A novel orally administered trimebutine compound (GIC‐1001) is anti‐nociceptive and features peripheral opioid agonistic activity and Hydrogen Sulphide‐releasing capacity in mice

Abstract

Background: Trimebutine maleate, a noncompetitive spasmolytic agent with some affinity for peripheral l-and j-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 (H 2 S), a gaseous mediator known to reduce nociception, has been developed. This drug salt (GIC-1001) is composed of trimebutine bearing a H 2 S-releasing counterion (3-thiocarbamoylbenzoate, 3TCB), the latter having the ability to release H 2 S. GIC-1001 has been tested here in a mouse model of colorectal distension. Results: In mice, while orally given trimebutine (the maleate salt, non-H 2 S-releaser) only slightly reduced the nociceptive response to increasing pressures of colorectal distension, oral administration of GIC-1001 (the H 2 S-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.

Enhanced Analgesic Effects and Gastrointestinal Safety of a Novel, Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352): A Role for Endogenous Cannabinoids

“…We have similarly examined distention-induced pain responses in rats using cardiovascular endpoints, and once again, there was a significantly greater reduction of pain with the H 2 S-releasing derivative than with the parent drug (26). This is consistent with studies we have performed using this assay to evaluate an H 2 S-releasing derivative of naproxen (ATB-346), suggesting an important contribution of H 2 S to analgesic effects of ATB-352 and other such compounds (3,14,26). Kida et al reported that H 2 S reduced microglial activation and central nervous system inflammation (14).…”

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…This direction is based on the hypothesis that the spasmolytic and colonic peripheral opioid agonistic activity of trimebutine combined with antinociceptive effects of H 2 S would be beneficial in clinical indications such as adjunct therapy of colonoscopy. Although the number of publications in the scientific literature with GIC-1001 is limited, in a murine study oral trimebutine maleate exerted only a slight inhibitory effect on the nociceptive response to increasing pressures of colorectal distension, whereas equimolar doses of orally administered GIC-1001 (30-60 mg/kg) significantly reduced nociceptive responses (Cenac et al, 2016). In Phase I singleand multiple-ascending dose clinical trials, GIC-1001 was orally administered to 80 healthy male and female subjects.…”

Toward Hydrogen Sulfide Based Therapeutics: Critical Drug Delivery and Developability Issues

“…In a clever design of a hybrid drug, Aptalis Pharma reported GIC‐1001 (Fig. ), a protonated form of trimebutine that uses 3‐thiocarbamoylbenzenesulfonate as the anion capable of releasing H 2 S. In a recent study, both GIC‐1001 and its parent drug trimebutine were tested in a mouse model (C57Bl6 male mice, 6–8 weeks) of colorectal distension . Oral administration of GIC‐1001 (30 and 60 mg/kg) was able to significantly reduce nociceptive response to all noxious stimuli, in a dose‐dependent manner, while oral treatment of equimolar doses of trimebutine (25 and 50 mg/kg) only showed slight effects.…”