REVIEW URRENT C OPINION
New treatment targets for the management of irritable bowel syndrome Supriya Rao and H. Christian Weber
Purpose of review Irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC) are highly prevalent medical conditions that reduce quality of life and represent a substantial economic burden on healthcare cost. Until recently, no specific treatment options were available. This review will provide an update of the most recent randomized clinical trials data showing efficacy and safety of novel, targeted treatment modalities in IBS and CIC with gastrointestinal receptor and ion channel agonists. Recent findings Recent discoveries of peptides and small molecules targeting gastrointestinal receptors and ion channels resulted in novel, specific pharmacological therapies of IBS and CIC. The bicyclical fatty acid lubiprostone and the synthetic 14-amino acid peptide linaclotide were identified to selectively activate a Chloride Channel-2 and the Guanylin Cyclase-C receptor, respectively, and demonstrate efficacy in the treatment of IBS with constipation and CIC. Summary Novel molecules including the bicyclical fatty acid lubiprostone and the synthetic 14-amino acid peptide linaclotide represent new treatment modalities for IBS with constipation and CIC with proven efficacy and acceptable side-effect profiles. Keywords chronic idiopathic constipation, gastrointestinal receptors, irritable bowel syndrome (IBS), linaclotide, lubiprostone, serotonin
INTRODUCTION Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder characterized by altered bowel habits with abdominal pain. Global prevalence is estimated to be anywhere from 5 to 20% [1–4]. IBS has a significant impact on quality of life and represents a substantial economic burden due to high utilization of healthcare resources and loss of productivity in patients with IBS [1,5–10]. Diagnosis of IBS is based on symptom assessment by the Rome III criteria. IBS is grouped into four different subtypes: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixture of diarrhea and constipation (IBS-M), and unsubtyped that has an insufficient abnormality of stool consistency to be in the other groups (IBS-U) [1,11]. The pathophysiology of IBS appears to be multifactorial, with environmental (i.e. dietary) and hereditary/genetic factors, dysregulation of the bidirectional communication system between the gastrointestinal tract and the brain, and disruption of cellular immune responses and the
gastrointestinal neuroendocrine system (NES) all playing key roles [2,12–18]. Conventional therapies, including laxatives, antidiarrheals, and analgesics, aimed at alleviating symptoms have had limited success in the past [19]. Antispasmodics, such as dicyclomine and hyoscyamine, act via anticholinergic or antimuscarinic properties, selectively inhibiting gastrointestinal smooth muscle, and therefore reducing motor activity. They have shown to be efficacious in short-term use [20]. Antidepressants, specifically tricyclics such as amitriptyline and desipramine, have been shown to be somewhat beneficial in IBS-D via anticholinergic properties Boston University School of Medicine, Section of Gastroenterology, Boston, Massachusetts, USA Correspondence to H. Christian Weber, MD, Boston University School of Medicine, Section of Gastroenterology, 650 Albany Street, EBRC, Room 508, Boston, MA 02118-2518, USA. Tel: +1 617 638 8330; fax: +1 617 638 7785; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:9–14 DOI:10.1097/MED.0000000000000034
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KEY POINTS IBS and CIC are highly prevalent medical conditions that reduce quality of life and represent a substantial economic burden on healthcare cost. Some 5-HT (serotonin) receptor agonists and antagonists demonstrated improved symptom relief in patients with IBS, but serious adverse events occurred that led to their withdrawal from the market. The bicyclical fatty acid lubiprostone and the synthetic 14-amino acid peptide linaclotide possess significant efficacy in the treatment of IBS-C and CIC and are well tolerated. Both, lubiprostone and linaclotide, are believed to act topically on the gut lumen without systemic absorption and are metabolized in the intestinal lumen. A new mechanisms of visceral pain relief by cGMP activation via GC-C agonists is proposed.
[21]. However, directly targeting cholinergic neurotransmission can lead to multiple side-effects with long-term use. Given the limited efficacy of the previous medications, other gut-directed therapies have been pursued for possible treatment. The gastrointestinal NES has often been utilized as a target for potential therapies in IBS [1,2]. This system regulates the motility, secretion, and absorption of the gastrointestinal tract. The gastrointestinal NES comprises scattered enteroendocrine cells that are present in the luminal mucosa of the gut and nerve cells in the gut wall containing various peptides including serotonin, glucagon-like peptide 1, somatostatin, ghrelin, and others [2,22 ,23,24]. Serotonin receptor agonists and antagonists, as well as the more recent ion channel agonists have shown to possess improved therapeutic efficacy in the treatment of IBS over conventional therapy [1,25–32]. &
MEDICAL MANAGEMENT OF IRRITABLE BOWEL SYNDROME WITH TARGETED PHARMACOLOGICAL THERAPY Conventional medical management of IBS and other functional bowel disorders aims to alleviate symptoms that are associated with these conditions such as abdominal pain and altered bowel habits. Traditionally, these therapies may include nonspecific antidiarrheals, laxatives, fiber products, antispasmodics, and other remedies. In contrast, novel compounds for the treatment of IBS and other functional bowel disorders possess specific pharmacological targets in the gastrointestinal tract such as 10
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5-hydroxytryptamine (5-HT serotonin) and Guanylin Cyclase (GC-C) receptors, and the Chloride Channel-2 (ClC-2).
5-hydroxytryptamine (serotonin) receptor agonists/antagonists 5-HT (serotonin) type 1 (5-HT1) receptor agonists, such as sumatriptan and buspirone, improve symptoms of early satiety and may improve gastric accommodation by relaxing the stomach and delaying gastric emptying [33]. This 5-HT receptor is mainly found in the inhibitory motor neurons of the myenteric plexus of the stomach, so it is unlikely that the positive effect in IBS is substantial. In contrast, the 5-HT3 receptor antagonists, such as alosetron, established an improvement of abdominal pain and diarrhea, specially in female patients with IBS-D by decreasing small intestinal secretion and intestinal motility [23,27,34–39]. However, this drug was found to have an association with ischemic colitis and intestinal perforation from severe constipation and was briefly removed from the USA market by the Food and Drug Administration (FDA) [23,36,39–41]. It was returned to the market under strict control after patient lobbying and further data. In a recent randomized clinical trial alosetron showed improved quality of life and reduced restriction of daily activities in women with severe diarrhea-predominant IBS [42]. Partial 5-HT4 receptor agonists, targeting afferent neurons in the myenteric plexus mediate the release of multiple colonic neurotransmitters such as acetylcholine, substance P and VIP. This class of medications, which includes tegaserod, were found to increase colonic motility and enhance proximal colonic emptying, appearing to be beneficial in patients with IBS with constipation (IBS-C). Tegaserod also stimulated intestinal secretion and improved relief of pain and abdominal discomfort [27,43–45]. However, tegaserod was removed from the USA market in 2007 because of cardiovascular side-effects [27,46,47].
