Drug development for the irritable bowel syndrome: Current challenges and future perspectives

Frontiers in Pharmacology

Volumn 4 FEB, Issue , 2013, Pages

  De Ponti, Fabrizio ^a  

^a UNIVERSITY OF BOLOGNA   (Italy)

Author keywords

5 hydroxytryptamine; Biomarkers; Brain gut interactions; Drug selectivity; Drug targets; Neuroimmune intestinal interactions; Transient receptor potential channels; Translational medical research

Indexed keywords

ALOSETRON; ASIMADOLINE; CAPSAZEPINE; CISAPRIDE; CLONIDINE; EZLOPITANT; GASTROINTESTINAL AGENT; GB 88; KETOTIFEN; LINACLOTIDE; LOPERAMIDE; LUBIPROSTONE; LX 1031; METHYLNALTREXONE ALVIMOPAN; NALOXONE; NARONAPRIDE; NEPADUTANT; PRUCALOPRIDE; RAMOSETRON; RN 1734; SEROTONIN; SEROTONIN 4 AGONIST; SEROTONIN ANTAGONIST; SOLABEGRON; TALNETANT; TD 8954; TRANSIENT RECEPTOR POTENTIAL CHANNEL; TRICYCLIC ANTIDEPRESSANT AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; VELUSETRAG;

BRAIN; CLINICAL RESEARCH; DISEASE MARKER; DISEASE MODEL; DNA POLYMORPHISM; DRUG DEVELOPMENT; DRUG MECHANISM; DRUG RESEARCH; DRUG RESPONSE; DRUG SAFETY; DRUG SELECTIVITY; DRUG TARGETING; DRUG WITHDRAWAL; FUNCTIONAL DISEASE; HUMAN; INFLAMMATION; INTESTINE; INTESTINE MOTILITY; IRRITABLE COLON; ISCHEMIC COLITIS; NEUROIMMUNOLOGY; NONHUMAN; PARAMEDICAL PERSONNEL; PATHOPHYSIOLOGY; PERSONALIZED MEDICINE; PHARMACODYNAMICS; PHARMACOGENOMICS; PHARMACOKINETICS; PHARMACOLOGIST; PHYSICIAN; PREDICTION; REVIEW; SCINTIGRAPHY; TORSADE DES POINTES; VISCERAL PAIN;

EID: 84881534838     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2013.00007     Document Type: Review

References (129)

1. Al-Judaibi, B., Chande, N., and Gregor, J. (2010). Safety and efficacy of tegaserod therapy in patients with irritable bowel syndrome or chronic constipation. Can. J. Clin. Pharmacol. 17, e194-e200.
2. Andresen, V., Camilleri, M., Busciglio, I. A., Grudell, A., Burton, D., McKinzie, S., et al. (2007). Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 133, 761-768.
3. Anonymous. (2001). Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89-95.
4. Balestra, B., Vicini, R., Cremon, C., Zecchi, L., Dothel, G., Vasina, V., et al. (2012). Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Neurogastroenterol. Motil. 24, 1118-e570.
5. Barbara, G., Cremon, C., Pallotti, F., De, G. R., Stanghellini, V., and Corinaldesi, R. (2009). Postinfectious irritable bowel syndrome. J. Pediatr. Gastroenterol. Nutr. 48(Suppl. 2), S95-S97.
6. Barbara, G., Stanghellini, V., De, G. R., Cremon, C., Cottrell, G. S., Santini, D., et al. (2004). Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693-702.
7. Barbara, G., Wang, B., Stanghellini, V., De, G. R., Cremon, C., Di, N. G., et al. (2007). Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132, 26-37.
8. Bashashati, M., Rezaei, N., Bashashati, H., Shafieyoun, A., Daryani, N. E., Sharkey, K. A., et al. (2012). Cytokine gene polymorphisms are associated with irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol. Motil. 24, 1102-e566.
9. Beattie, D. T., Armstrong, S. R., Vickery, R. G., Tsuruda, P. R., Campbell, C. B., Richardson, C., et al. (2011). The pharmacology of TD-8954, a potent and selective 5-HT4 receptor agonist with gastrointestinal prokinetic properties. Front. Pharmacol. 2:25. doi:10.3389/fphar.2011.00025
10. Bharucha, A. E., Camilleri, M., Zinsmeister, A. R., and Hanson, R. B. (1997). Adrenergic modulation of human colonic motor and sensory function. Am. J. Physiol. 273, G997-G1006.
