Non-steroidal anti-inflammatory drug, nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions

Ishiwata, Yoichi; Okamoto, Masayuki; Yokochi, Shoji; Hashimoto, Hiroyuki; Nakamura, Takashi; Miyachi, Atsushi; Naito, Yuji; Yoshikawa, Toshikazu

doi:10.1211/002235702478

Cited by 9 publications

(13 citation statements)

References 58 publications

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“…The activation of potential prodrugs by a promising exogenous enzyme can indeed be optimized computationally and experimentally. The accepted explanation for the low gastrointestinal toxicity of nabumetone is discussed in the next [114]. It has been used with promising success to target cytotoxic alkylating agents to tumor cells.…”

Section: Fig 525mentioning

confidence: 99%

“…It has been used with promising success to target cytotoxic alkylating agents to tumor cells. As for its active metabolite 6MNA, its presence was undetectable in rat gastric mucosa given nabumetone orally, as illustrated by the right panel [114]. The compounds investigated were prodrugs of 4-[bis(2-chloroethyl)amino]benzoic acid (5.71) and analogues designed as selective substrates of CPG2.…”

Section: Fig 525mentioning

confidence: 99%

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ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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Section: Fig 525mentioning

confidence: 99%

Section: Fig 525mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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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). We propose here that in addition to these mechanisms, the low direct cytotoxicity of nabumetone make it far less harmful on the gastric mucosa and therefore much safer for clinical use.…”

Section: Resultsmentioning

confidence: 90%

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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“…Whether nabumetone accumulates in the synovium itself was not determined in Miehlke's studies, and the fact that nabumetone (in contrast to 6MNA) is a nonacidic, hydrophobic molecule suggests that it may more readily accumulate in tissues than in body fluids. 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-kB 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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Non-steroidal anti-inflammatory drug, nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions

Cited by 9 publications

References 58 publications

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

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

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