salicylates and Chemical-and-Drug-Induced-Liver-Injury

The central role of the liver in drug metabolism sets the stage for drug-related hepatotoxicity. The incidence of hepatotoxicity associated with non-narcotic analgesics is low, but their widespread use both prescription and over-the-counter-makes analgesic-associated hepatotoxicity a clinically and economically important problem. Hepatotoxicity is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals. In fact, there are many differences in the incidence, histologic pattern, and mechanisms of hepatotoxicity between, as well as within, chemical classes. Most NSAID reactions are hepatocellular and occur because of individual patient susceptibility (idiosyncrasy). Aspirin, however, is a dose-related intrinsic hepatotoxin. Acetaminophen is also an intrinsic hepatotoxin but rarely demonstrates hepatotoxicity at therapeutic doses. It does cause hepatotoxicity with massive overdoses and with therapeutic doses in susceptible patients such as chronic users of alcohol. No hepatotoxicity has been reported to date with tramadol, another non-narcotic analgesic.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Diclofenac; Humans; Liver Diseases; Risk Factors; Salicylates; Sulindac

Topics: Acetaminophen; Aged; Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents; Apazone; Aspirin; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Diclofenac; Drug Hypersensitivity; Gastrointestinal Diseases; Hematologic Diseases; Humans; Ibuprofen; Indomethacin; Ketoprofen; Kidney Diseases; Kinetics; Naproxen; Phenylbutazone; Piroxicam; Salicylates; Thiazines

Non-narcotic analgesics can produce a variety of hepatic lesions but clinically significant liver damage is uncommon with normal therapeutic use. The pattern of hepatotoxicity caused by the salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen) and the pyrazolones differs but many of these drugs can cause generalised reactions which involve the liver. Depending on the drugs in question, the risks of liver injury may be conditioned by factors such as age, sex, dose and duration of treatment. Hepatotoxicity associated with the use of salicylates and most NSAIDs has been reported most often in females with collagen diseases but this may simply reflect the greater use of these drugs in such patients. Paracetamol-induced liver damage occurs almost exclusively as a result of overdosage. Except for the microvesicular fatty changes in hepatocytes in patients with Reye's syndrome attributed to salicylate, the acute centrilobular necrosis caused by paracetamol in overdosage and the marked cholestasis produced by benoxaprofen, the pathological changes in hepatic reactions to non-narcotic analgesics are rather variable and nonspecific. About 50% of patients given salicylate in full anti-inflammatory dosage develop minor abnormalities of liver function. There is usually a mild to moderate increase in plasma aminotransferase activity with patchy necrosis and degeneration of hepatocytes. These changes are related to plasma salicylate concentration and are usually rapidly reversible. In a small minority of patients, particularly the young, liver damage is more severe and may be associated with liver failure, acidosis, hypoglycaemia and encephalopathy. This picture closely resembles Reye's syndrome. In overdosage, paracetamol can cause acute hepatic necrosis. Without specific treatment, some 8% of adults suffer severe liver damage with plasma aminotransferase activity greater than 1000 U/L and about 1% die with hepatic failure and encephalopathy. The administration of sulfhydryl compounds such as N-acetylcysteine within 8 to 10 hours effectively prevents liver damage and death. Liver damage has been attributed to the therapeutic use of paracetamol. However, in most reports the dose was excessive and many patients were chronic alcoholics (who seem to be at increased risk). In these cases the features were typical of acute overdosage. A consistent and characteristic pattern of hepatotoxicity is evident with relatively few non-steroidal anti

Topics: Acetaminophen; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Male; Phenylbutazone; Reye Syndrome; Salicylates

Serious hepatotoxicity is uncommon with the proper therapeutic use of non-narcotic analgesics but experience with new non-steroidal anti-inflammatory drugs (NSAIDs) is limited. Drugs such as ibufenac, fenclofenac and benoxaprofen were withdrawn from the market because of hepatotoxicity, and liver damage has been reported on occasion with virtually all non-narcotic analgesics. However, a clear pattern of toxicity with characteristic clinical, biochemical and histopathological abnormalities has emerged with relatively few. With the exception of acute hepatic necrosis following overdosage of paracetamol, little is known of the mechanisms of liver injury induced by non-narcotic analgesics. Involvement of the liver in a generalised drug reaction does not imply specific hepatotoxicity. About 50% of patients given aspirin regularly in anti-inflammatory doses develop mild, dose-dependent reversible liver damage as shown by elevation of the plasma aminotransferase activity. Liver damage is more severe in a small minority and it may rarely be complicated by disseminated intravascular coagulation and encephalopathy with a fatal outcome. There have also been isolated reports of chronic active hepatitis associated with the use of salicylates. Salicylate hepatitis has been reported most often in young females with connective tissue diseases. Many patients with Reye's syndrome have been given aspirin during the prodromal phase, and this serious condition closely resembles subacute salicylate intoxication in children. Salicylate probably has a causal or contributory role in Reye's syndrome, but many refuse to accept this and the issue is the subject of heated debate. Paracetamol in overdosage causes acute hepatic necrosis, and liver damage has been attributed to its therapeutic use. However, most reports have involved chronic alcoholics who took excessive doses and in these patients the clinical, biochemical and pathological findings were typical of paracetamol overdosage. Many authors have failed to make the distinction between therapeutic use and a therapeutic dose. In other cases liver damage could have been caused by exposure to other agents, viral infection or naturally occurring liver disease. If these cases are excluded, there are very few reports of liver damage associated with the proper therapeutic use of paracetamol. In some cases, the picture resembled chronic active hepatitis but no causal relationship has been established between this condition and paraceta

