导师姓名：&
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授予学位：硕士
学位年度：2010
摘要:配景和目标百草枯（paraquat，PQ）是世界上应用最普遍的、也是人类急性中毒病逝世率最高（65％）的除草剂，至今尚没有一个胜利而有用的救治计划，已成为中毒医治界的一个世界性困难。今朝的一些医治计划都属于传统性或摸索性，如年夜剂量糖皮质激素（glucocorticoid）、免疫克制剂（immunodepressant）及血液污染（blood purification）医治都不克不及显著下降急性百草枯中毒（Acute paraquat poisoning，APP）的病逝世率。PQ进入体内后经由过程一系列的氧化复原反响，年夜量消费NADPH并发生多种自在基形成对机体严重的伤害，特别是对肺脏伤害最重，患者终究产生肺纤维化（pulmonary fibrosis）惹起呼吸衰竭或沾染而逝世亡，部门重度中毒病人逝世于急性肝肾功效衰竭。中毒后，机体涌现超氧化物岐化酶（Super oxide dismutase，SOD）、谷胱甘肽（Glutathione，GSH）降低，而丙二醛（Malondiadehyde，MDA）、细胞间粘附因子一1（Intercellular adhesionmolecule一1，ICAM一1）、血清基质金属酶一9（Matrix metalloproteinase一9，MMP一9）、羟脯氨酸（Hydroxyproline，HYP）等细胞因子明显降低，这些目标均被以为是介入了肺纤维化的细胞因子。浩瀚的植物试验及临床查询拜访成果发明，异甘草酸镁具有壮大的具有抗炎、抗氧化、抗纤维化、稳固细胞膜、免疫调理、避免细胞凋亡及增长内源性类固醇发生等药理感化。且这些感化不只在肝脏内施展，且在肝外也有异样的感化。国外有学者研讨了甘草酸在年夜鼠爱兰苔胶而至的肺毁伤的解毒及掩护感化，发明爱兰苔胶能惹起的ICAM一1、TNF一a、IL一1β、NF一κB、HYP的激活显著降低，而这些已证明为肺毁伤的目标均能被甘草酸明显下降。我们经由过程年夜量的文献温习及实际论证发明，异甘草酸镁的药理感化与百草枯中毒的病理机制及医治中须要针对的环节有许多惊人的吻合，如：抗氧化、抗炎性反响、抗纤维化等感化环节。故此，我们推想可以运用异甘草酸镁医治急性百草枯中毒，本研讨就旨在经由过程制备年夜鼠百草枯中毒后的肺毁伤模子，并用异甘草酸镁打针液停止干涉医治，并经由过程一系列的检测及实验，综合成果以验证上述推想，以期能找到一条新的医治门路。 试验办法 （1）试验一：树立合适本研讨的SD年夜鼠百草枯染毒肺毁伤模子。 取干净级雄性SD年夜鼠（180一200g/只）15只，按正常生涯前提停止豢养1周后，不雅察无异常，称体重，并按数字随机分组法分红3组，每组5只；各组分离以20％PQ液按质量分数低（15mg/kg）、中（20mg/kg）、高（25mg/kg）三种剂量停止腹腔打针染毒，染毒后不作任何处置。予以正常豢养15天，天天不雅察各组年夜鼠的普通情形，包含运动、呼吸、进食、毛色、二便、出血及逝世亡或存活等综合情形，15天后全体处逝世，行病理HE染色不雅察肺部情形。经由过程不雅察，得出合适本试验的染毒模子最好剂量。 （2）试验二：异甘草酸镁对年夜鼠百草枯中毒肺毁伤掩护感化的研讨。 取干净级雄性SD年夜鼠（180一200/只）30只，按正常生涯前提停止豢养1周后，不雅察无异常，称体重，并按数字随机分组法分红5组，每组6只，分离为正常对比组、染毒对比组、MgIG低剂量医治组（15mg/kg）、MgIG中剂量医治组（30mg/kg）及MgIG高剂量医治组（45 mg/kg）。除正常对比组外，其他各组均以20％百草枯按最好剂量停止一次性腹腔打针染毒。正常对比组正常饮食外不予以其他处置，染毒对比组持续腹腔内打针一致容量的心理盐水（按MgIG中剂量的容量来盘算），其他各医治组于染毒后24小时后分离予以响应剂量的MgIG行持续腹腔打针，1次/d。不雅察年夜鼠普通情形，运动、呼吸、进食、毛色、流血及存运动等情形并具体记载。于持续医治14天后，第15天全体予以戊巴比妥50mg/kg停止腹腔打针麻醉后，剖解腹腔，从下腔静脉取血送检SOD、MDA、GSH、ICAM一1、MMP一9；剖解胸腔，不雅察肺年夜体标本，取100mg右上肺组织，剪碎至10mg年夜小，以碱水解法检测羟脯氨酸（HYP）含量；取左肺以福尔马林液固定后，送病文科制备碏块后，停止HE染色不雅察肺泡炎的情形，行Mason染色以不雅察肺纤维化情形，并对两种染色依据Szapiel尺度停止打分。用肺组织停止免疫组化检测ICAM一1和MMP一9的卵白表达情形。最初停止统计学剖析并商量能够的机制。 试验成果 （1）试验一：经染毒后，各组年夜鼠染毒后均涌现分歧水平精力委靡、行为缓慢、进食差，以低剂量组反响最轻，而中、高剂量则涌现分歧水平的口、鼻出血和血尿。从病理HE染色来看，一切染毒年夜鼠肺内均有肺间质增厚、渗出增长，肺泡Ⅰ型及Ⅱ型细胞损坏，都可以为到达制备肺纤维化模子的请求。从逝世亡率来看，高剂量组在3天内逝世亡4只，中剂量组在5天内逝世亡3只，而小剂量组则在第3地利，逝世亡1只。本研讨的正式试验设计了2周的试验周期，但须要一切年夜鼠均能存活，综合看，以15mg/ml的染毒剂量停止染毒相符我们停止试验的时光上的请求，故采取15mg/ml的染毒剂量来制备染毒模子。 （2）试验二：与正常对比组比拟，一切染毒后的血清SOD及GSH显著下降（P0。05）。MgIG低剂量组、高剂量组与染毒对比组比拟，肺HYP及血清MMP一9降低有明显性差别（P0。05）。肺病理成果：一切染毒后年夜鼠均有分歧水平的肺瘀血水肿，部门见肺实变，以染毒对比组为显著；各MgIG医治组毁伤可见有大批散在的小出血点及白色小雀斑，但水肿不如模子组显著，个中以中剂量组改良为明显。HE染色及Masson染色分离反应肺泡炎及肺纤维化情形，成果显示，各医治组的肺泡炎及纤维化情形均较染毒对比组有分歧水平改良，个中以MgIG中剂量组变更改良最显著。以肺组织行免疫组化检测ICAM一1、MMP一9也显示中剂量组肺内表达最低，改良最显著。 结论异甘草酸镁打针液对年夜鼠百草枯中毒肺毁伤有必定掩护感化，特殊是肺纤维化情形的掩护，特别以MgIG中剂量组感化更显著。它重要经由过程下调ICAM一1、MMP一9的表达程度、同时也能克制脂质过氧化反响，削减释放炎性介质，使肺组织ECM各类成份的分解与降解的均衡状况得以保持，削减胶原的积聚，从而加重肺纤维化水平及过程。