Chloride Channel-2 agonist lubiprostone More recently, the locally acting chloride channel agonist lubiprostone has been approved for the treatment of chronic idiopathic constipation (CIC) (24 mg b.i.d.) in adults and for IBS-C (8 mg b.i.d.) in women at least 18 years old [AMITIZA (package insert). Bethesda, MD: SucampoPharma Americas, LLC; 2012] [48]. Lubiprostone is a bicyclical fatty acid compound that activates chloride rich fluid secretion in the intestine through selective agonist action on ClC-2 chloride channels, found in the apical membrane of epithelial cells lining the Volume 21 Number 1 February 2014
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Irritable bowel syndrome Rao and Weber
gut that play the central role in the activation of chloride transport [49,50]. The increased chloride movement into the intestinal lumen leads to increased water transport, softening stools, and decreasing the severity of constipation. Lubiprostone was approved for the treatment of CIC in adults in 2006 and for the treatment of IBS-C in women in 2008 [AMITIZA (package insert). Bethesda, MD: SucampoPharma Americas, LLC; 2012] [48]. Two double-blinded, randomized placebo-controlled multicenter trials were performed in 2008 to demonstrate the efficacy and safety of 12-week administration of oral lubiprostone. The data from these two trials supported the efficacy of 8 mg of lubiprostone b.i.d. in the treatment of IBS-C by increasing the chances of an IBS patient to become an overall symptoms responder compared with placebo (18 versus 10%). There was also significant improvement in the secondary endpoints of abdominal pain and severity of constipation [51]. In terms of safety, clinical trials deemed the medication to be well tolerated and major adverse effects of lubiprostone were not reported. Nausea was the most commonly noted side-effect [52]. The nausea appeared to be dose-dependent and reduced when the drug was taken with food. More recently, a 36-week randomized, placebo-controlled study was done to evaluate the safety and efficacy of the drug in constipated patients. Again, long-term use did not result in any clinically significant changes in electrolyte levels or did not cause any significant cardiovascular events [53]. Long-term safety, tolerability, and patient outcomes of lubiprostone in patients with IBS-C were further confirmed in an extension trial, whereby lubiprostone 8 mg b.i.d. was found to be safe and well tolerated over 9–13 months of treatment. The most common adverse events were diarrhea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%), and abdominal distention (5.8%). Diarrhea and nausea were the most common treatmentrelated adverse events [54 ]. A recent open-label trial showed lubiprostone was also efficacious and well tolerated in children and adolescents with functional constipation [55 ]. In previous clinical trials, lubiprostone reduced the severity of abdominal pain; however, in a recent study lubiprostone had no effect on visceral sensory thresholds. The authors therefore concluded that reductions in clinical pain that occur while taking lubiprostone appear to be secondary to changes in stool consistency [56]. Animal studies have shown increased fetal loss in guinea pigs with high doses of lubiprostone so it is under pregnancy category C [48]. Other recent animal studies also suggested that lubiprostone exhibits the additional distinct property of effective protection or repair of the epithelial barrier and cell &
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function after stress [57], although a recent case report of lubiprostone-induced ischemic colitis was published [58], and lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota [59]. It is thought that lubiprostone acts topically on the gut lumen and is completely metabolized in the lumen. The M3 metabolite is detected in low serum concentrations and may be responsible for some of the reported side-effects, including the rare side-effect of dyspnea [60].
Guanylin Cyclase-C receptor agonist linaclotide Linaclotide is a recently approved novel drug for treatment in patients with IBS-C and CIC in adults [61]. This drug is a synthetic14-amino acid peptide with potent GC-C receptor agonist properties that regulates cyclic guanosine-30 , 50 -monophosphate (cGMP), acting locally with low oral bioavailability. GC-C receptor sites are predominantly expressed on the apical surface of small intestine and colonic epithelial cells and are activated by the endogenous hormones guanylin and uroguanylin. Binding of the synthetic peptide linaclotide leads to the generation of cGMP, which triggers a signal transduction cascade activating the cystic fibrosis transmembrane conductance regulator, and causing the release of chloride and bicarbonate into the intestinal lumen. This increases fluid secretion and acceleration of gastrointestinal transit along with pain relief [62–64]. A very recent study by Busby et al. [65 ] examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration to exert the pharmacologic effects without systemic side-effects [65 ]. Linaclotide (1000 mg) increased stool frequency and decreased first time to bowel movement in a 5-day randomized, double-blinded, placebocontrolled study of 36 female patients with IBS-C without apparent safety issues [66]. In a subsequent phase IIb trial, 420 patients given oral linaclotide at doses of 75, 150, 300, or 600 mg or placebo once daily for 12 weeks showed similar improvement in bowel movements as well as significant reduction in abdominal pain and discomfort [67]. Two phase III randomized, multicenter, double-blinded, placebocontrolled trials, demonstrated that linaclotide (at 145 and 290 mg once daily) also significantly reduced
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bowel and abdominal symptoms in patients with CIC [68]. The primary efficacy endpoint was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks [68]. In patients with IBS-C, a phase III trial tested linaclotide (290 mg once daily) versus placebo with four primary endpoints including the FDA’s and three other primary endpoints, based on improvements in abdominal pain and CSBMs for 9/12 weeks [69 ]. Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the randomized withdrawal period. This trial showed that patients who received linaclotide had a significant improvement in IBS-C symptoms and were more likely to be overall responders than those who received placebo [69 ]. In a safety and efficacy randomized, double-blind, placebo-controlled trial of 804 patients, diarrhea was noted to be the most common treatment-related adverse sideeffect, causing discontinuation of the drug in a small percentage of individuals [70]. Two additional phase III trials in 1602 patients [797 receiving placebo and 805 receiving linaclotide (290 mg once a day)] with IBS-C severe abdominal symptoms were assessed. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms [71]. A prespecified further analysis to evaluate the efficacy and safety of linaclotide in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency submission also showed linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks [72]. Finally, a recent meta-analysis identified seven trials of linaclotide in patients with IBS-C or CIC of which six were included in the analysis. Two of three trials of IBS-C used the endpoint recommended by the US FDA and linaclotide showed improved bowel function and reduced abdominal pain, and overall severity of IBS-C or CIC, compared with placebo [73]. The most common adverse effects of linaclotide in clinical trials have been diarrhea, abdominal pain, flatulence, and abdominal distension. A black box in the labeling warns against use of the drug in patients below 18 years old because of deaths during studies in young mice. Linaclotide is classified as category C (risk cannot be ruled out) for use during pregnancy [61]. In animal and cell culture studies, lubiprostone but not linaclotide showed a distinct property of effective protection or repair of the epithelial barrier &
