Anti-inflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6MNA (6-methoxy-2-naphthylacetic acid): Comparison with indomethacin

Melarange, R.; Gentry, Clive; O’Connell, Caroline; Blower, P. R.; Neil, C.; Kelvin, A. S.; Toseland, C. D. N.

doi:10.1007/bf01996102

Cited by 7 publications

(3 citation statements)

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“…As described earlier, it is well known that nabumetone is experimentally and clinically safe and that its use is not as harmful to the gastric mucosa compared to other NSAIDs such as indomethacin and aspirin (20,29). In addition to its inability to inhibit gastric mucosal COX activity soon after oral administration, its inhibitory effect on neutrophil functions was also recently suggested (30).…”

Section: Resultsmentioning

confidence: 93%

“…Since the direct cytotoxicity of NSAID prodrugs has not been studied at all, we examined here the direct cytotoxicity of nabumetone which, along with its active metabolite 6-methoxy-2-naphthylacetic acid (6MNA), was found to not harm the gastrointestinal mucosa in clinical studies on humans and in animal models (20,21). Compared to indomethacin and celecoxib, both nabumetone and 6MNA showed very low activities for inducing necrosis, apoptosis and membrane permeabilization.…”

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confidence: 99%

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Low Direct Cytotoxicity of Nabumetone on Gastric Mucosal Cells

Arai¹,

Tanaka²,

Ushijima³

et al. 2005

Dig Dis Sci

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Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for clinical purposes because they are not harmful to the gastrointestinal mucosa. We recently showed that NSAIDs have direct cytotoxicity in NSAID-induced gastric lesions. We show here that under conditions where the NSAIDs indomethacin and celecoxib clearly induce cell death, an NSAID prodrug, nabumetone, and its active metabolite 6-methoxy-2-naphthylacetic acid (6MNA), did not have such effects. Moreover, nabumetone and 6MNA exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We recently reported that when an orally administered NSAID was used in combination with a low dose of intravenously administered indomethacin, the severity of gastric lesions produced in rats depended on the cytotoxicity of the orally administered NSAID. Using a similar protocol, we show here that gastric lesions were produced when the orally administered NSAID was celecoxib, but not when nabumetone was used. We thus propose that the low direct cytotoxicity of nabumetone observed in vitro is maintained in vivo, and that the use of nabumetone does not harm the gastric mucosa.

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Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

Low Direct Cytotoxicity of Nabumetone on Gastric Mucosal Cells

Arai¹,

Tanaka²,

Ushijima³

et al. 2005

Dig Dis Sci

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“… Ishiwata et al . (2003) have recently reported that nabumetone accumulates in the gastric lining in an animal model and reverses gastric damage induced by both 6MNA and indomethacin, suggesting that tissue persistence of unmetabolized nabumetone may contribute to the relatively benign gastric safety profile of this agent ( Melarange et al ., 1992 ; Helfgott, 1994 ; Basson et al ., 2001 ; Morgan et al ., 2001 ). The identification of nabumetone as an effective, nontoxic, in vitro inhibitor of Erk, MMP secretion and NF‐ κ B activation suggests that its clinical effects deserve further investigation, and that nabumetone may serve as a model compound in the development of other inhibitors of these aspects of inflammation and arthritis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of metalloproteinases and NF‐κB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA

Pillinger

Dinsell

Apsel

et al. 2004

British J Pharmacology

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1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 mM) had no effect on IL-1b/TNF-a (each 20 ng ml À1 )-stimulated Erk activation. Longer exposures depleted prostaglandin E 1 (PGE 1 ) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 mM) inhibited Erk activation by 60-80%. 3 6MNA (50-150 mM) stimulated (E200%) and nabumetone (150 mM) inhibited (E50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 6MNA stimulation of MMP-1 secretion was inhibited E30% by PGE 1 (1 mM) and E80% by the Erk pathway inhibitor UO126 (10 mM), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 mM) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 mM) and nabumetone (150 mM) inhibited (E70 and 40%, respectively), but 6MNA (150 mM) enhanced (E40%), NF-kB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated.

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Gastrointestinal Tract

2012

Comparative Pathophysiology and Toxicology of Cyclooxygenases

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Anti-inflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6MNA (6-methoxy-2-naphthylacetic acid): Comparison with indomethacin

Cited by 7 publications

References 2 publications

Low Direct Cytotoxicity of Nabumetone on Gastric Mucosal Cells

Low Direct Cytotoxicity of Nabumetone on Gastric Mucosal Cells

Regulation of metalloproteinases and NF‐κB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA

Gastrointestinal Tract

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