thioacetazone and Chemical-and-Drug-Induced-Liver-Injury

Topics: Chemical and Drug Induced Liver Injury; Costs and Cost Analysis; Drug Eruptions; Drug Resistance, Microbial; Ethambutol; Humans; Liver; Optic Neuritis; Rifampin; Thioacetazone; Tuberculosis

Topics: Adolescent; Adult; Africa, Eastern; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Eruptions; Drug Resistance, Microbial; Humans; Isoniazid; Middle Aged; Radiography; Sputum; Streptomycin; Thioacetazone; Tuberculosis, Pulmonary; Vertigo

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 To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles.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

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Thioacetazone; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Drug Eruptions; Female; Humans; Male; Middle Aged; Stevens-Johnson Syndrome; Thioacetazone

Topics: Chemical and Drug Induced Liver Injury; Child, Preschool; Humans; Male; Thioacetazone

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: 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: Albuminuria; Chemical and Drug Induced Liver Injury; Hemoglobinometry; Humans; Leukocyte Count; Liver Function Tests; Thioacetazone; Tuberculosis, Pulmonary

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Thioacetazone; Tuberculosis, Pulmonary

Topics: Africa; Africa, Eastern; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; D-Alanine Transaminase; Geriatrics; Hemoglobins; Hepatitis A; Humans; Hyperbilirubinemia; Isoniazid; Leukocyte Count; Thioacetazone; Thiosemicarbazones; Toxicology; United Kingdom