A novel, hydrogen sulfide-releasing mesalamine derivative (ATB-429) exhibits enhanced anti-inflammatory and analgesic activity in experimental colitis
Bibliographic record
Abstract
Mesalamine is the most common first-line therapy for IBD, but lacks potency. This limits the effectiveness of mesalamine, even when used at doses of 2-4 gram/day, to mild-to-moderate IBD. Hydrogen sulfide (H2S) has recently been shown to be an endogenous anti-inflammatory mediator, which inhibits leukocyte extravasation and reduces pain perception. We tested the hypothesis that an H2S-releasing derivative of mesalamine (ATB-429) would exert enhanced anti-inflammatory potency and efficacy in experimental colitis. The mouse models of DSS- and TNBS-induced colitis were used. After colitis was established, groups of mice were orally treated with mesalamine (0.33 mmol/kg) or ATB-429 (0.08 - 0.33 mmol/kg) daily for up to 10 days. In addition to macroscopic and microscopic scoring, tissue MPO activity and expression of mRNA for a variety of proand anti-inflammatory cytokines, chemokines and enzymes were measured. In separate studies, the effects of mesalamine vs. ATB-429 were compared in a rat model of colorectal-distention-induced visceral pain. Studies were performed in healthy rats and rats that had recovered from TNBS-induced colitis. ATB-429 exhibited an increase in potency and a broadening of efficacy as compared to mesalamine in both models of colitis. When a dose of 2 mg of TNBS was used, we observed mortality in vehicle-treated rats of 30%, which was not significantly reduced by treatment with mesalamine (25%) but was by ATB-429 (0%). Therapeutic administration of ATB-429 was more effective than equimolar doses of mesalamine in reducing the various parameters of TNBS-or DSS-induced colitis in mice (disease activity, macroscopic and microscopic scoring). In addition, ATB-429 more effectively reduced granulocyte infiltration (MPO) and mucosal expression of mRNA for TNFα, IFNγ, IL-2, IL-6, RANTES and iNOS. However, ATB-429 did not affect expression of mRNA for IL-10. Furthermore, ATB-429 but not mesalamine reduced the accumulation of CD11b+/Gr1+ cells in the lamina propria. In human peripheral blood monocytes, ATB-429 (but not mesalamine) concentration-dependently suppressed LPS-induced TNFα release. These effects of ATB-429 may be attributable to its ability to suppress NF-kB translocation, which was also observed. Mesalamine exerts only a minor analgesic effect in the colorectal-distention model in rats. In contrast, ATB-429 markedly reduced pain perception in this model, whether the studies were performed in healthy rats or rats that had recovered from colitis (the latter exhibited visceral hyperalgesia). These results demonstrate that the addition of an H2S-releasing moiety to mesalamine results in a significant increase in its potency (˜4-fold) as well as a marked broadening of its anti-inflammatory effects. Of particular importance in terms of potential use in the treatment of human disease is the observation that ATB-429 is able to significantly reduce visceral pain
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".