Protective effects of triflusal on secondary thrombus growth and vascular cyclooxygenase-2.

X Duran, S Sánchez, G Vilahur, L Badimon

Index: J. Thromb. Haemost. 6(8) , 1385-92, (2008)

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Abstract

Carotid residual mural thrombus predisposes to recurrent thrombosis and/or distal embolization (i.e. cerebrovascular ischemia).Our aims were (i) to analyze and compare the efficacy of aspirin, triflusal, and its main metabolite 2-hydroxy-4-trifluorometylbenzoic acid (HTB) on secondary thrombus growth; and (ii) evaluate to what extent the three Cox-1 inhibitors influenced vascular Cox-1/Cox-2 expression and endothelial prostacyclin synthesis.In a rabbit model of ex vivo thrombosis, a fresh mural thrombus was formed on damaged vessels at flow conditions typical of mild and severe carotid stenoses. The effects of Cox-1 inhibitors administered both intravenously (i.v.) (aspirin 5 mg kg(-1), triflusal 10 mg kg(-1), and HTB 10 mg kg(-1)) and orally (p.o.) (8 days; aspirin 30 mg kg(-1) day(-1), and triflusal 40 mg kg(-1) day(-1)) on secondary thrombus growth were assessed by In-(111)deposited platelets and compared with a placebo control. Arterial Cox-1/Cox-2 expression after 8-day treatment was evaluated at mRNA and protein levels. Additionally, a drug-related dose-dependent in vitro assay was performed for endothelial PGI(2) release measurement (Cox-2 activity).All Cox inhibitors similarly and significantly (P < 0.05) reduced secondary thrombus formation after i.v. and p.o. administration versus placebo control. Treatments exerted no effect on vascular Cox-1 mRNA whereas Cox-2 mRNA was moderately reduced by aspirin and triflusal (placebo 100% +/- 9%, aspirin 70% +/- 2% and triflusal 70% +/- 2%; P < 0.05). Cox-2 protein levels were slightly higher in the triflusal versus aspirin group (placebo 100% +/- 6%, aspirin 35% +/- 10% and triflusal 61% +/- 9%; P < 0.005 versus placebo). Interestingly, in vitro, HTB solely maintained endothelial PGI(2) synthesis levels similar to the control.At a similar level of efficacy in inhibiting secondary thrombosis, triflusal seems to better preserve Cox-2 expression than aspirin and its metabolite HTB was able to protect endothelial prostacyclin production.