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and cell function after stress [57]. On the contrary, recent studies provide some insight into the possible mechanisms of linaclotide-mediated improvement of abdominal pain in patients with IBS-C and CIC. Ligand activation of GC-C attenuated stretch responses and sensitization of mouse colorectal afferents suggesting that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization [74 ]. Furthermore, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity [75 ]. Intracolonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide’s target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors suggesting that the analgesic mechanism of linaclotide involves the activation of GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP [75 ]. &
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CONCLUSION IBS and CIC are common chronic medical conditions with various gastrointestinal symptoms associated with decreased quality of life. In the past, therapies were directed toward alleviating symptoms, but only recently have there been peptides that target the NES specifically. Although serotonin receptor agonists and antagonists were discovered to have considerable side-effects, other novel peptides and small molecules such as the ion channel agonists and bicyclic fatty acids have proven therapeutic efficacy in large randomized clinical trials with favorable side-effect profiles. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. El-Salhy M. Irritable bowel syndrome: diagnosis and pathogenesis. WJG 2012; 18:5151–5163. 2. El-Salhy M, Seim I, Chopin L, et al. Irritable bowel syndrome: the role of gut neuroendocrine peptides. Front Biosci (Elite Ed) 2012; 4:2783–2800. 3. Quigley EM, Abdel-Hamid H, Barbara G, et al. A global perspective on irritable bowel syndrome: a consensus statement of the World Gastroenterology Organisation Summit Task Force on irritable bowel syndrome. J Clin Gastroenterol 2012; 46:356–366.
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Irritable bowel syndrome Rao and Weber 4. Mayer EA. Clinical practice. Irritable bowel syndrome. N Engl J Med 2008; 358:1692–1699. 5. Agarwal N, Spiegel BM. The effect of irritable bowel syndrome on healthrelated quality of life and healthcare expenditures. Gastroenterol Clin North Am 2011; 40:11–19. 6. Spiegel B, Harris L, Lucak S, et al. Developing valid and reliable health utilities in irritable bowel syndrome: results from the IBS PROOF Cohort. Am J Gastroenterol 2009; 104:1984–1991. 7. Martin BC, Ganguly R, Pannicker S, et al. Utilization patterns and net direct medical cost to Medicaid of irritable bowel syndrome. Curr Med Res Opin 2003; 19:771–780. 8. Leong SA, Barghout V, Birnbaum HG, et al. The economic consequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med 2003; 163:929–935. 9. Longstreth GF, Wilson A, Knight K, et al. Irritable bowel syndrome, healthcare use, and costs: a U.S. managed care perspective. Am J Gastroenterol 2003; 98:600–607. 10. Camilleri M, Williams DE. Economic burden of irritable bowel syndrome. Proposed strategies to control expenditures. Pharmacoeconomics 2000; 17:331–338. 11. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130:1480–1491. 12. Elsenbruch S, Holtmann G, Oezcan D, et al. Are there alterations of neuroendocrine and cellular immune responses to nutrients in women with irritable bowel syndrome? Am J Gastroenterol 2004; 99:703–710. 13. Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med 2001; 52:319–338. 14. Chang L. Neuroendocrine and neuroimmune markers in IBS: pathophysiological role or epiphenomenon? Gastroenterology 2006; 130:596–600. 15. Feng B, La JH, Schwartz ES, Gebhart GF. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1085–G1098. 16. Spiller R. Serotonergic agents and the irritable bowel syndrome: what goes wrong? Curr Opin Pharmacol 2008; 8:709–714. 17. Park JH, Rhee PL, Kim G, et al. Enteroendocrine cell counts correlate with visceral hypersensitivity in patients with diarrhoea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2006; 18:539–546. 18. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med 2012; 367:1626–1635. 19. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/alternative approaches. Altern Med Rev 2011; 16:134–151. 20. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104 (Suppl 1):S1–S35. 21. Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Alimen Pharmacol Ther 1994; 8:409–416. 22. Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. & Curr Opin Endocrinol Diab Obes 2013; 20:14–21. A superb review on the importance of the gastrointestinal tract as the main source of serotonin and its biology. 23. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132:397–414. 24. Weber HC. Gastrointestinal regulatory peptides. Curr Opin Endocrinol Diab Obes 2011; 18:33–34. 25. Blackshaw LA, Brierley SM. Emerging receptor target in the pharmacotherapy of irritable bowel syndrome with constipation. Expert Rev Gastroenterol Hepatol 2013; 7:15–19. 26. Camilleri M. Review article: new receptor targets for medical therapy in irritable bowel syndrome. Alimen Pharmacol Ther 2010; 31:35–46. 27. Ford AC, Brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol 2009; 104:1831–1843. 28. Johnston JM, Shiff SJ, Quigley EM. A review of the clinical efficacy of linaclotide in irritable bowel syndrome with constipation. Curr Med Res Opin 2013; 29:149–160. 29. Lacy BE, Chey WD. Lubiprostone: chronic constipation and irritable bowel syndrome with constipation. Expert Opin Pharmacother 2009; 10:143–152. 30. Sainsbury A, Ford AC. Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents. Ther Adv Gastroenterol 2011; 4:115–127. 31. Ford AC, Talley NJ. IBS in 2010: advances in pathophysiology, diagnosis and treatment. Nature reviews. Gastroenterol Hepatol 2011; 8:76–78. 32. Talley NJ. Serotoninergic neuroenteric modulators. Lancet 2001; 358:2061– 2068. 33. Tack J, Coulie B, Wilmer A, et al. Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man. Gut 1998; 42:36–41. 34. Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008; 6:545–555.
