NCX-4016 (NO-Aspirin) Inhibits Lipopolysaccharide-Induced Tissue Factor Expression In Vivo

Abstract

Background-NCX-4016 is an acetylsalicylic acid (ASA) derivative containing a nitric oxide-releasing moiety. Compared with ASA, NCX-4016 has a broader spectrum of antithrombotic and antiinflammatory activities. We hypothesized that NCX-4016 might inhibit in vivo lipopolysaccharide (LPS)-induced expression of tissue factor (TF). Methods and Results-Rats were administered 90 mg/kg NCX-4016 orally for 5 days. Placebo, 50 mg/kg ASA, and 80 mg/kg isosorbide-5-mononitrate (ISMN) were used in control groups. On day 5, rats were injected intraperitoneally with 100 g/kg LPS and killed 6 hours later. The expression of TF in monocytes was measured by flow cytometry and Western blot analysis. Reverse transcriptase-polymerase chain reaction was performed to assess expression of TF and cyclooxygenase-2 (COX-2) genes. Plasma concentrations of interleukin-1␤ and tumor necrosis factor-␣ were measured. Urine samples were collected to evaluate the excretion of the thromboxane metabolite 11-dehydro-thromboxane (TX)B 2 . Gastric mucosa was inspected. LPS injection was followed by synthesis TF and COX-2 mRNAs in circulating monocytes, which were blunted by NCX-4016 but not by ASA or ISMN. Both NCX-4016 and ISMN reduced TF expression on surface of circulating monocyte. LPS increased the excretion 11-dehydro-TXB 2 , and this was prevented by NCX-4016 and ASA. Unlike ASA, NCX-4016 reduced plasma interleukin-1␤ and tumor necrosis factor-␣. In addition, NCX-4016 almost completely prevented mucosal damage, whereas ASA increased the extension of gastric lesions in LPS-injected rats. Conclusions-NCX-4016 prevents monocyte TF expression; this is accompanied by inhibition of TX and cytokine biosynthesis. These additive effects of nitric oxide release and COX inhibition may help explain efficacy and tolerability of NCX-4016. (Circulation. 2002;106:3120-3125.)

Cooperation between Aspirin-Triggered Lipoxin and Nitric Oxide (NO) Mediates Antiadhesive Properties of 2-(Acetyloxy)benzoic Acid 3-(Nitrooxymethyl)phenyl Ester (NCX-4016) (NO-Aspirin) on Neutrophil-Endothelial Cell Adherence

“…1a) is the prototype of a new class of antiplatelet and anti-inflammatory drugs obtained by coupling a NO-releasing moiety to acetylsalicylic acid (Wallace et al, 1999(Wallace et al, , 2002Fiorucci et al, 2000Fiorucci et al, , 2002bFiorucci et al, , 2003Fiorucci and Del Soldato, 2003). NCX-4016 inhibits COX-1 and COX-2 activity (Wallace et al, 1999(Wallace et al, , 2002Fiorucci et al, 2002a;Fiorucci and Del Soldato, 2003) and triggers ATL formation in vivo (Fiorucci et al, 2003). Previous studies in rodents have shown that NCX-4016 is more effective than aspirin in preventing myocardial infarction and restenosis after carotid angioplasty (Wallace et al, 2002).…”

“…Previous studies in rodents have shown that NCX-4016 is more effective than aspirin in preventing myocardial infarction and restenosis after carotid angioplasty (Wallace et al, 2002). In contrast to aspirin, but similarly to NO donors, NCX-4016 modulates the expression of tissue factor on monocytes (Fiorucci et al, 2002a) as well as cytokine secretion from activated macrophages (Fiorucci et al, 2000), thereby suggesting that both the aspirin and the NO moiety contribute to its pharmacological activity.…”

Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa

“…NCX-4016 is a NO-releasing derivative of aspirin (16)(17)(18)(19)(20)(21). Both the aspirin and the NO-releasing moieties of this compound contribute to its effectiveness (16).…”

“…Both the aspirin and the NO-releasing moieties of this compound contribute to its effectiveness (16). Thus, not only does NCX-4016 inhibit COX-1 and COX-2 activity in vivo (16)(17)(18) and in vitro (19), it also increases platelet cyclic guanosyl monophate concentrations (17), inhibits platelet aggregation induced by adenosine diphosphate and thrombin (i.e., aspirinresistant aggregation) (16), and modulates tissue factor expression and activity in vivo and in vitro (19). Consistent with the fact that NO is a multifunctional regulatory molecule and mediates many components of gastrointestinal mucosal defence (20), NCX-4016 spares the gastrointestinal tract in healthy human volunteers (21) while retaining antiplatelet activity.…”

Comparison between Flurbiprofen and its Nitric Oxide-Releasing Derivatives HCT-1026 and NCX-2216 on Aβ(1-42)-Induced Brain Inflammation and Neuronal Damage in the Rat

“…NO is an extremely reactive molecule which can directly or indirectly interact with a variety of targets, including transcriptional regulators, enzymes and receptors (32)(33)). An anti-inflammatory effect of NO at micromolar concentrations has been suggested by studies demonstrating inhibition of Th-l-dependent cytokines (IL-l, IL-18 and IFN -), T lymphocyte proliferation, T-cell-mediated diseases (32)(33)(35)(36) and lipopolysaccharide-induced expression of tissue factor (37). However, in our experiments, a significant increase in extracellular nitrite, indicating a large NO formation at the dose used, was detected only after the administration ofHCT-1026.…”