European Journal of Clinical Pharmacology

, Volume 62, Supplement 1, pp 145–154 | Cite as

Nitric oxide-donating aspirin (NCX 4016): an overview of its pharmacological properties and clinical perspectives

  • Manlio BollaEmail author
  • Stefania Momi
  • Paolo Gresele
  • Piero Del Soldato
Review Article


In more than a century of use, the benefits of aspirin have been exploited in different therapeutic areas, from inflammation to cardiovascular disease for which it is an approved treatment for acute coronary heart disease and a recommended treatment for secondary cardiovascular prevention in patients at risk. Nitric oxide (NO), a small gaseous free radical molecule, is an important messenger of cellular and biological function that demonstrates an interesting anti-inflammatory profile and vascular protective activity. In addition, NO exerts a protective action on the gastrointestinal mucosa. An elegant approach for exploiting the properties of both aspirin and NO, and for eventually increasing the overall activity of aspirin, has been to create a new molecule in which aspirin and a NO-donating group are covalently linked (NCX 4016). This molecule requires enzymatic metabolism to release both components in order to provide simultaneous actions. NCX 4016 has been shown to retain the anti-inflammatory properties of aspirin and therefore possesses the same efficacy as aspirin in animal models of pain and inflammation. In addition, the release of NO accounts for the inhibition of the release of some cytokines. In cardiovascular models, NCX 4016 shows a better efficacy than aspirin in counteracting thromboembolism, myocardial infarction and vascular reactivity and remodelling (restenosis). This review describes the pharmacological profile of the NO-donating aspirin, NCX 4016, by addressing principally the pharmacological activity in inflammation and cardiovascular models. Gastrointestinal safety is specifically addressed. The potential clinical use of NCX 4016 in vascular pathologies is also discussed.


NCX 4016 Cardiovascular pathologies Inflammation 


  1. 1.
    Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE (2001) Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomized trials. Heart 85:265–271PubMedCrossRefGoogle Scholar
  2. 2.
    Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel B, Russell RO, Smith EE III, Weaver WD, Gibbons RJ, Alpert JS, Eagle KA, Gardner TJ, Garson A Jr, Gregoratos G, Ryan TJ, Smith SC Jr (1999) 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 34:890–911PubMedCrossRefGoogle Scholar
  3. 3.
    Ivey KJ (1988) Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Actions of therapeutic agents. Am J Med 84:41–48PubMedCrossRefGoogle Scholar
  4. 4.
    Derry S, Loke YK (2000) Risk of gastrointestinal haemorrhage with long-term use of aspirin: meta-analysis. Br Med J 321:1183–1187CrossRefGoogle Scholar
  5. 5.
    Wolfe MM, Lichtenstein DR, Singh G (1999) Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888–1899PubMedCrossRefGoogle Scholar
  6. 6.
    Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 231:232–235Google Scholar
  7. 7.
    Vane JR, Flower RJ, Botting RM (1990) History of aspirin and its mechanism of action. Stroke 21:12–23Google Scholar
  8. 8.
    Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL (1991) Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 88:2692–2696CrossRefGoogle Scholar
  9. 9.
    Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 99:13926–13931PubMedCrossRefGoogle Scholar
  10. 10.
    Schwab JM, Schluesener HJ, Laufer S (2003) COX-3: just another COX or the solitary elusive target of paracetamol? Lancet 361:981–982PubMedCrossRefGoogle Scholar
  11. 11.
    Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954–956PubMedCrossRefGoogle Scholar
  12. 12.
    Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR (2002) COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 360:1071–1073PubMedCrossRefGoogle Scholar
  13. 13.
    Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J (2004) Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 109:2068–2073PubMedCrossRefGoogle Scholar
  14. 14.
    Rocha JL, Fernandez-Alonso J (2001) Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 357:1946–1947PubMedCrossRefGoogle Scholar
  15. 15.
    Cheng HF, Harris RC (2004) Cyclooxygenases, the kidney, and hypertension. Hypertension 43:525–530PubMedCrossRefGoogle Scholar
  16. 16.
