Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: A proof of concept endoscopic study

Gastroenterology

Volumn 124, Issue 3, 2003, Pages 600-607

  Fiorucci, Stefano ^a,d   Santucci, Luca ^a   Gresele, Paolo ^a   Faccino, Roberto Maffei ^b   Del Soldato, Piero ^c   Morelli, Antonio ^a  

^a UNIVERSITY OF PERUGIA   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c NicOx SA   (France)

^d POLICLINICO MONTELUCE   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; ACETYLSALICYLIC ACID 3 (NITROXYMETHYL)PHENYL ESTER;

ADULT; ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG ACTIVITY; DRUG EFFECT; DRUG SAFETY; DUODENUM DISEASE; ENDOSCOPY; FEMALE; GASTROINTESTINAL MUCOSA; GASTROINTESTINAL TOXICITY; HUMAN; MALE; NORMAL HUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SCORING SYSTEM; STOMACH DISEASE; THROMBOCYTE AGGREGATION; THROMBOCYTE FUNCTION;

EID: 0037373349     PISSN: 00165085     EISSN: None     Source Type: Journal    
DOI: 10.1053/gast.2003.50096     Document Type: Article

References (38)

1. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287-1294.
2. U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med 2002;136:157-160.
3. Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999;117:17-25.
4. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002;99:13926-13931.
5. Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A 1991;88:2692-2696.
6. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-442.
7. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528.
8. Wallace JL, Ignarro LJ, Fiorucci S. Potential cardioprotective actions of no-releasing aspirin. Nat Rev Drug Discov 2002;1:375-382.
9. Wallace JL, McKnight W, Del Soldato P, Baydoun AR, Cirino G. Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. J Clin Invest 1995;96:2711-2718.
10. Fiorucci S, Antonelli E, Santucci L, Morelli O, Miglietti M, Federici B, Mannucci R, Del Soldato P, Morelli A. Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats. Gastroenterology 1999;116:1089-1106.
11. 2 production. Thromb Haemost 1996;76:791-798.
12. Wallace JL, Muscara MN, McKnight W, Dicay M, Del Soldato P, Cirino G. In vivo antithrombotic effects of a nitric oxide-releasing aspirin derivative, NCX-4016. Thromb Res 1999;93:43-50.
13. Fiorucci S. NO-releasing NSAIDs are caspase inhibitors. Trends Immunol 2001;22:232-235.
14. Fiorucci S, Santucci L, Cirino G, Mencarelli A, Familiari L, Del Soldato P, Morelli A. 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 2000;165:5245-5254.
15. Fiorucci S, Santucci L, Antonelli E, Distrutti E, Del Sero G, Morelli O, Romani L, Federici B, Del Soldato P, Morelli A. NO-aspirin protects from T cell-mediated liver injury by inhibiting caspase-dependent processing of Th1-like cytokines. Gastroenterology 2000;118:404-421.
16. Fiorucci S, Mencarelli A, Mannucci R, Distrutti E, Morelli A, Del Soldato P, Moncada S. NCX-4016, a nitric oxide-releasing aspirin, protects endothelial cells against apoptosis by modulating mitochondrial function. FASEB J 2002;16:1645-1647.
17. Wallace JL, Miller MJS. Nitric oxide and mucosal defence: a little goes a long way. Gastroenterology 2000;119:512-520.
18. al-Swayeh OA, Clifford RH, del Soldato P, Moore PK. A comparison of the anti-inflammatory and anti-nociceptive activity of nitroaspirin and aspirin. Br J Pharmacol 2000;129:343-350.
19. Fiorucci S, Antonelli E, Burgaud JL, Morelli A. NO-releasing NSAIDs: a review of their current status. Drug Saf 2001;24:801-811.
