Biomarkers and mechanisms of drug-induced vascular injury in non-rodents.
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.
Louden
Calvert
C
Department of Safety Assessment, AstraZeneca Pharmaceuticals, Cheshire, UK. calvert.louden@astrazeneca.com
Brott
David
D
Katein
Anne
A
Kelly
Thomas
T
Gould
Sarah
S
Jones
Huw
H
Betton
Graham
G
Valetin
Jean-Pierre
JP
Richardson
Rudy J
RJ
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D014841:von Willebrand Factor / Q000032:analysis / Q000378:metabolism
D015415:Biomarkers; D015507:Drugs, Investigational; D014841:von Willebrand Factor; D009569:Nitric Oxide