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New Developments in the Treatment of Functional Dyspepsia

Drugs volume 63, pages 869–892 (2003)Cite this article

Abstract

Functional dyspepsia is a clinical syndrome defined by chronic or recurrent pain or discomfort in the upper abdomen of unknown origin. Although generally accepted, investigators differently interpret this definition and clinical trials are often biased by inhomogeneous inclusion criteria.

The poorly defined multifactorial pathogenesis of dyspeptic symptoms has hampered efforts to develop effective treatments. A general agreement exists on the irrelevant role played by Helicobacter pylori in the pathophysiology of functional dyspepsia. Gastric acid secretion is within normal limits in patients with functional dyspepsia but acid related symptoms may arise in a subgroup of them. Proton pump inhibitors appear to be effective in this subset of patients with dyspepsia. Non-painful dyspeptic symptoms are suggestive of underlying gastrointestinal motor disorders and such abnormalities can be demonstrated in a substantial proportion of patients. Postprandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety and weight loss to postcibal impaired accommodation of the gastric fundus. Prokinetics have been shown to exert beneficial effects, at least in some patients with dyspepsia. In contrast, drugs enhancing gastric fundus relaxation have been reported to improve symptoms, although conflicting results have also been published. An overdistended antrum may also generate symptoms, but its potential pathogenetic role and the effects of drugs on this abnormality have never been investigated formally. Visceral hypersensitivity plays a role in some dyspeptic patients and this abnormality is also a potential target for treatment. Both chemo- and mechanoreceptors can trigger hyperalgesic responses. Psychosocial abnormalities have been consistently found in functional digestive syndromes, including dyspepsia. Although useful in patients with irritable bowel syndromes (IBS), antidepressants have been only marginally explored in functional dyspepsia.

Among the new potentially useful agents for the treatment of functional dyspepsia, serotonin 5-HT4 receptor agonists have been shown to exert a prokinetic effect. Unlike motilides, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone and this may contribute to improve symptoms. 5-HT3 receptor antagonists have been investigated mainly in the IBS and the few studies performed in functional dyspepsia have provided conflicting results. Also, κ-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but available results in functional dyspepsia are scanty and inconclusive. Other receptors that represent potential clinical targets for antagonists include purinoceptors (i. e., P2X2/3 receptors), NMDA receptors (NR2B subtype), protease-activated receptor-2, the vanilloid receptor-1, tachykinin receptors (NK1/NK2) and cholecystokinin (CCK)1 receptors.

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References

  1. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. Gut 1999; 45 Suppl. II: 37–42

    Google Scholar 

  2. Knill-Jones RP. Geographical differences in the prevalence of dyspepsia. Scand J Gastroenterol Suppl 1991; 182: 17–24

    Article  PubMed  CAS  Google Scholar 

  3. Penston JG, Pounder RE. A survey of dyspepsia in Great Britain. Aliment Pharmacol Ther 1996; 10: 83–9

    Article  PubMed  CAS  Google Scholar 

  4. Stanghellini V. Three-month prevalence rates of gastrointestinal symptoms and the influence of demographic factors: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST). Scand J Gastroenterol Suppl 1999: 231: 20–8

    Article  PubMed  CAS  Google Scholar 

  5. Enck P, Dubois D, Marquis P. Quality of life in patients with upper gastrointestinal symptoms: results from the Domestic/ International Gastroenterology Surveillance Study (DIGEST). Scand J Gastroenterol Suppl 1999; 231: 48–54

    PubMed  CAS  Google Scholar 

  6. Talley NJ, Colin-Jones D, Koch KL, et al. Functional dyspepsia: a classification with guidelines for diagnosis and management. Gastroenterol Int 1991; 4: 145–60

    Google Scholar 

  7. Carlsson R, Dent J, Bolling-Sternevald E, et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol 1998; 33: 1023–9

    Article  PubMed  CAS  Google Scholar 

  8. Veldhuyzen van Zanten SJ, Flook N, Chiba N, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori: Canadian Dyspepsia Working Group. CMAJ 2000; 162 Suppl. 12: S3–S23

    Google Scholar 

  9. Stanghellini V, Tosetti C, De Giorgio R, et al. Functional dyspepsia: not all the roads lead to Rome. Dig Liver Dis 2002; 34: 316–8

    Article  PubMed  CAS  Google Scholar 

  10. Hungin AP, Rubin GP, O'Flanagan H. Long-term prescribing of proton pump inhibitors in general practice. Br J Gen Pract 1999; 49: 451–3

    PubMed  CAS  Google Scholar 

  11. Veldhuyzen van Zanten SJ, Talley NJ, Bytzer P, et al. Design of treatment trials for functional gastrointestinal disorders. Gut 1999; 45 Suppl. 2: 69–77

    Google Scholar 

  12. Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996; 110: 1036–42

    Article  PubMed  CAS  Google Scholar 

  13. Whitaker MJ, Brun J, Carelli F. Controversy and consensus in the management of upper gastrointestinal disease in primary care: The International Gastro Primary Care Group. Int J Clin Pract 1997; 51: 239–43

    PubMed  CAS  Google Scholar 

  14. Stanghellini V, Barbara G, De Giorgio R, et al. Helicobacter pylori, mucosal inflammation and symptom perception: new insights into an old hypothesis. Aliment Pharmacol Ther 2001; 15 Suppl. 1: 28–32

