大麻素受体在肝纤维化及肝硬化中的作用及研究进展

肝纤维化的发生与发展是一个复杂的病理和细胞生化过程,受到多种细胞因子及细胞内多种信号转导通路网络的调控。在这个复杂的调控网络中涉及到很多作用靶标,但很多靶点在肝纤维化中的作用尚没有完全定论。发生肝纤维化后,如无有效的治疗措施,最终将恶化为肝硬化。肝硬化患者的肝脏结构发生改变,导致肝脏解毒功能下降,从而使循环血液中内毒素增加,导致肝硬化失代偿期出现门脉高压、内毒血症、高动力循环综合征、肝性脑病等并发症。近年来研究发现大麻素受体参与急、慢性肝病及其并发症的改善与恢复过程,被认为是抗肝纤维化的潜在治疗靶点。该文从大麻素系统概述、大麻素受体与肝纤维化、大麻素受体防治肝纤维化的信号通路、大麻素及其受体在肝硬化并发症中的作用等方面综述了大麻素受体在肝纤维化及肝硬化中的作用及研究进展。     

TMP通过miR-145调控胆道闭锁动物模型肝纤维化及Smad3信号通路的研究

胆道闭锁(biliary atresia,BA)的肝纤维化呈进行性发展的趋势,最终会发展为终末期肝硬化。有研究表明,miR-145靶向Smad3可能是调控BA发病过程中肝纤维化的重要机制。川芎嗪(tetramethylpyrazine,TMP)对刀豆蛋白A、四氯化碳诱导的肝纤维化具有改善作用[1-2],但TMP在BA治疗中的作用未见报道。本研究将以miR-145为切入点、在BA动物模型中观察TMP对肝纤维化及Smad3信号通路的调控作用。     

丹参川芎嗪联合山莨菪碱治疗肝硬化32例临床疗效观察

目的探讨丹参川芎嗪联合山莨菪碱治疗肝硬化临床疗疗效。方法将肝硬化患者64例随机分成两组,对照组及治疗组各32例,两组均在常规治疗的基础上给予山莨菪碱治疗,治疗组在对照组的基础上加丹参川芎嗪治疗。结果对照组总有效率为71.9%,治疗组总有效率为87.5%。结论丹参川芎嗪联合山莨菪碱治疗肝硬化可明显改善肝纤维化。     

转化生长因子-β1微血管密度在肝纤维化的表达

目的 研究转化生长因子-β1及MVD在肝纤维化形成过程中的作用及意义.方法 采用免疫组织化学方法检测慢性病毒性肝炎、肝纤维化、肝硬化中TGF-β1及MVD的表达.结果 随着慢性病毒性肝炎、肝纤维化及肝硬化的形成,TGF-β1表达逐渐增强(P<0.01),MVD在肝纤维化组织中表达高于慢性病毒性肝炎及肝硬化组织.结论 肝脏中TGF-β1及MVD的表达与肝纤维化及肝硬化的形成密切相关,可作为诊断治疗肝纤维化的重要指征.     

安络化纤丸对慢性乙型肝炎及乙型肝炎后肝硬化患者血清肝纤维化指标的影响

<正>肝纤维化是一切慢性肝病的共同病理学基础,是发展到肝硬化的必经阶段。慢性乙型肝炎导致肝纤维化,而进展性肝纤维化可导致肝硬化,最终出现终末期肝病的表现。因此,寻找有效的治疗方法,阻断或逆转肝纤维化发生及发展,对防止肝硬化具有十分重要的意义。为此,我们应用安络化纤丸治疗慢性乙型肝炎及乙型肝炎后肝硬化患者,动态观察其治疗前后血清肝纤维化指标,以期找出更为有效可行的治疗方法,现报告如下。     

肝巨噬细胞与肝纤维化研究进展

肝纤维化是由各种病因所致慢性肝损伤的修复反应,其持续进展可发展为肝硬化甚至肝细胞癌,最终导致肝功能衰竭。目前,肝纤维化尚无有效治疗方法。肝巨噬细胞在肝内炎症反应、纤维化的进展和消退方面发挥关键作用,已成为抗肝纤维化的重要治疗靶细胞。主要就肝巨噬细胞在肝纤维化过程中的作用进行综述,以期能够为肝纤维化治疗提供思路。     

