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Figure 1 Flow chart of study protocols. In the study with multiple daily doses, aspirin (100 mg daily and once at 8 AM) was administered for 6 consecutive days and then naproxen (500 mg twice daily, once at 10 AM and 10 PM) was co-administered 2 h after aspirin for further 6 days to 4 healthy subjects. After a washout period of at least 14 days, the volunteers reversed the treatment, i.e., low-dose aspirin (100 mg daily at 10 AM) was administered 2 h after naproxen (500 mg twice daily, once at 8 AM and once at 8 PM) for further 6 days. Blood samples were collected before and up to 26 h after dosing with the first study drug on the 6th, 12th, 27th, and 32nd study day to assess the inhibition of serum thromboxane (TX)B2 (a capacity index of platelet cyclooxygenase [COX]-1 activity) and lipopolysaccharide-induced prostaglandin E2 production (a capacity index of monocyte COX-2 activity). Three consecutive urinary samples (time of collection: 0 to 6 h, 6 to 12 h, and 12 to 24 h) were collected before treatment and on days 6, 12, 27, and 32 to evaluate the urinary excretion of 11-dehydro-TXB2 (a major enzymatic metabolite of TXB2 that is an index of TXA2 biosynthesis in vivo). In the study with single dose, aspirin (100 mg) and naproxen (500 mg) were co-administered to 5 healthy subjects, and peripheral blood samples were collected before and up to 14 days after dosing to assess the time-dependent inhibition and recovery of serum TXB2 production and platelet aggregation ex vivo.
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