Bilirubin content and 4-nitrophenol glucuronosyltransferase activity in Gunn rat liver

The purpose of this study was to determine whether the hepatic content of bilirubin could influence liver 4-nitrophenolglucuronosyltransferase (4-NP-GT) in the Gunn rat. In animals fed on a 45% lipid diet, compared with rats fed on a normal lipid diet (3%), the bilirubin content of the hepatic microsomal fraction decreased and the bilirubin/protein ratio was reduced. 4-NP-GT activities were comparable in both groups. Administration of clofibrate to Gunn rats greatly enhanced the bilirubin content of liver microsomal fraction. Since this treatment raised the microsomal protein content, the bilirubin/protein ratio was not modified. No significant change in 4-NP-GT was noted. After bilirubin perfusion in Gunn and Wistar rats, no change was observed in hepatic monooxygenase activities or in 4-NP-GT, although the bilirubin/protein ratio was dramatically increased in the microsomal fraction. From these results the low activity of liver 4-NP-GT in Gunn rats does not seem directly related to the hepatic content of bilirubin.     

Apocynin administration prevents the changes induced by a fructose-rich diet on rat liver metabolism and the antioxidant system

In the present study, we investigated the role of NADPH oxidase in F (fructose)-rich-diet-induced hepatic OS (oxidative stress) and metabolic changes, and their prevention by apocynin co-administration. Wistar rats were fed for 21?days on (i) a control diet, (ii) a control diet plus 10% F in the drinking water, (iii) a control diet with apocynin in the drinking water (CA) and (iv) F plus apocynin in the drinking water (FA). Glycaemia, triglyceridaemia, NEFAs (non-esterified fatty acids) and insulinaemia were determined. In the liver, we measured (i) NADPH oxidase activity, and gene and protein expression; (ii) protein carbonyl groups, GSH and TBARSs (thiobarbituric acid-reactive substances); (iii) catalase, CuZn-SOD (superoxide dismutase) and Mn-SOD expression; (iv) liver glycogen and lipid content; (v) GK (glucokinase), G6Pase (glucose-6-phosphatase) and G6PDH (glucose-6-phosphate dehydrogenase) activities; (vi) FAS (fatty acid synthase), GPAT (glycerol-3-phosphate acyltransferase), G6Pase and G6PDH, IL-1β (interleukin-1β), PAI-1 (plasminogen-activator inhibitor-1) and TNFα (tumour necrosis factor α) gene expression; and (vii) IκBα (inhibitor of nuclear factor κB α) protein expression. F-fed animals had high serum TAG (triacylglycerol), NEFA and insulin levels, high liver NADPH oxidase activity/expression, increased OS markers, reduced antioxidant enzyme expression, and increased glycogen, TAG storage and GK, G6Pase and G6PDH activities. They also had high G6Pase, G6PDH, FAS, GPAT, TNFα and IL-1β gene expression and decreased IκBα expression. Co-administration of apocynin to F-fed rats prevented the development of most of these abnormalities. In conclusion, NADPH oxidase plays a key role in F-induced hepatic OS production and probably also in the mechanism of liver steatosis, suggesting its potential usefulness for the prevention/treatment of T2DM (Type 2 diabetes mellitus).     

Hepatoprotective effects of misoprostol and silymarin on carbon tetrachloride-induced hepatic damage in rats

