tetracycline and Chemical-and-Drug-Induced-Liver-Injury

Drug-induced liver injury (DILI) is a major concern in clinical studies as well as in postmarketing surveillance. It is necessary to establish an animal model of DILI for thorough investigation of mechanisms of DILI and searching for protective medications. This article reviews the current status and future perspective on establishment of DILI models based on different hepatotoxic drugs, as well as the underlying mechanisms of liver function damage induced by specific medicine. Therefore, information from this article can help researchers make a suitable selection of animal models for further study.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppression Therapy; Liver; Tetracycline

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents.

Topics: Amiodarone; Animals; Camptothecin; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Fatty Liver; Hepatocytes; Humans; Irinotecan; Lipid Metabolism; Liver; Methotrexate; Mitochondria, Liver; Organoplatinum Compounds; Oxaliplatin; Perhexiline; Tamoxifen; Tetracycline; Valproic Acid

Hepatotoxicity associated with any antibiotic is rare. With the wide-spread use of antimicrobial agents, however, hepatic injury is not an infrequent occurrence. Penicillins remain a widely used class of antimicrobials with a well defined record of low hepatotoxicity. The combination of clavulanate with amoxicillin may be associated with the greatest risk for liver injury from any antimicrobial agent. Significant hepatotoxicity also may occur with sulfamethoxazole/ trimethoprim and combination regimens used to treat tuberculosis. An autoimmune-like hepatitis may result from minocycline or nitrofurantoin exposure and most often resolves with cessation of therapy. Treatment with high doses of tetracycline and oxacillin may be associated with severe hepatotoxicity. Early suspicion of hepatocellular injury in the setting of antimicrobial exposure should prompt cessation of therapy and avoidance of rechallenge.

Topics: 4-Quinolones; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antitubercular Agents; Cephalosporins; Chemical and Drug Induced Liver Injury; Humans; Macrolides; Nitrofurantoin; Penicillins; Sulfonamides; Tetracycline

Topics: Arsenicals; Chemical and Drug Induced Liver Injury; Chloramphenicol; Cholestasis; Coumarins; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Halothane; Humans; Imipramine; Liver; Methotrexate; Methyldopa; Nicotinic Acids; Oxacillin; Phenylbutazone; Testosterone; Tetracycline

Topics: Ampicillin; Antitubercular Agents; Asparaginase; Chemical and Drug Induced Liver Injury; Chloramphenicol; Chlortetracycline; Erythromycin; Griseofulvin; Humans; Liver Diseases; Methicillin; Oleandomycin; Oxytetracycline; Penicillins; Rifampin; Tetracycline

Topics: Aminosalicylic Acids; Animals; Chemical and Drug Induced Liver Injury; Chlorpromazine; Cholestasis; Female; Halothane; Humans; Phenothiazines; Steroids; Testosterone; Tetracycline

Topics: Acetaminophen; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Contraceptives, Oral; Drug Interactions; Halothane; Humans; Hyperbilirubinemia; Methyldopa; Phenothiazines; Tetracycline

Topics: Administration, Oral; Chemical and Drug Induced Liver Injury; Child; Fatty Liver; Female; Glomerular Filtration Rate; Humans; Liver; Male; Pancreatitis; Pregnancy; Pregnancy Complications; Protein Biosynthesis; Tetracycline; Uremia

Topics: Absorption; Acne Vulgaris; Bacteria; Bacteriuria; Bronchial Diseases; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry; Chlortetracycline; Demeclocycline; Drug Eruptions; Humans; Infections; Kidney Diseases; Methacycline; Oxytetracycline; Protein Binding; Tetracycline; Tooth Discoloration

Topics: Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Granuloma; Hemorrhagic Disorders; Humans; Liver; Liver Diseases; Pharmaceutical Preparations; Tetracycline

Topics: Chemical and Drug Induced Liver Injury; Drug Resistance, Microbial; Humans; Tetracycline

Topics: Animals; Arsenicals; Chemical and Drug Induced Liver Injury; Chloroform; Chlorpromazine; Contraceptives, Oral; Drug Hypersensitivity; Humans; Isoniazid; Liver Diseases; Steroids; Tannins; Tetracycline

Topics: Abnormalities, Drug-Induced; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Gastrointestinal Diseases; Hepatitis; Humans; Kidney Diseases; Metabolic Diseases; Pharmacology; Photosensitivity Disorders; Pigmentation Disorders; Proteins; Tetracycline; Tooth Discoloration; Toxicology

Topics: Animals; Chemical and Drug Induced Liver Injury; Humans; Liver; Tetracycline