35. Spiller RC. Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome. Curr Opin Pharmacol 2011; 11:68–74. 36. Lewis JH. Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol 2010; 4:13–29. 37. Nakai A, Diksic M, Kumakura Y, et al. The effects of the 5-HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome. Neurogastroenterol Motil 2005; 17:212–221. 38. Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil 2003; 15:79–86. 39. Balfour JA, Goa KL, Perry CM. Alosetron. Drugs 2000; 59:511–518. 40. Lewis JH. The risk of ischaemic colitis in irritable bowel syndrome patients treated with serotonergic therapies. Drug Saf 2011; 34:545–565. 41. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and postmarketing surveillance data. Am J Gastroenterol 2006; 101:1069–1079. 42. Cremonini F, Nicandro JP, Atkinson V, et al. Randomised clinical trial: alosetron improves quality of life and reduces restriction of daily activities in women with severe diarrhoea-predominant IBS. Alimen Pharmacol Ther 2012; 36:437–448. 43. Evans BW, Clark WK, Moore DJ, Whorwell PJ. Tegaserod for the treatment of irritable bowel syndrome and chronic constipation. Cochrane Database Syst Rev 2007; CD003960. 44. Kale-Pradhan PB, Wilhelm SM. Tegaserod for constipation-predominant irritable bowel syndrome. Pharmacotherapy 2007; 27:267–277. 45. Patel S, Berrada D, Lembo A. Review of tegaserod in the treatment of irritable bowel syndrome. Expert Opin Pharmacother 2004; 5:2369– 2379. 46. Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58:491–496. 47. Pasricha PJ. Desperately seeking serotonin. A commentary on the withdrawal of tegaserod and the state of drug development for functional and motility disorders. Gastroenterology 2007; 132:2287–2290. 48. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/ 021908s010lbl.pdf [accessed 8 November 2013] 49. Lubiprostone (amitiza) for chronic constipation. Med Lett Drugs Ther 2006; 48:47–48. 50. Lubiprostone: RU 0211, SPI 0211. Drugs R D. 2005;6(4):245-8. Review. PubMed PMID: 15991886. 51. 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. Alimen Pharmacol Ther 2009; 29:329–341. 52. 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. Alimen Pharmacol Ther 2007; 25:1351–1361. 53. Fukudo S, Hongo M, Kaneko H, Ueno R. Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study. Neurogastroenterol Motil 2011; 23:544-e205. 54. Chey WD, Drossman DA, Johanson JF, et al. Safety and patient outcomes & with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Alimen Pharmacol Ther 2012; 35:587–599. Long-term efficacy and safety data in IBS-C patients treated with lubiprostone. 55. Hyman PE, Di Lorenzo C, Prestridge LL, et al. An open-label, multicenter, & safety and effectiveness study of lubiprostone for the treatment of functional constipation in children. J Pediatr Gastroenterol Nutrition 2013. [Epub ahead of print]. PubMed PMID: 24048162. First study to report of treatment of functional constipation with lubiprostone in the pediatric population. 56. Whitehead WE, Palsson OS, Gangarosa L, et al. Lubiprostone does not influence visceral pain thresholds in patients with irritable bowel syndrome. Neurogastroenterol Motil 2011; 23:944-e400. 57. Cuppoletti J, Blikslager AT, Chakrabarti J, et al. Contrasting effects of linaclotide and lubiprostone on restitution of epithelial cell barrier properties and cellular homeostasis after exposure to cell stressors. BMC Pharmacol 2012; 12:3. 58. Sherid M, Sifuentes H, Samo S, et al. Lubiprostone induced ischemic colitis. WJG 2013; 19:299–303. 59. Musch MW, Wang Y, Claud EC, Chang EB. Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci 2013; 58:668–677. 60. Chamberlain SM, Rao SS. Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome. Expert Opin Drug Saf 2012; 11:841–850. 61. Linaclotide (Linzess) for constipation. Med Letter Drugs Ther 2012; 54:91– 92; PubMed PMID: 23183319. 62. Bharucha AE, Waldman SA. Taking a lesson from microbial diarrheagenesis in the management of chronic constipation. Gastroenterology 2010; 138:813–817. 63. Brierley SM. Guanylate cyclase-C receptor activation: unexpected biology. Curr Opin Pharmacol 2012; 12:632–640.
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Gastrointestinal hormones 64. Busby RW, Bryant AP, Bartolini WP, et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol 2010; 649:328–335. 65. Busby RW, Kessler MM, Bartolini WP, et al. Pharmacologic properties, && metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther 2013; 344:196–206. This report characterizes the linaclotide metabolite MM-419447 (CCEYCCNPACTGC) in rat models of gastrointestinal function, showing significantly increased fluid secretion into small intestinal loops via cGMP activation. Therefore, MM-419447 contributes to linaclotide’s pharmacology. 66. 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. 67. Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 2010; 139:1877-1886 e1872. 68. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011; 365:527–536. 69. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a & 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012; 107:1714–1724. A critical randomized clinical trial that demonstrate efficacy and safety of linaclotide in IBS-C.
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70. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012; 107:1702– 1712. 71. Rao SS, Quigley EM, Shiff SJ, et al. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol 2013; 11:1984–1092. 72. Quigley EM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C – a prespecified further analysis based on European Medicines Agency-specified endpoints. Alimen Pharmacol Ther 2013; 37:49–61. 73. Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a metaanalysis. Clin Gastroenterol Hepatol 2013; 11:1084–1092e 1083. 74. Feng B, Kiyatkin ME, La JH, et al. Activation of guanylate cyclase-C attenuates & stretch responses and sensitization of mouse colorectal afferents. J Neurosci 2013; 33:9831–9839. A novel mechanism is suggested how GC-C receptor activation might result in visceral pain relief. 75. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic & nociceptors and relieves abdominal pain via guanylate cyclase-c and extracellular cyclic guanosine 30 ,50 -monophosphate. Gastroenterology 2013. doi: 10.1053/j.gastro.2013.08.017. [Epub ahead of print] A novel mechanism of visceral pain relief is proposed to occurr through extracellular cGMP activation in response to GC-C agonist treatment and inhibition of nociception.