Abstract:Background and objective paraquat (paraquat, PQ) is the most common, but also human acute poisoning disease death rate highest application on the world (65%) herbicide, is still not a victory and useful treatment plan, has become a world difficult healing circles poisoning. Some treatment plans now belong to the traditional or fumbled, if a large dose of Glucocorticoid (glucocorticoid), immune inhibitors (immunodepressant) and blood pollution (blood purification) cure cannot significantly decreased in acute paraquat poisoning (Acute paraquat poisoning, APP) of the world rate of illness. PQ enters the body through the process of a series of oxidation reduction reactions, a large amount of consumption of NADPH and free radical formation occurred in a variety of body serious injuries, especially to the lungs hurt the most, the patient eventually caused pulmonary fibrosis (pulmonary fibrosis) cause respiratory failure or contamination and death, Department of severe poisoning patients died in the acute hepatic and renal functions failure. After the poisoning, the body the emergence of superoxide dismutase (Super oxide dismutase, SOD), glutathione (Glutathione, GSH) decreased, while malondialdehyde (Malondiadehyde, MDA), intercellular adhesion molecule 1 (Intercellular adhesionmolecule 1, ICAM 1), Xue Qingji (Matrix metalloproteinase, a 9 metal enzyme 9, MMP 9), hydroxyproline (Hydroxyproline, HYP) and other cytokines decreased obviously, these goals are thought to be involved in lung fibrosis cytokines. Plant trials and clinical queries the vastness of the outcome of the visit of invention, magnesium isoglycyrrhizinate has stronger anti-inflammatory, antioxidant, anti fibrosis, stable cell membrane, immunomodulation, avoid apoptosis and growth occurred pharmacological effects of endogenous steroids. And these role not only in the liver play, and have the same effect in extrahepatic. Some scholars studied the role of detoxification and cover of glycyrrhizic acid in lung injury of rat carrageenan to abroad, activate invention carrageenin can cause ICAM - 1, TNF a a, IL 1 beta, NF kappa B, HYP decreased significantly, and these have been proved to be the target of lung damage can be the glycyrrhizic acid decreased obviously. We through the process of large amount of literature review and practical demonstration of invention, the pathological mechanism of magnesium isoglycyrrhizinate pharmacological action and paraquat poisoning and cure need for link with many amazing anastomosis, such as antioxidant, anti-inflammatory, anti fibrosis effects step response. Therefore, we suppose that can make use of magnesium isoglycyrrhizinate in treatment of acute paraquat poisoning, this research is aimed at through the pulmonary damage process model for preparation of rats with paraquat poisoning, and the use of magnesium isoglycyrrhizinate injection stop interfering in treatment, and through the detection and test process of a