Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs

Brzozowski, Tomasz; Konturek, Peter C.; Konturek, Stanisław J.; Śliwowski, Zbigniew; Drozdowicz, Danuta; Kwiecień, Sławomir; Pajdo, Robert; Ptak, Agata; Pawlik, Michał; Hahn, Eckhart G.

doi:10.1016/s1590-8658(00)80840-3

Cited by 34 publications

(38 citation statements)

References 30 publications

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“…NO donors have been shown to reduce the severity of experimental gastric injury (MacNaughton et al, 1989;Wallace et al, 1994b), and the use of NO donors in a clinical setting has been shown to result in a significant decrease in the risk of NSAID-associated gastrointestinal bleeding (Lanas et al, 2000). The gastric tolerability of NO-releasing derivatives of naproxen and aspirin was reversed in rats pretreated with 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (Brzozowski et al, 2000), a soluble guanylate cyclase inhibitor, further supporting the notion that NO released from NO-NSAIDs is responsible for the markedly reduced gastric toxicity of these compounds through a cGMPdependent pathway.…”

Section: Discussionmentioning

confidence: 99%

Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

Wallace¹,

Muscará²,

Nucci³

et al. 2004

J Pharmacol Exp Ther

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NCX-2216 [3-[4-(2-fluoro-␣-methyl-[1,1Ј-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester] is anNO-releasing flurbiprofen derivative that also contains a ferulic acid (antioxidant) moiety. NCX-2216 has been shown to be effective in reducing ␤-amyloid deposition in a transgenic mouse model of Alzheimer's disease. The tolerability of this compound in the stomach and its ability to suppress prostaglandin synthesis in the brain are not known. The purpose of this study was to assess the contribution of nitric oxide (NO) and ferulic acid to the pharmacological properties of NCX-2216 versus flurbiprofen; thus, we compared their gastric tolerability and suppression of prostaglandin synthesis, peripherally and centrally. Oral flurbiprofen produced extensive gastric damage and suppressed gastric prostaglandin synthesis. In contrast, while suppressing prostaglandin production, equimolar doses of NCX-2216 did not cause detectable gastric injury. The NO-releasing moiety of NCX-2216 (but not the ferulic acid moiety) was crucial for the gastric safety of this compound. NCX-2216 substantially inhibited prostanoid synthesis despite not being detectable in plasma and despite producing only low amounts of flurbiprofen in plasma and in the brain. Inhibition of brain prostaglandin synthesis by NCX-2216 (22 mg/ kg) persisted for a much longer period of time (up to 48 h) than was seen with flurbiprofen (Յ12 h). These results demonstrate that a single administration of NCX-2216 can produce prolonged suppression of brain prostaglandin synthesis without causing gastric injury. It is likely that an active metabolite of NCX-2216 contributes to the suppression of cyclooxygenase activity. NCX-2216 may represent an attractive alternative to conventional nonsteroidal anti-inflammatory drugs for long-term treatment of a variety of inflammatory disorders, especially those occurring in the central nervous system.

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Section: Discussionmentioning

confidence: 99%

Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

Wallace¹,

Muscará²,

Nucci³

et al. 2004

J Pharmacol Exp Ther

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“…It is fair to assume that those who conceived the idea of NO-NSAIDs expected them to release NO in the upper GI tract, protecting it from the mucosal damage brought about by conventional NSAIDs [45] [46]. As mentioned earlier, NO-ASA traverses the stomach intact [17,18], thus ruling out such a mechanism.…”

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

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“…The rationale behind this strategy is that NO released from these derivatives exerts a beneficial effect on the gastric mucosa by enhancing the mucosal defense ability and preventing pathogenic events resulting from suppression of prostanoid synthesis by NSAIDs such as the reduction in gastric microcirculation and the leukocyte-endothelium adherence [5]. Our previous studies demonstrated that NO-releasing NSAIDs despite inhibition of cyclooxygenase and prostaglandin generation, similar to NSAID alone, do not cause mucosal damage and do not delay the healing of experimental peptic ulcers [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Releasing Aspirin Protects the Gastric Mucosa against Stress and Promotes Healing of Stress-Induced Gastric Mucosal Damage: Role of Heat Shock Protein 70

et al. 2002

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Background/Aim: Nitric oxide (NO) releasing nonsteroidal anti-inflammatory drugs do not cause gastric mucosal damage, despite inhibition of the cyclooxygenase activity to a similar extent as conventional nonsteroidal anti-inflammatory drugs that induce such damage. We compared the effects of native aspirin (ASA) with those of NO-releasing ASA (NO-ASA) on the development and healing of acute gastric lesions induced by water immersion and restraint stress (WRS) and the mucosal expression of heat shock protein 70 (HSP70). Methods: Wistar rats received: (1) vehicle; (2) ASA (40 mg/kg i.g), and (3) NO-ASA (2.5–40 mg/kg i.g.), followed 0.5 h later by 3.5 h of WRS with or without glyceryl trinitrate, the donor of NO, and carboxy-PTIO, a NO scavenger. Healing of WRS lesions was assessed 0–24 h after termination of WRS. Number of gastric lesions, gastric mucosal blood flow (GBF), malondialdehyde (MDA) content, and RT-PCR expression of HSP70 mRNA were determined. Results: WRS caused typical bleeding erosions that were aggravated by aspirin and this was accompanied by a fall in the GBF and a significant rise in the mucosal MDA concentrations. In contrast, NO-ASA, which raised significantly the luminal content of NO_x, reduced number of WRS lesions and mucosal MDA levels while increasing significantly the GBF. These protective and hyperemic effects of NO-ASA against WRS lesions were mimicked by addition of glyceryl trinitrate to native ASA and significantly attenuated by carboxy-PTIO added to NO-ASA. HSP70 mRNA was significantly upregulated by WRS, and this was significantly attenuated by ASA, but not by NO-ASA. NO-ASA decreased significantly the MDA content and induced overexpression of HSP70 mRNA during healing of WRS lesions.Conclusion: NO-ASA exhibits mucosal protective and healing effects against WRS-induced gastric lesions due to the release of NO, which induces gastric hyperemia, and the attenuation of lipid peroxidation and counteracts the inhibition of HSP70 expression induced by native ASA.

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Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs

Cited by 34 publications

References 30 publications

Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Nitric Oxide Releasing Aspirin Protects the Gastric Mucosa against Stress and Promotes Healing of Stress-Induced Gastric Mucosal Damage: Role of Heat Shock Protein 70

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