Abstract
New therapies are being developed for irritable bowel syndrome (IBS). These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy. Prucalopride, the newest European Medicines Agency-approved 5-hydroxytryptamine receptor 4 (5-HT4) agonist, is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5-HT4 drugs; similarly, ramosetron, the 5-hydroxytryptamine receptor 3 (5-HT3) antagonist, appears efficacious in diarrhea-predominant IBS. Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion, such as chloride channels, the cystic fibrosis transmembrane regulator, and guanylate cyclase C. As a class, such secretagogues have high efficacy and safety for constipation. With more data obtained from phase 2 and 3 trials, we expect other classes of medications, including bile acid modulators, anti-inflammatory agents, visceral analgesics, and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Camilleri M: Treating irritable bowel syndrome: overview, perspective and future therapies. Br J Pharmacol 2004, 141:1237–1248.
Gershon MD, Tack J: The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007, 132:397–414.
Camilleri M, Andresen V: Current and novel therapeutic options for irritable bowel syndrome management. Dig Liver Dis 2009, 41:854–862.
Camilleri M: Review article: new receptor targets for medical therapy in irritable bowel syndrome. Aliment Pharmacol Ther 2010, 31:35–46.
•• Camilleri M, Kerstens R, Rykx A, et al.: A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008, 358:2344–2354. This article describes the first pivotal phase 3 trial demonstrating that about 30% of patients with constipation achieve three or more SCBMs per week on prucalopride, compared to 12% on placebo.
•• Quigley EM, Vandeplassche L, Kerstens R, et al.: Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation-a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009, 29:315–328. This article describes one of the three pivotal phase 3 trials reporting on the efficacy and tolerability of prucalopride in patients with severe constipation.
•• Tack J, van Outryve M, Beyens G, et al.: Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 2009, 58:357–365. This article describes one of the three pivotal phase 3 trials showing that prucalopride improves bowel function, associated symptoms, and satisfaction in chronically constipated patients.
Bouras EP, Camilleri M, Burton DD, et al.: Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology 2001, 120:354–360.
Sloots CE, Poen AC, Kerstens R, et al.: Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation. Aliment Pharmacol Ther 2002, 16:759–767.
Emmanuel AV, Roy AJ, Nicholls TJ, et al.: Prucalopride, a systemic enterokinetic, for the treatment of constipation. Aliment Pharmacol Ther 2002, 16:1347–1356.
Coremans G, Kerstens R, De Pauw M, et al.: Prucalopride is effective in patients with severe chronic constipation in whom laxatives fail to provide adequate relief. Results of a double-blind, placebo-controlled clinical trial. Digestion 2003, 67:82–89.
•• Camilleri M, Vazquez-Roque MI, Burton D, et al.: Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil 2007, 19:30–38. This phase 2 trial demonstrated that ATI-7505 accelerates overall colonic transit, and tends to accelerate gastric emptying and loosen stool consistency in healthy subjects.
Dennis D, Palme M, Irwin I, et al.: ATI-7505 is a novel, selective 5HT(4) receptor agonist that causes gastrointestinal prokinetic activity in dog. Gastroenterology 2004, 126:A641
•• Manini ML, Camilleri M, Goldberg M, et al.: Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. Neurogastroenterol Motil 2010, 22:42–49. This phase 2 trial demonstrated that velusetrag (TD-5108) accelerates intestinal and colonic transit after single dosing and accelerates gastric emptying after multiple dosing in healthy subjects and patients with constipation.
Goldberg MR, Li YP, Pitzer K, et al.: TD-5108, a selective 5-HT 4 agonist, is consistently better than placebo regardless of response definition in patients with chronic constipation. Gastroenterology 2008, 134:A545.
Goldberg MR, Wong SL, Ganju J, et al.: TD-5108, a selective 5-HT 4 agonist with high intrinsic activity, shows immediate and sustained prokinetic activity in healthy subjects. Gastroenterology 2007, 132:A60.
Hirata T, Funatsu T, Keto Y, et al.: Pharmacological profile of ramosetron, a novel therapeutic agent for IBS. Inflammopharmacol 2007, 15:5–9.
Hirata T, Keto Y, Nakata M, et al.: Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer. Neurogastroenterol Motil 2008, 20:557–565.
Matsueda K, Harasawa S, Hongo M, et al.: A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome. Digestion 2008, 77:225–235.
• Matsueda K, Harasawa S, Hongo M, et al.: A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol 2008, 43:1202–1211. This phase 3 trial demonstrated that ramosetron hydrochloride is effective and well tolerated in the treatment of abdominal pain, discomfort, and bowel habit in patients with diarrhea-predominant irritable bowel syndrome.
Mangel AW, Chaturvedi P: Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion 2008, 78:180–186.
Ueno R, Engelke KJ, Osama H: Effect of lubiprostone, a novel GI chloride channel activator, on isolated smooth muscle. Neurogastroenterol Motil 2005, 17:625.
Moeser AJ, Nighot PK, Engelke KJ, et al.: Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol 2007, 292:G647–G656.
Camilleri M, Bharucha AE, Ueno R, et al.: Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2006, 290:942–947.
