青蒿琥酯抗四氯化碳致大鼠肝纤维化的作用

青蒿素类主要用于治疗疟疾,对矽肺、烧伤后增生性瘢痕也有防治作用[1,2],尚未见其抗肝纤维化的报道.本研究采用CCl4 诱发大鼠肝纤维化模型,观察青蒿琥酯(Artesunate)的作用.     

Heterogeneity of changes on the disposition of aspirin in rats with CCl4-induced chronic liver damage

The profile of urinary salicylate metabolites was determined after the oral administration of acetylsalicylic acid (ASA) to CCl4-cirrhotic rats, CCl4-cirrhotic rats treated with colchicine for 1 month, and control groups. The following enzymatic activities were determined: liver and plasma ASA-esterase, liver UDP-glucuronyltransferase, and liver aniline hydroxylase. The time-course of plasma concentration of salicylates in similar groups was followed after the intraperitoneal administration of salicylic acid (SA) or gentisic acid (GA). The cirrhotic animals showed a lack of urinary glucuronates and an increase in urinary gentisic and salicylic acids. The activities of plasma and liver ASA-esterases were increased significantly in cirrhosis, whereas aniline hydroxylase was reduced and UDP-glucuronyltransferase remained unchanged. The plasma half-lives of salicylates were reduced in the cirrhotic animals regardless of the administered parent compound. Colchicine treatment reversed almost completely the alterations. The heterogeneity of liver metabolic dysfunctions present in chronic liver disease was demonstrated. It is emphasized that the pharmacokinetic alterations produced by liver damage are the result of a complex set of factors involving changes in the hepatic circulation, protein binding, and the existence of other routes of elimination.     

The metabolic disposition of flucloxacillin in patients with impaired kidney function

Summary The fate of flucloxacillin and its active metabolite hydroxyflucloxacillin was studied in a group of patients with impaired kidney function. Flucloxacillin was administered orally or intravenously. Peak levels of hydroxyflucloxacillin were obtained between 150 and 250 min after the administration of flucloxacillin. The plasma concentrations obtained after a therapeutic dose of flucloxacillin were well above the concentration (i.e. 1–2 µg/ml) generally considered to be the effective minimum for isoxalyl penicillins. The plasma half life of the metabolite was twice as long as that of flucloxacillin (295 min and 154 min, respectively). The nonprotein-bound fraction of hydroxyflucloxacillin in plasma from patients was twice as large as that of its parent compound (16.2 vs. 8.1%). This was also observed in normal human plasma, although protein binding in the latter was higher than in uraemic plasma. Some accumulation of hydroxyflucloxacillin may occur during flucloxacillin therapy with dosage intervals of 6 h.     

软肝片抗肝纤维化作用的实验研究

目的探讨软肝片对四氯化碳中毒性肝纤维化的防治作用。方法用四氯化碳皮下注射造成大鼠肝纤维化模型 ,以联苯双酯作为阳性对照 ,测定血清丙氨酸氨基转移酶 (ALT)、天冬氨酸氨基转移酶 (AST)、玻璃酸(HA)、唾液酸及肝组织羟脯氨酸 (Hyp)、丙二醛 (MDA)、超氧化物歧化酶 (SOD)含量 ,以反映肝细胞损伤及肝纤维化程度。结果软肝片可明显降低肝纤维化大鼠血清ALT、AST、HA、唾液酸水平及肝组织Hyp和MDA水平 ,提高肝组织中SOD活力。结论软肝片具有一定的抗肝纤维化及抗脂质过氧化作用。     

Prophylactic effect of tritoqualine (TRQ) on the CCl4-induced chronic liver injury model in rats

Tritoqualine (TRQ) administered at doses of 100 or 200 mg/kg, perorally, had a preventive effect on the liver injury in rats induced by the treatment with CCl4 for 12 weeks consecutively. Rats subjected to this chronic treatment with CCl4 showed a decrease in body weight gain and changes in several serum parameters that are indicators of hepatic function were observed: the increase of transaminases, as a parameter of hepatocyte breakdown; the increase of alkaline phosphatase, as a parameter of biliary system abnormalities, the reduction of prothrombin time, as a marker of protein biosynthesis in the liver; and the change of lipids concentrations, reflecting liver injury. After the administration of TRQ perorally, there was a notable suppression of the increment in leaked enzymes in the serum and a marked improvement of the parameters concerning protein biosynthesis and lipid metabolism in comparison with CCl4 control rats. Marked fibrosis in the liver was observed after CCl4 treatment for 12 weeks, and the collagen content in the liver was 5 times higher than that of control rats. TRQ suppressed the increment in collagen formation and also showed improvement of the decrease of the liver function with regards to protein biosynthesis in CCl4-treated rats. Judging from these results, it was concluded that TRQ had a remarkable protecting action on the liver injury chronically induced by CCl4 treatment and was a effective compound for restoring liver function.     