    Bing RJ, Lomnicka M (2002) Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events? J Am Coll Cardiol 39:521–522PubMedCrossRefGoogle Scholar
  17. 17.
    McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 96:272–277PubMedCrossRefGoogle Scholar
  18. 18.
    Mukherjee D, Topol EJ (2003) Cox-2: where are we in 2003? – cardiovascular risk and cox-2 inhibitors. Arthritis Res Ther 5:8–11PubMedCrossRefGoogle Scholar
  19. 19.
    Wallace JL, Zamuner SR, McKnight W, Dicay M, Mencarelli A, Del Soldato P, Fiorucci S (2004) Aspirin, but not NO-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation. Am J Physiol Gastrointest Liver Physiol 286:G76–81PubMedCrossRefGoogle Scholar
  20. 20.
    Burgaud JL, Ongini E, Del Soldato P (2002) Nitric oxide-releasing drugs: a novel class of effective and safe therapeutic agents. Ann N Y Acad Sci 962:360–371PubMedCrossRefGoogle Scholar
  21. 21.
    Keeble JE, Moore PK (2002) Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs. Br J Pharmacol 137:295–310PubMedCrossRefGoogle Scholar
  22. 22.
    Wallace JL, Del Soldato P (2003) The therapeutic potential of NO-NSAIDs. Fundam Clin Pharmacol 17:11–20PubMedCrossRefGoogle Scholar
  23. 23.
    Chiroli V, Benedini F, Ongini E, Del Soldato P (2003) Nitric oxide-donating non-steroidal anti-inflammatory drugs: the case of nitroderivatives of aspirin. Eur J Med Chem 38:441–446PubMedCrossRefGoogle Scholar
  24. 24.
    Moncada S, Palmer RMJ, Higgs CA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  25. 25.
    Reichenbach G, Momi S, Gresele P (2005) Nitric oxide and its antithrombotic action on the cardiovascular system. Curr Drugs Target Cardiovasc Hematol Dis 5:65–74CrossRefGoogle Scholar
  26. 26.
    Moncada S, Higgs A, Furchgott R (1997) International union of pharmacology nomenclature in nitric oxide Research. Pharmacol Rev 49:137–142PubMedGoogle Scholar
  27. 27.
    Brunori M, Giuffre A, Sarti P, Stubauer G, Wilson MT (1999) Nitric oxide and cellular respiration. Cell Mol Life Sci 56:549–557PubMedCrossRefGoogle Scholar
  28. 28.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265–9269PubMedCrossRefGoogle Scholar
  29. 29.
    Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526PubMedCrossRefGoogle Scholar
  30. 30.
    Loscalzo J (2001) Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 88:756–762PubMedCrossRefGoogle Scholar
  31. 31.
    Feedman JE, Loscalzo J (2003) Nitric oxide and its relationship to thrombotic disorders. J Thromb Haemost 1:1183–1188CrossRefGoogle Scholar
  32. 32.
    Zhao M, Kim M, Morgello S, Lee SC (2001) Expression of inducible nitric oxide synthase, interleukin-1 and caspase-1 in HIV-1 encephalitis. J Neuroimmunol 115:182–191PubMedCrossRefGoogle Scholar
  33. 33.
    Wallace JL, Miller MJ (2000) Nitric oxide in mucosal defence: a little goes a long way. Gastroenterology 119:512–520PubMedCrossRefGoogle Scholar
  34. 34.
    Wallace JL, Ma L (2001) Inflammatory mediators in gastrointestinal defence and injury. Exp Biol Med 226:1003–1015Google Scholar
  35. 35.
    Lanas A, Bajador E, Serrano P, Fuentes J, Carreno S, Guardia J, Sanz M, Montoro M, Sainz R (2000) Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 343:834–839PubMedCrossRefGoogle Scholar
  36. 36.
    Carini M, Aldini G, Orioli M, Piccoli A, Tocchetti P, Facino RM (2004) Chemiluminescence and LC-MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers. J Pharm Biomed Anal 35:277–287PubMedCrossRefGoogle Scholar
  37. 37.