Topics: Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Humans; Salicylates

Aspirin can be more closely controlled than other nonsteroidal anti-inflammatory drugs because serum salicylate levels can be measured. Dosages of 80 to 100 mg/kg per day usually lead to the desired serum salicylate levels of 20 to 25 mg/dl. Gastric irritation, the most frequent cause for cessation of aspirin therapy, is significantly reduced by the use of enteric-coated aspirin. At the onset of aspirin therapy in children, there is frequently moderate elevation of SGOT and SGPT liver enzyme levels. With continued treatment these levels usually fall into the range of mild elevations. Although these children with arthritis often take high doses of aspirin for years, Reye's syndrome is virtually never seen.

Topics: Arthritis, Juvenile; Aspirin; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Humans; Liver Diseases; Protein Binding; Salicylates; Serum Albumin

While there is room for questioning the need, or even advisability, of routine antipyretic therapy, the available data do not yet constitute any sort of a contraindication. There are reasons for individualizing the decision. However, having once decided, there is no compelling reason for selecting one antipyretic over any other, and aspirin remains the most satisfactory in light of the available evidence. Some serious theoretic questions persist about the safety of acetaminophen use in sick persons, and clearly there are some precautions that should be taken with regard to the doses of flavored preparations of this and any future products whose attractiveness to children is thus enhanced.

Topics: Acetaminophen; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature Regulation; Chemical and Drug Induced Liver Injury; Child; Drug Administration Schedule; Fever; Humans; Salicylates; Seizures, Febrile

Most reports of interactions involving analgesics deal with their effects on the actions of other drugs rather than vice versa. Aspirin and ethanol have synergistic effects on the development of gastritis, gastrointestinal bleeding, and chronic gastric ulcer. This must be the most common and most important interaction affecting analgesic toxicity. Combined overdosage of aspirin with central nervous system depressants may be particularly hazardous because suppression of the salicylate-induced respiratory stimulation further shifts the disordered acid-base balance towards acidosis. The toxicity of acetaminophen (paracetamol) depends primarily on the balance between the rate of formation of the hepatotoxic metabolite and the rate of glutathione synthesis in the liver. In animals, prolonged pretreatment with ethanol increases the metabolic activation and acute toxicity of acetaminophen, and there is some evidence that chronic alcoholics are more susceptible to hepatotoxicity following acute overdosage. It has been assumed that this sensitivity in chronic alcoholics is due to microsomal enzyme induction with enhanced metabolic activation of acetaminophen. However, the metabolic activation of acetaminophen, as judged by the urinary excretion of its cysteine and mercapturic acid conjugates, is not increased in heavy drinkers or in patients induced by long-term treatment with anticonvulsants or rifampicin. Microsomal enzyme induction is complex. There are important species differences and different agents may selectively induce different variants of the multiple forms of cytochrome P-450. The acute administration of ethanol greatly reduces the metabolic activation of acetaminophen in heavy drinkers with more than a 50 percent decrease in cysteine and mercapturic acid conjugate production. Thus ingestion of ethanol should reduce the risk of liver damage following acetaminophen overdosage. Cimetidine, which inhibits the oxidative metabolism of some drugs, reduces the hepatotoxicity and increases the dose of acetaminophen in mice required to kill 50 percent of the animals. However, contrary to expectations, cimetidine does not inhibit the oxidative metabolism of acetaminophen in man. Salicylamide competes with acetaminophen for sulphate conjugation but is unlikely to potentiate toxicity following overdosage since sulphate conjugation is rapidly saturated anyway. Animal studies suggest that the hepatotoxicity of acetaminophen after overdosage may be increased by othe

Topics: Acetaminophen; Alcoholic Intoxication; Alcoholism; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethanol; Humans; Salicylates