Effects of cianidanol (KB-53) on liver cirrhosis induced by CCl4 in rats: a pathological investigation

The therapeutic effects of cianidanol on the rat liver cirrhosis induced by CCl4 were investigated by means of pathological examination. Rats were administered with CCl4 subcutaneously twice a week for a consecutive 10 weeks. From a macroscopical viewpoint, pailing grayish discoloration, granular hyperplastic nodules and the disappearance of luster on the surface of the liver, and the formation of pseudolobule on the cut surface were observed in the control group. In the histopathological findings, degenerative fatty change and ballooning degeneration of parenchymal liver cells, a formation of pseudolobule caused by septal fibrosis proliferation, an acinar arrangement caused by pericellular fibrosis, and a cholangiollar proliferation were observed. All these abnormalities were diminished by the oral administration of 200 and 400 mg/kg of cianidanol for 7 days. The therapeutic effects of cianidanol were dose-dependent on the liver cirrhosis rats. Consequently, it is suggested that cianidanol has therapeutic effects on liver cirrhosis induced by CCl4 by relieving hepatocytes disorder, improving regeneration of hepatocytes and the absorption of proliferated fibrotic tissues.     

The protective effects of Hibiscus sabdariffa extract on CCl4-induced liver fibrosis in rats.

Dried flower Hibiscus sabdariffa L. (HSE) extracts, a local soft drink material and medicinal herb, were studied for their protective effects against liver fibrosis induced using carbon tetrachloride (CCl(4)) in rats. Male Wistar rats were administered CCl(4) by intraperitoneal injection for 7weeks and received a normal diet or normal diet with various HSE doses (1-5%) for 9weeks. HSE significantly reduced the liver damage including steatosis and fibrosis in a dose dependent manner. Moreover, HSE significantly decreased the elevation in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT). It also restored the decrease in glutathione content and inhibited the formation of lipid peroxidative products during CCl(4) treatment. In the primary culture, HSE also significantly inhibited the activation of the hepatic stellate cells. These results suggested that HSE may protect the liver against CCl(4)-induced fibrosis. This protective effect appears due to HSEs antioxidant properties.     

Ameliorative action of cyanobacterial phycoerythrin on CCl(4)-induced toxicity in rats

Carbon tetrachloride (CCl₄) is largely used as solvent in chemical industries. Carbon tetrachloride is also well known for hepatic and renal toxic actions. The in vivo metabolism of carbon tetrachloride to trichloromethyl (CCl₃) and peroxy trichloromethyl (OOCCl₃) radicals has been extensively reported to cause acute liver damage like cirrhosis, steatosis and necrosis. We have evaluated protective action of purified cyanobacterial phycoerythrin (C-PE) on carbon tetrachloride-induced hepatic and renal toxicity in male rats. Rats were orally treated with 25 and 50 mg/kg BW of C-PE along with CCl₄ (50% CCl₄, 0.5 ml/kg BW, intraperitoneally) for 28 consecutive days. Results demonstrated that C-PE dose-responsively ameliorates CCl₄-toxicity by significantly decreasing (P < 0.05) organs weight, aminotransferases, alkaline phosphatase, glucose, lipid profile, creatinine, uric acid and malondialdehyde (MDA) concentrations with rise in body weight, food intake, hemoglobin, protein, bilirubin and FRAP values. Neither C-PE nor CCl₄ influenced on serum minerals. Hepatic and renal tissues showed significant decline (P < 0.05) in malondialdehyde, lipid hydroperoxides and conjugated dienes with rise in SOD, catalase, GPx, GSH, vitamin-E and vitamin-C levels. Presently observed pharmacological effect on CCl₄ toxicity were from tetrapyrrole molecule and to some extent bilirubin biotransformations, as well as metabolic (dietary protein) actions of C-PE.     

