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

Table 1 Summary of the literature findings about anti-inflammatory therapies in irritable bowel syndrome

Drug	Ref.	No. of patients	Study design	Outcome
Corticosteroids (prednisolone)	Dunlop et al[24]	29 patients with post-infectious irritable bowel syndrome	Randomized, double-blind, placebo-controlled trial of 3 wk of oral prednisolone, 30 mg/d	Not associated with any significant treatment-related improvement in abdominal pain, diarrhoea, frequency or urgency
Antibiotics (Rifaximin)	Pimentel et al[29]	623 IBS patients in TARGET 1 and 637 IBS in TARGET 2	Phase 3 trials, 14 d with rifaximin 550 mg 3 times daily	Significantly increased the percentage of relief of global IBS symptoms and improved IBS-related bloating and abdominal pain, discomfort, and loose or watery stools, with regard to placebo for up to 10 wk post-treatment
	Target 1 e 2
Antibiotics (norfloxacin)	Ghoshal et al[32]	80 IBS patients evaluate for SIBO	Randomized, double-blind, placebo-controlled trial; patients were randomized to 800 mg/d norfloxacin for 10 d or placebo	Although norfloxacin was more effective at reducing the symptom score at 1 mo among patients with compared with those without SIBO but not placebo, the scores were comparable at 6 mo. Symptoms more often resolved to turn Rome III negative in SIBO patients treated with norfloxacin compared with placebo at 1 mo
Mast cell stabilizers (Ketotifen)	Klooker et al[33]	60 IBS patiens	Case Control study; abarostat study to assess rectal sensitivity before and after 8 wk of treatment and, after the initial barostat, patients were randomised to receive ketotifen or placebo	Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity, but this effect was not observed in normosensitive patients with IBS. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life
Mast cells stabilizers (DSCG)	Lobo et al[34]		Randomized, double-blind, placebo-controlled trial; with prolonged (6 mo) oral administration of DSCG	Induces Mast Cell-Mediated Recovery of Healthy-Like Innate Immunity Genes Expression Profile in the Jejunal Mucosa
Mast cells stabilizers (ebastin)	Wouters et al[35]	65 IBS patients	Double-blind placebo-controlled trial, after 2-wk run-in period, subjects were assigned randomly to groups ebastine (20 mg/d; n = 28) or placebo (n = 27) for 12 wk	Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief, and reduced abdominal pain scores
Mesalazine	Barbara et al[39]	185 patients with IBS	A phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 wk, and were followed for additional 12 wk	Mesalazine treatment was not superior than placebo on the study primary endpoint, but a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy
	Lam et al[40]	136 patients with IBS-D	A double-blind, randomised placebo-controlled trial of 2 g mesalazine twice daily compared with placebo for 3 mo	The authors concluded that mesalazine did not improve abdominal pain, stool consistency or percentage with satisfactory relief compared with placebo during the last 2 weeks’ follow-up, however a post hoc analysis in 13 post-infectious patients with IBS appeared to show benefit but this needs confirmation in a larger group[40]

IBS : Irritable bowel syndrome.

Table 2 Summary of the literature findings about therapies restoring intestinal permeability in irritable bowel syndrome

Drug	Ref.	No. of patients	Study design	Outcome
Probiotics	Ford et al[61]	Forty-three RCTs were eligible for inclusion	Metanalysis	Probiotics had beneficial effects on global IBS, abdominal pain, bloating, and flatulence scores. Data for prebiotics and synbiotics in IBS were sparse. Probiotics appeared to have beneficial effects in CIC (mean increase in number of stools per week = 1.49; 95%CI: 1.02-1.96), but there were only two RCTs. Synbiotics also appeared beneficial (RR of failure to respond to therapy = 0.78; 95%CI: 0.67-0.92). Again, trials for prebiotics were few in number, and no definite conclusions could be drawn
	Mazurak et al[67]	Fifty-six papers	Metanalysis	The heterogeneity of the studies of probiotics in IBS questions the value of meta-analyses and the use of different bacterial strains and different mixtures of these strains, as well as different dosages, are the main contributors to this heterogeneity
Glutamine	Akobeng et al[73]	Two randomized trial	Cochrane analysis	Not significant difference in the permeability and no effect in the clinical remission
Larazotide acetate	Leffler et al[78]	342 adults with celiac disease who had been on a gluten free diet (GFD) for 12 mo or longer and maintained their current GFD during the study	Randomized, double-blind, placebo-controlled study assessed larazotide acetate 0.5, 1, or 2 mg 3 times daily	Reduce signs and symptoms in celiac disease patients on a GFD better than a GFD alone

Table 3 Summary of the literature findings about irritable bowel syndrome-C therapies

