New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond

Table 4 Summary of the literature findings about irritable bowel syndrome-D therapies

Drug	Ref.	No. of pt	Study design	Outcomes
Ramosetron	Lee et al[213]	343 male pt	A multicenter, randomized, open-label trial male patients with IBS-D; pt were randomized to either a 4-wk treatment of ramosetron 5 mg once daily ,or a 4-wk treatment of mebeverine 135 mg three times daily	Global IBS symptoms, abdominal pain/discomfort and abnormal bowel habits in the ramosetron and mebeverine groups significantly increased during the treatment period. The severity scores of abdominal pain/discomfort and urgency, the stool form score, and the stool frequency in both treatment arms were significantly reduced, compared with the baselines
	Fukudo et al[222]	296 male pt	A randomized, double-blind, placebo-controlled trial in male patients with IBS-D Patients were given 5 mg oral ramosetron (n = 147) or placebo (n = 149) once daily for 12 wk after a 1-wk baseline period	Improving stool consistency in the first month. The ramosetron group had significantly higher monthly rates of relief of overall IBS symptoms and IBS-related quality of life than the placebo group. Adverse events occurring in 46.9% and 51.7% of ramosetron and placebo patients, respectively
	Fukudo et al[223]	576 female pt	A randomized, double-blind, placebo-controlled trial. The subjects received either 2.5 μg ramosetron or placebo once daily for 12 wk.	Global improvement, an increased stool consistency a significant reductions in abdominal pain and discomfort and greater improvement in QOL compared with placebo
Lx1031	Brown et al[229]	155 patients	A phase-II multicenter, randomized, double-blind, placebo-controlled, the subjects were assigned randomly in a double-blind fashion to 1 of 2 doses of LX1031 (250 mg 4 times/d or 1000 mg 4 times/d) or placebo, taken daily during the 28-d treatment period	Improved significantly in patients given 1000 mg LX1031 compared with those given placebo, at week 1, together with nonsignificant improvements at weeks 2, 3 and 4. Adverse Effects reported were generally mild, self-limited, and evenly distributed across the placebo and both LX1031 treatment arms
ASP-7147	Lembo et al[230]	64 patients	RCT performed on during a 4-wk	Demonstrating improvement in multiple symptoms of IBS-D. The persistence of treatment effect suggests the possibility of retained efficacy with less frequent dosing in follow-on trials
JNJ-27018966	[232]	807 patients	A randomized, controlled, double-blind study, 25, 100, and 200 mg twice daily to placebo	The composite of diarrhea and pain was significantly improved in the JNJ-27018966 25 and 200 mg twice-daily groups compared to placebo
ROSE-010	Hellström et al[233]	160 patients	A randomized placebo-controlled trial. Patients were randomized to ROSE-010 100 μg once daily, 300 μg once daily or placebo	Treatment with ROSE-010 resulted in a two fold greater response to abdominal pain compared to placebo and significantly greater patient-reported satisfaction with ROSE-010. The most common treatment-related adverse effect was nausea
AST-120	Tack et al[95]	115 non-constipation-related IBS patients	A randomized, double-blind, controlled study	AST-120 2 g three times daily significantly improved the proportion of patients with at least a 50% reduction in the number of days with abdominal pain compared to placebo. AST-120 resulted in significantly improved bloating and numerically improved stool consistency compared to placebo. The safety profile AST-120 was similar to placebo
Ibodutant	Trinkley et al[231]	559 IBS-D patients	A randomized, double-blind, controlled trial	Improved abdominal pain, satisfactory relief of overall symptoms, and quality of life compared to placebo. All three doses of ibodutant (1, 3, 10 mg once daily) were superior to placebo, but 10 mg once daily was most effective and females responded better than males
Asimadoline	Trinkley et al[231]	596 IBS-D patients	A randomized, controlled, double-blind trial compared asimadoline 0.15, 0.5 and 1 mg twice daily to placebo	Asimadoline 0.5 mg twice daily significantly improved by two fold the total number of months with adequate relief of IBS pain, pain scores, urgency and frequency
Colesevelam	Odunsi-Shiyanbade et al[155]	12 IBS-D patients	Single center trial	Colesevelam modestly affected overall colonic transit (emptying of the ascending colon took an average 4 h longer in patients given colesevelam compared to placebo). Furthermore, colesevelam was associated with greater ease of stool passage and somewhat firmer stool consistency. No effects on mucosal permeability or safety were identified
	Camilleri et al[240]	12 IBS-D patients	A 10-d single-center, unblinded, single-dose trial	Colesevelam increases delivery of BAs to stool while improving stool consistency, and increases hepatic BA synthesis, avoiding steatorrhea in patients with IBS-D
Solinefacin	Fukushima et al[249]	20 IBS-D patients	An open-label trial. After a 2-wk observation period, all participants received solifenacin for 6 wk. Subsequently, the administration of solifenacin was discontinued and ramosetron, a serotonin 3 receptor antagonist, was administered for 4 wk	The efficacy of solifenacin in the treatment of IBS with diarrhea was not inferior to that of ramosetron
Tiropamide	Lee et al[251]	287 patients	A multicenter, randomized, non-inferiority Patients randomly allocated to either tiropramide 100 mg or octylonium 20 mg t.i.d (means 3 times a day) for 4 wk	Tiropamide led to symptom improvement in terms of total symptom scores for 4 wk, compared with 3 wk in the placebo group; in addition, at week 4 abdominal pain was only improved in the tiropramide group. The incidence of adverse events was similar in the 2 groups, and no severe adverse events involving either drug were observed

IBS : Irritable bowel syndrome.