The aim of this study was to investigate the effect of misoprostol, silymarin or the co‐administration of misoprostol + silymarin on the carbon tetrachloride (CCl₄)‐induced hepatic injury in rats. Misoprostol (10, 100, 1000 μg/kg), silymarin (25 mg/kg) or misoprostol (100 μg/kg) + silymarin (25 mg/kg) was given once daily orally simultaneously with CCl₄ and for 15 days thereafter. The results showed that misoprostol (10, 100 or 1000 μg/kg) conferred significant protection against the hepatotoxic actions of CCl₄ in rats, reducing serum alanine aminotransferase (ALT) levels by 24.7%, 42.6% and 49.4%, respectively compared with controls. Misoprostol, given at 100 or 1000 μg/kg, decreased aspartate aminotransferase (AST) by 28 and 43.6% and alkaline phosphatase (ALP) by 19.3% and 53.4% respectively. Meanwhile, silymarin reduced ALT, AST and ALP levels by 62.7%, 66.1% and 65.1% respectively. The co‐administration of misoprostol (100 μg/kg) and silymarin (25 mg/kg) resulted in 61.4%, 66.1% and 57.5% reduction in ALT, AST and ALP levels respectively. Histopathological alterations and depletion of hepatocyte glycogen and DNA content by CCl₄ were markedly reduced after treatment with misoprostol, silymarin or misoprostol + silymarin. Image analysis of liver specimens revealed a marked reduction in liver necrosis; area of damage: 32.4%, 24% and 10.2% after misoprostol (10, 100 or 1000 μg/kg), 7.2% after silymarin and 10.9% after treatment with misoprostol 100 μg/kg + silymarin, compared with CCl₄ control group (46.7%). These results indicate that treatment with misoprostol protects against hepatocellular necrosis induced by CCl₄. This study suggests a potential therapeutic use for misoprostol in liver injury.     

Nilotinib counteracts thioacetamide‐induced hepatic oxidative stress and attenuates liver fibrosis progression

The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150 mg/kg, twice weekly) for 12 weeks. Daily treatments with imatinib (10 mg/kg), nilotinib (10 mg/kg), and silymarin (100 mg/kg) were administered orally during the last 4 weeks of TAA‐administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4‐hydroxynonenal (4‐HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA‐induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4‐HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA‐treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA‐treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti‐fibrotic drug.     

Time course of gamma glutamyl transpeptidase in the serum of low birth weight infants

The time course of gamma-glutamyl transpeptidase (GGTP) was traced during a number of weeks after birth in 31 apparently healthy low birth weight infants. Also glutamic-pyruvic transaminase (GPT), 5'-nucleotidase (5 'ND) and alkaline phosphatase (AP) were determined in most of the same samples.In many of the prematures, but not in all, the GGTP showed a transient elevation, reaching maximal levels up to 150 I.U. Most values of GPT and 5'ND, however, were within the normal range, whereas for AP rather large variations were found. No age dependency could be established for the appearance of the GGTP maximum; neither the period of its occurrence nor its height showed a correlation to birth weight and to the degree of prematurity. The significance of transient GGTP activity in prematures is discussed. The results of our investigations suggest that in such infants increased values of GGTP have to be interpreted very carefully.Other enzyme and chemical parameters have to be considered simultaneously in order to establish cholestatic liver disease.     

The action of silymarin on Galactosamine-induced hepatitis in the rat (author's transl)]

The hepatoprotective action of Silymarin was studied in 65 male Wistar rats, prior to and following D-galactosamine intoxication. There was a marked reduction in the histological and ultrastructural changes in the nucleolus, nuclear membrane, mitochondria, granular and agranular endoplasmic reticulum and lysosomes of the liver cell and also in the Kupffer stellate cells. The reduction in glycogen and RNA loss was determined biochemically. The activities of many enzymes were kept constant (oxidoreductases, NADH2 diaphorase, G-6-phosphatase, Mg++ and K+/Na+-dependent ATPases, acid phosphatases).     

Effects of silymarin and pentoxifylline on matrix metalloproteinase-1 and -2 expression and apoptosis in experimental hepatic fibrosis

