The effect of ticagrelor on the adenosine system

Preclinical studies have shown that the P2Y12 receptor antagonist ticagrelor
can increase the extracellular concentration of the endogenous nucleoside
adenosine by inhibiting the cellular uptake of adenosine via the equilibrative
nucleoside transporter (ENT). This mechanism can contribute to the beneficial
effects and to the side effects (dyspnea) of ticagrelor in patients with an
acute myocardial infarction.

To investigate whether ticagrelor increases adenosine receptor stimulation in
humans in vivo by ENT inhibition.

Single centre, double-blinded, randomized placebo-controlled cross-over trial.
- Medical screening: history taking, physical examination, electrocardiogram,
venous puncture of three 3 ml-vacutainers for the determination of creatinin,
ALAT, thrombocytes, cholesterol and glucose.
- Experiment:
* Insertion of venous cannula into the antecubital vein of the dominant arm for
blood drawing (20 ml before administration of the study drug for ex vivo ENT
transport measurements, and measurement of the circulating caffeine and
ticagrelor concentration; 20 ml immediately before the administration of
adenosine for measurement of ticagrelor and ENT transport characteristics, and
10 ml before the administration of dipyridamole, the administration of
acetylcholine, and before forearm ischemia for determination of the ticagrelor
concentration.)
* Insertion of 27 Gauge needle into the brachial artery of the nondominant arm
for drug administration of adenosine, dipyridamole, and acetylcholine (please
see previous paragraph for dosages).
* Venous occlusion plethysmography of the forearm to determine the forearm
blood flow responses to the administration of these drugs, and to 2 and 5
minutes of forearm ischemia.

The single dose administration of ticagrelor (180 mg) or placebo

Given the administration of a single dose of ticagrelor to healthy male
subjects without bleeding problems and with normal circulating thrombocytes,
and given the very small 27 gauge needle used for intrabrachial administration
of adenosine, dipyridamole, and acetylcholine, we think that the potential
risks for the volunteers are low. Also, the methods used (venous blood drawing,
venous occlusion plethysmography, and insertion of a cannula into the brachial
artery) are well-established and have been performed very often by our research
group, without any serious events.