ethionamide and Chemical-and-Drug-Induced-Liver-Injury

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

During treatment of multibacillary leprosy with the combination rifampin (RMP) 600 mg, ethionamide (ETH) 500 mg, and either dapsone (DDS) or clofazimine (CLO) 100 mg, hepatotoxicity was observed in 4.5% of 596 patients. Hepatitis appeared after 5-186 days, with a mean of 93 days and a median of 76 days. Mortality was 26%. ETH and DDS or CLO were administered daily in all regimens in which hepatitis occurred. RMP was given either daily or daily during the first two weeks or eight weeks, followed by a once-weekly dose. It is concluded that the combination RMP + ETH is the toxic component. In some patient groups there was a high correlation of toxicity with age. A regimen in which RMP was administered only twice a week during three months was not accompanied by hepatotoxicity. Future studies should show if reduction of the daily dose of ETH or reduction of the duration of the administration of RMP + ETH might reduce the incidence of hepatotoxicity while conserving the efficacy.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Female; Humans; Leprosy; Male; Middle Aged; Prospective Studies; Rifampin

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Tolerance; Ethionamide; Humans; Isoniazid; Middle Aged; Tuberculosis, Pulmonary

Topics: Aged; Amides; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethionamide; Gastrointestinal Diseases; Humans; Isonicotinic Acids; Liver Function Tests; Male; Middle Aged; Nervous System Diseases; Skin Diseases; Tuberculosis, Pulmonary

The aim of the study was to elucidate the profile of adverse drug reactions (ADRs) associated with second-line anti-tubercular treatment for drug-resistant tuberculosis.. ADR profile of diagnosed drug-resistant tuberculosis cases on supervised second-line anti-tubercular drug regimen under Programmatic Management of Drug-resistant Tuberculosis under Revised National Tuberculosis Control Programme, were studied over two years' period. Adverse reactions were categorised into mild, moderate and severe types with subsequent systematic data-analysis.. Out of total 207 patients in the study, 81.16% reported with adverse drug reactions. Out of total 195 adverse events, 63.58%, 18.46% and 17.94% were of mild, moderate and severe types respectively. Gastrointestinal events, hepatitis, hearing impairment, arthralgia, psychosis, hypothyroidism, visual disturbances, giddiness, peripheral neuropathy, skin reactions, swelling or pain at injection site, anorexia and sleep disturbances were important amongst these. High proportion of drug and/or alcohol abuse was an important observation. The offending drug(s) had to be terminated in 12.08% of the patients.. Early detection, management and pharmaco-vigilance reporting of ADRs remain key factors in the management of drug-resistant tuberculosis with remarkable relevance of the need for early diagnosis and treatment of 'drug-sensitive tuberculosis', to prevent emergence of drug-resistant tuberculosis.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Arthralgia; Ataxia; Chemical and Drug Induced Liver Injury; Child; Cycloserine; Drug Eruptions; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Gastrointestinal Diseases; Hearing Loss; Humans; Hypothyroidism; India; Kanamycin; Levofloxacin; Male; Middle Aged; Peripheral Nervous System Diseases; Psychoses, Substance-Induced; Pyrazinamide; Severity of Illness Index; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vision Disorders; Young Adult

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

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

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Pyrazinamide; Risk Factors; Tuberculosis, Pulmonary

The possible development of hepatotoxic effects as a result of high dosages of isoniazid, rifampin, pyrazinamide, and ethionamide was assessed in 56 young children (median age, 22 months) treated for severe tuberculous meningitis (TBM). Only one of the 56 children became jaundiced, probably as result of hepatitis A infection. Of 33 children observed for at least eight weeks, only five (15%) had normal serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase levels throughout, but in only three patients were AST or ALT values greater than 200 U/L, and enzyme levels tended to normalize toward the end of the period. In this group of 33 children, those at stage III TBM had higher enzyme levels than did those at stage II. The remaining 23 children were observed for a mean period of only four weeks, and 18 (75%) had at least one abnormal liver function test result.

