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Molecular docking to investigate HLA-associated idiosyncratic drug reactions.
Drug Metab Rev
January 2025
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Idiosyncratic drug reactions (IDRs) pose severe threats to patient health. Unlike conventionally dose-dependent side effects, they are unpredictable and frequently manifest as life-threatening conditions, such as severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). Some HLA alleles, such as , , and , are known risk factors for adverse reactions induced by multiple drugs.
View Article and Find Full Text PDFTAK-994 Mechanistic Investigation into Drug-Induced Liver Injury.
Toxicol Sci
January 2025
Takeda Development Center Americas, Inc, Cambridge, MA, USA.
The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding.
View Article and Find Full Text PDFDynamic collateral sensitivity profiles highlight opportunities and challenges for optimizing antibiotic treatments.
PLoS Biol
January 2025
Department of Biophysics, University of Michigan, Ann Arbor, Michigan, United States of America.
As failure rates for traditional antimicrobial therapies escalate, recent focus has shifted to evolution-based therapies to slow resistance. Collateral sensitivity-the increased susceptibility to one drug associated with evolved resistance to a different drug-offers a potentially exploitable evolutionary constraint, but the manner in which collateral effects emerge over time is not well understood. Here, we use laboratory evolution in the opportunistic pathogen Enterococcus faecalis to phenotypically characterize collateral profiles through evolutionary time.
View Article and Find Full Text PDFA Complex Case of Acute Liver Failure Following Idiosyncratic Drug-Induced Liver Injury, Potentiated by Herpes Simplex Virus Infection.
Cureus
December 2024
Internal Medicine, Unidade Local de Saúde de São José, Lisbon, PRT.
Acute liver failure (ALF) is a rare, life-threatening condition that may be secondary to drug-induced liver injury (DILI) and certain viral infections. We present the case of a 73-year-old male with a history of fibrotic hypersensitivity pneumonitis with a progressive phenotype, type 2 diabetes mellitus, hypertension, and hyperlipidemia, who was admitted with ALF potentially secondary to DILI. Prior to admission, he was receiving therapy that may be related to idiosyncratic DILI (I-DILI) and ALF, namely nintedanib, which appears to have a most probable relation to I-DILI in this case, considering it was the most recently started drug.
View Article and Find Full Text PDFA Rapid and Reliable Absorbance Assay to Identify Drug-Drug Interactions with Thiopurine Drugs.
Metabolites
December 2024
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Background: Thiopurine methyltransferase (TPMT) plays a crucial role in the detoxification of thiopurine drugs, including the antimetabolites azathioprine and 6-mercaptopurine (6-MP) used to treat autoimmune diseases and various cancers. These drugs interfere with DNA synthesis by inhibiting the production of purine-containing nucleotides, leading to the death of rapidly dividing cells. TPMT inactivates thiopurine drugs by methylating at the thiol group.
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