Although antibiotic-induced hepatotoxicity is recoverable with mild impairment, and some cases were reported to cause morbidity. However, an adjuvant is essential in reducing such incidences.. The aim of this study is to evaluate the protective effect of ascorbic acid on antibiotic induced liver toxicity using liver slices.. Fresh liver slices were incubated with different concentrations of sulfamethoxazole tetracycline and clavulanic acid along with ascorbic acid (200μg/ml) for 2 hours. The liver homogenate was assessed for markers like ALT, AST, MDA and CAT levels. Cytotoxicity assessment was performed using MTT assay.. Incubating liver slices with all three antibiotics shows elevated levels of aminotransferases, MDA and CAT enzyme when compared to the control groups which indicates the level of hepatotoxicity. In the presence of ascorbic acid, the elevated levels of TBARS, ALT and AST were significantly reduced which showcases the protective effect of ascorbic acid. The percentage survival of cell was also shown to have improved while accessed using cell viability assay.. Obtained data suggests that consuming vitamin C or vitamin C containing food like citrus fruits or green leafy vegetables equivalent to 3g/day during antibiotic treatment, perhaps put down the risk of liver toxicity to a greater extent.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Cell Survival; Chemical and Drug Induced Liver Injury; Chickens; Clavulanic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Hepatocytes; Humans; Lipid Peroxidation; Liver; Mice; Oxidative Stress; Primary Cell Culture; Sulfamethoxazole; Tetracycline

The effect of Hypecoum erectum L. extract on the morphofunctional condition of the liver in rats with experimental tetracycline-associated hepatitis was studied. The experiment included 40 albino rats Wistar. The animals treated with tetracycline hydrochloride (1.0 g/kg body weight) were exposed to the extract in a dose of 50 mg/kg for 5 days. On the 7th day of the experiment the following indices were determined: malonic dialdehyde concentration, catalase activity, the levels of ATP, pyruvate and lactate in the liver homogenate, as well as the blood levels of reduced glutathione. The liver pathomorphological investigation was applied. The H. erectum extract was shown to inhibit lipid peroxidation, to increase the activity of the host endogenous antioxidant system, to normalize the hepatocyte energy provision and to limit the liver degeneration.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Catalase; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Glutathione; Lactic Acid; Lipid Peroxidation; Liver; Male; Malondialdehyde; Papaveraceae; Plant Extracts; Protective Agents; Pyruvic Acid; Rats; Rats, Wistar; Tetracycline

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Tetracycline is a commonly used drug for rosacea and subantimicrobial doses may resolve the disease in many cases. Although this class of antibiotics has been linked to adverse effects, tetracycline is considered a safe drug. It can be associated with hepatotoxicity, but its role in these rare cases is unclear.. To report the case of a patient with rare tetracycline-induced hepatotoxicity.. A 49-year-old female with a history of multiple prednisone and methotrexate trials for relapsing polychondritis took oral tetracycline for rosacea. She developed facial and extremity swelling, weakness, and fatigue that corresponded with liver function test (LFT) abnormalities including hypoalbuminemia, low total protein, and elevated alkaline phosphatase. Tetracycline was discontinued and rapid resolution of symptoms and LFT abnormalities occurred after cessation of the drug.. The dose-dependency of rare tetracycline hepatotoxicity and the desire to reduce antibiotic resistance may prompt safe, yet effective, subantimicrobial doses for rosacea.

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Liver Function Tests; Middle Aged; Rosacea; Tetracycline; Treatment Outcome; Withholding Treatment

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Assay; Biological Transport; Cell Line; Cell Membrane; Chemical and Drug Induced Liver Injury; Cytoplasmic Vesicles; Drug Evaluation, Preclinical; Humans; Liver; Rats; Reproducibility of Results; Spodoptera; Transfection; Xenobiotics

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

The hepatoprotective action of Hepatophyt was studied on Wistar rats with experimental hepatitis caused by exposure of the animals to tetracycline. Hepatophyt was administered per os in a dose of 0.1 g/kg. Its significant pharmacotherapeutic action was due to the content of biologically active substances, mainly of polyphenol nature. As natural antioxidants, they provided stabilization of the biomembranes and increased the energetic potential of the hepatic cells and the contractile capacity of the pericanal microfilaments, thus stimulating the synthesis and transport of the cholates and excretion of bilirubin and cholesterol with bile.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Bile; Bilirubin; Chemical and Drug Induced Liver Injury; Cholesterol; Female; Flavonoids; Liver; Male; Phenols; Plant Extracts; Polyphenols; Rats; Rats, Wistar; Tetracycline

An FDA Working Group, along with representatives of PhRMA and the American Association for the Study of Liver Diseases, as well as the Institute of Medicine Report 'To Err is Human: Building a Safer Health Care System' have suggested that post-marketing drug surveillance is a important method to decrease adverse drug events. While tetracyclines are known to cause hepatotoxicity, no post-marketing drug surveillance studies have examined the risk of developing hepatotoxicity with tetracyclines. Therefore, the objective of this study is to determine the difference in risk of hepatotoxicity in patients receiving doxycycline or tetracycline using California Medicaid claims.. This study used a retrospective, matched case-control study using California Medicaid claims data. The cases were defined as recipients who had at least one diagnosis of hepatotoxicity any time from 1 July 1999 to 31 December 2001. One control was identified for each case, matched on age, gender and race. Logistic regression was used to determine the adjusted odds ratio (OR) and 95% confidence intervals for current users and past users of tetracycline and doxycycline. Covariates controlled for in the analysis were age, use of other hepatotoxic drugs, renal dysfunction, pregnancy, and alcohol or illicit drug use.. A total of 3377 cases of hepatotoxicity were identified. Current users and past users of tetracycline had a statistically significant increased risk of developing hepatotoxicity (current use OR 3.70, 95% CI 1.19-11.45; past use OR 2.72, 95% CI 1.26-5.85). Current users or past users of doxycycline did not have an increased risk of developing hepatotoxicity (current use OR 1.49, 95% CI 0.61-3.62; past use OR 1.74, 95% CI 0.99-3.06). Tetracycline was commonly used for acne, acute bronchitis and upper respiratory infections. Doxycycline was commonly used for acute bronchitis, vaginitis and acne.. Doxycycline was potentially less hepatotoxic than tetracycline. Doxycycline could potentially be a safe substitute for tetracycline, when appropriate.

