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PubMed2002

Milk thistle for the treatment of liver disease: a systematic review and meta-analysis.

PURPOSE: Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS: We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS: Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P = 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with placebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (-9 IU/L, 95% CI: -18 to -1 IU/L; P = 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION: Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease.

Biomarkers↗
PubMed2001

Production and certification of an enzyme reference material for adenosine deaminase 1 (BCR 647).

BACKGROUND: We describe the preparation of a lyophilised reference material containing purified human adenosine deaminase 1 and the certification of its catalytic concentration. METHODS: The enzyme was purified from human erythrocytes. RESULTS: The enzyme was >99% pure on polyacrylamide gel electrophoresis. Only trace amounts (<0.4%) of alanine aminotransferase, aspartate aminotransferase and L-lactate dehydrogenase were detected in the purified fraction. The purified adenosine deaminase had a molar mass of 41600 g/mol and an isoelectric pH at 4.7, 4.85 and 5.0. The material was prepared by diluting the purified adenosine deaminase in a matrix containing 50 mmol/l Tris-HCl buffer pH 7.4 and 30 g/l human serum albumin; dispensing in vials and freeze-drying. The batch was homogeneous and the predicted loss of adenosine deaminase activity per year on the basis of accelerated degradation studies was 0.006% at -20 degrees C and 0.04% at 4 degrees C. The certified value for adenosine deaminase catalytic concentration in the reconstituted reference material is (2.55+/-0.09) microkat/l when measured by the method that uses adenosine as substrate and glutamate dehydrogenase as auxiliary enzyme at 37 degrees C. CONCLUSIONS: The material can be used to verify the comparability of results from different laboratories, for intra-laboratory quality control, or for calibration of the adenosine deaminase catalytic concentration measurements.

Adenosine Deaminase↗
PubMed1988

Lethality and hepatotoxicity of complex waste mixtures.

Male F344 rats were exposed by gavage to samples of complex mixtures and evaluated 24 hr later. Seven of the 10 samples caused death at doses ranging from 1 to 5 ml/kg body wt. Eight of the 10 samples were hepatotoxic based on histopathologic evaluation; 6 were centrilobular and 2 were periportal hepatotoxicants. The waste samples exerted toxicity through different mechanisms, as indicated by differences in the severity and lobular location of the tissue damage. Nine of the 10 samples caused an increase in the ratio of liver weight to body weight (relative liver weight). With histopathological evaluation as the criterion, relative liver weight was the single best indicator of hepatotoxicity. Exposure to several of the waste samples increased serum total bilirubin and serum enzyme activities of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, and ornithine carbamyl transferase. As a battery, but not individually, the serum indicators separated the 8 hepatotoxic samples from the 2 nonhepatotoxic samples. In general, the hepatotoxicity of the waste samples did not appear to be readily predicted from (partial) chemical characterization data. An approach that includes both chemical characterization and biological testing should provide valuable information regarding the hazardous nature of complex wastes.

Animals↗
PubMed2003

6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.

BACKGROUND & AIMS: Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD. METHODS: Liver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities. RESULTS: Laboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (<200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1-7.3; P < 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2-7.4; P < 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P < 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2. CONCLUSIONS: NRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.

Adolescent↗
PubMed2003

Cortisol treatment affects glucocorticoid receptor and glucocorticoid-responsive genes in the liver of rainbow trout.

We investigated whether longer-term cortisol exposure modified hepatic glucocorticoid receptor (GR) status and tissue responsiveness to cortisol stimulation in rainbow trout. Fish were given intraperitoneal implants of cortisol (50mg/kg body mass) and this led to elevated plasma cortisol levels mimicking chronically stressed salmonids. There was significantly higher hepatic GR mRNA abundance, despite a drop in GR protein content in the liver of cortisol-treated fish. The tissue responsiveness to cortisol stimulation was apparent from the higher plasma glucose concentration and liver glycogen content. Also, the higher phosphoenolpyruvate carboxykinase (PEPCK) mRNA abundance, a key glucocorticoid-responsive gene, by cortisol suggests activation of the GR signalling pathway. There was no significant effect of cortisol treatment on liver PEPCK, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities compared to the sham fish. The higher heat shock protein (hsp) 90 mRNA abundance and a corresponding elevation in this protein and constitutive hsp70 (hsc70) protein content in the cortisol-treated fish reflects a role for glucocorticoids in the hepatic stress response process. Taken together, the molecular and biochemical responses evident in the liver of trout imply changes favouring tissue responsiveness to glucocorticoids and may be a mechanism to offset GR protein downregulation evident with chronic cortisol stimulation in rainbow trout.