Drug	Ref.	No. of patients	Study design	Outcome
Linaclotide	Andresen et al[82]	36 women with IBS-C	Phase IIa randomized, double-blind, placebo- controlled trial. Patients were randomized in a 1:1:1 fashion to placebo, linaclotide 100 μg, and linaclotide 1000 μg and was evaluated the effect of 5 d	No treatment effects were seen for gastric emptying or colonic filling with linaclotide. Significant treatment effects were found for ascending colon emptying t½ times (P = 0.015) and overall total colonic transit times at 48 h (P = 0.02), for the 1000 μg dose (P = 0.004) but not the 100 μg dose, as well as overall treatment effects on increased stool frequency, decreased stool consistency, improved ease of passage, and acceleration of time to first bowel movement (P < 0.001)[82]
	Johnston et al[83]	420 patients with IBS-C	Phase IIb randomized, double-blind, parallel-group, multicenter, placebo-controlled trial evaluate 12 wk of linaclotide at a daily dose range of 75-600 μg	Compared with placebo, all doses of linaclotide significantly improved bowel habits, including frequency of SBMs and CSBMs, severity of straining, stool consistency, as well as abdominal pain scores. Abdominal discomfort, bloating, and global IBS-C measures were also improved, for all doses except for the 75 μg (abdominal discomfort) and 150 μg dose (bloating). Effects were present for the first week, and sustained throughout the 12 wk of treatment
	Chey et al[84]	804 adults with IBS-C	Phase III trials randomized, double-blind, placebo-controlled to receive linaclotide 290 lg or placebo daily for 26 wk, with change-from-baseline end points measuredat 12 and 26 wk	Over 12 wk, the FDA combined primary end point was achieved by 33.7% of patients receiving linaclotide compared with 13.9% of patients receiving placebo (P < 0.0001)
	Videlock et al[109]	7 trials of linaclotide in patients with IBS-C or CC	A meta-analysis from MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials	The NNT for the primary endpoint of these trials (3 SCBMs/wk and an increase of C1 SCBM/wk, for 75% of weeks) was 7 (95%CI: 5-8)
	Rao et al[86]	803 adults with IBS-C	Phase III trials randomized, double-blind, placebo-controlled to receive linaclotide 290 lg or placebo once/d for 12 wk	Linaclotide demonstrated statistically significant improvements in all primary and secondary efficacy end points compared with placebo Severity of straining, constipation, and stool consistency also improved in the linaclotide group compared with the placebo group
Plecanatide	Miner et al[92]	951 patients with CIC	Phase III, randomized, double-blind trial, received plecanatide 0.3, 1 or 3 mg, or placebo once/d for 12 wk	The proportion of overall responders was significantly greater with plecanatide 3 mg compared with placebo (19% vs 10.7%, P = 0.009); weekly responder rates were also significantly greater for plecanatide 3 mg than placebo for weeks 1-12. Improvements in stool frequency, consistency, straining, and quality of life were also noted with the 3-mg dose vs placebo. Data for other plecanatide doses were not reported
Prucalopride	Quigley et al[88]	620 patients with CC	A double-blind, placebo-controlled study. Patients receiving 2 or 4 mg of prucalopride for 12 wk	Increased one or more CSBMs per week compared to patients in the control group
	Camilleri et al[98]	713 patients with CC	A double-blind, placebo-controlled study. Patients receiving 2 or 4 mg of prucalopride for 12 wk	Increased frequency of three or more CSBMs per week, and improved evacuation completeness, perceived disease severity, and quality of life
	Müller-Lissner et al[97]	Elderly patients aged 65 years and older with CC	A double-blind, placebo-controlled study	No changes in electrocardiogram or corrected QT (QTc) interval were reported, indicating its safety for the treatment of CC in the elderly
			Patients receiving 2 or 4 mg of prucalopride for 12 wk
	Ke et al[102]	4 Randomized, Placebo-controlled Studies	A Pooled Analysis	Safe and well-tolerated It was also effective in improving the abdominal symptoms of CC such as abdominal discomfort, bloating, straining, and painful bowel movements
YKP10811	Shin et al[114]	55 patients	A single-center, randomized, parallel-group, double-blinded, placebo-controlled study were assigned randomly to groups given YKP10811 10 mg (n = 15), 20 mg (n = 16), 30 mg (n = 15), or placebo (n = 11) daily for 8 d	Enhanced gastrointestinal and colonic transit and improved bowel function during an 8-d treatment trial. In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed
Renzapride	Camilleri et al[101]	46 women with IBS-C	In a phase II study	Renzapride 4 mg q.d. accelerated colonic transit and increased ascending colon emptying vs placebo
	George et al[130]	510 patients	Multicentre, randomized, placebo-controlled, double-blind study men and women were randomized to placebo or renzapride (1, 2 or 4 mg/d) for 12 wk	4 mg renzapride q.d. in terms of improving frequency of bowel movements and stool consistency
	Ford et al[131]	29 RCTs were eligible for inclusion	Meta-analysis of placebo-controlled clinical	Renzapride and cisapride were not more effective than placebo in IBS patients
