A fishy recommendation: omega-3 fatty acidintake in pregnancyDepartment of Obstetrics and Gynecology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, CanadaCorrespondence: Dr SJ Genuis, University of Alberta, 2935-66 Street, Edmonton, Alberta, Canada T6K 4C1. Email firstname.lastname@example.orgPlease cite this paper as: Genuis S. A fishy recommendation: omega-3 fatty acid intake in pregnanc
Australian people can buy antibiotics in Australia online here: http://buyantibioticsaustralia.com/ No prescription required and cheap price!
Peripherally acting therapies for the treatment of irritable bowel syndromeP e r i p h e r a l l y A c t i n gT h e r a p i e s f o r t h eTre a t m e n t o f I r r i t a b l eB o w e l S y n d ro m e KEYWORDS Irritable bowel syndrome Lubiprostone Alosetron The irritable bowel syndrome (IBS) is a chronic, relapsing, and variably disabling boweldisorder characterized by the presence of abdominal pain or discomfort in associationwith altered bowel habits. IBS is further subtyped based on the predominant stoolpattern into one of IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), or mixedIBS (IBS-M).Given the nature of symptoms related to IBS, gut-acting therapies havebeen traditionally used and remain among the most common therapies for this chroniccondition. Most of these peripheral acting agents, including fiber supplements, laxa-tives, antidiarrheals, and antispasmodics, are primarily targeted at individual symp-toms. The evidence supporting the use of these agents in IBS is largely anecdotal,based on dated studies of marginal methodological quality because high-quality clin-ical trials are generally lacking. Serotonergic agents and the chloride channel activatorlubiprostone have shown efficacy in global as well as various individual symptoms ofIBS. Moreover, the clinical evidence supporting the use of these agents is based ondata from high-quality clinical trials. The use of serotonergic agents for IBS in theUnited States is limited to the 5-hydroxytryptamine-3 (5-HT3) antagonist alosetron inthe treatment of women with severe IBS-D refractory to traditional therapy.
The use of fiber supplements and laxatives in the treatment of IBS has evolved fromthe perception of altered gastrointestinal motility as a cause of the abnormal bowelsymptoms associated with this heterogeneous Specifically, several clin-ical observations have reported a decrease in bowel motility and a prolonged transittime in patients with IBS-C compared with controls.Furthermore, given the proven Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center,1500 East Medical Center Drive, SPC 5362, Ann Arbor, MI 48109, USAE-mail address: Gastroenterol Clin N Am 40 (2011) 163–182 0889-8553/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
efficacy of fiber supplements and other laxatives in regulating bowel habits and alle-viating constipation, clinicians have traditionally turned to these agents to addressthe bowel symptoms associated with IBS-C and IBS-M. However, the clinicalevidence for this practice is based on limited data because high-quality clinical trialsassessing these agents in the treatment of IBS are nearly nonexistent.
Dietary fiber supplements represent a heterogeneous group of complex carbohy- drates that are resistant to hydrolysis during digestion. These nondigested productsresult in increased stool bulk and water content, effectively decreasing stool consis-tency and increasing stool frequency.Of the various commercially available fibersupplements including psyllium, ispaghula husk, bran (wheat and corn), methylcellu-lose, calcium polycarbophil, and partially hydrolyzed guar gum; psyllium and branare the best studied in the treatment of IBS. The results of the 6 trials comparing psyl-lium and ispaghula husk (the husk of psyllium seed) with placebo were pooled, yieldinga total of 321 patients with IBS, with 161 in the treatment In this pooled analysis,52% of patients treated with psyllium had persistent IBS symptoms after treatmentcompared with 64% of those receiving placebo. Although significant heterogeneityexisted amongst the studies, the relative risk (RR) of symptoms not improving withpsyllium was 0.78 (95% confidence interval [CI] 0.63–0.96) compared with placebowith a number needed to treat (NNT) of 6 (95% CI 3–50). The investigators notedthat limiting this analysis to the 5 higher-quality trials resulted in a loss of this significantdifference between psyllium and placebo. The pooled analysis of the 5 trialscomparing bran with placebo or a low-fiber diet found no difference in treatmentoutcomes with bran.Guar gum has been assessed (daily dose of 5–10 g) in 2 opentrials involving patients with constipation-predominant and diarrhea-predominantIBS, suggesting short-term benefits in gastrointestinal symptoms as well as inquality-of-life (QOL) measures.The effects of calcium polycarbophil on IBS havebeen assessed in 2 clinical The first study was a 6-month, placebo-controlled, randomized, double-blind crossover trial in 23 patients with eitherconstipation-predominant IBS or IBS with alternating diarrhea and constipation.Polycarbophil (6 g/d) was preferred over placebo in 71% of patients for treatment oftheir IBS symptoms. Compared with placebo, polycarbophil was reported to improveease of bowel movements and relieve symptoms of nausea, pain, and bloating. In thesecond trial, calcium polycarbophil was given to 26 patients with IBS (14 with IBS-Dand 12 with IBS-C).Compared with baseline there was significant improvement infrequency of bowel movement, stool form, and abdominal pain in both IBS subgroups(P<.05). There are no clinical trials assessing the efficacy of methylcellulose in thetreatment of IBS.