Animals↗
PubMed1992

Laminin and procollagen-III-peptide as a serum marker for hepatic fibrosis in congenital biliary atresia.

The extracellular matrix (ECM) is a complex of macromolecules that includes collagens, proteoglycans, and complex glycoproteins. In fibrotic liver tissue there is an increase in all of these matrix components, and they increase in serum in the patients with alcoholic hepatitis or liver cirrhosis. These ECM components have been used as a serum marker of hepatic fibrosis. Prolonged obstruction of bile flow results in morphologic and biochemical changes and the development of secondary biliary cirrhosis. In congenital biliary atresia (CBA) there is a close correlation between the degree of the hepatic fibrosis and bile flow after the operation. We estimated that, in CBA, ECM increased in serum, and it would reflect the degree of the hepatic fibrosis. To clarify this we examined the serum procollagen-III-peptide (P-III-P) and laminin in CBA patients. P-III-P was elevated in all preoperative patients but in two of the three postoperative patients whose jaundice disappeared P-III-P was in the normal range. In the all 3 patients whose jaundice continued, P-III-P was in normal range. Serum laminin was elevated in 12 preoperative patients with CBA, but there is no correlation between day of diagnosis and level of laminin. Mean concentration in CBA without jaundice after operation was 3.18 U/mL, 3.226 U/mL in CBA with jaundice and 3.3 U/mL in infantile hepatitis. There were no significant differences among three groups. With the elevation of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin, serum laminin level was also increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Biliary Atresia↗
PubMed2003

Control of common freshwater predatory fish, Channa punctatus, through Nerium indicum leaf extracts.

The diethyl ether, chloroform, acetone and methanol extract of Nerium indicum leaf were evaluated for their piscicidal activity against common freshwater air breathing predatory fish Channa punctatus. The rank of order of toxicity (LC50) of the leaf extract was, diethyl ether extract (17.34 mg/l)>acetone (40.01 mg/l)>chloroform (40.61 mg/l)>and methanol (106.37 mg/l). There was a significant negative correlation between LC50 values and exposure periods. Thus increase in exposure period, LC50 decreases from 17.34 mg/l (24 h) to >13.58 mg/l (96 h) in the diethyl ether extract. Similar trends were also observed in acetone, chloroform and methanol extracts. Exposure of sub-lethal doses (40% and 80% of LC50) of the diethyl ether extract of N. indicum leaf (which has maximum piscicidal activity) for 24 or 96 h caused significant alteration in the level of total protein, total free amino acid, nucleic acid, glycogen, pyruvate, lactate and activity of enzyme protease, phosphatases, alanine aminotransferase, aspartate aminotransferase and acetylcholinesterase in liver and muscle tissue. The alterations in all the above biochemical parameters were significantly (P<0.05) time and dose dependent. There was a significant recovery in all the above biochemical parameters, in both liver and muscle tissues of fish after the seventh day of the withdrawal of treatment. Thus, the leaf extracts of N. indicum have potent piscicidal activity against fish C. punctatus and also significantly affect both aerobic and anaerobic pathway of respiration in fish.

Animals↗
PubMed2001

Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: a randomized trial.

