Emerging Pharmacological Therapies for the Irritable Bowel Syndrome




The irritable bowel syndrome (IBS) is a symptom-based disorder defined by the presence of abdominal pain and altered bowel habits. Clinical presentations of IBS are diverse, with some patients reporting diarrhea, some constipation, and others a mixture of both. Like the varied clinical phenotypes, the pathogenesis of IBS is also diverse. IBS is not a single disease entity, but rather likely consists of several different disease states. This fact has important implications for the choices and efficacy of IBS treatment. This article reviews the IBS drugs that have reached phase II or III clinical trials.


The irritable bowel syndrome (IBS) is a symptom-based disorder defined by the presence of abdominal pain and altered bowel habits. Clinical presentations of IBS are diverse, with some patients reporting diarrhea, some constipation, and others a mixture of both. Like the varied clinical phenotypes, the pathogenesis of IBS is also diverse. IBS is not a single disease entity, but rather likely consists of several different disease states. This fact has important implications for the choices and efficacy of IBS treatment.


Traditional IBS therapies, such as fiber, antidiarrheals, laxatives, and antispasmodics, have tended to focus on individual symptoms, such as abdominal pain, stool frequency, or stool consistency. Recent drug development has attempted to take better advantage of the increasing understanding of the pathogenesis of IBS, and therefore more comprehensively addresses the spectrum of symptoms reported by patients. Drugs such as alosetron, tegaserod, and lubiprostone represent the initial attempts. This article reviews the IBS drugs that have reached phase II or III clinical trials ( Table 1 ).



Table 1

Emerging therapies for irritable bowel syndrome











































































Drug Class Name Mechanism of Action Treatment Effects
IBS-C
Serotonin receptor modulator Prucalopride, mosapride, pumosetrag 5-HT 4 and 5-HT 3 agonists accelerate gastrointestinal transit and may alter visceral sensation Prucalopride: Three phase III trials in CC showed benefits for stool frequency and other constipation-related symptoms at doses of 2 and 4 mg
Mosapride: Phase III trial completed enrollment in the Middle East
Pumosetrag: Phase II trial, dose-escalation study in 14 patients with CC showed improvements in constipation symptoms and colonic transit
Guanylate cyclase C receptor agonists Linaclotide, plecanatide (SP-304) Guanylate cyclase C agonist: Stimulates luminal chloride secretion with passive diffusion of sodium and water and secondary effects on peristalsis Linaclotide: Phase III trials in IBS-C showed that linaclotide (266 μg once daily) for up to 26 weeks was superior to placebo for a composite responder end point encompassing abdominal pain and stool frequency, and multiple secondary constipation-related end points
Plecanatide: Phase IIa study in patients with CC improved constipation symptoms
Bile acid modulators Chenodeoxycholic acid (CDA), A3309 A3309 (intestinal bile acid transporter inhibitor):
Bile acids accelerate colonic transit time, increase motility index, and increase secretion
CDA: Accelerated colon transit but up to 45% of patients developed abdominal cramps/pain
A3309: Phase IIb trial of A3309, 5, 10, and 15 mg/d, once daily showed dose-dependent effects on stool frequency and other constipation-related secondary outcomes
Dopaminergic antagonist Itopride Dopaminergic antagonist leads to prokinetic effects Phase II trial evaluating efficacy of itopride (50 and 100 mg) has been completed; results have not been reported
IBS-D or nonconstipated IBS
κ-opioid receptor agonist Asimadoline Activates opioid receptors, which may reduce visceral perception Phase II study showed no overall effect in IBS but efficacy was shown in IBS-D with at least moderate severity and, to a lesser extent, in IBS-A
Carbon-based adsorbent AST-120 Adsorbs luminal substances, including serotonin and bile acids Phase II trials showed that AST-120 was associated with a greater proportion of responders (percentage of patients reporting ≥50% reduction in days with pain) and greater reduction in bloating severity than placebo after 4 weeks
Proanthocyanidin oligomer Crofelemer Reduces chloride ion secretion through CFTR and CaCC channels Phase IIa showed that patients with IBS-D, particularly women, had more pain- and discomfort-free days, but no effect was seen on stool consistency or other IBS symptoms
CRF antagonists Pexacerfont, GW876008 Blocks CRF 1 receptors to decrease gastrointestinal motility and visceral sensitivity Phase IIa study showed no significant effect on gastrointestinal transit or IBS symptoms
An initial clinical trial with GW876008 suggests that this drug is not effective in IBS, although the study may not have been appropriately designed to evaluate this effect
2,3-Benzodiazepine modulator Dextofisopam Modulates autonomic responses Phase IIb study showed significant benefit in patients with IBS-D/A in the first month of treatment, but less benefit in second and third months
Tryptophan hydroxylase-1 inhibitor LX1031 Reduces gastrointestinal levels of serotonin Phase II trial showed that higher dose of LAX1031 (1000 mg qid) significantly improved global IBS symptoms and stool consistency over a 4-week period in nonconstipating IBS
Symptom improvement correlated with 24-hour urinary 5-HIAA levels
5HT 3 antagonist Ramosetron Blocks 5-HT 3 receptors to slow gastrointestinal transit and decrease visceral perception Phase II trial showed significantly a higher proportion of responders reported global relief of IBS with ramosetron, 5 and 10 μg, versus placebo
Abdominal pain
Glucagon-like peptide-1 (GLP-1) analogue ROSE-010 Inhibits small intestinal motility A significantly higher proportion of patients reported >50% of the maximum total pain relief response after 100 and 300 μg of ROSE-010 treatments than after placebo

Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT 3 , serotonin type 3 receptor; 5-HT 4 , serotonin type 4 receptor; CaCC, calcium-activated chloride channel; CFTR, cystic fibrosis transmembrane conductance regulator channel; CRF, corticotropin-releasing factor; IBS, irritable bowel syndrome; IBS-A, irritable bowel syndrome with alternating bowel habits; IBS-D, irritable bowel syndrome with diarrhea; κ-opioid, kappa opioid.


Emerging therapies for constipation-predominant IBS


The overlap between constipation-predominant IBS (IBS-C) and chronic constipation (CC), both in terms of pathophysiology and clinical presentation, is well established. This overlap undoubtedly contributes to why most drugs being developed for IBS-C are being codeveloped for CC. This section focuses on candidate drugs that have advanced to phase II or III of clinical development for patients with IBS-C or CC.


Serotonin Receptor Modulators


Serotonin (5-HT) plays an important role in gastrointestinal motility, intestinal secretion, and visceral sensation, and therefore modulation of 5-HT is an attractive target for drug development in patients with IBS-C and CC. In normal subjects, 90% to 95% of the body’s 5-HT is stored in enterochromaffin cells, which line the gastrointestinal tract. Mechanical stimulation (ie, mucosal stroking from luminal contents) is a potent stimulus for enterochromaffin cells to release 5-HT into the intestinal lumen, where it stimulates primary neurons to initiate peristalsis and secretory reflexes. To date, seven families with 14 serotonin receptor subtypes have been identified. Of these receptor subtypes, 5-HT 1p , 5-HT 3 , and 5-HT 4 have the greatest evidence supporting a role in gastrointestinal and colonic function and sensation.