Background: Many therapeutic strategies have been proposed to treat liver fibrosis, but no drugs have been proved effective. Matrix metalloproteinases (MMPs) have been reported to play a role in some cellular cascades of hepatic inflammation and fibrosis.Objective: The purpose of this study was to investigate whether silymarin and pentoxifylline (PTX) have hepatoprotective and antifibrotic effects in experimental hepatic fibrosis.Methods: Sprague-Dawley rats were divided into 4 groups: silymarin group (silymarin 4 mg/kg · d⁻¹ orally, common bile duct ligation [CBDL]); PTX group (PTX 2 mg/kg · d⁻¹ intraperitoneally, CBDL); sham group (common bile duct [CBD] exploration only); and control group (saline 1 mL/d orally, CBDL). The CBD was explored and dissected sufficiently to allow passage of a 3/0 silk suture via midline laparotomy. On day 10, all animals were euthanized via cervical dislocation. Then, 5-cm³ liver samples from the right lobe were removed for histomorphologic evaluation and 3-mL blood samples were taken via cardiac puncture for biochemical analyses. Apoptosis was determined using the terminal deoxynucleotidyltransferase-biotin nick end-label (TUNEL) staining method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase; total and indirect bilirubin concentration; hepatic MMP-1 and -2 and tissue inhibitor of MMP (TIMP)-l and -2 activity; and transforming-growth factor (TGF)-β₁ concentration were measured. Collagen content was determined by measuring hydroxyproline in liver samples. Malondialdehyde (MDA) was used to estimate lipid peroxidation.Results: Thirty-two adult male Sprague-Dawley rats were divided into 4 groups: silymarin group (n = 7), PTX group (n = 7), sham group (n = 9), and control group (n = 9). Compared with the control group (14.6 [2.44]), mean (SD) hepatocyte apoptosis (as measured by the ratio of TUNEL-positive cells) was significantly suppressed in the silymarin group (1.2 [0.13]; P = 0.001) and the PTX group (3.8 [0.34]; P = 0.001). Mean (SD) MMP-2 activity in the silymarin group (57.35 [9.89] μg/mL; P = 0.04) and the PTX group (46.88 [9.56] μg/mL; P = 0.04) was significantly lower than that observed in the control group (232.32 [79.76] μg/mL). Compared with the control group (1.37 [0.38] μg/mL), TIMP-2 activity was significantly lower in the silymarin group (0.55 [0.13] μg/mL; P = 0.04) and the PTX group (0.42 [0.09] μg/mL; P = 0.01). Compared with the control group (909.17 [117.35] μg/mL), TGF-β₁ was significantly lower in the silymarin group (518.24 [30.34] μg/mL; P = 0.01) and the PTX group (519.57 [47.27] μg/mL; P = 0.01). Histomorphologic changes were significantly greater in the sham group than in the silymarin and PTX groups: hemorrhage (2.44 [0.29] vs 1.29 [0.18] and 1.57 [0.20], respectively; both, P = 0.04); sinusoidal dilatation (2.22 [0.22] vs 1.57 [0.20] and 1.71 [0.18]; both, P = 0.04); presinusoidal polymorphonuclear cell infiltration (3-44 [0.24] vs 2.57 [0.20] and 2.14 [0.26]; P = 0.03 and P = 0.008, respectively); and inflammation (3.44 [0.24] vs 2.57 [0.20] and 2.14 [0.26]; P = 0.03 and P = 0.008, respectively). In the control group, all biochemical markers were elevated, supporting the presence of liver injury. Compared with the control group (630.00 [46.80] U/L), plasma AST activity was significantly lower in the silymarin group (443.11 [78.73]; P = 0.04) and the PTX group (349.42 [34.00]; P = 0.03). Compared with the control group (191.12 [32.93] U/L), plasma ALT activity was significantly lower in the silymarin group (86.14 [4.97]; P = 0.04) and the PTX group (84.14 [11.21]; P = 0.04). MDA concentration was significantly lower in the silymarin group compared with the control group (0.08 [0.01] vs 0.22 [0.03] nmol/mL; P = 0.004); MDA was also significantly lower in the silymarin group than in the PTX group (0.11 [0.02]; P = 0.03).Conclusions: Silymarin and PTX were associated with lower histopathologic liver damage, hepatocyte apoptosis, and regulation of extracellular matrix proteins. Lipid peroxidation in hepatocytes was significantly lower in the silymarin group compared with the PTX group. Silymarin and PTX appeared to have hepatoprotective effects in this experimental liver fibrosis model, but further clinical and experimental studies are needed.     

GSK-3抑制剂对大鼠肝脏创伤的保护作用

目的 探讨糖原合成酶激酶-3(glycogen synthase kinase-3,GSK-3)抑制剂和葡萄糖联合应用对大鼠肝脏创伤救治的影响及其机制.方法 健康SD大鼠49 只,全部建立大鼠肝脏撞击破裂伤模型.先取42 只建模大鼠随机分为三组,即对照组(氯化钠组)、葡萄糖组、GGI组(葡萄糖+GSK-3抑制剂联合应用组)(n=14).各组再随机分为缺血前和再灌注4 h两个亚组(n=7).剩余7 只建模大鼠为再灌注4 h假手术组.测定各组外周血中AST及ALT含量、肝组织糖原及ATP含量、Ca2+-ATP酶活性及Ca2+浓度.结果 与缺血前比较,再灌注4 h各组肝糖原和ATP含量均明显降低(P<0.01);而除假手术组外,各组外周血ALT、AST水平及肝组织Ca2+浓度均明显增高,肝组织Ca2+-ATP酶活性均明显降低(P<0.01).缺血前,肝组织糖原含量:对照组<葡萄糖组葡萄糖组>GGI组>假手术组(P<0.01或P<0.05);肝脏组织ATP含量和Ca2+-ATP酶活性:对照组<葡萄糖组相似文献   

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

In chronic schistosomiasis, hepatic fibrosis is linked to the portal hypertension that causes morbidity in Schistosoma mansoni infection. Silymarin (SIL) is a hepatoprotective and antioxidant medicament largely prescribed against liver diseases that has previously been shown to prevent fibrosis during acute murine schistosomiasis. Here we employed silymarin to try to reverse established hepatic fibrosis in chronic schistosomiasis. Silymarin or vehicle was administered to BALB/c mice every 48 h, starting on the 40th (80 days of treatment), 70th (50 days), or 110th (10 days) day postinfection (dpi). All mice were sacrificed and analyzed at 120 dpi. Treatment with silymarin reduced liver weight and granuloma sizes, reduced the increase in alanine aminotransferase and aspartate aminotransferase levels, and reduced the established hepatic fibrosis (assessed by hydroxyproline contents and picrosirius staining). Treatment with silymarin also reduced the levels of interleukin-13 (IL-13) in serum and increased the gamma interferon (IFN-γ)/IL-13 ratio. There was a linear correlation between IL-13 levels in serum and hydroxyproline hepatic content in both infected untreated and SIL-treated mice, with decreased IL-13 levels corresponding to decreased hydroxyproline hepatic contents. Treatment with either SIL or N-acetylcysteine reduced both proliferation of fibroblast cell lines and basal/IL-13-induced production of collagen I, indicating that besides inhibiting IL-13 production during infection, SIL antioxidant properties most likely contribute to inhibition of collagen production downstream of IL-13. These results show that silymarin interferes with fibrogenic cytokines, reduces established fibrosis, and inhibits downstream effects of IL-13 on fibrogenesis, indicating the drug as a safe and cheap treatment to liver fibrotic disease in schistosomiasis.     

Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CCl4 in rats: role of TGF-beta modulation and oxidative stress

Curcumin is a phytophenolic compound, which is highly efficacious for treating several inflammatory diseases. The aim of this study was to evaluate the efficacy of curcumin in preventing or reversing liver cirrhosis. A 4-week bile duct ligation (BDL) rat model was used to test the ability of curcumin (100 mg/kg, p.o., daily) to prevent cirrhosis. To reverse cirrhosis, CCl₄ was administered chronically for 3 months, and then it was withdrawn and curcumin administered for 2 months. Alanine aminotransferase, γ-glutamyl transpeptidase, liver histopathology, bilirubin, glycogen, reduced and oxidized glutathione, and TGF-β (mRNA and protein) levels were assessed. Curcumin preserved normal values of markers of liver damage in BDL rats. Fibrosis, assessed by measuring hydroxyproline levels and histopathology, increased nearly fivefold after BDL and this effect was partially but significantly prevented by curcumin. BDL increased transforming growth factor-beta (TGF-β) levels (mRNA and proteins), while curcumin partially suppressed this mediator of fibrosis. Curcumin also partially reversed the fibrosis induced by CCl₄. Curcumin was effective in preventing and reversing cirrhosis, probably by its ability of reducing TGF-β expression. These data suggest that curcumin might be an effective antifibrotic and fibrolitic drug in the treatment of chronic hepatic diseases.     