The potential for hepatic injury associated with the therapeutic use of salicylates and acetaminophen has recently attracted considerable attention. About 300 cases have been reported in which elevated transaminase levels or other evidence of hepatic injury developed following treatment with salicylates. Review of the spectrum of abnormalities reveals a group of patients (4 percent) with symptomatic liver damage in whom progressive or chronic liver disease is a possibility with continued use of the drug. In a few patients in this group, jaundice developed; several had abnormal prothrombin times; 11 (70 percent) had transaminase values in excess of 500 units; and five patients (30 percent) had encephalopathy and/or Reye's syndrome. In several reports liver damage has also been associated with the use of acetaminophen in therapeutic or near-therapeutic dosages. Of 18 patients, nine appeared to have ingested acetaminophen in amounts approaching overdose. Of the remaining nine patients, six were alcoholics. In the entire group, only five patients did not have a history of alcohol abuse; in three, glutathione depletion was suggested as a possible explanation for hepatotoxicity. The association with alcoholism or glutathione depletion suggests that host susceptibility may play a critical role. In two patients, long-term use of acetaminophen resulted in liver injury suggestive of chronic active hepatitis, possibly on the basis of an idiosyncratic reaction. In a study of chronic liver disease, acetaminophen half-life was prolonged (168 percent) without accumulation at 4 g a day over five days. In a double-blind, two-week, cross-over study, no clinical or laboratory evidence of adverse effects was found. There is, therefore, no evidence that chronic liver disease increases the risk of hepatotoxicity following the administration of acetaminophen in therapeutic doses. Thus, acetaminophen is the preferred antipyretic analgesic in patients with liver disease. Salicylates should be avoided since many of the adverse effects associated with these drugs are similar to the complications of chronic liver disease.

Topics: Acetaminophen; Alcohol Drinking; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Chronic Disease; Humans; Liver Diseases; Salicylates

Topics: Butyrophenones; Chemical and Drug Induced Liver Injury; Cholestasis; Contraceptives, Oral, Hormonal; Humans; Novobiocin; Prognosis; Rifampin; Salicylates; Steroids

Topics: Anti-Inflammatory Agents; Arthritis, Juvenile; Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Cryoglobulinemia; Felty Syndrome; Giant Cell Arteritis; Humans; Liver Diseases; Lupus Erythematosus, Systemic; Polymyalgia Rheumatica; Rheumatic Diseases; Rheumatic Fever; Salicylates; Scleroderma, Systemic; Sjogren's Syndrome; Vasculitis

Salicylates have been the most widely studied of the nonnarcotic analgesics in pregnancy, and in the last 20 years evidence has accumulated indicating that their ingestion in pregnancy may have adverse effects on the mother and her child. Salicylates have been found to reduce the mean birth weight of the offspring in animal studies and in 1 human study. In the third trimester of pregnancy the maternal and fetal effects are mediated through the antiprostaglandin properties of salicylates and include prolongation of gestation and labor, increased blood loss at delivery, and increased perinatal mortality. Bleeding manifestations and withdrawal symptoms in newborn infants are associated with raised fetal blood salicylate levels. These effects of salicylates warrant routine antenatal urinary screening for salicylates in communities known to use them heavily. Adverse maternal or fetal effects form acetaminophen use in pregnancy have not been reported, but formal clinical or epidemiologic studies of its use have not been conducted.

Topics: Abnormalities, Drug-Induced; Acetaminophen; Animals; Birth Weight; Chemical and Drug Induced Liver Injury; Female; Fetal Blood; Fetal Growth Retardation; Fetus; Humans; Infant, Newborn; Infant, Newborn, Diseases; Liver; Obstetric Labor Complications; Pregnancy; Pregnancy, Prolonged; Retrospective Studies; Salicylates

1 Hepatotoxicity is rare when mild analgesics are used in normal therapeutic doses. 2 The potential of aspirin and salicylates to cause hepatotoxicity has been only recently recognized. 3 Salicylate hepatitis is often asymptomatic, and may only be revealed by finding elevated levels of aminotransferases. 4 Most cases have occurred in children or young adults with connective tissue diseases, who take high doses of salicylates for long periods. 5 Hepatic injury is not recognized as a complication of acute aspirin poisoning. 6 Following overdosage of paracetamol, a toxic intermediate metabolite causes acute hepatic necrosis which may be fatal. 7 Cysteamine, methionine and N-acetylcysteine confer protection against this severe liver damage, but the time between overdosage and treatment is critical. 8 The chronic therapeutic use of paracetamol should be considered a potential but very rare cause of active chronic hepatitis. 9 There is no clear evidence of phenacetin hepatotoxicity in man. 10 Phenylbutazone may cause liver injury and other analgesics can cause hypersensitivity reactions in which the liver is involved.

