli culture, counting the number of colony; colon tissue Is fixed, sliced, HE stained, and observed the structure and morphology of colonic mucosa. Results: 1) delayed diarrhea: tail vein of mice after injection of CPT-11, appeared in 24h after delayed diarrhea, diarrhea model mice delayed diarrhea rate was 100%, and the severe diarrhea the incidence rate was 80%; shishenwan, high dose group and severe diarrhea incidence was 40%; compared with the model group: shishenwan diarrhea, diarrhea in high dose group reduced significantly (P=0.021, P=0.019).2) in colonic mucosal injury diarrhea mice model 5-6 mucosal injury incidence rate was 70%, and four pills in high dose group was 30%, compared with the diarrhea model group, the difference was statistically significant (P0.05).3) of Sishen pill mice serum IL-1 beta in high dose group serum IL-1 beta respectively: (72.61 + 10.15) /g - L-1 (71.86, /g, L-1 8.78) compared with the model of diarrhea group (1 16.57 鍦，

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