川芎嗪治疗后肝纤维化组织中I型胶原平均光密度表达的比较

目的:观察川芎嗪对大鼠实验性肝纤维化作用的治疗效果,并探讨其作用机制。方法:采用四氯化碳(CCL4)诱导大鼠肝纤维化模型,将实验动物随机分为正常对照组(N)5只、肝纤维化模型组(H)20只、川芎嗪治疗组(TM P)20只,除正常对照组以外其它两组均给予40%四氯化碳(CCL4)花生油溶液0.3m l/100g腹腔注射,每周2次,共6周。川芎嗪组于肝纤维化模型建立后给予盐酸川芎嗪(TM P)60m g/kg经口灌胃,1次/d,连续治疗60天;其余两组同时给予同等剂量的生理盐水。于60天后分别处死各组大鼠。用HE石蜡组织切片观察各组光镜下肝组织结构变化;用免疫组织化学方法染色观察肝组织中I型胶原(C o llagen type I,C oI)表达的变化,并利用计算机图像分析技术测量正常对照组、肝纤维化模型组及川芎嗪治疗组C oI表达的平均光密度。结果:免疫组织化学S-P法染色显示TM P能明显抑制肝组织中C oI水平的表达,C oI在川芎嗪治疗组中的表达明显低于肝纤维化模型组,C oI在川芎嗪治疗组与肝纤维化模型组之间有显著性差异(P<0.01);C oI在川芎嗪治疗组与正常对照组中呈高表达,C oI在川芎嗪治疗组与正常对照组之间差异无显著性(P>0.05)。结论:川芎嗪对四氯化碳(CCL4)诱导的大鼠实验性肝纤维化有明显的保护和治疗作用。     

川芎嗪对CCl4诱导的肝纤维化大鼠肝组织Nrf2/ARE信号通路的影响

目的：观察川芎嗪对四氯化碳诱导的肝纤维化大鼠肝组织Nrf2/ARE信号通路的影响,探讨川芎嗪治疗肝纤维化的作用机制。方法四氯化碳皮下注射制备大鼠肝纤维化模型,设立正常对照组、肝纤维化模型组和川芎嗪治疗组,川芎嗪治疗组在造模过程中每天给予盐酸川芎嗪注射液腹腔注射,6周后,乙醚麻醉,腹主动脉采血,产色基质偶氮法鲎试剂定量测定血浆内毒素;肝组织常规HE染色观察肝脏病变,天狼猩红胶原染色、肝组织羟脯氨酸含量测定评测肝纤维化程度;West-blotting法检测肝组织内Nrf2蛋白的表达, TBA法检测肝组织丙二醛（MDA）水平,酶显色定量分析法检测肝组织谷胱甘肽-S-转移酶（GST）含量。结果川芎嗪治疗组与肝纤维化模型组相比,肝损伤较轻,肝纤维化程度明显降低,血浆内毒素含量降低, Nrf2蛋白表达量增多,肝组织中MDA含量降低, GST的含量升高。结论川芎嗪的抗肝纤维化作用可能与其降低内毒素血症,激活肝内Nrf2/ARE抗氧化通路进而使得抗氧化酶GST等含量增加有关。     

川芎嗪治疗后肝纤维化组织中Ⅰ型胶原平均光密度表达的比较

目的：观察川芎嗪对大鼠实验性肝纤维化作用的治疗效果，并探讨其作用机制。方法：采用四氯化碳（CCL4）诱导大鼠肝纤维化模型，将实验动物随机分为正常对照组（N）5只、肝纤维化模型组（H）20R、川芎嗪治疗组（TMP）20只，除正常对照组以外其它两组均给予40％四氯化碳（CCL4）花生油溶液0．3ml／100g腹腔注射，每周2次，共6周。川芎嗪组于肝纤维化模型建立后给予盐酸川芎嗪（TMP）60mg／kg经口灌胃，1次／d，连续治疗60天；其余两组同时给予同等剂量的生理盐水。于60天后分别处死各组大鼠。用HE石蜡组织切片观察各组光镜下肝组织结构变化；用免疫组织化学方法染色观察肝组织中Ⅰ型胶原（Collagen typeⅠ，CoⅠ）表达的变化，并利用计算机图像分析技术测量正常对照组、肝纤维化模型组及川芎嗪治疗组CoⅠ表达的平均光密度。结果：免疫组织化学S-P法染色显示TMP能明显抑制肝组织中CoⅠ水平的表达，CoⅠ在川芎嗪治疗组中的表达明显低于肝纤维化模型组，CoⅠ在川芎嗪治疗组与肝纤维化模型组之间有显著性差异（P〈0．01）；CoⅠ在川芎嗪治疗组与正常对照组中呈高表达，CoⅠ在川芎嗪治疗组与正常对照组之间差异无显著性（P〉0．05）。结论：川芎嗪对四氯化碳（CCL4）诱导的大鼠实验性肝纤维化有明显的保护和治疗作用。     

