ArticleToxicological sciences : an official journal of the Society of Toxicology2012
A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 62 citations in OpenAlex.
- Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized, Comparator-Controlled, International Phase 3 Clinical Trial.PLoS neglected tropical diseases · 2016Trial
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- Natural variation suggests candidate genes underlyingbioRxiv : the preprint server for biology · 2025Article
- Transforming the chemotherapy of human African trypanosomiasis.Clinical microbiology reviews · 2025Review
- Model systems and organisms for addressing inter- and intra-species variability in risk assessment.Regulatory toxicology and pharmacology : RTP · 2022Review
- Drug delivery systems for RNA therapeutics.Nature reviews. Genetics · 2022Review
- Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.Toxicology · 2021Article
- Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.Tropical medicine and infectious disease · 2020Review
- Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Drug-Induced Liver Injury: Highlights of the Recent Literature.Drug safety · 2019Review
- Linking the low-density lipoprotein receptor-binding segment enables the therapeutic 5-YHEDA peptide to cross the blood-brain barrier and scavenge excess iron and radicals in the brain of senescent mice.Alzheimer's & dementia (New York, N. Y.) · 2019Article
- miR-122 Release in Exosomes Precedes Overt Tolvaptan-Induced Necrosis in a Primary Human Hepatocyte Micropatterned Coculture Model.Toxicological sciences : an official journal of the Society of Toxicology · 2018Article
- Targeting Channels and Transporters in Protozoan Parasite Infections.Frontiers in chemistry · 2018Review
- Novel lead compounds in pre-clinical development against African sleeping sickness.MedChemComm · 2017Review
- Genetic and epigenetic determinants of inter-individual variability in responses to toxicants.Current opinion in toxicology · 2017Article
- New Rodent Population Models May Inform Human Health Risk Assessment and Identification of Genetic Susceptibility to Environmental Exposures.Environmental health perspectives · 2017Review
- Editor's Highlight: Collaborative Cross Mouse Population Enables Refinements to Characterization of the Variability in Toxicokinetics of Trichloroethylene and Provides Genetic Evidence for the Role of PPAR Pathway in Its Oxidative Metabolism.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
- Editor's Highlight: Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
- Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis.Journal of medicinal chemistry · 2017Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next-in-class compounds for renal injury.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.