oxytetracycline--anhydrous and Chemical-and-Drug-Induced-Liver-Injury

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

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: 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

Oxytetracycline (OTC) and Quinocetone (QCT) are antimicrobials, whose residues have been found in food and environment. These two are sometimes used simultaneously in livestock and aquaculture, potentially resulting in the simultaneous consumption of multi-antimicrobials by consumers. However, the combined toxic effects of this phenomenon have yet to be addressed. Since the liver is a major target of both OTC and QCT, we tested their hepatotoxic effect using both cell cultures and animal models. Results showed that the QCT (5-25 μM) or OTC (20-100 μM) treatments alone caused dose-dependent reductions in cell numbers, while their combination strongly further enhanced inhibitory effects. Mechanistically, the combination enhanced the generation of reactive oxygen species (ROS) and activated mitochondrial cell death pathways. It also showed that the combination of OTC (800 mg/kg, i.g., 5d) and QCT (5000 mg/kg, i.g., 5d) resulted in significantly enhanced liver toxicity in C57BL/6N mice, the serum alanine transaminase (ALT) and aspartate transaminase (AST) were significantly increased by the OTC/QCT. These findings indicate the necessity of considering the combined toxicity of these two antimicrobials in safety assessments.

Topics: Animals; Chemical and Drug Induced Liver Injury; Mice; Mice, Inbred C57BL; Oxytetracycline; Quinoxalines; Reactive Oxygen Species

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market.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

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

Naringenin is a naturally occurring citrus flavanone, which has been reported to have a wide range of pharmacological properties. The present work was carried out to evaluate the effect of naringenin on antioxidant and lipid peroxidation status in liver of oxytetracycline-intoxicated rats. Intraperitonial administration of oxytetracycline 200 mg/kg for 15 days resulted a significant elevation in serum hepatospecific markers such as aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and bilirubin and the levels of lipid peroxidation markers (thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides) in liver. Oxytetracycline also caused a significant reduction in the activities of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione (GSH), vitamin C and vitamin E in liver. Oral administration of naringenin (50 mg/kg b.w.t.) with oxytetracycline significantly decreased the activities of serum aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and the levels of bilirubin along with significant decrease in the levels of lipid peroxidation markers in the liver. In addition, naringenin significantly increased the activities of superoxide dismutase, catalase and GSH peroxidase as well as the level of GSH, vitamin C and vitamin E in liver of the oxytetracycline-treated rats. Our results demonstrate that naringenin exhibited antioxidant property and decrease the lipid peroxidation against oxytetracycline-induced oxidative stress in liver.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Catalase; Chemical and Drug Induced Liver Injury; Flavanones; Glutathione; Glutathione Peroxidase; Lipid Peroxidation; Liver; Liver Diseases; Male; Oxidative Stress; Oxytetracycline; Rats; Rats, Wistar; Superoxide Dismutase

This experimental project was designed to evaluate: a) the capacity of oxytetracycline to induce microvesicle steatosis in rat liver when administered over long time periods; b) whether female rats are more susceptible to this substance, and c) the possible ultrastructural alterations and their relation to the mechanisms of steatosis.. Sixty-two Wistar rats (31 males and 31 females) were distributed into six groups, two control groups and four experimental groups. The experiment lasted three months. Blood and hepatic tissue samples were extracted under anesthesia for morphologic study (optical and electron microscopy).. Steatosis was of the microvesicular type with mainly periportal distribution. Steatosis developed in the treated groups and the degree was significantly greater in the females (p = 0.004). No relationship was found with dose. Ultrastructural study revealed microsome dilation in all experimental groups, with no differences according to sex. Despite the steatosis, no proliferation of peroxisomes or mitochondrial alterations were observed.. Oxytetracycline produced predominantly periportal microvesicular hepatic steatosis, appearing mostly in the females. As a possible mechanism for tetracycline-induced steatosis, we postulate a decrease in mitochondrial, peroxisome and microsome function as a result of protein synthesis inhibition in these cell compartments.