川芎嗪抗实验性肝纤维化组织中TGF-β1阳性面积率表达的比较

目的:观察川芎嗪对大鼠实验性肝纤维化作用的治疗效果。方法:采用四氯化碳(CCL4)诱导大鼠肝纤维化模型,将实验动物随机分为正常对照组(N)5只、肝纤维化模型组(H)20只、川芎嗪治疗组(TM P)20只,除正常对照组以外其它两组均给予40%四氯化碳(CCL4)花生油溶液0.3m l/100g腹腔注射,每周2次,共6周。川芎嗪组于肝纤维化模型建立后给予盐酸川芎嗪(TM P)60m g/kg经口灌胃,1次/d,连续治疗60天;其余两组同时给予同等剂量的生理盐水。于60天后分别处死各组大鼠。用免疫组织化学方法染色观察肝组织中转化生长因子β1(TGF-β1)表达的变化,并利用计算机图像分析技术测量正常对照组、肝纤维化模型组及川芎嗪治疗组TGF-β1表达的平均阳性面积。结果:免疫组织化学S-P法染色显示TM P能明显抑制肝组织中TGF-β1水平的表达,TGF-β1在川芎嗪治疗组中的表达明显低于肝纤维化模型组,TGF-β1在川芎嗪治疗组与肝纤维化模型组之间有显著性差异(P<0.01);TGF-β1在川芎嗪治疗组与正常对照组中呈高表达,TGF-β1在川芎嗪治疗组与正常对照组之间差异无显著性(P>0.05)。结论:川芎嗪对四氯化碳(CCL4)诱导的大鼠实验性肝纤维化有明显的保护和治疗作用。     

Role of glutathione in reduction of arsenate and of gamma-glutamyltranspeptidase in disposition of arsenite in rats

Arsenate (AsV), the environmentally prevalent form of arsenic, is converted sequentially in the body to arsenite (AsIII), monomethylarsonic acid (MMAsV), monomethylarsonous acid (MMAsIII), and dimethylarsinic acid (DMAsV) and some trimethylated metabolites. Although the biliary excretion of arsenic in rats is known to be glutathione (GSH)-dependent, involving transport of arsenic-GSH conjugates, the role of GSH in the reduction of AsV to the more toxic AsIII in vivo has not been defined. Therefore, we studied how the fate of AsV is influenced by buthionine sulfoximine (BSO), which depletes GSH in tissues. Control and BSO-treated rats were given AsV (50 micromol/kg, i.v.) and arsenic metabolites in bile, urine, blood and tissues were analysed by HPLC-HG-AFS. BSO increased retention of AsV in blood and tissues and decreased appearance of AsIII in blood, bile (by 96%) and urine (by 63%). The biliary excretion of MMAsIII was also nearly abolished, the appearance of MMAsIII and MMAsV in the blood was delayed and the renal concentrations of these monomethylated arsenicals were decreased by BSO. Interestingly, appearance of DMAsV in blood and urine remained unchanged and the concentrations of this metabolite in the kidneys and muscle were even increased in response to BSO. To test the role of gamma-glutamyltranspeptidase (GGT) in arsenic disposition, the effect of the of the GGT inhibitor acivicin was investigated in rats injected with AsIII (50 micromol/kg, i.v.). Acivicin lowered the hepatic and renal GGT activities and increased the biliary as well as urinary excretion of GSH, but failed to alter the disposition (i.e. blood and tissue concentrations, biliary and urinary excretion) of AsIII and its metabolites. In conclusion, shortage of GSH decreases not only the hepatobiliary transport of arsenic, but also reduction of AsV and the formation of monomethylated arsenic, while not hindering the production of dimethylated arsenic. While GSH plays an important role in the disposition and toxicity of arsenic, GGT, which hydrolyses GSH and GSH conjugates, apparently does not influence the fate of the GSH-reactive trivalent arsenicals in rats.     

