The use of novel promotility and prosecretory agents for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation
- 333 Downloads
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 However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects.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.
KeywordsC-IBS CIC constipation 5-HT4 agonists linaclotide lubiprostone prucalopride TD.5108
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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.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.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.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
- 32.ATI-7505 — gastrointestinal disorders. Addressing safety issues of first generation drugs. ARYx Therapeutics website. Available at: http://www.aryx.com/wt/page/ati7505. Accessed February 22, 2009.
- 33.ARYx Therapeutics, Inc. announces successful results of chronic constipation clinical trial on ATI-7505. Medical News Today. August 26, 2008. Available at: http://www.medicalnewstoday.com/articles/119214.php.
- 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
- 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.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.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
- 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
- 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