Biomarkers for safety and toxicology: Drug induced cardiac injury and dysfunction

Duffy, Paul; Betton, Graham; Horner, Steve; Horner, Judith; Cotton, Peter; McMahon, Nick; Lawrence, Chris L.; Prior, Helen; Armstrong, Duncan; Philp, Karen; Roberts, Ruth

doi:10.1016/s1359-6349(07)70034-4

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…The cardiac secretome has recently generated substantial interest as new high‐throughput methods for detecting small changes in secreted proteins have been developed . The secretome can be utilized to detect new signaling pathways associated with cardiac pathology and therefore new drug targets, as well as to search for novel biomarkers, which could then potentially be detected in the plasma. However, current techniques used in animal models such as pericardial fluid analysis or plasma sampling have significant limitations.…”

Section: Resultsmentioning

confidence: 99%

Protein Corona Influences Cell–Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds

Serpooshan

Mahmoudi

Zhao

et al. 2015

Adv Funct Materials

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Biomaterials are extensively used to restore damaged tissues, in the forms of implants (e.g. tissue engineered scaffolds) or biomedical devices (e.g. pacemakers). Once in contact with the physiological environment, nanostructured biomaterials undergo modifications as a result of endogenous proteins binding to their surface. The formation of this macromolecular coating complex, known as ‘protein corona’, onto the surface of nanoparticles and its effect on cell-particle interactions are currently under intense investigation. In striking contrast, protein corona constructs within nanostructured porous tissue engineering scaffolds remain poorly characterized. As organismal systems are highly dynamic, it is conceivable that the formation of distinct protein corona on implanted scaffolds might itself modulate cell-extracellular matrix interactions. Here, we report that corona complexes formed onto the fibrils of engineered collagen scaffolds display specific, distinct, and reproducible compositions that are a signature of the tissue microenvironment as well as being indicative of the subject's health condition. Protein corona formed on collagen matrices modulated cellular secretome in a context-specific manner ex-vivo, demonstrating their role in regulating scaffold-cellular interactions. Together, these findings underscore the importance of custom-designing personalized nanostructured biomaterials, according to the biological milieu and disease state. We propose the use of protein corona as in situ biosensor of temporal and local biomarkers.

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Section: Resultsmentioning

confidence: 99%

Protein Corona Influences Cell–Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds

Serpooshan

Mahmoudi

Zhao

et al. 2015

Adv Funct Materials

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“…Biomarkers are used in the drug development process as noninvasive indicators of possible efficacy of a new chemical entity, and also as warning signs of potential toxicity (Duffy et al 2007). In particular, translational biomarkers can be used in preclinical drug development and in clinical trials, thus representing a useful tool for mitigating late stage drug Fig.…”

Section: Discussionmentioning

confidence: 99%

NT-proBNP as a biomarker for the assessment of a potential cardiovascular drug-induced liability in beagle dogs

et al. 2011

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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.

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“…Biomarkers are used in drug development as indicators of likely response to drug; therefore they have utility both as predictors of possible efficacy and also as warning signs of potential toxicity (Duffy et al , ). In particular, translational biomarkers can bridge between preclinical drug development and clinical application, thus providing a useful tool for speeding up the drug development process.…”

Section: Discussionmentioning

confidence: 99%

Atrial natriuretic peptides in Han Wistar, Sprague–Dawley and spontaneously Hypertensive rats

Crivellente

Bocchini

Bonato

et al. 2011

J of Applied Toxicology

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The atrial natriuretic peptide (ANP) and its precursor (N-terminal fragment of atrial natriuretic peptide, NT-proANP) are natriuretic peptides released into the circulation as a consequence of an acute atrial stretch. As for the brain natriuretic peptide and its N-terminal fragment, the biological significance of ANP and NT-proANP has been widely studied in humans, but the literature is lacking information about the determination of these biomarkers in veterinary medicine and, in particular, in the toxicological species used in preclinical pharmaceutical drug development. This paper describes the evaluation of ANP and NT-proANP levels in a healthy population of Han Wistar and Sprague-Dawley rats, as well as in a rodent model of hypertension (Spontaneously Hypertensive rats). Both biomarkers were measured by mean of two commercially available enzyme immunoassays and serum levels were correlated with heart weight and histopathological findings in the heart, with the aim of building an integrated assessment of the significance of these biomarkers. Results obtained demonstrated that NT-proANP and ANP can be accurately measured in the different rat strains, with NT-proANP concentrations higher than those of ANP, as expected because of its longer half-life. In addition, both correlated well with cardiac hypertrophy evaluated by means of heart weight and histopathological examination. NT-proANP and ANP represent reliable markers of cardiac hypertrophy in the rat.

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Biomarkers for safety and toxicology: Drug induced cardiac injury and dysfunction

Cited by 4 publications

References 7 publications

Protein Corona Influences Cell–Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds

Protein Corona Influences Cell–Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds

NT-proBNP as a biomarker for the assessment of a potential cardiovascular drug-induced liability in beagle dogs

Atrial natriuretic peptides in Han Wistar, Sprague–Dawley and spontaneously Hypertensive rats

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