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

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.