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Functional dyspepsia: drugs for new (and old) therapeutic targets

https://doi.org/10.1016/j.bpg.2004.04.003Get rights and content

Abstract

The therapeutic management of functional dyspepsia remains a major challenge for the gastroenterologist. Current therapies available are based on putative underlying pathophysiologic mechanisms, including gastric acid sensitivity, slow gastric emptying and Helicobacter pylori infection, but only a small proportion of patients achieve symptomatic benefit from these therapeutic approaches. Relatively novel mechanistic concepts under testing include impaired gastric accomodation, visceral hypersensitivity, and central nervous system dysfunction. Serotonergic modulators (e.g. the 5-HT4 agonist tegaserod, the 5-HT3 antagonist alosetron and the 5-HT1P agonist sumatriptan), CCK-1 antagonists (e.g. dexloxiglumide), opioid agonists (e.g. asimadoline), N-methyl-d-aspartate (NMDA) receptor antagonists (e.g dextromethorphan), neurokinin antagonists (e.g. talnetant), capsaicin-like agents and antidepressants are among the agents currently under investigation. It seems unlikely, however, that targeting a single mechanism with an individual drug will result in complete symptom remission in most cases.

Section snippets

Acid secretion

Acid suppression is the most commonly prescribed empiric approach for the treatment of functional dyspepsia. The efficacy has been confirmed in meta-analyses6., 7. but the benefit does not have an unequivocal pathophysiologic explanation. In fact, gastric acid secretion is usually normal in subjects with functional dyspepsia8, and other mechanisms, such as hypersensitivity to normal acid concentration, impaired acid clearance from the duodenum or misdiagnosed gastroesophageal acid reflux may

Conclusions

Targeting relevant pathophysiological mechanisms is the most reasonable and widely pursued approach for drug development and testing in functional dyspepsia. However, only a proportion of the patients is likely to have a detectable abnormality of gastric physiology. Thus, targeting a single pathophysiologic pathway or a single abnormality may not provide complete improvement in most cases. The number and sophistication of treatment alternatives for functional dyspepsia will likely continue to

References (114)

  • T.H. Moran

    Cholecystokinin and satiety: current perspectives

    Nutrition

    (2000)
  • M. Delvaux et al.

    The kappa agonist fedotozine relieves hypersensitivity to colonic distention in patients with irritable bowel syndrome

    Gastroenterology

    (1999)
  • C.J. Woolf et al.

    The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states

    Pain

    (1991)
  • P. Holzer et al.

    Tachykinins in the gut. Part I. Expression, release and motor function

    Pharmacology and Therapeutics

    (1997)
  • P. Holzer et al.

    Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation

    Pharmacology and Therapeutics

    (1997)
  • A. Szallasi et al.

    Vanilloid (capsaicin) receptors in the rat: distribution in the brain, regional differences in the spinal cord, axonal transport to the periphery, and depletion by systemic vanilloid treatment

    Brain Research

    (1995)
  • P. Holzer

    Gastrointestinal afferents as targets of novel drugs for the treatment of functional bowel disorders and visceral pain

    European Journal of Pharmacology

    (2001)
  • H. Mertz et al.

    Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia

    American Journal of Gastroenterology

    (1998)
  • J.L. Jackson et al.

    Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis

    American Journal of Medicine

    (2000)
  • N.J. Talley

    Serotoninergic neuroenteric modulators

    Lancet

    (2001)
  • N.J. Talley

    Therapeutic options in nonulcer dyspepsia

    Journal of Clinical Gastroenterology

    (2001)
  • N.J. Talley et al.

    Impact of functional dyspepsia on quality of life

    Digestive Diseases and Sciences

    (1995)
  • O. Nyren et al.

    Economic costs of functional dyspepsia

    Pharmacoeconomics

    (1992)
  • N.J. Talley et al.

    Non-ulcer dyspepsia: potential causes and pathophysiology

    Annals of Internal Medicine

    (1988)
  • P. Moayyedi et al.

    Pharmacological interventions for non-ulcer dyspepsia [update of Cochrane Database Syst Rev. 2000;(2):CD001960; PMID: 10796840]

    Cochrane Database of Systematic Reviews

    (2003)
  • N.J. Talley et al.