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Doxycycline; Drug Prescriptions; Humans; Insurance Claim Reporting; Medicaid; Patient Selection; Retrospective Studies; Risk Factors; Tetracycline

In experiments on albino rats with toxic hepatitis due to their exposure to tetracycline hydrochloride it was shown that a course of therapeutic and preventive administration of Dig-da-shi-tan decoction had a strong hepatoprotective effect. Antioxidative, membrane integrative, cholagogic and antiinflammatory activities of the remedy were revealed.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Drugs, Chinese Herbal; Rats; Rats, Wistar; Tetracycline

In experimental injury of the liver in Wistar-line white rats induced by tetracycline the course therapeutic and prophylatic administration of the dry extract "Hepatophyt" in a dose of 0.1 g/kg inhibits the negative effect of tetracycline and promotes stimulation of choleretic and antitoxic functions of the liver. The dry extract was derived from the herbal mix of the same name, used in the practice of Tibetan medicine against liver diseases.

Topics: Administration, Oral; Animals; Bile; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Female; Liver; Male; Medicine, Tibetan Traditional; Plant Extracts; Rats; Rats, Wistar; Tetracycline

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Lipid Metabolism; Male; Rats; Tetracycline; Triglycerides

Topics: Animals; Chemical and Drug Induced Liver Injury; Male; Microsomes, Liver; Mitochondria, Liver; Oxidation-Reduction; Rats; Tetracycline

Acute self-limited liver disease has been associated with tetracycline use. However, severe prolonged cholestatic hepatitis and bile duct paucity have not been previously attributed to tetracyclines. Hepatitis, characterized by prolonged jaundice, severe pruritus, and moderate increased transaminase values, occurred within 2 months of ingesting tetracyclines in two female patients. Serum bilirubin levels normalized 12 and 34 months after tetracycline ingestion. Liver histology revealed bile duct paucity, severe cholestasis, and minimal necrosis and inflammation. Tetracyclines may infrequently induce bile duct paucity and prolonged, severe, and reversible cholestasis.

Topics: Adult; Bile Ducts; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Liver; Middle Aged; Necrosis; Tetracycline

Administration of tetracycline was believed to be associated with an adverse drug reaction in a cat. Clinical signs consisted of anorexia, ptyalism, and signs of depression. The most noticeable biochemical abnormality was a markedly high serum alanine transaminase activity. Treatment consisted of vitamin E and selenium injections and feeding via a gastrostomy tube. Abnormalities noticed on histologic examination of hepatic tissue were centrilobular fibrosis, mild diffuse cholangiohepatitis, and mild hepatic lipidosis. The lipidosis was believed to have resulted from tetracycline administration, whereas the more chronic lesions (hepatic fibrosis and mild cholangiohepatitis) were believed to have resulted from preexisting, subclinical hepatic disease. Because serum alanine transaminase activity returned to reference ranges and the anorexia and ptyalism resolved with cessation of tetracycline administration, these abnormalities were believed to have represented an adverse drug reaction. Treatment of the cat with vitamin E and selenium was instituted on the basis of reported preventive and therapeutic effects in albino rats with tetracycline-induced hepatic lesions. Whether these compounds had any role in accelerating clinical recovery in this cat is uncertain.

Topics: Alanine Transaminase; Animals; Cat Diseases; Cats; Chemical and Drug Induced Liver Injury; Female; Liver; Liver Diseases; Selenium; Tetracycline; Vitamin E

Minocycline (25 to 100 micrograms/g) dose dependently increased serum glutamic oxalacetic transaminase, urea, and bilirubin levels, and the hepatic triglyceride content in mice. In animals pretreated with phenobarbital to enhance minocycline metabolism, the effects on liver triglycerides were attenuated, while the changes in serum glutamic oxalacetic transaminase, urea, and bilirubin were enhanced. It is concluded that part of the toxic effects of minocycline may be produced by a metabolite of minocycline.

Topics: Animals; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Doxycycline; Female; Injections, Intravenous; Liver; Mice; Minocycline; Tetracycline; Triglycerides; Urea

Pharmacotherapeutic efficacy of antihepatoxic tea was studied on an experimental model of tetracycline-induced hepatitis. It was concluded that the tea had a marked pharmacotherapeutic effect on the process of tetracycline-induced hepatitis in animals. It lowered the level of the cytolytic syndrome, prevented the progress of cholestasis and stimulated the bile secretory function of the liver. The favourable effect of the plant antihepatotoxic preparation was due to the presence of a complex of its biologically active substances.

