Pharmacokinetics of enteric-coated aspirin and inhibition of platelet thromboxane A2 and vascular prostacyclin generation in humans (original) (raw)
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Journal of Clinical Investigation, 1986
In rats intravenous aspirin was only slightly more effective an inhibitor of platelet thromboxane B2 (TxB2) than of aorta 6keto-prostaglandin (PGF)1. generation (1.9 versus 2.1 mg/kg). In contrast, oral aspirin was about five times more effective on platelet than on aorta cyclooxygenase activity. The "biochemical selectivity" of aspirin as an inhibitor of platelet and vascular cyclooxygenase thus was not apparent after intravenous administration ofthe drug. However, this could be achieved by relatively low doses of oral (or intraduodenal) aspirin, on account of "presystemic" acetylation of platelet cyclooxygenase. Even in this condition, though, aspirin selectivity was relative to "systemic" peripheral vessels but not to the vessels of the enterohepatic circulation. Indeed after an oral or intraduodenal dose of 5 mg/ kg aspirin, genertion of portal vein 6-keto-PGFI. was inhibited to much the same extent as platelet TxB2, while inferior vena cava 6-keto-PGFIa formation was spared.
The Journal of clinical investigation, 1983
To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increa...
Effects of enteric-coated, low-dose aspirin on parameters of platelet function
Alimentary Pharmacology and Therapeutics, 2002
Background: Aspirin is widely used as an anti-thrombotic drug; however, it has been suggested that entericcoated formulations of aspirin may be less bioavailable and less effective as anti-thrombotic agents. Aim: To assess the effect of a formulation of entericcoated, low-dose (81 mg) aspirin on serum generated thromboxane B 2 and platelet aggregation in healthy subjects. Methods: Twenty-four subjects participated in a doubleblind, randomized, placebo-controlled, parallel-group, multiple-dose study. Twelve subjects in each of two groups received a daily oral dose of enteric-coated aspirin (81 mg) or matching placebo for 7 days. Serum thromboxane B 2 and platelet aggregation (using 1 mm arachidonic acid and 1 lg ⁄mL collagen as agonists)
Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease
Journal of the American …, 2005
We investigated whether use of low-dose enteric-coated (EC) aspirin for secondary prevention of cardiovascular events has sufficient bioavailability to achieve complete platelet cyclooxygenase (COX) inhibition in all individuals. BACKGROUND Aspirin reduces cardiovascular morbidity and mortality in patients with pre-existing vascular disease; however, there is variability in the way individuals respond. Persistent normal platelet function despite therapy, referred to as "aspirin resistance," is associated with an increased risk of major cardiovascular events.
Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin
New England Journal of Medicine, 2001
Background Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies.
Journal of Clinical Investigation, 1982
A B S T R A C T Acetylation of platelet cyclooxygenase by oral aspirin is dose dependent and cumulative with repeated administration. However, no single dose of aspirin has been found to be completely selective of platelet thromboxane (TX) synthesis inhibition in man. We determined the dose dependence, cumulative nature and selectivity of aspirin effects on platelet TXB2 and renal prostaglandin (PG) and prostacyclin (PGI2) production. We measured, by radioimmunoassay, serum TXB2 levels after whole blood clotting and urinary excretion of PGE2, PGF2a, and 6-keto-PGF,a, before and after single or repeated oral aspirin doses given to 46 healthy subjects. Single doses of 6-100 mg aspirin resulted in a linear (r = 0.92, P < 0.01) inhibition of platelet TXB2 production, ranging from 12 to 95% after 24 h. A daily dose of 0.45 mg/kg given for 7 d produced a cumulative and virtually complete inhibition of platelet TXB2 production, without significantly reducing the urinary excretion of PGE2, PGF2a, and 6-keto-PGF,a in both healthy men and women. The platelet inhibitory effect of this regimen was maintained unaltered throughout 1 mo of therapy, with no evidence of cumulative inhibition of renal PGsynthesis. Moreover, furosemide-induced renal PGI2 synthesis and renin release were unaffected by chronic low-dose aspirin. Following cessation of aspirin therapy, platelet TXB2 production returned toward control values at a similar rate as after a single higher dose.
British Journal of Clinical Pharmacology, 2001
Aims A new formulation, low dose microencapsulated aspirin, permits slow absorption of aspirin and presystemic acetylation of platelet cyclo-oxygenase within the portal circulation, potentially avoiding deleterious effects on gastric and systemic prostaglandin synthesis. The objective of this study was to determine whether the administration of microencapsulated aspirin was as effective as enteric coated (EC) aspirin as an inhibitor of platelet function in patients with atherosclerosis. Methods One hundred and four patients were enrolled and randomised after a run in period of at least 14 days on aspirin EC 75 mg (day 0), to receive either microencapsulated aspirin 162.5 mg (n=34), aspirin EC 150 mg (n=36) or continue on aspirin EC 75 mg (n=34) for 28 days. Serum thromboxane B 2 and collageninduced platelet aggregation and release of 5-hydroxytryptamine (EC 50 values) were measured on days 0 and 28. Aggregation/release EC 50 s were then repeated in the presence of a large dose of aspirin added in vitro to determine the EC 50 at the maximum level of platelet inhibition. Results Median thromboxane B 2 levels were low after 14 days run-in therapy with aspirin EC 75 mg, but significant further reductions were seen on day 28 in patients randomised to microencapsulated aspirin 162.5 mg ( P=0.0368) and aspirin EC 150 mg ( P=0.0004) compared with those remaining on aspirin EC 75 mg. Median EC 50 s on day 28 showed small but significant increases from baseline (day 0) in aggregation in patients randomised to microencapsulated aspirin 162.5 mg (0.62-0.85, P=0.0482) and in both aggregation and release in patients randomised to aspirin EC 150 mg (0. 95-1.20, P=0.0002, 8.4-11.7, P<0.0001, respectively) signifying enhanced antiplatelet activity. No changes were seen in patients continuing on aspirin EC 75 mg. Results following addition of high dose aspirin in vitro suggest that mechanisms other than thromboxane synthesis may be operative in the long term effects of microencapsulated aspirin 162.5 mg and aspirin EC 150 mg over aspirin EC 75 mg.