A significant proportion of chronic constipation patients are dissatisfied with their treatment. Recently, a number of new medications have been introduced for patients refractory to conventional laxatives, such as prucalopride, lubiprostone, linaclotide, and elobixibat. Prucalopride is a novel gastrointestinal prokinetic agent that acts as a 5-hydroxytryptamine type 4 (5-HT4) agonist. Compared with older nonselective 5-HT4 agonists, the higher selectivity of prucalopride for 5-HT4 receptors can reduce the risk of significant adverse cardiovascular events. Prucalopride improves stool frequency and consistency, and reduces the need for rescue medications. Lubiprostone, a chloride channel activator, increases the secretion of intestinal fluid, improves the stool frequency and consistency, and reduces straining. Linaclotide, a guanylate cyclase-C agonist, is effective in treating patients with chronic constipation and its effect on visceral sensitivity, as shown mainly in animal studies, provides an attractive pharmaceutical option for patients with irritable bowel syndrome with constipation. Elobixibat is an ileal sodium-dependent bile acid transporter inhibitor that blocks the enterohepatic circulation of bile acids, increasing the bile acid concentration in the intestine, which accelerates colonic transit and softens the stool. A phase III trial of the treatment of chronic constipation and irritable bowel syndrome with constipation is underway. The clinical application of new-generation laxatives will contribute to the management of chronic constipation refractory to conventional laxatives.
Animals ; Bile ; Bile Acids and Salts ; Chloride Channels ; Colon ; Constipation ; Enterohepatic Circulation ; Humans ; Intestines ; Irritable Bowel Syndrome ; Laxatives* ; Receptors, Serotonin, 5-HT4 ; Serotonin ; Serotonin 5-HT4 Receptor Agonists ; Lubiprostone

BACKGROUND/AIMS: To compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC). METHODS: Data of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of > or = 3 spontaneous complete bowel movements (SCBMs)/week; average increases of > or = 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). RESULTS: Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of > or = 3 SCBMs/week in Asian (34% vs. 11%, P < 0.001) and non-Asian (24.6% vs. 10.6%, P < 0.001) subgroups. The number of patients reporting an increase of > or = 1 SCBMs/week from baseline was significantly higher in the prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups. CONCLUSIONS: Prucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improvement of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.
Abdominal Pain ; Asian Continental Ancestry Group* ; Constipation* ; Female ; Gastrointestinal Diseases ; Humans ; Serotonin ; Serotonin 5-HT4 Receptor Agonists

A number of studies have demonstrated that 5-hydroxytryptamine (5-HT) can induce muscle contraction or relaxation response and enhance secretion in the gastrointestinal tract via a multiplicity of 5-HT receptor subtypes. In the present study, we investigated the pharmacological characterization of the 5-HT-induced contractile response in longitudinal smooth muscle isolated from the feline ileum. Addition of 5-HT into muscle chambers enhanced the basal tone and spontaneous activity in a concentration-dependent manner. The neurotoxin tetrodotoxin did not alter the 5-HT-induced contraction of the longitudinal muscles. Neither atropine nor guanethidine affected the contraction. The 5-HT agonists, 5-methylserotonin hydrochloride and mosapride, also evoked concentration-dependent contractions. The 5-HT-induced contraction was enhanced by the 5HT2 receptor antagonist ketanserin and the 5-HT3 receptor antagonist ondansetron but was inhibited by the 5-HT1 receptor antagonist methysergide and 5-HT4 receptor antagonist GR113808. These results indicate that 5-HT1 and 5-HT4 receptors may mediate the contraction of the 5-HT-induced response and 5-HT2 and 5-HT3 receptors may mediate 5-HT-induced relaxation in feline ileal longitudinal smooth muscles.
Atropine ; Benzamides ; Contracts ; Gastrointestinal Tract ; Guanethidine ; Ileum ; Indoles ; Ketanserin ; Methysergide ; Morpholines ; Muscle Contraction ; Muscle, Smooth ; Muscles ; Ondansetron ; Receptors, Serotonin ; Receptors, Serotonin, 5-HT1 ; Receptors, Serotonin, 5-HT3 ; Receptors, Serotonin, 5-HT4 ; Relaxation ; Serotonin ; Serotonin Receptor Agonists ; Sulfonamides ; Tetrodotoxin

Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders. It is a multi-factorial disorder due to abnormal gastrointestinal motility, low-grade inflammation, visceral hypersensitivity, and communication between the gut-brain axis. IBS is traditionally treated with dietary and lifestyle modifications, fiber supplementation, and psychological and pharmacological therapies. Diet therapy including the low FODMAP diet and excluding certain food constituents is often used. Antispasmodics plus stool consistency modifiers to treat the major symptoms and defecation are first-line drug treatments. 5-Hydroxytryptamine (5-HT) receptors in the gastrointestinal tract, particularly 5-HT3 and 5-HT4 receptors are involved not only in modulating gut motility but in visceral sensory pathways. Drugs that act on both receptor classes appear to reduce visceral sensitivity and have inhibitory effects on motor activity in the distal intestine. 5-HT4 agonists may improve constipation-predominant IBS by normalizing bowel habits and thereby reduce abdominal pain. IBS continues to be a therapeutic challenge because of its diverse symptomatology and lack of a single pathophysiological target for drug intervention.
Abdominal Pain ; Axis, Cervical Vertebra ; Defecation ; Diet ; Diet Therapy ; Gastrointestinal Diseases ; Gastrointestinal Motility ; Gastrointestinal Tract ; Hypersensitivity ; Inflammation ; Intestines ; Irritable Bowel Syndrome* ; Korea ; Life Style ; Motor Activity ; Parasympatholytics ; Receptors, Serotonin, 5-HT4 ; Serotonin ; Serotonin 5-HT4 Receptor Agonists

Chronic constipation is a very common clinical problem with its prevalence of up to 14% in the general population. It is not a life-threatening disease, but since patient's satisfaction to the treatment is known to be as low as 50%, chronic constipation still remains a clinically challenging problem. Fortunately, many new treatments have been introduced or are to be introduced in the near future. This article will review the basic concepts and the results of recent studies on the new treatments for chronic constipation.
Chloride Channel Agonists/therapeutic use ; Chronic Disease ; Constipation/*drug therapy/epidemiology ; Humans ; Laxatives/*therapeutic use ; Polyethylene Glycols/therapeutic use ; Prevalence ; Probiotics/therapeutic use ; Serotonin 5-HT4 Receptor Agonists/therapeutic use

Irritable bowel syndrome is a group of symptoms that includes abdominal pain and changes in the form and frequency of stool. Since its symptoms are usually long-lasting, the disease significantly degrades quality of life. Several pharmacological therapies have been suggested according to the type of symptoms (e.g., abdominal pain, constipation, or diarrhea). In order to control abdominal pain, smooth muscle antispasmodics, antidepressants including tricyclic antidepressants and selective serotonin reuptake inhibitors, or 5-HT3 antagonists can be used. To improve constipation, dietary fiber or laxatives, 5-HT4 agonists, and chloride channel activators are available. Opioid agonists, mixed opioid agonists/antagonists such as eluxadoline, and bile salt sequestrants can be considered for diarrhea. In addition, probiotics and non-absorbable oral antibiotics can be used for the normalization of the gut microbiome and the treatment of small intestinal bacterial overgrowth, respectively. It is necessary to understand the characteristics of each drug and their combinations, because any single regimen cannot improve all symptoms in patients with irritable bowel syndrome. In this review, the mechanisms of action, efficacy, and adverse events associated with drugs used for irritable bowel syndrome are summarized.
Abdominal Pain ; Anti-Bacterial Agents ; Antidepressive Agents ; Antidepressive Agents, Tricyclic ; Bile ; Chloride Channel Agonists ; Constipation ; Diarrhea ; Dietary Fiber ; Drug Therapy* ; Gastrointestinal Microbiome ; Humans ; Irritable Bowel Syndrome* ; Laxatives ; Muscle, Smooth ; Parasympatholytics ; Probiotics ; Quality of Life ; Serotonin 5-HT3 Receptor Antagonists ; Serotonin 5-HT4 Receptor Agonists ; Serotonin Uptake Inhibitors

Irritable bowel syndrome is a group of symptoms that includes abdominal pain and changes in the form and frequency of stool. Since its symptoms are usually long-lasting, the disease significantly degrades quality of life. Several pharmacological therapies have been suggested according to the type of symptoms (e.g., abdominal pain, constipation, or diarrhea). In order to control abdominal pain, smooth muscle antispasmodics, antidepressants including tricyclic antidepressants and selective serotonin reuptake inhibitors, or 5-HT3 antagonists can be used. To improve constipation, dietary fiber or laxatives, 5-HT4 agonists, and chloride channel activators are available. Opioid agonists, mixed opioid agonists/antagonists such as eluxadoline, and bile salt sequestrants can be considered for diarrhea. In addition, probiotics and non-absorbable oral antibiotics can be used for the normalization of the gut microbiome and the treatment of small intestinal bacterial overgrowth, respectively. It is necessary to understand the characteristics of each drug and their combinations, because any single regimen cannot improve all symptoms in patients with irritable bowel syndrome. In this review, the mechanisms of action, efficacy, and adverse events associated with drugs used for irritable bowel syndrome are summarized.
Abdominal Pain ; Anti-Bacterial Agents ; Antidepressive Agents ; Antidepressive Agents, Tricyclic ; Bile ; Chloride Channel Agonists ; Constipation ; Diarrhea ; Dietary Fiber ; Drug Therapy* ; Gastrointestinal Microbiome ; Humans ; Irritable Bowel Syndrome* ; Laxatives ; Muscle, Smooth ; Parasympatholytics ; Probiotics ; Quality of Life ; Serotonin 5-HT3 Receptor Antagonists ; Serotonin 5-HT4 Receptor Agonists ; Serotonin Uptake Inhibitors