Topics: Acetaminophen; Adult; Analgesics; Aspirin; Chemical and Drug Induced Liver Injury; Child; Humans; Phenacetin; Phenylbutazone; Salicylates

Topics: Animals; Cells; Chemical and Drug Induced Liver Injury; Drug Resistance; Environmental Pollution; Epithelium; Gases; Hematopoietic System; Irritants; Ischemia; Kidney; Liver; Lung; Maleates; Mercury; Organ Specificity; Rabbits; Rats; Receptors, Drug; Salicylates; Tachyphylaxis; Toxicology; Uranium

Aspirin can be more closely controlled than other nonsteroidal anti-inflammatory drugs because serum salicylate levels can be measured. Dosages of 80 to 100 mg/kg per day usually lead to the desired serum salicylate levels of 20 to 25 mg/dl. Gastric irritation, the most frequent cause for cessation of aspirin therapy, is significantly reduced by the use of enteric-coated aspirin. At the onset of aspirin therapy in children, there is frequently moderate elevation of SGOT and SGPT liver enzyme levels. With continued treatment these levels usually fall into the range of mild elevations. Although these children with arthritis often take high doses of aspirin for years, Reye's syndrome is virtually never seen.

Topics: Arthritis, Juvenile; Aspirin; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Humans; Liver Diseases; Protein Binding; Salicylates; Serum Albumin

Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice.

Topics: Administration, Oral; Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Liver; Male; Metabolome; Metabolomics; Mice, Inbred ICR; Nuclear Magnetic Resonance, Biomolecular; Salicylates

Gene expression profiles of Sprague-Dawley (SD) rats treated with a standardized willow bark extract (WB), its salicin rich ethanol fraction (EtOH-FR) or the tricyclic antidepressant imipramine were evaluated for their potential to induce adverse events. Treatments had shown antidepressant-like effects.. Gene expression profiles (Agilent Whole Genome Array, n=4/group) obtained from the peripheral blood of male SD rats treated with WB (STW 33-I), EtOH-FR (30 mg/kg bw) or imipramine (20 mg/kg bw) were analysed comparatively by the Ingenuity Systems Programme, which allows to conduct model calculations of thresholds for theoretical potential adverse events (AE).. The number of genes regulated by the three treatments were 1673 (WB), 117 (EtOH-FR) and 1733 (imipramine). The three treatments related to 47 disease clusters. The WB extract reached the threshold for a potential AE in one disease cluster (cardiac hypertrophy), whereas the EtOH-FR exceeded the threshold in 5 disease clusters (cardiac arteriopathy and stenosis, glomerular injury, pulmonary hypertension, alkaline phosphatase levels ⇑). Imipramine treatment hit 13 disease clusters: tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, precipitation of congestive heart failure; urinary retention, altered liver functions. Those correspond to known potential adverse events. Glomerular injury and altered liver functions are part of the side effect profile of salicylic acid derivatives in agreement with the findings for the salicin rich EtOH-FR.. There is no linear relationship between the number of constituents of a drug (preparation) and the number of different targets hit in a biological system on the gene expression level. Therefore, the number of genetic targets in a biological system does not necessarily increase with the complexity of the treatment corresponding to the non-linear behaviour of biological systems. Regarding gene expression levels AE of single treatments are not necessarily additive in combination treatments. The applied method appears to be an interesting screening tool for the prediction of potential AE. The phenomena that imipramine crossed the potential threshold for AEs several times whereas the WB extract did reach the threshold level only once, however not backed by clinical data for this AE, deserves to be further investigated. It questions the commonly assumed principle that substances with low number or without AE will have a poor efficacy.

Topics: Animals; Antidepressive Agents, Tricyclic; Benzyl Alcohols; Chemical and Drug Induced Liver Injury; Ethanol; Gene Expression Profiling; Gene Expression Regulation; Glucosides; Heart Diseases; Hypertension, Pulmonary; Imipramine; Male; Nephritis; Phytotherapy; Plant Bark; Plant Extracts; Rats; Rats, Sprague-Dawley; Salicylates

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; HIV Infections; Humans; Liver; Male; Middle Aged; Salicylates; Transaminases

Liver cell necrosis was induced in rats by a galactosamine injection. Cell death was due to an increase of Ca++ intracellular levels and was also under the control of genes. Rats were then either exposed or not to a 6 mT 100 HZ pulsed magnetic field (PMF) and they either received or not methylsilane-triol injections. Animals were sacrificed twenty-seven hours after a galactosamine injection. On the one hand it appeared from transaminase levels that the PMF increased the number of animals which were sensitized to galactosamine but decreased transaminase levels. On the other hand PMF decreased the protective effect of MST against galactosamine. We may suggest that PMF should be considered as an additional cellular signal received through genes which would determine the evolution towards or against apoptosis according to the age of the cell itself but also the Ca++ intracellular level.