Sweetser S, Busciglio IA, Camilleri M, et al.: Effect of a chloride channel activator, lubiprostone, on colonic sensory and motor function in healthy subjects. Am J Physiol Gastrointest Liver Physiol 2009, 296:G295–G301.
Johanson JF, Drossman DA, Panas R, et al.: Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2008, 27:685–696.
•• Andersen V, Camilleri M, Busciglio IA, et al.: Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 2007, 133:761–768. This phase 2a trial showed that linaclotide, 1000 μg once daily, significantly accelerated ascending colonic transit and altered bowel function.
Johnston JM, Kurtz CB, Drossman DA, et al.: Pilot study on the effect of linaclotide in patients with chronic constipation. Am J Gastroenterol 2009, 104:125–132.
•• Lembo AJ, Kurtz CB, Macdougall JE, et al.: Efficacy of linaclotide for patients with chronic constipation. Gastroenterology 2010, 138:886–895.e1. This article reports a phase 2b trial of efficacy of linaclotide therapy with few adverse events in patients with chronic constipation.
•• Odunsi-Shiyanbade ST, Camilleri M, McKinzie S, et al.: Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function. Clin Gastroenterol Hepatol 2010, 8:159–165. Two randomized, double-blind, placebo-controlled studies showed that sodium chenodeoxycholate in health and colesevelam in diarrhea-predominant irritable bowel syndrome have opposite effects on colonic transit and fecal parameters.
Rao A, Odunsi ST, Camilleri M, et al.: Dose-related effects of chenodeoxycholate on gastrointestinal and colonic transit and bowel function in female patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2010, 138:S224.
• Fernández-Bañares F, Esteve M, Salas A, et al.: Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics. Am J Gastroenterol 2007, 102:2520–2528. This prospective study assessed the presence of gluten-sensitive enteropathy, bile acid malabsorption, and sugar malabsorption in consecutive patients with chronic watery diarrhea of obscure origin fulfilling Rome II criteria.
Camilleri M, Nadeau A, Tremaine WJ, et al.: Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil 2009, 21:734–739.
Dunlop SP, Jenkins D, Spiller RC: Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol 2003, 98:1578–1583.
O’Mahony L, McCarthy J, Kelly P, et al.: Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005, 128:541–551.
Lobo B, Vicario M, Martinez C, et al.: Clinical benefit in IBS after disodium cromoglycate involves mast cell-medicated recovery of healthy-like innate immunity genes expression profile in the jejunal mucosa. Gastroenterology 2009, 136(Suppl 1):156.
Klooker TK, Koopman KE, Heide S, et al.: Treatment with the mast cell stabilizer ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in IBS patients. Proceedings of the United European Gastroenterology Federation (UEGF) Meeting. Vienna, Austria; 2008:OP397.
Corinaldesi R, Stanghellini V, Cremon C, et al.: Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study. Aliment Pharmacol Ther 2009, 30:245–252.
Dunlop SP, Jenkins D, Neal KR, et al.: Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther 2003, 18:77–84.
Delvaux M, Louvel D, Lagier E, et al.: The kappa agonist fedotozine relieves hypersensitivity to colonic distention in patients with irritable bowel syndrome. Gastroenterology 1999, 116:38–45.
Delgado-Aros S, Chial HJ, Camilleri M, et al.: Effects of a κ-opioid agonist, asimadoline, on satiation and GI motor and sensory functions in humans. Am J Physiol Gastrointest Liver Physiol 2003, 284:558–566.
Mangel AW, Bornstein JD, Hamm LR, et al.: Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome. Aliment Pharmacol Ther 2008, 28:239–249.
• Szarka LA, Camilleri M, Burton D, et al.: Efficacy of on-demand asimadoline, a peripheral κ-opioid agonist, in females with irritable bowel syndrome. Clin Gastroenterol Hepatol 2007, 5:1268–1275. This randomized study compared the effect of the κ-opioid agonist, asimadoline, and placebo on episodes of abdominal pain in patients with IBS.
Kanto J, Kangas L, Leppanen T, et al.: Tofizopam: a technical review for practice guideline development. Gastroenterology 1997, 112:2120–2137.
Leventer SM, Raudibaugh K, Frissora CL, et al.: Clinical trial: dextofisopam in the treatment of patients with diarrhea-predominant or alternating irritable bowel syndrome. Aliment Pharmacol Ther 2008, 27:197–206.
Acknowledgments
We thank Mrs. Cindy Stanislav for her excellent secretarial support.
Disclosure
Dr. Camilleri has received research grants related to the subject matter of this article from Microbia, Theravance, and ARYx. He also serves as a consultant to Ironwood, ARYx, and Theravance, earning less than the federal threshold for significant financial conflict of interest as an aggregate from the three companies together. Dr. Camilleri has signed a confidentiality disclosure agreement with Movetis to have access to prucalopride data, but does not receive any financial remuneration. No other potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Manabe, N., Rao, A.S., Wong, B.S. et al. Emerging Pharmacologic Therapies for Irritable Bowel Syndrome. Curr Gastroenterol Rep 12, 408–416 (2010). https://doi.org/10.1007/s11894-010-0124-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11894-010-0124-1