Liver Toxicity (liver + toxicity)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection

HEPATOLOGY, Issue 1 2000
Wai-Man Wong
Liver toxicity is a common side effect of antituberculosis (anti-TB) drugs. We studied the differences in liver dysfunction observed during anti-TB treatment between hepatitis B virus carriers (HBV) and noncarriers. Three hundred twenty-four patients on anti-TB drugs were recruited and followed up for 1 year. Forty-three patients with HBV and 276 non-HBV patients were included for analysis. Liver function tests and viral markers were monitored monthly. Liver biopsy was requested whenever the alanine transaminase (ALT) was persistently abnormal. Eighty-six HBV carriers who were not given anti-TB drugs were chosen as a second control and evaluated prospectively. The incidence of liver dysfunction was significantly higher in HBV carriers given anti-TB drugs (34.9%) when compared to noncarriers (9.4%, P < .001) and with HBV carriers not given anti-TB drugs (8.1%, P < .001). For patients given anti-TB drugs, HBV carriers who developed liver dysfunction were younger (P = .011) and had more severe liver injury compared with noncarriers (P = .008). By multiple logistic regression analysis, age (P = .002) and hepatitis B infection (P < .001) were the only 2 significant risk factors for hepatotoxicity related to anti-TB therapy. [source]


Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2009
C. Girish
Abstract Oxidative stress is implicated as a common pathologic mechanism contributing to the initiation and progression of hepatic damage in a variety of liver disorders. Present study attempts to evaluate the hepatoprotective activity of picroliv, curcumin and ellagic acid in comparison to silymarin using paracetamol (PCM) induced acute liver damage. Hepatotoxicity was induced by administering a single oral dose of PCM (500 mg/kg) and was assessed by quantifying the serum enzyme activities, phenobarbitone induced sleeping time and histopathological analysis of liver tissues. The antioxidant parameters, malondialdehyde (MDA), reduced glutathione (GSH) and catalase of the liver tissue were also assessed. The herbal drugs were administered for 7 days by oral route at 50 and 100 mg/kg. PCM induced hepatic damage was manifested by a significant increase in the activities of marker enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase) in serum and MDA level in liver. There was also a significant decrease in activity of GSH and catalase levels. The histopathological examination on toxic models revealed centrizonal necrosis and fatty changes. Pretreatment of mice with picroliv, curcumin and ellagic acid reversed these altered parameters towards normal values, which were compared with silymarin. The normalization of phenobarbitone induced sleeping time suggests the restoration of liver cytochrome P450 enzymes. This study supports the use of these active phytochemicals against toxic liver injury, which may act by preventing the lipid peroxidation and augmenting the antioxidant defense system or regeneration of hepatocytes. These active phytochemicals may be developed as drugs for the treatment of liver diseases. [source]


Hepatitis C and human immunodeficiency virus infection

HEPATOLOGY, Issue 5B 2002
424 N. Bond St., David L. Thomas M.D., Suite 10
In the United States, an estimated 200,000 persons are infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV). As the lives of HIV-infected persons have been prolonged by use of highly active antiretroviral therapy, liver disease has emerged as an important, and in some settings, the leading cause of morbidity and mortality. Human immunodeficiency virus infection appears to adversely affect all stages of hepatitis C infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease. In turn, hepatitis C may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiretroviral medications. The medical management of hepatitis C in HIV-infected persons remains controversial, in part because of the complexity of both infections and potential drug interactions, but chiefly because there is so little published information. Nonetheless, the burden of liver disease is too high to delay management of HIV/HCV-coinfected persons while awaiting better data. Instead, the management of hepatitis C today must be based on data generated on persons without HIV and an understanding of both infections. Properly designed studies of therapy in HIV/HCV-coinfected persons are needed to help guide management of these patients in the future. [source]


