Study of Biochemical Markers to Determine the Acetylsalicylic Acid Chemopreventive Effect Through Antiplatelet Action

• Status: Completed
• Trial end date: 2013-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Aragon Institute of Health Sciences
• Treatments: Aspirin

Criteria

Inclusion Criteria:

• Men and women, aged ≥ 18 and ≤ 45.

• No potential contraindication to ASA.

• Unaltered history and physical examination.

• Unchanged hematological and biochemical laboratory parameters.

• Hematological parameters consistent with the current rules for blood donation.

• Negative urine pregnancy test.

• Negative serology for HIV, hepatitis B and C, alcohol intake and drug abuse.

Exclusion Criteria:

• Active cigarette smokers.

• Coagulation disorders.

• Allergy to ASA or any other NSAID.

• History of any gastrointestinal disorder.

• Pregnant women