11. Bouras, E. P., Camilleri, M., Burton, D. D., and McKinzie, S. (1999). Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans. Gut 44, 682-686.
12. Brandt, L. J., Chey, W. D., Foxx-Orenstein, A. E., Schiller, L. R., Schoenfeld, P. S., Spiegel, B. M., et al. (2009). An evidence-based position statement on the management of irritable bowel syndrome. Am. J. Gastroenterol. 104(Suppl. 1), S1-S35.
13. Buhner, S., Li, Q., Berger, T., Vignali, S., Barbara, G., De, G. R., et al. (2012). Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol. Motil. 24, 1134-e572.
14. Bulmer, D. C., and Grundy, D. (2011). Achieving translation in models of visceral pain. Curr. Opin. Pharmacol. 11, 575-581.
15. Busby, R. W., Kessler, M. M., Bartolini, W. P., Bryant, A. P., Hannig, G., Higgins, C. S., et al. (2013). 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. 344, 196-206.
16. Camilleri, M. (2010a). Scintigraphic biomarkers for colonic dysmotility. Clin. Pharmacol. Ther. 87, 748-753.
17. Camilleri, M. (2010b). Review article: new receptor targets for medical therapy in irritable bowel syndrome. Aliment. Pharmacol. Ther. 31, 35-46.
18. Camilleri, M. (2012). Pharmacology of the new treatments for lower gastrointestinal motility disorders and irritable bowel syndrome. Clin. Pharmacol. Ther. 91, 44-59.
19. Camilleri, M., Atanasova, E., Carlson, P. J., Ahmad, U., Kim, H. J., Viramontes, B. E., et al. (2002). Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology 123, 425-432.
20. Camilleri, M., Bharucha, A. E., Di, L. C., Hasler, W. L., Prather, C. M., Rao, S. S., et al. (2008). American Neurogastroenterology and Motility Society consensus statement on intraluminal measurement of gastrointestinal and colonic motility in clinical practice. Neurogastroenterol. Motil. 20, 1269-1282.
21. Camilleri, M., Bueno, L., De Ponti, F., Fioramonti, J., Lydiard, R. B., and Tack, J. (2006a). Pharmacological and pharmacokinetic aspects of functional gastrointestinal disorders. Gastroenterology 130, 1421-1434.
22. Camilleri, M., Bueno, L., De Ponti, F., Fioramonti, J., Lydiard, R. B., and Tack, J. (2006b). "Pharmacological and pharmacokinetic aspects of functional gastrointestinal disorders," in ROME III, The Functional Gastrointestinal Disorders, Chap. 4, eds D. A. Drossman, E. Corazziari, M. Delvaux, R. C. Spiller, N. J. Talley, W. G. Thompson, and W. E. Whitehead (Lawrence: Allen Press), 161-230.
23. Camilleri, M., and Katzka, D. A. (2012). Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1075-G1084.
24. Camilleri, M., Lasch, K., and Zhou, W. (2012). Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G775-G785.
25. Camilleri, M., and Mayer, E. A. (2009). Developing irritable bowel syndrome guidelines through meta-analyses: does the emperor really have new clothes? Gastroenterology 137, 766-769.
26. Camilleri, M., Northcutt, A. R., Kong, S., Dukes, G. E., McSorley, D., and Mangel, A. W. (2000). Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 355, 1035-1040.
27. Cann, P. A., Read, N. W., and Holdsworth, C. O. (1984a). What is the benefit of coarse wheat bran in patients with irritable bowel syndrome? Gut 25, 168-173.
28. Cann, P. A., Read, N. W., Holdsworth, C. D., and Barends, D. (1984b). Role of loperamide and placebo in management of irritable bowel syndrome. Dig. Dis. Sci. 29, 239-247.
29. Cenac, N., Andrews, C. N., Holzhausen, M., Chapman, K., Cottrell, G., Andrade-Gordon, P., et al. (2007). Role for protease activity in visceral pain in irritable bowel syndrome. J. Clin. Invest. 117, 636-647.