Topics: Animals; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Liver; Male; Microcirculation; Oxytetracycline; Rats; Rats, Wistar

To estimate the frequency of cholestatic hepatitis of uncertain origin occurring among persons who had recently received flucloxacillin, a drug which has recently been reported as causing cholestatic hepatitis, and to compare this frequency with that related to oxytetracycline, a drug which has seldom been reported as causing this disorder.. A retrospective cohort study using data automatically recorded on general practitioners' office computers.. Some 600 general practices in the United Kingdom.. 132,087 people who received flucloxacillin and 145,844 people who received oxytetracycline.. Clinically documented cholestatic hepatitis of uncertain origin diagnosed 1-45 days after a prescription for flucloxacillin, 46-90 days after a prescription for flucloxacillin and, for comparison, 1-45 days after a prescription for oxytetracycline.. There were 10 cases of cholestatic hepatitis of uncertain origin diagnosed within 45 days of receiving flucloxacillin that were either characteristic of or consistent with a syndrome recently described as being associated with this drug; there was one such case 46-90 days after a prescription for flucloxacillin; there were three such cases 1-45 days after a prescription for oxytetracycline.. Flucloxacillin is a likely cause of cholestatic hepatitis. The risk is estimated to be in the range of 7.6 per 100,000 users (95% confidence interval, 3.6-13.9).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Child; Cholestasis; Cohort Studies; Female; Floxacillin; Humans; Male; Middle Aged; Oxytetracycline; Retrospective Studies

Isolated rat hepatocytes in suspension were studied with regard to various measures of hepatic toxicity. We compared enzyme leakage (ASAT, ALAT, LDH), cell viability (trypan blue exclusion), intracellular ATP content, and incorporation of 14C-valine into stationary and export proteins while the cells were exposed to six different drugs at two different concentrations. The drugs were oxytetracycline, paracetamol, carbon tetrachloride, ethanol, methotrexate and fentanyl. The results were compared to known in vivo responses, in particular to see whether concentrations resulting in dose-related in vivo effects would similarly affect the functions tested in vitro. Leakage of enzymes exhibited a graded increase with a corresponding rise in the concentration of oxytetracycline and carbon tetrachloride. Reduction in incorporation of 14C-valine into cell and medium proteins showed a similar graded effect with rising concentrations of paracetamol, carbon tetrachloride, and ethanol. Intracellular levels of ATP gradually decreased with increasing concentrations of carbon tetrachloride and ethanol. An obvious reduction in viability was only registered with increasing concentrations of carbon tetrachloride, while paracetamol tended to give a similar response. We found no major discrepancies between already known in vivo effects and our in vitro results when testing paracetamol, carbon tetrachloride, ethanol, methotrexate, and fentanyl. We could not, however, demonstrate inhibition of protein synthesis by oxytetracycline at the concentrations tested. No single measurement was adequate for testing all drugs. The test of 14C-valine incorporation into hepatocyte export proteins plus LDH leakage seemed to constitute a useful combination in detecting drug toxicity in hepatocyte suspensions.

Topics: Acetaminophen; Adenosine Triphosphate; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Cell Survival; Chemical and Drug Induced Liver Injury; Ethanol; Fentanyl; In Vitro Techniques; L-Lactate Dehydrogenase; Liver; Methotrexate; Oxytetracycline; Protein Biosynthesis; Rats; Valine

Topics: Agranulocytosis; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Hypersensitivity; Female; Humans; Lymphocyte Activation; Middle Aged; Oxytetracycline; Prednisolone

Topics: Animals; Chemical and Drug Induced Liver Injury; Female; Male; Nandrolone; Oxytetracycline; Rats; Sex Factors

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: 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; 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: Aminosalicylic Acid; Aminosalicylic Acids; Biopsy; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Hypersensitivity; Ethionamide; France; Hepatitis; Isoniazid; Japan; Kanamycin; Liver Function Tests; Oxytetracycline; Pathology; Prednisone; Streptomycin; Sulfisoxazole; Toxicology; Tuberculosis

Topics: Acute Kidney Injury; Anuria; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Dyspnea; Hepatitis; Myocarditis; Nephrosis; Oxytetracycline; Pathology; Pericarditis; Pleural Effusion; Renal Insufficiency; Sulfadimethoxine; Thoracic Injuries; Toxicology; Wounds, Gunshot

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Chloramphenicol; Chlortetracycline; Liver; Oxytetracycline; Streptomycin

Topics: Animals; Chemical and Drug Induced Liver Injury; Chloramphenicol; Chlortetracycline; Dogs; Liver; Mice; Oxytetracycline

Topics: Chemical and Drug Induced Liver Injury; Chlortetracycline; Chronic Disease; Fatty Liver; Liver Diseases; Oxytetracycline