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Toxicologic Pathology
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Articles

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

Calvert Louden1,3
David Brott2,3
Anne Katein2
Thomas Kelly2
Sarah Gould1
Huw Jones1
Graham Betton1
Jean-Pierre Valetin1
Rudy J. Richardson3

1 Departments of Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK
2 Wilmington, Delaware 19850, USA
3 Toxicology Program, Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan 48105, USA

Correspondence: Address correspondence to: Calvert Louden, Department of Safety Assessment-UK, Mereside, Alderley Park, Cheshire SK10 4TF, England; e-mail:calvert.louden{at}astrazeneca.com

In preclinical safety studies, drug-induced vascular injury can negatively impact candidate-drug selection because there are no obvious diagnostic markers for monitoring this pathology preclinically or clinically. Furthermore, our current understanding of the pathogenesis of this lesion is limited. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary target cells, smooth muscle (SMC) and endothelial cell (EC), are unknown. Evaluation of potential novel markers for clinical monitoring with a mechanistic underpinning would add value in risk assessment and risk management. This mini review focuses on the efforts and progress to identify diagnostic markers as well as understanding the mechanism of action in nonrodent drug-induced vascular injury.

Key Words: Drug-induced vascular injury • biomarker • von Willebrand Factor • von Willebrand Factor propeptide • caveolin-1 • nitric oxide

Abbreviations: AC, adenylyl cyclase • ADMA, asymetric dimethyl arginine • CRP, C-reactive protein • cav-1, caveolin-1 • CBF, coronary blood flow • DDAVP, 1-Deamino-8-Desmethylarginine vasopressin • EC, endothelial cells • ET, endothelin • ETRA, endothelin receptor antagonist • HR, heart rate • MAP, mean arterial pressure • NO, nitric oxide • NOS, nitric oxide synthase • PCO, potassium channel opener • SMA, smooth muscle {alpha} actin • SMC, smooth muscle cells • VEGF, vascular endothelial growth factor • vWF, von Willebrand factor • vWFpp, von Willebrand factor propeptide

Toxicologic Pathology, Vol. 34, No. 1, 19-26 (2006)
DOI: 10.1080/01926230500512076
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