Topics: Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child, Preschool; Drug Combinations; Ethionamide; gamma-Glutamyltransferase; Humans; Infant; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Topics: Acute Disease; Adult; Aged; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Halothane; Humans; Liver; Lymphocyte Activation; Male; Middle Aged; Necrosis; Prognosis; Tegafur

The effect of disulfiram (DSF), sodium diethyldithiocarbamate (DDTC), methyl diethyldithiocarbamate (Me-DDTC), and ethionamide on the hepatotoxic response of alpha-naphthylisothiocyanate (ANIT) was studied in the rat. The hyperbilirubinemic response of ANIT was significantly inhibited by ip or po DSF pretreatment. A more marked inhibition of toxicity occurred when DSF was given via ip injection. DDTC, Me-DDTC, and ethionamide significantly inhibited ANIT-induced hyperbilirubinemia. Me-DDTC is approximately three times more potent than DDTC as an inhibitor of toxicity. Approximately 16% of a dose of [35S]ANIT was excreted in the urine as inorganic sulfate 48 hr after dosing. Me-DDTC administered simultaneously with [35S]ANIT significantly reduced urinary [35S]sulfate excretion in the first 24 hr. Ethionamide reduced urinary [35S]sulfate excretion. Pretreatment with phenobarbital which stimulates toxicity in vivo increased urinary [35S]sulfate excretion 300% in the first 12 hr. Thus, this study shows that agents which sensitize or protect rats from the toxic effects of ANIT, correspondingly stimulate or inhibit the oxidative desulfuration of [35S]ANIT in vivo.

Topics: 1-Naphthylisothiocyanate; Animals; Chemical and Drug Induced Liver Injury; Disulfiram; Ditiocarb; Ethionamide; Male; Rats; Rats, Inbred Strains; Sulfates; Thiocarbamates; Thiocyanates

Topics: Aminoglycosides; Anti-Bacterial Agents; Arsphenamine; Cephalosporins; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Japan; Liver Diseases; Penicillins; Thorium Dioxide

Topics: Aminosalicylic Acids; Animals; Antitubercular Agents; Capreomycin; Chemical and Drug Induced Liver Injury; Cycloserine; Deafness; Drug Hypersensitivity; Ethambutol; Ethionamide; Gastrointestinal Diseases; Goiter; Humans; Isoniazid; Kanamycin; Liver; Mental Disorders; Mice; Nervous System Diseases; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis; Viomycin

Drug hepatitis occurred in 0-32 per cent of 7492 patients receiving antituberculous therapy, while the overall incidence of drug reactions was estimated at 9 per cent. PAS was the most common cause of drug hepatitis among the 38 patients analysed. The clinical, biochemical and haematological picture of antituberculous drug hepatitis was found to be fairly uniform. However, the patients with definite PAS hepatitis had lower SGOT values than those in whom there was uncertainty whether PAS or INH was implicated. Premonitory symptoms were present in all but four patients before the onset of jaundice. One or more of the features associated with dry hypersensitivity reactions, such as fever, rashes, lymphadenopathy, arthralgia, leucocytosis, eosinophilia and atypical monocytes were present in 89 per cent of cases so that confusion with viral hepatitis seldom arose. Sensitization time was less than three months in all except three patients, who were considered to be suffering from viral hepatitis. While no patients with PAS hepatitis died, the overall mortality was 17 per cent. A review of the literature stresses the frequency of asymptomatic elevations of SGOT, the value of clinical surveillance during the early months of therapy and the importance of stopping all therapy immediately warning symptoms appear.

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Ethambutol; Ethionamide; Female; Gastrointestinal Diseases; Humans; Isoniazid; Jaundice; Lymphatic Diseases; Male; Pyrazinamide; Skin Diseases; Streptomycin; Thioacetazone; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Isonicotinic Acids; Jaundice; Prothionamide

Topics: Aminosalicylic Acids; Antitubercular Agents; Arthritis; Chemical and Drug Induced Liver Injury; Child; Cycloserine; Drug Hypersensitivity; Drug Resistance, Microbial; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Liver; Lupus Vulgaris; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Viomycin

Topics: Aspartate Aminotransferases; Biopsy; Chemical and Drug Induced Liver Injury; Ethionamide; Follow-Up Studies; Humans; Liver; Long-Term Care; Necrosis; Pyrazinamide; Tuberculosis

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Liver; Necrosis; Pyrazinamide; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Ethambutol; Ethionamide; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Isoniazid; Liver; Pyrazinamide; Streptomycin; Thioacetazone; Tuberculosis

Topics: Adolescent; Adult; Aged; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Resistance, Microbial; Ethionamide; Female; Gastrointestinal Diseases; Humans; Kanamycin; Male; Middle Aged; Psychoses, Substance-Induced; Pyrazinamide; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Eruptions; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Ethionamide; Female; Gastrointestinal Diseases; Humans; Hypothyroidism; Isoniazid; Kanamycin; Male; Microbial Sensitivity Tests; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Viomycin

