irritable bowel syndrome ( ibs ) is a functional disease with persisting gastrointestinal symptoms , mainly abdominal pain / discomfort and abnormal defecation , not accompanied by an organic disease.1 the cause of ibs is unknown , but a number of factors are thought to play a role , such as altered gastrointestinal motility , increased sensitivity of the gut , psychosocial factors , and neurotransmitter imbalances.2 according to the rome iii criteria,1 ibs is classified into four subtypes : diarrhea - predominant ibs ( ibs - d ) , constipation - predominant ibs , mixed ibs , and unsubtyped ibs .
therapies for the treatment of ibs should therefore be targeted at improving symptoms that diminish quality of life . a number of new agents with a wide range of modes of action are currently in clinical development.3,4 ramosetron , a potent and selective serotonin ( 5-hydroxytryptamine [ 5-ht])3-receptor antagonist58 has been used as a medication for gastrointestinal symptoms caused by antitumor agents , and it is also in development for use in patients suffering from ibs - d . in this article
, we review the long - term efficacy and safety of ramosetron in the treatment of patients with ibs - d .
5-ht plays important physiological roles in the contraction and relaxation of smooth muscle , platelet aggregation , and neurotransmission .
receptors mediating the actions of 5-ht are classified into seven major groups , termed 5-ht1 to 5-ht7 , which include a total of 14 receptor subtypes.9 it is well known that colonic pain signals are transmitted to the spinal cord via primary nociceptive afferent neurons , and various neurotransmitters , eg , glutamate , substance p , neurotrophins , and 5-ht , are involved in the process . among them , 5-ht is considered one of the most important neurotransmitters of visceral nociception .
intraluminal distension of the intestine , which causes abdominal pain , is known to stimulate the release of endogenous 5-ht from enterochromaffin cells , activating 5-ht3 receptors located on primary afferent neurons.10 the activation of 5-ht3 receptors stimulates the release of various neurotransmitters , such as acetylcholine , to induce the acceleration of colonic transit11 and abnormal water transport,12 which in turn leads to defecation abnormalities .
furthermore , it has been reported that selective 5-ht3-receptor antagonists suppress abdominal pain induced by colonic distension , suggesting that 5-ht3 receptors are involved in visceral nociceptive transmission.13 it has been reported that 5-ht3 receptors are widely distributed within the neurons of the gastrointestinal tract , as well as in the spinal cord and brain,9 and activation of gastrointestinal 5-ht3 receptors results in intestinal secretion and peristaltic activity.14,15 the 5-ht3 receptor is unique among the various 5-ht - receptor subtypes .
it is a ligand - gated cation channel that belongs to the nicotine/-aminobutyric acid - receptor superfamily , while all other 5-ht - receptor subtypes belong to the family of g - protein - coupled receptors.9 the neurotransmitter 5-ht has received much attention as one of the factors contributing to ibs pathogenesis .
furthermore , 5-ht3-receptor antagonists have been reported to normalize defecation and to increase the perceptual threshold of the colon,16,17 suggesting the involvement of 5-ht3 receptors in the pathogenesis of ibs . in clinical settings , opioid - receptor agonists ( eg , loperamide and trimebutine ) , muscarinic receptor antagonists ( eg , tiquizium ) , and synthetic polymers (
eg , polycarbophil calcium ) are used widely for the treatment of ibs - d.18 in addition , several 5-ht3-receptor antagonists , including ramosetron,5 alosetron,19 and cilansetron,20 have been developed as therapeutic agents for ibs - d , and their effectiveness has now been established .
these reports indicate that endogenous 5-ht and 5-ht3 receptors are involved in the pathogenesis of ibs .
the inhibitory effect of 5-ht3-receptor antagonists on stress - induced abnormal defecation in rats is attributable to their ameliorating effects on stress - enhanced colonic transit , but the effects of 5-ht3-receptor antagonists on abnormal water / electrolyte transport induced by stress are poorly understood.11 ramosetron is a potent and selective 5-ht3-receptor antagonist , acting mainly in peripheral tissues.5,21 it has already been proven effective in treating ibs - d in both animal and clinical studies.16 , 22 , 23 ramosetron may achieve long - lasting occupancy of 5-ht3 receptors because it possesses a distinctive ability to maintain the active three - dimensional chemical conformation necessary for binding.24 in fact , it has been reported that ramosetron dissociates slowly from 5-ht3 receptors5,25 and shows long - lasting 5-ht3-receptor antagonism.8,26 in vehicle - treated rats , the colonic pain threshold was significantly decreased after 1 hour s restraint stress , whereas oral administration of ramosetron ( 0.3 to 3 g / kg ) dose - dependently prevented this decrease in colonic pain threshold .
alosetron and cilansetron ( 330 g / kg , orally ) had similar effects , whereas loperamide ( 10 mg / kg , orally ) had no effect on restraint stress - induced decrease in colonic pain threshold .
oral administration of ramosetron ( 3 g / kg ) , alosetron ( 30 g / kg ) , or cilansetron ( 30 g / kg ) to rats without restraint stress did not significantly affect the colonic pain threshold.12 several 5-ht3-receptor antagonists have been studied in ibs - d following observations that they slowed gastrointestinal transit .
initial studies with granisetron and ondansetron found decreased postprandial sigmoid motility , delay in colonic transit , and increased stool consistency in ibs - d.27
in experimental animal models , ramosetron exhibits properties that are consistent with the expected effects of a drug in this class : inhibition of stress - induced or exogenous corticotropin - releasing hormone - induced water secretion , inhibition of stress - induced acceleration of colonic transit , and inhibition of colonic nociception.12,22 oral administration of ramosetron ( 3,000 g / kg , once daily for 7 days ) did not affect normal defecation in dogs.12 oral administration of ramosetron ( 10 g / kg to 100 g / kg ) dose - dependently and significantly inhibited conditioned fear stress ( cfs)-induced defecation in mice.28,29 alosetron , cilansetron , and loperamide also inhibited cfs - induced defecation , but their potency was less than that of ramosetron.28,29 in normal rats without cfs , however , 5-ht3-receptor antagonists ( 1,000 g / kg , orally ) had no effect on proximal colonic transit .
ramosetron ( 0.3 g / kg100 g / kg , orally ) showed potent inhibitory effects on abnormal defecation on restraint stress- and 5-ht ( 3 mg / kg , intraperitoneally)-induced diarrhea in rats and mice , and corticotropin - releasing factor ( 30 g / kg , intracerebroventricularly)-induced defecation in rats .
furthermore , ramosetron ( 3 g / kg and 30 g / kg , orally ) significantly prevented corticotropin - releasing factor - induced decrease in colonic fluid loss in rats.12
in a double - blind , placebo - controlled , parallel - group study of 418 patients with ibs - d , once - daily 5 g and 10 g doses of ramosetron increased the monthly responder rates of  patient - reported global assessment of relief of ibs symptoms  compared to placebo ; the benefit was similar in men and women.30 in a second double - blind , placebo - controlled , parallel - group study of 539 patients with ibs - d , a once - daily 5 g dose of ramosetron was effective and well tolerated in the treatment of abdominal pain , discomfort , and altered bowel habits.23 in a 12-week randomized controlled trial of 539 patients , a positive response to treatment was reported by 47% of ramosetron - treated individuals compared to 27% of patients receiving placebo ( p<0.001 ) , relief of abdominal pain or discomfort was reported by 46% patients with ramosetron versus 33% with placebo ( p=0.005 ) , and improved abnormal bowel habits were reported by 44% with ramosetron compared to 24% with placebo ( p<0.001),23 which was similar to alosetron.31 the responder rates for global ibs symptoms , abdominal pain / discomfort , and abnormal bowel habits in the ramosetron and mebeverine groups significantly increased during the treatment period .
the severity scores of abdominal pain / discomfort and urgency , stool form score , and stool frequency in both treatment arms were significantly reduced , compared with baselines.32 furthermore , the responder rate was increased in the oral administration of 5 g of ramosetron for at least 28 weeks ( up to 52 weeks ) , and long - term efficacy for overall improvement of ibs symptoms was also demonstrated in the postmarketing survey .
the rate was further increased subsequently.33 further studies to evaluate the long - term effects of ramosetron are needed in the form of randomized controlled trials ( table 1 ) .
there are various factors that may contribute to sex differences in treatment response for patients with ibs , including biobehavioral responses to stress , sexual cycle , and sex differences in roles and emotions .
whether any of these factors may affect the response to 5-ht3-receptor antagonists in either sex has not been elucidated.31 ramosetron acts only on peripheral tissues , whereas alosetron also acts in the brain .
sex differences in the central pathophysiology of ibs have been reported.34,35 a significant association has been observed between female patients with ibs - d and polymorphisms in the serotonin - reuptake transporter protein , suggesting that the serotonin transporter is a potential candidate gene for ibs - d in women.36,37 however , it is not known whether differences in serotonin - reuptake transporter polymorphisms between women and men with ibs contribute to the observed differences in clinical response to 5-ht3-receptor antagonists.23 ondansetron was the first 5-ht3-receptor antagonist to show benefit in ibs - d ; however , most of the clinical studies were performed with alosetron , which is three- to tenfold more potent and provides longer - lasting receptor inhibition .
trials showed improved stool consistency and urgency within the first week , which was only significant in females with ibs - d.38 a meta - analysis reported both alosetron and cilansetron showed significant benefit in providing satisfactory relief of ibs symptoms ( pooled relative risk 1.60 , 95% confidence interval 1.491.72 ) and relief of abdominal pain and discomfort ( pooled relative risk 1.30 , 95% confidence interval 1.221.39 ) .