Quantitation of bilirubin conjugates with high-performance liquid chromatography in patients with low total serum bilirubin levels

Bilirubin mono- and diconjugates were determined by alkaline methanolysis and high-performance liquid chromatography (HPLC) in serum from patients with metastatic liver disease and liver cirrhosis. Conjugates could be detected and quantitated at normal or low total bilirubin levels. Comparison with serum alkaline phosphatase activity revealed that in cirrhosis bilirubin conjugates were sometimes detectable at normal or slightly elevated alkaline phosphatase activities. In patients with metastatic liver disease alkaline phosphatase activity was a more sensitive indicator. In normal controls and in patients with Gilbert's syndrome no bilirubin conjugates were detected whereas serum of patients with haemolysis contained conjugated bilirubin. Therefore HPLC appears to be an excellent method to diagnose Gilbert's syndrome. In liver cirrhosis HPLC is a useful liver function test.     

The effect of amiodarone and/or antioxidant treatment on splenocyte blast transformation

Previous studies have shown that free radical reactions may play an important role in the pathogenesis of the adverse effects of the antiarrhythmic agent amiodarone. The aim of this study was to investigate the role of free radical reactions in amiodarone-induced changes in the cell-mediated immune response. Therefore, we investigated the effects of amiodarone alone and in combination with either vitamin E or silymarin on (a) spontaneous blast transformation of splenocytes, (b) concanavalin A (con A)-induced proliferation of splenocytes at three different lectin concentrations, and (c) the content of conjugated dienes in liver homogenate. Forty-eight male Fischer 344 rats were randomized to one of the following groups: 1, control; 2, amiodarone; 3, vitamin E; 4, amiodarone+vitamin E; 5, silymarin; 6, amiodarone+silymarin. The con A-induced splenocyte proliferation was significantly decreased in amiodarone-treated rats at all three lectin concentrations. In the amiodarone-treated group, the change of spontaneous blast transformation was not significantly different from the control. In groups treated with amiodarone plus either antioxidant, both the spontaneous and con A-induced splenocyte proliferation were significantly increased compared with the amiodarone-treated group, and were similar to those in the control group. Amiodarone treatment significantly increased, and both silymarin and vitamin E combined with amiodarone significantly decreased, the conjugated diene content of liver homogenate compared with amiodarone treatment alone. In conclusion, free radicals generated by amiodarone may be implicated in the adverse effects of amiodarone on cell-mediated immune response, and antioxidants applied together with amiodarone may protect against or reduce both the unfavorable immunological effects of amiodarone and amiodarone toxicity.     

Liver transduction with a simian virus 40 vector encoding insulin-like growth factor I reduces hepatic damage and the development of liver cirrhosis

Liver transplantation is the only treatment for advanced liver cirrhosis. Therapies halting the progression of the disease are urgently needed. Administration of recombinant insulin-like growth factor-I (rIGF-I) induces hepatoprotective effects in experimental cirrhosis. Therefore, we analyzed the efficacy of a recombinant simian virus 40 vector (rSV40) encoding IGF-I (rSVIGF-I) to prevent cirrhosis progression. First, transgene expression was evaluated in mice injected with rSV40 encoding luciferase, which showed long-term hepatic expression of the transgene. Interestingly, luciferase expression increased significantly in CCl(4)-damaged livers and upon IGF-I administration, thus liver injury and IGF-I expression from rSVIGF-I should favor transgene expression. rSVIGF-I therapeutic efficacy was studied in rats where liver cirrhosis was induced by CCl(4) inhalation during 36 weeks. At the end of the study, the hepatic levels of IGF-I and IGF-binding protein 3 were higher in rSVIGF-I-treated rats than in control cirrhotic animals. Cirrhotic rats treated with rSVIGF-I had reduced serum bilirubin, transaminases and liver fibrosis scores and increased hepatic expression of hepatocyte growth factor and STAT3alpha as compared to cirrhotic animals. Furthermore, cirrhotic animals showed testis atrophy and altered spermatogenesis, whereas testicular size and histology were normal in cirrhotic rats that received rSVIGF-I. Therefore, rSV40-mediated sustained expression of IGF-I in the liver slowed cirrhosis progression.     

Regulation of the hepatic endothelin system in advanced biliary fibrosis in rats.