PURPOSE: Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. The aim of this study was to investigate the effects of different 5-hydroxytryptamine 4 (5-HT4) receptor agonists, which stimulate excitatory pathways, on a POI model. MATERIALS AND METHODS: The experimental model of POI in guinea pigs was created by laparotomy, gentle manipulation of the cecum for 60 seconds, and closure by suture, all under anesthesia. Different degrees of restoration of GI transit were measured by the migration of charcoal. Colonic transit was indirectly assessed via measurement of fecal pellet output every hour for 5 hours after administration of various doses of mosapride, tegaserod, prucalopride, and 5-HT. RESULTS: Charcoal transit assay showed that various 5-HT4 receptor agonists can accelerate delayed upper GI transit in a dose-dependent manner. However, fecal pellet output assay suggested that only prucalopride had a significant effect in accelerating colonic motility in POI. CONCLUSION: Although mosapride, tegaserod, and prucalopride produce beneficial effects to hasten upper GI transit in the POI model, prucalopride administered orally restores lower GI transit as well as upper GI transit after operation in a conscious guinea pig. This drug may serve as a useful candidate for examination in a clinical trial for POI.
Administration, Oral ; Animals ; Benzamides/pharmacology ; Benzofurans/administration & dosage/*pharmacology ; Charcoal/pharmacokinetics ; Colon/drug effects ; Dose-Response Relationship, Drug ; Gastrointestinal Motility/*drug effects ; Guinea Pigs ; Ileus/*surgery ; Indoles/pharmacology ; Laparotomy ; Male ; Morpholines/pharmacology ; Postoperative Complications/drug therapy ; Serotonin/pharmacology ; Serotonin 5-HT4 Receptor Agonists/*pharmacology

Traditional symptom-based therapies of irritable bowel syndrome (IBS) are directed at the relief of individual IBS symptoms, but they are often of limited efficacy in addressing the entire symptom complex. Combinations of drugs to target bothersome symptoms are suggested as the first-line pharmacologic treatment. Increasing knowledge of the pathophysiology and molecular mechanisms of IBS has resulted in the development of several new therapeutic approaches. Thirteen consensus statements for the treatment of IBS were developed using the modified Delphi approach. Exclusion diets have modest efficacy in improving symptoms in some IBS patients. Symptom-based therapies with dietary fiber, bulking agents, laxatives, antispasmodics and laxatives are effective in the improvement of some individual symptoms, e.g. dietary fiber and bulking agents for constipation, laxatives for constipation, antispasmodics for abdominal pain and discomfort, antidiarrheals for diarrhea. 5HT3 receptor antagonists and 5HT4 receptor agonists are effective in the relief of global IBS symptoms and individual symptoms such as abdominal pain and abnormal bowel habits. A short term course of nonabsorbable antibiotics may improve global IBS symptoms, particularly in patients with diarrhea- predominant IBS. Some probiotics appear to have the potential benefit in improving global IBS symptoms. Selective C-2 chloride channel activator is more effective than placebo at relieving global IBS symptoms in patients with constipation-predominant IBS. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are equally effective in relieving global IBS symptoms, and have some benefits in treating abdominal pain. Certain types of psychologic therapy may be effective in improving global symptoms in some IBS patients. Further studies are strongly needed to develop better treatment strategies for Korean patients with IBS.
Anti-Infective Agents/therapeutic use ; Antidepressive Agents/therapeutic use ; Antidiarrheals/therapeutic use ; Dietary Fiber/therapeutic use ; Humans ; Irritable Bowel Syndrome/*therapy ; Laxatives/therapeutic use ; Parasympatholytics/therapeutic use ; Probiotics/therapeutic use ; Serotonin 5-HT4 Receptor Agonists/therapeutic use ; Serotonin Antagonists/therapeutic use