Abstract
Safety pharmacology is an essential part of drug development and aims to identify and investigate adverse events of a drug before entering trials which involve human subjects. In particular, negative effects on the cardiovascular system have stopped many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect undesirable cardiovascular effects, but there is still room for improvement. Regulations recommend conducting an assessments of drug-induced changes on the heart rate and blood pressure in awake animals. Evaluation of cardiovascular function in animal experimentation leads to acceptable translation to humans, yet it provides limited mechanistic insight and risk assessment may be challenging.
The current research aims to evaluate arterial stiffness as a possible marker of drug-induced cardiovascular effects. Arterial stiffness increases with age and is a blood pressure-independent prognostic factor for cardiovascular disease. However, it has not been widely considered in safety pharmacology. Interestingly, arterial stiffness is a single parameter and integrates information on both structural (matrix) stiffness as well as active regulation of vascular tone. Moreover, vascular tone reflects the balance between the action of contractile vascular smooth muscle cells and vasodilation-promoting endothelial cells. In the current project we will evaluate drug-induced changes in arterial stiffness both in vivo by measuring pulse wave velocity (PWV) by ultrasound imaging and ex vivo in a proprietary organ bath set-up. More specifically, the research will focus on the investigation of a number of anti-cancer drugs (doxorubicin, VEGF-inhibitors and proteasome inhibitors) and their respective effects on endothelial cell function, matrix stiffness and arterial stiffness since growing evidence suggests that cardiotoxic effects of anti-cancer drugs extend beyond the heart and may predispose to (or facilitate) cardiovascular disease.
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