Topics: Animals; Chemical and Drug Induced Liver Injury; Hepatitis, Animal; Liver; Male; Plant Extracts; Plants, Medicinal; Rats; Tea; Tetracycline

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Drug Evaluation, Preclinical; Flavonoids; Liver; Liver Diseases; Male; Rats; Tetracycline

Comparative efficacy of hepatoprotective agents in tetracycline affection of the liver is discussed. The affection was induced by daily intragastric administration of the antibiotic in a dose of 0.5 g/kg body weight to Wistar albino rats. The level of the hepatocyte affection and the efficacy of the hepatoprotective agents were judged by changes in the biligenic, glycogen producing, antitoxic and absorbing-excretory functions of the liver and the activity of lipid peroxidation (LPO) and serum enzymes. In acute tetracycline intoxication there was observed suppression of cholopoiesis, induction of LPO, increased permeability of hepatocyte membranes, lowered stabilizing activity of bile and decreased detoxicating and absorbing-excretory capacity of the liver. The highest correcting effect of the hepatoprotective agents was shown with respect to cholopoiesis, carbohydrate metabolism and lipoperoxidation of hepatocyte membranes. The efficacy of silibor in tetracycline affection of the liver was close to that of Essentiale and legalon and superior to that of LIV-52.

Topics: Animals; Bile; Catechin; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Liver; Male; Phosphatidylcholines; Plant Extracts; Rats; Rats, Inbred Strains; Silymarin; Tetracycline

It was shown in the experiments with albino rats that legalon and essentiale had a pronounced hepatoprotective effect in tetracycline affections of the liver. They retarded the increase in the activity of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in blood serum, prevented suppression of cholopoiesis by tetracycline and inhibited lipid peroxidation. The drugs may be used for prevention and treatment of tetracycline affections of the liver.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Drug Evaluation, Preclinical; Drug Therapy, Combination; Flavonoids; Liver Diseases; Male; Phosphatidylcholines; Plants, Medicinal; Rats; Silymarin; Tetracycline

The combined effects of high doses of tetracycline and progesterone on parameters indicative for liver function (serum transaminases and urea, serum and liver triglycerides and cholesterol) have been studied in mice. Apart from disturbance of cholesterol metabolism tetracycline-induced liver dysfunction was not aggravated by progesterone.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cholesterol; Cholesterol Esters; Drug Interactions; Female; Mice; Progesterone; Tetracycline; Triglycerides; Urea

The experiments with male albino rats showed that in toxic doses tetracycline induced affections of the liver evident from activation of transferases and alkaline phosphatases in the blood serum, inhibition of bile secretion, synthesis and secretion of bile acids and excretion of bilirubin and cholesterol with the bile. Moreover, the content of the products of lipid peroxidation in liver homogenates increased. Acute intoxication with ethyl alcohol also induced hepatic disorders. However, they were less pronounced. The intoxication was accompanied by inhibition of cholopoiesis associated with increasing free radical oxidation of lipids. On combined use of tetracycline and ethyl alcohol no potentiation or summation of their hepatotoxicity was observed.

Topics: Alcoholic Intoxication; Animals; Bile; Bile Acids and Salts; Bilirubin; Chemical and Drug Induced Liver Injury; Cholesterol; Free Radicals; Humans; Lipid Peroxides; Liver; Male; Rats; Tetracycline

It was shown in experiments on male albino rats that the plant bioflavonoids flamin, flakumin and tanaflon had hepatoprotective properties in liver function impairment caused by tetracycline intoxication. This was evident from a significant improvement of biliary secretion, synthesis and secretion of bile acids and bile secretion of bilirubin and cholesterol not only in the animals untreated with tetracycline but also in the controls. A decrease in the activity of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in the serum was indicative of the pronounced hepatoprotective effect of the bioflavonoids. They inhibited lipid peroxidation in the hepatocyte membranes evident from a decrease in the content of malonic dialdehyde and diene conjugates in liver homogenates. The antioxidant properties were especially pronounced in tanaflon. Correlation between lipid peroxidation, activity of the transferases and alkaline phosphatase and cholopoiesis both in tetracycline intoxication and in the prophylaxis and treatment with flamin, flakumin and tanaflon was shown.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Flavonoids; Liver; Male; Plant Extracts; Rats; Tetracycline

The seasonal characteristic features of the efficacy of antioxidants in tetracycline affections of the liver were revealed in the experiments with 182 noninbred albino male rats. It was shown that sodium selenite had the most pronounced hepatoprotective effect in autumn and winter, while vitamin E was most effective in spring and summer. The combination of sodium selenite with vitamin E recovered impaired bile excretion in autumn, spring and summer. In winter, the recovery was less effective. It is concluded that the time factor plays a significant role in tetracycline hepatotoxicity and efficacy of antioxidants in tetracycline affections of the liver.