BACKGROUND: A new extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia. OBJECTIVE: The purpose of this study was to compare the lipid-lowering efficacy and tolerability of fluvastatin ER (80 mg once daily) versus fluvastatin immediate-release (IR) (40 mg once or twice daily). METHODS: Following a 4-week placebo/dietary run-in period, patients with primary hypercholesterolemia type IIa or IIb (low-density lipoprotein cholesterol ILDL-C] > or = 160 mg/dL and triglycerides [TG] < or = 400 mg/dL) were randomized (2:1:1) to receive fluvastatin ER 80 mg once daily at bedtime (QPM), fluvastatin IR 40 mg QPM, or fluvastatin IR 40 mg BID for 24 weeks. Patients who had homozygous familial hypercholesterolemia; type I, III, IV, V, or secondary hyperlipoproteinemia; diabetes; or evidence of liver or renal impairment were excluded. At weeks 0, 2, 4, 8, 12, 16, 20, and 24 of the active-treatment period, levels of LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) were measured. RESULTS: Of the 1183 patients enrolled, 695 were randomly assigned to treatment--346 to fluvastatin ER 80 mg QPM, 174 to fluvastatin IR 40 mg QPM, and 175 to fluvastatin IR 40 mg BID. Patients were well matched between groups, with a mean age of approximately 56 years and body mass index of 27 kg/m2; 56.0% of patients (389/695) were female and 97.7% (679/695) were white. Fluvastatin ER 80 mg QPM lowered LDL-C levels significantly more than did fluvastatin IR 40 mg QPM (33.7% vs 24.4%; P < 0.001) and as effectively as fluvastatin IR 40 mg BID (33.9%). More than half of the patients administered fluvastatin ER 80 mg QPM and IR 40 mg BID achieved reductions in LDL-C levels of > or = 35%; more than half of those administered fluvastatin IR 40 mg QPM experienced reductions in LDL-C levels of > or = 25%. The mean reductions in LDL:HDL ratio, TC, and apolipoprotein B levels in the fluvastatin ER 80 mg QPM group were significantly greater than the reductions in the IR 40 mg QPM group (P < 0.001). In patients with mixed dyslipidemia, fluvastatin ER 80 mg reduced triglycerides by 21.8% (median 28%) and increased HDL-C by 14.5%. Fluvastatin ER 80 mg QPM was well tolerated, with incidences of clinically notable elevations in alanine aminotransferase, aspartate aminotransferase, and creatine kinase levels and musculoskeletal adverse events comparable to those in the IR 40 mg QPM group. CONCLUSION: The ER 80-mg formulation of fluvastatin is effective and well tolerated as a once-daily starting and maintenance treatment for primary hypercholesterolemia.

Adult↗
PubMed2004

Enfuvirtide: a fusion inhibitor for the treatment of HIV infection.

BACKGROUND: Drug resistance continues to be a major challenge in the treatment of HIV-1 infection. Virtually all currently available antiretroviral medications inhibit the viral reverse transcriptase or protease. Enfuvirtide is the first fusion inhibitor approved by the US Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients. OBJECTIVE: This paper describes the pharmacologic properties and clinical usefulness of enfuvirtide. METHODS: Relevant information was identified through searches of MEDLINE (1990 to October 2003), International Pharmaceutical Abstracts (1970 to October 2003), and meeting abstracts of major HIV/AIDS conferences (1996-2003) using the search terms enfuvirtide, pentafuside, T-20, DP-178, and fusion inhibitor. RESULTS: In vitro, enfuvirtide exhibits activity against HIV-1 isolates that are resistant to all other classes of anti-retroviral medications. Enfuvirtide blocks the entry of HIV-1 into host cells by interfering with virus-cell fusion, making it unique among licensed antiretroviral medications. In human adults, enfuvirtide has a volume of distribution of 5.48 L, is highly bound to plasma protein (92%), has a plasma elimination half-life of 3.8 hours, and is catabolized by peptidases and proteinases in various tissues. Dose adjustment does not appear necessary on the basis of age, race, or body weight, but may be warranted in women weighing <50 kg. A literature review did not identify any data on the disposition of enfuvirtide in patients with hepatic or renal insufficiency. Clinical trials suggest that enfuvirtide reduces plasma HIV-1 RNA levels in highly treatment-experienced patients taking an optimized antiretroviral regimen. Pivotal trials indicated a mean change in HIV-1 RNA of -1.48 log(10) copies/mL in the enfuvirtide arm at week 48, compared with -0.63 log(10) copy/mL in the control arm ( P<0.001 ). The mean absolute increase on CD4 cell count was 46 cells/mm(3) (91 cells/mm(3)) in the enfuvirtide arm vs 45 cells/mm(3) in the control arm; P<0.001 ). The most commonly reported (>15 cases per 100 patient-years of exposure) adverse events (AEs) in clinical trials included injection-site reactions, diarrhea, nausea, fatigue, insomnia, peripheral neuropathy, headache, vomiting, and fever. The most commonly reported (> or =2%) laboratory abnormalities (grade III or IV) were eosinophilia, anemia, and increases in amylase, lipase, triglycerides, creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase. In clinical trials, serious AEs leading to study discontinuation occurred in 12.9% ( 114/885 ) of patients in the enfuvirtide arm, compared with 10.7% ( 12/112 ) in the control arm ( P = NS ). The recommended dosage of enfuvirtide is 90 mg SC BID in adults and 2 mg/kg SC BID in children. Efficacy studies in children are ongoing. CONCLUSION: Although additional studies are needed, enfuvirtide appears to be a promising agent, in combination with other antiretroviral agents, for the treatment of HIV infection in treatment-experienced patients.

