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.
OBJECTIVE
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/ 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.


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.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Epatologia, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
Mencarelli
Andrea
A
Meneguzzi
Alessandra
A
Lechi
Alessandro
A
Renga
Barbara
B
del Soldato
Piero
P
Morelli
Antonio
A
Minuz
Pietro
P
D000284:Administration, Oral; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004386:Duodenum / Q000187:drug effects; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000187:drug effects*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012016:Reference Values; D016037:Single-Blind Method; D013270:Stomach / Q000187:drug effects*; D013928:Thromboxane A2 / Q000378:metabolism; D013929:Thromboxane B2 / Q000652:urine
D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; D013928:Thromboxane A2; C102148:nitroaspirin; D001241:Aspirin