prucalopride and alosetron

Topics: Antidepressive Agents; Benzofurans; Carbazoles; Carbolines; Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Physical Examination; Pyridines

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 Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias.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.

Topics: Antidepressive Agents; Benzofurans; Carbolines; Cisapride; Constipation; Drug Industry; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.

Topics: Benzofurans; Carbolines; Clinical Trials as Topic; Colonic Diseases, Functional; Female; Humans; Indoles; Male; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain

Topics: Benzofurans; Carbolines; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Guanidines; Humans; Indoles; Male; Serotonin Antagonists