Pharmacological treatment of irritable bowel syndrome--from concept to sales.
Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.
Kamm
Michael A
MA
Physiology Unit, St Mark's Hospital, London, UK. kamm@ic.ac.uk
D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use; D002243:Carbolines / Q000009:adverse effects / Q000627:therapeutic use; D020117:Cisapride / Q000009:adverse effects / Q000627:therapeutic use; D003248:Constipation / Q000139:chemically induced; D004345:Drug Industry / Q000191:economics; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000191:economics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000191:economics; D058831:Serotonin 5-HT3 Receptor Antagonists; D058828:Serotonin 5-HT4 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
D000928:Antidepressive Agents; D001572:Benzofurans; D002243:Carbolines; D005765:Gastrointestinal Agents; D007211:Indoles; D058831:Serotonin 5-HT3 Receptor Antagonists; D058828:Serotonin 5-HT4 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C406662:prucalopride; C090840:alosetron; C105050:tegaserod; D020117:Cisapride