Of great relevance to IBS-C and CC are the 5-HT 4 receptors. 5-HT 4 receptors can be found in the central nervous system, gastrointestinal tract, heart, and bladder. In the gastrointestinal tract, 5-HT 4 receptors are found on enteric neurons and smooth muscle cells, and their stimulation leads to acetylcholine release causing prokinetic effects. Several 5-HT 4 agonists have been developed as potential treatments for patients with IBS-C and CC. Based on biochemical structure, 5-HT 4 agonists can be broadly categorized as benzamides (metoclopramide, cisapride, renzapride, mosapride, clebopride, and ATI-7505), carbazimidamides (tegaserod), benzofurancarboxamides (prucalopride), and other agonists such as velusetrag. 5-HT 4 agonists vary greatly in their affinity and selectivity for the 5-HT 4 receptor. Cisapride, a strong 5-HT 4 agonist and weak 5-HT 3 antagonist, and tegaserod, a partial 5-HT 4 agonist, were once available in the United States, but were removed from the market because of different and distinct cardiovascular safety concerns. 5-HT 3 agonists are another interesting class of serotonin modulators with potential application in patients with IBS-C.


5-HT 4 agonists


Prucalopride


Prucalopride is more selective for the 5-HT 4 receptor than cisapride or tegaserod. Although all three agents have affinity for the 5-HT 4 receptor and are similar in their prokinetic properties, cisapride and tegaserod interact with both human Ether-á-go-go-Related Gene potassium and 5-HT 1b channels, which are both postulated to be responsible for the development of adverse cardiovascular effects. Thus, prucalopride’s unique chemical structure is hypothesized to limit the development of these events.


Prucalopride’s prokinetic activity has been confirmed in animals and humans. In a placebo-controlled study in healthy volunteers, prucalopride accelerated total intestinal transit time and overall colonic transit time, particularly in the proximal colon.


Clinical trials with prucalopride have focused on patients with CC. In the first of three large, multicenter, randomized, double-blind, placebo-controlled studies evaluating the safety and efficacy of prucalopride, Camilleri and colleagues enrolled 620 patients who met criteria for CC. Participants were randomized to oral placebo or 2 or 4 mg once daily, of prucalopride for 12 weeks. The primary end point was the proportion of patients passing an average of three or more spontaneous complete bowel movements (SCBMs) per week during the 12 weeks of treatment. Various secondary end points were also assessed, including responses to the validated Patient Assessments of Constipation Symptoms (PAC-SYM) and Quality of Life (PAC-QOL) surveys. Statistically significant improvements in the primary end point were identified, with 28.4%, 30.9%, and 12.0% of patients taking 4 mg of prucalopride, 2 mg of prucalopride, or placebo, respectively, achieving the primary end point. Significant changes were also apparent in multiple secondary end points, including PAC-SYM and PAC-QOL scores. The most common adverse events were headaches, abdominal pain, and diarrhea, with most occurring within the first 24 hours of treatment. One cardiovascular event occurred, involving an episode of supraventricular tachycardia in a patient with a history of mitral valve prolapse and supraventricular tachycardia who took 2 mg of prucalopride. No significant differences in electrocardiographic findings were seen among the three groups and no deaths were reported.


Two additional phase III trials have been published (N = 713 patients, 641 with CC) using the same inclusion and exclusion criteria, trial design, and primary end point. Both showed a 10% to 14% improvement in the primary end point in patients receiving prucalopride compared with those taking placebo. Side effects were similar in nature and frequency to those seen in the Camilleri study. More patients who received prucalopride, 4 mg, discontinued treatment because of the drug than those receiving 2 mg or placebo. No differences were seen in hematologic changes, clinical chemistry, urinalysis, vital signs, or electrocardiogram parameters across the study groups. A prolonged QT interval was identified in 0.5% to 1.5% of patients at 12 weeks among the three trials, with no differences identified between the placebo and prucalopride groups.


Recently, Camilleri and colleagues presented data from a study assessing the safety of prucalopride compared with placebo in 89 elderly patients with a mean age of 82 years, 80% of whom had a prior history of cardiovascular disease. No differences in proarrhythmic effects or prolonged QTc intervals were identified between groups. Based on these studies, the European Medicines Agency approved prucalopride as a treatment for CC. Appropriately designed and powered studies evaluating the efficacy and safety of prucalopride in patients with IBS-C are eagerly awaited.