Hepatitis C and human immunodeficiency virus infection

HEPATOLOGY, Issue S1 2002
David L. Thomas M.D.
In the United States, an estimated 200,000 persons are infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV). As the lives of HIV-infected persons have been prolonged by use of highly active antiretroviral therapy, liver disease has emerged as an important, and in some settings, the leading cause of morbidity and mortality. Human immunodeficiency virus infection appears to adversely affect all stages of hepatitis C infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease. In turn, hepatitis C may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiretroviral medications. The medical management of hepatitis C in HIV-infected persons remains controversial, in part because of the complexity of both infections and potential drug interactions, but chiefly because there is so little published information. Nonetheless, the burden of liver disease is too high to delay management of HIV/HCV-coinfected persons while awaiting better data. Instead, the management of hepatitis C today must be based on data generated on persons without HIV and an understanding of both infections. Properly designed studies of therapy in HIV/HCV-coinfected persons are needed to help guide management of these patients in the future. (HEPATOLOGY 2002;36:S201-S209). [source]


Potentiation of isoniazid-induced liver toxicity by rifampicin in a combinational therapy of antitubercular drugs (rifampicin, isoniazid and pyrazinamide) in Wistar rats: A toxicity profile study

HEPATOLOGY RESEARCH, Issue 10 2007
Sheikh Abdullah Tasduq
Aim:, Biochemical characterization of long-term toxic manifestations of anti-tubercular (anti-TB) drugs , rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) , individually and in two combinations: (i) RIF + INH, and (ii) RIF + INH + PZA in Wistar rats. Methods:, Animals received anti-TB drugs , alone or in combination , once daily p.o. for up to 90 days (doses, in mg/kg: RIF, 250; INH, 50; PZA, 100). Assays for alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin (serum) and lipid peroxidation (LPO), glutathione (GSH), glutathione peroxidase (GPx), catalase, Na+K+-ATPase and CYP 2E1 (liver) were performed to assess liver toxicity. Clinical biochemistry was done by commercial kits. Determinations were made at 0, 15, 30 and 90 days of treatment schedule. Results:, Anti-TB drugs-treated animals showed abnormal rises or falls (>1.5,2 fold) in the serum/liver parameters. Mild hyperlipidemia, hypercholesterolemia and hyperuricemia were the other pathologies. Of all the treated groups, INHalone or in combination with other drugs produced a progressive enhancement of toxicity over 15,90 days. The in vivo results were further supported by in vitro results (MTT assay, GSH and LPO) in primary cultures of rat hepatocyte. Results indicated that anti-TB drugs in combination: (i) caused membrane damage resulting in leakage of ALT, ALP and bilirubin; (ii) caused imbalance in endogenous enzymatic oxidant,antioxidant defense via increased lipid peroxidation and in glutathione homeostasis; and (iii) enhanced the CYP 2E1-mediated bioactivation mechanism. Conclusion:, Toxicity manifestations seemed to be heptocytic injury targeted at hepatocytes, bile ducts or sinusoidal cells related to hepatitis and primary biliary cholestasis. [source]


Long-term follow-up of nevirapine-treated patients in a single-centre cohort

HIV MEDICINE, Issue 8 2009
M Colafigli
Objectives We reviewed the safety and efficacy of nevirapine (NVP)-based therapy in all patients initiating NVP-containing combined antiretroviral therapy [cART (,3 drugs)] in our clinic since 1994. Methods Patient characteristics and laboratory values from the start of the NVP-based cART regimen to the last available follow-up or to NVP discontinuation were retrieved from an observational database. Results Five hundred and seventy-three patients were treated with NVP-based cART for a median of 18.4 (range 0.1,128.8) months. The 1-year cumulative estimated probability of discontinuing NVP-containing regimens for toxicity was 0.203. Only 1.9% developed a grade 3 alanine aminotransferase (ALT) elevation. Significant increases in high-density lipoprotein cholesterol were observed up to month 12 except in treatment-naïve patients, where the increase was limited to 3 months. Discontinuation because of cutaneous reaction was predicted independently by female gender [Hazard Ratio (HR) 3.21, P<0.001] and Centers for Disease Control class C (HR 0.50, P=0.012). Discontinuation because of liver toxicity was predicted independently by anti-hepatitis C virus positivity (HR 3.84, P<0.001). In patients starting NVP-containing cART with undetectable viral loads, the 5-year estimated probability of viral load >400 HIV-1 RNA copies/mL was 0.34. Conclusions Long-term follow-up with an NVP-containing cART showed a low rate of discontinuation caused by liver toxicity and the maintenance of virological suppression in patients switched with undetectable viral loads. [source]


Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

HIV MEDICINE, Issue 1 2007
CL Cooper
In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation. [source]


Human immunodeficiency virus,hepatitis C coinfection: swapping new problems for newer ones

INTERNAL MEDICINE JOURNAL, Issue 7 2001
J. Sasadeusz
Abstract Recent successes in HIV therapy have uncovered other health problems for HIV-infected individuals. Hepatitis C has become an especially significant problem, partly due to its faster progression in an immunocompromised setting. In addition, the higher viral loads in coinfected patients likely result in more efficient perinatal and perhaps even sexual transmission. Therapy has largely been neglected, despite data suggesting its efficacy in HIV,HCV coinfected patients. Studies of combination interferon and ribavirin studies are lacking, although underway. A major concern is the potential inactivation of certain thymidine analogues by ribavirin. Some antiretroviral therapies, such as ritonavir, indinavir and nevirapine, may enhance liver toxicity in coinfected patients and should be avoided if possible. The role of chronic low-grade liver function abnormalities remains uncertain and requires further investigation. (Intern Med J 2001; 31: 418,421) [source]


Cutting through the statistical fog: understanding and evaluating non-inferiority trials

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 10 2010
W. S. Weintraub
Summary Every year, results from many important randomised, controlled trials are published. Knowing the elements of trial design and having the skills to critically read and incorporate results are important to medical practitioners. The goal of this article is to help physicians determine the validity of trial conclusions to improve patient care through more informed medical decision making. This article includes a review of 162 randomised, controlled non-inferiority (n = 116) and equivalence (n = 46) hypothesis studies as well as the larger Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation V study and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial. Evaluation of data from small and large trials uncovers significant flaws in design and models employed and uncertainty about calculations of statistical measures. As one example of questionable study design, discussion includes a large (n = 3922), double-blind, randomised, multicentre trial comparing the efficacy of ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and additional stroke risk factors. Investigators concluded that ximelagatran was effective compared with well-controlled warfarin for prevention of thromboembolism. However, deficiencies in design, as well as concerns about liver toxicity, resulted in the rejection of the drug by the US Food and Drug Administration. Many trials fail to follow good design principles, resulting in conclusions of questionable validity. Well-designed non-inferiority trials can provide valuable data and demonstrate efficacy for beneficial new therapies. Objectives and primary end-points must be clearly stated and rigorous standards met for sample size, establishing the margin, patient characteristics and adherence to protocol. [source]


Recent trends in the treatment of testosterone deficiency syndrome

INTERNATIONAL JOURNAL OF UROLOGY, Issue 11 2007
Bum Sik Hong
Abstract: Testosterone deficiency syndrome (TDS) is defined as a clinical and biochemical syndrome associated with advancing age and is characterized by typical symptoms and deficiency in serum testosterone levels. TDS is a result of the interaction of hypothalamo-pituitary and testicular factors. Now, treatment of TDS with testosterone is still controversial due to a lack of large, controlled clinical trials on efficacy. The risks of treatment with testosterone appear to be minimal, although long-term studies on the safety of testosterone therapy are lacking. The aim of the therapy is to establish a physiological concentration of serum testosterone in order to correct the androgen deficiency, relieve its symptoms and prevent long-term sequelae. All of the available products, despite their varying pharmacodynamic and pharmacokinetic profiles, are able to reach this goal. Newer testosterone patches seem not to cause severe skin irritation. Testosterone gels minimize the skin irritation while providing flexibility in dosing and a low discontinuation rate. Oral testosterone undecanoate (TU) is free of liver toxicity. Recent formulation of oral TU markedly increased shelf-live, a major drawback in the older preparation. Producing swings in testosterone levels rising rapidly to the supraphysiological range is not the case with the new injectable long-acting preparation of TU. To be able to rapidly react and stop treatment in cases where side-effects and contraindications are detected, the short-acting transdermal and oral delivery modes have certain advantages. However, there is no evidence that the use of an injectable long-acting TU in men with TDS has limitations in clinical application for this reason. The use of dehydroepiandrosterone is still controversial because of a lack of well designed long-term trials, although some recent studies suggest positive effects on various body systems. Only a few studies have been carried out to investigate the effect of hCG (human chorionic gonadotropin) in TDS with some positive results on various body systems. [source]