series of comprehensive results, to verify the above supposition. In order to find a new treatment avenues. Test methods (1) experiment 1: This study set up the appropriate SD rats lung injury model in paraquat poisoning. Take a clean grade male SD rats (180 a 200g/ only) 15, according to the normal career premise stop after 1 weeks of captivity, not Yacha without exception, weighed, and according to the number of random grouping method were divided into 3 groups, 5 each group with 20%PQ liquid separation according to the low mass fraction (15mg/kg), (20mg/ kg), high (25mg/kg) of three doses of stop intraperitoneal injection exposure, exposure without any disposal. Normal keep 15 days, general situation every day not Yacha groups rats, including exercise, breathing, eating, hair color, two, hemorrhage and death or survival of the comprehensive situation, 15 days after the death of all, for the pathological HE staining observation pulmonary cases. Through the process of observation, that the appropriate test mold the best exposure dose. (2) two: the experiment research of magnesium isoglycyrrhizinate poisoning lung damage shield effect on rats with paraquat. Take a clean grade male SD rats (180 a 200/ only) 30, according to the normal career premise stop after 1 weeks of captivity, not Yacha without exception, weighed, and according to the number of random grouping method were divided into 5 groups, 6 rats in each group, separated into the normal contrast group, contrast group, MgIG low dose exposure treatment group (15mg/kg), MgIG medium dose treatment group (30mg/kg) and high dose MgIG treatment group (45 mg/kg). Except the normal control group, other groups were taking 20% paraquat in the best dose intraperitoneal injection exposure to stop. The normal contrast group to normal diet will not be exposed to other disposal, contrast group continuous intraperitoneal injection of physiological saline favorable capacity (by MgIG to calculate the dose of capacity), other each treatment group in 24 hours after exposure after separation to response dose of MgIG for continuous intraperitoneal injection, 1 /d. Not Yacha big rat ordinary circumstances, movement, breathing, eating, hair color, blood and stored movement situation and specific records. In the continuous treatment after 14 days, fifteenth days to stop all 50mg/kg pentobarbital intraperitoneal injection anesthesia, anatomize the abdominal cavity, the inferior vena cava blood samples were taken from the SOD, MDA, GSH, ICAM 1, MMP 9; anatomize chest, not Yacha lung specimens from 100mg Nianye body, right lung, shear to the eve of the 10mg small, alkaline hydrolysis to detect hydroxyproline (HYP) take the left lung fixed with formalin, preparing the old man block to send disease arts system, stop the HE staining observation alveolitis situation, with Mason staining...