Topics: Animals; Antioxidants; Bile; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Drug Evaluation, Preclinical; Drug Therapy, Combination; Liver Diseases; Male; Rats; Seasons; Selenious Acid; Selenium; Tetracycline; Time Factors; Vitamin E

The seasonal characteristics of the efficacy of vitamin E and sodium selenite in tetracycline affections of the liver were studied on 128 noninbred male albino rats. It was shown that in comparison to vitamin E sodium selenite more actively retarded activation of lipid peroxidation in the liver and activation of alanine aminotransferase and alkaline phosphatase in the blood serum in autumn and winter. A more pronounced inhibition of the increased levels of the dienic conjugates and alanine aminotransferase was observed in spring and summer and malonic dialdehyde and aspartate aminotransferase in summer by tocopherol acetate as compared to sodium selenite. The level of the thiol-disulfide equilibrium on the separate use of the drugs in spring and summer was higher than the control one. However, it did not reach the control level in autumn and winter. The combined use of sodium selenite and vitamin E prevented the toxic effect of tetracycline on the liver in autumn, spring and summer. Still, in the winter no such prevention was observed. The mechanisms of the seasonal differences in the tetracycline effect on the liver and the efficacy of the antioxidants in such affections are discussed.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Free Radicals; Lipid Peroxides; Liver; Male; Rats; Seasons; Selenic Acid; Selenium; Selenium Compounds; Tetracycline; Vitamin E

It was shown on 99 male albino rats that vitamin E, sodium selenite and Astragalus. L. infusion used separately lowered the toxic effect of tetracycline on the liver, while the use of vitamin E in combination with sodium selenite or Astragalus L. infusion prevented such an effect of the antibiotic. This was evident from the decreased levels of lipid peroxidation products, i.e. diene conjugates and malonic dialdehyde in the blood and liver, and a simultaneous increase in the ratio of sulfhydryl and disulfide groups in these biosubstrates. Parallelism of the changes in these indices of the blood and liver was observed. It is suggested that lipid peroxidation plays an important part in the pathogenesis of liver affection with tetracyclines. The combined use of vitamin E and selenium-containing drugs is considered advisable for the prophylaxis and treatment of such affections.

Topics: alpha-Tocopherol; Animals; Chemical and Drug Induced Liver Injury; Chlortetracycline; Drug Evaluation, Preclinical; Lipid Peroxides; Liver; Male; Oxidation-Reduction; Plant Extracts; Rats; Selenious Acid; Selenium; Tetracycline; Tocopherols; Vitamin E

Studies on albino rats showed that high doses of tetracycline-induced damages of the liver evident from increased activity of serum enzymes (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) and inhibition of bile secretion, synthesis and secretion of bile acids and cholesterol excretion. Administration of vitamin E, sodium selenite, infusion of Astragalus L. and especially vitamin E combinations with sodium selenite markedly or completely arrested the occurrence of hepatotoxic properties of tetracycline. It is suggested that the use of vitamin E combinations with selenium-containing preparations is advisable in the prophylaxis and treatment of tetracycline-induced damages of the liver.

Topics: Animals; Bile; Chemical and Drug Induced Liver Injury; Chlortetracycline; Drug Evaluation, Preclinical; Liver; Liver Diseases; Male; Plant Extracts; Rats; Selenious Acid; Selenium; Tetracycline; Vitamin E

It was shown on pubertal albino rats that the intensity of excretion with the bile of radioactive Bengal rose was different at different seasons: the maximum and minimum levels were observed in winter and summer, respectively. When the liver was affected with tetracycline, this process was suppressed especially in summer. The use of antioxidants, such as tocopherol acetate in combination with sodium selenite promoted the recovery of liver excretion function in winter, spring and autumn. In summer, the recovery was only partial.

Topics: Animals; Bile; Chemical and Drug Induced Liver Injury; Liver; Liver Diseases; Male; Rats; Rose Bengal; Seasons; Selenious Acid; Selenium; Tetracycline; Vitamin E

Topics: Anesthesia, General; Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged; Tetracycline

The aim of the present investigation was to determine whether tetracycline accelerated the hepatic toxicity of portacaval anastomosis and whether this could be reflected by changes in pharmacokinetics of the drug. Side-to-side portacaval shunts were constructed and converted to end-to-side by ligating the hepatic side of the portal vein in dogs. The results of this study showed that the i.v. infusion of tetracycline (50 mg/kg) to shunted animals caused rapid deterioration in hepatic and renal functions followed by the eventual transition of these animals from stage I to stage II liver disease. This was reflected by a 3- to 6-fold increase in the serum level of bilirubin, alkaline phosphatase, serum glutamic-oxalacetic transaminase, blood urea nitrogen and creatinine as compared with the levels of those produced in serum of dogs before and after the construction of the shunt before the administration of tetracycline. Kinetic analysis revealed a significant prolongation in the elimination half-life (38.2 +/- 4.2 hr) of the shunted dogs as compared with controls (14.5 +/- 1.5 hr) after the i.v. administration of tetracycline. This was accompanied by an appreciable reduction of elimination rate constant. In contrast to shunted animals, control animals exhibited no behavioral side effects after the administration of tetracycline.