    Grosser N, Schröder H (2000) A common pathway for nitric oxide release from NO-aspirin and glyceryl trinitrate. Biochem Biophys Res Commun 274:255–258PubMedCrossRefGoogle Scholar
  38. 38.
    Schröder H (1992) Cytochrome P-450 mediates bioactivation of organic nitrates. J Pharmacol Exp Ther 262:298–302PubMedGoogle Scholar
  39. 39.
    Gao J, Kashfi K, Rigas B (2005) In vitro metabolism of nitric oxide-donating aspirin: the effect of positional isomerism. J Pharmacol Exp Ther 312:989–997PubMedCrossRefGoogle Scholar
  40. 40.
    Tagliaro F, Cuzzolin L, Adami A, Scarcella D, Crivellente F, Benoni G (1997) Pharmacokinetics of a new nitroderivative of acetylsalicylic acid after a single dose in rats. Life Sci 60:101–106PubMedCrossRefGoogle Scholar
  41. 41.
    Carini M, Aldini G, Orioli M, Facino RM (2002) In vitro metabolism of a nitroderivative of acetylsalicylic acid (NCX4016) by rat liver: LC and LC-MS studies. J Pharm Biomed Anal 29:1061–1071PubMedCrossRefGoogle Scholar
  42. 42.
    Carini M, Aldini G, Stefani R, Orioli M, Facino RM (2001) Nitrosylhemoglobin, an unequivocal index of nitric oxide release from nitroaspirin: in vitro and in vivo studies in the rat by ESR spectroscopy. J Pharm Biomed Anal 26:509–518PubMedCrossRefGoogle Scholar
  43. 43.
    Muscara’ MN, Lovren F, McKnight W, Dicay M, Del Soldato P, Triggle CR, Wallace JL (2001) Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats. Br J Pharmacol 133:1314–1322PubMedCrossRefGoogle Scholar
  44. 44.
    Carini M, Aldini G, Orioli M, Piccoli A, Rossoni G, Maffei Facino R (2004) Nitric oxide release and distribution following oral and intraperitoneal administration of nitroaspirin (NCX 4016) in the rat. Life Sci 74:3291–3305PubMedCrossRefGoogle Scholar
  45. 45.
    Fiorucci S, Mencarelli A, Mannucci R, Distrutti E, Morelli A, Del Soldato P, Moncada S (2002) NCX-4016, a nitric oxide-releasing aspirin, protects endothelial cells against apoptosis by modulating mitochondrial function. FASEB J 16:1645–1647PubMedGoogle Scholar
  46. 46.
    Mezzasoma AM, Momi S, Guglielmini G, Leone M, Del Soldato P, Gresele P (1999) Characterization of the activity of NCX 4016, a nitric oxide-releasing derivative of aspirin, on human blood platelets in vitro. Thromb Haemost 81(S):230Google Scholar
  47. 47.
    Lechi C, Andrioli G, Gaino S, Tommasoli R, Zuliani V, Ortolani R, Degan M, Benoni G, Bellavite P, Lechi A, Minuz P (1996) The antiplatelet effects of a new nitroderivative of acetylsalicylic acid – an in vitro study of inhibition on the early phase of platelet activation and on TXA2 production. Thromb Haemost 76:791–798PubMedGoogle Scholar
  48. 48.
    Lechi C, Gaino S, Tommasoli R, Zuliani V, Bonapace S, Fontana L, Degan M, Lechi A, Minuz P (1996) In vitro study of the anti-aggregating activity of two nitroderivatives of acetylsalicylic acid. Blood Coagul Fibrinol 7:206–209CrossRefGoogle Scholar
  49. 49.
    Mezzasoma AM, Leone M, Guglielmini G, Momi S, Del Soldato P, Gresele P (2000) Effects of nitroaspirin on platelet activation: potentiation by nitric oxide of the inhibitory effects of cyclo-oxygenase inhibition. Haematologica 85(S5):84Google Scholar
  50. 50.
