Suppression of Thromboxane A<sub>2</sub>but Not of Systemic Prostacyclin by Controlled-Release Aspirin

Clarke, Robert; Mayo, Gail; Price, Peter M.; FitzGerald, Garret A.

doi:10.1056/nejm199110173251605

Cited by 309 publications

(67 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This finding suggests that the increased PGI 2 formation in part reflects COX-2 expression. However, urinary 2,3-dinor-6-keto-PGF 1␣ was not reduced to the low levels seen in normal subjects taking aspirin 8,37 either before or after surgery. Thus, the increase in PGI 2 biosynthesis seen in atherosclerosis appears to reflect the activity of both COX isoforms.…”

Section: Discussionmentioning

confidence: 64%

“…Thus, platelet-specific preparations of aspirin with no effect on vascular COX maximally suppress TXA 2 formation, 8 whereas the selective inhibition of COX-2 has very little effect. [21][22][23] The results of similar studies with regular-and low-dose aspirin suggest that platelet COX is also a major source of the increased TXA 2 biosynthesis seen in patients with atherosclerosis, possibly reflecting enhanced platelet activity.…”

Section: Discussionmentioning

confidence: 99%

“…This relatively high dose of aspirin was selected because the study was conducted for only 3 days and because optimal inhibition of platelet COX may be delayed with low-dose aspirin regimens. 8 Patients with a history of active peptic ulcer disease or with renal or hepatic impairment were excluded from the study. Blood for serum TXB 2 and endotoxin-induced PGE 2 (COX-1 and -2 bioactivity, respectively) levels was collected at baseline and 1 hour after the first dose of drug.…”

Section: Subjectsmentioning

confidence: 99%

See 2 more Smart Citations

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

et al. 2000

View full text Add to dashboard Cite

Background-The formation of prostacyclin (PGI 2 ), thromboxane (TX) A 2 , and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis. Methods and Results-The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1␣ , metabolites of TXA 2 and PGI 2 , respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211Ϯ533 versus 679Ϯ63 pg/mg creatinine, PϽ0.001; 594Ϯ156 versus 130Ϯ22 pg/mg creatinine, PϽ0.05, respectively), as was the level of the isoprostane 8-iso-PGF 2␣ . Nimesulide reduced 2,3-dinor-6-keto-PGF 1␣ excretion by 46Ϯ5% (378.3Ϯ103 to 167Ϯ37 pg/mg creatinine, PϽ0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB 2 before (2678Ϯ694 to 2110Ϯ282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF 2␣ excretion. Conclusions-Both COX-1 and -2 are expressed and contribute to the increase in PGI 2 in patients with atherosclerosis, whereas TXA 2 is generated by COX-1. (Circulation. 2000;102:840-845.)

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

See 1 more Smart Citation

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

et al. 2000

View full text Add to dashboard Cite

show abstract

“…The benefits of aspirin as secondary prevention for cardiovascular disease are related to inhibition of the production of TXA 2 , a potent, locally acting vasoconstrictor and platelet activator [3]. TXA 2 is produced in platelets from arachidonic acid by the sequential action of the enzymes COX-1 and thromboxane synthase [20], and is rapidly degraded to the stable metabolite TXB 2 . Aspirin (ASA) is a potent irreversible inhibitor of COX-1, preventing the synthesis of TXA 2 , hence reducing the production of TXB 2 [20].…”

Section: Discussionmentioning

confidence: 99%

“…TXA 2 is produced in platelets from arachidonic acid by the sequential action of the enzymes COX-1 and thromboxane synthase [20], and is rapidly degraded to the stable metabolite TXB 2 . Aspirin (ASA) is a potent irreversible inhibitor of COX-1, preventing the synthesis of TXA 2 , hence reducing the production of TXB 2 [20]. The current study showed that serum TXB 2 and urine 11-dehydro-TXB 2 levels were inhibited in a dose-dependent manner following single doses of both ASA formulations.…”

Section: Discussionmentioning

confidence: 99%

A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation

Patrick¹,

Dillaha²,

Armas

et al. 2015

Postgraduate Medicine

View full text Add to dashboard Cite

Aims. Low-dose acetylsalicylic acid (ASA; aspirin) for secondary prevention reduces cardiovascular disease mortality risk. ASA acetylates cyclooxygenase in the portal circulation and is rapidly (halflife, 20 min) hydrolyzed. Certain patients with cardiovascular disease may exhibit high on-therapy platelet reactivity as a result of high platelet turnover, a process whereby platelets are produced and are active beyond the duration of antiplatelet coverage provided by once-daily immediaterelease (IR) ASA. A once-daily, extended-release (ER) ASA formulation using ER microcapsule technology was developed to release ASA over the 24-h dosing interval and reduce maximal plasma concentrations to spare peripheral endogenous endothelial prostacyclin production. Methods. Healthy adults (n = 50) were randomized in a crossover study to receive two different ER-ASA single doses (up to 325 mg) and two different IR-ASA single doses (up to 81 mg) in four periods, each separated by ‡14 days. Pharmacodynamics was assessed by measuring serum thromboxane B 2 (TXB 2 ), urine 11-dehydro-TXB 2 , and arachidonic acid-induced platelet aggregation. Pharmacokinetics was determined for ASA and salicylic acid (SA). Results: Both formulations produced dose-dependent inhibition on all pharmacodynamic parameters. Marked inhibition of TXB 2 and 11-dehydro-TXB 2 was maintained over the 24-h dosing interval after a dose of ‡81 mg ER-ASA or ‡40 mg IR-ASA. The dose required to achieve 50% of maximum TXB 2 inhibition with ER-ASA was 49.9 mg versus 29.6 mg for IR-ASA, for a similar maximum pharmacodynamic effect (98.9% TXB 2 inhibition). This suggests that an approximately twofold greater ER-ASA dose (162.5 mg) is necessary to obtain the same response as that of IR-ASA 81 mg. Peak ASA concentrations were lower and T max was longer with ER-ASA versus IR-ASA. Administration of IR-ASA resulted in a dosenormalized mean C max of ASA that was approximately sixfold higher than that for ER-ASA and a C max of SA approximately two-to threefold higher than that for ER-ASA. Conclusion. Both ASA formulations showed dose-dependent antiplatelet activity. Compared with the IR-ASA, ER-ASA released active drug more slowly, resulting in prolonged absorption and lower systemic drug concentrations, which is expected for an ER (24-h) formulation.

show abstract

Optimal Dose for Starting and Maintaining Low-Dose Aspirin

Kearon¹,

Hirsh²

1993

Arch Intern Med

View full text Add to dashboard Cite

Suppression of Thromboxane A₂but Not of Systemic Prostacyclin by Controlled-Release Aspirin

Cited by 309 publications

References 40 publications

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation

Optimal Dose for Starting and Maintaining Low-Dose Aspirin

Contact Info

Product

Resources

About

Suppression of Thromboxane A2but Not of Systemic Prostacyclin by Controlled-Release Aspirin

Cited by 309 publications

References 40 publications

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation

Optimal Dose for Starting and Maintaining Low-Dose Aspirin

Contact Info

Product

Resources

About

Suppression of Thromboxane A₂but Not of Systemic Prostacyclin by Controlled-Release Aspirin