    Article  PubMed  Google Scholar 

  15. Son HJ, Rhee PL, Kim JJ, et al. Hypersensitivity to acid in ulcer-like functional dyspepsia. Korean J Intern Med 1997; 12: 188–92

    PubMed  CAS  Google Scholar 

  16. George AA, Tsuchiyose M, Dooley CP. Sensitivity of the gastric mucosa to acid and duodenal contents in patients with nonulcer dyspepsia. Gastroenterology 1991; 101: 3–6

    PubMed  CAS  Google Scholar 

  17. Tucci A, Corinaldesi R, Stanghellini V, et al. Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992; 103: 768–74

    PubMed  CAS  Google Scholar 

  18. El-Omar E, Penman I, Ardill JE, et al. A substantial proportion of non-ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients. Gut 1995; 36: 534–8

    Article  PubMed  CAS  Google Scholar 

  19. Talley NJ, Meineche-Schmidt V, Pare P, et al. Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the BOND and OPERA studies). Aliment Pharmacol Ther 1998; 12: 1055–65

    Article  PubMed  CAS  Google Scholar 

  20. Farup PG, Hovde O, Torp R, et al. Patients with functional dyspepsia responding to omeprazole have a characteristic gastro-oesophageal reflux pattern. Scand J Gastroenterol 1999; 34: 575–9

    Article  PubMed  CAS  Google Scholar 

  21. Mehta AJ, De Caestecker JS, Camm AJ, et al. Sensitization to painful distention and abnormal sensory perception in the esophagus. Gastroenterology 1995; 108: 311–9

    Article  PubMed  CAS  Google Scholar 

  22. Coffin B, Azpiroz F, Guarner F, et al. Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia. Gastroenterology 1994; 107: 1345–51

    PubMed  CAS  Google Scholar 

  23. Talley NJ. Dyspepsia: how to manage and how to treat? Aliment Pharmacol Ther 2002; 16 Suppl. 4: 95–104

    Article  PubMed  Google Scholar 

  24. Nyren O. Functional dyspepsia: bye-bye to PPIs. Gut 2002; 51: 464–5

    Article  PubMed  CAS  Google Scholar 

  25. Talley NJ. Dyspepsia management in the millennium: the death of test and treat? Gastroenterology 2002; 122: 1521–5

    Article  PubMed  Google Scholar 

  26. Veldhuyzen van Zanten SJ, Talley NJ, Blum AL, et al. Combined analysis of the ORCHID and OCAY studies: does eradication of Helicobacter pylori lead to sustained improvement in functional dyspepsia symptoms? Gut 2002; 50 Suppl. 4: 26–30

    Google Scholar 

  27. Talley NJ, Lauritsen K. The potential role of acid suppression in functional dyspepsia: the BOND, OPERA, PILOT, and ENCORE studies. Gut 2002; 50 Suppl. 4: 36–41

    Google Scholar 

  28. Soo S, Moayyedi P. Pharmacological interventions for nonulcer dyspepsia. Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 3. Oxford: Update Software, 2002

    Google Scholar 

  29. Blum AL, Arnold R, Stolte M, et al. Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status. The Frosch Study Group. Gut 2000; 47: 473–80

    CAS  Google Scholar 

  30. Wong WM, Wong BC, Hung WK, et al. Double blind, randomised, placebo controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients. Gut 2002; 51: 502–6

    Article  PubMed  CAS  Google Scholar 

  31. Stanghellini V, Ghidini C, Maccarini MR, et al. Fasting and postprandial gastrointestinal motility in ulcer and non-ulcer dyspepsia. Gut 1992; 33: 184–90

    Article  PubMed  CAS  Google Scholar 

  32. Malagelada JR, Stanghellini V. Manometric evaluation of functional upper gut symptoms. Gastroenterology 1985; 88: 1223–31

    PubMed  CAS  Google Scholar 

  33. Troncon LE, Thompson DG, Ahluwalia NK, et al. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut 1995; 37: 17–22

    Article  PubMed  CAS  Google Scholar 

  34. Tack J, Piessevaux H, Coulie B, et al. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998; 115: 1346–52

    Article  PubMed  CAS  Google Scholar 

  35. Pinto D, Tosetti C, Stanghellini V, et al. Ultrasonographic evaluation of gastric antral distension induced by a water load test in health subjects and patients with functional dispepsia [abstract]. Gastroenterology 2001; 120 Suppl. 1: A237

    Google Scholar 

  36. Villanova N, Azpiroz F, Malagelada JR. Gastrogastric reflexes regulating gastric tone and their relationship to perception. Am J Physiol 1997; 273: G464–9

    PubMed  CAS  Google Scholar 

  37. Azpiroz F, Malagelada JR. Isobaric intestinal distension in humans: sensorial relay and reflex gastric relaxation. Am J Physiol 1990; 258: G202–7

    PubMed  CAS  Google Scholar 

  38. Thumshirn M, Camilleri M, Choi MG, et al. Modulation of gastric sensory and motor functions by nitrergic and alpha2-adrenergic agents in humans. Gastroenterology 1999; 116: 573–85

    Article  PubMed  CAS  Google Scholar 

  39. Kuo B, Camilleri M, Burton D, et al. Effects of 5-HT3 antagonism on postprandial gastric volume and symptoms in humans. Aliment Pharmacol Ther 2002; 16: 225–33