	Mozaffari et al[133]	2528 C-IBS and non C-, non D-IBS patients	Meta-analysis from randomized placebo-controlled clinical trials	Renzapride has no significant advantage over placebo in relieving symptoms in IBS patients
Velusetrag	Manini et al[115]	60 healthy volunteers	Phase II clinical trials, pt were randomly assigned, in double-blind fashion, to placebo, 5, 15, 30 or 50 mg velusetrag, with transit measurements after single and 6-d dosing	Single doses of velusetrag (30 and 50 mg), but not placebo, accelerated colonic transit, as measured by colonic filling at 6 h and geometric center at 24 h
	Goldberg et al[140]	401 subjects with CC	In a Phase II randomized, double-blind, placebo-controlled trial	Short bowel movement (SBM) frequency, complete SBM and other associated symptoms with CC were significantly improved in comparison with placebo in patients who received velusetrag for 4 wk
Naronapride	Dennis et al[149]	210 patients with CC.	Phase II, randomized, double-blind, placebo-controlled, dose definition study (orally 20, 40, 80 and 120 mg twice a day) to evaluate the clinical effects of 9 days’	There were borderline effects on gastric emptying at half-time; however, ATI-7505 accelerated colonic transit at 24 h and ascending colonic emptying
Chenodeoxycolic acid	Odunsi-Shiyanbade et al[155]	60 healthy volunteers	Randomized controlled trial, CDCA 500 mg and 1000 mg given for 4 d	Significant increases in stool frequency, decreases in stool consistency, and improvements in ease of stool passage were reported with CDCA
	Rao et al[153]	36 female patients	Double-blind placebo-controlled study	Accelerated colonic transit and improved bowel function
Elobixibat	Simrén et al[162]	30 patients	Dose-finding randomized trial five dose-levels (range: 0.1-10 mg/d) or to placebo	Increased C4, reduced LDL cholesterol and increased colonic transit from 3 to 1.9 d, and increased the number of SBM and CSBM/W in patients with CIC
	Chey et al[157]	190 patients	Were randomized to 5, 10, or 15 mg A3309 or placebo once daily. 8-wk, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study,	A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 wk of treatment
Lubiprostone	Drossman et al[173]	1171 patients in total	Two double-blind, randomized, multicenter, placebo-controlled phase III clinical trials,, a 12-wk randomized 2:1 to receive either lubiprostone 8 lg or matching placebo twice/d with food; a 36-wk open-label extension study	Lubiprostone was superior to placebo in the primary end point of overall responders, greater improvements in all secondary outcome measures compared with placebo
	Chey et al[174]
	Johanson et al[175]	479 patients in total	Two 4-wk phase III, randomized, double-blind, placebo-controlled, multicenter clinical trials	Patients treated with lubiprostone had a statistical higher frequency of SBMs during the first week of treatment compared with placebo
	Barish et al[82]
	Hyman et al[176]	127 pediatric patients with CIC (mean age 10.2 yr)	An open-label 4-wk clinical trial	Demonstrated that lubiprostone was efficacious and well tolerated at total daily doses of 12-48 lg
AZD1722	Rosenbaum et al[185]	181 patients with IBS-C	Phase IIa In a IIa double-blind, randomized placebo-controlled study, Tenapanor was given orally at the doses of 10, 30 and 100 mg once daily for 4 consecutive weeks with 2 wk follow-up	The primary end point [change in complete spontaneous bowel movements (CSBM) from baseline to week 4] was not met in this study and the incidence of diarrhea was comparable with placebo group. However, improvement in bloating and abdominal pain was noted in IBS-C patients
	Rosenbaum et al[186]	371 IBS-C patients	Phase IIb In a IIb randomized, double-blind, placebo-controlled, multicenter study	The overall responder was met in 50.0% of tenapanor-treated group (50 mg) vs 23.6% for placebo (after 12 wk). After 12 wk, adequate relief in IBS-C symptoms was observed in 63.1% of tenapanor-treated group (50 mg twice daily) vs 39.3% in placebo
	Rosenbaum et al[187]	356 patients	A double-blind, placebocontrolled, randomized phase 2b trial 12-wk dose-ranging study evaluating tenapanor 5 mg, 20 mg or 50 mg b.i.d. vs placebo (1/2)	Tenapanor 50 mg b.i.d. significantly improved CSBM responder rate (primary endpoint) compared with placebo in patients with IBS-C. Tenapanor 50 mg b.i.d. also improved key secondary endpoints compared with placebo, including overall responder rate, abdominal pain responder rate and stool frequency. In addition, improvements were observed in several exploratory endpoints addressing a range of symptoms in patients with IBS-C. Tenapanor was generally well tolerated and had minimal systemic availability. Tenapanor shows promise as a future treatment option for patients with IBS-C
Neu p11 (piromalatine)	Camilleri et al[202]	40 IBS patients	In double blind placebo controlled study were randomly assigned to receive either melatonin 3 mg (n = 20) or matching placebo (n = 20) at bedtime for two weeks	Melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin On abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles

IBS : Irritable bowel syndrome.

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.