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.

The validated LC-MS/MS method to determine plasma BH4 concentration described herein has been used to support many nonclinical and clinical toxicokinetic and pharmacokinetic studies. BH4 is sensitive to oxidation and has a complicated biology. The method successfully supported the approval of Kuvan for the treatment of phenylketonuria.

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An acidification step was introduced in the extraction procedure to completely hydrolyze the glucuronide and measure the total NDMT in plasma, rendering this method a successful fit-for-purpose assay.

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