Serotoninergic neuroenteric modulators

Irritable bowel syndrome (IBS) is common and can be disabling. Several drug s that modulate serotonin (5HT) and other neurotransmitters In the gut (neu roenteric modulators) have either become available or are in development, b ut progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, Increases fluid absorption and Increases left colon compl iance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but no t 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 unexpec tedly was associated with Ischaemic colitis and, very rarely, severe consti pation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation re sults In accelerated colonic transit, and tegaserod, a partial 5HT(4) recep tor agonist, has modest but clinically significant advantage over placebo i n 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 modula tors 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 b etter defined.