30. Chan, C. L., Facer, P., Davis, J. B., Smith, G. D., Egerton, J., Bountra, C., et al. (2003). Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 361, 385-391.
31. Chey, W. D., Lembo, A. J., Lavins, B. J., Shiff, S. J., Kurtz, C. B., Currie, M. G., et al. (2012). Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am. J. Gastroenterol. 107, 1702-1712.
32. Coffin, B., Bouhassira, D., Chollet, R., Fraitag, B., De Meynard, C., Geneve, J., et al. (1996). Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans. Aliment. Pharmacol. Ther. 10, 919-925.
33. Corazziari, E. (1999). Role of opioid ligands in the irritable bowel syndrome. Can. J. Gastroenterol. 13(Suppl. A), 71A-75A.
34. Cremon, C., Carini, G., Wang, B., Vasina, V., Cogliandro, R. F., De Giorgio, R., et al. (2011). Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am. J. Gastroenterol. 106, 1290-1298.
35. Cremonini, F., Delgado-Aros, S., and Camilleri, M. (2003). Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol. Motil. 15, 79-86.
36. Cremonini, F., Mullan, B. P., Camilleri, M., Burton, D. D., and Rank, M. R. (2002). Performance characteristics of scintigraphic transit measurements for studies of experimental therapies. Aliment. Pharmacol. Ther. 16, 1781-1790.
37. Cuppoletti, J., Blikslager, A. T., Chakrabarti, J., Nighot, P. K., and Malinowska, D. H. (2012). Contrasting effects of linaclotide and lubiprostone on restitution of epithelial cell barrier properties and cellular homeostasis after exposure to cell stressors. BMC Pharmacol. 12:3. doi:10.1186/1471-2210-12-3
38. Dang, J., Ardila-Hani, A., Amichai, M. M., Chua, K., and Pimentel, M. (2012). Systematic review of diagnostic criteria for IBS demonstrates poor validity and utilization of Rome III. Neurogastroenterol. Motil. 24, 853-e397.
39. Dapoigny, M., Abitbol, J. L., and Fraitag, B. (1995). Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome: a multicenter dose-response study. Dig. Dis. Sci. 40, 2244-2248.
40. De Ponti, F. (2002). Methylnaltrexone progenics. Curr. Opin. Investig. Drugs 3, 614-620.
41. De Ponti, F. (2004). Pharmacology of serotonin: what a clinician should know. Gut 53, 1520-1535.
42. De Ponti, F., and Malagelada, J. R. (1998). Functional gut disorders: from motility to sensitivity disorders. A review of current and investigational drugs for their management. Pharmacol. Ther. 80, 49-88.
43. De Ponti, F., Poluzzi, E., Cavalli, A., Recanatini, M., and Montanaro, N. (2002). Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf. 25, 263-286.
44. De Ponti, F., Poluzzi, E., and Montanaro, N. (2001). Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus. Eur. J. Clin. Pharmacol. 57, 185-209.
45. De Schryver, A. M., Andriesse, G. I., Samsom, M., Smout, A. J., Gooszen, H. G., and Akkermans, L. M. (2002). The effects of the specific 5HT4 receptor agonist, prucalopride, on colonic motility in healthy volunteers. Aliment. Pharmacol. Ther. 16, 603-612.
46. Degen, L., Matzinger, D., Merz, M., Appel-Dingemanse, S., Osborne, S., Luchinger, S., et al. (2001). Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment. Pharmacol. Ther. 15, 1745-1751.
47. Delgado-Aros, S., Chial, H. J., Camilleri, M., Szarka, L. A., Weber, F. T., Jacob, J., et al. (2003). Effects of a kappa-opioid agonist, asimadoline, on satiation and GI motor and sensory functions in humans. Am. J. Physiol. 284, G558-G566.
48. Delvaux, M., Jacob, J., Beck, A., Bouzamondo, H., Weber, F. T., and Frexinos, J. (2002). Effect of asimadoline, a new agonist of kappa opiate receptors on pain induced by rectal distension in IBS patients. Gastroenterology 122, A221.