The clinical trials assessing fiber supplements have been evaluated collectively in several systematic reviews, with varying conclusions. The American College ofGastroenterology (ACG) Task Force recently reported on their findings from anevidence-based systematic review on the effectiveness of fiber supplements in themanagement of IBS, concluding that “Psyllium hydrophilic mucilliod (ispaghulahusk) is moderately effective and can be given a conditional recommendation (Grade2C) ). Wheat bran or corn bran is no more effective than placebo in the relief ofglobal symptoms of IBS and cannot be recommended for routine use (Grade 2C). Asingle study reported improvement with calcium Using dichotomousoutcomes for relief of abdominal pain, improvement in global assessment of IBSsymptoms, and improvement in symptom scores, a Cochrane review of 11 studiesdid not find fiber supplements effective in the treatment of IBS.These investigatorscautioned that considerable heterogeneity of patients with IBS existed in the includedtrials and the effectiveness of fiber supplements have not been completely defined in Strong recommendation RCTs without important overwhelming evidencefrom observationalstudies Strong recommendation RCTs with important results, methodologicalflaws, indirect, orimprecise) orexceptionally strongevidence fromobservational studies Strong recommendation Observational or case flaws, indirect, orimprecise) orexceptionally strongevidence fromobservational studies Strong recommendation Observational or case Adapted from Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statementon the management of irritable bowel syndrome. Am J Gastroenterol 2009;104(Suppl 1):S10; withpermission.
specific IBS subtypes. In an earlier systematic review performed by the ACG Func-tional Gastrointestinal Disorders Task Force, this panel of experts concluded thatbulking agents were not more effective than placebo at relieving the global symptomsof IBS.
The use of laxatives in the treatment of IBS-C has evolved from their known effect on the symptoms of constipation. Only 1 laxative, polyethylene glycol (PEG), has beenassessed in the treatment of IBS. This was a sequential study assessing the effectsof PEG 3350 on 27 postpubertal adolescents (59% female) with IBS-C (based onRome II criteria).After 4 weeks of therapy, the group treated with 17 g of PEG 3350once daily experienced a significant increase in mean bowel movement frequencyfrom 2.07 to 5.04 bowel movements a week (P<.05). However, there was no changein mean pain level for the group with the PEG therapy. Regarding laxatives, theACG Task Force concluded that “PEG laxative was shown to improve stool frequency–but not abdominal pain–in one small sequential study in adolescents withIBS-C.” The fiber supplement psyllium may have some beneficial effects on the symptoms of constipation and alternating bowel habits in patients with IBS-C and IBS-M, respec-tively. Bran does not seem to offer symptomatic benefit in IBS and the effect of otheravailable fiber supplements remains largely unknown. Potential adverse effectsincluding bloating, abdominal distention, and flatulence may limit use of these agents.
Their widespread availability, relative inexpense, and perceived safety make them anattractive treatment options in IBS-C and IBS-M. There are virtually no evidence-based data evaluating traditional laxatives in the treatment of IBS. However, the rela-tive safety, universal availability, and low cost of laxatives make them an attractivetherapeutic option for constipation-related complaints in patients with IBS.
