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At least 73 records · Page 4Linked to original sources
PubMed1996

Mechanisms of interleukin-2-induced hepatic toxicity.

Interleukin 2 (IL-2) mediates the regression of metastatic cancer, but its clinical use is limited by associated toxicities including hepatic dysfunction. To determine the mechanism for IL-2-induced hepatic dysfunction, we hypothesized that IL-2 activation of Kupffer cells causes leukocyte-endothelial adhesion and decreases hepatic sinusoidal blood flow. C57BL/6 mice were given injections of latex particles and prepared for intravital hepatic microscopy 2 h after i.p. IL-2 administration. Liver tissue was also prepared to quantitate hepatic tumor necrosis factor (TNF) mRNA and processed for light and electron microscopy. Phagocytosing Kupffer cells and leukocytes adherent to the endothelium were counted, and surface sinusoidal blood flow was quantitated. Kupffer cell activity was quantitated as the ratio of phagocytosing Kupffer cells to sinusoidal blood flow. IL-2 significantly increased Kupffer cell activity (0.56 +/- 0.05 for controls versus 0.84 +/- 0.05 for IL-2), significantly caused leukocyte-endothelial adhesion (26.7 +/- 7.9 for controls versus 87.0 +/- 27.6 for IL-2, WBC/mm2 endothelial surface), and significantly decreased the number of sinusoids containing blood flow per microscopic field (6.66 +/- 0.15 for controls versus 5.79 +/- 0.13 for IL-2) without causing changes in systemic hemodynamic parameters. In IL-2 treated livers, light and electron microscopy showed the constriction of sinusoids associated with swollen or ruptured mitochondria, which was consistent with hypoxic deterioration near central venules. Adherent platelets, neutrophils, and lymphocytes within sinusoids and central venules were also observed. PCR revealed that IL-2 significantly induced TNF mRNA expression in the liver. These data suggest that IL-2 activates Kupffer cells in association with the release of monokines including TNF, which causes activation of circulating leukocytes as well as hepatic sinusoidal endothelial cells. The resultant leukocyte and platelet adhesion to the endothelium may then physically impede the sinusoidal microcirculation, resulting in microscopic areas of hepatic ischemia and explaining the mechanism of IL-2-induced hepatic dysfunction.

Animals↗
PubMed1977

Study of an epidemic of jaundice, presumably due to toxic hepatitis, in Northwest India.

An epidemic of jaundice probably due to toxic hepatitis occurred in three adjoining districts of Northwest India during the period November and December, 1974. The dogs of the villages were affected first, then the human beings. Detailed clinical features, appropriate laboratory tests, and liver biopsies were studied. A retrospective epidemiological survey was carried out. The disease had a subacute onset starting with high fever, followed by rapidly progressive jaundice. Ascites appeared simultaneously and soon became quite massive. Hepatomegaly was recorded when ascites decreased. Liver function tests suggested cholestatic jaundice. The mortality rate in the hospital was 10%. Clinical features in dogs were similar, but mortality was almost 100%. Liver histology was characterized by (1) edema and collagenization of the central veins, never with thrombosis, (2) cholangiolar proliferation, (3) moderate to severe ballooning of the hepatocytes, (4) perisinusoidal fibrosis, (5) cholestasis, and finally, (6) cirrhosis with reverse lobulation. Etiology of this epidemic of hepatitis could not be unequivocally established. Critical analysis of the data suggests that some food toxin may have been a factor in the outbreak of this unusual epidemic of toxic hepatitis.

Adolescent↗
PubMed2004

Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV-infected individuals.