    Corazzi T, Leone M, Roberti R, Del Soldato P, Gresele P (2003) Effect of nitric oxide-donating agents on human monocyte cyclooxygenase-2. Biochem Biophys Res Commun 311:897–903PubMedCrossRefGoogle Scholar
  51. 51.
    Gray PA, Warner TD, Vojnovic I, Del Soldato P, Parikh A, Scadding GK, Mitchell JA (2002) Effects of non-steroidal anti-inflammatory drugs on cyclo-oxygenase and lipoxygenase activity in whole blood from aspirin-sensitive asthmatics vs healthy donors. Br J Pharmacol 137:1031–1038PubMedCrossRefGoogle Scholar
  52. 52.
    Minuz P, Degan M, Gaino S, Meneguzzi A, Zuliani V, Santonastaso CL, Del Soldato P, Lechi A (2001) NCX4016 (NO-Aspirin) has multiple inhibitory effects in LPS-stimulated human monocytes. Br J Pharmacol 134:905–911PubMedCrossRefGoogle Scholar
  53. 53.
    Minuz P, Degan M, Gaino S, Meneguzzi A, Zuliani V, Lechi Santonastaso C, Del Soldato P, Lechi A (2001) NCX4016 (NO-aspirin) inhibits thromboxane biosynthesis and tissue factor expression and activity in human monocytes. Med Sci Monit 7:573–577PubMedGoogle Scholar
  54. 54.
    Fiorucci S, Mencarelli A, Meneguzzi A, Lechi A, Morelli A, Del Soldato P, Minuz P (2002) NCX-4016 (NO-aspirin) inhibits lipopolysaccharide-induced tissue factor expression in vivo: role of nitric oxide. Circulation 106:3120–3125PubMedCrossRefGoogle Scholar
  55. 55.
    Fiorucci S, Santucci L, Federici B, Antonelli E, Distrutti E, Morelli O, Renzo GD, Coata G, Cirino G, Del Soldato P, Morelli A (1999) Nitric oxide-releasing NSAIDs inhibit interleukin-1beta converting enzyme-like cysteine proteases and protect endothelial cells from apoptosis induced by TNFalpha. Aliment Pharmacol Ther 13:421–435PubMedCrossRefGoogle Scholar
  56. 56.
    Fiorucci S, Santucci L, Cirino G, Mencarelli A, Familiari L, Del Soldato P, Morelli A (2000) IL-1 beta converting enzyme is a target for nitric oxide-releasing aspirin: new insights in the antiinflammatory mechanism of nitric oxide-releasing nonsteroidal antiinflammatory drugs. J Immunol 165:5245–5254PubMedGoogle Scholar
  57. 57.
    Fiorucci S, Distrutti E, Mencarelli A, Rizzo G, Lorenzo AR, Baldoni M, Del Soldato P, Morelli A, Wallace JL (2004) 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. J Pharmacol Exp Ther 309:1174–1182PubMedCrossRefGoogle Scholar
  58. 58.
    al-Swayeh OA, Clifford RH, Del Soldato P, Moore PK (2000) A comparison of the anti-inflammatory and anti-nociceptive activity of nitroaspirin and aspirin. Br J Pharmacol 129:343–350PubMedCrossRefGoogle Scholar
  59. 59.
    Fiorucci S, Antonelli E, Santucci L, Morelli O, Miglietti M, Federici B, Mannucci R, Del Soldato P, Morelli A (1999) Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats. Gastroenterology 116:1089–1096PubMedCrossRefGoogle Scholar
  60. 60.
    Brown JF, Hanson PJ, Whittle BJR (1992) Nitric oxide donors increase mucus gel thickness in rat stomach. Eur J Pharmacol 223:103–104PubMedCrossRefGoogle Scholar
  61. 61.
    Whittle BJR (1993) Thirteenth gaddum memorial lecture. neuronal and endothelium-derived mediators in the modulation of the gastric microcirculation: integrity in the balance. Br J Pharmacol 110:3–17PubMedGoogle Scholar
  62. 62.