    Article  PubMed  CAS  Google Scholar 

  40. Thumshirn M, Camilleri M, Saslow SB, et al. Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function. Gut 1999; 44: 55–64

    Article  PubMed  CAS  Google Scholar 

  41. Mearin F, de Ribot X, Balboa A, et al. Does Helicobacter pylori infection increase gastric sensitivity in functional dyspepsia? Gut 1995; 37: 47–51

    Article  PubMed  CAS  Google Scholar 

  42. Mearin F, Cucala M, Azpiroz F, et al. The origin of symptoms on the brain-gut axis in functional dyspepsia. Gastroenterology 1991; 101: 999–1006

    PubMed  CAS  Google Scholar 

  43. Mertz H, Fullerton S, Naliboff B, et al. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 1998; 42: 814–22

    Article  PubMed  CAS  Google Scholar 

  44. Samsom M, Verhagen MA, vanBerge Henegouwen GP, et al. Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients. Gastroenterology 1999; 116: 515–20

    Article  PubMed  CAS  Google Scholar 

  45. Tack J, Piessevaux H, Coulie B, et al. Role of visceral hypersensitivity in patients with functional dyspepsia [abstract]. Gastroenterology 1998; 114: G1232

    Google Scholar 

  46. Tack J, Coulie B, Piessevaux H, et al. Postprandial gastric tone determines the sensitivity to postprandial distension in functional dyspepsia [abstract]. Neurogastroenterol Motil 1998; 10: 102

    Google Scholar 

  47. Holtmann G, Goebell H, Talley NJ. Functional dyspepsia and irritable bowel syndrome: is there a common pathophysiological basis? Am J Gastroenterol 1997; 92: 954–9

    PubMed  CAS  Google Scholar 

  48. Trimble KC, Farouk R, Pryde A, et al. Heightened visceral sensation in functional gastrointestinal disease is not sitespecific: evidence for a generalized disorder of gut sensitivity. Dig Dis sci 1995; 40: 1607–13

    Article  PubMed  CAS  Google Scholar 

  49. Stangheilini V, Malagelada JR, Zinsmeister AR, et al. Stress-induced gastroduodenal motor disturbances in humans: possible humoral mechanisms. Gastroenterology 1983; 85: 83–91

    Google Scholar 

  50. Bennett EJ, Piesse C, Palmer K, et al. Functional gastrointestinal disorders: psychological, social, and somatic features. Gut 1998; 42: 414–20

    Article  PubMed  CAS  Google Scholar 

  51. Talley NJ, Boyce P, Jones M. Dyspepsia and health care seeking in a community: how important are psychological factors? Dig Dis sci 1998; 43: 1016–22

    Article  PubMed  CAS  Google Scholar 

  52. Lemann M, Dederding JP, Flourie B, et al. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia: the irritable stomach syndrome. Dig Dis sci 1991; 36: 1249–54

    Article  PubMed  CAS  Google Scholar 

  53. Talley NJ, Fett SL, Zinsmeister AR, et al. Gastrointestinal tract symptoms and self-reported abuse: a population-based study. Gastroenterology 1994; 107: 1040–9

    PubMed  CAS  Google Scholar 

  54. Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000; 355: 1035–40

    Article  PubMed  CAS  Google Scholar 

  55. Talley NJ, Haque M, Wyeth JW, et al. Development of a new dyspepsia impact scale: the Nepean Dyspepsia Index. Aliment Pharmacol Ther 1999; 13: 225–35

    Article  PubMed  CAS  Google Scholar 

  56. Heading RC, Wager E, Tooley PJ. Reliability of symptom assessment in dyspepsia. Eur J Gastroenterol Hepatol 1997; 9: 779–81

    Article  PubMed  CAS  Google Scholar 

  57. Jaeschke R, Singer J, Guyatt GH. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10: 407–15

    Article  PubMed  CAS  Google Scholar 

  58. Veldhuyzen van Zanten SJ, Cleary C, Talley NJ, et al. Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials. Am J Gastroenterol 1996; 91: 660–73

    Google Scholar 

  59. Kellow JE, Cowan H, Shuter B, et al. Efficacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther 1995; 9: 153–60

    Article  PubMed  CAS  Google Scholar 

  60. Distrutti E, Fiorucci S, Hauer SK, et al. Effect of acute and chronic levosulpiride administration on gastric tone and perception in functional dyspepsia. Aliment Pharmacol Ther 2002; 16: 613–22

    Article  PubMed  CAS  Google Scholar 

  61. Manes G, Dominguez-Munoz JE, Leodolter A, et al. Effect of cisapride on gastric sensitivity to distension, gastric compliance and duodeno-gastric reflexes in healthy humans. Dig Liver Dis 2001; 33: 407–13

    Article  PubMed  CAS  Google Scholar 

  62. Tack J, Broeckaert D, Coulie B, et al. The influence of cisapride on gastric tone and the perception of gastric distension. Aliment Pharmacol Ther 1998; 12: 761–6

    Article  PubMed  CAS  Google Scholar 

  63. Cipolla G, Sacco S, Crema F, et al. Gastric motor effects of triptans: open questions and future perspectives. Pharmacol Res 2001; 43: 205–10

