title: Characterization of the anti-inflammatory properties of NCX 429, a dual-acting compound releasing nitric oxide and naproxen.
abstract: OBJECTIVE
  Cyclooxygenase (COX)-inhibiting nitric oxide donors (CINODs) are a new class of drugs that structurally combine a COX inhibitor with a nitric oxide (NO) donating moiety. This combination reduces potential toxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) whilst maintaining the analgesic and anti-inflammatory effects. The present study was undertaken to investigate the anti-inflammatory effects of NCX 429, a naproxen-based CINOD, and to assess the additional properties of NO donation beyond those related to naproxen.
  
  
  METHODS
  We evaluated the in vitro effects of NCX 429 on oxy-radical production, phagocytosis, cytokine release, MMP-9, PPARγ expression and NF-κB activation in human monocytes/MDM and compared to naproxen. Moreover, we compared the in vivo efficacy of NCX 429 and naproxen in a murine model of peritonitis.
  
  
  RESULTS
  In all the experiments performed in vitro, NCX 429 reduced the inflammatory responses with equal or higher efficacy compared to naproxen. Moreover, in in vivo experiments, NCX 429, at the lowest dose tested, was able to significantly inhibit cell influx in response to IL-1β administration although naproxen was found to be more potent than NCX 429 at reducing PGE2 in inflammatory exudates.
  
  
  CONCLUSIONS
  These results demonstrate that both in vitro and in vivo--in a murine model of peritonitis--NCX 429 elicits significant anti-inflammatory activity, beyond the simple COX inhibition or pure NO release. Therefore, NO donation along with COX inhibition may represent a strategy for investigating inflammatory diseases in which pain and function are not fully resolved by analgesics/anti-inflammatory drugs.
authors.affiliation: Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Amoruso
authors.affiliation: Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy. Electronic address: fresu@med.unipmn.it.
authors.forename: Luigia Grazia
authors.initials: LG
authors.lastname: Fresu
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Preoperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Louis Pasteur Avenue, Boston, MA 02115, USA.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Nicox Research Institute, Via L. Ariosto, 20091 Bresso, Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Miglietta
authors.affiliation: Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bardelli
authors.affiliation: The William Harvey Research Institute, Barts and The London Medical School, Charterhouse Square, London EC1M 6QB, UK.
authors.forename: Donata
authors.initials: D
authors.lastname: Federici Canova
authors.affiliation: The William Harvey Research Institute, Barts and The London Medical School, Charterhouse Square, London EC1M 6QB, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy; Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD), Novara, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Brunelleschi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009288:Naproxen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D009566:Nitrates / Q000493:pharmacokinetics / Q000494:pharmacology; D009569:Nitric Oxide / Q000493:pharmacokinetics*; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects
chemical_list: C574441:6-(nitrooxy)hexyl 2-(6-methoxynaphthalen-2-yl)propanoate; D000894:Anti-Inflammatory Agents, Non-Steroidal; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D009566:Nitrates; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D009288:Naproxen; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone
keywords: Human monocyte/macrophages; Inflammation; Mouse peritonitis model; NCX 429; Naproxen; Nitric oxide