As already noted, there is a general perception that the alterations in bowel habitsexperienced in IBS are in part a result of altered gastrointestinal motility. Studiesaround the world have reported accelerated small bowel and colon transit times aswell as exaggerated motility patterns in those with IBS-D compared withIt is largely a result of these observations that antidiarrheals remainamong the more commonly used gut-acting agents used in the treatment of patientswith IBS-D.
Of the 2 most commonly used antidiarrheals in the United States, including lopera- mide and diphenoxylate, only loperamide has been evaluated in randomizedcontrolled trials (RCTs) for the treatment of IBS. A total of 4 studies have been pub-lished, all European, none recent, and all containing methodological limitations.The first study, from England and published in 1984, was a crossover, placebo-controlled trial involving 28 patients with IBS (75% Compared with placebo,5 weeks of loperamide (dose range of 2–12 mg/d) reduced small bowel (P>.01) andwhole gut transit time (P<.01) and was superior at improving diarrhea (P<.01), urgency(P<.01), and boborygmi (P<.05). There was no improvement in pain with loperamide.
Eighteen patients (62%) reported an overall improvement and 9 of them continuedtherapy for 12 months. The first of 2 Norwegian studies was 1 of 2 double-blind,placebo-controlled trials published in This study assessed a total of 58patients with IBS divided into 4 categories: painless diarrhea (n 5 16), pain with alter-nating bowels (n 5 21), alternating bowels without pain (n 5 12), and constipation withpain (n 5 9). Three weeks of loperamide 4 mg once nightly was significantly better thanplacebo at improving stool frequency and stool consistency in those with painlessdiarrhea and in those with alternating bowel habits and pain. Loperamide led to signif-icantly fewer days of pain in those with alternating bowel habits and pain. Those withalternating bowel habits and no pain experienced no benefit from loperamide,whereas those with constipation experienced worsening symptoms with loperamide.
The other double-blind, placebo-controlled study published in 1987 enrolled 25Swedish patients with IBS with diarrhea as the predominant symptom.In the 21patients completing the 13-week treatment period, loperamide (titrated dose rangingfrom 2 to 8 mg nightly) was superior to placebo at improving stool consistency(P<.001), pain (P<.02), urgency (P<.05), and overall response (P<.03). The mostrecently published study was a double-blind, placebo-controlled trial enrolling 90Norwegian patients with Although IBS was not subtyped in this study and 21patients were not included in the analysis, 5 weeks of loperamide (dose range of2–6 mg nightly) was superior to placebo at improving stool frequency (P<.05), and stool consistency (P<.05). Those receiving loperamide reported an increase innocturnal abdominal pain compared with placebo (P<.05).
The ACG Task Force recently performed a systematic review of antidiarrheals in the treatment of IBS and concluded that “The antidiarrheal agent loperamide is not moreeffective than placebo at reducing abdominal pain or global symptoms of IBS, but isan effective agent for treatment of diarrhea, improving stool frequency and stoolconsistency (Grade 2C). RCTs with other antidiarrheal agents have not been per-formed. Safety and tolerability data on loperamide are lacking.”An earlier systematicreview by the ACG Functional Disorders Task Force in 2002 concluded that althoughnone of the trials reported high-quality data, loperamide was an effective treatment ofdiarrhea, but no more effective than placebo for the treatment of global IBS symptomsor abdominal pain.The investigators further concluded that adverse event data onloperamide were limited and it was safest for use in IBS-D.
Abdominal pain or discomfort is a cardinal feature of IBS, a symptom that has beentraditionally ascribed to intestinal smooth-muscle spasm. Observation and clinicalstudies have suggested that an exaggerated motility response of the small boweland colon to environmental stimuli may be responsible for the symptoms experiencedin For this reason antispasmodics have been and remain a mainstay oftherapy for the symptoms of IBS. Antispasmodics encompass several different drugclasses, including antimuscarinics, smooth-muscle relaxants, anticholinergics, andunique agents such as pinaverium, an ammonium derivative with calcium channelblocking action, and trimebutine, a peripheral opiate Of these various anti-spasmodics, only 4 specific anticholinergic agents are currently available in the UnitedStates: hyoscyamine, dicyclomine, belladonna, and propantheline. Given their mech-anism of action, these agents are directed at those subgroups of IBS, with a predom-inant symptom of abdominal pain and stool patterns that are either mixed or morediarrheal in nature. The anticholinergic properties of these agents restrict their useful-ness in clinical practice. Common side effects, including dry mouth, dizziness, blurryvision, confusion (particularly in elderly patients), urinary retention, and constipation,often limit the usefulness of these agents in the treatment of IBS. The propensity ofthese agents to promote constipation makes them a less attractive option for patientswith IBS-C. Further, anticholinergics should be avoided in elderly patients, who aremore prone to the development of significant side effects.