Mosapride


Mosapride is a selective 5-HT 4 receptor agonist that has documented stimulatory effects on gastric and colonic motility. Unlike cisapride, mosapride does not bind to K + channels or D 2 dopaminergic receptors. Mosapride was primarily developed for upper gastrointestinal tract conditions, such as functional dyspepsia, gastroesophageal reflux disease, and nausea and vomiting and is available for these indications in several countries in Central and South America, Europe, and the Far East. Pharmacodynamic studies in animals have shown that mosapride accelerates colonic transit time and augments motility in the proximal and distal colon in a dose-dependent manner. Furthermore, Kojima and colleagues showed the stimulatory effect of mosapride on the defecatory reflex (intrinsic rectorectal contraction and rectoanal sphincter relaxation) post denervated lumbosacral plexus in guinea pigs.


No fully published studies have addressed the role of mosapride in the treatment of IBS-C or idiopathic CC. In 14 constipated patients with Parkinsonism or multiple system atrophy, mosapride, 15 mg/d, for 3 months significantly accelerated colonic transit time by radio-opaque marker testing, blunted first sensation of rectal filling, increased the amplitude of rectal contractions, and decreased postdefecation residuals on video anorectal manometry. Mosapride also led to clinical improvements in bowel movement frequency and difficulty with defecation. Another study found that 8 weeks of mosapride, 15 mg/d, improved the frequency of bowel movements in 20 patients with diabetes experiencing constipation.


Mosapride is generally well tolerated. Side effects include diarrhea, dry mouth, and headache. No QT abnormalities have been reported in association with mosapride treatment. However, a single case of torsades de pointes was reported in a patient who had hypokalemia and was prescribed mosapride along with flecainine.


A randomized, placebo-controlled phase III trial evaluating mosapride, 5 mg, three times daily for 8 weeks recently completed enrollment in the Middle East, and results are awaited.


Partial 5-HT 3 agonist


Pumosetrag (MKC-733, DDP-733)


Pumosetrag is a potent, partial 5-HT 3 agonist with prokinetic effects in animals and humans. Three phase I trials (n = 40) have evaluated pumosetrag’s pharmacodynamic effects on gastrointestinal transit and have attempted to identify an appropriate dose in humans. In a small, double-blind, crossover study conducted in healthy volunteers, pumosetrag (0.2, 1, and 4 mg) stimulated fasting antroduodenal migrating motor activity and delayed the gastric emptying of liquids but accelerated small bowel transit.


Similar results were shown using echo planar MRI, in which 12 volunteers receiving pumosetrag developed slowing of gastric emptying and acceleration of small bowel transit. A single-blind, dose-escalation study in which 14 constipated subjects sequentially received placebo (1 week) followed by pumosetrag, 0.2 and 0.5 mg, twice daily (2 weeks each), showed increases in stool frequency and improvements in straining, sensation of incomplete evacuation, and stool consistency among patients treated with pumosetrag. Only pumosetrag, 0.5 mg, twice daily increased the elimination of radio-opaque markers, demonstrating its effects on colonic transit.


The most common side effects with pumosetrag across all studies were flushing, nausea, diarrhea, headache, and anorexia. Mild, transient liver enzymes elevations were also reported, but no subjects were withdrawn from the study, nor were changes in QT interval reported. Whether further studies to evaluate pumosetrag in patients with IBS-C or CC are planned is unclear.


Guanylate Cyclase-C Receptor Agonists


The family of guanylin peptides comprise four members: guanylin, uroguanylin, lymphoguanylin, and renoguanylin. They have similar structure to the heat-stable enterotoxin produced by Escherichia coli and other enteric bacteria that cause secretory diarrhea.


These peptides, particularly guanylin and uroguanylin, have the conformation to bind with guanylate cyclase-C (GC-C) receptors, which are abundantly found on enterocytes lining the intestine. Binding of GC-C receptors stimulates production of cyclic guanosine monophosphate, which triggers a cascade of intracellular events, including activation of the cystic fibrosis transmembrane conductance regulator channel. This function results in transepithelial chloride (Cl ) and potassium (K ) ion efflux from enterocytes, with secondary passive water secretion into the intestinal lumen.


