John L Wallace1,2, Peter Nagy3,4, Troy D Feener5, Thibault Allain5, Tamás Ditrói3, David J Vaughan2, Marcelo N Muscara6, Gilberto de Nucci7, Andre G Buret3,4. 1. Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada. 2. Antibe Therapeutics Inc., Toronto, ON, Canada. 3. National Institute of Oncology, Budapest, Hungary. 4. Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. 5. Department of Biological Sciences, University of Calgary, Calgary, AB, Canada. 6. Department of Pharmacology, University of São Paulo, São Paulo, Brazil. 7. Department of Pharmacology, University of Campinas, Campinas, Brazil.
Abstract
BACKGROUND AND PURPOSE:ATB-346 is a hydrogen sulfide (H2 S)-releasing anti-inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti-inflammatory effects. In humans, ATB-346 (250 mg once daily) was found to inhibit COX to the same extent as naproxen (550 mg twice daily). EXPERIMENTAL APPROACH: Two hundred forty-four healthy volunteers completed a 2-week, double-blind study, taking either ATB-346 (250 mg once daily) or naproxen (550 mg twice daily), with upper GI ulceration being examined endoscopically. KEY RESULTS: Forty-two per cent of the subjects taking naproxen developed at least one ulcer (≥3-mm diameter), while only 3% of the subjects taking ATB-346 developed at least one ulcer. The two drugs produced comparable and substantial (>94%) suppression of COX activity. Subjects in the naproxen group developed more ulcers per subject than ATB-346-treated subjects and a greater incidence of larger ulcers (≥5-mm diameter). The incidence of dyspepsia, abdominal pain, gastro-oesophageal reflux, and nausea was lower with ATB-346 than with naproxen. Subjects treated with ATB-346 had significantly higher plasma levels of H2 S than those treated with naproxen. CONCLUSIONS AND IMPLICATIONS: This Phase 2B study provides unequivocal evidence for a marked reduction of GI toxicity of the H2 S-releasing analgesic/anti-inflammatory drug, ATB-346, as compared to the conventional dose of naproxen that produced equivalent suppression of COX. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
RCT Entities:
BACKGROUND AND PURPOSE:ATB-346 is a hydrogen sulfide (H2 S)-releasing anti-inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti-inflammatory effects. In humans, ATB-346 (250 mg once daily) was found to inhibit COX to the same extent as naproxen (550 mg twice daily). EXPERIMENTAL APPROACH: Two hundred forty-four healthy volunteers completed a 2-week, double-blind study, taking either ATB-346 (250 mg once daily) or naproxen (550 mg twice daily), with upper GI ulceration being examined endoscopically. KEY RESULTS: Forty-two per cent of the subjects taking naproxen developed at least one ulcer (≥3-mm diameter), while only 3% of the subjects taking ATB-346 developed at least one ulcer. The two drugs produced comparable and substantial (>94%) suppression of COX activity. Subjects in the naproxen group developed more ulcers per subject than ATB-346-treated subjects and a greater incidence of larger ulcers (≥5-mm diameter). The incidence of dyspepsia, abdominal pain, gastro-oesophageal reflux, and nausea was lower with ATB-346 than with naproxen. Subjects treated with ATB-346 had significantly higher plasma levels of H2 S than those treated with naproxen. CONCLUSIONS AND IMPLICATIONS: This Phase 2B study provides unequivocal evidence for a marked reduction of GI toxicity of the H2 S-releasing analgesic/anti-inflammatory drug, ATB-346, as compared to the conventional dose of naproxen that produced equivalent suppression of COX. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
Authors: John L Wallace; Peter Nagy; Troy D Feener; Thibault Allain; Tamás Ditrói; David J Vaughan; Marcelo N Muscara; Gilberto de Nucci; Andre G Buret Journal: Br J Pharmacol Date: 2019-04-11 Impact factor: 8.739
Authors: Rory W Blackler; Jean-Paul Motta; Anna Manko; Matthew Workentine; Premysl Bercik; Michael G Surette; John L Wallace Journal: Br J Pharmacol Date: 2014-11-24 Impact factor: 8.739
Authors: Jean-Paul Motta; Kyle L Flannigan; Terence A Agbor; Jennifer K Beatty; Rory W Blackler; Matthew L Workentine; Gabriela J Da Silva; Rui Wang; Andre G Buret; John L Wallace Journal: Inflamm Bowel Dis Date: 2015-05 Impact factor: 5.325
Authors: Steven E Nissen; Neville D Yeomans; Daniel H Solomon; Thomas F Lüscher; Peter Libby; M Elaine Husni; David Y Graham; Jeffrey S Borer; Lisa M Wisniewski; Katherine E Wolski; Qiuqing Wang; Venu Menon; Frank Ruschitzka; Michael Gaffney; Bruce Beckerman; Manuela F Berger; Weihang Bao; A Michael Lincoff Journal: N Engl J Med Date: 2016-11-13 Impact factor: 91.245
Authors: John L Wallace; Peter Nagy; Troy D Feener; Thibault Allain; Tamás Ditrói; David J Vaughan; Marcelo N Muscara; Gilberto de Nucci; Andre G Buret Journal: Br J Pharmacol Date: 2019-04-11 Impact factor: 8.739