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New treatment targets for the management of irritable bowel syndrome Supriya Rao and H. Christian Weber
Purpose of review Irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC) are highly prevalent medical conditions that reduce quality of life and represent a substantial economic burden on healthcare cost. Until recently, no specific treatment options were available. This review will provide an update of the most recent randomized clinical trials data showing efficacy and safety of novel, targeted treatment modalities in IBS and CIC with gastrointestinal receptor and ion channel agonists. Recent findings Recent discoveries of peptides and small molecules targeting gastrointestinal receptors and ion channels resulted in novel, specific pharmacological therapies of IBS and CIC. The bicyclical fatty acid lubiprostone and the synthetic 14-amino acid peptide linaclotide were identified to selectively activate a Chloride Channel-2 and the Guanylin Cyclase-C receptor, respectively, and demonstrate efficacy in the treatment of IBS with constipation and CIC. Summary Novel molecules including the bicyclical fatty acid lubiprostone and the synthetic 14-amino acid peptide linaclotide represent new treatment modalities for IBS with constipation and CIC with proven efficacy and acceptable side-effect profiles. Keywords chronic idiopathic constipation, gastrointestinal receptors, irritable bowel syndrome (IBS), linaclotide, lubiprostone, serotonin
INTRODUCTION Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder characterized by altered bowel habits with abdominal pain. Global prevalence is estimated to be anywhere from 5 to 20% [1–4]. IBS has a significant impact on quality of life and represents a substantial economic burden due to high utilization of healthcare resources and loss of productivity in patients with IBS [1,5–10]. Diagnosis of IBS is based on symptom assessment by the Rome III criteria. IBS is grouped into four different subtypes: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixture of diarrhea and constipation (IBS-M), and unsubtyped that has an insufficient abnormality of stool consistency to be in the other groups (IBS-U) [1,11]. The pathophysiology of IBS appears to be multifactorial, with environmental (i.e. dietary) and hereditary/genetic factors, dysregulation of the bidirectional communication system between the gastrointestinal tract and the brain, and disruption of cellular immune responses and the
gastrointestinal neuroendocrine system (NES) all playing key roles [2,12–18]. Conventional therapies, including laxatives, antidiarrheals, and analgesics, aimed at alleviating symptoms have had limited success in the past [19]. Antispasmodics, such as dicyclomine and hyoscyamine, act via anticholinergic or antimuscarinic properties, selectively inhibiting gastrointestinal smooth muscle, and therefore reducing motor activity. They have shown to be efficacious in short-term use [20]. Antidepressants, specifically tricyclics such as amitriptyline and desipramine, have been shown to be somewhat beneficial in IBS-D via anticholinergic properties Boston University School of Medicine, Section of Gastroenterology, Boston, Massachusetts, USA Correspondence to H. Christian Weber, MD, Boston University School of Medicine, Section of Gastroenterology, 650 Albany Street, EBRC, Room 508, Boston, MA 02118-2518, USA. Tel: +1 617 638 8330; fax: +1 617 638 7785; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:9–14 DOI:10.1097/MED.0000000000000034
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KEY POINTS IBS and CIC are highly prevalent medical conditions that reduce quality of life and represent a substantial economic burden on healthcare cost. Some 5-HT (serotonin) receptor agonists and antagonists demonstrated improved symptom relief in patients with IBS, but serious adverse events occurred that led to their withdrawal from the market. The bicyclical fatty acid lubiprostone and the synthetic 14-amino acid peptide linaclotide possess significant efficacy in the treatment of IBS-C and CIC and are well tolerated. Both, lubiprostone and linaclotide, are believed to act topically on the gut lumen without systemic absorption and are metabolized in the intestinal lumen. A new mechanisms of visceral pain relief by cGMP activation via GC-C agonists is proposed.
[21]. However, directly targeting cholinergic neurotransmission can lead to multiple side-effects with long-term use. Given the limited efficacy of the previous medications, other gut-directed therapies have been pursued for possible treatment. The gastrointestinal NES has often been utilized as a target for potential therapies in IBS [1,2]. This system regulates the motility, secretion, and absorption of the gastrointestinal tract. The gastrointestinal NES comprises scattered enteroendocrine cells that are present in the luminal mucosa of the gut and nerve cells in the gut wall containing various peptides including serotonin, glucagon-like peptide 1, somatostatin, ghrelin, and others [2,22 ,23,24]. Serotonin receptor agonists and antagonists, as well as the more recent ion channel agonists have shown to possess improved therapeutic efficacy in the treatment of IBS over conventional therapy [1,25–32]. &
MEDICAL MANAGEMENT OF IRRITABLE BOWEL SYNDROME WITH TARGETED PHARMACOLOGICAL THERAPY Conventional medical management of IBS and other functional bowel disorders aims to alleviate symptoms that are associated with these conditions such as abdominal pain and altered bowel habits. Traditionally, these therapies may include nonspecific antidiarrheals, laxatives, fiber products, antispasmodics, and other remedies. In contrast, novel compounds for the treatment of IBS and other functional bowel disorders possess specific pharmacological targets in the gastrointestinal tract such as 10
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5-hydroxytryptamine (5-HT serotonin) and Guanylin Cyclase (GC-C) receptors, and the Chloride Channel-2 (ClC-2).
5-hydroxytryptamine (serotonin) receptor agonists/antagonists 5-HT (serotonin) type 1 (5-HT1) receptor agonists, such as sumatriptan and buspirone, improve symptoms of early satiety and may improve gastric accommodation by relaxing the stomach and delaying gastric emptying [33]. This 5-HT receptor is mainly found in the inhibitory motor neurons of the myenteric plexus of the stomach, so it is unlikely that the positive effect in IBS is substantial. In contrast, the 5-HT3 receptor antagonists, such as alosetron, established an improvement of abdominal pain and diarrhea, specially in female patients with IBS-D by decreasing small intestinal secretion and intestinal motility [23,27,34–39]. However, this drug was found to have an association with ischemic colitis and intestinal perforation from severe constipation and was briefly removed from the USA market by the Food and Drug Administration (FDA) [23,36,39–41]. It was returned to the market under strict control after patient lobbying and further data. In a recent randomized clinical trial alosetron showed improved quality of life and reduced restriction of daily activities in women with severe diarrhea-predominant IBS [42]. Partial 5-HT4 receptor agonists, targeting afferent neurons in the myenteric plexus mediate the release of multiple colonic neurotransmitters such as acetylcholine, substance P and VIP. This class of medications, which includes tegaserod, were found to increase colonic motility and enhance proximal colonic emptying, appearing to be beneficial in patients with IBS with constipation (IBS-C). Tegaserod also stimulated intestinal secretion and improved relief of pain and abdominal discomfort [27,43–45]. However, tegaserod was removed from the USA market in 2007 because of cardiovascular side-effects [27,46,47].