20. Fiorucci S, Palazzetti B, Mencarelli A, Fanini C, Morelli A, Del Soldato P. NO-aspirin (NCX4016) modulates pro-inflammatory cytokines and COX isoenzymes. A human study. Nitric oxide based drug therapy. William Harwey Research Institute Conference. William Harvey Research Conferences 2002;27:10-14.
21. Vezza R, Nenci GG, Gresele P. Thromboxane synthase inhibitors suppress more effectively the aggregation of thromboxane receptor-desensitized than that of normal platelets. Role of adenylylcyclase up-regulation. J Pharmacol Exp Ther 1995;275:1497-1505.
22. Pirola R, Bareggi SR, De Benedittis G. Determination of acetylsalicylic acid and salicylic acid in skin and plasma by highperformance liquid chromatography. J Chromatogr B Biomed Sci Appl 1998;705:309-315.
23. Carini M, Aldini G, Stefani R, Orioli M, Facino RM. 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 2001;26:509-518.
24. O'Brien R, Muller K. Unified power analysis for t-tests through multivariate hypotheses. In: Edward LK, ed. Applied analysis of variance in the behavioural sciences. New York: Marcel Dekker, 1993:279-344.
25. Hawkey C, Jones JIW, Atherton TC, Skelly MM, Bebb JR, Fagerholm U, Jonzon B, Karlsson P, Bjarnason IT. Gastrointestinal safety of AZD3582: a new chemical entity with a novel multipathway mechanism of action (abstr). Gastroenterology 2002;122:A446.
26. Lanas A, Bajador E, Serrano P, Fuentes J, Carreno S, Guardia J, Sanz M, Montoro M, Sainz R. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 2000;343:834-839.
27. Wallace JL, McKnight W, Wilson TL, Del Soldato P, Cirino G. Reduction of shock-induced gastric damage by a nitric oxidereleasing aspirin derivative: role of neutrophils. Am J Physiol 1997;273:G1246-G1251.
28. Tashima K, Fujita A, Umeda M, Takeuchi K. Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 2000;67:1639-1652.
29. Kato S, Suzuki K, Ukawa H, Komoike Y, Takeuchi K. Low gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in rats with cirrhosis and arthritis. Dig Dis Sci 2001;46:1690-1699.
30. Wallace JL, Keenan CM, Granger DN. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am J Physiol 1990;259:G462-G467.
31. Santucci L, Fiorucci S, Di Matteo FM, Morelli A. Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin-induced gastric injury in rats. Gastroenterology 1995;108:393-401.
32. Momi S, Emerson M, Paul W, Leone M, Mezzasoma AM, Del Soldato P, Page CP, Gresele P. Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin. Eur J Pharmacol 2000;397:177-185.
33. Mezzasoma AM, Leone M, Guglielmini G, Momi S, Del Soldato P, Gresele P. Effects of nitroaspirin on platelet activation: potentiation by nitric oxide of the inhibitory effects of cyclo-oxygenease inhibition. Haematologica 2000;85(Suppl 5):84.
34. Minuz P, Degan M, Gaino S, Meneguzzi A, Zuliani V, Santonastaso CL, Soldato PD, Lechi A. NCX4016 (NO-aspirin) has multiple inhibitory effects in LPS-stimulated human monocytes. Br J Pharmacol 2001;134:905-911.
35. Fiorucci S, Mencarelli A, Meneguzzi A, Lechi A, Morelli A, del Soldato P, Minuz P. NCX-4016 (NO-aspirin) inhibits lipopolysaccharide-induced tissue factor expression in vivo: role of nitric oxide. Circulation 2002;106:3120-3125.
36. Fiorucci S, Del Soldato P. NO-aspirin: mechanism of action and gastrointestinal safety. Dig Liver Dis (in press).
37. Napoli C, Cirino G, Del Soldato P, Sorrentino R, Sica V, Condorelli M, Pinto A, Ignarro LJ. Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice. Proc Natl Acad Sci U S A 2001;98:2860-2864.
38. 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. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc Natl Acad Sci U S A 2002;99:1689-1694.