The use of novel promotility and prosecretory agents for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation.
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 constipation-associated 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 However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects.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-HT(4) 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.
Gale
Jeremy D
JD
Pfizer Global Research and Development, Sandwich, UK. jeremy.gale@pfizer.com
D000527:Alprostadil / Q000031:analogs & derivatives / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000627:therapeutic use; D001572:Benzofurans / Q000627:therapeutic use; D018118:Chloride Channels / Q000187:drug effects; D002908:Chronic Disease; D003248:Constipation / Q000150:complications* / Q000188:drug therapy*; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006162:Guanylate Cyclase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D043183:Irritable Bowel Syndrome / Q000150:complications* / Q000188:drug therapy*; D054368:Laxatives / Q000009:adverse effects; D000068238:Lubiprostone; D010455:Peptides / Q000627:therapeutic use; D012449:Safety; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D053961:Azabicyclo Compounds; D001572:Benzofurans; D018118:Chloride Channels; D005765:Gastrointestinal Agents; D007211:Indoles; D054368:Laxatives; D010455:Peptides; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C533727:TD-5108; C406662:prucalopride; C105050:tegaserod; D000068238:Lubiprostone; D006162:Guanylate Cyclase; D000527:Alprostadil; C523483:linaclotide