Topics: Alanine Transaminase; Amides; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Ethionamide; Humans; Isonicotinic Acids; Liver Diseases; Sulfides; Tablets, Enteric-Coated

Topics: Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Humans; Liver; Liver Function Tests; Male; Tuberculosis, Pulmonary

Topics: Aged; Biopsy; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Humans; Isoniazid; Jaundice; Liver; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Biopsy; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Liver Diseases; Necrosis; Pyrazinamide; Tuberculosis, Pulmonary

Topics: Acute Disease; Adult; Alcoholism; Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Liver; Liver Function Tests; Male; Middle Aged; Pyrazinamide; Tuberculosis, Pulmonary

Topics: Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Humans; Liver Function Tests; Male; Niacinamide; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Cycloserine; Ethionamide; Gastrointestinal Diseases; Humans; Isoniazid; Mycobacterium tuberculosis; Psychoses, Substance-Induced; Pyrazinamide; Recurrence; Tuberculosis, Pulmonary

Topics: Adolescent; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Humans; Isoniazid; Liver; Necrosis; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Drug Tolerance; Ethionamide; Female; Humans; Isoniazid; Male; Middle Aged; Streptomycin; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Antagonism; Ethionamide; Guinea Pigs

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Biliary Tract Diseases; Chemical and Drug Induced Liver Injury; Cholesterol; Ethionamide; Humans; Liver Function Tests; Middle Aged

Topics: Bile Acids and Salts; Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Ethionamide; Fatty Liver; Humans; Liver Diseases; Pyrazinamide; Transaminases; Tuberculosis, Miliary; Tuberculosis, Pulmonary

Topics: Adult; Chemical and Drug Induced Liver Injury; Drug Resistance, Microbial; Ethionamide; Female; Humans; Hyperbilirubinemia; Isonicotinic Acids; Jaundice; Liver; Male; Middle Aged; Pyrazinamide; Transaminases

Topics: Bile Ducts, Intrahepatic; Chemical and Drug Induced Liver Injury; Ethionamide; Humans; Jaundice; Liver Function Tests; Male; Middle Aged

Topics: Aged; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Humans; Liver Function Tests; Male; Middle Aged; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chlordiazepoxide; Chlorpromazine; Drug Eruptions; Drug Hypersensitivity; Drug Therapy; Ethionamide; Geriatrics; Hematologic Diseases; Hepatitis; Imipramine; Iproniazid; Isocarboxazid; Isoniazid; Leukocytosis; Pneumonia; Prochlorperazine; Sepsis; Shock, Septic; Streptomycin; Toxicology; Tranquilizing Agents; Viomycin

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethionamide; Hepatitis; Jaundice; Toxicology; Tuberculosis; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Choline; Ethionamide; Fatty Liver; Hepatitis; Nucleosides; Promethazine; Pyridoxal Phosphate; Rats; Research; Toxicology

Topics: Alanine Transaminase; Alcoholism; Aminosalicylic Acid; Aminosalicylic Acids; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child; Diabetes Mellitus; Ethionamide; Hepatitis; Hepatitis A; Isoniazid; Jaundice; Liver Cirrhosis; Pyrazinamide; Pyridoxine; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Pulmonary

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: Alanine Transaminase; Aminosalicylic Acid; Aminosalicylic Acids; Anti-Bacterial Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ethionamide; Fructose-Bisphosphatase; Hepatitis A; Isoniazid; Liver; Liver Function Tests; Nucleotidases; Oxidoreductases; Pyrazinamide; Sorbitol; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Pulmonary

Topics: Alcoholism; Alopecia; Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; China; Dermatitis, Exfoliative; Drug Therapy; Ethionamide; Hepatitis A; Hong Kong; Isoniazid; Jaundice; Phenylthiourea; Psychoses, Substance-Induced; Psychotic Disorders; Pyrazinamide; Streptomycin; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy; Ethionamide; Hepatitis A; Liver Function Tests; Toxicology; Tuberculosis; Tuberculosis, Pulmonary

Topics: Adolescent; Adrenal Cortex Hormones; Aminosalicylic Acid; Aminosalicylic Acids; Anti-Bacterial Agents; Blindness; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Eruptions; Ethionamide; Hepatitis; Isoniazid; Optic Neuritis; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Ethionamide; Feeding and Eating Disorders; Hepatitis; Isoniazid; Joint Diseases; Kanamycin; Nausea; Psychoses, Substance-Induced; Psychotic Disorders; Pyrazinamide; Streptomycin; Toxicology; Vertigo; Viomycin