BACKGROUND: Nevirapine is a nonnucleoside reverse transcriptase antiretroviral agent. Among HIV-infected individuals, rare instances (<1%) of serious cutaneous and hepatic toxicity have been reported. Because of its favorable pharmacokinetic profile, non-HIV-infected individuals have received nevirapine-containing postexposure prophylaxis (PEP). OBJECTIVE: To describe the clinical features of cutaneous and hepatic toxicity that occurred when nevirapine was administered to non-HIV-infected individuals. METHODS: Reports of nevirapine-associated cutaneous or hepatic toxicity occurring among non-HIV-infected individuals were obtained from the US Food and Drug Administration's adverse event reporting system, the pharmaceutic manufacturer, occupational health programs in Chicago, physicians, and case reports. The Eastern Cooperative Oncology Group (ECOG) scoring system was used to grade toxicity. RESULTS: Twelve non-HIV-infected individuals developed severe cutaneous toxicity, including 3 with Stevens-Johnson syndrome, after 7 to 12 days of nevirapine-containing PEP regimens. Thirty non-HIV-infected individuals developed hepatotoxicity after 8 to 35 days of single-agent nevirapine (n = 8) or a nevirapine-containing PEP regimen (n = 22). Findings included ECOG grade 3 or 4 hepatotoxicity (n = 14), fevers (n = 11), skin rashes (n = 8), eosinophilia (n = 6), and fulminant hepatic necrosis requiring an orthotopic liver transplant (n = 1). Rates of severe hepatotoxicity (grade 3 or 4) in non-HIV-infected individuals ranged from 10% (4/41) to 62% (5/8). Liver biopsy material from 2 individuals was consistent with a hypersensitivity syndrome. CONCLUSIONS: Serious hepatic and cutaneous toxicities can occur in non-HIV-infected individuals who receive short-term nevirapine therapy. The rate of severe hepatotoxicity appears to be greater in non-HIV-infected individuals than in HIV-infected persons and may be associated with higher CD4 counts. The use of PEP regimens containing nevirapine should be discouraged.

Adult↗
PubMedDate not supplied

[Molecular mechanisms of metabolic adaptation in pathological changed liver during toxic hepatitis ].

Possible molecular mechanisms underlying changes in catalytical properties of alcohol dehydrogenase (ADH) and lactate dehydrogenase (LDH) were studied at toxic hepatitis. The development of toxic hepatitis is accompanied by significant changes in the activity of ADH and LDH assayed in subcellular fractions and kinetic characteristics of these enzymes. This can result in an increase cellular level of acetylaldehyde and lactate which promotes the development of liver cirrhosis.

Alcohol Dehydrogenase↗
PubMed2006

[Toxic hepatitis associated with carp juice ingestion].

The potential hepatotoxicity of herbal remedies and/or health foods is usually ignored in daily life. There have been cases showing the toxic hepatitis and renal failure associated with the ingestion of raw carp bile. We experienced a case of toxic hepatitis without any evidence of renal failure that was associated with carp juice ingestion. The clinical manifestations were characterized by nausea and vomiting after the ingestion of carp juice for 3 months. The diagnosis of toxic hepatitis was made on the basis of the patient's history, laboratory data, RUCAM (Russel Uclaf Causality Assessment) and the results of ultrasonography guided liver biopsy. The patient showed rapid improvement after instituting supportive therapy.

Adult↗
PubMedDate not supplied

[Age-dependent structural-functional characteristics of the small intestine in rats born to females with chronic toxic hepatitis].

In 60 baby-rats born to pregnant animals with toxic hepatitis, the development and process of forming of the small intestine was studied together with a number of morphometric and functional parameters. In a comparative investigation, the intrauterine development of the animals, of their small intestine, other parameters studied were found out to have lagged behind. Going further into the organ structures development and formation we succeeded in identifying significant differences in parameters for villi and crypts, the absorbing surface, enzymatic system of the small intestine in those animals born to mothers having had toxic hepatitis during pregnancy.

Aging↗
PubMed2000

Effects of lipopolysaccharide on TNF-alpha production, hepatic NOS2 activity, and hepatic toxicity in rats with cirrhosis.