49. Delvaux, M., Louvel, D., Lagier, E., Scherrer, B., Abitbol, J. L., and Frexinos, J. (1999). The k-agonist fedotozine relieves hypersensitivity to colonic distention in patients with irritable bowel syndrome. Gastroenterology 116, 38-45.
50. Delvaux, M., Louvel, D., Mamet, J. P., Campos-Oriola, R., and Frexinos, J. (1998). Effect of alosetron on reponses to colonic distension in patients with irritable bowel syndrome. Aliment. Pharmacol. Ther. 12, 849-855.
51. Dinning, P. G., and Scott, S. M. (2011). Novel diagnostics and therapy of colonic motor disorders. Curr. Opin. Pharmacol. 11, 624-629.
52. Drossman, D. A. (2006). "The functional gastrointestinal disorders and the Rome III process," in Rome III. The Functional Gastrointestinal Disorders, eds D. A. Drossman, E. Corazziari, M. Delvaux, R. C. Spiller, N. J. Talley, W. G. Thompson, and W. E. Whitehead (Lawrence: Allen Press), 1-29.
53. Eberlin, M., Muck, T., and Michel, M. C. (2012). A comprehensive review of the pharmacodynamics, pharmacokinetics, and clinical effects of the neutral endopeptidase inhibitor racecadotril. Front. Pharmacol. 3:93. doi:10.3389/fphar.2012.00093
54. EMA. (2003). Points to Consider on the Evaluation of Medicinal Products for the Treatment of the Irritable Bowel Syndrome. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003187.pdf [accessed December 13, 2012].
55. Emmanuel, A. V., Roy, A. J., Nicholls, T. J., and Kamm, M. A. (2002). Prucalopride, a systemic enterokinetic, for the treatment of constipation. Aliment. Pharmacol. Ther. 16, 1347-1356.
56. FDA. (2012). Irritable Bowel Syndrome: Clinical Evaluation of Drugs for Treatment. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM205269.pdf [accessed December 13, 2012].
57. Fichna, J., Mokrowiecka, A., Cygankiewicz, A. I., Zakrzewski, P. K., Malecka-Panas, E., Janecka, A., et al. (2012). Transient receptor potential vanilloid 4 blockade protects against experimental colitis in mice: a new strategy for inflammatory bowel diseases treatment? Neurogastroenterol. Motil. 24, e557-e560.
58. Fichna, J., and Storr, M. A. (2012). Brain-gut interactions in IBS. Front. Pharmacol. 3:127. doi:10.3389/fphar.2012.00127
59. Floch, M. H., Walker, W. A., Madsen, K., Sanders, M. E., MacFarlane, G. T., Flint, H. J., et al. (2011). Recommendations for probiotic use-2011 update. J. Clin. Gastroenterol. 45(Suppl.), S168-S171.
60. Ford, A. C., and Moayyedi, P. (2010). Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome. Aliment. Pharmacol. Ther. 32, 144-158.
61. Ford, A. C., and Talley, N. J. (2011). Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review. J. Gastroenterol. 46, 421-431.
62. Frytak, S., Moertel, C. G., O'Fallon, J. R., Rubin, J., Creagan, E. T., O'Connell, M. J., et al. (1979). Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo. Ann. Intern. Med. 91, 825-830.
63. Gale, J. D., and Houghton, L. A. (2011). Alpha 2 delta (α(2)δ) ligands, gabapentin and pregabalin: what is the evidence for potential use of these ligands in irritable bowel syndrome. Front. Pharmacol. 2:28. doi:10.3389/fphar.2011.00028
64. Garcia-Serna, R., Ursu, O., Oprea, T. I., and Mestres, J. (2010). iPHACE: integrative navigation in pharmacological space. Bioinformatics 26, 985-986.
65. Gershon, M. D., and Jonakait, G. M. (1979). Uptake and release of 5-hydroxytryptamine by enteric 5-hydroxytryptaminergic neurones: effects of fluoxetine (Lilly 110140) and chlorimipramine. Br. J. Pharmacol. 66, 7-9.
66. Giaroni, C., De Ponti, F., Cosentino, M., Lecchini, S., and Frigo, G. (1999). Plasticity in the enteric nervous system. Gastroenterology 117, 1438-1458.