    Article  PubMed  CAS  Google Scholar 

  64. Tack J, Coulie B, Wilmer A, et al. Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000; 46: 468–73

    Article  PubMed  CAS  Google Scholar 

  65. Tack J, Peeters T. What comes after macrolides and other motilin stimulants? Gut 2001; 49: 317–8

    PubMed  CAS  Google Scholar 

  66. Holzer P, Holzer-Petsche U. Tachykinin receptors in the gut: physiological and pathological implications. Curr Opin Pharmacol 2001; 1: 583–90

    Article  PubMed  CAS  Google Scholar 

  67. Laird JM, Olivar T, Lopez-Garcia JA, et al. Responses of rat spinal neurons to distension of inflamed colon: role of tachykinin NK2 receptors. Neuropharmacology 2001; 40: 696–701

    Article  PubMed  CAS  Google Scholar 

  68. Read NW, Abitbol JL, Bardhan KD, et al. Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia. Gut 1997; 41: 664–8

    Article  PubMed  CAS  Google Scholar 

  69. Junien JL, Riviere P. Review article: the hypersensitive gut: peripheral kappa agonists as a new pharmacological approach. Aliment Pharmacol Ther 1995; 9: 117–26

    Article  PubMed  CAS  Google Scholar 

  70. Viramontes BE, Malcolm A, Camilleri M, et al. Effects of an alpha(2)-adrenergic agonist on gastrointestinal transit, colonie motility, and sensation in humans. Am J Physiol 2001; 281: G1468–76

    CAS  Google Scholar 

  71. Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol sci 2001; 22: 636–42

    Article  PubMed  CAS  Google Scholar 

  72. Feinle C, Meier O, Otto B, et al. Role of duodenal lipid and cholecystokinin A receptors in the pathophysiology of functional dyspepsia. Gut 2001; 48: 347–55

    Article  PubMed  CAS  Google Scholar 

  73. McQuay HJ, Moore RA. Antidepressants and chronic pain. BMJ 1997; 314: 763–4

    Article  PubMed  CAS  Google Scholar 

  74. Laird JM, Carter AJ, Grauert M, et al. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats. Br J Pharmacol 2001; 134: 1742–8

    Article  PubMed  CAS  Google Scholar 

  75. Bielefeldt K, Ozaki N, Gebhart GF. Experimental ulcers alter voltage-sensitive sodium currents in rat gastric sensory neurons. Gastroenterology 2002; 122: 394–405

    Article  PubMed  CAS  Google Scholar 

  76. Bielefeldt K, Ozaki N, Gebhart GF. Mild gastritis alters voltage-sensitive sodium currents in gastric sensory neurons in rats. Gastroenterology 2002; 122: 752–61

    Article  PubMed  CAS  Google Scholar 

  77. Yiangou Y, Facer P, Baecker PA, et al. ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease. Neurogastroenterol Motil 2001; 13: 365–9

    Article  PubMed  CAS  Google Scholar 

  78. Burnstock G. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol sci 2001; 22: 182–8

    Article  PubMed  CAS  Google Scholar 

  79. Chizh BA, Illes P. P2X receptors and nociception. Pharmacol Rev 2001; 53: 553–68

    PubMed  CAS  Google Scholar 

  80. Yiangou Y, Facer P, Dyer NH, et al. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet 2001; 357: 1338–9

    Article  PubMed  CAS  Google Scholar 

  81. De Ponti F, Malagelada JR. Functional gut disorders: from motility to sensitivity disorders: a review of current and investigational drugs for their management. Pharmacol Ther 1998; 80: 49–88

    Article  PubMed  Google Scholar 

  82. Allescher HD, Bockenhoff A, Knapp G, et al. Treatment of non-ulcer dyspepsia: a meta-analysis of placebo-controlled prospective studies. Scand J Gastroenterol 2001; 36: 934–41

    Article  PubMed  CAS  Google Scholar 

  83. Cutts TF, Abell TL, Karas JG, et al. Symptom improvement from prokinetic therapy corresponds to improved quality of life in patients with severe dyspepsia. Dig Dis sci 1996; 41: 1369–78

    Article  PubMed  CAS  Google Scholar 

  84. Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, et al. Efficacy of cisapride and domperidone in functional (nonulcer) dyspepsia: a meta-analysis. Am J Gastroenterol 2001; 96: 689–96

    Google Scholar 

  85. Briejer MR, Akkermans LM, Schuurkes JA. Gastrointestinal prokinetic benzamides: the pharmacology underlying stimulation of motility. Pharmacol Rev 1995; 47: 631–51

    PubMed  CAS  Google Scholar 

  86. Willems JL, Buylaert WA, Lefebvre RA, et al. Neuronal dopamine receptors on autonomic ganglia and sympathetic nerves and dopamine receptors in the gastrointestinal system. Pharmacol Rev 1985; 37: 165–216

    PubMed  CAS  Google Scholar 

  87. Valenzuela JE. Dopamine as a possible neurotransmitter in gastric relaxation. Gastroenterology 1976; 71: 1019–22

    PubMed  CAS  Google Scholar 

  88. Lanfranchi GA, Marzio L, Cortini C, et al. Motor effect of dopamine on human sigmoid colon: evidence for specific receptors. Am J Dig Dis 1978; 23: 257–63

    Article  PubMed  CAS  Google Scholar 

  89. Lanfranchi GA, Bazzocchi G, Fois F, et al. Effect of domperidone and dopamine on colonie motor activity in patients with the irritable bowel syndrome. Eur J Clin Pharmacol 1985; 29: 307–10