    Takeuchi K, Ukawa H, Konaka A, Kitamura M, Sugawa Y (1998) Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: comparison with plain aspirin. J Pharmacol Exp Ther 286:115–121PubMedGoogle Scholar
  63. 63.
    Wallace JL, McKnight W, Wilson TL, Del Soldato P, Cirino G (1997) Reduction of shock-induced gastric damage by a nitric oxide-releasing aspirin derivative: role of neutrophils. Am J Physiol Gastrointest Liver Physiol 273:G1246–1251Google Scholar
  64. 64.
    Kato S, Suzuki K, Ukawa H, Komoike Y, Takeuchi K (2001) Low gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in rats with cirrhosis and arthritis. Dig Dis Sci 46:1690–1699PubMedCrossRefGoogle Scholar
  65. 65.
    Tashima K, Fujita A, Umeda M, Takeuchi K (2000) Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 67:1639–1652PubMedCrossRefGoogle Scholar
  66. 66.
    Napoli C, Aldini G, Wallace JL, de Nigris F, Maffei R, Abete P, Bonaduce D, Condorelli G, Rengo F, Sica V, D’Armiento FP, Mignogna C, de Rosa G, Condorelli M, Lerman LO, Ignarro LJ (2002) Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc Natl Acad Sci USA 99:1689–1694PubMedCrossRefGoogle Scholar
  67. 67.
    Ukawa H, Yamakuni H, Kato S, Takeuchi K (1998) Effects of cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal antiinflammatory drugs on mucosal ulcerogenic and healing responses of the stomach. Dig Dis Sci 43:2003–2011PubMedCrossRefGoogle Scholar
  68. 68.
    Takeuchi K, Suzuki K, Yamamoto H, Araki H, Mizoguchi H, Ukawa H (1998) Cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs and gastric mucosal responses. J Physiol Pharmacol 49:501–513PubMedGoogle Scholar
  69. 69.
    Wallace JL, Zamuner SR, McKnight W, Dicay M, Mencarelli A, Del Soldato P, Fiorucci S (2004) Aspirin, but not NO-releasing aspirin (NCX 4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation. Am J Physiol Gastrointest Liver Physiol 286:G76–81PubMedCrossRefGoogle Scholar
  70. 70.
    Fiorucci S, Santucci L, Wallace JL, Sardina M, Romano M, Del Soldato P, Morelli A (2003) Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa. Proc Natl Acad Sci USA 100:10937–10941PubMedCrossRefGoogle Scholar
  71. 71.
    Elkayam U, Aronow WS (1982) Glyceryl trinitrate (nitroglycerin) ointment and isosorbide dinitrate: a review of their pharmacological properties and therapeutic use. Drugs 23:165–194PubMedCrossRefGoogle Scholar
  72. 72.
    Sardina M, Acuto G, Daussogne C, Santus G (2002) Safety, tolerability, pharmacokinetics and preliminary pharmacodynamic profile of NCX 4016 in healthy volunteer studies. Presented at William Harvey Research Conferences, Nitric Oxide Based Drug Therapy, Porto, PortugalGoogle Scholar
  73. 73.
    Muscara MN, McKnight W, Dicay M, Wallace JL (2001) GI and cardiovascular profiles of new NSAIDs: selective COX-2 inhibitors and NO-NSAIDs. In: Samuelsson B et al. (eds) Advances in prostaglandin and leukotriene research. Kluwer, Dordrecht, pp 163–169Google Scholar
  74. 74.
    Gresele P, Momi S, Mezzasoma AM (2003) NCX4016: a novel antithrombotic agent. Dig Liver Dis 35 (S2):S20–26PubMedCrossRefGoogle Scholar
  75. 75.
    Wong SM, Appleberg M, Ward CM, Lewis DR (2004) Aspirin resistance in cardiovascular disease: a review. Eur J Vasc Endovasc Surg 27:456–465PubMedCrossRefGoogle Scholar
  76. 76.
