Study of Biochemical Markers to Determine the Acetylsalicylic Acid Chemopreventive Effect Through Antiplatelet Action
Status:
Completed
Trial end date:
2013-12-01
Target enrollment:
Participant gender:
Summary
This study in healthy volunteers is the first step in developing a collaborative research
program, which seeks to test the hypothesis that chemopreventive effect of acetylsalicylic
acid (ASA) on colon cancer is due predominantly to its antiplatelet effect.
The following features of the clinical evidence are consistent with the platelet-mediated
hypothesis:
1. The apparent saturability of the chemopreventive effect of ASA at low doses given once
daily, found in long-term analyses of cardiovascular and adenoma recurrence randomized
clinical trial, as well as in the vast majority of observational studies performed in
different settings and with different methodology. A remarkably similar saturability of
the cardioprotective effect of low dose ASA given once daily is explained by the
irreversible nature of cyclooxygenase (COX)-1 inactivation in platelets, and limited
capacity of human platelets for de novo protein synthesis.
2. Given the short half-life of ASA in the human circulation (approximately 20 min) and the
capacity of nucleated cells to resynthesize the acetylated COX-isozyme(s), it seems
unlikely that a nucleated target could be suppressed throughout the 24-h dosing
interval.
3. One of the cardiovascular randomized clinical trial (Thrombosis Prevention Trial) in
which the chemopreventive effect of ASA was detected on long-term follow-up, involved
the administration of a controlled-release formulation of ASA (75 mg) with negligible
systemic bioavailability.
4. Enhanced platelet activation and thromboxane (TX)A2 generation in vivo has been
demonstrated in patients with colorectal cancer and in Familial Adenomatous Polyposis
patients.
So, the main objective of this study is to assess the extent of acetylation at serine-529 of
platelet COX-1 after the 1st and 7th dose of low-doseof enteric-coated ASA 100 mg daily.
Changes of this novel biomarker of ASA action will be correlated to other known parameters of
ASA PK and PD: i) Tmax, Cmax and AUC of ASA and salicylate in the peripheral circulation
after oral dosing; ii) time to obtain the maximal antiplatelet effect by ASA and its
persistence throughout the dosing interval as assessed by measuring the inhibition of
platelet COX-1 activity in whole blood ex vivo, the inhibition of platelet aggregation in
whole blood ex vivo and the inhibition of the systemic generation of TXB2.