Topics: Animals; Chemical and Drug Induced Liver Injury; Galactosamine; Magnetics; Male; Organosilicon Compounds; Rats; Rats, Wistar; Salicylates

Choline magnesium trisalicylate is a non-acetylated salicylate used widely as a nonsteroidal anti-inflammatory drug. Although mild transient hepatotoxicity associated with aspirin and other salicylates has been well documented, most commonly with high-dose treatment for rheumatologic disorders 112), we report a case of severe hypersensitivity hepatitis with striking tissue and peripheral eosinophilia after ingestion of choline magnesium trisalicylate.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Choline; Eosinophilia; Female; Humans; Osteoarthritis; Salicylates

Female Wistar rats received an oral dose of 700 mg salicylic acid/kg body wt., given as sodium salicylate. Some of the salicylate-treated rats received two subcutaneous injections of 100 mumol kg-1 ZnCl2 (24 h before and simultaneously with the salicylate administration). Other animals were given one subcutaneous injection of 100 mumol kg-1 ZnCl2 simultaneously with the salicylate treatment. Control rats were similarly injected with ZnCl2. Twenty four hours after salicylate treatment, serum and livers were taken for histochemical and biochemical analysis. The most remarkable effects of the treatment were enrichment of lipid droplets and iron and a reduction of glycogen, particularly in the periportal hepatocytes. The effects of salicylate were partially prevented by two ZnCl2 injections. The protective effects of ZnCl2 may be due to lower iron uptake into hepatocytes and by the induction of zinc metallothionein, which can serve as a scavenger for oxygen radicals.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Cations; Chemical and Drug Induced Liver Injury; Female; Histocytochemistry; Iron; Lipids; Liver Diseases; Liver Glycogen; Metallothionein; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Zinc

Topics: Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Liver; Male; Rats; Salicylates; Salicylic Acid; Time Factors

The effect of sodium salicylate (SS) pretreatment on acetaminophen (APAP) metabolism and hepatotoxicity in mice was studied. Mice were given a single oral dose of SS (100 mg/kg) 1 hr before graded doses of APAP (150-500 mg/kg). Liver histology, serum hepatic enzymes (serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase and isocitric dehydrogenase) and APAP metabolites in urine were examined 24 hr after APAP treatment. Free plasma APAP and liver glutathione were determined over 24 hr after treatment with 400 mg/kg of APAP alone or after SS pretreatment. At 500 mg of APAP per kg, mortality rate was 38% in SS + APAP group; no mortality was seen among animals treated with APAP alone. Centrilobular hepatic hemorrhagic necrosis and/or vacuolation were observed in both treatments. Mitosis of hepatocytes was increased in all APAP-treated mice. Incidence of hepatic necrosis and mean lesion grades at 300- and 500-mg/kg doses increased in mice pretreated with SS. Mice that received SS + APAP had significantly higher levels of serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase and isocitric dehydrogenase at all doses compared to mice treated with APAP alone. APAP glucuronide and sulfate conjugates decreased and APAP mercapturate conjugate increased in urine of mice receiving SS + APAP treatment. Free plasma APAP was significantly higher 2 hr after APAP treatment in SS + APAP-treated mice as compared to mice that received APAP alone. Hepatic glutathione levels were similarly decreased over 24 hr in both groups. These data demonstrate that SS pretreatment alters APAP biotransformation profile and potentiates the hepatotoxic effect of APAP in mice.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Drug Synergism; Glutathione; Liver; Male; Metabolic Clearance Rate; Mice; Salicylates

In a 4 1/2-year retrospective study of hospitalized patients with rheumatic fever treated with salicylates, we determined that five of 34 children manifested salicylate-induced hepatitis. The average serum salicylate level in those patients with hepatotoxicity was 30.9 mg/dL, while the average serum salicylate level in the rest of the patients was 19.7 mg/dL. An awareness of this potential complication is important when treating children with salicylates at doses previously considered to be nontoxic. Serum salicylate levels should be maintained at approximately 15 to 25 mg/dL during such therapy.

Topics: Adolescent; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Liver Function Tests; Male; Retrospective Studies; Rheumatic Fever; Salicylates

Topics: Anti-Inflammatory Agents; Aspirin; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Indoles; Liver; Liver Function Tests; Male; Middle Aged; Phenylacetates; Phenylpropionates; Pyrazoles; Pyrroles; Salicylates; Sulindac

Topics: Anti-Inflammatory Agents; Arthritis; Aspirin; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Interactions; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Humans; Kidney Diseases; Salicylates

Topics: Acetaminophen; Animals; Biotransformation; Chemical and Drug Induced Liver Injury; Electron Transport; Oxidation-Reduction; Phenacetin; Salicylates

Salicylate is the drug of first choice in the initial treatment of juvenile rheumatoid arthritis. In therapeutic dosage it will adequately control joint symptoms in the majority of patients. For children who do not respond to or are intolerant of salicylate, a change to one of the other nonsteroidal anti-inflammatory agents is appropriate. In progressive polyarthritis unresponsive to the above agents, the addition of gold, antimalarials, or penicillamine is indicated, preferably in that order. Corticosteroid therapy should be reserved for selected patients meeting specific criteria. Pharmacotherapy of juvenile rheumatoid arthritis should always be individualized. For optimal treatment of the whole child it must be combined with both physical and educational measures.