Topics: Animals; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Dogs; Kidney Diseases; Kinetics; Male; Portacaval Shunt, Surgical; Tetracycline; Time Factors

Topics: Adolescent; Ampicillin; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Therapy, Combination; Female; Humans; Liver; Male; Middle Aged; Oleandomycin; Tetracycline

The effects of numerous drugs and drug metabolites on the liver cleansing system are reviewed. Topics covered include metabolite-related drug toxicity, drug hypersensitivity, chronic liver disease, and hepatic tumors and oral contraceptives (OCs). Currently available evidence implicating OCs in the pathogenesis of hepatic tumors is large but inconclusive. However, both benign and malignant hepatic tumors have been encountered in women taking OCs, inviting further speculation that in some patients malignant transformation may occur. In a study covering 1937-1976, only 400 cases of hepatic cell adenoma and focal nodular hyperplasia were reported in patients, not taking OCs, but more than 200 cases have been reported in women taking OCs in the past 3 years. This may, however, present a biased view in favor of reporting contraceptive-associated tumors. An 8-year prospective study in Great Britain has so far not revealed tumors either in women receiving these agents or in any of their control groups. Studies with animals have been inconclusive so far; norethynodrel with mestranol (Enovid) failed to increase the incidence of hepatic tumors in susceptible mice, though a number of C17 alpha alkyl derivatives of testosterone will increase the expected frequency of hepatic tumors in susceptible mice. The reported regression of benign hepatic tumors on withdrawal of therapy and recurrences of tumors after primary resection in patients who continued to use such agents support the etiological role of OCs. However, more accurate statistics, which can only be obtained by large regional or national registries of hepatic tumors, are essential before this problem can be adequately evaluated.

Topics: Acetaminophen; Adult; Animals; Chemical and Drug Induced Liver Injury; Chronic Disease; Contraceptives, Oral; Drug Hypersensitivity; Female; Halothane; Humans; Isoniazid; Liver; Liver Neoplasms; Methotrexate; Pharmaceutical Preparations; Tetracycline

Topics: Adrenal Cortex Hormones; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Humans; Liver; Methotrexate; Pyrrolizidine Alkaloids; Tetracycline; Vitamin A

Drug hepatitis emphasized the importance of a careful history including the question to the use of laxatives in all patients with both acute and chronic hepatitis. From predictable and unpredictable hepatotoxicity we should learn to be alert to the possibility of new and unrecorded hepatic lesions resulting from drugs and other chemical or environmental toxins.

Topics: Acetaminophen; Acute Disease; Amanita; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Halothane; Humans; Liver; Methane; Methyldopa; Mushroom Poisoning; Oxyphenisatin Acetate; Tetracycline

A large number of chemical agents, administered for therapeutic or diagnostic purposes, can produce various types of hepatic injury by several mechanisms. Some agents are intrinsically hepatotoxic, and others produce hepatic injury only in the rare, uniquely susceptible individual. Idiosyncrasy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberation of the host permitting the accumulation of hepatotoxic metabolites. The syndromes of hepatic disease produced by drugs have been classified hepatocellular, hepatocanalicular, mixed and canalicular. Measurement of serum enzyme activities has provided a powerful tool for studies of hepatotoxicity. Their measurement requires awareness of relative specificity, knowledge of the mechanisms involved, and knowledge of the relationship between known hepatotoxic states and elevated enzyme activities.

Topics: Anti-Bacterial Agents; Anticonvulsants; Antidepressive Agents; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Contraceptives, Oral, Hormonal; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Ethanol; Female; Humans; Liver Diseases; Mitochondria, Liver; Rifampin; Steroids; Tetracycline; Tranquilizing Agents

Philosophic concepts and pragmatic approaches toward improved understanding of the effect of drugs in the hepatocyte are reviewed. No set pattern of studies is advocated but rather observations are encouraged within the framework of studies that provide for varied exposure of the hepatocyte. Clinical usage should be imitated to provide earliest possible indications of toxicity in man. The need for definitive characterization through utilization of appropriate methodology derived from cross-fertilization of related disciplines is stressed. Both minimal and maximal dose effects should be established. Selected use of electron microscopy has become essential for characterizing responses of the liver to injury. The advantages of the toluidine blue-stained Epon "thick" sections are emphasized. Such observations are used to implement the utility of serial biopsies from the beagle dog prior to and during long-term study of potential hepatic injury. Examples of the critical effects of drug concentration within the hepatocyte are presented.

