DIFFERENTIAL SUPPRESSION OF THROMBOXANE BIOSYNTHESIS BY INDOBUFEN ANDASPIRIN IN PATIENTS WITH UNSTABLE ANGINA

Background We have previously reported aspirin failure in suppressing enhanced thromboxane (TX) biosynthesis in a subset of episodes of plat elet 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 reexamin e TXA(2) biosynthesis in unstable angina as modified by two cyclooxyge nase inhibitors differentially affecting PGHS-2 despite a comparable i mpact on platelet PGHS-1. Methods and Results We randomized 20 patient s (15 men and 5 women aged 59 +/- 10 years) with unstable angina to sh ort-term treatment with aspirin (320 mg/d) or indobufen (200 mg BID) a nd collected 6 to 18 consecutive urine samples. Urinary 11-dehydro-TXB 2 was extracted and measured by a previously validated radioimmunoassa y as a reflection of in vivo TXA(2) biosynthesis. Metabolite excretion averaged 102 pg/mg creatinine (median value; n=76) in the aspirin gro up 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 suc h samples (6%) among those treated with indobufen (P<.001). In vitro a nd ex vivo studies in healthy subjects demonstrated the capacity of in dobufen to largely suppress monocyte PGHS-2 activity at therapeutic pl asma concentrations. In contrast, aspirin could only inhibit monocyte PGHS-2 transiently at very high concentrations. Conclusions We conclud e that in unstable angina, episodes of aspirin-insensitive TXA(2) bios ynthesis may reflect extraplatelet sources, possibly expressing the in ducible PGHS in response to a local inflammatory milieu, and a selecti ve PGHS-2 inhibitor would be an ideal tool to test the clinical releva nce of this novel pathway of arachidonic acid metabolism in this setti ng.