Chronic toxicity/oncogenicity study of styrene in cd-1 mice by inhalation exposure for 104 weeks

JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2001
George Cruzan
Abstract Groups of 70 male and 70 female Charles River CD-1 mice were exposed whole body to styrene vapor at 0, 20, 40, 80 or 160 ppm 6 h per day 5 days per week for 98 weeks (females) or 104 weeks (males). The mice were observed daily; body weights, food and water consumption were measured periodically, a battery of hematological and clinical pathology examinations were conducted at weeks 13, 26, 52, 78 and 98 (females)/104 (males). Ten mice of each gender per group were pre-selected for necropsy after 52 and 78 weeks of exposure and the survivors of the remaining 50 of each gender per group were necropsied after 98 or 104 weeks. An extensive set of organs from the control and high-exposure mice were examined histopathologically, whereas target organs, gross lesions and all masses were examined in all other groups. Styrene had no effect on survival in males. Two high-dose females died (acute liver toxicity) during the first 2 weeks; the remaining exposed females had a slightly higher survival than control mice. Levels of styrene and styrene oxide (SO) in the blood at the end of a 6 h exposure during week 74 were proportional to exposure concentration, except that at 20 ppm the SO level was below the limit of detection. There were no changes of toxicological significance in hematology, clinical chemistry, urinalysis or organ weights. Mice exposed to 80 or 160 ppm gained slightly less weight than the controls. Styrene-related non-neoplastic histopathological changes were found only in the nasal passages and lungs. In the nasal passages of males and females at all exposure concentrations, the changes included respiratory metaplasia of the olfactory epithelium with changes in the underlying Bowman's gland; the severity increased with styrene concentration and duration of exposure. Loss of olfactory nerve fibers was seen in mice exposed to 40, 80 or 160 ppm. In the lungs, there was decreased eosinophilia of Clara cells in the terminal bronchioles and bronchiolar epithelial hyperplasia extending into alveolar ducts. Increased tumor incidence occurred only in the lung. The incidence of bronchioloalveolar adenomas was significantly increased in males exposed to 40, 80 or 160 ppm and in females exposed to 20, 40 and 160 ppm. The increase was seen only after 24 months. In females exposed to 160 ppm, the incidence of bronchiolo-alveolar carcinomas after 24 months was significantly greater than in the controls. No difference in lung tumors between control and styrene-exposed mice was seen in the intensity or degree of immunostaining, the location of tumors relative to bronchioles or histological type (papillary, solid or mixed). It appears that styrene induces an increase in the number of lung tumors seen spontaneously in CD-1 mice. Copyright © 2001 John Wiley & Sons, Ltd. [source]


Carotenoid lutein protects rats from paracetamol-, carbon tetrachloride- and ethanol-induced hepatic damage

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2010
Edakkadath R. Sindhu
Abstract Objectives, Carotenoids are a class of natural fat-soluble pigments that are found in many fruits and vegetables. Consumption of a diet rich in carotenoids has been epidemiologically correlated with a lower risk for several diseases. In the present study the carotenoid lutein (3,3,-dihydroxy- ,,, -carotene) was evaluated for its hepatoprotective activity in rats. Methods, Paracetamol, 20% ethanol and carbon tetrachloride were used to induce liver toxicity. Key findings, Levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase and alkaline phosphatases, which were increased in the serum, were found to be significantly reduced by the treatment of lutein in a dose-dependent manner, indicating that lutein may reduce the hepatotoxicity induced by these agents. Serum bilirubin was also significantly lower in lutein-treated groups compared with control. Increased lipid peroxidation, conjugated diene and hydroperoxides in the liver tissue produced by the administration of paracetamol were found to be reduced in the lutein-treated groups. Levels of antioxidant enzymes, like superoxide dismutase, catalase, glutathione peroxidase and glutathione, were found to be increased in lutein-treated groups compared with control group during alcohol- and CCl4 -induced liver toxicity. Hydroxyproline, which is an indicator of fibrosis in liver tissue, was high in the ethanol-treated control group. Hydroxyproline levels were decreased by simultaneous lutein administration. Conclusions, Histopathological evidence confirmed the protection offered by lutein from the tissue damage caused by hepatotoxins. The hepatoprotective action may be due to lutein's ability to scavenge reactive oxygen radicals. [source]