目录:封面1-2文摘2-5英文文摘5-8缩略词表8-9前言9-11第一部分 大鼠百草枯急性肺损伤模型的制备11-17&&&&1.实验材料11-11&&&&2 实验方法11-13&&&&3.实验结果13-16&&&&4 讨论16-17第二部分 异甘草酸镁对大鼠百草枯中毒肺损伤保护作用17-36&&&&1.实验材料17-18&&&&2.实验方法与步骤18-26&&&&3.实验结果26-34&&&&4 讨论34-36综合讨论36-38参考文献38-40在学期间发表的文章40-45个人简历45-46致谢46
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[1].马华丰. [D]. 三峡大学.
2013[2].曹建霞. [D]. 河北北方学院.
2013[3].杨继斌. [D]. 南昌大学.
2013[4].卢芳. [D]. 温州医学院.
2013[5].王韧韬. [D]. 中国人民解放军军医进修学院,解放军总医院,军医进修学院.
2013[6].黄昌保. [D]. 中国人民解放军军事医学科学院,解放军军事医学科学院.
2013[7].宋振举. [D]. 复旦大学.
2011[8].吴瑞平. [D]. 山西医科大学.
2012[9].于鸿敏. [D]. 河北医科大学.
2012[10].孙唯嘉. [D]. 大连医科大学.58iData_不同剂量异甘草酸镁对导管肝动脉化_省略_塞术后原发性肝癌患者肝功能的-第2页
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58iData_不同剂量异甘草酸镁对导管肝动脉化_省略_塞术后原发性肝癌患者肝功能的-2
TheeffectofMagnesiumIsog；ontheliverfunctionofthep；ABSTRACT；Objective:Primaryhepatic；commoncancersintheworld,；stage.Thetranscatheterar；Methods:Twohundredandfif；TACEwereenrolledinthe
　The effect of Magnesium Isoglycyrrhizinate in different doseson the liver function of the patients with primary hepatic
carcinoma post Transcatheter arterial chemoembolization ABSTRACT Objective: Primary hepatic carcinoma(PHC) was one of the mostcommon cancers in the world, with the gradually increased incidence and mortality. Most patients absence of specific symptoms at early stage had lost the opportunity of surgical therapy when PHC was diagnosed at advancedstage. The transcatheter arterial chemoembolization (TACE) was showed to
increase the overall survival of patients significantly, but the liver injury post TACE limited further therapy. The magnesium isoglycyrrhetate (MgIG) had been found to be a protective effect on acute and chronic liver injury. However, there was little reports about the different doses of MgIG in protecting liver function of patients with TACE. In this study, the effects of MgIG in
different doses on liver function of patients were observed, meantime the effects between simple embolization and combined infusion chemotherapy on liver function were compared, which would be helpful to the therapy of patients with advanced primary hepatic carcinoma.Methods: Two hundred and fifty-five patients with PHC who underwentTACE were enrolled in the Forth Hospital of Hebei University from January, 2007 to December, 2013, including 30 females and 225 males with average age being 58.9±10.9 years, 94 patients performed simple embolization and 161 patients performed combined infusion chemotherapy. According to different doses and kinds of medicines, all patients were divided into 3 groups: group A (including 94 cases), group B(including 86 cases) and