微透析取样技术在中药体内分析中的应用研究进展

本文综述了微透析取样技术在中药体内分析中的应用,介绍微透析取样技术的原理、组成、探针类型、特点,重点阐述了微透析取样技术在测定脑、血液、皮肤等组织器官中中药有效成分浓度的应用实例。表明微透析取样技术在中药药效研究中具有广阔的前景。     

应用PASS系统分析我院2010年住院医嘱

目的:了解我院2010年住院患者的合理用药情况,探讨如何利用合理用药监测系统( PASS)提高合理用药水平.方法:利用PASS对我院2010年15 966例住院患者的1 184 997条用药医嘱进行监测,以黑色警示医嘱为依据,收集不合理用药信息,并对监测结果进行统计、分析.结果:不合理用药医嘱50 261条,发生率为4.24％.绝对禁止黑色医嘱5441条,主要为药物相互作用(66.54％)、注射液体外配伍(17.86％)、用法用量(15.46％)、儿童警告(1.14％).结论:应用PASS系统能有效监测医嘱中的不合理用药情况,有利于提高临床合理用药水平,但PASS系统尚存在局限性,有待进一步完善.     

Changes in levels of dependency and predictors of mortality in elderly people in institutional care in Dunedin

The 1983 study of dependency of subjects in institutional care in Dunedin was repeated two years later. A significant increase in levels of dependency in residential homes, particularly in the Religious and Welfare sector was found. In 1983 there were 29 high dependency residents and 73 medium dependency residents in residential homes. In 1985 these numbers had increased to 55 and 86 respectively. There was no change in the number of low dependency residents. In 1983, 6 high dependency residents had been admitted to residential home care in the year prior to the study. In 1985 the number of high dependency residents recently admitted had increased to 23. There had also been a significant increase in the dependency of patients in Religious and Welfare continuing care hospitals. Of the 933 subjects in institutional care in 1983 who were able to be followed, 354 (37.9%) died in the following 2 years. Mortality rate was higher for those in hospital care (48.1%) than for those in residential home care (29.6%). Mortality rates were higher in more dependent subjects and this was evident for each measure of dependency.     

应用PASS系统对我院2008年住院医嘱的分析

目的监测分析2008年我院住院患者用药情况。方法将PASS系统嵌入医生工作站、临床药学工作站等子系统,构建合理用药计算机网络系统,对住院医嘱进行及时监测,将监测结果向医生反馈,并对其进行统计、分析。结果2008年共监测医嘱3 620 241条,不合理医嘱908条,占0.02%。不合理医嘱中,配伍禁忌(381条)占41.96%,用法用量(381条)占41.96%,药物相互作用(108条)占11.89%,儿童用药(38条)占4.19%。经与医生沟通后,更改不合理医嘱856条,占94.27%。结论PASS系统可有效监测医嘱中的不合理用药,通过与医生交流,大大减少药物不良事件的发生,值得临床推广应用,也为临床药师开展工作带来了极大的便利。但PASS系统尚存在局限性,有待进一步完善。     

Role of desacetylation in the detoxification of cephalothin in renal cells in culture

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.     

2009年某院住院患者抗真菌药用药调查

目的:分析讨论某院抗真菌药使用的合理性,为临床安全有效地使用抗真菌药提供参考。方法:回顾性统计分析某院2009年住院患者抗真菌药用药信息。结果:2009年某院住院患者抗真菌药DDDs排名前3名分别为:氟康唑、制霉菌素和伊曲康唑;使用金额排名前3名分别为:氟康唑、米卡芬净及卡泊芬净;更换一种抗真菌药进行治疗的患者数为176人,在全部患者中占13.4%。结论:应进一步强化用药指征的意识,提高标本送检率,同时改善某些抗真菌用药不合理更换的现象,以避免耐药性发生,从而更好更长远地体现抗真菌药的治疗价值。     

Kinetics of in vitro metabolism of methoxyphenamine in rats

1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.     

Comparison of in vitro cell models in predicting in vivo brain entry of drugs

Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates.