Drug discovery approaches to irritable bowel syndrome

Expert Opinion on Drug Discovery

Volumn 10, Issue 8, 2015, Pages 809-824

  Hornby, Pamela J ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (United States)

Author keywords

barrier function; crofelemer; dorsal root ganglion; eluxadoline; endotoxemia; enteric nervous system; gastrointestinal secretion; linaclotide; microbiome; motility; secretomotor reflex; vagus nerve; visceral pain

Indexed keywords

BILE ACID; BIOLOGICAL MARKER; CROFELEMER; ELUXADOLINE; PROBIOTIC AGENT; GASTROINTESTINAL AGENT;

DRUG RESEARCH; DYSBIOSIS; HUMAN; IMMUNOREGULATION; INTESTINAL SECRETION; INTESTINE MOTILITY; IRRITABLE COLON; MALABSORPTION; MICROBIOME; PRIORITY JOURNAL; REVIEW; ABDOMINAL PAIN; ANIMAL; DISEASE COURSE; DRUG DESIGN; DRUG DEVELOPMENT; IRRITABLE BOWEL SYNDROME; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY;

ABDOMINAL PAIN; ANIMALS; DISEASE PROGRESSION; DRUG DESIGN; DRUG DISCOVERY; GASTROINTESTINAL AGENTS; HUMANS; IRRITABLE BOWEL SYNDROME; MOLECULAR TARGETED THERAPY; PROBIOTICS;

EID: 84937692017     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2015.1049528     Document Type: Review

References (139)