The aim of the present study was to analyze the hepatic endothelin system and its regulation in liver cirrhosis due to bile duct obstruction. Wistar rats were subjected for 6 weeks to: 1) sham operation; 2) bile duct obstruction; 3) bile duct obstruction and the selective oral endothelin A receptor antagonist LU 135252; 4) bile duct obstruction and oral silymarin, a hepatoprotective and antifibrotic compound. We determined tissue concentrations of endothelin-1 and big-endothelin-1 by ELISA and the density of both endothelin receptor subtypes in plasma membrane fractions by Scatchard analysis. The hepatic endothelin system in liver cirrhosis due to chronic bile duct obstruction is characterized by a simultaneous up-regulation of both endothelin-1 tissue concentration (7.2 fold compared to sham operation; p<0.001) as well as the density of both endothelin receptor subtypes (ET(A) 7.4-fold, ET(B) 4.9-fold, p<0.001, respectively) suggesting a synergistic activation of the hepatic endothelin system in this rat model of non-inflammatory cirrhosis. Treatment with proven antifibrotic agents such as silymarin or a selective endothelin-A-receptor blocker (LU 135252) did not reduce the activity of the hepatic endothelin system, suggesting that the hepatic endothelin system is not activated by the fibrotic process itself.     

四氯化碳综合法制备大鼠肝硬化模型

【目的】探讨建立一种理想的大鼠肝硬化模型的复制方法并加以评价,为下一步探索肝硬化门脉高压症治疗方法提供可靠、稳定的模型动物。【方法】90只雄性SD大鼠随机分为两组:实验组(70 只)采用四氯化碳(CCl4)+苯巴比妥钠+食用白酒进行诱导,诱导期间CCl4 浓度在一定范围内逐步增加,并用食用白酒替代医用乙醇溶液;对照组(20只) 给与普通饮水和饲料,频度及剂量同实验组。同时采用一系列的检查方法加以评估。【结果】实验组70只大鼠造模结束时,死亡9只,死亡率12.86%。实验结束时,按照成模标准,造模成功大鼠共61只,均可观察到肝硬化结节及镜下假小叶形成,成模率87.14%。实验组门静脉压力比对照组明显增高(P<0.05); 血清总胆红素、谷丙转氨酶及谷草转氨酶较正常对照组明显升高(P<0.05),而血清白蛋白较之正常对照组明显降低(P<0.05)。对照组20 只全部存活。【结论】该方法可形成稳定的肝硬化门脉高压症模型,可用于肝硬化门脉高压症方面的相关研究。此模型制作周期短(仅需9周),成模率高,死亡率低, 具有简便、快捷、高效的优点,适于大批量制作。     

Targeting AngII/AT1R signaling pathway by perindopril inhibits ongoing liver fibrosis in rat

The renin–angiotensin system (RAS) has a substantial role in liver fibrosis, cirrhosis, and portal hypertension. Hence, targeting RAS through angiotensin‐converting enzyme (ACE) inhibitors can mend hepatic fibrosis; the current study was designed to examine the potential fibrosis inhibition activity of perindopril using a rat model of liver fibrosis induced by thioacetamide (TAA). Four groups of rats were used throughout this study, Group I (control group); rats received the vehicle. TAA was used for inducing liver fibrosis in rats by intraperitoneal injection of 200‐mg/kg body weight twice a week for 6 weeks. Group II served as (TAA group). Rats of Groups III and IV were given perindopril at doses of 2 and 8 mg/kg 2 weeks after TAA administration and continued concomitantly with TAA till the end of the experiment. Injection of TAA resulted in a significant increase in aminotransferases' activities and bilirubin with a significant decrease in serum albumin and total protein and a significant decrease in hepatic content of GSH and SOD. Additionally, TAA injection raised the hepatic content of TGF‐β1, α‐SMA, TNF‐α, and level of MDA. Histological and immunohistochemical data presented marked fibrosis in liver sections of TAA‐administrated rats with increased collagen deposition, elevated METAVIR scoring, and increased expression of α‐SMA, caspase‐3, and AT1R. Oral dosing of perindopril for 4 weeks concomitant with TAA could mend the altered parameters near to normal values and abolished the ongoing fibrosis extension. In conclusion, these results demonstrated that perindopril, as ACE inhibitor, could grant a superior remedial nominee in preventing liver fibrosis progression through targeting angiotensin II formation.     

