Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide owing to their anti-inflammatory, antipyretic and analgesic properties. However, their use is hampered by gastrointestinal (GI) toxicity, the most common drug-related serious adverse event in industrialised nations.
Nitric oxide (NO)—releasing NSAIDs, a recently described class of drugs, are generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NO-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in animals, thus the abbreviation NO-NSAIDs used here refers to the latter group of NSAID derivatives.
NO-NSAIDs retain the anti-inflammatory and antipyretic activity of original NSAIDs, although they exhibit markedly reduced gastrointestinal toxicity. NO-NSAIDs are nonselective cyclo-oxygenase (COX) inhibitors, and they also exert COX-independent activities that are NO-dependent. Indeed, NO-NSAIDs suppress production of the cytokines interleukin (IL)-1β, IL-18 and interferon-γ by causing the S-nitrosilation/inhibition of caspase-1. In acute and chronic animal models of inflammation, it has been demonstrated that NO-NSAIDs abrogated prostaglandin E2 as well as thromboxane B2 generation. In a murine model, NO-naproxen was approximately 10-fold more potent than naproxen in reducing animal writhing after intraperitoneal injection of acetic acid. Similar data have been obtained in chronic models of pain such as rat adjuvant arthritis. In vivo and in vitro studies suggest that NO-aspirin (acetylsalicylic acid) exerts more potent antithrombotic action than aspirin, probably by coupling the ability to inhibit COX-1 with the anti-adhesive effect of NO. Moreover, in a model of renal injury NO-flurbiprofen not only has been demonstrated to be devoid of nephrotoxicity but also to ameliorate renal function. Finally, in an animal model of chronic neurodegenerative disease, NO-flurbiprofen and NO-aspirin attenuated the brain inflammatory response. The GI toxicity of NO-flurbiprofen and NO-naproxen is currently being investigated in healthy individuals.
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References
Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002–12
Sessa WC. The nitric oxide synthase family of proteins. J Vasc Res 1994; 31: 131–43
Ignarro LJ, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987; 84: 9265–9
Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524–6
Katsuki S, Arnold W, Mittal C, et al. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 1977; 3: 23–35
Wallace JL. Mechanisms of nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal damage potential for development of gastrointestinal tract safe NSAIDs. Can J Physiol Pharmacol 1994; 72: 1493–1498
Laine L. Nonsteroidal anti-inflammatory drug gastropathy. Gastrointest Endosc Clin North Am 1996; 6: 489–504
Lanas A, Bajador E, Serrano P, et al. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 2000; 343: 834–9
Singh G, Ramey DR. NSAID induced gastrointestinal complications: the ARAMIS perspective 1997. J Rheumatol 1998; 25: 8–16
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 31: 232–9
Gilroy DW, Colville-Nash PR, Willis D, et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 1999; 5: 698–701
Wallace JL, McKnight W, Reuter BK, et al. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000; 119: 706–14
Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a COX-2-specific inhibitor, to ibuprofen on the gastroduodenal mucosa of osteoarthritis patients. Gastroenterology 1999; 117: 776–83
Wallace JL, Reuter B, Cicala C, et al. A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol 1994; 257: 249–55
Elliott SN, McKnight W, Cirino G, et al. A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 1995; 109: 524–30
Benoni G, Terzi M, Adami A, et al. Plasma concentrations and pharmacokinetic parameters of nitrofenac using a simple and sensitive HPLC method. J Pharm Sci 1995; 84(1): 93–5
Wallace JL, McKnight W, Del Soldato P, et al. Anti-thrombotic effects of a nitric oxide-releasing gastric-sparing aspirin derivatives. J Clin Invest 1995; 96: 2711–8
Data on file, Nicox SA, 2001 Jun
Al-sa’doni H, Ferro A. S-Nitrosothiol: a class of nitric donor drugs. Clin Sci 2000; 98: 507–20
Fung HL. Clinical pharmacology of organic nitrate. Am J Cardiol 1993; 72: 9C–15C
Bandarage UK, Chen L, Fang X, et al. Nitrosothiol esters of diclofenac: synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J Med Chem 2000; 43: 4005–16
Fiorucci S, Antonelli E, Santucci L, et al. Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases. Gastroenterology 1999; 116: 1089–106
Fiorucci S, Santucci L, Antonelli E, et al. NO-aspirin protects from T-cell mediated liver injury by inhibiting caspase-dependent processing of Th1-like cytokines. Gastroenterology 2000; 118: 404–22
Fiorucci S, Santucci L, Cirino G, et al. IL-1beta 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: 5245–54