Although antispasmodics remain among the most commonly prescribed drugs for IBS, the clinical evidence supporting their use is limited. Of the 4 antispasmodics avail-able in the United States, only dicyclomine has been assessed in placebo-controlledclinical trials involving patients with IBS.The first trial was a double-blind, cross-over, placebo-controlled trial involving 29 patients divided into a spastic colon groupor painless diarrhea group, each receiving 2 weeks of Although severalmethodological limitations exist in this study, including the lack of an IBS definition,a crossover study design, inadequate sample size, and short duration of therapy,a dose of dicyclomine 20 mg 3 times was superior to placebo in addressing bowelurgency and relief of pain with urgency. This second trial was a double-blind,placebo-controlled trial showing the superiority of 2 weeks of dicyclomine to placeboin the treatment of 71 patients with IBS with predominant constipation.Despiteseveral methodological limitations associated with this study (only 71 of 97 enrolledpatients were analyzed, short treatment period), dicyclomine was superior to placebowith regard to overall improvement of symptoms and decreased abdominal pain.
However, the dose of dicyclomine used in this study (40 mg 4 times daily) led tofrequent anticholinergic side effects and is not practically useful in routine clinicalpractice.
Given the lack of high-quality studies addressing the efficacy of specific antispas- modic agents, attempts to estimate the efficacy of this class of drugs for IBS havebeen undertaken through systematic review and meta-analysis. The most recentsystematic review and meta-analysis of antispasmodics as a class was performedby the ACG IBS Task Force.The Task Force concluded that “Certain antispas-modics (hyoscine, cimetropium, and pinaverium) may provide short-term relief ofabdominal pain/discomfort in IBS (Grade 2C). Evidence for long-term efficacy is notavailable (Grade 2B). Evidence for safety and tolerability are limited (Grade 2C).”The Task Force identified 22 studies suitable for inclusion in their systematic review.
Only 1 of these studies involved a drug available in the United States.Three studiesevaluated hyoscine, a different preparation than the agent, hyoscyamine, which isavailable in the United Drugs not available in the United States that wereincluded in this analysis included pinaverium,trimebutine,alverine,pirenzipine,prifinium,propinox,anda trimebutine/rociverine combination.Most of these clinical trials are dated, withonly 3 of the studies performed in the last 10 years. The Task Force also acknowl-edged that these clinical trials were collectively fraught with methodological flaws,including diagnostic criteria used, inclusion criteria used, dosing schedule used, dura-tion of therapy studied, study end points used to assess response, and study size (only3 studies enrolled more than 100 patients). With these limitations in mind, the 22 trialscollectively included data from 1778 patients with IBS. The pooled analysis of thesestudies revealed an RR of symptoms persisting with antispasmodics compared withplacebo of 0.68 (95% CI 0.57–0.81) and an NNT of 5 to prevent IBS symptoms frompersisting in 1 patient. A pooled analysis was also performed on the 13 studies,including 1379 patients in whom adverse effects were reported. The Task Forceacknowledged significant heterogeneity among these patients; however, the RR ofa patient experiencing side effects with antispasmodics was 1.62 (95% CI 1.05–2.50),with a number needed to harm with antispasmodics of 18 (95% CI 7–217).
Other systematic reviews have yielded mixed results regarding the efficacy of anti- spasmodics for IBS. A systematic review has recently been performed on mebeverinein the treatment of This analysis included the pooled results of 8 randomizedclinical trials (6 compared with placebo) involving a total of 555 patients (63% female)of all IBS subtypes. The investigators reported that although well tolerated, the effectof mebeverine on global improvement and the specific symptom of abdominal painwas not statistically significant compared with placebo. A meta-analysis of smooth-muscle relaxants was performed on 23 randomized clinical trials, including the drugscimetropium, hyoscine, mebeverine, otilium, pinaverium, and trimebutine.Collec-tively, global improvement and pain relief was reported in 56% and 53%, respectively,by those receiving the smooth-muscle relaxants compared with response rates of38% and 41%, respectively, in the placebo group (P<.001 in both cases). A smallersystematic review of 16 RCTs evaluating smooth-muscle relaxants reported an NNTof 1.6 to 6.7 to achieve symptom relief in patients with IBS with pain as predominantIn this study, muscle relaxants were found to be efficacious in 13 of the 16studies, although only 7 studies were considered to be of high quality.