67. Gonsalkorale, W. M., Perrey, C., Pravica, V., Whorwell, P. J., and Hutchinson, I. V. (2003). Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut 52, 91-93.
68. Gorard, D. A., Libby, G. W., and Farthing, M. J. (1994). 5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake. Gut 35, 496-500.
69. Gore, S., Gilmore, I. T., Haigh, C. G., Brownless, S. M., Stockdale, H., and Morris, A. I. (1990). Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist. Aliment. Pharmacol. Ther. 4, 139-144.
70. Grudell, A. B., Camilleri, M., Jensen, K. L., Foxx-Orenstein, A. E., Burton, D. D., Ryks, M. D., et al. (2008). Dose-response effect of a beta3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1114-G1119.
71. Hirata, T., Funatsu, T., Keto, Y., Nakata, M., and Sasamata, M. (2007). Pharmacological profile of ramosetron, a novel therapeutic agent for IBS. Inflammopharmacology 15, 5-9.
72. Holschneider, D. P., Bradesi, S., and Mayer, E. A. (2011). The role of experimental models in developing new treatments for irritable bowel syndrome. Expert Rev. Gastroenterol. Hepatol. 5, 43-57.
73. Holzer, P. (2004a). "Tachykinin receptor antagonists: silencing neuropeptides with a role in the disturbed gut," in Pathophysiology of the Enteric Nervous System, eds R. Spiller and D. Grundy (London: Blackwell), 212-227.
74. Holzer, P. (2004b). Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci. Lett. 361, 192-195.
75. Holzer, P. (2011). Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol. Ther. 131, 142-170.
76. Horikawa, Y., Mieno, H., Inoue, M., and Kajiyama, G. (1999). Gastrointestinal motility in patients with irritable bowel syndrome studied by using radiopaque markers. Scand. J. Gastroenterol. 34, 1190-1195.
77. Johnston, J. M., Shiff, S. J., and Quigley, E. M. (2013). A review of the clinical efficacy of linaclotide in IBS-C. Curr. Med. Res. Opin. 29, 149-160.
78. Kawasaki, Y., and Freire, E. (2011). Finding a better path to drug selectivity. Drug Discov. Today 16, 985-990.
79. Kellow, J., Lee, O. Y., Chang, F. Y., Thongsawat, S., Mazlam, M. Z., Yuen, H., et al. (2003). An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 52, 671-676.
80. Kimball, E. S., Wallace, N. H., Schneider, C. R., D'Andrea, M. R., and Hornby, P. J. (2010). Small intestinal cannabinoid receptor changes following a single colonic insult with oil of mustard in mice. Front. Pharmacol. 1:132. doi:10.3389/fphar.2010.00132
81. Lecci, A., Capriati, A., and Maggi, C. A. (2004). Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome. Br. J. Pharmacol. 141, 1249-1263.
82. Lee, K. J., Kim, N. Y., Kwon, J. K., Huh, K. C., Lee, O. Y., Lee, J. S., et al. (2011). Efficacy of ramosetron in the treatment of male patients with irritable bowel syndrome with diarrhea: a multicenter, randomized clinical trial, compared with mebeverine. Neurogastroenterol. Motil. 23, 1098-1104.
83. Lesbros-Pantoflickova, D., Michetti, P., Fried, M., Beglinger, C., and Blum, A. L. (2004). Meta-analysis: the treatment of irritable bowel syndrome. Aliment. Pharmacol. Ther. 20, 1253-1269.
84. Louvel, D., Delvaux, M., Staumont, G., Camman, F., Fioramonti, J., Bueno, L., et al. (1996). Intracolonic injection of glycerol: a model for abdominal pain in irritable bowel syndrome? Gastroenterology 110, 351-361.
85. Malcolm, A., Camilleri, M., Kost, L., Burton, D. D., Fett, S. L., and Zinsmeister, A. R. (2000). Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and sensory function. Aliment. Pharmacol. Ther. 14, 783-793.
86. Matricon, J., Meleine, M., Gelot, A., Piche, T., Dapoigny, M., Muller, E., et al. (2012). Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome. Aliment. Pharmacol. Ther. 36, 1009-1031.