    Article  PubMed  CAS  Google Scholar 

  90. Marzio L, Neri M, Di Giammarco AM, et al. Dopamine-induced migrating myoelectrical complex-like activity in human duodenum. Dig Dis sci 1986; 31: 349–54

    Article  PubMed  CAS  Google Scholar 

  91. Wiley J, Owyang C. Dopaminergic modulation of rectosigmoid motility: action of domperidone. J Pharmacol Exp Ther 1987; 242: 548–51

    PubMed  CAS  Google Scholar 

  92. Marzio L, Neri M, Pieramico O, et al. Dopamine interrupts gastrointestinal fed motility pattern in humans: effect on motilin and somatostatin blood levels. Dig Dis sci 1990; 35: 327–32

    Article  PubMed  CAS  Google Scholar 

  93. Mansi C, Borro P, Giacomini M, et al. Comparative effects of levosulpiride and cisapride on gastric emptying and symptoms in patients with functional dyspepsia and gastroparesis. Aliment Pharmacol Ther 2000; 14: 561–9

    Article  PubMed  CAS  Google Scholar 

  94. Arienti V, Corazza GR, Sorge M, et al. The effects of levosulpiride on gastric and gall-bladder emptying in functional dyspepsia. Aliment Pharmacol Ther 1994; 8: 631–8

    Article  PubMed  CAS  Google Scholar 

  95. Corazza GR, Biagi F, Albano O, et al. Levosulpiride in functional dyspepsia: a multicentric, double-blind, controlled trial. Ital J Gastroenterol 1996; 28: 317–23

    PubMed  CAS  Google Scholar 

  96. Song CW, Chun HJ, Kim CD, et al. Effects of levosulpiride in patients with functional dyspepsia accompanied by delayed gastric emptying. Korean J Intern Med 1998; 13: 15–21

    PubMed  CAS  Google Scholar 

  97. Schuurkes JAJ, Meulemans AL, Obertop H, et al. 5-HT4 receptors on the human stomach [abstract]. J Gastroint Motil 1991; 3: 199

    Google Scholar 

  98. Sakurai-Yamashita Y, Takada K, Takemura K, et al. Ability of mosapride to bind to 5-HT4 receptor in the human stomach. Jpn J Pharmacol 1999; 79: 493–6

    Article  PubMed  CAS  Google Scholar 

  99. Pillans PI, Wood SM. Cisapride increases micturition frequency. J Clin Gastroenterol 1994; 19: 336–8

    Article  PubMed  CAS  Google Scholar 

  100. Tonini M, Messori E, Franceschetti GP, et al. Characterization of the 5-HT receptor potentiating neuromuscular cholinergic transmission in strips of human isolated detrusor muscle. Br J Pharmacol 1994; 113: 1–2

    Article  PubMed  CAS  Google Scholar 

  101. Tonini M, De Ponti F, Di Nucci A, et al. Review article: cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther 1999; 13: 1585–91

    Article  PubMed  CAS  Google Scholar 

  102. Fraser R, Horowitz M, Maddox A, et al. Dual effects of cisapride on gastric emptying and antropyloroduodenal motility. Am J Physiol 1993; 264: G195–201

    PubMed  CAS  Google Scholar 

  103. Fraser RJ, Horowitz M, Maddox AF, et al. Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis: effects of cisapride. Gut 1994; 35: 172–8

    Article  PubMed  CAS  Google Scholar 

  104. Malbert CH, Serthelon JP, Dent J. Changes in antroduodenal resistance induced by Cisapride in conscious dogs. Am J Physiol 1992; 263: G202–8

    PubMed  CAS  Google Scholar 

  105. Holtmann G, Gschossmann J, Karaus M, et al. Randomised double-blind comparison of simethicone with cisapride in functional dyspepsia. Aliment Pharmacol Ther 1999; 13: 1459–65

    Article  PubMed  CAS  Google Scholar 

  106. Chen JD, Ke MY, Lin XM, et al. Cisapride provides symptomatic relief in functional dyspepsia associated with gastric myoelectrical abnormality. Aliment Pharmacol Ther 2000; 14: 1041–7

    Article  PubMed  CAS  Google Scholar 

  107. Wiseman LR, Faulds D. Cisapride: an updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders. Drugs 1994; 47: 116–52

    Article  PubMed  CAS  Google Scholar 

  108. Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58: 491–6

    Article  PubMed  CAS  Google Scholar 

  109. Camilleri M. Review article: tegaserod. Aliment Pharmacol Ther 2001; 15: 277–89

    Article  PubMed  CAS  Google Scholar 

  110. Poen AC, Felt-Bersma RJ, Van Dongen PA, et al. Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther 1999; 13: 1493–7

    Article  PubMed  CAS  Google Scholar 

  111. Camilleri M, McKinzie S, Burton D, et al. Prucalopride accelerates small bowel and colonie transit in patients with chronic functional constipation (FC) or constipation-predominant irritable bowel syndrome (C-IBS) [abstract]. Gastroenterology 2000; 118 Suppl. 2: A845