    Yu J, Rudic RD, Sessa WC (2002) Nitric oxide-releasing aspirin decreases vascular injury by reducing inflammation and promoting apoptosis. Lab Invest 82:825–832PubMedGoogle Scholar
  77. 77.
    Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, Del Soldato P (2001) Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc Natl Acad Sci USA 98:4202–4208PubMedCrossRefGoogle Scholar
  78. 78.
    Muzaffar S, Shukla N, Angelini G, Jeremy JY (2004) Nitroaspirins and morpholinosydnonimine, but not aspirin, inhibit the formation of superoxide and the expression of gp91phox induced by endotoxin and cytokines in pig pulmonary artery vascular smooth muscle cells and endothelial cells. Circulation 110:1140–1147PubMedCrossRefGoogle Scholar
  79. 79.
    Rossoni G, Manfredi B, Colonna VD, Bernareggi M, Berti F (2001) The nitroderivative of aspirin, NCX 4016, reduces infarct size caused by myocardial ischemia-reperfusion in the anesthetized rat. J Pharmacol Exp Ther 297:380–387PubMedGoogle Scholar
  80. 80.
    Burger PC, Wagner DD (2003) Platelet P-selectin facilitates atherosclerotic lesion development. Blood 101:2661–2666PubMedCrossRefGoogle Scholar
  81. 81.
    Huo Y, Schober A, Forlow B, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K (2003) Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 9:61–67PubMedCrossRefGoogle Scholar
  82. 82.
    Anderson HV, McNatt J, Clubb FJ, Herman M, Maffrand JP, DeClerck F, Ahn C, Buja LM, Willerson JT (2001) Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries. Circulation 104:2331–2337PubMedCrossRefGoogle Scholar
  83. 83.
    Momi S, Pitchford S, Alberti PF, Minuz P, Del Soldato P, Gresele P (2005) Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice. Thromb Haemost 93:535–543PubMedGoogle Scholar
  84. 84.
    Pieper GM, Siebeneich W, Olds CL, Felix CC, Del Soldato P (2002) Vascular protective actions of a nitric oxide aspirin analog in both in vitro and in vivo models of diabetes mellitus. Free Radic Biol Med 32:1143–1156PubMedCrossRefGoogle Scholar
  85. 85.
    Falcinelli E, Momi S, Del Soldato P, Gresele P (2003) LPS induced MMPs release in mice: role of platelets and inhibition by NCX4016 (nitroaspirin). J Thromb Haemost 1 (S1):P1253Google Scholar
  86. 86.
    Rossoni G, Manfredi B, Del Soldato P, Berti F (2002) NCX 4016, a nitric oxide–releasing aspirin, modulates adrenergic vasoconstriction in the perfused rat tail artery. Br J Pharmacol 137:229–236PubMedCrossRefGoogle Scholar
  87. 87.
    Rossoni G, Manfredi B, Del Soldato P, Polvani G, Berti F (2003) Nitric oxide-releasing aspirin inhibits vasoconstriction in perfused tail artery of normotensive and spontaneously hypertensive rats. Eur J Pharmacol 477:59–68PubMedCrossRefGoogle Scholar
  88. 88.
    Momi S, Emerson M, Paul W, Leone M, Mezzasoma AM, Del Soldato P, Page CP, Gresele P (2000) Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin. Eur J Pharmacol 397:177–185PubMedCrossRefGoogle Scholar
  89. 89.
    Momi S, Mezzasoma AM, Leone M, Del Soldato P, Gresele P (2002) Effect of the combination of NCX4016, aspirin (ASA) and clopidogrel in a model of pulmonary thromboembolism in mice. Haematologica 87(S5):64Google Scholar
  90. 90.
    Momi S, Pitchford SC, Alberti PF, Minuz P, Del Soldato P, Gresele P (2005) Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice. Throm Haemost 93:535–543Google Scholar
  91. 91.
    Rossoni G, Berti M, Colonna VD, Bernareggi M, Del Soldato P, Berti F (2000) Myocardial protection by the nitroderivative of aspirin, NCX 4016: in vitro and in vivo experiments in the rabbit. Ital Heart J 1:146–155PubMedGoogle Scholar
  92. 92.