Topics: Animals; Chemical and Drug Induced Liver Injury; Dogs; Female; Humans; Liver; Liver Diseases; Microscopy, Electron; Rats; Tetracycline

Topics: Age Factors; Chemical and Drug Induced Liver Injury; Child, Preschool; Drug Eruptions; Drug Hypersensitivity; Humans; Liver; Pediatrics; Societies, Medical; Tetracycline; Tooth Discoloration

Topics: Acute Kidney Injury; Adult; Chemical and Drug Induced Liver Injury; Female; Humans; Hypoglycemia; Liver Diseases; Male; Middle Aged; Military Medicine; Tetracycline; United States

Twenty-six patients are described who had otherwise unexplained hepatitis after halothane anaesthesia. Twenty-four (92 per cent) had multiple exposures, and 11 (42 per cent) died. In eight patients a characteristic pattern of delayed postoperative pyrexia has been found. Obesity was common, but the clinical features and complications were those of any severe hepatitis. Obesity, early onset of jaundice after anaesthesia, and low thrombotest, were associated with a fatal outcome. None of those who were followed up after recovery developed clinical or biochemical evidence of chronic liver disease. The differential diagnosis of postoperative jaundice is discussed, and it is shown that halothane patients with hepatic encephalopathy are significantly older (25.4 plus or minus 11.6 years) than those referred to this unit with viral hepatitis of equal severity (34.1 plus or minus 16.4 years). Unexplained jaundice or delayed pyrexia after a previous administration of halothane should be a contraindication to its further use.

Topics: Adult; Aged; Anesthesia, General; Bilirubin; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Glucose; Halothane; Humans; Jaundice; Male; Middle Aged; Neomycin; Penicillins; Phenothiazines; Phenytoin; Postoperative Complications; Sulfonamides; Tetracycline; Trimethoprim

Topics: Acetaminophen; Adult; Alcoholism; Azathioprine; Bilirubin; Chemical and Drug Induced Liver Injury; Chlorpromazine; Cholestasis; Dihydroxyphenylalanine; Enzyme Induction; Fatty Liver; Female; Granuloma; Halothane; Hepatomegaly; Humans; Male; Middle Aged; Oxyphenisatin Acetate; Pregnancy; Sulfonamides; Tetracycline

Topics: Agranulocytosis; Amphotericin B; Anemia, Aplastic; Anemia, Hemolytic; Anti-Bacterial Agents; Ataxia; Bacitracin; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Chloramphenicol; Deafness; Gastrointestinal Diseases; Gentamicins; Humans; Kanamycin; Kidney Diseases; Leukopenia; Lung Diseases; Neomycin; Neuromuscular Diseases; Nitrofurantoin; Optic Neuritis; Peripheral Nervous System Diseases; Skin Diseases; Streptomycin; Sulfonamides; Tetracycline; Thrombocytopenia; Vertigo

Topics: Chemical and Drug Induced Liver Injury; Chloramphenicol; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Hematuria; Humans; Nalidixic Acid; Neurologic Manifestations; Nitrofurantoin; Penicillins; Skin Manifestations; Sulfonamides; Sweden; Tetracycline

Topics: Ampicillin; Candida albicans; Candidiasis; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Diagnosis, Differential; Fatty Liver; Female; Halothane; Humans; Hydronephrosis; Injections, Intravenous; Jaundice; Liver; Nitrofurantoin; Postoperative Complications; Sulfisoxazole; Tetracycline; Urinary Tract Infections; Vesico-Ureteral Reflux

Topics: Anemia, Hemolytic; Chemical and Drug Induced Liver Injury; Disseminated Intravascular Coagulation; Fatty Liver; Female; Humans; Kidney Failure, Chronic; Liver; Pregnancy; Pregnancy Complications, Hematologic; Tetracycline

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Female; Hepatitis A; Humans; Liver Diseases; Male; Recurrence; Tetracycline

Topics: Adult; Age Factors; Bilirubin; Cell Membrane; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Female; Halothane; Humans; Infant, Newborn; Liver; Liver Cirrhosis; Male; Methotrexate; Microsomes, Liver; Pharmaceutical Preparations; Pregnancy; Tetracycline

Topics: Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Cholestasis; Contraceptives, Oral; Fatty Liver; Female; Halothane; Hepatitis A; Humans; Jaundice; Jaundice, Chronic Idiopathic; Liver; Liver Cirrhosis; Liver Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Rupture, Spontaneous; Tetracycline

Topics: Adipose Tissue; Brain Diseases; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hepatitis; Humans; Infant; Kidney Diseases; Liver; Tetracycline; Virus Diseases

Topics: Abnormalities, Drug-Induced; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dental Enamel Hypoplasia; Female; Fetus; Humans; Infant; Infant, Newborn; Maternal-Fetal Exchange; Photosensitivity Disorders; Pregnancy; Respiratory Tract Infections; Tetracycline

Topics: Adrenal Cortex Hormones; Adult; Antigens, Viral; Chemical and Drug Induced Liver Injury; Chloramphenicol; Female; gamma-Globulins; Germany, West; Hepatitis A; Herpes Simplex; Humans; Idoxuridine; Male; Pregnancy; Simplexvirus; Sweden; Tetracycline; Trifluoperazine

Topics: Adult; Chemical and Drug Induced Liver Injury; Drug Interactions; Exanthema; Humans; Liver Function Tests; Male; Penicillins; Sepsis; Stevens-Johnson Syndrome; Sulfonamides; Tetracycline

