Efficacy and Safety of Serotonin Receptor Ligands in the Treatment of Irritable Bowel Syndrome: A Review.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. OBJECTIVE: This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. RESULTS AND CONCLUSION: We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

[Levosulpiride in the management of functional dyspepsia and delayed gastric emptying]. / Levosulpirida en el manejo de la dispepsia funcional y la gastroparesia.

Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: 1) as a D(2) dopamine receptor antagonist and 2) as a serotonin 5HT(4) receptor agonist, conferring this drug with a cholinergic effect. At a dosage of 25mg three times daily, levosulpiride accelerates gastric and gallbladder emptying. Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia, while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists. The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists. Therefore, this drug is a useful therapeutic option in the management of patients with functional dyspepsia, as well as in those with delayed gastric emptying.

An aqueous extract of Poncirus fructus activates the prokinetic activity of 5-HT receptor subtype 4 without hERG interaction.

AIM OF THE STUDY: Poncirus fructus (PF)--also known as the dried, immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae)--is a natural substance that has long been used for various gastrointestinal disorders in eastern Asia. An aqueous extract of PF (PF-W) has particularly potent gastroprokinetic effects, but its molecular mechanism was not well understood. Identification of the underlying prokinetic mechanism of PF-W was pursued in the present study. MATERIALS AND METHODS: Changes in in vitro cAMP levels and in vivo intestinal transit rate (ITR) caused by PF-W were measured after pretreatment with GR125487, an antagonist for serotonin receptor subtype 4 (5-HT4R). An [(3)H] astemizole binding assay and electrophysiology experiments were performed to determine if PF-W has any interaction with the human ether-à-go-go related gene (hERG) potassium channel. RESULTS: PF-W induced an increase in intracellular cAMP in 5-HT4R-expressing HEK293T cells, indicating that PF-W does activate 5-HT4R. Moreover, pretreatment with GR125487 successfully blocked the increase, suggesting that the response was 5-HT4R-specific. More importantly, pretreatment of GR125487 in rats inhibited the elevation of ITR by PF-W, indicating that the prokinetic effect of PF-W was indeed exerted via 5-HT4R. On the other hand, both [(3)H]-astemizole binding assay and electrophysiological experiments revealed that PF-W did not interfere at all with the hERG channel. CONCLUSION: It was found that PF-W exerts its prokinetic activity through a 5-HT4R-mediated pathway, with no interaction with hERG channels. Therefore, PF-W is a good candidate that might be developed as a prokinetic agent with fewer expected cardiac side effects.