Topics: Adrenal Cortex Hormones; Antimalarials; Arthritis, Juvenile; Chemical and Drug Induced Liver Injury; Child; Delayed-Action Preparations; Gold; Humans; Ibuprofen; Indomethacin; Penicillamine; Salicylates; Sulindac; Tolmetin

Topics: Adult; Alkaline Phosphatase; Arthritis, Juvenile; Aspirin; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Diseases; Salicylates; Transaminases

110 patients with various arthropathies, mostly rheumatoid arthritis, treated with salicylates, were investigated for the presence of signs of liver disease attributable to this drug. An increased serum alkaline phosphatase level was observed in 9 of 96 ASA-treated patients with rheumatoid arthritis. However, this alteration could not be related to the use of salicylates, nor to the ingestion of any other antirheumatic drug. The hyperphosphatasemia persisted during a three-year follow-up in five of the nine patients.

Topics: Aged; Alanine Transaminase; Alkaline Phosphatase; Arthritis; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Follow-Up Studies; Humans; Liver; Liver Function Tests; Lupus Erythematosus, Systemic; Male; Middle Aged; Salicylates

High-dose, long-term aspirin therapy easily overloads the patient's individual capacity to metabolize salicylates and may lead to complex metabolic disturbances including fulminant hepatic failure, hyperammonemia and toxic metabolic encephalopathy. In the two cases presented there was a severe outbreak of hepatotoxic encephalopathy despite the fact that the dosage of salicylates did not exceed that generally recommended for children with rheumatic diseases. The justification of high-dose salicylate therapy is discussed, taking into account the fact that children with juvenile rheumatoid arthritis and allied conditions may have increased susceptibility to liver damage from drugs. EEG abnormalities in these two cases corresponded to those described in other metabolic encephalopathies including Reye's syndrome. The quality of the EEG changes gives prognostic signs, but is of restricted value in establishing the etiology without the anamnestic data of salicylate ingestion. Active therapeutic measures including exchange transfusions are needed to prevent irreversible metabolic and pressure changes in the brain.

Topics: Adolescent; Ammonia; Chemical and Drug Induced Liver Injury; Child; Electroencephalography; Female; Hepatic Encephalopathy; Humans; Joint Diseases; Liver; Male; Salicylates

Topics: Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Female; Humans; Middle Aged; Salicylates

Thirty-one patients with rheumatoid arthritis in the Veterans General Hospital from July 1978 to June 1979 were treated with acetylsalicylic acid. The serum salicylate level was determined twice a week. The dose of acetylsalicylic acid was adjusted to keep the serum salicylate level around 15-30 mg%. All patients were started with an initial dose of 65 mg/kg/day. The serum salicylate levels at the 4th day varied greatly from 5.6 to 29.5 mg%. Tinnitus was noted in 24 patients. It occurred when the serum salicylate level reached 28.41 +/- 1.84 mg%. Abnormal liver function was noted in 19.35% (6/31) patients during treatment. It returned to normal after withdrawal of acetylsalicylic acid in 3 cases, after decrease of the dosage in 2 cases and on the same dosage in 1 case. Patients with positive FANA and RF were more prone to develop abnormal liver function during treatment. Monitoring of serum salicylate level may decrease the incidence of hepatic toxicity and maintain the dosage of acetylsalicylic acid in optimal range.

Topics: Adult; Arthritis, Rheumatoid; Aspirin; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Rheumatoid Factor; Salicylates; Tinnitus

Seventeen patients suffering from an initial attack of acute rheumatic fever were studied during treatment with phenoxymethyl penicillin and salicylates (600 mg orally every 4 or 6 hours). Elevated transaminase (SGOT) levels occurred in nine patients. The SGOT levels were directly related to serum salicylate levels (r = 0.668) and inversely to the serum albumin level (r = -0.418). SGOT response was greater in patients with a serum albumin of less than 3.5 g/dl (P < 0.001). In hypoalbuminemia, the ratio of free salicylate to bound salicylate rises and the free salicylate might be more active and thus more hepatotoxic even at relatively low total serum salicylate levels. In all patients with hypoalbuminemia of less than 3.5 g/dl, close monitoring the SGOT is advisable, especially if the level of total serum salicylate is 15 mg/dl or higher.