Clinical Trials as Topic↗
PubMed1994

Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period.

Primary sclerosing cholangitis is a cholestatic disease of the liver characterized by progressive fibrotic inflammation and obliteration of the extra- and/or intrahepatic bile ducts. There is no effective therapy. We, therefore, studied the safety and efficacy of ursodeoxycholic acid in patients with primary sclerosing cholangitis with or without additional ulcerative colitis. In a 1-year ursodeoxycholic acid treatment period, which preceded the controlled study period, ursodeoxycholic acid was well tolerated in 22 of 24 patients with ulcerative colitis and in all three patients without ulcerative colitis. In two patients with ulcerative colitis the dose of 750 mg ursodeoxycholic acid/day led to diarrhea, but following reduction of the dose to 500 and 250 mg/day ursodeoxycholic acid was well tolerated. After 1 year of ursodeoxycholic acid treatment, 20 patients were randomly assigned to receive either ursodeoxycholic acid 750 mg/day or placebo. All of them finished a double-blind, placebo-controlled study period. During ursodeoxycholic acid treatment, the liver enzymes improved markedly. The difference in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyltransferase between the placebo and ursodeoxycholic acid group was significant (p < 0.05). Following ursodeoxycholic acid treatment, pruritus and fatigue improved in half of the patients but the difference between the placebo and ursodeoxycholic acid group was not significant. According to the ethical guidelines, after 3 months of placebo treatment, the controlled study had to be discontinued because of a more than twofold increase of serum transaminases in 8/10 patients on placebo. After the end of the controlled study, all patients were continuously treated with ursodeoxycholic acid for up to 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

An experimental soft-release of oil-spill rehabilitated American coots (Fulica americana): II. Effects on health and blood parameters.