BACKGROUND/AIMS: Septic shock results in high mortality in patients with cirrhosis. Nitric oxide synthase 2 (NOS2) is induced by bacterial lipopolysaccharides (LPS) and plays a major role in the inflammatory response to bacterial infections. Little is known about the regulation of NOS2 in cirrhosis under septic conditions. Thus, the aim of this study was to determine tissue NOS2 activity, serum nitrate and tumor necrosis factor (TNF-alpha) levels and hepatic toxicity in cirrhotic rats after LPS administration. METHODS: Serum nitrates, TNF-alpha and transaminases were determined after LPS-administration in rats with secondary biliary cirrhosis and in sham-operated rats. Liver, lung, aortic and peritoneal macrophage NOS2 activities were determined by converting L[14C] arginine into L[14C] citrulline in a calcium free medium. Nitrate and TNF-alpha production were determined in a culture medium of peritoneal macrophages after in vivo LPS administration. RESULTS: LPS (1.5 mg/kg) induced 50% mortality in cirrhotic rats and no mortality in sham-operated rats. After LPS, TNF-alpha, nitrate and transaminase levels were significantly higher in cirrhotic rats compared to sham-operated rats. After LPS administration, there were no differences in NOS2 activity in the aorta, lungs, or peritoneal macrophages of the two groups, whereas NOS2 activity was significantly higher in the cirrhotic liver compared to the normal liver. CONCLUSIONS: In rats with cirrhosis, LPS administration induces higher mortality, hepatic toxicity, hepatic NOS2 activation and TNF-alpha release than in sham-operated rats. These results confirm the harmful role of septic shock in liver disease.

Animals↗
PubMed1980

Toxic hepatitis from oral methoxsalen photochemotherapy (PUVA).

A 59-year-old white woman with long-standing psoriasis, who had a damaged liver from methotrexate, developed a toxic hepatitis while on oral methoxsalen photochemotherapy (PUVA). Fever and marked elevation of liver enzymes occurred after the fifteenth PUVA treatment and spontaneously returned to normal within 5 days. One week later, following the next PUVA treatment, the same toxic hepatitis developed and again spontaneously resolved. Topical methoxsalen photochemotherapy with ultraviolet A (UVA) did not produce the toxic hepatitis and provided a suppression of the psoriasis on a maintenance basis.

Administration, Oral↗
PubMedDate not supplied

[Effect of Arnica montana on the state of lipid peroxidation and protective glutathione system of rat liver in experimental toxic hepatitis].

Effects of Tinctura Arnica on lipids peroxidation and on the protective glutathions system of liver in rats in case of experimental toxic hepatitis have been studied. Toxic hepatitis is accompanied by deep alterations of the oxidant-antioxidant status of the body. Intoxication of the body by CCl4 results in intensification of the free radicals formation particularly in liver: accumulation of lipids peroxidation molecular products, glutathione system enzyme activity inhibition in early terms and its partial restoration in remote terms has been seen. Our studies revealed that Arnica montana infusion inhibits the rate of lipids perioxidation products formation, affects the glutathione system enzymes activity.

Animals↗
PubMed1995

Induction of a hepatic toxic syndrome in the Dutch-belted rabbit by a quinoxalinone anxiolytic.

The non-benzodiazepine anxiolytic, panadiplon, was discontinued from clinical development due to evidence of hepatic toxicity in human volunteers that was not predicted by rat or monkey preclinical development studies. The present study was conducted to examine potential toxicity in the rabbit. Three groups of female rabbits were administered vehicle, 10 mg/kg per day or 20 mg/kg per day of panadiplon by oral gavage for 14 days. Animals in the 20 mg/kg group lost weight, and 6/10 developed a profound lethargy. Hepatic toxicity was observed in treated animals, evidenced by dose- and time-related increases in serum transaminase activities, gross hepatic lesions and multifocal centrilobular necrosis. Hepatic microvesicular steatosis was evident in treated animals; lipid analysis revealed a 123% increase in hepatic triglyceride. A time-dependent increase in serum triglyceride levels was observed in the high-dose group beginning on day 4. Hepatic glycogen was reduced, and histochemical examination revealed the reduction to be heterogeneous across the lobule with some areas showing a complete absence of glycogen. One rabbit in each drug-treated group showed mild hypoglycemia at day 12, and 4/10 rabbits in the high-dose group showed hyperglycemia at days 12-14. We conclude that panadiplon produced a microvesicular steatosis and hepatic toxicity in the rabbit. The observed toxicity resembled a Reye's syndrome-like toxicity produced by a variety of mitochondrial fatty acid oxidation inhibitors.