87. Mayer, E. A., and Tillisch, K. (2011). The brain-gut axis in abdominal pain syndromes. Annu. Rev. Med. 62, 381-396.
88. McCallum, R. W., Soykan, I., Sridhar, K. R., Ricci, D. A., Lange, R. C., and Plankey, M. W. (1999). Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment. Pharmacol. Ther. 13, 77-80.
89. McVey Neufeld, K. A., Mao, Y. K., Bienenstock, J., Foster, J. A., and Kunze, W. A. (2013). The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol. Motil. 25, 183-189.
90. Mearin, F., and Lacy, B. E. (2012). Diagnostic criteria in IBS: useful or not? Neurogastroenterol. Motil. 24, 791-801.
91. Menees, S. B., Maneerattannaporn, M., Kim, H. M., and Chey, W. D. (2012). The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am. J. Gastroenterol. 107, 28-35.
92. Morphy, R., Kay, C., and Rankovic, Z. (2004). From magic bullets to designed multiple ligands. Drug Discov. Today 9, 641-651.
93. Morteau, O., Hachet, T., Caussette, M., and Bueno, L. (1994). Experimental colitis alters visceromotor response to colorectal distension in awake rats. Dig. Dis. Sci. 39, 1239-1248.
94. Moynihan, R. (2002). Alosetron: a case study in regulatory capture, or a victory for patients' rights? BMJ 325, 592-595.
95. Muller-Lissner, S. A., Fumagalli, I., Bardhan, K. D., Pace, F., Pecher, E., Nault, B., et al. (2001). Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment. Pharmacol. Ther. 15, 1655-1666.
96. Ness, T. J. (1999). Kappa opioid receptor agonists differentially inhibit two classes of rat spinal neurons excited by colorectal distention. Gastroenterology 117, 388-394.
97. Novick, J., Miner, P., Krause, R., Glebas, K., Bliesath, H., Ligozio, G., et al. (2002). A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment. Pharmacol. Ther. 16, 1877-1888.
98. Poen, A. C., Felt-Bersma, R. J., Van Dongen, P. A., and Meuwissen, S. G. (1999). Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment. Pharmacol. Ther. 13, 1493-1497.
99. Poynard, T., Regimbeau, C., and Benhamou, Y. (2001). Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment. Pharmacol. Ther. 15, 355-361.
100. Prather, C. M., Camilleri, M., Zinsmeister, A. R., McKinzie, S., and Thomforde, G. (2000). Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 118, 463-468.
101. Quigley, E. M., Tack, J., Chey, W. D., Rao, S. S., Fortea, J., Falques, M., et al. (2013). Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment. Pharmacol. Ther. 37, 49-61.
102. Rahimi, R., and Abdollahi, M. (2012). Herbal medicines for the management of irritable bowel syndrome: a comprehensive review. World J. Gastroenterol. 18, 589-600.
103. Rao, A. S., Camilleri, M., Eckert, D. J., Busciglio, I., Burton, D. D., Ryks, M., et al. (2011). Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G919-G928.
104. Rao, S., Lembo, A. J., Shiff, S. J., Lavins, B. J., Currie, M. G., Jia, X. D., et al. (2012). 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. 107, 1714-1724.
105. Read, N. W., Abitbol, J. L., Bardhan, K. D., Whorwell, P. J., and Fraitag, B. (1997). Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia. Gut 41, 664-668.
106. Rouzade, M. L., Fioramonti, J., and Bueno, L. (1998). A model for evaluation of gastric sensitivity in awake rats. Neurogastroenterol. Motil. 10, 157-163.
107. Scarpignato, C., and Pelosini, I. (1999). Management of irritable bowel syndrome: novel approaches to the pharmacology of gut motility. Can. J. Gastroenterol. 13(Suppl. A), 50A-65A.
108. Schey, R., and Rao, S. S. (2011). Lubiprostone for the treatment of adults with constipation and irritable bowel syndrome. Dig. Dis. Sci. 56, 1619-1625.
109. Schicho, R., and Storr, M. (2011). Alternative targets within the endocannabinoid system for future treatment of gastrointestinal diseases. Can. J. Gastroenterol. 25, 377-383.