    The potential role of acid suppression in functional dyspepsia: the BOND, OPERA, PILOT, and ENCORE studies

    Gut

    (2002)
  • N.J. Talley

    Review article: functional dyspepsia—should treatment be targeted on disturbed physiology?

    Alimentary Pharmacology and Therapeutics

    (1995)
  • M. Simren et al.

    Acid infusion enhances duodenal mechanosensitivity in healthy subjects

    American Journal of Physiology. Gastrointestinal and Liver Physiology

    (2003)
  • K.J. Lee et al.

    Influence of duodenal acidification on the sensorimotor function of the proximal stomach in man

    American Journal of Physiology. Gastrointestinal and Liver Physiology

    (2003)
  • Y.X. Lu et al.

    Duodenal acid-induced gastric relaxation is mediated by multiple pathways

    American Journal of Physiology

    (1999)
  • N.J. Talley et al.

    Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the Bond and Opera studies)

    Alimentary Pharmacology and Therapeutics

    (1998)
  • W.M. Wong et al.

    Double blind, randomised, placebo controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients

    Gut

    (2002)
  • P. Moayyedi et al.

    Eradication of Helicobacter pylori for non-ulcer dyspepsia [update of Cochrane Database Syst Rev. 2001;(1):CD002096; PMID: 11279751]

    Cochrane Database of Systematic Reviews

    (2003)
  • M. Sjolund et al.

    Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori

    Annals of Internal Medicine

    (2003)
  • N. Vakil

    Gastroesophageal reflux disease and Helicobacter pylori infection

    Rev Gastroenterol Disord

    (2003)
  • J. Gilvarry et al.

    Eradication of Helicobacter pylori affects symptoms in non-ulcer dyspepsia [comment]

    Scandinavian Journal of Gastroenterology

    (1997)
  • N.J. Talley et al.

    Lack of association between gastric emptying of solids and symptoms in nonulcer dyspepsia

    Journal of Clinical Gastroenterology

    (1989)
  • R. Jian et al.

    Symptomatic, radionuclide and therapeutic assessment of chronic idiopathic dyspepsia. A double-blind placebo-controlled evaluation of cisapride

    Digestive Diseases and Sciences

    (1989)
  • L.P. Duan et al.

    A study of gastric emptying in non-ulcer dyspepsia using a new ultrasonographic method

    Scandinavian Journal of Gastroenterology

    (1993)
  • S.K. Sarin et al.

    Clinical trial on the effect of domperidone on non-ulcer dyspepsia

    Indian Journal of Medical Research

    (1986)
  • H.P. Parkman et al.

    Effect of gastric acid suppressants on human gastric motility

    Gut

    (1998)
  • L.R. Wiseman et al.

    Cisapride. An updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders

    Drugs

    (1994)
  • D.K. Wysowski et al.

    Cisapride and fatal arrhythmia

    New England Journal of Medicine

    (1996)
  • M. Orihata et al.

    Contractile mechanisms of action of gastroprokinetic agents: cisapride, metoclopramide, and domperidone

    American Journal of Physiology

    (1994)
  • G. Holtmann et al.

    Functional dyspepsia. Current treatment recommendations

    Drugs

    (1993)
  • M.L. Orme et al.

    Metoclopramide and tardive dyskinesia in the elderly

    British Medical Journal Clinical Research Edition

    (1984)
  • M. Alizadeh-Naeeni et al.

    Effect of Helicobacter pylori eradication or of ranitidine plus metoclopramide on Helicobacter pylori-positive functional dyspepsia. A randomized, controlled follow-up study

    Digestion

    (2002)
  • D.L. Dumitrascu et al.

    The effect of metoclopramide on antral emptying of a semisolid meal in patients with functional dyspepsia. A randomized placebo controlled sonographic study

    Romanian Journal of Internal Medicine

    (1998)
  • I. Fumagalli et al.

    Cisapride versus metoclopramide in the treatment of functional dyspepsia. A double-blind comparative trial

    Scandinavian Journal of Gastroenterology

    (1994)
  • A. Archimandritis et al.

    Cisapride, metoclopramide, and ranitidine in the treatment of severe nonulcer dyspepsia

    Clinical Therapeutics

    (1992)
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