1. Hungin AP, Molloy-Bland M, Claes R, et al. Systematic review: the perceptions, diagnosis and management of irritable bowel syndrome in primary care - a Rome foundation working team report. Aliment Pharmacol Ther 2014;40(10):1133-45
2. Camilleri M. Current and future pharmacological treatments for diarrheapredominant irritable bowel syndrome. Expert Opin Pharmacother 2013;9):1151-60
3. Fortea J, Prior M. Irritable bowel syndrome with constipation: A European-focused systematic literature review of disease burden. J Med Econom 2013;16(3):329-41
4. Barboza JL, Talley NJ, Moshiree B. Current and emerging pharmacotherapeutic options for irritable bowel syndrome. Drugs 2014;74(16):1849-70
5. Kachur JF, Allbee WE, Gaginella TS. Antihistaminic and antimuscarinic effects of amitriptyline on Guinea pig ileal electrolyte transport and muscle contractility in vitro. J Pharmacol Exp Ther 1988;245(2):455-9
6. Mozaffari S, Nikfar S, Abdollahi M. The safety of novel drugs used to treat irritable bowel syndrome. Expert Opin Drug Saf 2014;13(5):625-38
7. 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. Aliment Pharmacol Ther 2012;35(5):587-99
8. Hoffman JM, Tyler K, MacEachern SJ, et al. Activation of colonic mucosal 5-ht (4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 2012;142(4):844-54; e844
9. Swan C, Duroudier NP, Campbell E, et al. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): Association with TNFSF15 and TNFalpha. Gut 2013;62(7):985-94
10. Hayes PA, Fraher MH, Quigley EM. Irritable bowel syndrome: The role of food in pathogenesis and management. Gastroenterol Hepatol 2014;10(3):164-74
11. Yang J, Fox M, Cong Y, et al. Lactose intolerance in irritable bowel syndrome patients with diarrhoea: The roles of anxiety, activation of the innate mucosal immune system and visceral sensitivity. Aliment pharmacol Ther 2014;39(3):302-11
12. Wong BS, Camilleri M, Carlson P, et al. Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol 2012;10(9):1009-15; e1003
13. Pinn DM, Aroniadis OC, Brandt LJ. Is fecal microbiota transplantation (FMT) an effective treatment for patients with functional gastrointestinal disorders (FGID)? Neurogastroenterol Motil 2015;27(1):19-29
14. Camilleri M, Madsen K, Spiller R, et al. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil 2012;24(6):503-12
15. Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left the door open? Am J Gastroenterol 2006;101(6):1295-8
16. Bashashati M, Rezaei N, Shafieyoun A, et al. Cytokine imbalance in irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol Motil 2014;26(7):1036-48
17. Vicario M, Gonzalez-Castro AM, Martinez C, et al. Increased humoral immunity in the jejunum of diarrhoeapredominant irritable bowel syndrome associated with clinical manifestations. Gut 2014;doi: 10.1136/gutjnl-2013-306236. [Epub ahead of print]
18. Ludidi S, Mujagic Z, Jonkers D, et al. Markers for visceral hypersensitivity in patients with irritable bowel syndrome. Neurogastroenterol Motil 2014;26(8):1104-11
19. Buckley MM, O'Mahony SM, O'Malley D. Convergence of neuro-endocrine-immune pathways in the pathophysiology of irritable bowel syndrome. World J Gastroenterol 2014;20(27):8846-58
20. Delgado-Aros S, Camilleri M, Garcia MA, et al. High body mass alters colonic sensory-motor function and transit in humans. Am J Physiol Gastrointest Liver Physiol 2008;295(2):G382-8
21. Nasser Y, Boeckxstaens GE, Wouters MM, et al. Using human intestinal biopsies to study the pathogenesis of irritable bowel syndrome. Neurogastroenterol Motil 2014;26(4):455-69
22. Sanger GJ, Broad J, Kung V, Knowles CH. Translational neuropharmacology: The use of human isolated gastrointestinal tissues. Br J Pharmacol 2013;168(1):28-43
23. Khan WI, Collins SM. Gut motor function: Immunological control in enteric infection and inflammation. Clin Exp Immunol 2006;143(3):389-97
24. Mullin GE, Shepherd SJ, Chander Roland B, et al. Irritable bowel syndrome: Contemporary nutrition management strategies. JPEN J Parenter Enteral Nutr 2014;38(7):781-99
25. Halmos EP, Power VA, Shepherd SJ, et al. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 2014;146(1):67-75; e65
26. Li F, Jiang C, Krausz KW, et al. Microbiome remodelling leads to inhibition of intestinal farnesoid x receptor signalling and decreased obesity. Nat Commun 2013;4:2384
27. Magge S, Lembo A. Complementary and alternative medicine for the irritable bowel syndrome. Gastroenterol Clin North Am 2011;40(1):245-53
28. Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap - bile acids in metabolic control. Nat Rev Endocrinol 2014;10(8):488-98
29. Matsubara T, Li F, Gonzalez FJ. Fxr signaling in the enterohepatic system. Mol Cell Endocrinol 2013;368(1-2):17-29
30. Renga B, Mencarelli A, Cipriani S, et al. The bile acid sensor fxr is required for immune-regulatory activities of tlr-9 in intestinal inflammation. PLoS One 2013;8(1):e54472
31. Lundasen T, Galman C, Angelin B, Rudling M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Int Med 2006;260(6):530-6
32. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137-74
33. Bajor A, Gillberg PG, Abrahamsson H. Bile acids: Short and long term effects in the intestine. Scand J Gastroenterol 2010;45(6):645-64
34. Poole DP, Godfrey C, Cattaruzza F, et al. Expression and function of the bile acid receptor GPBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 2010;22(7):814-25; e227-818
35. Simren M, Bajor A, Gillberg PG, et al. Randomised clinical trial: The ileal bile acid transporter inhibitor a3309 vs. Placebo in patients with chronic idiopathic constipation - a double-blind study. Aliment Pharmacol Ther 2011;34(1):41-50
36. Wedlake L, A'Hern R, Russell D, et al. Systematic review: The prevalence of idiopathic bile acid malabsorption as diagnosed by sehcat scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009;30(7):707-17
37. Kurien M, Evans KE, Leeds JS, et al. Bile acid malabsorption: An underinvestigated differential diagnosis in patients presenting with diarrhea predominant irritable bowel syndrome type symptoms. Scand J Gastroenterol 2011;46(7-8):818-22
38. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. Eng J Med 2012;367(17):1626-35
39. Camilleri M, Vazquez-Roque MI, Carlson P, et al. Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders. Neurogastroenterol Motil 2011;23(11):995-9; e458
40. Wong BS, Camilleri M, Carlson PJ, et al. Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea. Dig Dis Sci 2012;57(5):1222-6
41. Bajor A, Tornblom H, Rudling M, et al. Increased colonic bile acid exposure: A relevant factor for symptoms and treatment in IBS. Gut 2015;64(1):84-92
42. Camilleri M. Advances in understanding of bile acid diarrhea. Expert Rev Gastroenterol Hepatol 2014;8(1):49-61
43. van Schaik FD, Gadaleta RM, Schaap FG, et al. Pharmacological activation of the bile acid nuclear farnesoid x receptor is feasible in patients with quiescent Crohn's colitis. PLoS One 2012;7(11):e49706
44. Huang H, Xu Y, Zhu J, Li J. Recent advances in non-steroidal fxr antagonists development for therapeutic applications. Curr Top Med Chem 2014;14(19):2175-87
45. Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21(2):159-65
46. Chey WD, Camilleri M, Chang L, et al. A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. Am J Gastroenterol 2011;106(10):1803-12
47. Gerber GK. The dynamic microbiome. FEBS Lett 2014;588(22):4131-9
48. Rajilic-Stojanovic M, Biagi E, Heilig HG, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 2011;141(5):1792-801
49. Carroll IM, Ringel-Kulka T, Keku TO, et al. Molecular analysis of the luminaland mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2011;301(5):G799-807
50. Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 2015;64(1):93-100
51. Ohman L, Simren M. Intestinal microbiota and its role in irritable bowel syndrome (IBS). Curr Gastroenterol Rep 2013;15(5):323
52. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology 2014;146(6):1500-12
53. Lozupone CA, Hamady M, Cantarel BL, et al. The convergence of carbohydrate active gene repertoires in human gut microbes. Proc Natl Acad Sci U S A 2008;105(39):15076-81
54. Theodorou V, Ait Belgnaoui A, Agostini S, Eutamene H. Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome. Gut Micro 2014;5(3):430-6
55. Miyamoto J, Mizukure T, Park SB, et al. A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via gpr40-mek-erk pathway. J Biol Chem 2015;290(5):2902-18
56. Wong RK, Yang C, Song GH, et al. Melatonin regulation as a possible mechanism for probiotic (vsl#3) in irritable bowel syndrome: A randomized double-blinded placebo study. Dig Dis Sci 2015;60(1):186-94
57. Ludidi S, Jonkers DM, Koning CJ, et al. Randomized clinical trial on the effect of a multispecies probiotic on visceroperception in hypersensitive ibs patients. Neurogastroenterol Motil 2014;26(5):705-14