110. Scolapio, J. S., Camilleri, M., der Ohe, M. R., and Hanson, R. B. (1995). Ascending colon response to feeding: evidence for a 5-hydroxytryptamine-3 mechanism. Scand. J. Gastroenterol. 30, 562-567.
111. Shah, E., Kim, S., Chong, K., Lembo, A., and Pimentel, M. (2012). Evaluation of harm in the pharmacotherapy of irritable bowel syndrome. Am. J. Med. 125, 381-393.
112. Simren, M., Barbara, G., Flint, H. J., Spiegel, B. M., Spiller, R. C., Vanner, S., et al. (2013). Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 62, 159-176.
113. Stanghellini, V., Barbara, G., Cremon, C., Cogliandro, R., Antonucci, A., Gabusi, V., et al. (2010). Gut microbiota and related diseases: clinical features. Intern. Emerg. Med. 5(Suppl. 1), S57-S63.
114. Sweetser, S., Busciglio, I. A., Camilleri, M., Bharucha, A. E., Szarka, L. A., Papathanasopoulos, A., et al. (2009). Effect of a chloride channel activator, lubiprostone, on colonic sensory and motor functions in healthy subjects. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G295-G301.
115. Tack, J., Camilleri, M., Chang, L., Chey, W. D., Galligan, J. J., Lacy, B. E., et al. (2012). Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment. Pharmacol. Ther. 35, 745-767.
116. Tack, J., Janssen, P., Wouters, M., and Boeckxstaens, G. (2011). Targeting serotonin synthesis to treat irritable bowel syndrome. Gastroenterology 141, 420-422.
117. Tack, J., Vos, R., Janssens, J., Salter, J., Jauffret, S., and Vandeplassche, G. (2003). Influence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment. Pharmacol. Ther. 18, 1031-1037.
118. Talley, N. J., Phillips, S. F., Haddad, A., Miller, L. J., Twomey, C., Zinsmeister, A. R., et al. (1990). GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. Dig. Dis. Sci. 35, 477-480.
119. Tillisch, K., Labus, J., Nam, B., Bueller, J., Smith, S., Suyenobu, B., et al. (2012). Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study. Aliment. Pharmacol. Ther. 35, 360-367.
120. Tonini, M., De Ponti, F., Di Nucci, A., and Crema, F. (1999). Review article: cardiac adverse effects of gastrointestinal prokinetics. Aliment. Pharmacol. Ther. 13, 1585-1591.
121. Vazquez-Roque, M. I., Camilleri, M., Smyrk, T., Murray, J. A., O'Neill, J., Carlson, P., et al. (2012). Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G1262-G1269.
122. Viramontes, B., Camilleri, M., McKinzie, S., Pardi, D. S., Burton, D., and Thomforde, G. M. (2001a). Gender-related differences in slowing colonic transit by a 5-HT3 antagonist in subjects with diarrhea-predominant irritable bowel syndrome. Am. J. Gastroenterol. 96, 2671-2676.
123. Viramontes, B. E., Malcolm, A., Camilleri, M., Szarka, L. A., McKinzie, S., Burton, D. D., et al. (2001b). Effects of an a2-adrenergic agonist on gastrointestinal transit, colonic motility, and sensation in humans. Am. J. Physiol. 281, G1468-G1476.
124. von der Ohe, M. R., Camilleri, M., Kvols, L. K., and Thomforde, G. M. (1993). Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N. Engl. J. Med. 329, 1073-1078.
125. von der Ohe, M. R., Hanson, R. B., and Camilleri, M. (1994). Serotonergic mediation of postprandial colonic tonic and phasic responses in humans. Gut 35, 536-541.
126. Walsh, J. H. (1994). Gastrointestinal Hormones. Physiology of the Gastrointestinal Tract. New York: Raven, 1-128.
127. Wehling, M. (2009). Assessing the translatability of drug projects: what needs to be scored to predict success? Nat. Rev. Drug Discov. 8, 541-546.
128. Wensel, T. M., and Luthin, D. R. (2011). Linaclotide: a novel approach to the treatment of irritable bowel syndrome. Ann. Pharmacother. 45, 1535-1543.
129. Wong, B. S., Camilleri, M., Busciglio, I., Carlson, P., Szarka, L. A., Burton, D., et al. (2011). Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology 141, 1638-1647.