Chloride Channel-2 agonist lubiprostone More recently, the locally acting chloride channel agonist lubiprostone has been approved for the treatment of chronic idiopathic constipation (CIC) (24 mg b.i.d.) in adults and for IBS-C (8 mg b.i.d.) in women at least 18 years old [AMITIZA (package insert). Bethesda, MD: SucampoPharma Americas, LLC; 2012] [48]. Lubiprostone is a bicyclical fatty acid compound that activates chloride rich fluid secretion in the intestine through selective agonist action on ClC-2 chloride channels, found in the apical membrane of epithelial cells lining the Volume 21 Number 1 February 2014
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Irritable bowel syndrome Rao and Weber
gut that play the central role in the activation of chloride transport [49,50]. The increased chloride movement into the intestinal lumen leads to increased water transport, softening stools, and decreasing the severity of constipation. Lubiprostone was approved for the treatment of CIC in adults in 2006 and for the treatment of IBS-C in women in 2008 [AMITIZA (package insert). Bethesda, MD: SucampoPharma Americas, LLC; 2012] [48]. Two double-blinded, randomized placebo-controlled multicenter trials were performed in 2008 to demonstrate the efficacy and safety of 12-week administration of oral lubiprostone. The data from these two trials supported the efficacy of 8 mg of lubiprostone b.i.d. in the treatment of IBS-C by increasing the chances of an IBS patient to become an overall symptoms responder compared with placebo (18 versus 10%). There was also significant improvement in the secondary endpoints of abdominal pain and severity of constipation [51]. In terms of safety, clinical trials deemed the medication to be well tolerated and major adverse effects of lubiprostone were not reported. Nausea was the most commonly noted side-effect [52]. The nausea appeared to be dose-dependent and reduced when the drug was taken with food. More recently, a 36-week randomized, placebo-controlled study was done to evaluate the safety and efficacy of the drug in constipated patients. Again, long-term use did not result in any clinically significant changes in electrolyte levels or did not cause any significant cardiovascular events [53]. Long-term safety, tolerability, and patient outcomes of lubiprostone in patients with IBS-C were further confirmed in an extension trial, whereby lubiprostone 8 mg b.i.d. was found to be safe and well tolerated over 9–13 months of treatment. The most common adverse events were diarrhea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%), and abdominal distention (5.8%). Diarrhea and nausea were the most common treatmentrelated adverse events [54 ]. A recent open-label trial showed lubiprostone was also efficacious and well tolerated in children and adolescents with functional constipation [55 ]. In previous clinical trials, lubiprostone reduced the severity of abdominal pain; however, in a recent study lubiprostone had no effect on visceral sensory thresholds. The authors therefore concluded that reductions in clinical pain that occur while taking lubiprostone appear to be secondary to changes in stool consistency [56]. Animal studies have shown increased fetal loss in guinea pigs with high doses of lubiprostone so it is under pregnancy category C [48]. Other recent animal studies also suggested that lubiprostone exhibits the additional distinct property of effective protection or repair of the epithelial barrier and cell &
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function after stress [57], although a recent case report of lubiprostone-induced ischemic colitis was published [58], and lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota [59]. It is thought that lubiprostone acts topically on the gut lumen and is completely metabolized in the lumen. The M3 metabolite is detected in low serum concentrations and may be responsible for some of the reported side-effects, including the rare side-effect of dyspnea [60].
Guanylin Cyclase-C receptor agonist linaclotide Linaclotide is a recently approved novel drug for treatment in patients with IBS-C and CIC in adults [61]. This drug is a synthetic14-amino acid peptide with potent GC-C receptor agonist properties that regulates cyclic guanosine-30 , 50 -monophosphate (cGMP), acting locally with low oral bioavailability. GC-C receptor sites are predominantly expressed on the apical surface of small intestine and colonic epithelial cells and are activated by the endogenous hormones guanylin and uroguanylin. Binding of the synthetic peptide linaclotide leads to the generation of cGMP, which triggers a signal transduction cascade activating the cystic fibrosis transmembrane conductance regulator, and causing the release of chloride and bicarbonate into the intestinal lumen. This increases fluid secretion and acceleration of gastrointestinal transit along with pain relief [62–64]. A very recent study by Busby et al. [65 ] examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration to exert the pharmacologic effects without systemic side-effects [65 ]. Linaclotide (1000 mg) increased stool frequency and decreased first time to bowel movement in a 5-day randomized, double-blinded, placebocontrolled study of 36 female patients with IBS-C without apparent safety issues [66]. In a subsequent phase IIb trial, 420 patients given oral linaclotide at doses of 75, 150, 300, or 600 mg or placebo once daily for 12 weeks showed similar improvement in bowel movements as well as significant reduction in abdominal pain and discomfort [67]. Two phase III randomized, multicenter, double-blinded, placebocontrolled trials, demonstrated that linaclotide (at 145 and 290 mg once daily) also significantly reduced
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bowel and abdominal symptoms in patients with CIC [68]. The primary efficacy endpoint was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks [68]. In patients with IBS-C, a phase III trial tested linaclotide (290 mg once daily) versus placebo with four primary endpoints including the FDA’s and three other primary endpoints, based on improvements in abdominal pain and CSBMs for 9/12 weeks [69 ]. Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the randomized withdrawal period. This trial showed that patients who received linaclotide had a significant improvement in IBS-C symptoms and were more likely to be overall responders than those who received placebo [69 ]. In a safety and efficacy randomized, double-blind, placebo-controlled trial of 804 patients, diarrhea was noted to be the most common treatment-related adverse sideeffect, causing discontinuation of the drug in a small percentage of individuals [70]. Two additional phase III trials in 1602 patients [797 receiving placebo and 805 receiving linaclotide (290 mg once a day)] with IBS-C severe abdominal symptoms were assessed. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms [71]. A prespecified further analysis to evaluate the efficacy and safety of linaclotide in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency submission also showed linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks [72]. Finally, a recent meta-analysis identified seven trials of linaclotide in patients with IBS-C or CIC of which six were included in the analysis. Two of three trials of IBS-C used the endpoint recommended by the US FDA and linaclotide showed improved bowel function and reduced abdominal pain, and overall severity of IBS-C or CIC, compared with placebo [73]. The most common adverse effects of linaclotide in clinical trials have been diarrhea, abdominal pain, flatulence, and abdominal distension. A black box in the labeling warns against use of the drug in patients below 18 years old because of deaths during studies in young mice. Linaclotide is classified as category C (risk cannot be ruled out) for use during pregnancy [61]. In animal and cell culture studies, lubiprostone but not linaclotide showed a distinct property of effective protection or repair of the epithelial barrier &
