(Circulation. 1997;96:1109-1116.)
© 1997 American Heart Association, Inc.
Articles |
Differential Suppression of Thromboxane Biosynthesis by Indobufen and Aspirin in Patients With Unstable Angina
From the Departments of Pharmacology (P.P., A.G., M.R.P., R.P., C.P.) and Medicine (F. Cipollone, F. Cuccurullo), University of Chieti G. D'Annunzio School of Medicine, Chieti, and the Department of Cardiology, Catholic University School of Medicine (A.G.R., G.L., G.Q., A.M.), Rome, Italy.
Correspondence to Francesco Cipollone, MD, Istituto di Fisiopatologia Medica, Università degli Studi G. D'Annunzio, Via dei Vestini, 31, 66013 Chieti, Italy.
Background We have previously reported aspirin failure in suppressing enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation during the acute phase of unstable angina. The recent discovery of a second prostaglandin H synthase (PGHS-2), inducible in response to inflammatory or mitogenic stimuli, prompted us to reexamine TXA2 biosynthesis in unstable angina as modified by two cyclooxygenase inhibitors differentially affecting PGHS-2 despite a comparable impact on platelet PGHS-1.
Methods and Results We randomized 20 patients (15 men and 5 women aged 59±10 years) with unstable angina to short-term treatment with aspirin (320 mg/d) or indobufen (200 mg BID) and collected 6 to 18 consecutive urine samples. Urinary 11-dehydro-TXB2 was extracted and measured by a previously validated radioimmunoassay as a reflection of in vivo TXA2 biosynthesis. Metabolite excretion averaged 102 pg/mg creatinine (median value; n=76) in the aspirin group and 55 pg/mg creatinine (median value; n=99) in the indobufen group (P<.001). There were 16 samples (21%) with 11-dehydro-TXB2 excretion >200 pg/mg creatinine among patients treated with aspirin versus 6 such samples (6%) among those treated with indobufen (P<.001). In vitro and ex vivo studies in healthy subjects demonstrated the capacity of indobufen to largely suppress monocyte PGHS-2 activity at therapeutic plasma concentrations. In contrast, aspirin could only inhibit monocyte PGHS-2 transiently at very high concentrations.
Conclusions We conclude that in unstable angina, episodes of aspirin-insensitive TXA2 biosynthesis may reflect extraplatelet sources, possibly expressing the inducible PGHS in response to a local inflammatory milieu, and a selective PGHS-2 inhibitor would be an ideal tool to test the clinical relevance of this novel pathway of arachidonic acid metabolism in this setting.
Key Words: thromboxane • indobufen • aspirin • angina
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