Topics: Acute Disease; Adolescent; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Female; Humans; Hypoproteinemia; Male; Protein Binding; Rheumatic Fever; Salicylates; Serum Albumin

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Dermatomyositis; Female; Hepatitis; Humans; Salicylates

Topics: Arthritis, Juvenile; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Liver Diseases; Salicylates

The influence of graded doses of sodium salicylate on rat liver cells cultured in monolayers was assessed by measuring lactic dehydrogenase activity in a culture media after incubation. Morphological alterations were studied by electron microscopy. The influence of different albumin concentrations in the media on toxicity was also evaluated. Lactic dehydrogenase concentrations rose with increasing doses of salicylate up to 40 mg per dl. High concentrations of albumin were associated with reduced salicylate toxicity. These findings suggest that salicylate-induced hepatic injury is dose related and my be influenced by serum albumin levels

Topics: Albumins; Animals; Chemical and Drug Induced Liver Injury; Culture Media; Culture Techniques; L-Lactate Dehydrogenase; Liver; Male; Rats; Salicylates; Serum Albumin

Topics: Adolescent; Adult; Animals; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Guinea Pigs; Humans; Male; Rabbits; Salicylates

Topics: Adult; Chemical and Drug Induced Liver Injury; Humans; Liver Function Tests; Male; Rheumatic Fever; Salicylates

Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Salicylates

Topics: Chemical and Drug Induced Liver Injury; Humans; Salicylates

Topics: Adolescent; Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Drug Synergism; Drug Therapy, Combination; Female; Humans; Penicillamine; Salicylates

Topics: Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Halothane; Humans; Isoniazid; Methyldopa; Oxyphenisatin Acetate; Prognosis; Salicylates; Sulfonamides

Two patients developed acute hepatic injury as a result of salicylate therapy. In each patient serum salicylate levels were below 25 mg per 100 ml during the development of hepatic dysfunction. Liver biopsies, obtained a few days after the peak abnormalities in serum transaminases, revealed nonspecific acute hepatitis. Normal liver tissue was found before the beginning of salicylate treatment in 1 patient, who had systemic lupus erythematosus and drug rechallenge was not attempted. In the other patient, who had rheumatoid arthritis, rechallenge with salicylate evoked hepatic dysfunction and recurrent symptoms. Salicylate-induced liver injury should be considered in the differential diagnosis of hepatic disease occurring in patients receiving high dose salicylate therapy, regardless of serum salicylate levels.

Topics: Adult; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Humans; Liver; Male; Middle Aged; Salicylates

Evidence of hepatic disease was sought in 102 children with juvenile rheumatoid arthritis (JRA) who were treated with aspirin. Serum glutamic oxaloacetic transaminase level was elevated (greater than 39 IU/liter) in 59% of the children. The degree and prevalence of SGOT elevations correlated with aspirin dose and serum salicylate level. Nevertheless, increased SGOT values were frequently present in children receiving moderate aspirin doses and having serum salicylate levels less than 25 mg/100 ml. Elevated SGOT values decreased in proportion to the degree of reduction in aspirin dose. The SGOT values above the 100 IU/liter were statistically associated with reduced sedimentation rates. Concomitant improvement in the clinical manifestations of JRA was noted in some children.

Topics: Arthritis, Juvenile; Aspartate Aminotransferases; Aspirin; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Liver; Male; Salicylates

Topics: Acetaminophen; Analgesics; Chemical and Drug Induced Liver Injury; Humans; Kidney; Liver; Salicylates; Suicide

Of 11 patients with acute rheumatic fever, 9 were treated with a total daily salicylate dosage of 3,6 g or less, 1 patient required a total daily dosage of 5,4 g and another required 9,0 g daily. Six of the 11 patients had elevated serum transaminase levels, and all were asymptomatic. The elevated transaminase levels appear to bear a direct relationship to the serum salicylate level, and a serum salicylate level of 19,2 mg/100 ml appears to be the critical point. In 5 out of the 6 patients with elevated transaminases, the serum salicylate level exceeded 19,2 mg/100 ml, while in the 5 patients with normal transaminases the serum salicylate level did not exceed 19,2 mg/100 ml. Also, in 10 of the 11 patients eosinophilia was noted, but this decreased despite continued or increased salicylate administration. A narrow margin thus appears to exist between therapeutic serum salicylate levels and hepatotoxic levels, and serial serum transaminase estimations are advocated in patients on long-term salicylate therapy.

