Co-Administration of Nitric Oxide-Aspirin (NCX-4016) and Aspirin Prevents Platelet and Monocyte Activation and Protects Against Gastric Damage Induced by Aspirin in Humans

Abstract

The goal of this study was to test the hypothesis that NCX-4016 may have broader anti-inflammatory and antithrombotic effects as well as better gastric tolerability than aspirin in humans. NCX-4016 is an aspirin derivative containing a nitric oxide-releasing moiety that prevents platelet activation and modulates tissue factor (TF) expression and cytokine release from lipopolysaccharide (LPS)-stimulated monocytes. This was a blind-observer, placebo-controlled, parallel-group study in which 48 healthy subjects were randomized to receive NCX-4016 800 mg twice a day, NCX-4016 800 mg twice a day plus aspirin 325 mg, aspirin 325 mg, or placebo for 21 days. Similar to aspirin alone, NCX-4016 effectively inhibited platelet aggregation induced by 0.6 mmol/ arachidonic acid, clot-stimulated thromboxane (TX) B2 generation in whole blood, and urinary excretion of 11-dehydro-TXB2. Unlike aspirin alone, the administration of NCX-4016 significantly inhibited TF expression in monocytes stimulated ex vivo with 10 micromol/l LPS (determined by flow-cytometry analysis of TF on CD14 positive cells). NCX-4016 also inhibited the rapid TF expression induced in monocytes by a proteinase activated receptor agonist (thrombin receptor activator protein, 2 micromol/l) as well as LPS-induced expression of CD11b . Ex vivo, release of MCP-1 and interleukin-6 were significantly inhibited by NCX-4016, but not by aspirin. NCX-4016 was not associated with gastric damage, and significantly reduced gastric injury when co-administered with aspirin, although both drugs reduced gastric PGE2 production to the same extent. NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation. Larger multicenter trials are warranted to establish clinical efficacy and safety of NCX-4016.