N Cenac1,2,3, M Castro1,2,3, C Desormeaux1,2,3, P Colin4, M Sie1,2,3, M Ranger4, N Vergnolle1,2,3,5. 1. INSERM U1043, Toulouse, France. 2. CNRS U5282, Toulouse, France. 3. Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, France. 4. GIcare pharma Inc, Montréal, Canada. 5. Department of Physiology and Pharmacology, University of Calgary, Canada.
Abstract
BACKGROUND: Trimebutine maleate, a noncompetitive spasmolytic agent with some affinity for peripheral μ- and κ-opioid receptors has been evaluated as a treatment in a limited number of patients undergoing sedation-free full colonoscopy. The efficiency of such treatment was comparable to sedation-based colonoscopies to relieve from pain and discomfort. METHODS: A new and improved trimebutine salt capable of releasing in vivo hydrogen sulphide (H2S), a gaseous mediator known to reduce nociception, has been developed. This drug salt (GIC-1001) is composed of trimebutine bearing a H2S-releasing counterion (3-thiocarbamoylbenzoate, 3TCB), the latter having the ability to release H2S. GIC-1001 has been tested here in a mouse model of colorectal distension. RESULTS: In mice, while orally given trimebutine (the maleate salt, non-H2 S-releaser) only slightly reduced the nociceptive response to increasing pressures of colorectal distension, oral administration of GIC-1001 (the H2S-releaser) was able to significantly reduce nociceptive response to all noxious stimuli, in a dose-dependent manner. This effect of GIC-1001 was significantly better than the effects of its parent compound trimebutine administered at equimolar doses. CONCLUSIONS: Taken together, these results demonstrated increased antinociceptive properties for GIC-1001 compared to trimebutine, suggesting that this compound would be a better option to relieve from visceral pain and discomfort induced by lumenal distension.
BACKGROUND:Trimebutine maleate, a noncompetitive spasmolytic agent with some affinity for peripheral μ- and κ-opioid receptors has been evaluated as a treatment in a limited number of patients undergoing sedation-free full colonoscopy. The efficiency of such treatment was comparable to sedation-based colonoscopies to relieve from pain and discomfort. METHODS: A new and improved trimebutine salt capable of releasing in vivo hydrogen sulphide (H2S), a gaseous mediator known to reduce nociception, has been developed. This drug salt (GIC-1001) is composed of trimebutine bearing a H2S-releasing counterion (3-thiocarbamoylbenzoate, 3TCB), the latter having the ability to release H2S. GIC-1001 has been tested here in a mouse model of colorectal distension. RESULTS: In mice, while orally given trimebutine (the maleate salt, non-H2 S-releaser) only slightly reduced the nociceptive response to increasing pressures of colorectal distension, oral administration of GIC-1001 (the H2S-releaser) was able to significantly reduce nociceptive response to all noxious stimuli, in a dose-dependent manner. This effect of GIC-1001 was significantly better than the effects of its parent compound trimebutine administered at equimolar doses. CONCLUSIONS: Taken together, these results demonstrated increased antinociceptive properties for GIC-1001 compared to trimebutine, suggesting that this compound would be a better option to relieve from visceral pain and discomfort induced by lumenal distension.
Authors: Tereza Bautzova; James R F Hockley; Teresa Perez-Berezo; Julien Pujo; Michael M Tranter; Cleo Desormeaux; Maria Raffaella Barbaro; Lilian Basso; Pauline Le Faouder; Corinne Rolland; Pascale Malapert; Aziz Moqrich; Helene Eutamene; Alexandre Denadai-Souza; Nathalie Vergnolle; Ewan St John Smith; David I Hughes; Giovanni Barbara; Gilles Dietrich; David C Bulmer; Nicolas Cenac Journal: Sci Signal Date: 2018-12-18 Impact factor: 8.192
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: Chadwick R Powell; Kuljeet Kaur; Kearsley M Dillon; Mingjun Zhou; Mohammed Alaboalirat; John B Matson Journal: ACS Chem Biol Date: 2019-06-10 Impact factor: 5.100