Mercaptopurine rescue after azathioprine-induced liver injury in inflammatory bowel disease

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010
F. BERMEJO
Summary Background, Azathioprine (AZA) liver toxicity arises in approximately 3% of inflammatory bowel disease patients and may result in treatment discontinuation. Aim, To describe the tolerance to mercaptopurine (MP) in patients with previous AZA-related liver injury. Methods, Retrospective description of 31 patients (14 Crohn's, 17 ulcerative colitis), in which AZA therapy was interrupted because of liver injury, with MP started as alternative therapy. Results, Mean AZA dose was 2.2 ± 0.4 mg·kg/day. Median (interquartile range) of AZA exposure when liver injury was detected was 2 months (1,5.2). The type of AZA-related injury was cytolitic in 32%, cholestatic in 39% and mixed in 29%. After a median of 2.5 months (0.7,5.2), the therapy was switched to MP at a mean dose of 1.3 ± 0.2 mg·kg/day. Median of follow-up of MP therapy was 32 months (8,54). In 87.1% of patients (95%CI: 70,96%), MP was tolerated without further liver injury; of these, 77.4% tolerated full MP doses and 9.7% tolerated lower doses. In a further cohort of 12.9% of patients, (95%CI: 3,29%), liver injury reappeared (two cholestasis, two mixed), 1,3 months after the onset of MP exposure. Conclusion, The administration of MP is a good alternative in patients with AZA-related liver injury, before thiopurines are definitely discarded. [source]


Review article: drug hepatotoxicity

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2007
C. Y. CHANG
SUMMARY Background Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. Aims (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre-existing liver disease and in the post-liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. Methods A Medline search was performed to identify relevant literature using search terms including ,drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics'. Results Amoxicillin-clavulanic acid is one of the most frequently implicated causes of drug-induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co-infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. Conclusions Drug-induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs. [source]


Curcumin reduces the toxic effects of iron loading in rat liver epithelial cells

LIVER INTERNATIONAL, Issue 1 2009
Donald J. Messner
Abstract Background/Aims: Iron overload can cause liver toxicity and increase the risk of liver failure or hepatocellular carcinoma in humans. Curcumin (diferuloylmethane), a component of the food spice turmeric, has antioxidant, iron binding and hepatoprotective properties. The aim of this study was to quantify its effects on iron overload and the resulting downstream toxic effects in cultured T51B rat liver epithelial cells. Methods: T51B cells were loaded with ferric ammonium citrate (FAC) with or without the iron delivery agent 8-hydroxyquinoline. Cytotoxicity was measured by methylthiazolyldiphenyl-tetrazolium bromide assay. Iron uptake and iron bioavailability were documented by chemical assay, quench of calcein fluorescence and ferritin induction. Reactive oxygen species (ROS) were measured by a fluorescence assay using 2,,7,-dichlorodihydrofluorescein diacetate. Oxidative stress signalling to jnk, c-jun and p38 was measured by a Western blot with phospho-specific antibodies. Results: Curcumin bound iron, but did not block iron uptake or bioavailability in T51B cells given FAC. However, it reduced cytotoxicity, blocked the generation of ROS and eliminated signalling to cellular stress pathways caused by iron. Inhibition was observed over a wide range of FAC concentrations (50,500 ,M), with an apparent IC50 in all cases between 5 and 10 ,M curcumin. In contrast, desferoxamine blocked both iron uptake and toxic effects of iron at concentrations that depended on the FAC concentration. The effects of curcumin also differed from those of ,-tocopherol, which did not bind iron and was less effective at blocking iron-stimulated ROS generation. Conclusions: Curcumin reduced iron-dependent oxidative stress and iron toxicity in T51B cells without blocking iron uptake. [source]


