Advances in Therapy

, Volume 26, Issue 5, pp 519–530 | Cite as

The use of novel promotility and prosecretory agents for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation

  • Jeremy D. GaleEmail author


Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (C-IBS) are commonly reported gastrointestinal (GI) disorders that have a major impact on health and quality of life. Patients experience a range of symptoms of which infrequency of bowel movement is but one and report that straining, the production of hard stools, and unproductive urges are more bothersome than stool infrequency. Additionally, in C-IBS, patients report abdominal pain and bloating as particularly troubling. Traditional treatments, such as laxatives, are often ineffective, especially in more severe constipation over the long term. In a population-based survey of constipation sufferers, half were not satisfied with their current treatment, due predominantly to poor efficacy. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists stimulate GI motility and intestinal secretion, and tegaserod has demonstrated efficacy in improving bowel habit. Tegaserod also improves constipationassociated symptoms including bloating, abdominal discomfort, stool consistency, and straining in patients with both CIC and C-IBS. However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects. Further 5-HT4 receptor agonists, including prucalopride and TD-5108 are in development and show exciting results in clinical studies in CIC patients, suggesting further product approvals are likely. Headache and diarrhea are the most commonly reported adverse event with this class of agent. Recently a novel prosecretory agent has been approved for the treatment of both CIC and C-IBS. Lubiprostone stimulates chloride secretion through activation of type-2 chloride channels, increasing intestinal secretion and transit, and its use has been associated with improvements in bowel habit and symptoms of constipation. Nausea, diarrhea, and headache are the most commonly reported adverse events. Linaclotide also stimulates intestinal chloride secretion, but this molecule achieves this indirectly, through the activation of guanylate cyclase C. Data are emerging, but the efficacy and safety profile of this agent in the treatment of CIC and C-IBS appears encouraging.


C-IBS CIC constipation 5-HT4 agonists linaclotide lubiprostone prucalopride TD.5108 


