Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation

FASEB J. 2021 Oct;35(10):e21913. doi: 10.1096/fj.201902918RR.


ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Dinoprostone / metabolism
  • Escherichia coli / immunology
  • Escherichia coli / radiation effects
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Inflammation / drug therapy*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / microbiology
  • Male
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / immunology
  • Naproxen / analogs & derivatives*
  • Naproxen / metabolism
  • Naproxen / pharmacology
  • Naproxen / therapeutic use
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Pain / metabolism
  • Phenotype
  • Solubility
  • Ultraviolet Rays
  • Vasoconstriction / drug effects
  • Young Adult


  • 2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester
  • Naproxen
  • Dinoprostone
  • Hydrogen Sulfide