Sialoadenectomy enhances hepatic injury induced by lipopolysaccharide/galactosamine in mice

LIVER INTERNATIONAL, Issue 6 2008
Olga Sánchez
Abstract Background: Submandibular salivary glands (SMGs) synthesize, accumulate and secrete a large amount of epidermal growth factor (EGF) in mice. It is known that surgical removal of SMG (sialoadenectomy) alters cell turnover in the liver and exacerbates liver injury induced by lipopolysaccharide/galactosamine (LPS/GalN). Results: Here we show that such increased hepatotoxicity is not the consequence of the lack of EGF production from SMG. On the contrary, it appears to be the consequence of an inadequate cytokine production by the liver of sialoadenectomized mice. Thus, we found that the increase of plasma tumour necrosis factor-, and interleukin-6 was slower in sialoadenectomized than in sham-operated mice. This is because of a decreased rate of production of both cytokines by the liver. We found that the increase of plasma corticosterone (CS) concentration is lower in sialoadenectomized than that in sham-operated mice. Adrenalectomy exacerbated liver injury induced by LPS/GalN. In these animals, sialoadenectomy did not further increase the effect of LPS/GalN. Conclusions: Our results suggest that the effect of sialoadenectomy on LPS/GalN-induced liver toxicity may be the consequence of an altered cytokine production by the liver and a reduced CS release from adrenal glands. [source]


Enfuvirtide: A safe and effective antiretroviral agent for human immunodeficiency virus,infected patients shortly after liver transplantation

LIVER TRANSPLANTATION, Issue 10 2009
Elina Teicher
The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV),coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir,exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence. Liver Transpl 15:1330,1335, 2009. © 2009 AASLD. [source]


Acute liver failure induced by green tea extracts: Case report and review of the literature

LIVER TRANSPLANTATION, Issue 12 2006
Michele Molinari
In industrialized countries, over-the-counter dietary supplements have become popular in preventing and treating an expanding list of medical conditions. Although most commercially available supplements have not been rigorously tested for safety and efficacy, they have found an enlarging market because they are considered natural. Oral supplements containing green tea extract have been marketed as effective for weight loss and to prevent and cure some solid tumors. Although there is little scientific evidence of the effectiveness of green tea extracts to improve the quality of health of regular consumers, there is an increasing body of medical literature supporting the hypothesis that they can cause serious side effects. Our experience adds to previous reports of acute liver toxicity observed in individuals consuming supplements containing green tea extract. We highlight the importance of obtaining a detailed history of dietary supplement consumption when evaluating a patient presenting with acute liver dysfunction. Liver Transpl 12:1892,1895, 2006. © 2006 AASLD. [source]


Impact of treatment-related liver toxicity on the outcome of HCV-positive non-Hodgkin's lymphomas,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2010
Luca Arcaini
We studied 160 Hepatitis C virus (HCV)-positive patients with NHL (59 indolent NHL, 101 aggressive). Median age was 67 years. HCV-RNA was present in 146. HBsAg was positive in seven patients. At diagnosis, ALT value was above UNL in 67 patients. One hundred and twenty patients received an anthracycline-based therapy, alkylators, 28 received chemotherapy plus rituximab. Cytotoxic drugs dose was reduced in 63 patients. Among 93 patients with normal ALT at presentation, 16 patients developed WHO grade II,III liver toxicity. Among 67 patients with abnormal ALT, eight patients had a 3.5 times elevation during treatment. Among 28 patients treated with rituximab and chemotherapy, five patients (18%) developed liver toxicity. Thirty four patients (21%) did not complete treatment (eight for liver toxicity). Median progression-free survival (PFS) for patients who experienced liver toxicity is significantly shorter than median PFS of patients without toxicity (respectively, 2 years and 3.7 years, P = 0.03). After a median F-UP of 2 years, 32 patients died (three for hepatic failure). A significant proportion of patients with HCV+ NHL develop liver toxicity often leading to interruption of treatment. This could be a limit to the application of immunochemotherapy programs. HCV+ lymphomas represent a distinct clinical subset of NHL that deserves specific clinical approach to limit liver toxicity and ameliorate survival. Am. J. Hematol., 2010. © 2009 Wiley-Liss, Inc. [source]


Analgesic and hepatotoxic effects of Ononis spinosa L.