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  1. 1.
    Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol. 1999;94:3530–3540.PubMedCrossRefGoogle Scholar
  2. 2.
    Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004;99:750–759.PubMedCrossRefGoogle Scholar
  3. 3.
    Wald A, Scarpignato C, Kamm MA, et al. The burden of constipation on quality of life: results of a multinational survey. Aliment Pharmacol Ther. 2007;26:227–236.PubMedCrossRefGoogle Scholar
  4. 4.
    Dennison C, Prasad M, Lloyd A, et al. The health-related quality of life and economic burden of constipation. Pharmacoeconomics. 2005;23:461–476.PubMedCrossRefGoogle Scholar
  5. 5.
    Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther. 2007;25:599–608.PubMedGoogle Scholar
  6. 6.
    Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491.PubMedCrossRefGoogle Scholar
  7. 7.
    El-Seraq HB. Impact of irritable bowel syndrome: prevalence and effect on health-related quality of life. Rev Gastroenterol Disord. 2003;3(suppl. 2):S3–S11.Google Scholar
  8. 8.
    Dapoigney M, Bellanger J, Bonaz B, et al. Irritable bowel syndrome in France: a common, debilitating and costly disorder. Eur J Gastroenterol Hepatol. 2004;16:995–1001.CrossRefGoogle Scholar
  9. 9.
    Wilson S, Roberts L, Roalfe A, Bridge P, Singh S. Prevalence of irritable bowel syndrome: a community survey. Br J Gen Pract. 2004;54:495–502.PubMedGoogle Scholar
  10. 10.
    Camilleri M. Tegaserod. Aliment Pharmacol Ther. 2001;15:277–289.PubMedCrossRefGoogle Scholar
  11. 11.
    Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind controlled trial. Clin Gastroenterol Hepatol. 2004;2:796–805.PubMedCrossRefGoogle Scholar
  12. 12.
    Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362–372.PubMedCrossRefGoogle Scholar
  13. 13.
    Lesbros-Pantoflickova D, Michetti P, Fried M, Belinger C, Blum AL. Meta analysis: the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2004;20:1253–1269.PubMedCrossRefGoogle Scholar
  14. 14.
    Evans BW, Clark WK, Moore DJ, Whorwell PJ. Tegaserod for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2007;4:CD003960.PubMedGoogle Scholar
  15. 15.
    Prins NH, van Der Grijn A, Lefebvre RA, Akkermans LM, Schuurkes JA. 5-HT4 receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study. Br J Pharmacol. 2001;132:1941–1947.PubMedCrossRefGoogle Scholar
  16. 16.
    Briejer MR, Prins NH, Schuurkes JA. Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil. 2001;13:465–472.PubMedCrossRefGoogle Scholar
  17. 17.
    Emmanuel AV, Kamm MA, Roy AJ, Antonelli K. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut. 1998;42:511–516.PubMedGoogle Scholar
  18. 18.
    Bouras EP, Camilleri M, Burton DD, McKinzie S. Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy volunteers. Gut. 1999;44:682–686.PubMedGoogle Scholar
  19. 19.
    Emmanuel AV, Roy AJ, Nicholls TJ, Kamm MA. Prucalopride, a systemic enterokinetic, for the treatment of constipation. Aliment Pharmacol Ther. 2002;16:1347–1356.PubMedCrossRefGoogle Scholar
  20. 20.
    Coremans G, Kerstens R, De Pauw M, Stevens M. Prucalopride is effective in patients with severe chronic constipation in whom laxatives fail to provide adequate relief. Digestion. 2003;67:82–89.PubMedCrossRefGoogle Scholar
  21. 21.
    Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med. 2008;358:2344–2354.PubMedCrossRefGoogle Scholar
  22. 22.
    Quigley EMM, Vandeplassche L, Kerstens R, Ausma J. 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. 2008;29:315–328.PubMedCrossRefGoogle Scholar
  23. 23.
    Tack J, van Outryve M, Beyens G, Kerstens R, Vandeplassche L. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut. 2009;58:357–365.PubMedCrossRefGoogle Scholar
  24. 24.
    Beattie DT, Armstrong SR, Shaw J-P, et al. The in vivo gastrointestinal activity of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity. Naunyn-Schmiedeberg’s Arch Pharmacol. 2008;378:139–147.CrossRefGoogle Scholar
  25. 25.
    Goldberg MR, Wong SL, Ganju J, Li Y-P, Ballow CH, Kitt MM. TD-5108, a selective 5-HT4 agonist with high intrinsic activity, shows immediate and sustained prokinetic activity in healthy subjects. Gastroenterology. 2007;132(suppl. 2):A60. Abstract.Google Scholar
  26. 26.
    O’Donnel LJD, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ. 1990;300:439–440.CrossRefGoogle Scholar
  27. 27.
    Camilleri M, Manini M, McKinzie S, et al. Dose-related effects of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity, on gastrointestinal (GI) and colonic transit in healthy volunteers. Neurogastroenterol Motil. 2008;20(suppl. 2):6. Abstract.Google Scholar
  28. 28.
    Goldberg MR, Li Y-P, Pitzer K, Johanson JF, Mangel AW, Kitt MM. TD-5108, a selective 5-HT4 agonist, is consistently better than placebo regardless of response definition in patients with chronic constipation. Gastroenterology. 2008;134(suppl. 1): A545. Abstract.Google Scholar
  29. 29.
    Goldberg MR, Li Y-P, Mangel AW, Johanson JF, Pitzer K, Kitt MM. In patients with chronic constipation, TD-5108, a selective 5-HT4 agonist with high intrinsic activity, relieves straining and bloating, normalizes stool consistency and reduces laxative use. Gastroenterology. 2008;134(suppl. 1):A547. Abstract.Google Scholar
  30. 30.
    Dennis D, Palme M, Irwin I, Druzgala I, Teichman S. ATI-7505 is a novel, selective 5HT4 receptor agonist that causes gastrointestinal prokinetic activity in dogs. Gastroenterology. 2004;126(suppl. 2):A641. Abstract.Google Scholar
  31. 31.
    Camilleri M, Vazquez-Roque MI, Burton D, Ford T, McKinzie S, Zinsmeister AR. Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil. 2007;19:30–38.PubMedCrossRefGoogle Scholar
  32. 32.
    ATI-7505 — gastrointestinal disorders. Addressing safety issues of first generation drugs. ARYx Therapeutics website. Available at: Accessed February 22, 2009.
  33. 33.
    ARYx Therapeutics, Inc. announces successful results of chronic constipation clinical trial on ATI-7505. Medical News Today. August 26, 2008. Available at:
  34. 34.
    Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther. 2007;25:1351–1361.PubMedCrossRefGoogle Scholar
  35. 35.
    Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebocontrolled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol. 2008;103:170–177.PubMedCrossRefGoogle Scholar
  36. 36.
    Panas R, Johanson JF, Wahle A, Ueno R. Long-term safety and efficacy of lubiprostone for the treatment of chronic idiopathic constipation. Gut. 2008;57(suppl. I):A284. Abstract.Google Scholar
  37. 37.
    Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation- associated irritable bowel syndrome - results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009;29:329–341.PubMedCrossRefGoogle Scholar
  38. 38.
    Bryant AP, Busby RW, Cordero EA et al. MD-1100, a therapeutic agent in development for the treatment of IBS-C, enhances intestinal secretion and transit, decreases visceral pain and is minimally absorbed in rats. Gastroenterology. 2005;128(suppl. 2):A464. Abstract.Google Scholar
  39. 39.
    Busby RW, Bryant AP, Cordero EA, et al. The molecular target of MD-1100 is guanylate cyclase C (gc-C), an apical receptor on intestinal epithelial cell. Gastroenterology. 2005;128(suppl. 2):A464. Abstract.Google Scholar
  40. 40.
    Bueno L, Beaufraud C, Mahajan-Miklos S, et al. Antinociceptive actions of MD-1100, a novel therapeutic agent for C-IBS, in animal models of visceral pain. Am J Gastroenterol. 2004;99:A283. Abstract.Google Scholar
  41. 41.
    Andresen 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.PubMedCrossRefGoogle Scholar
  42. 42.
    Johnston JM, MacDougal JE, Lavins BJ, et al. Linaclotide significantly improved abdominal pain/discomfort and global assessments in adults with irritable bowel syndrome with constipation. Neurogastroenterol Motil. 2008;20(suppl. 2):13. Abstract.Google Scholar
  43. 43.
    Johnston JM, Kurtz CB, Drossman DA, et al. Pilot study on the effects of linaclotide in patients with chronic constipation. Am J Gastroenterol. 2009;104:125–132.PubMedCrossRefGoogle Scholar
  44. 44.
    Lembo AJ, Johnston JM, MacDougall JE, et al. Linaclotide significantly improved bowel habits and relieved abdominal symptoms in adults with chronic constipation: data from a large 4-week, randomized, double-blind, placebo-controlled study. Gastroenterology. 2008;135:295. Abstract.CrossRefGoogle Scholar

Copyright information

© Springer Healthcare Communications 2009

Authors and Affiliations

  1. 1.Pfizer Global Research and DevelopmentSandwichUK

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