58. Sisson G, Ayis S, Sherwood RA, Bjarnason I. Randomised clinical trial: A liquid multi-strain probiotic vs. Placebo in the irritable bowel syndrome-a 12 week double-blind study. Aliment Pharmacol Ther 2014;40(1):51-62
59. Sanders ME, Guarner F, Guerrant R, et al. An update on the use and investigation of probiotics in health and disease. Gut 2013;62(5):787-96
60. Zhou Q, Zhang B, Verne GN. Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome. Pain 2009;146(1-2):41-6
61. Hedin CR, McCarthy NE, Louis P, et al. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings. Gut 2014;63(10):1578-86
62. Kelly CP, Green PH, Murray JA, et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: A randomised placebo-controlled study. Aliment Pharmacol Ther 2013;37(2):252-62
63. Gummesson A, Carlsson LM, Storlien LH, et al. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity 2011;19(11):2280-2
64. Everard A, Cani PD. Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol 2013;27(1):73-83
65. Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability - a new target for disease prevention and therapy. BMC Gastroenterol 2014;14:189
66. Ukena SN, Singh A, Dringenberg U, et al. Probiotic Escherichia coli nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PloS One 2007;2(12):e1308
67. Ewaschuk JB, Diaz H, Meddings L, et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 2008;295(5):G1025-34
68. Bansal T, Alaniz RC, Wood TK, Jayaraman A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc Natl Acad Sci U S A 2010;107(1):228-33
69. Da Silva S, Robbe-Masselot C, Ait-Belgnaoui A, et al. Stress disrupts intestinal mucus barrier in rats via mucin o-glycosylation shift: Prevention by a probiotic treatment. Am J Physiol Gastrointest Liver Physiol 2014;307(4):G420-9
70. Shen L, Weber CR, Raleigh DR, et al. Tight junction pore and leak pathways: A dynamic duo. Annu Rev Physiol 2011;73:283-309
71. Su L, Shen L, Clayburgh DR, et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology 2009;136(2):551-63
72. Ferrier L, Mazelin L, Cenac N, et al. Stress-induced disruption of colonic epithelial barrier: Role of interferongamma and myosin light chain kinase in mice. Gastroenterology 2003;125(3):795-804
73. Ait-Belgnaoui A, Han W, Lamine F, et al. Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: A possible action through interaction with epithelial cell cytoskeleton contraction. Gut 2006;55(8):1090-4
74. Villani AC, Lemire M, Thabane M, et al. Genetic risk factors for postinfectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis. Gastroenterology 2010;138(4):1502-13
75. Thabane M, Simunovic M, Akhtar-Danesh N, et al. An outbreak of acute bacterial gastroenteritis is associated with an increased incidence of irritable bowel syndrome in children. Am J Gastroenterol 2010;105(4):933-9
76. Jalanka-Tuovinen J, Salojarvi J, Salonen A, et al. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut 2014;63(11):1737-45
77. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. Eng J Med 2011;364(1):22-32
78. Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut 2003;52(4):523-6
79. van der Veek PP, van den Berg M, de Kroon YE, et al. Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol 2005;100(11):2510-16
80. Russo F, Chimienti G, Clemente C, et al. Adipokine profile in celiac patients: Differences in comparison with patients suffering from diarrhea-predominant IBS and healthy subjects. Scand J Gastroenterol 2013;48(12):1377-85
81. Andoh A, Ogawa A, Bamba S, Fujiyama Y. Interaction between interleukin-17-producing CD4+ T cells and colonic subepithelial myofibroblasts: What are they doing in mucosal inflammation? J Gastroenterol 2007;42(Suppl 17):29-33
82. Fiocchi C, Ina K, Danese S, et al. Alterations of mesenchymal and endothelial cells in inflammatory bowel diseases. Adv Exp Med Biol 2006;579:168-76
83. Blackshaw LA, Brierley SM. Emerging receptor target in the pharmacotherapy of irritable bowel syndrome with constipation. Expert Rev Gastroenterol Hepatol 2013;7(5 Suppl 1):15-19
84. Joshi SK, Honore P. Animal models of pain for drug discovery. Expert Opin Drug Dis 2006;1(4):323-34
85. Sengupta JN, Su X, Gebhart GF. Kappa, but not mu or delta, opioids attenuate responses to distention of afferent fibers innervating the rat colon. Gastroenterology 1996;111(4):968-80
86. Delgado-Aros S, Chial HJ, Camilleri M, et al. Effects of a kappa-opioid agonist, asimadoline, on satiation and gi motor and sensory functions in humans. Am J Physiol Gastrointest Liver Physiol 2003;284(4):G558-66
