Pharmacokinetics, Pharmacodynamics and Drug MetabolismA Randomized, Quadruple Crossover Single-Blind Study on Immediate Action of Chewed and Unchewed Low-Dose Acetylsalicylic Acid Tablets in Healthy Volunteers
Section snippets
INTRODUCTION
Acetylsalicylic acid (ASA) irreversibly acetylates and inactivates platelet cyclooxygenase (COX), which catalyzes the first step in the conversion of arachidonic acid to thromboxane A2.1., 2., 3., 4., 5., 6. Thromboxane A2 stimulates platelet recruitment, activation, aggregation, and vasoconstriction. The ASA-induced inhibition lasts for the life of the platelet or about 7–10 days.7,8 At the same time, inactivation of COX in vascular endothelial cells also prevents the synthesis of
Materials
Bufferin® 81 mg tablets (NBA) and Bayaspirin® 100 mg (ECA) were purchased from Eisai Company, Ltd. (Tokyo, Japan) and Bayer Yakuhin, Ltd. (Osaka, Japan), respectively. Thromboxane EIA Kit was purchased from Cayman Chemical Company (Ann Arbor, Michigan). 2-Methylbenzoic acid and blank human serum were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan) and Sigma–Aldrich (St Louis, Missouri), respectively. All other chemicals were commercial products of reagent grade or
Serum Concentration–Time Profiles of ASA and SA After Ingestion of Intact and Chewed NBA and ECA
Twelve healthy volunteers each received four separate oral drug administrations, that is, intact and chewed NBA and intact and chewed ECA. One volunteer withdrew in the middle of blood sampling after ingestion of intact ECA because of vascular pain owing to multiple venous punctures. Another volunteer withdrew in the middle of the intact ECA period because of feeling unwell, and also retracted her consent to participate in the period of chewed ingestion of NBA. Figures 1 and 2 illustrate the
DISCUSSION
The US Food and Drug Administration approved general ASA formulations as an antiplatelet drug in 1998. In Japan, “Baby Bufferin,” which contained 81 mg ASA at that time, and Bayaspirin® 100 mg tablet were used as off-label pharmaceuticals before 1999, when Ministry of Health, Labour and Welfare, Japan, approved their use. These approvals were not based on a new clinical trial, but were based on literature data. Indeed, the American College of Cardiology and the American Heart Association as well
CONCLUSION
Our quadruple crossover clinical trial provides pharmacokinetic and pharmacodynamic evidence to support the recommendation of the Clinical Guidelines for Acute Myocardial Infarction that the initial dose of aspirin following admission to hospital should be chewed. Chewing ECA accelerated ASA absorption and onset of antiplatelet action even in the nonfasting state. Ingestion of either intact or chewed NBA provided outcomes comparable to that after ingestion of chewed ECA.
Acknowledgements
We thank Ms. Junko Matsuo, Yukie Kitayama, Kumiko Iwatani, Misako Dai, Yuki Oohata, Teruko Kitagawa, Miyuki Ueda, Noriko Teranishi, Hiroko Maeba, Motoko Suzuki, Miyuki Muramatsu, and Yoko Konishi for their help with blood sampling. This study was supported in part by Eisai Co. Ltd.
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