The Unocal-Metrolink oil spill of 21 February 1995 resulted in approximately 7800 barrels of San Joaquin crude oil being deposited into the San Gabriel River in Huntington Beach, CA, USA. In order to determine long-term pathological effects of oil exposure and rehabilitation, hematological and serum biochemical parameters for both rehabilitated (RHB) American coots (Fulica americana) and reference (REF) coots were examined every 3-4 weeks (56, 81, 108 and 140 days post oil exposure) after birds were cleaned, rehabilitated and soft-released. Most significant differences in monthly comparisons between RHB and REF birds occurred 56 days following oil exposure. Total white blood cell (WBC) count, albumin:globulin (A:G) ratio and calcium concentration were higher in RHB birds compared to REF birds 56 days post oil exposure. In addition, mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and creatine kinase activities, and creatinine, total protein (TP) and globulin concentrations were lower in RHB birds. Blood results from 56 days post oil exposure for RHB coots which subsequently died were compared to blood results from days 108 and 140 for REF coots which survived. Oiled and rehabilitated birds which died had significantly higher WBCs, packed cell volume, TP and globulin concentrations, and lower A:G ratio, MCH, MCHC, glucose and sodium concentrations compared to REF birds which survived. Blood result differences detected at 3-4-week intervals between RHB and REF survivors, and differences detected between RHB coots which died and REF coots which survived, suggested that RHB coots developed an inflammatory response (infectious or non-septic) and, concurrently, may have experienced decreased immune responsiveness. Additionally, RHB coots experienced either an iron (Fe) utilization or Fe metabolism problem. These pathophysiological mechanisms were consistent with increased hemosiderin (stored Fe) present in the liver, spleen and kidney of necropsied RHB birds, and may have contributed to RHB coot mortality. When blood parameter differences were examined for their impact on survival time, it was determined that RHB coots had shorter survival times if they had very high cholesterol (> or =449 mg/dl) or chloride (> or =110 MEQ/l) concentrations on day 56 post oil exposure. Interestingly, the lack of differences between RHB and REF coots from day 81 through day 140 suggested that, from a hematologic and clinical chemistry perspective, coots which were oiled, rehabilitated, released and survived at least 3.5 months could not be differentiated from wild (REF) coots. From these findings it appears that blood analysis, coupled with post-release survival data, may help discern reasons for increased mortality of oiled and rehabilitated birds, compared to non-oiled reference birds.

Journal Article↗
PubMed1994

Quantitation of hepatitis C viral RNA in sera of hemodialysis patients: gender-related differences in viral load.

Hepatitis C virus (HCV) infection is common in hemodialysis patients, as determined by antibody assays and qualitative polymerase chain reaction (PCR) analysis of serum HCV RNA. To further characterize HCV infection in this population, we measured the viral load in infected hemodialysis patients by a quantitative, competitive PCR assay (QC-PCR) for HCV RNA. Hepatitis C virus RNA levels were correlated with serologic, biochemical, and demographic features of a cohort of hemodialysis patients. Sera from 208 hemodialysis patients were screened for HCV RNA (5' conserved region) by reverse transcriptase PCR (RT-PCR) and HCV-specific antibody. Forty-four patients were antibody positive (21%); among these patients, 34 (77%) were HCV RNA positive. No viremic, seronegative patients were identified. Hepatitis C virus RNA levels quantitated by QC-PCR ranged from 3 x 10(5) to 10(8) molecules of HCV RNA/mL. Male patients had significantly higher mean and median HCV RNA levels (10(7) molecules/mL) compared with female patients (3.6 x 10(6) molecules/mL and 3 x 10(6) molecules/mL, respectfully; P = 0.02). No other demographic or clinical feature of this cohort correlated with HCV RNA levels. Intravenous drug abuse was the most frequently identified risk factor (29% of seropositive patients) for infection with HCV in this population. No association between HCV RNA levels and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase) was apparent. Hepatitis C virus infection is highly prevalent in our hemodialysis population, and hemodialysis patients, particularly males, have high levels of HCV in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Subchronic toxicity studies of sucrose acetate isobutyrate (SAIB) in the rat and dog.