Although the individual studies have primarily involved antispasmodics not available in the United States and have been criticized for their low quality, as a group they haveshown efficacy in the treatment of abdominal pain in IBS. These agents are thereforelikely to be most effective in those patients with IBS with a predominant symptom of abdominal pain. These agents can worsen constipation and should therefore be usedcautiously in patients with IBS with a predominance of constipation.
Serotonin (5-HT) is the neurotransmitter primarily produced and stored in enterochro-maffin cells located throughout the intestinal epithelium, with 95% of total bodyconcentration of 5-HT residing in the gastrointestinal Acting through theintrinsic and extrinsic afferent nervous system of the gastrointestinal tract, 5-HT playsan important role in various aspects of gastrointestinal sensory, secretory, absorptive,and motility Recent research has identified abnormal serotonergic activityin association with IBS.Several studies describe increased serotonergic activity inassociation with IBS-D.Likewise, a decrease in serotonergic activity has beenobserved in IBS-C.The use of pharmacologic agents targeting serotonin recep-tors has therefore evolved from these observations of the role of 5-HT in gastrointes-tinal health and disease. Of the identified serotonin-receptor subtypes, the 5-HT1p,5-HT3, 5-HT4, and 5-HT7 receptors are the most clinically relevant for gastrointestinaltract functioning.Receptor agonists of 5-HT1 have been shown to improve gastricslow gastric emptying,and stimulate activity of the migratorymotor complex.Receptor antagonists of 5-HT3 have been reported to slow smallbowel transit, decrease intestinal secretion, and decrease colonic tone andtransit.Agonists of the 5-HT4 receptor have shown an ability to accelerategastric emptying,improve gastric accommodation,accelerate small boweltransit,accelerate colonic and possibly decrease visceral sensation.No 5-HT1 or 5-HT4 receptor agents are approved for the treatment of IBS in the UnitedStates or Canada. The 5-HT4 agonist tegaserod was removed from the market in 2009for safety issues. The 5-HT3 antagonist alosetron is available through a restricted-access program for use in women with severe IBS-D who have failed conventionaltherapies.
Alosetron is the only 5-HT3 antagonist approved by the US Food and Drug Adminis-tration (FDA) for the treatment of IBS-D (Rigorous, large clinical trials haveconsistently shown the efficacy of alosetron in the global and individual symptomsof IBS-D in women. A multicenter, placebo-controlled, randomized trial of 647 womenwith IBS-D or IBS-M reported superiority of alosetron in providing adequate relief ofabdominal pain and discomfort compared with placebo for the 3 months of therapy(41% vs 29%).Alosetron also significantly decreased urgency, reduced stoolfrequency, and increased stool consistency. Constipation occurred in 30% of thosetaking alosetron compared with 3% in the placebo group. A second multicenter,randomized, placebo-controlled trial of 626 women (71% with IBS-D, 26% withIBS-M) also reported a superiority of alosetron over placebo in providing adequaterelief of abdominal pain and discomfort for the 3 months of therapy (43% vsAlosetron significantly decreased urgency, reduced stool frequency, andincreased stool firmness within 1 week of therapy, which persisted throughout thetreatment period. Constipation occurred in 25% of those taking alosetron comparedwith 5% in the placebo group. The pooled effects of alosetron on QOL were alsoassessed in these 2 clinical trials.Compared with placebo, a significantly higherpercentage of those receiving alosetron experienced improvement in 3 QOL domains,including food/diet, social functioning, and role-physical on the validated generic QOLinstrument, the SF-36. Another 12-week, randomized, placebo-controlled trial was Table 2FDA-approved peripheral acting therapies in the treatment of IBS abnormalities of thegastrointestinal tractmust be excluded beforeinitiating therapy if no relief of symptomsexperienced with 4weeks of therapy ata dose of 1 mg twicea day a negative pregnancytest documented beforeinitiating therapy anduse contraception whileon therapy performed on 801 women with