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and cell function after stress [57]. On the contrary, recent studies provide some insight into the possible mechanisms of linaclotide-mediated improvement of abdominal pain in patients with IBS-C and CIC. Ligand activation of GC-C attenuated stretch responses and sensitization of mouse colorectal afferents suggesting that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization [74 ]. Furthermore, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity [75 ]. Intracolonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide’s target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors suggesting that the analgesic mechanism of linaclotide involves the activation of GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP [75 ]. &
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CONCLUSION IBS and CIC are common chronic medical conditions with various gastrointestinal symptoms associated with decreased quality of life. In the past, therapies were directed toward alleviating symptoms, but only recently have there been peptides that target the NES specifically. Although serotonin receptor agonists and antagonists were discovered to have considerable side-effects, other novel peptides and small molecules such as the ion channel agonists and bicyclic fatty acids have proven therapeutic efficacy in large randomized clinical trials with favorable side-effect profiles. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. El-Salhy M. Irritable bowel syndrome: diagnosis and pathogenesis. WJG 2012; 18:5151–5163. 2. El-Salhy M, Seim I, Chopin L, et al. Irritable bowel syndrome: the role of gut neuroendocrine peptides. Front Biosci (Elite Ed) 2012; 4:2783–2800. 3. Quigley EM, Abdel-Hamid H, Barbara G, et al. A global perspective on irritable bowel syndrome: a consensus statement of the World Gastroenterology Organisation Summit Task Force on irritable bowel syndrome. J Clin Gastroenterol 2012; 46:356–366.
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Irritable bowel syndrome Rao and Weber 4. Mayer EA. Clinical practice. Irritable bowel syndrome. N Engl J Med 2008; 358:1692–1699. 5. Agarwal N, Spiegel BM. The effect of irritable bowel syndrome on healthrelated quality of life and healthcare expenditures. Gastroenterol Clin North Am 2011; 40:11–19. 6. Spiegel B, Harris L, Lucak S, et al. Developing valid and reliable health utilities in irritable bowel syndrome: results from the IBS PROOF Cohort. Am J Gastroenterol 2009; 104:1984–1991. 7. Martin BC, Ganguly R, Pannicker S, et al. Utilization patterns and net direct medical cost to Medicaid of irritable bowel syndrome. Curr Med Res Opin 2003; 19:771–780. 8. Leong SA, Barghout V, Birnbaum HG, et al. The economic consequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med 2003; 163:929–935. 9. Longstreth GF, Wilson A, Knight K, et al. Irritable bowel syndrome, healthcare use, and costs: a U.S. managed care perspective. Am J Gastroenterol 2003; 98:600–607. 10. Camilleri M, Williams DE. Economic burden of irritable bowel syndrome. Proposed strategies to control expenditures. Pharmacoeconomics 2000; 17:331–338. 11. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130:1480–1491. 12. Elsenbruch S, Holtmann G, Oezcan D, et al. Are there alterations of neuroendocrine and cellular immune responses to nutrients in women with irritable bowel syndrome? Am J Gastroenterol 2004; 99:703–710. 13. Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med 2001; 52:319–338. 14. Chang L. Neuroendocrine and neuroimmune markers in IBS: pathophysiological role or epiphenomenon? Gastroenterology 2006; 130:596–600. 15. Feng B, La JH, Schwartz ES, Gebhart GF. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1085–G1098. 16. Spiller R. Serotonergic agents and the irritable bowel syndrome: what goes wrong? Curr Opin Pharmacol 2008; 8:709–714. 17. Park JH, Rhee PL, Kim G, et al. Enteroendocrine cell counts correlate with visceral hypersensitivity in patients with diarrhoea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2006; 18:539–546. 18. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med 2012; 367:1626–1635. 19. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/alternative approaches. Altern Med Rev 2011; 16:134–151. 20. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104 (Suppl 1):S1–S35. 21. Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Alimen Pharmacol Ther 1994; 8:409–416. 22. Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. & Curr Opin Endocrinol Diab Obes 2013; 20:14–21. A superb review on the importance of the gastrointestinal tract as the main source of serotonin and its biology. 23. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132:397–414. 24. Weber HC. Gastrointestinal regulatory peptides. Curr Opin Endocrinol Diab Obes 2011; 18:33–34. 25. Blackshaw LA, Brierley SM. Emerging receptor target in the pharmacotherapy of irritable bowel syndrome with constipation. Expert Rev Gastroenterol Hepatol 2013; 7:15–19. 26. Camilleri M. Review article: new receptor targets for medical therapy in irritable bowel syndrome. Alimen Pharmacol Ther 2010; 31:35–46. 27. Ford AC, Brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol 2009; 104:1831–1843. 28. Johnston JM, Shiff SJ, Quigley EM. A review of the clinical efficacy of linaclotide in irritable bowel syndrome with constipation. Curr Med Res Opin 2013; 29:149–160. 29. Lacy BE, Chey WD. Lubiprostone: chronic constipation and irritable bowel syndrome with constipation. Expert Opin Pharmacother 2009; 10:143–152. 30. Sainsbury A, Ford AC. Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents. Ther Adv Gastroenterol 2011; 4:115–127. 31. Ford AC, Talley NJ. IBS in 2010: advances in pathophysiology, diagnosis and treatment. Nature reviews. Gastroenterol Hepatol 2011; 8:76–78. 32. Talley NJ. Serotoninergic neuroenteric modulators. Lancet 2001; 358:2061– 2068. 33. Tack J, Coulie B, Wilmer A, et al. Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man. Gut 1998; 42:36–41. 34. Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008; 6:545–555.
