The effects of EP3 receptor blockade on platelet function in man - measurement in a remote setting

Prof. Dr. Heptinstall, Stan. University of Nottingham Cardiovascular Medicine, Queens Medical Centre, Nottingham, NG7 2UH, Great Britain.

The EP3 antagonist 2,3-dichlorothiophene-5-sulfonic acid, 3-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acryloylamide (DG-041) is being developed for use in atherothrombotic disease. Unlike other antiplatelet agents, DG-041 may avoid bleeding complications.

Here I report on a study performed at deCODE Genetics in Reykjavik, Iceland using kits designed and supplied by the Platelet Research Group at the University of Nottingham, UK. The aim was to determined the antiplatelet effects of DG-041 used as monotherapy and in combination with clopidogrel ± aspirin. The kits were designed for remote platelet testing with fixation of the samples prior to transfer to Nottingham for analysis.

DG-041 or placebo were administered sequentially for 5 days (in a crossover manner) to healthy volunteers who received no background treatment, or standard treatment with clopidogrel, or with clopidogrel and aspirin (each n=14). Blood samples were taken before administration of any drug and then after treatment. Platelet CD62P (P-selectin) expression was measured by flow cytometry (%+ve cells) and platelet aggregation (%) by platelet counting. The agonists included U46619 (1uM) used with sulprostone (1uM) or with PGE2 (1uM). In the Table *p<0.05 cf 0; "p<0.05 cf Plac.

DG-041 inhibited platelet function as both monotherapy and in combination with clopidogrel ± aspirin. Clopidogrel also inhibited as monotherapy and there was additive benefit with DG-041. Aspirin did not influence the results obtained. DG-041 did not increase bleeding time although clopidogrel and aspirin did so.

We conclude that inhibitory effects of DG-041 on platelet function can be successfully demonstrated ex vivo as monotherapy and in the presence of clopidogrel and aspirin.