87. Camilleri M. Novel pharmacology: Asimadoline, a kappa-opioid agonist, and visceral sensation. Neurogastroenterol Motil 2008;20(9):971-9
88. 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(2):239-49
89. Fei G, Raehal K, Liu S, et al. Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in Guinea pig and mouse. J pharmacol Exp Ther 2010;334(1):333-40
90. Beesley A, Hardcastle J, Hardcastle PT, Taylor CJ. Influence of peppermint oil on absorptive and secretory processes in rat small intestine. Gut 1996;39(2):214-19
91. Soderholm JD, Hedman L, Artursson P, et al. Integrity and metabolism of human ileal mucosa in vitro in the ussing chamber. Acta Physiol Scand 1998;162(1):47-56
92. Akiho H, Khan WI, Al-Kaabi A, et al. Cytokine modulation of muscarinic receptors in the murine intestine. Am J Physiol Gastrointest Liver Physiol 2007;293(1):G250-5
93. Foxx-Orenstein AE, Jin JG, Grider JR. 5-ht4 receptor agonists and delta-opioid receptor antagonists act synergistically to stimulate colonic propulsion. Am J Physiol 1998;275(5 Pt 1):G979-83
94. Cellek S, Thangiah R, Jarvie EM, et al. Synergy between 5-HT4 receptor activation and acetylcholinesterase inhibition in human colon and rat forestomach. Neurogastroenterol Motil 2008;20(5):539-45
95. Tsuchida Y, Hatao F, Fujisawa M, et al. Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via alpha7nach receptors on muscularis macrophages associated with postoperative ileus. Gut 2011;60(5):638-47
96. Okubo H, Nakatsu Y, Sakoda H, et al. Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model. Am J Physiol Gastrointest Liver Physiol 2015;308(2):G151-8
97. Puig MM, Pol O. Peripheral effects of opioids in a model of chronic intestinal inflammation in mice. J Pharmacol Exp Ther 1998;287(3):1068-75
98. Greenwood-Van Meerveld B, Gardner CJ, Little PJ, et al. Preclinical studies of opioids and opioid antagonists on gastrointestinal function. Neurogastroenterol Motil 2004;16(Suppl 2):46-53
99. Fujita W, Gomes I, Dove LS, et al. Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem pharmacol 2014;92(3):448-56
100. Pol O, Ferrer I, Puig MM. Diarrhea associated with intestinal inflammation increases the potency of mu and delta opioids on the inhibition of gastrointestinal transit in mice. J Pharmacol Exp Ther 1994;270(1):386-91
101. Izzo AA, Fezza F, Capasso R, et al. Cannabinoid cb1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Phar 2001;134(3):563-70
102. Kimball ES, Palmer JM, D'Andrea MR, et al. Acute colitis induction by oil of mustard results in later development of an IBS-like accelerated upper gi transit in mice. Am J Physiol Gastrointest Liver Physiol 2005;288(6):G1266-73
103. Kimball ES, Wallace NH, Schneider CR, et al. Small intestinal cannabinoid receptor changes following a single colonic insult with oil of mustard in mice. Front Pharmacol 2010;1:132
104. Capasso R, Orlando P, Pagano E, et al. Palmitoylethanolamide normalizes intestinal motility in a model of postinflammatory accelerated transit: Involvement of CB(1) receptors and TRPV1 channels. Br J Phar 2014;171(17):4026-37
105. Wade P, Palmer J, McKenney S, et al. Modulation of gastrointestinal function by mudelta, a mixed micro opioid receptor agonist/delta opioid receptor antagonist. Br J Phar 2012;167(5):1111-25
106. Barbara G. IBS: Biomarkers for IBS: Ready for prime time? Nat Rev Gastroenterol Hepatol 2015;12(1):9-10
107. Camilleri M, Shin A, Busciglio I, et al. Validating biomarkers of treatable mechanisms in irritable bowel syndrome. Neurogastroenterol Motil 2014;26(12):1677-85
108. Corsetti M, Van Oudenhove L, Tack J. The quest for biomarkers in IBS-where should it lead us? Neurogastroenterol Motil 2014;26(12):1669-76
109. Jones MP, Chey WD, Singh S, et al. A biomarker panel and psychological morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads. Aliment Pharmacol Ther 2014;39(4):426-37
110. Sood R, Law GR, Ford AC. Diagnosis of IBS: Symptoms, symptom-based criteria, biomarkers or 'psychomarkers'? Nat Rev Gastroenterol Hepatol 2014;11(11):683-91
111. Shiotani A, Kusunoki H, Ishii M, et al. Pilot study of biomarkers for predicting effectiveness of ramosetron in diarrheapredominant irritable bowel syndrome: Expression of s100a10 and polymorphisms of TPH1. Neurogastroenterol Motil 2015;27(1):82-91
