{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:37:34Z","timestamp":1777718254362,"version":"3.51.4"},"reference-count":20,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T00:00:00Z","timestamp":1424908800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1177\/1091581815573029","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T23:18:23Z","timestamp":1424992703000},"page":"151-161","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrated Approach to Early Detection of Cardiovascular Toxicity Induced by a Ghrelin Receptor Agonist"],"prefix":"10.1177","volume":"34","author":[{"given":"Alan H.","family":"Stokes","sequence":"first","affiliation":[{"name":"GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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