Combined therapy of silymarin and desferrioxamine in patients with β-thalassemia major: a randomized double-blind clinical trial

Silymarin, a flavonolignan complex isolated from Silybum marianum , has a strong antioxidant, hepatoprotective, and iron chelating activities. The present study was designed to investigate the therapeutic activity of orally administered silymarin in patients with thalassemia major under conventional iron chelation therapy. A 3-month randomized, double-blind, clinical trial was conducted in 59 β-thalassemia major patients in two well-matched groups. Patients were randomized to receive a silymarin tablet (140 mg) three times a day plus conventional desferrioxamine therapy. The second group received the same therapy but a placebo tablet instead of silymarin. Clinical laboratory tests were assessed at the beginning and the end of the trial, except for serum ferritin level that was assessed at the middle of the trial as well. Results of this study revealed that the combined therapy was well tolerated and more effective than desferrioxamine in reducing serum ferritin level. Significant improvement in liver alkaline phosphatase and glutathione levels of red blood cells was also observed in silymarin-treated β-thalassemia patients. However, no significant difference in serum ferritin levels was detected between silymarin and placebo groups after 1.5 and 3 months treatment, probably because of insufficient sample size to detect subtle changes in ferritin levels between groups. This is the first report showing the beneficial effects of silymarin in thalassemia patients and suggests that silymarin in combination with desferrioxamine can be safely and effectively used in the treatment of iron-loaded patients.     

Plasma gamma-glutamyl transpeptidase in heroin addicts.

Plasma gamma-glutamyl transpeptidase was measured in 25 heroin addicts. The purpose was to find out if the long term administration of heroin would lead to a stimulation of GGTP due to the detoxication of this drug in the endoplasmatic reticulum of the liver. In 10 patients the elevation of GGTP could be attributed to liver damage, since other liver enzymes were also increased. 15 patients had normal GGTP activities, in 4 of them accompanied by minor elevations of single other hepatic enzymes. In 11 patients the GGTP activity as weel as that of the other enzymes was normal despite heavy chronic herioin abuse. It is therefore improbable that GGTP can be used to diagnose abuse of this drug and to evaluate the progress of drug detoxication treatments and drug abstention as has been proposed in chronic alcoholism.     

五酯胶囊、水飞蓟素防治药物性肝损害的疗效评价

目的:评价五酯胶囊、水飞蓟素对抗结核药物所致肝损害的预防和治疗效果。方法:112例住院HB-sAg( )初治浸润型肺结核随机分为两组,均以2HRZE(S)/4HR方案抗结核治疗,治疗组于强化期加用五酯胶囊、水飞蓟素(西利宾胺或利加隆)。结果:治疗组47例发生可逆性中度转氨酶升高7例(14.9%);对照组65例,发生可逆性中度转氨酶升高25例(38.5%),两组差异显著(P<0.05)。同时观察HBsAg(-)住院初治浸润型肺结核102例,发生可逆性中度转氨酶升高9例(8.8%)。结论:HBsAg( )病例接受抗结核治疗易发生药物性肝损害,五酯胶囊、水飞蓟素只对部分药物性肝损害有预防和治疗作用,而对药物过敏反应在抗结核药所致药物性肝损害中起一定作用。     

A new silymarin preparation based on solid dispersion technique

Silymarin is a hepatoprotective agent that is poorly soluble in water. The present study describes a new preparation of solid dispersions in the form of “dripping pills” designed to enhance solubility. Dripping pills of silymarin were prepared at a 1:4 ratio by the traditional fusion method with the use of a mixture of silymarin and polyethylene glycol 6000 (PEG 6000). The prepared dripping pills were spherical and 3 to 4 mm in diameter, with an average weight of 30 mg per pill and with each pill containing 5 mg of silymarin. The dissolution rates of silymarin in dripping pill and of 3 other silymarin preparations, including Yiganling Film-Coating Tablet, Yiganling Sugar-Coating Tablet, and Legalon Capsule, were determined in pH 1.2 medium. The dissolution rate (T₅₀) of the silymarin dripping pill was found to be significantly higher (by a factor of 7.5–11) than those of the other 3 preparations.