    Article  Google Scholar 

  112. De Ponti F, Tonini M. Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs 2001; 61: 317–32

    Article  PubMed  Google Scholar 

  113. Kamm MA. The complexity of drug development for irritable bowel syndrome. Aliment Pharmacol Ther 2002; 16: 343–51

    Article  PubMed  CAS  Google Scholar 

  114. Peeters TL. Erythromycin and other macrolides as prokinetic agents. Gastroenterology 1993; 105: 1886–99

    PubMed  CAS  Google Scholar 

  115. Itoh Z. Motilin and clinical application. Peptides 1997; 18: 593–608

    Article  PubMed  CAS  Google Scholar 

  116. Itoh Z, Suzuki T, Nakaya M, et al. Structure-activity relation among macrolide antibiotics in initiation of interdigestive migrating contractions in the canine gastrointestinal tract. Am J Physiol 1985; 248: G320–5

    PubMed  CAS  Google Scholar 

  117. Clark MJ, Wright T, Bertrand PP, et al. Erythromycin derivatives ABT 229 and GM 611 act on motilin receptors in the rabbit duodenum. Clin Exp Pharmacol Physiol 1999; 26: 242–5

    Article  PubMed  CAS  Google Scholar 

  118. Siani MA, Skillman AG, Carreras CW, et al. Development and screening of a polyketide virtual library for drug leads against a motilide pharmacophore. J Mol Graph Model 2000; 18: 497–40

    Article  PubMed  CAS  Google Scholar 

  119. Costa A, De Ponti F, Gibelli G, et al. In vivo characterization of the colonie prokinetic effect of erythromycin in the rabbit. Pharmacology 1997; 54: 64–75

    Article  PubMed  CAS  Google Scholar 

  120. Depoortere I, Peeters TL, Vantrappen G. Motiliin receptors of the rabbit colon. Peptides 1991; 12: 89–94

    Article  PubMed  CAS  Google Scholar 

  121. Coulie B, Tack J, Peeters T, et al. Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans. Gut 1998; 43: 395–400

    Article  PubMed  CAS  Google Scholar 

  122. Janssens J, Peeters TL, Vantrappen G, et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin: preliminary studies. N Engl J Med 1990; 322: 1028–31

    Article  PubMed  CAS  Google Scholar 

  123. Bruley des Varannes S, Parys V, Ropert A, et al. Erythromycin enhances fasting and postprandial proximal gastric tone in humans. Gastroenterology 1995; 109: 32–9

    Article  PubMed  CAS  Google Scholar 

  124. Demedts I, Tack J, Coulie B, et al. Role of fundic tone in mealinduced satiety in man [abstract]. Gastroenterology 1997; 112: A720

    Google Scholar 

  125. Piessevaux H, Tack J, Coulie B, et al. Influence of erythromycin on the perception of gastric distension [abstract]. Gastroenterology 1997; 112: A806

    Google Scholar 

  126. Talley NJ, Verlinden M, Snape W, et al. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial. Aliment Pharmacol Ther 2000; 14: 1653–61

    Article  PubMed  CAS  Google Scholar 

  127. Camilleri M. Motilin agonists and dyspepsia: throwing out the baby with the bath water. Gut 2002; 51: 612–3

    Article  PubMed  CAS  Google Scholar 

  128. Talley N, Verlinden M. Authors' reply. Gut 2002; 51: 612–3

    Article  Google Scholar 

  129. Camilleri M, Coulie B, Tack JF. Visceral hypersensitivity: facts, speculations, and challenges. Gut 2001; 48: 125–31

    Article  PubMed  CAS  Google Scholar 

  130. Kirkup AJ, Brunsden AM, Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies: I, receptors on visceral afferents. Am J Physiol 2001; 280: G787–94

    CAS  Google Scholar 

  131. Tack J, Caenepeel P, Fischler B, et al. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001; 121: 526–35

    Article  PubMed  CAS  Google Scholar 

  132. Gershon MD. Review article: roles played by 5-hydroxy-tryptamine in the physiology of the bowel. Aliment Pharmacol Ther 1999; 13 Suppl. 2: 15–30

    PubMed  Google Scholar 

  133. Moss HE, Sanger GJ. The effects of granisetron, ICS 205-930 and ondansetron on the visceral pain reflex induced by duodenal distension. Br J Pharmacol 1990; 100: 497–501

    Article  PubMed  CAS  Google Scholar 

  134. Miura M, Lawson DC, Clary EM, et al. Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist. Dig Dis sci 1999; 44: 20–4

    Article  PubMed  CAS  Google Scholar 

  135. Delvaux M, Louvel D, Mamet JP, et al. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1998; 12: 849–55

    Article  PubMed  CAS  Google Scholar 

  136. Prior A, Read NW. Reduction of rectal sensitivity and postprandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome. Alim Pharmacol Ther 1993; 7: 175–80

    Article  CAS  Google Scholar 

  137. Goldberg PA, Kamm MA, Setti-Carraro P, et al. Modification of visceral sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism (ondansetron). Digestion 1996; 57: 478–83

    Article  PubMed  CAS  Google Scholar 

  138. Feinle C, Read NW. Ondansetron reduces nausea induced by gastroduodenal stimulation without changing gastric motility. Am J Physiol 1996; 261: G591–7

    Google Scholar 

  139. Banner SE, Sanger GJ. Differences between 5-HT3 receptor antagonists in modulation of visceral hypersensitivity. Br J Pharmacol 1995; 114: 558–62