group C (including 75 cases).The patients of group A were infused with glutathione 1.2g/d for 3 dayspost TACE, the group B were infused with MgIG 100mg/d, and the group C were infused with MgIG 200mg/d. The other therapeutic methods were thesame in 3 groups. The blood samples were collected from patients before and three days after TACE, and the liver function such as ALT, AST, TBIL, DBIL, ALP, GGT, CHE were measured. The level of statistical significance was set up at P＜0.05, and all calculations were carried out using the SPSS17.0 software.Results:1 As for the Age, Gender, Child-Pugh grading, Portal vein tumor thrombosis, Arteriovenous fistula, and Ascites, there were no statistical differences in three groups（P&0.05）.2 The effect of different doses and kinds of medicines on liver function between pre-TACE and post TACEThe effects on liver function in 3 groups were assessed through the difference of liver function between pre-TACE and post TACE, the larger the difference, the weaker of protection on liver function. The difference of the ALT[14U/L] in group C was lower than group B[26U/L] and group A[43.5U/L](P&0.05), and so as the AST in group C[11U/L], group B[25U/L], and group A[39U/L](P&0.05); Simultaneously the difference of the ALP[-7U/L] in group C was less than group A[-2U/L](P&0.05). As for the TBIL, DBIL, GGT, there were no statistical differences in 3 groups. The higher dose of magnesium isoglycyrrhetate had advantage in protecting the liver cell membrane and preventing the liver injury, but no advantage in maintaining the liver reserve function and regulating the metabolism of bilirubin.3 The effect of simple embolization and combined infusion chemotherapy on liver functionThe different effects on liver function between simple embolization and combined infusion chemotherapy were assessed through the difference of liver function between pre-TACE and post TACE. The difference of ALT[42.69±71.33U/L] in combined infusion chemotherapy group was lower than the simple embolization group[88.48±135.29U/L], and so as the AST in combined infusion chemotherapy group(38.07±71.99U/L) and simpleembolization[71.38±108.01U/L](P&0.05). As for the TBIL, DBIL, ALP, GGT, CHE, there were no statistical differences between the two therapeutic methods. 27 Child-Pugh B cases[28.72%] and 23 ascites cases[24.47%] were enrolled in simple embolization, 28 Child-Pugh B cases[17.39%] and 23 ascites cases[14.29%] were enrolled in combined infusion chemotherapy, more Child-Pugh B cases and ascites cases were enrolled in simple embolization(P&0.05）. As for the Age, Portal vein tumor thrombosis, Arteriovenous fistula, there were no statistical differences between simple embolization and combined infusion chemotherapy（P&0.05）.Conclusion:1 Higher dose of magnesium isoglycyrrhetate was superior to lower dose in protecting the liver cell and preventing the liver injury, and not in maintaining the liver reserve function and regulating the metabolism of
