NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Minuz, Pietro; Degan, Maurizio; Gaino, Stefania; Meneguzzi, Alessandra; Zuliani, Valeria; Santonastaso, Clara; Soldato, Piero Del; Lechi, Alessandro

doi:10.1038/sj.bjp.0704326

Cited by 32 publications

(31 citation statements)

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“…19,20 It has been shown that inhibition of cytokine release is associated with cysteine-nitration and inhibition of caspase-I. Therefore, suppression of IL-1␤ and IL-18 processing may explain the antiinflammatory effects of NCX-4016, 19,34 and TF inhibition may contribute to NCX-4016 antiinflammatory activity.…”

Section: Fiorucci Et Al Tissue Factor Inhibition By Ncx-4016mentioning

confidence: 99%

“…This is consistent with previous evidence that ASA and NCX-4016 have similar inhibitory capacities on TX generation when tested in vitro in LPS-stimulated monocytes and ex vivo in thrombin-stimulated platelets. 20,21 The observed reduction in TX metabolite excretion may imply that COX activity is the major target of NCX-4016. However, the reduction in urinary 11-dh-TxB 2 may result also from inhibition of COX-2 expression.…”

Section: Fiorucci Et Al Tissue Factor Inhibition By Ncx-4016mentioning

confidence: 99%

“…It has been shown that 100 to 300 mol/L NCX-4016 is able to reduce in vitro both the expression of TF and its activity in human monocytes stimulated with LPS. 20 Although ASA lacks in vivo activity, an inhibitory effect has been observed at millimolar concentrations in vitro. 10 This is the first evidence that NO donors prevent TF expression in vivo.…”

Section: Fiorucci Et Al Tissue Factor Inhibition By Ncx-4016mentioning

confidence: 99%

“…The dosages and timing were chosen to allow absorption of equimolar concentration of ASA and NO and on the basis of previous study demonstrating that at least 3 days were required by NCX-4016 to obtain full inhibitory activity on TXA 2 production. 20,21 Drugs were dissolved in carboxy-methyl-cellulose and administered by gavage at a final volume of 500 L. On day 5, rats were fasted overnight; 3 hours after oral administration of the last dose of the indicate drug, the rats were given an intraperitoneal injection of 100 g/kg of bacterial endotoxin (LPS) [Escherichia coli Serotype 055:B5 (Sigma)]. Animals were killed 6 hours later, and blood samples were taken by cardiac puncture.…”

Section: Study Protocolmentioning

confidence: 99%

“…16 -18 In addition, NCX-4016 has also been shown to have multiple inhibitory activities on LPS-stimulated monocytes, being able to reduce the release of prostanoids and cytokines as well as the expression and the activity of TF. 19,20 This suggests that NCX-4016 might blunt in vivo monocyte activation preventing induction of TF expression. We tested this hypothesis by comparing the effects of NCX-4016 with equimolar ASA and isosorbide-5-mononitrate (ISMN) in a rodent model of acute inflammation.…”

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

et al. 2002

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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.)

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Section: Fiorucci Et Al Tissue Factor Inhibition By Ncx-4016mentioning

confidence: 99%

Section: Fiorucci Et Al Tissue Factor Inhibition By Ncx-4016mentioning

confidence: 99%

Section: Fiorucci Et Al Tissue Factor Inhibition By Ncx-4016mentioning

confidence: 99%

Section: Study Protocolmentioning

confidence: 99%

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

et al. 2002

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Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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Nitric oxide-donating aspirins spare the gastrointestinal (GI) system and improve the treatment of inflammation-related GI and cardiovascular pathologies

Bolla¹,

Acuto²,

Soldato³

2004

Pharmacotherapy of Gastrointestinal Inflammation

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NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Cited by 32 publications

References 29 publications

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

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

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Nitric oxide-donating aspirins spare the gastrointestinal (GI) system and improve the treatment of inflammation-related GI and cardiovascular pathologies

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