Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346)
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BACKGROUND AND PURPOSE: Hydrogen sulphide is an important mediator of gastric mucosal defence. The use of non-steroidal anti-inflammatory drugs continues to be limited by their toxicity, particularly in the upper gastrointestinal tract. We evaluated the gastrointestinal safety and anti-inflammatory efficacy of a novel hydrogen sulphide-releasing derivative of naproxen, ATB-346 [2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester]. EXPERIMENTAL APPROACH: The ability of ATB-346 versus naproxen to cause gastric damage was evaluated in healthy rats and in rats with compromised gastric mucosal defence. Effects on the small intestine and on the healing of ulcers were also assessed. The ability of ATB-346 to inhibit cyclooxygenase-1 and 2 and to reduce inflammation in vivo was also evaluated. KEY RESULTS: ATB-346 suppressed gastric prostaglandin E(2) synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. In situations in which the gastric mucosa was rendered significantly more susceptible to naproxen-induced damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K(IR)6.x channels), ATB-346 did not cause significant damage. Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity. Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats. CONCLUSIONS AND IMPLICATIONS: ATB-346 exhibits anti-inflammatory properties similar to naproxen, but with substantially reduced gastrointestinal toxicity.
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Suppression of endogenous H2S synthesis impairs gastric and colonic mucosal defence, and impairs healing of ulcers.
“Suppression of endogenous H2S synthesis has been shown to impair gastric and colonic mucosal defence, and to impair healing of ulcers [26], [27], [34], [35].”
From Cytoprotective Effects of Hydrogen Sulfide in Novel Rat Models of Non-Erosive Esophagitis (2014) · cites this paper as [27]
The Discussion reports that inhibiting endogenous H2S synthesis significantly worsened NSAID-induced gastric damage, supporting the gastric mucosal-defence part. The Introduction says H2S promotes resolution of colitis and contributes to gastric-ulcer healing, but the cited copy does not show that suppressing its endogenous synthesis impairs colonic defence or ulcer healing. The indexed passages do not specify page numbers. (LLM, conf=0.85)
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- H2S-releasing naproxen 1244 JL Wallace et al British Journal of Pharmacology (2010) 159 1236-1246
- H2S-releasing naproxen 1246 JL Wallace et al British Journal of Pharmacology (2010) 159 1236-1246
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“Suppression of endogenous H2S synthesis has been shown to impair gastric and colonic mucosal defence, and to impair healing of ulcers [26,27,34,35].”
BackgroundSelf-citation
- Authors
- Wallace, J. L., Caliendo, G., Santagada, V., & Cirino, G.
- Affiliations
- McMaster University (CA)
- University of Naples Federico II (IT)
- Corresponding author
- Wallace, John L
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2010-03
- Volume
- 159
- Issue
- 6
- Pages
- 1236-1246
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC2848928
- OpenAlex
- W1488365705
- Cited by
- 231
- References
- 53
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 15 · 2021: 11 · 2020: 12 · 2019: 11 · 2018: 10 · 2017: 19 · 2016: 20 · 2015: 25 · 2014: 26 · 2013: 19 · 2012: 10
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- naproxen derivatives, gastrointestinal toxicity, cyclooxygenase inhibition, prostaglandin E2 synthesis, gastric ulcer healing, anti-inflammatory efficacy, adjuvant-induced arthritis, leukocyte infiltration, blood pressure, celecoxib comparison
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Experimental, Blood Pressure, Gastric Mucosa, Hydrogen Sulfide, Hypertension, Intestinal Mucosa, Intestine, Small, Male, Naproxen, Stomach Ulcer, Dinoprostone, Molecular Structure, Rats, Wistar, Mice, Rats, Cyclooxygenase 1, Cyclooxygenase 2
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