    Rossoni G, Muscara MN, Cirino G, Wallace JL (2002) Inhibition of cyclo-oxygenase-2 exacerbates ischaemia-induced acute myocardial dysfunction in the rabbit. Br J Pharmacol 135:1540–1546PubMedCrossRefGoogle Scholar
  93. 93.
    Wainwright CL, Miller AM, Work LM, Del Soldato P (2002) NCX4016 (NO-aspirin) reduces infarct size and suppresses arrhythmias following myocardial ischaemia/reperfusion in pigs. Br J Pharmacol 135:1882–1888PubMedCrossRefGoogle Scholar
  94. 94.
    Bertuglia S, Giusti A, Del Soldato P (2004) Antioxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation. Am J Physiol Gastrointest Liver Physiol 286:G437–443PubMedCrossRefGoogle Scholar
  95. 95.
    Napoli C, Cirino G, Del Soldato P, Sorrentino R, Sica V, Condorelli M, Pinto A, Ignarro LJ (2001) Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice. Proc Natl Acad Sci USA 98:2860–2864PubMedCrossRefGoogle Scholar
  96. 96.
    Napoli C, Ackah E, De Nigris F, Del Soldato P, D’Armiento FP, Crimi E, Condorelli M, Sessa WC (2002) Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation–specific epitopes, and atherogenesis in hypercholesterolemic mice. Proc Natl Acad Sci USA 99:12467–12470PubMedCrossRefGoogle Scholar
  97. 97.
    Wan S, Yim A, Bulbulia R, Johnson JL, Angelini GD, Jeremy JY (2001) Nitrated aspirin (NCX 4016) inhibits neointima formation in porcine vein grafts, in vivo. EPHAR, Lyon, France, Abstract no. 9P084Google Scholar
  98. 98.
    Cook S, Del Soldato P, Hugli O, Turini P, Nicod P, Vollenweider P, Scherrer U (2001) Nitric-Oxide-releasing aspirin reverses arterial hypertension and insulin resistance in eNOS deficient mice. Circulation 104(SII):208Google Scholar
  99. 99.
    Fiorucci S, Santucci L, Gresele P, Faccino RM, Del Soldato P, Morelli A (2003) Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 124:600–607PubMedCrossRefGoogle Scholar
  100. 100.
    Marsik C, Derhaschnig U, Cardone F, Schweeger I, Acuto G, Sardina M, Jilma B (2002) Clinical pharmacology of NCX 4016. Presented at William Harvey Research Conferences, Nitric Oxide Based Drug Therapy, Porto, PortugalGoogle Scholar
  101. 101.
    Fiorucci S, Palazzetti B, Mencarelli A, Fanini C, Morelli A, Del Soldato P (2002) NO-aspirin (NCX-4016) modulates pro–inflammatory cytokines and COX isoenzymes. An human study. Presented at William Harvey Research Conferences, Nitric Oxide Based Drug Therapy, Porto, PortugalGoogle Scholar
  102. 102.
    Gresele P, Migliacci R, Bonizzoni E, Sardina M (2004) Nitroaspirin prevents effort-induced endothelial dysfunction in intermittent claudication. Circulation 110(S):520Google Scholar
  103. 103.
    Gresele P, Guglielmini G, De Angelis M, Ciferri S, Ciofetta M, Falcinelli E, Lalli C, Ciabattoni G, Davi G, Bolli GB (2003) Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus. J Am Coll Cardiol 41:1013–1020PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Manlio Bolla
    • 1
    Email author
  • Stefania Momi
    • 2
  • Paolo Gresele
    • 2
  • Piero Del Soldato
    • 3
  1. 1.NicOx SASophia-Antipolis CedexFrance
  2. 2.Department of Internal Medicine, Division of Internal and Cardiovascular MedicineUniversity of PerugiaPerugiaItaly
  3. 3.New York Medical CollegeValhallaUSA

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