IBS (98% with IBS-D and 2% with IBS-M) and showedsuperiority of 1 mg twice a day of alosetron over placebo in adequately controllingurgency (73% vs 57%) and improving the global IBS symptoms (76% vs Participants in this trial also reported overall treatment satisfaction and satisfactionwith 11 specific medication attributes of A 48-week, randomized, placebo-controlled clinical trial has been performed on 714 women with IBS (80% with IBS-D, 20% with more frequent urgency) to assess long-term safety and efficacy of alosetron at a dose of 1 mg twice daily.Those receivingalosetron experienced greater adequate relief of IBS pain in 9 of the 12 months of thestudy and greater control of urgency in all 12 months compared with placebo. Therewere no differences in adverse events or serious adverse events between the 2 groupsexcept for constipation occurring more frequently in the alosetron group. A recentrandomized, placebo-controlled trial of 705 women with IBS-D has reported efficacyof lower doses of alosetron in providing global improvement in IBS symptoms,adequate relief of IBS pain and discomfort, and improvement in bowel symptoms(0.5 mg and 1 mg total daily dose).Constipation was reported with less frequencyin these lower treatment doses (9% on 0.5 mg/d and 16% on 1 mg/d). A dose-ranging, randomized, placebo-controlled trial has recently been performed on 662men with IBS-D.In this 12-week treatment trial, those receiving 1 mg of alosetrontwice daily were more like than those receiving placebo to report adequate relief ofpain in discomfort (53% vs 40%). Firmer stool was reported at all doses of alosetron,although there was no significant effect of alosetron on urgency, bowel movementnumber, or bloating. Constipation was the most common side effect reported, andwas dose related, occurring in 15% of those receiving 1 mg twice daily. There was a possible episode of ischemic colitis in a patient receiving alosetron at a dose of 0.5mg twice daily.
An evidence-based systematic review has been performed by the ACG Task Force on IBS, with the Task Force concluding that “alosetron is more effective than placeboat relieving global IBS in male (Grade 2B) and female (Grade 2A) patients with IBS withdiarrhea. Potentially serious side effects including constipation and colonic ischemiaoccur more commonly in patients treated with alosetron compared with placebo(Grade 2A). The benefits and harms balance for alosetron is most favorable in womenwith IBS-D who have not responded to conventional therapies (Grade 1B). The qualityof evidence for efficacy of 5-HT3 antagonists in IBS is high.”The most recent meta-analysis pooled the data from 8 clinical trials of alosetron and 3 clinical trials of the5-HT3 antagonist cilansetron (which was never marketed).This analysis, whichincluded a total of 7216 patients with IBS, found 5-HT3 antagonists more effectivethan placebo in treating IBS-D. The RR of IBS symptoms persisting with 5-HT3 antag-onists was 0.78 (95% CI 0.71–0.86) compared with placebo.
Alosetron was initially approved for the treatment of women with IBS-D in February 2000 and subsequently withdrawn from the US marketplace in November 2000because of the infrequent occurrence of significant side effects, including severecomplications of constipation and ischemic colitis. During this postmarketing period,80 cases of ischemic colitis and 100 cases of serious complications of constipationhad been reported. These postmarketing surveillance data were later reviewed byan expert panel, which reported a postadjudication rate of 1.1 cases of ischemic colitisper 1000 patient-years of alosetron use and 0.66 cases of serious complications ofconstipation with 1000 patient-years of alosetron use.A small number of hospitali-zations, surgical interventions, and deaths were identified in affected patients takingalosetron. The panel also reported an increased rate of ischemic colitis in the alosetrontreatment group compared with the placebo group in a pooled analysis of the availableclinical trials (0.15% vs 0.0%, P 5 .03). In the clinical trial dataset, there was no differ-ence in the occurrence of serious side effects between the alosetron and placebogroups, and all cases of ischemic colitis were reversible without long-term sequelae.