Linaclotide (MD-1100)


Linaclotide is a synthetic 14–amino acid peptide that avidly binds GC-C receptors. Linaclotide is believed to act locally, because systemic levels are not detectable after oral dosing. In mice, linaclotide stimulated intestinal electrolyte and fluid secretion and accelerated gastrointestinal transit time. Of potential relevance to IBS, recent work has shown that linaclotide reduced or abolished visceral hyperalgesic responses through GC-C dependent activation in several different stress models: colorectal distension, water avoidance, acute partial restraint, and TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis. Although the degree of attenuation in hyperalgesia varied among the different models, these results raise some interesting questions about linaclotide’s potential usefulness for treating pain associated with IBS.


Clinical studies have investigated linaclotide in patients with IBS-C and CC. In a phase IIa study of 36 women with IBS-C, a 5-day course of linaclotide, 1000 μg, but not 100 μg, significantly accelerated ascending colon ( P = .004) and total colonic transit time at 48 hours ( P = .01) measured by a validated scintigraphy protocol. Linaclotide at either dose had no effect on gastric emptying or small bowel transit time. Linaclotide accelerated the time to first bowel movement, decreased stool consistency, and enhanced ease of stool passage. In a double-blind, placebo-controlled pilot study in 42 chronic constipation patients, linaclotide, 100, 300, or 1000 μg, once daily for 14 days improved stool consistency, stool frequency, and ease of stool passage. The clinical benefits of linaclotide were seen at all doses, with some degree of dose-dependence (except for ease of stool passage, which was effective only at the 300 and 1000 μg doses).


Recently, Lembo and colleagues reported results from a methodologically rigorous randomized, double-blind, placebo-controlled phase IIb trial in 310 patients with chronic constipation assessing the efficacy and safety of four dosages of linaclotide (75, 150, 300, and 600 μg/d). Linaclotide improved the primary end point of weekly spontaneous bowel movements (SBMs) and various other constipation-related clinical parameters, including stool consistency and straining in a dose-dependent fashion (not including the 75 μg/d dosage for straining and CSBM rate). In addition, patients treated with linaclotide experienced improvements in abdominal discomfort, bloating, and constipation severity. Linaclotide significantly improved disease-related quality of life (PAC-QOL) compared with placebo. Constipation symptoms tended to return to baseline, without evidence of a rebound, after discontinuation of linaclotide.


The overall frequency of adverse events reported with linaclotide and placebo were similar, with diarrhea the most common adverse event reported with linaclotide. In most cases, the diarrhea was mild to moderate in severity, occurred within the first week of therapy, and resolved without specific intervention. Although more patients treated with linaclotide discontinued trial participation because of diarrhea than those treated with placebo, there were no reports of dehydration or electrolyte imbalance.


The results of the phase IIb trial were confirmed by two recently presented phase III clinical trials that randomized more than 1200 patients with CC to linaclotide, 133 μg or 266 μg, or placebo once daily for 12 weeks. Of great relevance to IBS-C, a separate pair of phase III clinical trials that randomized more than 1600 patients with IBS-C also reported benefits for constipation-related complaints and abdominal pain with linaclotide, 266 μg, versus placebo for up to 26 weeks. These studies showed that linaclotide significantly improved several prespecified primary end points, including a composite responder end point encompassing abdominal pain and CSBMs, and individual responder end points for abdominal pain and CSBMs ( P <.0001). Linaclotide also significantly improved all prespecified secondary end points, including abdominal pain, abdominal discomfort, bloating, and bowel symptoms ( P <.001). Based on these promising results, a new drug application for the indications of IBS-C and CC is expected to be submitted to the U.S. Food and Drug Administration (FDA) in the near future.


