title: Current status and future directions for diagnostic markers of drug-induced vascular injury.
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.
authors.affiliation: Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, DE 19850-5437, USA. david.brott@astrazeneca.com
authors.forename: D A
authors.initials: DA
authors.lastname: Brott
authors.forename: H B
authors.initials: HB
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Gould
authors.forename: J P
authors.initials: JP
authors.lastname: Valentin
authors.forename: G
authors.initials: G
authors.lastname: Evans
authors.forename: R J
authors.initials: RJ
authors.lastname: Richardson
authors.forename: C
authors.initials: C
authors.lastname: Louden
mesh_terms: D000210:Acute-Phase Reaction / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D014652:Vascular Diseases / Q000139:chemically induced* / Q000175:diagnosis* / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins