Effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on retinal vascularity in diabetic rats.

BACKGROUND: The aim of the present study is to investigate the effectiveness of terutroban, a selective antagonist of the thromboxane/prostaglandin endoperoxide receptor, in preventing retinal ischaemia in a model of diabetes in rats. METHODS: Experimental diabetes was induced with streptozotocin. Rats were distributed into five groups (n = 20): (1) non-diabetic rats, (2) rats with diabetes (DR) treated with vehicle, (3) DR treated with aspirin (2 mg/kg/day p.o.), (4) DR treated with terutroban (5 mg/kg/day p.o.), (5) DR treated with terutroban (30 mg/kg/day p.o.). The follow-up period was 3 months. The main assessment was the percentage of retinal surface covered with vessels permeable to peroxidase. Platelet aggregation, aortic prostacyclin and nitric oxide production, plasma levels of lipid peroxides (thiobarbituric-acid-reactive substances) and 3-nitrotyrosine and serum levels of IL-6 were evaluated. RESULTS: Diabetes induced a reduction in retinal vascularity (76.9%), aortic prostacyclin (37.8%) and nitric oxide production (35.0%), and increased platelet aggregation, lipid peroxides, 3-nitrotyrosine. When compared with vehicle-treated DR, terutroban increased the percentage of retinal surface covered by PVPP (38% for terutroban-5 and 61% for terutroban-30), aortic prostacyclin (188% for terutroban-5 and 146% for terutroban-30) and nitric oxide production (320% for terutroban-5 and 390% for terutroban-30). Moreover, terutroban reduced platelet reactivity (27.8­95.1%, according to the inducer), lipid peroxides (60.7% for terutroban-5 and 50.0% for terutroban-30), 3-nitrotyrosine (43.8% for terutroban-5 and 36.8% for terutroban-30) and IL-6 concentration (18.0% for terutroban-30). The effect of terutroban in retinal, nitrosative and aortic parameters was significantly higher than that of aspirin. CONCLUSIONS: Terutroban significantly protected retinal vascularity from ischaemia in experimental diabetes, and this result could be attributed not only to its antiplatelet/antithrombotic activities but also to its vascular properties.

Differences in the in vitro antiplatelet effect of dexibuprofen, ibuprofen, and flurbiprofen in human blood.

BACKGROUND: In this study, we compared the in vitro pharmacodynamic profile of dexibuprofen, ibuprofen, and flurbiprofen to identify possible differences in antiplatelet activity. METHODS: In whole blood samples from healthy volunteers, we measured platelet aggregation induced by adenosine diphosphate, collagen and arachidonic acid, platelet thromboxane B(2) (TxB(2)), lipopolysaccharide-induced prostaglandin E(2), leukocyte 6-keto-prostaglandin F(1α) (PGF(1α)), and nitric oxide induced by both constitutive and inducible pathways before and after incubation with increasing concentrations of acetylsalicylic acid, dexibuprofen, ibuprofen, or flurbiprofen. The concentration that inhibited (IC(50)) or increased each variable by 50% was calculated. RESULTS: All 3 drugs inhibited platelet aggregation in a dose-dependent manner, TxB(2), prostaglandin E(2), and 6-keto-PGF(1α), and increased calcium-induced nitric oxide production. Dexibuprofen showed greater antiplatelet potency than ibuprofen and flurbiprofen, and its profile was similar to that of aspirin. For example, IC(50) values for arachidonic acid-induced platelet aggregation were 0.85 ± 0.06 µM for dexibuprofen, 14.76 ± 1.22 µM for ibuprofen, 6.39 ± 0.51 µM for flurbiprofen, and 0.38 ± 0.03 µM for aspirin. All drugs inhibited both thromboxane and prostacyclin synthesis, but the IC(50) anti-TxB(2)/IC(50) anti-6-keto-PGF(1α) ratio was 0.21 ± 0.03 for dexibuprofen, 1.05 ± 0.08 for ibuprofen, 0.79 ± 0.11 for flurbiprofen, and 0.46 ± 0.06 for aspirin. All drugs increased calcium-dependent nitric oxide production. CONCLUSIONS: The aryl propionic acid derivative dexibuprofen was the most potent antiplatelet drug, and its pharmacodynamic profile is similar to aspirin.