bilirubin.2 As for primary hepatic carcinoma patients, either simple embolization or combined infusion chemotherapy could injury the liver cell, how to choose suitable methods to different patients remained further research. Key words: Magnesium I G Prima Transarterial arteri Liver function 不同剂量异甘草酸镁对导管肝动脉化疗栓塞术后原发性肝癌患者肝功能的影响 前
言 原发性肝癌（primary hepatic carcinoma, PHC）为世界范围内常见的恶性肿瘤之一，发病率在男性和女性肿瘤患者中居第五位，死亡率在男性肿瘤患者中居第二位，在女性肿瘤患者中居第六位[1]。我国为原发性肝癌高发地区，其发病人数及死亡人数约占世界的一半。早期PHC患者因临床症状及体征缺乏特异性，就诊时已属中晚期，且多因肿瘤体积大、合并肝硬化、肝功能欠佳、肝外转移等，完全手术及肝移植机会小。TACE因具有较高的肿瘤控制率及较低的副反应率使其在临床上的应用价值明显提高，其选择性的将栓塞剂和/或化疗药物直接注入到肿瘤供血靶动脉，阻断了肝动脉对肿瘤组织的营养及氧供应，延长了药物与肿瘤组织的接触时间，提高了肿瘤区域化疗药物的浓度，但同时不可避免的损伤正常肝细胞，加之动脉闭塞后造成肝细胞缺血缺氧，导致出现肝功能受损的症状。异甘草酸镁( magnesium isoglycyrrhizinate, MgIG)是第四代18α-GA单一立体异构体甘草酸制剂，肝脏为18α-GA类药物的特异性靶器官。异甘草酸镁较前三代甘草酸制剂具有更明显的抗炎、稳定肝细胞膜、解毒、抗生物氧化等作用，且药物副作用轻微，短期内显著降低ALT、AST，其糖皮质激素作用可通过免疫调节减轻TACE术后恶心、呕吐、发热、腹痛等不良。我们曾经观察了异甘草酸镁100mg 1/日可有效降低TACE术后ALT水平。为了获得更佳的结果，我们旨在通过该研究观察异甘草酸镁200mg 1/日是否在不增加药物不良反应的前提下对TACE术后肝功能具有更强的保护作用。 材料与方法 1 研究对象所有病例选自2007年1月至2013年12月在河北医科大学第四医院消化内科、肝胆外科、介入科住院的原发性肝癌初治患者，均符合人民卫生教育出版社出版的第七版内科学原发性肝癌诊断标准[4]及行导管肝动脉化疗栓塞术适应征。所有患者均于我院放射科行TACE术且临床资料完整，后续治疗及随访均于我院进行。A组患者于TACE术后3天输注5%葡萄糖注射液100ml+注射用还原型谷胱甘肽（重庆药友医药公司）1.2g 1/日，B组患者输注10%葡萄糖注射液250ml+异甘草酸镁注射液（正大天晴医药公司）100mg 1/日，C组患者输注10%葡萄糖注射液250ml+异甘草酸镁注射液（正大天晴医药公司）200mg 1/日，余治疗方法三组相同。2 病例临床资料共纳入255例病例，其中A组94例，平均年龄60.4±11.0岁，男性83例，女性11例，Child-Pugh A级69例，B级25例；B组86例，平均年龄57.4±10.9岁，男性80例，女性6例，Child-Pugh A级65例，B级21例；C组75例，平均年龄58.8±10.8岁，男性63例，女性12例，Child-Pugh A级65例，B级10例。行单纯栓塞者94例，其中Child-Pugh A级67例，B级27例，有腹水者23例，无腹水者71例；联合化疗药物灌注者161例，其中Child-Pugh A级133例，B级28例，有腹水者23例，无腹水者138例。3 病例纳入标准3.1 符合人民卫生教育出版社出版的第七版内科学原发性肝癌诊断标准3.1.1 影像学标准：超声、CT、MRI、肝血管造影其中两项影像学检查均显示有&2cm的肝癌特征性占位性病变；3.1.2 血清AFP诊断标准：前提为排除妊娠、活动性肝炎、生殖腺胚胎瘤、转移性肝癌，①大于500ug/L持续4周以上；②AFP维持200ug/L以上的中等水平8周以上；③AFP由低浓度逐渐升高不降；3.1.3 影像学结合AFP诊断标准：上述一种影像学检查提示存在&2cm的肝癌特征性占位性病变，并伴有AFP≥400ug/L（排除妊娠、活动性肝炎、生殖腺胚胎瘤及转移性肝癌）；3.1.4 组织学诊断标准：此为原发性肝癌诊断的金标准，对影像学尚不能定性的≤2cm的肝内占位病变应行肝穿活检证实组织学特性；3.2 无手术切除适应征的或术后预计肝功能无法代偿的或不愿手术的原发性肝癌患者；3.3 手术切除困难以试行TACE术缩小肿瘤体积创造二期手术者；3.4 TACE术前化验肝功能为Child-Pugh A级或B级且凝血功能正常者；包含各类专业文献、专业论文、文学作品欣赏、应用写作文书、生活休闲娱乐、行业资料、中学教育、高等教育、幼儿教育、小学教育、58iData_不同剂量异甘草酸镁对导管肝动脉化_省略_塞术后原发性肝癌患者肝功能的等内容。　
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