Table I.

Summary of Mechanism of Action and Clinical Efficacy of New or Promising Medications in Treatment of IBS (adapted from ref. 2, Camilleri M, Chang L. Gastroenterology 2008;135:1877-91

Drug Class	Examples	Rationale or Putative Action	Pharmacodynamic (intestine or colon)	Clinical Efficacy: Phase IIB or III Primary Endpoints	Safety Issues/Comments
CCK1 antagonist	dexloxiglumide	Competitive antagonist of the CCK1- receptor	Slower ascending colon emptying with no significant effect on overall colonic transit	Two initial IIB or III trials: not efficacious in IBS-C; a randomized withdrawal design trial showed longer time to loss of therapeutic response, longer for dexloxiglumide
NK antagonists	NK1 antagonist, ezlozipant	NK1-receptors’ role in nociception	Reduce the emotional response of IBS patients to rectosigmoid distension	None
	NK2-antagonist, nepadutant	NK2-receptors’ influence on smooth muscle contractility	Reduce contraction frequency and amplitude on MMC in SB in healthy males	None
	NK3-antagonist, talnetant	NK3-receptors’ role in nociception	No effect on rectal compliance, sensory thresholds or intensity ratings in healthy controls	Two IIB trials in 1350 IBS patients: no benefit
5-HT4-agonists	prucalopride	Stimulate intrinsic cholinergic neurons to enhance motility	Increases SB, colon motility and transit in healthy controls and patients with chronic constipation	IIB and III in CC (thousands of pts): BM frequency and satisfaction with bowel function both improved	Greater selectivity for 5-HT4 than 5-HT1B or hERG channel
	ATI-7505	Stimulate intrinsic cholinergic neurons to enhance motility	Increases colon transit in healthy controls	None reported	Greater selectivity for 5-HT4; not metabolized by CTP 3A4
	velusetrag (TD-5108)	Stimulate intrinsic cholinergic neurons to enhance motility	Dose-related increase in SB and colon transit in healthy controls	IIB, dose-ranging study in 401 CC patients increased BM frequency and proportion with adequate relief	Greater selectivity for 5-HT4
5-HT3-antagonist	ramosetron	Inhibits secretion, motility, nociception	None reported	IIB, dose-ranging studies document benefit on global relief and bowel function endpoints in IBS-D	Safety concern regarding ischemic colitis with same drug class
C1-C2 channel activator	lubiprostone	Increases intestinal water and electrolyte secretion	Accelerates SB and colonic transit in healthy controls	Two phase III in several hundred CC and IBS-C patients: efficacious	Nausea that is usually mild; FDA approved
Guanylate cyclase-C agonist	linaclotide	Increases intestinal water and electrolyte secretion	Accelerated ascending colonic transit and altered bowel function in 36 women with IBS-C	IIA and IIB studies in CC or IBS: increased BM frequency
K-opioid agonist	asimadoline	κ-opioid receptors in visceral perception	Reduce sensation in response to colon distensions in the non-noxious range; relax colon tone in healthy controls; increase sensory thresholds in patients with IBS	On-demand dosing not effective in reducing severity of abdominal pain in 100 IBS patients; IIB, dose-ranging study, 596 IBS patients: at least average moderate pain benefit in IBS-D and IBS-A
2,3-Benzodiazepine modulator	dextofisopam	Potential to reduce stimulation-induced colonic motility and visceral sensitivity	None reported	IIB study in 140 IBS patients: increased number of months of adequate overall relief of IBS symptoms; efficacy lower over time	? more abdominal pain or headaches vs placebo