Darapladib Treatment Stabilizes and Reduces Atherosclerotic Plaques

Cardiovascular disease researchers have found that inhibiting the activity of the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2) reduced the number and size of advanced atherosclerotic plaques in a pig model of human atherosclerosis.

Investigators at the University of Pennsylvania (Philadelphia, PA, USA) treated diabetic and hypercholesterolemic swine with GlaxoSmithKline's (King of Prussia, PA, USA) experimental drug darapladib. Darapladib is a specific inhibitor of Lp-PLA2.

Results published in the September 21, 2008, online edition of the journal Nature Medicine revealed that darapladib markedly inhibited plasma and lesion Lp-PLA2 activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, significantly, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with the type of unstable phenotype that are prone to rupture, which can then lead to heart attack, stroke, and death.

"We have used a model that closely mimics clinical disease,” explained first author Dr. Robert L. Wilensky, MD, professor of medicine at the University of Pennsylvania. "First, darapladib reduced the overall amount and size of plaques that block the coronary arteries of animals in the study. More importantly, it reduced the number and size of the type of advanced plaques that cause heart attacks and strokes.”

GlaxoSmithKline is planning a Phase 1 safety and efficacy trial with darapladib in humans in the near future.

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