112. Kokkotou E, Conboy LA, Ziogas DC, et al. Serum correlates of the placebo effect in irritable bowel syndrome. Neurogastroenterol Motil 2010;22(3):285-e281
113. Breslin HJ, Diamond CJ, Kavash RW, et al. Identification of a dual delta or antagonist/mu or agonist as a potential therapeutic for diarrhea-predominant irritable bowel syndrome (ibs-d). Bioorg Med Chem Lett 2012;22(14):4869-72
114. Breslin HJ, Cai C, Miskowski TA, et al. Identification of potent phenyl imidazoles as opioid receptor agonists. Bioorg Med Chem Lett 2006;16(9):2505-8
115. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009;155(1-3):11-17
116. DeHaven-Hudkins DL, Burgos LC, Cassel JA, et al. Loperamide (adl 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Phar Exp Ther 1999;289(1):494-502
117. Callahan MJ. Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds. J Clin Gastroenterol 2002;35(1 Suppl):S58-67
118. Talley NJ. Pharmacologic therapy for the irritable bowel syndrome. Am J Gastroenterol 2003;98(4):750-8
119. Sternini C, Spann M, Anton B, et al. Agonist-selective endocytosis of mu opioid receptor by neurons in vivo. Proc Natl Acad Sci U S A 1996;93(17):9241-6
120. Shahbazian A, Heinemann A, Schmidhammer H, et al. Involvement of mu- and kappa-, but not delta-, opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the Guinea-pig intestine. Br J Phar 2002;135(3):741-50
121. Feng P, Rahim RT, Cowan A, et al. Effects of mu, kappa or delta opioids administered by pellet or pump on oral salmonella infection and gastrointestinal transit. Eur J Phar 2006;534(1-3):250-7
122. Pol O, Valle L, Puig MM. Antisense oligodeoxynucleotides to mu- and deltaopioid receptor mRNA block the enhanced effects of opioids during intestinal inflammation. Eur J Phar 2001;428(1):127-36
123. Pol O, Puig MM. Expression of opioid receptors during peripheral inflammation. Curr Top Med Chem 2004;4(1):51-61
124. Abul-Husn NS, Sutak M, Milne B, Jhamandas K. Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and deltaopioid receptor antagonists. Br J Phar 2007;151(6):877-87
125. Rozenfeld R, Devi LA. Receptor heterodimerization leads to a switch in signaling: Beta-arrestin2-mediated erk activation by mu-delta opioid receptor heterodimers. FASEB J 2007;21(10):2455-65
126. Dove LS, Lembo A, Randall CW, et al. Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology 2013;145(2):329-38; e321
127. Lembo A, Dove S, Andrae D, et al. Eluxadoline for the treatment of diarrhepredominant irritable bowel syndrome: Results of 2 randomized, double-blind, placebo-controlled phase 3 clinical trials of efficacy and safety. Gastroentol 2014;146(5):S-159
128. 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(11):1714-24; quiz p 1725
129. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: A 26-week, randomized, double-blind, placebocontrolled trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107(11):1702-12
130. Lucas KA, Pitari GM, Kazerounian S, et al. Guanylyl cyclases and signaling by cyclic GMP. Phar Rev 2000;52(3):375-414
131. Guerrant RL, Hughes JM, Chang B, et al. Activation of intestinal guanylate cyclase by heat-stable enterotoxin of escherichia coli: Studies of tissue specificity, potential receptors, and intermediates. J Infect Dis 1980;142(2):220-8
132. Lin JE, Valentino M, Marszalowicz G, et al. Bacterial heat-stable enterotoxins: Translation of pathogenic peptides into novel targeted diagnostics and therapeutics. Toxins 2010;2(8):2028-54
133. Silos-Santiago I, Hannig G, Eutamene H, et al. Gastrointestinal pain: Unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-c/cgmp activation. Pain 2013;154(9):1820-30
134. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3′,5′-monophosphate. Gastroenterology 2013;145(6):1334-46; e1331-1311
135. 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(6):1877-86; e1872
136. Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from croton lechleri, targets two distinct intestinal chloride channels. Mol Phar 2010;77(1):69-78
137. Gabriel SE, Davenport SE, Steagall RJ, et al. A novel plant-derived inhibitor of camp-mediated fluid and chloride secretion. Am J Physiol 1999;276(1 Pt 1):G58-63
138. Cottreau J, Tucker A, Crutchley R, Garey KW. Crofelemer for the treatment of secretory diarrhea. Expert Rev Ggastroenterol Hepatol 2012;6(1):17-23
139. Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrheapredominant irritable bowel syndrome patients. Digestion 2008;78(4):180-6