Topics: Adolescent; Adult; Ampicillin; Anemia, Hemolytic; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Diarrhea; Drug Eruptions; Epilepsy; Erythromycin; Female; Hepatic Encephalopathy; Humans; Hyperkalemia; Kanamycin; Lincomycin; Male; Middle Aged; Penicillins; Potassium; Sodium; Tetracycline

Topics: Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Tetracycline

Topics: Acidosis, Renal Tubular; Aged; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hemorrhagic Disorders; Humans; Hypoproteinemia; Jaundice; Kidney Diseases; Male; Middle Aged; Tetracycline; Uremia

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Aspartate Aminotransferases; Bacteroides; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Enterococcus faecalis; Female; Humans; Hyperbilirubinemia; Jaundice; Liver; Liver Diseases; Liver Function Tests; Male; Mercaptopurine; Postoperative Complications; Pseudomonas; Sepsis; Staphylococcus; Streptococcus; Tetracycline; Transfusion Reaction

Topics: Adolescent; Adult; Animals; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Demeclocycline; Dogs; Female; Humans; Kidney Diseases; Male; Methacycline; Oxytetracycline; Photosensitivity Disorders; Pregnancy; Tetracycline; Tooth Calcification; Tooth Discoloration

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Humans; L-Lactate Dehydrogenase; Liver; Male; Meningioma; Middle Aged; Phenytoin; Tetracycline

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Liver Diseases; Male; Necrosis; Ornithine Carbamoyltransferase; Perfusion; Rats; Tetracycline

Topics: Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Adult; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy; Fatty Liver; Female; Hepatitis; Hepatitis A; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Tetracycline; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Electrons; Hepatitis; Intestinal Obstruction; Microscopy; Microscopy, Electron; Pathology; Tetracycline; Toxicology

Topics: Amides; Calcium; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chloroform; Edetic Acid; Fluorescence; Formates; Hepatitis; Hepatitis A; Metabolism; Necrosis; Pathology; Pharmacology; Promethazine; Rats; Research; Sulfhydryl Compounds; Tetracycline; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Humans; Pyelonephritis; Tetracycline

Topics: Anesthesia; Atropine; Barbiturates; Chemical and Drug Induced Liver Injury; Colonic Neoplasms; Halothane; Hepatitis; Massive Hepatic Necrosis; Necrosis; Neomycin; Phenazocine; Postoperative Complications; Promethazine; Sigmoidoscopy; Surgical Procedures, Operative; Tetracycline; Toxicology

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Child; Chloramphenicol; Chlortetracycline; Fatty Liver; Female; Hepatitis; Oxytetracycline; Pregnancy; Pregnancy Complications; Prochlorperazine; Tetracycline; Toxicology

Topics: Anti-Bacterial Agents; Candidiasis; Chemical and Drug Induced Liver Injury; Chloramphenicol; Diagnosis, Differential; Erythromycin; Halothane; Hepatitis; Hydrocortisone; Hypertension; Kidney Diseases; Metaraminol; Novobiocin; Pathology; Pyelonephritis; Surgical Procedures, Operative; Surgical Wound Infection; Tetracycline; Toxicology; Tracheotomy; Urinary Bladder Neoplasms; Urinary Diversion

Topics: Anti-Bacterial Agents; Black People; Chemical and Drug Induced Liver Injury; Chlortetracycline; Demeclocycline; Female; Hepatitis; Hepatitis A; Humans; Kidney Diseases; Liver; Maternal-Fetal Exchange; Oxytetracycline; Pharmacology; Pregnancy; Pregnancy Complications; Tetracycline; Tetracyclines; Tooth; Toxicology; Urine

Topics: Anaphylaxis; Anti-Bacterial Agents; Aspirin; Chemical and Drug Induced Liver Injury; Chloramphenicol; Colistin; Drug Eruptions; Drug Hypersensitivity; Hepatitis; Nitrofurantoin; Novobiocin; Penicillins; Polymyxins; Protein Synthesis Inhibitors; Serum Sickness; Streptomycin; Tetracycline; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hepatitis; Liver Diseases; Pathology; Pregnancy; Pregnancy Complications; Pyelonephritis; Tetracycline; Toxicology

Topics: Anemia; Anemia, Aplastic; Anti-Bacterial Agents; Antibiotics, Antitubercular; Bacitracin; Chemical and Drug Induced Liver Injury; Chloramphenicol; Chlortetracycline; Erythromycin; Hearing Disorders; Hepatitis; Kidney Diseases; Neomycin; Oleandomycin; Streptomycin; Tetracycline; Toxicology

Topics: Carbon; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Growth; Hepatitis; Hepatitis A; Mineral Waters; Pharmacology; Rats; Research; Tetracycline; Toxicology; Water

Topics: Administration, Intravenous; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Hepatitis; Histocytochemistry; Humans; Liver Diseases; Pathology; Pregnancy; Pregnancy Complications; Pyelonephritis; Research; Tetracycline

Topics: Chemical and Drug Induced Liver Injury; Fatty Liver; Hepatitis; Insulin; Liver Glycogen; Pharmacology; Rats; Research; Tetracycline; Toxicology