The course of CCl4 induced hepatotoxicity is altered in mGSTA4-4 null (-/-) mice

Glutathione S-transferases (GSTs) play a key role in cellular detoxification of environmental toxicants through their conjugation to glutathione (GSH). Recent studies have shown that the alpha-class GSTs also provide protection against oxidative stress and lipid peroxidation (LPO). GSTA4-4 is a member of a sub group of the alpha-class GSTs. It has been shown to metabolize 4-hydroxynonenal (4-HNE) with high catalytic efficiency through its conjugation to glutathione (GSH) and has been suggested to be a major component of cellular defense against toxic electrophiles such as 4-HNE generated during LPO. Since the hepatotoxicity of carbon tetrachloride (CCl(4)) has been suggested to be due to the generation of free radicals leading to membrane LPO, the present studies were designed to compare hepatotoxicity of CCl(4) in GSTA4-4 null (-/-) and wild type (+/+) mice. The results show that administration of a single dose of CCl(4) (1 ml/kg i.p.) resulted in time dependent hepatotoxicity in both -/- and +/+ mice; the extent of cellular damage by serum enzymes suggests that progression was more rapid in -/- mice, although injury was similar by 24 h. Histopathologic examination showed similar degrees of centrilobular necrosis by 24 h but much greater surrounding degenerative change, including cellular swelling, disarray, and vacuolization, in the liver of -/- mice. As expected -/- mice did not show any expression of mGSTA4-4; after CCl(4) a compensatory increase in the activities of total GST activity was noted at 24 h. Major alterations in other antioxidant enzymes was not observed. 4-HNE levels in the liver of -/- mice were about four-fold higher than in +/+ mice, suggesting a positive correlation between 4-HNE levels and the altered course of CCl(4) hepatotoxicity. These studies suggest that GSTA4-4 is an important component during the early stages (1-6 h) of cellular defense against oxidative stress and LPO although, it is not effective in protecting against the ultimate degree of overall cell injury.     

The disposition and metabolism of durene (1,2,4,5-tetramethylbenzene) in rats

The organ and tissue distribution, excretion and metabolism of [3H]1,2,4,5-tetramethylbenzene ([3H]durene) in male Wistar albino rats were investigated following a single i.p. administration (40 mg/kg) and within 9 days after five daily repeated administrations. Urine proved to be the main route of tritium excretion. Within the first 24 h after a single administration 69% of the radioactivity was excreted in the urine and only 9% in the feces. The highest level of tritium binding was found in the fat tissue, liver, kidneys and adrenal glands. The accumulation of tritium in the plasma proceeded with a kinetic constant of 0.49 h(-1), whereas the half-life of radioactivity decay amounted to about 6.3 h. In erythrocytes, the tritium level was found to be about three times lower than in blood plasma. The total amount eliminated during the 9 days following repeated administration was about 94% of the five doses given. The highest level of tritium was found in fat tissue and adrenal glands, followed by the liver, kidneys, sciatic nerve and muscle. A gradual decline in tritium levels was observed during the following 4 days in most tissues to reach about 2% of the dose given. The main urinary metabolites resulting from the administration of durene were 2,4,5-trimethylbenzyl alcohol (about 22%), 4,5-dimethyl-1,2-benzdialdehyde (about 19%), 2,4,5-trimethylbenzaldehyde (about 19%) and 2,4,5-trimethylbenzoic acid (about 16%). The oxygen-containing metabolites accounted for almost 80%, whereas sulphur-containing metabolites accounted for approximately 10% of the products of biotransformation. In conclusion, most of the durene administered has a relatively rapid turnover rate, with minor levels retained in the tissues for longer time periods.     

丹酚酸A抗四氯化碳中毒致大鼠肝损伤和肝纤维化的作用

目的：研究丹酚酸Ａ（ＳＡＡ）抗肝损伤、肝纤维化作用．方法：采用ＣＣｌ４诱导大鼠肝损伤及肝纤维化，期间予ＳＡＡ灌胃治疗，另设秋水仙碱（Ｃｏｌ）组、丹参组作对照，６周后进行肝组织病理学和Ⅰ、Ⅲ型胶原免疫组化观察，肝组织羟脯氨酸（Ｈｙｄ）、丙二醛（ＭＤＡ）含量及血清ＡｌａＡＴ、ＡｓｐＡＴ和白蛋白含量测定．结果：ＳＡＡ降低血清ＡｌａＡＴ、ＡｓｐＡＴ水平及肝组织ＭＤＡ、Ｈｙｄ含量，减轻肝纤维化程度，抑制Ⅰ、Ⅲ型胶原在基质中沉积．其抗肝纤维化强度与Ｃｏｌ、丹参一致，对ＭＤＡ作用优于Ｃｏｌ．结论：ＳＡＡ有显著的抗肝损伤、肝纤维化作用，与抗脂质过氧化有关     

Mechanism investigation of dioscin against CCl(4)-induced acute liver damage in mice