PHYTOTHERAPY RESEARCH, Issue 6 2006
Betül Sever Yõlmaz
Abstract The present study investigated the analgesic and hepatoprotective activities of a water extract of Ononis spinosa L. (OS) in mice. Analgesic activity was based on the pain thresholds measured with the tail-flick test before administration at 30, 90 and 150 min. The results were analysed with one-way variance analysis. The extract of Ononis spinosa showed analgesic activity equivalent to aspirin at 30 and 90 min and even higher than aspirin with the 50 mg/kg dose. At a dose of 100 mg/kg OS showed an analgesic effect equivalent to aspirin at all time points. The hepatoprotective influence of OS on carbon tetrachloride (CCl4)-induced acute liver toxicity was also studied. The extract had no significant effect on the increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin in CCl4 treated animals (p > 0.05). Thus, the results reveal that the extract of OS had no hepatoprotective effect on CCl4 -induced acute liver toxicity. Copyright © 2006 John Wiley & Sons, Ltd. [source]


Hepatoprotective effect of New Liv,t®, a polyherbal formulation, is mediated through its free radical scavenging activity

PHYTOTHERAPY RESEARCH, Issue 5 2004
Y. K. Gupta
Abstract The effect of New Liv,t®, a polyherbal formulation, was studied on pyrogallol-induced hepatotoxicity in rats. Administration of pyrogallol 100 mg/kg, i.p. caused a signi,cant increase in liver enzymes as well as a signi,cant increase in lipid peroxidation. Simultaneous administration of oral New Liv,t® and pyrogallol prevented these changes in hepatic damage. The results of the study showed that New Liv,t® exerted a hepatoprotective effect against pyrogallol induced liver toxicity, which was mediated through its free radical scavenging property. Copyright © 2004 John Wiley & Sons, Ltd. [source]


Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicity

THE JOURNAL OF GENE MEDICINE, Issue 1 2007
Anna Kanerva
Abstract Background Adenoviruses can cause severe toxicity in immunocompromised individuals. Although clinical trials have confirmed the potency and safety of selectively oncolytic adenoviruses for treatment of advanced cancers, increasingly effective agents could result in more toxicity and therefore it would be useful if replication could be abrogated if necessary. Methods We analyzed the effect of chlorpromazine, an inhibitor of clathrin-dependent endocytosis and apigenin, a cell cycle regulator, on adenovirus replication and toxicity. First, we evaluated the in vitro replication of a tumor targeted Rb-p16 pathway selective oncolytic adenovirus (Ad5/3-,24) and a wild-type adenovirus in normal cells, fresh liver samples and in ovarian cancer cell lines. Further, we analyzed the in vitro cell killing efficacy of adenoviruses in the presence and absence of the substances. Moreover, the effect on in vivo efficacy, replication and liver toxicity of the adenoviruses was evaluated. Results We demonstrate in vitro and in vivo reduction of adenovirus replication and associated toxicity with chlorpromazine and apigenin. Effective doses were well within what would be predicted safe in humans. Conclusions Chlorpromazine and apigenin might reduce the replication of adenovirus, which could provide a safety switch in case replication-associated side effects are encountered in patients. In addition, these substances could be useful for the treatment of systemic adenoviral infections in immunosuppressed patients. Copyright © 2006 John Wiley & Sons, Ltd. [source]


Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis

BRITISH JOURNAL OF DERMATOLOGY, Issue 3 2005
R.J.G. Chalmers
Summary Background, Patients receiving long-term methotrexate for psoriasis are at risk of developing hepatic fibrosis. Repeated liver biopsy has long been regarded as the only reliable method of detecting this and it is still recommended by the American Academy of Dermatology (AAD). More recently, monitoring by serum procollagen III aminopeptide (PIIINP) measurement (Orion Diagnostica, Espoo, Finland) has been advocated as a means of significantly reducing the need for liver biopsy. Objectives, To assess the validity of guidelines developed in Manchester for the use of PIIINP to monitor patients with psoriasis receiving long-term methotrexate; to assess the anticipated benefits to patients of introducing this change in practice, including reduction in requirement for liver biopsy; and to determine the impact of its introduction on healthcare costs. Methods, A multicentre audit was conducted over a 24-month period to compare the healthcare costs and outcomes of two intervention groups from centres where serial PIIINP measurement was employed with those of two control groups from centres in which AAD guidelines were followed. Results, A sevenfold reduction in the need for liver biopsy was observed in the two intervention groups (n = 166; 0·04 and 0·02 biopsies/patient/year, respectively) compared with the two control groups (n = 87; 0·26 and 0·30 biopsies/patient/year, respectively). Abnormalities of sufficient severity to influence management were identified in one in five patients biopsied in the main intervention group compared with one in 16 in the control groups. The overwhelming majority of patients surveyed expressed a preference for being monitored by methods that would minimize the need for liver biopsy. The adoption of PIIINP for monitoring would result in significant cost savings. Conclusions, This audit has shown that patients managed by the Manchester protocol using serial PIIINP measurement and selective liver biopsy were not disadvantaged in comparison with those managed according to AAD guidelines; they were subjected to sevenfold fewer liver biopsies without evidence that important liver toxicity was missed in the process. If PIIINP monitoring were widely adopted, methotrexate would become a more acceptable option for many patients who are dissuaded from considering it because of the threat of repeated liver biopsy; it would also result in significant savings to the healthcare budget. [source]


High activity 90Y-ibritumomab tiuxetan (Zevalin®) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomas

BRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2007
Pier F. Ferrucci
Summary Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B-cell non-Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y-ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed , 30 MBq/kg (0·8 mCi/kg), 45 MBq/kg (1·2 mCi/kg) and 56 MBq/kg (1·5 mCi/kg) , and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin® administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non-haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high-activity Zevalin® with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high-dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy. [source]


Unexpectedly frequent hepatitis B reactivation by chemoradiation in postgastrectomy patients,

CANCER, Issue 9 2004
Jason Chia-Hsien Cheng M.D., M.S.
Abstract BACKGROUND Postgastrectomy patients undergoing chemoradiation risk chemoradiation-induced liver disease (CRILD). The objectives of this study were to investigate dosimetric implications and assess biologic susceptibility to CRILD in these patients. METHODS Sixty-two patients with Stage IB,IV gastric/gastroesophageal adenocarcinoma without metastases underwent radical total/subtotal gastrectomy; regional lymph node dissection; and postoperative, adjuvant, concomitant chemoradiotherapy (CCRT). Among these, 8 patients developed CRILD (defined as Grade 3,4 liver toxicity), and 11 patients were chronic hepatitis B virus (HBV) carriers (HBV+). Chemotherapy consisted of 1 cycle of etoposide, leucovorin, and 5-fluorouracil (ELF); followed by 5 weekly high doses of 5-fluorouracil (2000,2600 mg/m2) and leucovorin concurrent with radiotherapy (median dose, 45 grays [Gy] to the tumor bed/regional lymphatics); followed by 3 cycles of ELF separated by a 21-day interval. Patients were followed for , 4 months after CCRT. Patient-related and dosimetric factors were correlated with CRILD. RESULTS HBV+ status was the only independent factor associated with CRILD. HBV+ patients had a higher CRILD incidence (6 of 11 patients vs. 2 of 51 patients; P < 0.001). HBV-negative patients with CRILD were recipients of a higher mean liver dose (MLD) (23.8 Gy vs. 15.2 Gy; P = 0.009) and a higher volume fraction of liver that received > 30 Gy (36.5% vs. 19.7%; P = 0.009) compared with noncarriers without CRILD, but no MLD difference was found between HBV+ patients with or without CRILD. Moreover, in four of six carriers with CRILD, HBV infection was reactivated during CRILD. Two of the toxicities were fatal. CONCLUSIONS HBV carriers had a higher incidence of CRILD after postgastrectomy CCRT, probably related to HBV reactivation. Dosimetric parameters modulated the risk of CRILD in noncarriers, but not in carriers. These factors deserve attention in CRILD/HBV+ patients, and the underlying pathogenesis warrants investigation. Cancer 2004. © 2004 American Cancer Society. [source]