Preliminary short-term toxicity studies of sucrose acetate isobutyrate (SAIB) in the dog demonstrated that addition of this additive to the diet was associated with an increase in liver size and elevated serum alkaline phosphatase activity with no evidence of pathological change by light microscopy. To determine the basis for these changes, a 12-week oral toxicity study of SAIB was conducted in the dog and a similar study was performed in the rat. SAIB was fed in the diet to groups of six beagle dogs of each sex at 0, 0.5, 1.0, 2.0 and 4.0%. SAIB was also fed to groups of 40 Sprague-Dawley rats of each sex at levels of 0, 2.5, 5.0 and 10.0%. In the rat study, in addition to routine toxicology parameters, hepatic microsomal enzyme induction was determined using a zoxazolamine hypnotic test, urinary ascorbic acid excretion and determination of hepatic carboxylesterase activity. Sodium phenobarbital was fed to groups of 20 rats of each sex at a dose of 100 mg/kg body weight/day by gavage as a positive control for hepatic microsomal enzyme induction. In the dog study, routine toxicological tests were supplemented by tests for bromsulfophthalein (BSP) retention, histochemical staining of liver sections for glycogen, phosphorylase, succinate dehydrogenase, and acid and alkaline phosphatases. Levels of liver lipid, protein, glycogen and carboxylesterase activity were also determined. Electron microscopic examinations were made on liver sections from the dog study at the end of the 12-week SAIB feeding period and after a 2-week withdrawal period. Administration of SAIB to rats did not reveal evidence of any effect on hepatobiliary function, and there was no indication of microsomal enzyme induction. Body weight gain of male rats fed SAIB was decreased, probably as the result of decreased palatability of the diet; SAIB did not affect body weight gain in females. The changes observed in the dogs fed SAIB included increased serum alkaline phosphatase activity with no change in serum alanine aminotransferase, aspartate aminotransferase or lactic dehydrogenase activity and no change in serum electrolyte, serum protein, glucose or bilirubin levels. No haematological changes were observed. BSP retention was observed at all SAIB dose levels. There were no SAIB-related pathological changes in any organ when examined by light microscopy. Examination by electron microscope revealed dilatation of bile canaliculi and an increase in smooth endoplasmic reticulum compared with controls. Histochemical studies also indicated increased enzyme activity of the bile canaliculi. The electron-microscope-revealed changes were completely reversed during a 2-week treatment withdrawal period. The dog study did not establish a no-effect level for changes in hepatobiliary function induced by feeding SAIB.

Alkaline Phosphatase↗
PubMed2002

Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats.

Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.

Acetaminophen↗
PubMed1997

An ultrastructural evaluation of acute 1-nitronaphthalene induced hepatic and pulmonary toxicity in the rat.

1-Nitronaphthalene is a mutagenic particulate of diesel exhaust which causes acute liver and lung toxicity in rodents. The studies presented here describe morphological changes in the lung and liver at several time intervals following a single injection of 1-nitronaphthalene (100 mg/kg, i.p.) in male Sprague-Dawley rats using transmission and scanning electron microscopy. Although both the lungs and liver are injured by 1-nitronaphthalene, the lungs appear to be the primary target organ. Within 4 h of treatment, all 1-nitronaphthalene treated animals exhibited respiratory distress characterized by labored breathing, severe gasping and chromodacryorrhea. The primary ultrastructural alteration were hydropic changes in the non-ciliated bronchiolar (Clara) cells of the distal-most bronchioles of the lung. These were apparent as early as 1 h after 1-nitronaphthalene injection, while adjacent ciliated cells showed no alterations. Over a 24 h period, the bronchioles showed progressive ultrastructural changes leading to necrosis and exfoliation of both ciliated and Clara cells. Interstitial pneumonitis and edema were observed in all animals treated with 1-nitronaphthalene, and was usually associated with bronchioles containing necrotic epithelium. In the liver, ultrastructural changes were observed in the centrilobular hepatocytes at 8 h and consisted of cytomegaly, loss of continuous inner membrane and reduced matrix density of the mitochondria. At 48 h, cellular damage to centrilobular hepatocytes was severe and nearly all mitochondria were damaged. Elevated levels of alanine aminotransferase, aspartate aminotransferase and bilirubin were detected in the serum of animals treated with 1-nitronaphthalene at 8-48 h. In conclusion, 1-nitronaphthalene is a pulmonary toxicant with a unique progression of injury, which primarily damages Clara cells followed by ciliated cells. This disparity is likely due to a difference in the bioactivation of 1-nitronaphthalene. Furthermore, this systemic toxicant also has injurious effects on the centrilobular region of the liver which precedes lung injury.

Animals↗
PubMed2003

Effect of indapamide SR in the treatment of hypertensive patients with type 2 diabetes.