    Article  PubMed  CAS  Google Scholar 

  140. Gunput MD. Review article: clinical pharmacology of alosetron. Aliment Pharmacol Ther 1999; 13 Suppl. 2: 70–6

    Article  PubMed  Google Scholar 

  141. Humphrey PP, Bountra C, Clayton N, et al. Review article: the therapeutic potential of 5-HT3 receptor antagonists in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 1999; 13 Suppl. 2: 31–8

    Article  PubMed  Google Scholar 

  142. Balfour JA, Goa KL, Perry CM. Alosetron. Drugs 2000; 59: 511–8

    Article  PubMed  CAS  Google Scholar 

  143. Kozlowski CM, Green A, Grundy D, et al. The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat. Gut 2000; 46: 474–80

    Article  PubMed  CAS  Google Scholar 

  144. Zerbib F, Bruley des Verannes S, Oriola RC, et al. Alosetron does not affect the visceral perception of gastric distension in healthy subjects. Aliment Pharmacol Ther 1994; 8: 403–7

    Article  PubMed  CAS  Google Scholar 

  145. Thumshirn M, Coulie B, Camilleri M, et al. Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome. Aliment Pharmacol Ther 2000; 14: 869–78

    Article  PubMed  CAS  Google Scholar 

  146. Talley NJ, Van Zanten SV, Saez LR, et al. A dose-ranging, placebo-controlled, randomized trial of alosetron in patients with functional dyspepsia. Aliment Pharmacol Ther 2001; 15: 525–37

    Article  PubMed  CAS  Google Scholar 

  147. Tonini M, De Ponti F. Serotonin modulation of gastrointestinal motility. In: Gaginella TS, Galligan JJ, editors. Serotonin and gastrointestinal function. Boca Raton (FL): CRC Press, 1995: 53–84

    Google Scholar 

  148. Buchheit KH, Costall B, Engel G, et al. 5-Hydroxytryptamine receptor antagonism by metoclopramide and ICS 205-930 in the guinea-pig leads to enhancement of contractions of stomach muscle strips induced by electrical field stimulation and facilitation of gastric emptying in vivo. J Pharm Pharmacol 1985; 37: 664–7

    Article  PubMed  CAS  Google Scholar 

  149. Costall B, Gunning SJ, Naylor RJ, et al. The effect of GR38032F, novel 5-HT3-receptor antagonist on gastric emptying in the guinea-pig. Br J Pharmacol 1987; 91: 263–4

    Article  PubMed  CAS  Google Scholar 

  150. Schiavone A, Volonte M, Micheletti R. The gastrointestinal motor effect of benzamide derivatives is unrelated to 5-HT3 receptor blockade. Eur J Pharmacol 1990; 187: 323–9

    Article  PubMed  CAS  Google Scholar 

  151. Akkermans LM, Vos A, Hoekstra A, et al. Effect of ICS 205-930 (a specific 5-HT3 receptor antagonist) on gastric emptying of a solid meal in normal subjects. Gut 1988; 29: 1249–52

    Article  PubMed  CAS  Google Scholar 

  152. Nielsen OH, Hvid-Jacobsen K, Lund P, et al. Gastric emptying and subjective symptoms of nausea: lack of effects of a 5-hydroxytryptamine-3 antagonist ondansetron on gastric emptying in patients with gastric stasis syndrome. Digestion 1990; 46: 89–96

    Article  PubMed  CAS  Google Scholar 

  153. Stacher G, Bergmann H, Granser-Vacariu GV, et al. Lack of systematic effects of the 5-hydroxytryptamine 3 receptor antagonist ICS 205-930 on gastric emptying and antral motor activity in patients with primary anorexia nervosa. Br J Clin Pharmacol 1991; 32: 685–9

    PubMed  CAS  Google Scholar 

  154. Eeckhout C, Gregory P, David S. 5-HT3 antagonists prevent intraduodenal lipid induced slowing of gastric emptying in dogs [abtract]. Gastroenterology 1994; 106: A492

    Google Scholar 

  155. Houghton LA, Fowler P, Keene ON, et al. Effect of sumatriptan, a new selective 5HT1-like agonist, on liquid gastric emptying in man. Aliment Pharmacol Ther 1992; 6: 685–91

    Article  PubMed  CAS  Google Scholar 

  156. Coulie B, Tack J, Maes B, et al. Sumatriptan, a selective 5-HT1 receptor agonist, induces a lag phase for gastric emptying of liquids in humans. Am J Physiol 1997; 272: G902–8

    PubMed  CAS  Google Scholar 

  157. Boeckxstaens GE, Hirsch DP, Kuiken SD, et al. The proximal stomach and postprandial symptoms in functional dyspeptics. Am J Gastroenterol 2002; 97: 40–8

    Article  PubMed  CAS  Google Scholar 

  158. Coulie B, Tack J, Sifrim D, et al. Role of nitric oxide in fasting gastric fundus tone and in 5-HT1 receptor-mediated relaxation of gastric fundus. Am J Physiol 1999; 276: G373–7

    PubMed  CAS  Google Scholar 

  159. De Ponti F, Crema F, Nardelli G, et al. Blockade by the selective 5-HT1B/D receptor antagonist GR127935 of the effect of sumatriptan on canine gastric compliance [abstract]. Neurogastroenterol Motil 2000; 12: 383