Fiorucci S. NO-releasing NSAIDs are caspase inhibitors. Trends Immunol 2001; 22: 232–5
Nicholson DW. From bench to clinic with apoptosis-based therapeutic agents. Nature 2000; 407: 810–6
Wallace JL, Reuter B, Cicala C, et al. Novel nonsteroidal antiinflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994; 107: 173–9
Davies NM, Roseth AG, Appleyard CB, et al. NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects. Aliment Pharmacol Ther 1997; 11: 69–79
Takeuchi K, Ukawa H, Konaka A, et al. Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: comparison with plain aspirin. J Pharmacol Exp Ther 1998; 286(1): 115–21
Wallace JL, Cirino G, McKnight G, et al. Reduction of gastrointestinal injury in acute endotoxic shock by flurbiprofen nitroxybutylester. Eur J Pharmacol 1995; 280: 63–8
Tashima K, Fujita A, Umeda M, et al. Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 2000; 67: 1639–52
al-Swayeh OA, Futter LE, Clifford RH, et al. Nitroparacetamol exhibits anti-inflammatory and anti-nociceptive activity. Br J Pharmacol 2000; 130: 1453–6
Fujihara CK, Malheiros DM, Donato JL et al. Nitroflurbiprofen, a new nonsteroidal anti-inflammatory, ameliorates structural injury in the remnant kidney. Am J Physiol 1998; 274(3 Pt 2): F573–9
Muscara MN, McKnight W, Del Soldato P, et al. Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat. Life Sci 1998; 62: 235–40
Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000; 321: 1183–7
Lechi C, Andrioli G, Gaino S, et al. 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 1996; 76: 791–8
Cuzzolin L, Conforti A, Adami A, et al. Anti-inflammatory potency and gastrointestinal toxicity of a new compound, NO-naproxen. Pharmacol Res 1995; 31: 61–5
Cicala C, Iannaro A, Fiorucci S, et al. NO-naproxen modulates inflammation, nociception and downregulates T cell response in rat Freund’s adjuvant arthritis. Br J Pharmacol 2000; 130: 1399–405
Perretti M, Getting ST, Warner TD. Nitro-flurbiprofen inhibits moncyte migration in acute inflammation. 4th World Congress on Inflammation; 1999 Jun 27-30; Paris, France
Flynn BL, Theesen KA. Pharmacologic management of Alzheimer disease part III: nonsteroidal antiinflammatory drugs: emerging protective evidence? Ann Phamacother 1999; 33: 840–9
Hauss-Wegrzyniak B, Willard LB, Del Soldato P, et al. Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS. Brain Res 1999; 815: 36–43
Hauss-Wegrzyniak B, Vraniak P, Wenk G. The effects of a novel NSAID on chronic neuroinflammation are age dependent. Neurobiol Aging 1999; 20: 305–13
Wenk G, McGann K, Mencarelli A, et al. Mechanisms to prevent the toxicity of chronic neuroinflammation on forebrain cholinergic neurons. Eur J Pharmacol 2000; 402: 77–85
van’t Hof RJ, Ralston SH. Nitric oxide and bone. Immunology 2001; 103: 255–61
van’t Hof RJ, Del Soldato P, Ralston SH. NO-NSAIDs: a novel class of osteoclast inhibitors. Mediators of Inflamm 1999; 8Suppl. 1: S128
Ralston SH, Torbergsen A, van’t Hof RJ, et al. New NO-NSAIDs and bone. 11th International Conference on Advances in Prostaglandin and Leukotriene Research: Basic Science and New Clinical Applications; 2000 Jun 20-22; Florence, Italy
Williams CS, Smalley W, DuBois RN. Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest 1997; 100: 1325–9
Hanif R, Pittas A, Feng Y, et al. Effects of nonsteroidal antiinflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 1996; 52: 237–45
Bak AW, McKnight W, Li P, et al. Cyclooxygenase-independent chemoprevention with an aspirin derivative in a rat model of colonic adenocarcinoma. Life Sci 1998; 62: 367–73
Williams JL, Borgo S, Hasan I, et al. Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter their kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: implications for colon cancer chemoprevention. Cancer Res 2001; 61: 3285–9
Simmons DL, Botting RM, Robertson PM, et al. Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs. Proc Natl Acad Sci U S A 1999; 96: 3275–80
Futter LE, al-Swayeh OA, Moore PK. A comparison of the effect of nitroparacetamol and paracetamol on liver injury. Br J Pharmacol 2001; 132: 10–2
Donnely MT, Stack WA, Courtauld EM, et al. Safety, tolerability and pharmacokinetics of nitroflurbiprofen (HCT 1026), a novel nitro-NSAID in healthy human subjects. 6th United European Gastroenterology Week; 1997 Oct 18-23; Birmingham, UK. Gut 1997; 41Suppl. 3: A8
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This work was supported by a Grant from Ministero of Pubblica Istruzione (MURST) to Dr Fiorucci.
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Fiorucci, S., Antonelli, E., Burgaud, JL. et al. Nitric Oxide—Releasing NSAIDs. Drug-Safety 24, 801–811 (2001). https://doi.org/10.2165/00002018-200124110-00002
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DOI: https://doi.org/10.2165/00002018-200124110-00002