Animals↗
PubMed1997

Toxic Hepatitis from Dimethylacetamide.

Two cases of toxic hepatitis from dimethylacetamide (DMAC) occurred among 25 employees on a new acrylic-fiber production line at a western U.S. manufacturing plant. Interesting features of these cases include: 1) inadequate personal protective equipment (PPE) for dermal exposures, resulting in skin penetration during maintenance and repair procedures; 2) the subjects of these case reports are female; all workers at the manufacturer's European plant were male, and DMAC-related liver dysfunction had not been encountered at that site; 3) the new American production line required more frequent maintenance and repair work than existing production lines at the European parent company, resulting in greater opportunities for DMAC exposure. Hepatotoxicity due to dermal absorption of DMAC and other amide-type solvents deserves special consideration in industrial settings.

Journal Article↗
PubMedDate not supplied

[Effect of Arnica montana tincture on some hydrolytic enzyme activities of rat liver in experimental toxic hepatitis].

Effects of tinctura arnica on arginase, adenosine triphosphatase, glucose-6-phosphatase and 5'-nucleotidase activities of rats liver in case of experimental toxic hepatitis have been studied. Toxic hepatitis was caused by 2 times interstomach administration of 0.25 ml oil solution of carbon tetrachloride per 100 g of animal weight. 20 mkl/100 g of tinctura arnica was administered every day per os for 14 days. The enzyme activities have been investigated at 3, 7 and 17 days. A significant demention of a studied hydrolytic enzyme activities in rats liver at intoxication of the body by CCI4 has been shown. It has been established that tinctura arnica administered per os to intoxicated animals sped up the normalization of hydrolytic enzyme activities in rat liver.

5'-Nucleotidase↗
PubMed1978

The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Acetylation↗
PubMed2006

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver.

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.

Adenoviridae↗
PubMed2000

[Effectiveness of dietary non-starch polysaccharides in experimental toxic hepatitis].

The efficiency of some polysaccharides was investigated in mice with an experimental toxic hepatitis. Hepatitis was induced by the oral administration of 10% solution CCl4 in olive oil at a dosage of 3 ml/kg body weight every day during 7 days. After that tested substances were administrated every day 30-40 min before a feeding at a dosage of 150 mg/kg body weight during 14-21 days. Results showed that a calcium alginate, two low-methoxyl pectins (one with the degree of esterification about 50% and other with the degree of esterification less 5%), fucoidan, and chitozan, but not lambda-carrageenan and kappa-carrageenan, have beneficial affects on liver total lipid, glycogen, malondialdehyde, and diene conjugates as well as on blood total lipid and alanine aminotransferase activity in animals with experimental toxic hepatitis.

Alanine Transaminase↗
PubMed1996

[Toxic hepatitis due to dimethylformamide: case reports and literature review].

We report two patients with toxic hepatitis due to the solvent dimethylformamide (DMF). Other causes of hepatitis such as viral, drug induced or alcoholic hepatitis, could be excluded or were considered to be unlikely. Hepatotoxicity due to professional exposure to solvents e.g. dimethylformamide should be considered in any patient with unexplained hepatitis. The fast improvement of the clinical symptoms and the progressive normalisation of the liver function tests once the exposure to the product has been stopped, supports the diagnosis. Yet, non-drug induced toxic hepatitis remains an exclusion diagnosis. Therapy consists of avoiding every contact with the causative agent. Table 3 (Addendum) gives an overview of some industrial agents able to cause hepatitis.

Adolescent↗
PubMedDate not supplied

[Toxic hepatitis caused by ketoconazole: a report of 4 cases].

The authors describe four cases of toxic hepatitis due to ketoconazole. All patients were female and were given the drug from 8 to 16 weeks (200mg/day). The clinical condition of the four patients was similar to that of viral hepatitis. Normalization of clinical and laboratory findings occurred 60 to 90 days after discontinuation of the drug and no patient died. One patient received ketoconazole again after her clinical and laboratory results were normalized, and a new toxic hepatitis appeared within 15 days; the second discontinuation of the drug lead to cure of the hepatitis.

Chemical and Drug Induced Liver Injury↗