• IRRITABLE BOWEL SYNDROME
• SEROTONIN
• PHARMACOTHERAPY
• CLINICAL TRIALS
• DIARRHOEA

While drug development for chronic constipation and IBS with constipation has moved ahead with the marketing of prucalopride and linaclotide in many countries, the development of agents for functional diarrhoea and IBS-D has been more troubled. With the limited availability of the serotonin (5-HT)3 antagonist alosetron, the global market of drugs for diarrhoeal disorders is still led by agents developed 40–60 years ago, including opioid receptor agonists (eg, loperamide), bile acid binders (eg, cholestyramine) and tricyclic antidepressants (eg, amitriptyline). Clearly, the development of new effective and safe drugs for diarrhoeal disorders is greatly needed to provide more options for patients and physicians, higher efficacy and fewer side effects. The problem is of great relevance as diarrhoea is the second leading gastrointestinal symptom after abdominal pain prompting an outpatient clinic visit in the USA. IBS-D affects about 3% of the general population and accounts for approximately 20% of gastroenterology outpatient visits in Europe.1 ,2

The understanding of basic mechanisms underlying IBS-D pathophysiology advanced enormously in recent years. Appreciation of the importance of host–microbiota interactions, epithelial barrier alterations, low-grade immune activation and 5-HT metabolism together with the revival of bile acid malabsorption provides cautious enthusiasm for future drug development for functional diarrhoeal disorders.3 Basic and clinical aspects of the pharmacological modulation of 5-HT receptors continue to generate great interest among scientists and the pharmaceutical industry alike. A meta-analysis of 4440 patients showed the benefit of the 5-HT3 antagonists alosetron and cilansetron in non-constipated IBS, …