Plecanatide (SP-304)


Plecanatide is an orally administered, synthetic analog of uroguanylin that, like linaclotide, is a GC-C agonist. A distinct characteristic of uroguanylin is that it seems to work most effectively in acidic regions of the intestine, including the proximal duodenum, which is exposed to acidic gastric effluent, and the cecum, in which bacterial fermentation occurs. The structure of plecanatide contains an NDE terminus that retains pH modulation capability. The pharmacologic and clinical relevance of this finding requires further elucidation.


A phase I, double-blind, placebo-controlled trial in healthy volunteers showed that plecanatide was well tolerated in the range of dosages tested, with little systemic absorption. Data from a recently completed phase IIa study showed that oral plecanatide given at dosages of 0.3, 1.0, 3.0, and 9.0 mg once daily for 14 days improved stool frequency, straining, and abdominal discomfort in patients with chronic constipation. Plecanatide treatment was associated with no severe adverse events and, somewhat surprisingly, no patients reported diarrhea. Additionally, no systemic absorption of plecanatide was detected at any of the dose levels studied. The status of plecanatide as a treatment for IBS-C is currently unknown.


Bile Acid Modulators


Bile acids have long been known to alter gut motility and secretion. Hydrophobic primary bile acids, including chenodeoxycholic acid (CDCA) and cholic acid, are derived from cholesterol through hepatic hydroxylation and conjugation, and enter the small intestine though the biliary tract. These primary bile acids are modified by intestinal commensal bacteria to become hydrophilic, secondary bile acids, including deoxycholic acid (DCA), lithocholic acid, and, to a lesser extent, ursodeoxycholic acid. Of all bile acids, 95% will eventually be reclaimed through active transport in the ileum and returned to the liver through the portal vein. Additionally, any bile acids that are not removed through active transport are subject to passive transport in the terminal ileum. Because of the efficiency of bile acid reclamation by the terminal ileum, only a small amount reaches the colon.


In the setting of bile acid–related diarrhea after ileal resection, high concentrations of bile acids decrease net colonic fluid and electrolyte absorption and induce secretion. This effect is inducible only if high concentrations (3–10 mM) of DCA and CDCA are present under optimal pH. Keating and colleagues recently showed that colonic epithelial chloride secretion could be acutely stimulated by a high concentration of DCA, but that chronic exposure to a low concentration of DCA inhibited colonic chloride secretion. Furthermore, instillation of bile acids directly into the colon increases intracolonic pressure and motility index and may have effects on defecatory function.


CDCA


Hepner and Hofmann conducted the first controlled trial to explore the effect of bile acids for constipation in 1973. The study reported that five of six participants experienced a greater laxative effect with cholic acid compared with bisacodyl or placebo. Ten years later, Bazzoli and colleagues reported on the benefits of CDCA for constipation in patients with cholesterol gallstones.


A more recent study in healthy volunteers showed that sodium chenodeoxycholate (CDC) at doses of 500 and 1000 mg significantly accelerated scintigraphically measured colonic transit compared with placebo. Dose-dependent differences from placebo were apparent at 24 hours ( P <.01) and even more pronounced at 48 hours ( P <.001). Acceleration of colon transit was accompanied by improvements in clinical outcomes, such as stool frequency, stool consistency, ease of stool passage, and sense of complete evacuation.


Rao and colleagues recently reported the main results from a study evaluating the effects of CDC on colonic transit and clinical parameters in women with IBS-C. CDC significantly accelerated overall colonic transit and improved clinical outcomes, including stool frequency and stool consistency, and facilitated the passage of stool. In contrast to colonic transit time, gastric emptying time was delayed in the CDC group compared with the placebo group. Furthermore, the investigators also found a correlation between fasting serum 7 alpha-hydroxy-4-cholesten-3-one (7αC 4 ), a biomarker of bile acid synthesis, and colonic transit time in the placebo group: subjects with an increased 7αC 4 showed a faster overall colonic transit time. In the CDC group, 7αC4 showed a modest influence on colonic transit at 24 hours ( P = .055) and 48 hours ( P = .019). In another study, serum concentrations of 7αC 4 were greater in patients with IBS-C and CC whose oroanal transit time was delayed than in those whose transit time was normal.