BACKGROUND: To evaluate the effect of the sustained-release formulation of indapamide (indapamide SR) in type 2 diabetic patients with mild-to-moderate hypertension and its possible side effects, particularly on glucose metabolism and lipid profiles. METHODS: A total of 64 patients randomly received 1.5 mg of indapamide SR or placebo once daily for 3 months. The effects were evaluated by 24-h ambulatory blood pressure monitor, fasting blood sampling for biochemistry, lipid profiles, and frequently sampled intravenous glucose tolerance test. RESULTS: The changes in standing and supine blood pressure (BP) were significant (154.7 +/- 9.4/94 +/- 2.9 mm Hg v 134.4 +/- 5.1/82.4 +/- 5 mm Hg and 155 +/- 9.8/94.6 +/- 3.6 mm Hg v 135.1 +/- 4.9/82.1 +/- 4.7 mm Hg) in the indapamide group, but not in the placebo group. According to the 24-h ambulatory blood pressure monitor reading, a significant reduction was observed in not only in the whole-day mean BP (mean systolic BP/mean diastolic BP, 149 +/- 19.3/87.6 +/- 11.3 mm Hg v 135.7 +/- 12.6/79.6 +/- 9 mm Hg) but also the whole-day mean median arterial pressure (109 +/- 12.7 mm Hg v 98.7 +/- 8.2 mm Hg) for the indapamide group, but not the placebo group. There were no changes in biochemical data including serum sodium, potassium, chloride, uric acid, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, lipid profiles, fasting blood glucose, insulin, hemoglobin Alc, and glucose metabolism parameters (insulin sensitivity, glucose effectiveness, and acute insulin response) from frequently sampled intravenous glucose tolerance test after indapamide or placebo therapy. CONCLUSIONS: Indapamide SR can significantly lower the whole-day BP in hypertensive patients with type 2 diabetes. Also, it did not alter or aggravate patients' lipid profiles, glucose metabolism, and did not exert possible side effects of hypokalemia and hyperuricemia. Therefore, monotherapy with indapamide SR should be suggested in type 2 diabetic patients with mild-to-moderate hypertension.

Aged↗
PubMed2001

Serum dioxin and hepatic abnormalities in veterans of Operation Ranch Hand.

PURPOSE: We studied hepatic abnormalities and indices of hepatic function in relation to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971. METHODS: The prevalence of ever having liver disease through March 1993, and level of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase (GGT), lactic dehydrogenase (LDH), alkaline phosphatase, and total bilirubin were examined according to serum dioxin levels. RESULTS: We found an increased risk of "other liver disorders" among veterans with the highest dioxin levels [adjusted odds ratio (OR) = 1.6, 95% confidence interval (CI) 1.2 to 2.1], due primarily to increased transaminases or LDH (adjusted OR = 2.7, 95% CI 1.4 to 5.1) and to other nonspecific liver abnormalities (adjusted OR = 1.4, 95% CI 1.0 to 2.0). CONCLUSIONS: Whether the associations observed were causal is unclear from these data.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed2001

Effect of methylprednisolone on the kinetics of cytokines and liver function of regenerating liver in rats.

The participation of cytokines in the early stage mechanism of hepatocyte proliferation has already attracted attention. We investigated the effect of methylprednisolone (MDS), which inhibits the inflammatory response, given before and after a 70% partial hepatectomy in rats on the kinetics of tumor necrosis factor-alpha and Interleukin-6, liver cell function and the rate of liver regeneration. Serum Interleukin-6 levels of the MDS groups were significantly lower than those of the control group. Serum alanine aminotransferase, aspartate aminotransferase and hyaluronic acid levels were also significantly decreased, however, the serum albumin level showed high values in the MDS groups. In the MDS groups, MIB-5 labeling indices, a novel antibody reactive with the equivalent Ki-67 protein, which detects immunohistochemically all active parts of the cell cycle in the rat liver, were more pronounced than in the control group at an earlier time. However, in regard to 5-bromo-2-deoxyuridine (BrdU), there were no significant differences among the three groups. There were no differences in residual liver weight/body weight between the three groups after 336 h. In our study, MDS administration before or after a 70% partial hepatectomy decreased serum Interleukin-6 levels, and inhibited hepatic dysfunction. Therefore, we considered that beneficial effects of physiological doses of MDS in the peri-operative period should be confirmed in humans.

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