    Google Scholar 

  160. Meulemans AL, Elsen LF, de Ridder WJA, et al. Effects of sumatriptan on the guinea-pig isolated stomach [abstract]. Neurogastroenterol Motil 1996; 8: A183

    Google Scholar 

  161. Crema F, Nardelli G, Moro E, et al. Enhanced gastric accommodation by antimigraine triptans: role of 5-HT1B/D receptors [abstract]. Pharmacol Res 2001; 43 Suppl. A: 113

    Google Scholar 

  162. Coulie B, Tack J, Janssen J. Influence of buspirone-induced fundus relaxation on the perception of gastric distention in man [abstract]. Gastroenterology 1997; 112: A715

    Google Scholar 

  163. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology 1997; 112: 2120–37

    Article  PubMed  CAS  Google Scholar 

  164. Jackson JL, O'Malley PG, Tomkins G, et al. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med 2000; 108: 65–72

    Article  PubMed  CAS  Google Scholar 

  165. Mertz H, Fass R, Kodner A, et al. Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsi. Am J Gastroenterol 1998; 93: 160–5

    Article  PubMed  CAS  Google Scholar 

  166. Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther 1994; 8: 159–66

    Article  PubMed  CAS  Google Scholar 

  167. Gorard DA, Libby GW, Farthing MJ. Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea-predominant irritable bowel syndrome. Dig Dis sci 1995; 40: 86–95

    Article  PubMed  CAS  Google Scholar 

  168. Peghini PL, Katz PO, Castell DO. Imipramine decreases oesophageal pain perception in human male volunteers. Gut 1998; 42: 807–13

    Article  PubMed  CAS  Google Scholar 

  169. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain 1992; 49: 205–19

    Article  PubMed  CAS  Google Scholar 

  170. Pacher P, Ungvari Z, Nanasi PP, et al. Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects: is there any? Curr Med Chem 1999; 6: 469–80

    PubMed  CAS  Google Scholar 

  171. Altar CA. Neurotrophins and depression. Trends Pharmacol sci 1999; 20: 59–61

    Article  PubMed  CAS  Google Scholar 

  172. Coulie B, Szarka LA, Camilleri M, et al. Recombinant human neurotrophic factors accelerate colonie transit and relieve constipation in humans. Gastroenterology 2000; 119: 41–50

    Article  PubMed  CAS  Google Scholar 

  173. Delvaux M. Pharmacology and clinical experience with fedotozine. Expert Opin Investig Drugs 2001; 10: 97–110

    Article  PubMed  CAS  Google Scholar 

  174. Coffin B, Bouhassira D, Chollet R, et al. Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans. Aliment Pharmacol Ther 1996; 10: 919–25

    Article  PubMed  CAS  Google Scholar 

  175. Fraitag B, Homerin M, Hecketsweiler P. Double-blind dose-response multicenter comparison of fedotozine and placebo in treatment of nonulcer dyspepsia. Dig Dis sci 1994; 39: 1072–7

    Article  PubMed  CAS  Google Scholar 

  176. May B, Kohler S, Schneider B. Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Aliment Pharmacol Ther 2000; 14: 1671–7

    Article  PubMed  CAS  Google Scholar 

  177. Bortolotti M, Coccia G, Grossi G, et al. The treatment of functional dyspepsia with red pepper. Aliment Pharmacol Ther 2002; 16: 1075–82

    Article  PubMed  CAS  Google Scholar 

  178. Thompson Coon J, Ernst E. Systematic review: herbal medicinal products for non-ulcer dyspepsia. Aliment Pharmacol Ther 2002; 16: 1689–99

    Article  PubMed  CAS  Google Scholar 

  179. Bueno L, Fioramonti J, Garcia-Villar R. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications: III, visceral afferent pathways: a source of new therapeutic targets for abdominal pain. Am J Physiol 2000; 278: G670–6

    CAS  Google Scholar 

  180. Fiorucci S, Distrutti E. Role of PAR2 in pain and inflammation. Trends Pharmacol sci 2002; 23: 153–5

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

V. Stanghellini is the recipient of a research grant from Janssen Foundation and is currently acting as a consultant for Altana, Astra-Zeneca and Janssen-Cilag.

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Authors and Affiliations

  1. Department of Internal Medicine and Gastroenterology, University of Bologna, Policlinico S. Orsola-Malpighi, Via Massarenti 9, Bologna, I-40138, Italy

    Vincenzo Stanghellini, Roberto De Giorgio, Giovanni Barbara & Roberto Corinaldesi

  2. Department of Pharmacology, University of Bologna, Bologna, Italy

    Fabrizio De Ponti

  3. National Health Service, Bologna, Italy

    Cesare Tosetti

Authors
  1. Vincenzo Stanghellini
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  2. Fabrizio De Ponti
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  3. Roberto De Giorgio
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  4. Giovanni Barbara
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  5. Cesare Tosetti
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  6. Roberto Corinaldesi
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Correspondence to Vincenzo Stanghellini.

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Stanghellini, V., De Ponti, F., De Giorgio, R. et al. New Developments in the Treatment of Functional Dyspepsia. Drugs 63, 869–892 (2003). https://doi.org/10.2165/00003495-200363090-00003

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Keywords

  • Irritable Bowel Syndrome
  • Gastric Emptying
  • Dyspepsia
  • Sumatriptan
  • Cisapride