Monday, 25 February 2013 12:34

King’s Thrombosis Centre initiates research on Blood Brain Barrier and intracranial haemorrhage

The project is being led by Dr Jig Patel, Senior Lecturer, Institute of Pharmaceutical Science at King's College London.

Project description

Intracranial haemorrhage is a devastating consequence of oral anticoagulation, with a reported incidence of 0.2 to 0.5% per year. The NOACs, dabigatran and rivaroxaban have both demonstrated significantly lower rates of ICH compared to the current standard of warfarin therapy. Both dabigatran etexilate and rivaroxaban are substrates for the intestinal transmembrane efflux protein, P-glycoprotein, which is highly expressed on the luminal membrane of the BBB. The BBB protects the brain from harmful substances and it could be that P-glycoprotein and other efflux proteins are protecting against ICH.

This study aims to investigate the specific P-glycoprotein binding of rivaroxaban and dabigatran within the BBB in comparison to warfarin, identify which other BBB transport proteins the NOACs interact with and explore what implications this might have for clinical practice.

Using a multi-disciplinary approach our objectives will be to:

YEAR 1: i) examine the integrity of human brain endothelial cell membranes on exposure of the luminal and abluminal surfaces to clinically relevant concentrations of dabigatran, rivaroxaban, and warfarin and ii) quantify the cellular accumulation of these drugs in an in vitro human BBB model.

YEARS 2 & 3: iii)identify transporters involved in the accumulation of dabigatran, rivaroxaban, and warfarin using chemical inhibition methods and Western blotting and iv) use whole animal methods to quantify delivery of each drug across the BBB in vivo.

YEAR 4: v)compare and contrast real world and clinical trial ICH outcome data for dabigatran, rivaroxaban and warfarin, to the laboratory findings, so specific recommendations for clinical practice can be made.