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Issue title: Toxicity Biomarkers
Article type: Research Article
Authors: Brott, D.A.a; b; * | Jones, H.B.c | Gould, S.c | Valentin, J.P.c | Evans, G.c | Richardson, R.J.b | Louden, C.a; b
Affiliations: [a] Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, DE, USA | [b] Toxicology Program, Department of Environmental Health Sciences, The University of Michigan, Ann Arbor, MI, USA | [c] Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderely Park, UK | Merck and Co., Inc.
Correspondence: [*] Corresponding author: David A. Brott. Current address: AstraZeneca Pharmaceuticals, 1800 Concord Pike, CRDL121, PO Box 15437, Wilmington, DE 19850-5437, USA. Tel.: +1 302 885 5188; Fax: +1 302 886 2341; E-mail: [email protected].
Abstract: Recently, there has been an increased incidence of vascular toxicity in pre-clinical toxicology studies. This is of concern because of the uncertain relevance and extrapolation of this finding to humans. In dogs, profound heart rate (HR) and mean arterial pressure (MAP) changes were considered surrogate markers for drug-induced vascular injury until the early 1990s when endothelin receptor antagonists (ETRA) did not significantly alter HR or MAP but induced identical lesions in the coronary arteries of dogs. Thus significant alterations in HR and MAP were found not to be a prerequisite for this lesion. Clinically, the potential for vascular injury coupled with the lack of an unequivocal non-invasive diagnostic marker is an issue of concern to pharmaceutical companies and the regulatory authorities. Therefore, qualification and validation of biomarkers as diagnostic tools for drug-induced vascular injury would add great value to risk management and expedite the drug development process. This review focuses on the status, progress and future trends in vascular biology aimed at identification and development of diagnostic markers that are specific, sensitive and possess potential utility in both a pre-clinical and clinical setting.
DOI: 10.3233/CBM-2005-1104
Journal: Cancer Biomarkers, vol. 1, no. 1, pp. 15-28, 2005
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