35. Spiller RC. Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome. Curr Opin Pharmacol 2011; 11:68–74. 36. Lewis JH. Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol 2010; 4:13–29. 37. Nakai A, Diksic M, Kumakura Y, et al. The effects of the 5-HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome. Neurogastroenterol Motil 2005; 17:212–221. 38. Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil 2003; 15:79–86. 39. Balfour JA, Goa KL, Perry CM. Alosetron. Drugs 2000; 59:511–518. 40. Lewis JH. The risk of ischaemic colitis in irritable bowel syndrome patients treated with serotonergic therapies. Drug Saf 2011; 34:545–565. 41. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and postmarketing surveillance data. Am J Gastroenterol 2006; 101:1069–1079. 42. Cremonini F, Nicandro JP, Atkinson V, et al. Randomised clinical trial: alosetron improves quality of life and reduces restriction of daily activities in women with severe diarrhoea-predominant IBS. Alimen Pharmacol Ther 2012; 36:437–448. 43. Evans BW, Clark WK, Moore DJ, Whorwell PJ. Tegaserod for the treatment of irritable bowel syndrome and chronic constipation. Cochrane Database Syst Rev 2007; CD003960. 44. Kale-Pradhan PB, Wilhelm SM. Tegaserod for constipation-predominant irritable bowel syndrome. Pharmacotherapy 2007; 27:267–277. 45. Patel S, Berrada D, Lembo A. Review of tegaserod in the treatment of irritable bowel syndrome. Expert Opin Pharmacother 2004; 5:2369– 2379. 46. Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58:491–496. 47. Pasricha PJ. Desperately seeking serotonin. A commentary on the withdrawal of tegaserod and the state of drug development for functional and motility disorders. Gastroenterology 2007; 132:2287–2290. 48. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/ 021908s010lbl.pdf [accessed 8 November 2013] 49. Lubiprostone (amitiza) for chronic constipation. Med Lett Drugs Ther 2006; 48:47–48. 50. Lubiprostone: RU 0211, SPI 0211. Drugs R D. 2005;6(4):245-8. Review. PubMed PMID: 15991886. 51. 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. Alimen Pharmacol Ther 2009; 29:329–341. 52. 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. Alimen Pharmacol Ther 2007; 25:1351–1361. 53. Fukudo S, Hongo M, Kaneko H, Ueno R. Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study. Neurogastroenterol Motil 2011; 23:544-e205. 54. Chey WD, Drossman DA, Johanson JF, et al. Safety and patient outcomes & with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Alimen Pharmacol Ther 2012; 35:587–599. Long-term efficacy and safety data in IBS-C patients treated with lubiprostone. 55. Hyman PE, Di Lorenzo C, Prestridge LL, et al. An open-label, multicenter, & safety and effectiveness study of lubiprostone for the treatment of functional constipation in children. J Pediatr Gastroenterol Nutrition 2013. [Epub ahead of print]. PubMed PMID: 24048162. First study to report of treatment of functional constipation with lubiprostone in the pediatric population. 56. Whitehead WE, Palsson OS, Gangarosa L, et al. Lubiprostone does not influence visceral pain thresholds in patients with irritable bowel syndrome. Neurogastroenterol Motil 2011; 23:944-e400. 57. Cuppoletti J, Blikslager AT, Chakrabarti J, et al. Contrasting effects of linaclotide and lubiprostone on restitution of epithelial cell barrier properties and cellular homeostasis after exposure to cell stressors. BMC Pharmacol 2012; 12:3. 58. Sherid M, Sifuentes H, Samo S, et al. Lubiprostone induced ischemic colitis. WJG 2013; 19:299–303. 59. Musch MW, Wang Y, Claud EC, Chang EB. Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci 2013; 58:668–677. 60. Chamberlain SM, Rao SS. Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome. Expert Opin Drug Saf 2012; 11:841–850. 61. Linaclotide (Linzess) for constipation. Med Letter Drugs Ther 2012; 54:91– 92; PubMed PMID: 23183319. 62. Bharucha AE, Waldman SA. Taking a lesson from microbial diarrheagenesis in the management of chronic constipation. Gastroenterology 2010; 138:813–817. 63. Brierley SM. Guanylate cyclase-C receptor activation: unexpected biology. Curr Opin Pharmacol 2012; 12:632–640.
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Gastrointestinal hormones 64. Busby RW, Bryant AP, Bartolini WP, et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol 2010; 649:328–335. 65. Busby RW, Kessler MM, Bartolini WP, et al. Pharmacologic properties, && metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther 2013; 344:196–206. This report characterizes the linaclotide metabolite MM-419447 (CCEYCCNPACTGC) in rat models of gastrointestinal function, showing significantly increased fluid secretion into small intestinal loops via cGMP activation. Therefore, MM-419447 contributes to linaclotide’s pharmacology. 66. 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. 67. Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 2010; 139:1877-1886 e1872. 68. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011; 365:527–536. 69. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a & 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012; 107:1714–1724. A critical randomized clinical trial that demonstrate efficacy and safety of linaclotide in IBS-C.
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70. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012; 107:1702– 1712. 71. Rao SS, Quigley EM, Shiff SJ, et al. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol 2013; 11:1984–1092. 72. Quigley EM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C – a prespecified further analysis based on European Medicines Agency-specified endpoints. Alimen Pharmacol Ther 2013; 37:49–61. 73. Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a metaanalysis. Clin Gastroenterol Hepatol 2013; 11:1084–1092e 1083. 74. Feng B, Kiyatkin ME, La JH, et al. Activation of guanylate cyclase-C attenuates & stretch responses and sensitization of mouse colorectal afferents. J Neurosci 2013; 33:9831–9839. A novel mechanism is suggested how GC-C receptor activation might result in visceral pain relief. 75. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic & nociceptors and relieves abdominal pain via guanylate cyclase-c and extracellular cyclic guanosine 30 ,50 -monophosphate. Gastroenterology 2013. doi: 10.1053/j.gastro.2013.08.017. [Epub ahead of print] A novel mechanism of visceral pain relief is proposed to occurr through extracellular cGMP activation in response to GC-C agonist treatment and inhibition of nociception.
Volume 21 Number 1 February 2014
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