Integrated Approach to Early Detection of Cardiovascular Toxicity Induced by a Ghrelin Receptor Agonist
| Autor: | Neal F. Cariello, Heidi M. Colton, Holly L. Jordan, Brenda Faiola, Alan H. Stokes, Brian R. Berridge, Lawrence Yoon, J. Greg Falls |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Agonist medicine.medical_specialty Necrosis medicine.drug_class Biology Fatty Acid-Binding Proteins Real-Time Polymerase Chain Reaction Toxicology Cardiovascular System Piperazines Troponin T Troponin complex Internal medicine Troponin I medicine Natriuretic peptide Animals Protein Precursors Receptors Ghrelin Sulfonamides Dose-Response Relationship Drug Myocardium Heart Rats Microscopy Electron Endocrinology Toxicity Ghrelin medicine.symptom Transcriptome Fatty Acid Binding Protein 3 Atrial Natriuretic Factor |
| Zdroj: | International Journal of Toxicology. 34:151-161 |
| ISSN: | 1092-874X 1091-5818 |
| Popis: | Cardiovascular (CV) safety concerns are among the leading causes of compound attrition in drug development. This work describes a strategy of applying novel end points to a 7-day rodent study to increase the opportunity to detect and characterize CV injury observed in a longer term (ie, 28 days) study. Using a ghrelin receptor agonist (GSK894281), a compound that produces myocardial degeneration/necrosis in rats after 28 days at doses of 0.3, 1, 10, or 60 mg/kg/d, we dosed rats across a range of similar doses (0, 0.3, 60, or 150 mg/kg/d) for 7 days to determine whether CV toxicity could be detected in a shorter study. End points included light and electron microscopies of the heart; heart weight; serum concentrations of fatty acid-binding protein 3 (FABP3), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and N-terminal proatrial natriuretic peptide (NT-proANP); and a targeted transcriptional assessment of heart tissue. Histologic evaluation revealed a minimal increase in the incidence and/or severity of cardiac necrosis in animals administered 150 mg/kg/d. Ultrastructurally, mitochondrial membrane whorls and mitochondrial degeneration were observed in rats given 60 or 150 mg/kg/d. The FABP3 was elevated in rats given 150 mg/kg/d. Cardiac transcriptomics revealed evidence of mitochondrial dysfunction coincident with histologic lesions in the heart, and along with the ultrastructural results support a mechanism of mitochondrial injury. There were no changes in cTnI, cTnT, NT-proANP, or heart weight. In summary, enhancing a study design with novel end points provides a more integrated evaluation in short-term repeat dose studies, potentially leading to earlier nonclinical detection of structural CV toxicity. |
| Databáze: | OpenAIRE |
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