Topics: Acute Disease; Adolescent; Adult; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Eosinophilia; Female; Humans; Male; Rheumatic Fever; Salicylates

Topics: Arthritis, Reactive; Chemical and Drug Induced Liver Injury; Histocompatibility Antigens; HLA Antigens; Humans; Liver; Salicylates

Topics: Arthritis, Juvenile; Biopsy; Brain; Brain Diseases; Chemical and Drug Induced Liver Injury; Child; Humans; Liver; Reye Syndrome; Salicylates

Topics: Aspirin; Chemical and Drug Induced Liver Injury; Female; Heart Diseases; Humans; Kidney Diseases; Male; Pregnancy; Salicylates; Stomach Diseases

Topics: Chemical and Drug Induced Liver Injury; Humans; Liver; Salicylates

A case of hepatotoxicity and encephalopathy (Reye's syndrome?) associated with salicylate therapy is presented and the aetiology of this syndrome is discussed. Hepatotoxicity developed with salicylate serum concentrations not exceeding therapeutic serum levels. The importance of controlling serum salicylate concentration and transaminase activity particularly during the first fourteen days of therapy is emphasized.

Topics: Acute Disease; Adolescent; Aspirin; Brain Diseases; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Reye Syndrome; Salicylates

Topics: Chemical and Drug Induced Liver Injury; Humans; Rheumatic Fever; Salicylates

Topics: Animals; Chemical and Drug Induced Liver Injury; Dogs; Gastric Acidity Determination; Gastric Juice; Histamine; Liver Diseases; Meat; Pepsin A; Salicylates; Time Factors

Topics: Animals; Aspirin; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Humans; Liver; Rabbits; Salicylates

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Eosinophilia; Feeding and Eating Disorders; Humans; Nausea; Salicylates; Vomiting

Topics: Adolescent; Alanine Transaminase; Arthritis, Juvenile; Aspartate Aminotransferases; Blood Cell Count; Blood Platelets; Blood Sedimentation; Chemical and Drug Induced Liver Injury; Disseminated Intravascular Coagulation; Fibrinogen; Humans; L-Lactate Dehydrogenase; Male; Salicylates

Topics: Chemical and Drug Induced Liver Injury; Eosinophils; Humans; Salicylates; Transaminases

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Aged; Cathartics; Chemical and Drug Induced Liver Injury; Cholestasis; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Humans; Iatrogenic Disease; Indomethacin; Insecticides; Pancreatitis; Peptic Ulcer; Phenylbutazone; Potassium Chloride; Reserpine; Salicylates; Thiazines

In 8 out of 32 juvenile patients suffering from chronic polyarthritis and in one patient with dermatomyositis, raised transaminase levels were found; the salicylate level was above 35 mg/100 ml in all except one. Reduction in the salicylate level led to a prompt fall in the serum transaminases. Despite a rise in alkaline phosphatase in three cases there was no other evidence of liver dysfunction in the children. Only one of the adults showed a rise in transaminase levels, and she had mild cirrhosis.

Topics: Adolescent; Adult; Age Factors; Aged; Alanine Transaminase; Alkaline Phosphatase; Arthritis, Juvenile; Aspartate Aminotransferases; Aspirin; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dermatomyositis; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Salicylates

Topics: Abnormalities, Drug-Induced; Animals; Chemical and Drug Induced Liver Injury; Female; Fetal Death; Fetal Diseases; Gastrointestinal Hemorrhage; Gestational Age; Hemorrhage; Injections, Intramuscular; Liver; Mice; Pentobarbital; Pregnancy; Salicylates

Topics: Analgesics; Aniline Compounds; Anti-Inflammatory Agents; Aspirin; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gastrointestinal Diseases; Humans; Indomethacin; Inflammation; Lysosomes; ortho-Aminobenzoates; Peptic Ulcer; Pyrazoles; Salicylates

Topics: Adipose Tissue; Aspirin; Brain Diseases; Chemical and Drug Induced Liver Injury; Fatty Liver; Humans; Infant; Kidney Diseases; Peritoneal Dialysis; Salicylates

Topics: Anticoagulants; Bismuth; Chemical and Drug Induced Liver Injury; Chlorothiazide; Drug Therapy; Esophagus; Gastroenterology; Hepatitis; Intestinal Diseases; Mercury Poisoning; Morphine; Mouth; Pancreas; Phenylbutazone; Phenytoin; Reserpine; Salicylates; Steroids; Stomach; Tooth; Toxicology

Topics: Aminopyrine; Animals; Antipyrine; Barbiturates; Chemical and Drug Induced Liver Injury; Ethylamines; Hepatitis A; Liver; Nitrofurantoin; Pentobarbital; Poisons; Rabbits; Research; Salicylates; Sulfaguanidine; Toxicology; Trichloroacetic Acid

Topics: Adrenal Cortex Hormones; Anemia; Anemia, Aplastic; Anticoagulants; Antipyrine; Blood Group Incompatibility; Chemical and Drug Induced Liver Injury; Chloramphenicol; Drug Eruptions; Drug Hypersensitivity; Drug Therapy; Hepatitis; Neurologic Manifestations; Penicillins; Phenylbutazone; Radiation Injuries; Salicylates; Shock; Streptomycin; Sulfanilamide; Sulfanilamides; Sulfonamides; Testosterone; Thiamine; Toxicology; Vaccines