Gastrointestinal side effects were most common with CDC. Up to 45% of the CDC group reported development of lower abdominal cramping/pain, compared with none in the placebo group. Although not significantly different from placebo, larger numbers of patients in the CDC group reported diarrhea, nausea, gaseous sensation, and headache. Other issues that have been raised include the potential impact of bile acids on gut immune function and colonic neoplasia. In the dose range that has been tested, the side effect of abdominal cramping or pain may limit the practical application of CDC as a treatment for IBS-C.


Ileal bile acid transporter inhibitor: A3309


A3309 is a novel small molecule that inhibits ileal bile acid transporters. A3309 was initially evaluated for the treatment of dyslipidemia but is now being developed as a treatment of constipation and perhaps IBS-C. Through inhibiting bile acid reabsorption in the terminal ileum, A3309 leads to a greater delivery of bile acids to the right colon.


In a transgenic mouse model, oral A3309 showed a dose-dependent inhibitory effect on intestinal bile acid absorption and a dose-dependent reduction of plasma cholesterol. In a study using a meat-induced constipated dog model, A3309 (1.5, 5, 15, or 50 μmol/kg) or tegaserod (0.3, 1.0, 66 μmol/kg) dosed orally once daily for 3 days increased fecal output. In addition, A3309 led to higher levels of serum C 4 than placebo, reflecting an increase in bile acid synthesis.


A phase I/IIa study evaluating the effects of A3309 (0.1, 0.3, 1.0, 3.0 and 10 mg) versus placebo for 14 days in 30 patients with CC was recently reported. The higher dose of A3309 accelerated colonic transit, as measured with radio-opaque markers, and improved constipation complaints, including stool frequency and stool consistency. Adverse events were similar for the various dosages of A3309 and placebo.


Top-line data from a randomized, placebo-controlled phase IIb dose-range study in 190 patients with CC also recently became available. A3309 once daily at dosages of 5, 10, and 15 mg/d showed dose-dependent effects on the primary outcome of weekly SBMs and several other constipation-related secondary outcomes. The two higher doses were most effective. No serious adverse events were reported. Modest reductions in serum cholesterol level were also noted. Phase III clinical trials in patients with CC are expected in the near future. Whether A3309 will be developed as a therapy for IBS-C remains unclear.


Dopaminergic Antagonist: Itopride


Itopride is a dopamine D 2 antagonist and acetylcholinesterase inhibitor that was primarily developed to treat upper gastrointestinal tract conditions, such as gastroesophageal reflux disease, gastroparesis, and functional dyspepsia. Studies have suggested that itopride may impact lower gastrointestinal function. In a guinea pig model, itopride significantly accelerated the propagation velocity of ileal peristalsis and reduced colonic transit time. Similar results were found in conscious dogs and rats, in which Itopride dose-dependently stimulated small bowel and colonic motility. Itopride also triggered giant migrating contractions, which resulted in defecation in some dogs.


Generally, adverse effects of itopride have been mild. Studies in patients with functional dyspepsia showed that the most common adverse effects were abdominal pain, nausea, diarrhea, and constipation, which were not significantly different from those seen in the placebo group. A distinct side effect from itopride is dose-dependent elevation of serum prolactin level, although recently reported trials noted no clinical consequences from this laboratory change. No significant electrocardiographic changes, particularly in QT interval, were reported.


The efficacy of itopride (50 and 100 mg) is being investigated in a randomized, placebo-controlled study in patients with IBS-C.

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Sep 7, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Emerging Pharmacological Therapies for the Irritable Bowel Syndrome
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