The mechanisms of the ameliorating effects of dioscin against CCl(4) induced acute liver damage are investigated in this study. Dioscin significantly inhibited (p<0.01) the increases of serum ALT and AST activities compared with the CCl(4)-treated animals. The hepatic lipid peroxidation formation and, concentrations of TNF-α and IL-6 were also decreased. Liver histopathologic studies and a DNA laddering assay indicated that dioscin protected hepatocytes against CCl(4)-induced apoptosis and necrosis. Furthermore, dioscin decreased the protein expressions of Fas/FasL, increased Bcl-2/Bax ratio, inhibited the release of cytochrome c from mitochondrion to cytosol and attenuated CCl(4)-induced caspase-3 and -8 activities. The expressions of ICAM-1, vimentin, prohibitin, HGF, c-MET and GSTA1 were also regulated by dioscin and iNOS was also involved in the effects of this agent. These protective effects against CCl(4) induced acute liver damage might be through inhibiting lipid peroxidation, inflammatory cytokines, necrosis and apoptosis, and dioscin shows promise for development toward the treatment of acute chemically mediated liver injury.     

Hepatoprotective activity of Stereospermum suaveolens against CCl4-induced liver damage in albino rats

The present study aims to evaluate the hepatoprotective activity of Stereospermum suaveolens DC (Bignoniaceae). Hepatoprotective activity is studied by carbon tetrachloride (CCl₄)-induced liver damage in albino rats. The degree of protection in this activity has been measured by using biochemical parameters such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, LDL-cholesterol and SOD, CAT, GSH, total thiols, NO, and lipid peroxidation in liver tissue homogenate. The results suggest that the methanol stem bark extract of Stereospermum suaveolens at the doses 125, 250, and 500?mg/kg and reference standard Liv-52 treated group produced significant (p <0.001) hepatoprotection against CCl₄-induced liver damage by decreasing the activities of serum enzymes, bilirubin and lipid peroxidation. The extract significantly (p <0.001) increased levels of SOD, CAT, GSH and total thiols, as compared to control group. Histopathological studies further substantiate the protective effect of the extract. It was concluded that methanol stem bark extract of Stereospermum suaveolens showed effective hepatoprotective activity.     

肝舒胶囊对CCl4致大鼠慢性肝损伤的影响

目的 研究肝舒胶囊对大鼠慢性肝损伤的保护作用.方法 采用sc CCl4致大鼠慢性肝损伤,比色法测定血清中的ALT、AST、ALP、TP、ALB的含量,碱水解法测定肝组织中羟脯氨酸(HYP)的含量,并根据肝脏的脂变、炎症、水肿、细胞坏死、纤维组织增生观察病理组织学的形态变化.结果 肝舒胶囊对血清中生化指标有一定的降低趋势,可明显降低血清中ALP和肝组织中的HYP;可明显改善肝组织的病理学变化.结论 肝舒胶囊对慢性肝损伤有一定的保护作用.     

四氯化碳诱导大鼠肝硬化腹水模型的改进与优化

目的应用四氯化碳（CCl4）联合苯巴比妥及乙醇的方法,以期建立稳定性、均一性、重复性良好且成模率较高的大鼠肝硬化腹水模型,为相关血浆蛋白制品的药效学评价等研究奠定基础。方法将90只雄性Wistar大鼠随机分为5组：正常对照组10只,腹腔注射橄榄油,正常饮水;模型组分为CCl4组、CCl4＋苯巴比妥组、CCl4＋乙醇组、CCl4＋苯巴比妥＋乙醇组,每组20只,给予不同饮用水处理,腹腔注射40%CCl4橄榄油混合液。各实验组腹腔注射剂量均为2 ml/kg,每周注射2次,共12周。建模过程中,定期测量体质量和腹围,采集静脉血监测肝功能指标和血浆胶体渗透压（COP）。建模结束后,随机处死各组大鼠,取肝右叶组织进行病理学鉴定。应用统计学方法对数据进行分析。结果各模型组在建模的第8～12周先后出现符合筛选标准的模型。其中,第8周时,CCl4＋苯巴比妥＋乙醇组大鼠开始出现腹水阳性体征,个别达到建模标准;第9周时,CCl4＋苯巴比妥组和CCl4＋乙醇组均有符合要求的模型产生;CCl4组至第10周时开始出现建模成功的大鼠。至12周建模结束时,与正常对照组相比,各模型组体质量、腹围、肝功能指标、COP等差异均具有统计学意义,以CCl4＋苯巴比妥＋乙醇组的差异最为明显。各模型组的成模率分别是65%、75%、75%和80%。镜下观察模型组大鼠的肝组织病理学切片,可见假小叶形成等典型的肝硬化形成特征。结论四氯化碳联合苯巴比妥与乙醇诱导大鼠肝硬化腹水动物模型较传统的方法可以有效提高实验动物的成模率,缩短建模周期。