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CLINICAL RESEARCH

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

Stefano Fiorucci, MD^*, Andrea Mencarelli, BS^*, Alessandra Meneguzzi, BS, Alessandro Lechi, MD, Barbara Renga, BS^*, Piero del Soldato, PhD, Antonio Morelli, MD^* and Pietro Minuz, MD^,*

^* Clinica di Gastroenterologia ed Epatologia, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
Section of Internal Medicine, Department of Biomedical and Surgical Sciences, University of Verona, Verona, Italy
NicOx S.A., Sophia Antipolis, France
New York Medical College, Valhalla, New York, USA

Manuscript received January 30, 2004; revised manuscript received February 27, 2004, accepted March 2, 2004.

^* Reprint requests and correspondence: Dr. Pietro Minuz, Medicina Interna C, Policlinico GB Rossi, Piazzale LA Scuro, 10, 37134 Verona, Italy.
pietro.minuz{at}univr.it

OBJECTIVES: 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.

BACKGROUND: 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.

METHODS: 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.

RESULTS: Similar to aspirin alone, NCX-4016 effectively inhibited platelet aggregation induced by 0.6 mmol/l 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 µmol/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 µmol/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.

CONCLUSIONS: 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.

Abbreviations and Acronyms   ASA = aspirin/acetylsalicylic acid   COX = cyclooxygenase   IL = interleukin   LPS = lipopolysaccharide   NO = nitric oxide   PAR = proteinase activated receptor   TF = tissue factor   TRAP = thrombin receptor activator protein   TX = thromboxane

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