title: NT-proBNP as a biomarker for the assessment of a potential cardiovascular drug-induced liability in beagle dogs.
abstract: The amino-terminal pro-brain natriuretic peptide (NT-proBNP) is released into the plasma predominantly from ventricular cardiomyocytes, particularly in patients with chronic cardiac diseases, although small amounts are detectable in the plasma of healthy subjects. While NT-proBNP has been widely exploited in human medicine, limited literature is available related to its characterization in veterinary medicine (e.g., correlation with damage and specificity) and, particularly, in the context of preclinical drug safety assessment. This paper describes the analytical performance characteristics and the biological variability of NT-proBNP in male beagle dogs by using a commercially available enzyme-linked immunosorbent assay. Male beagle dogs were treated with Casopitant, an NK1 receptor antagonist under development for depression and anxiety, which, when administered chronically to dogs, caused cardiac toxicity. Heart weight increase, myocardial necrosis, degeneration, and inflammation associated with high serum levels of cardiac troponin I characterized the end stage pathology observed in dogs treated orally at 40 mg/kg for 39 weeks. Based on these data, ad hoc studies were designed in order to evaluate the possible relationship between NT-proBNP serum levels and both standard toxicology endpoints, such as the organ weight and histology, as well as nonstandard endpoints such as macroscopic morphometry and echocardiography. Early changes of NT-proBNP serum levels were observed following 2 weeks of treatment onward, preceding most, if not all of the anatomical and functional changes. The results obtained demonstrate that NT-proBNP acts as an early biomarker of cardiac changes, representing a sensitive and predictive marker of drug-induced cardiac liability.
authors.affiliation: Safety Assessment Department, GlaxoSmithKline Research Centre, Verona, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Crivellente
authors.forename: Marcello
authors.initials: M
authors.lastname: Tontodonati
authors.forename: Nicola
authors.initials: N
authors.lastname: Fasdelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Casartelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Dorigatti
authors.forename: Ivo
authors.initials: I
authors.lastname: Faustinelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cristofori
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001008:Anxiety Disorders / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood*; D003863:Depression / Q000188:drug therapy; D004285:Dogs; D004334:Drug Administration Schedule; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D006331:Heart Diseases / Q000097:blood* / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood* / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000097:blood* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects*; D011237:Predictive Value of Tests; D012307:Risk Factors; D019210:Troponin I / Q000097:blood; D014508:Urea
chemical_list: D000928:Antidepressive Agents; D015415:Biomarkers; D020097:Natriuretic Peptide, Brain; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010879:Piperazines; D010880:Piperidines; D019210:Troponin I; C109794:pro-brain natriuretic peptide (1-76); C531951:casopitant; D014508:Urea