5-ht3-receptor antagonists increased the risk of constipation fourfold , with a number needed to harm of 4.7 .
constipation accounted for a significant proportion of those discontinuing treatment . in this pooled analysis , both males and females showed benefit , and 0.2% had possible ischemic colitis.39
adverse events that occurred frequently during treatment with ramosetron were abdominal distension , constipation , and hard stool , which are considered to be classic effects of 5-ht3-receptor antagonists .
the incidence of constipation with the administration of alosetron was 29% , whereas the incidence with ramosetron was only 5.2% .
ischemic colitis and severe constipation , which have been reported with alosetron use , were not observed in individuals treated with ramosetron . although the pathogenesis of ischemic colitis in patients with ibs treated with alosetron
is uncertain , ischemic colitis might arise secondary to constipation , due to the slow transit induced by alosetron .
the incidence of constipation in the ramosetron group is considered to be lower than that in the alosetron group , and as a result ischemic colitis is unlikely to be caused by ramosetron.12,40 adverse events were reported by 7% of patients in the ramosetron - treatment group during the 4-week treatment period .
constipation was the most commonly recorded adverse event in the ramosetron group ( 2% ) . the major adverse event associated with these withdrawals in the ramosetron group was constipation .
no serious adverse events , eg , severe constipation or ischemic colitis , were reported in the ramosetron and mebeverine groups .
neither severe constipation nor ischemic colitis was reported by ramosetron - treated patients.32 thus , for safety , ramosetron was well tolerated , as demonstrated by the lack of the increase in the incidence of adverse events associated with long - term treatment.33 5-ht3-receptor antagonists improve symptoms in ibs - d , but have constipation as a side effect , with alosetron > cilansetron > ramosetron > ondansetron . while both alosetron and cilansetron have been associated with ischemic colitis , this has not been reported with either ramosetron or ondansetron .
the original doses recommended may well have been excessive , and careful dose titration starting with very low doses may well avoid severe side effects in the future.41
the long - term effectiveness of ramosetron in ibs has been useful in attaining relief of abdominal pain or discomfort , and improvements in abnormal bowel habits .
finally , ramosetron is associated with a low incidence of adverse events , such as abdominal distension , constipation , and hard stool , and ischemic colitis is unlikely to be caused by ramosetron .
thus , ramosetron would be the candidate of first choice for treating ibs - d clinically .
further studies to evaluate the long - term efficacy and safety of ramosetron are warranted in the form of randomized controlled trials .
 irritable bowel syndrome ( ibs ) is a functional disease with persisting gastrointestinal symptoms that has been classified into four subtypes . 
 serotonin ( 5-hydroxytryptamine [ 5-ht ] ) plays important physiological roles in the contraction and relaxation of smooth muscle . 
 intraluminal distension of the intestine is known to stimulate the release of endogenous 5-ht from enterochromaffin cells , activating 5-ht3 receptors located on primary afferent neurons and leading to increases in intestinal secretions and peristaltic activity . 
 ramosetron , a potent and selective 5-ht3-receptor antagonist , has been in development for use in patients suffering from diarrhea - predominant ibs . in a double - blind 
 , placebo - controlled , parallel - group study of 418 patients with diarrhea - predominant ibs - d , once - daily 5 g and 10 g doses of ramosetron increased the monthly responder rates of ibs symptoms compared to placebo . in a 12-week randomized controlled trial of 539 patients , a positive response to treatment was reported by 47% of a once - daily 5 g dose of ramosetron - treated individuals compared to 27% of patients receiving placebo ( p<0.001 ) . 
 furthermore , the responder rate was increased in the oral administration of 5 g of ramosetron for at least 28 weeks ( up to 52 weeks ) , and long - term efficacy for overall improvement of ibs symptoms was also demonstrated . 
 the rate was further increased subsequently . 
 adverse events were reported by 7% in ramosetron treatment . 
 no serious adverse events , eg , severe constipation or ischemic colitis , were reported for long - term treatment with ramosetron . in conclusion , 
 further studies to evaluate the long - term efficacy and safety of ramosetron are warranted in the form of randomized controlled trials . 
Introduction
Mechanism of action
Animal studies
Clinical studies and efficacy
Safety
Conclusion