Largely as a consequence of phone calls and letters from patients, alosetron was reapproved by the FDA in June 2002 for the treatment of women with severe IBS-Dfailing to respond to conventional therapies. It is available for this specific indicationthrough a risk management plan that includes specific dosing instructions, an educa-tional program for prescribing physicians and patients to improve awareness andmanagement of constipation and ischemic colitis, and a standardized patient moni-toring program while on therapy. Alosetron is initially prescribed at a dose of 0.5 mgonce or twice daily. After 4 weeks of therapy, this dose can be increased to a maximumof 1 mg twice daily if well tolerated and a higher dose is needed for symptom manage-ment. If adequate relief of IBS-D symptoms has not occurred after 4 weeks of therapyat a dose of 1 mg twice daily, alosetron should be discontinued. The complication riskof alosetron under this risk management plan has been carefully monitored since reap-proval. Safety data from November 2002 to June 2008 including 203,939 prescriptionsfor 29,072 patients were recently reported.Compared with the postmarketing periodbefore the withdrawal of alosetron, this analysis found a reduction in the absolutenumbers of cases of ischemic colitis and complications of constipation, but no signif-icant differences in the incidence rates for either complication (0.95 and 0.36 cases per1000 patient-years, respectively). All cases were of short duration, with improvementafter prompt withdrawal of alosetron under this risk management plan. There were noepisodes of mesenteric ischemia, bowel perforation, surgical intervention, need fortransfusion, toxic megacolon, or death.
Tegaserod was the only 5-HT4 receptor agonist available in North America for thetreatment of women with IBS-C until it was voluntarily withdrawn from the market in2009. Tegaserod is a selective 5-HT4 receptor partial agonist approved in 2002 forthe treatment of women with IBS-C. The efficacy and tolerability of tegaserod in thetreatment of women with IBS-C was initially reported in 3 multicenter, double-blind,placebo-controlled trials involving more than 3000 patients from the WesternThese pivotal clinical trials consistently reported the superiority oftegaserod over placebo at improving global IBS symptoms and individual symptomsof abdominal pain, stool frequency, stool consistency, straining, and bloating. Theresults led to the FDA’s approval of tegaserod in April 2002 for short-term use inwomen suffering from IBS-C. The precise reason for the effect of tegaserod on theglobal symptoms of IBS has remained incompletely defined. In preclinical trials tega-serod has had promotility effects in the small and large intestineand modulationof visceral sensation.There was evidence to suggest tegaserod was also effec-tive in the treatment of women with The safety and tolerability of tegaserod was reported in multiple large 12-week clin- ical as well as a 12-month safety trial.The most commonly reportedside effects included diarrhea, headache, and abdominal pain. Tegaserod was desig-nated as a pregnancy category B drug by the FDA. Of the 31 pregnancies occurringduring the clinical trials, there was a nonsignificant increased miscarriage rate of17% (4/23) in women receiving tegaserod versus 12% (1/8) in the placebo group(not significant). No pregnancy-related complications were reported in the clinicaltrials. Although there were no reports of ischemic colitis in the clinical trials, 26 casesof possible colonic ischemia were reported during postmarketing surveillance, with anestimated incidence of 7 to 8 cases of colonic ischemia per 100,000 patient-years oftegaserod This finding led to the addition of a precaution on tegaserod labelingregarding the risk of colonic ischemia.
On March 30, 2007 the sales and marketing of tegaserod were suspended after a review of the clinical trials database uncovered unexpected increased incidenceof cardiovascular and cerebrovascular events in the tegaserod treatment groupcompared with those taking placebo.A pooled analysis had been performed on clin-ical trials involving tegaserod. This analysis revealed a total of 13 cardiovascularischemic events (3 myocardial infarctions, 1 sudden cardiac death, 6 cases ofunstable angina, and 3 cerebrovascular accidents) in 11,614 patients treated withtegaserod compared with 1 event in the 7031 patients receiving placebo. Althoughthe event rates were low (0.1% in the tegaserod group compared with 0.01% in theplacebo group), the difference was found to be statistically significant (P 5 .02).
Furthermore, it was reported that all patients experiencing a cardiovascular ischemicevent were either at risk or had a history of cardiovascular disease before study enroll-ment. The significance and explanation for this discrepancy remain unknown. Therehas been speculation that tegaserod may induce platelet aggregation through actionson 5-HT4 receptors found on Several studies have used various patientdatabases to assess for increased cardiovascular ischemic events in those prescribedtegaserod. A case-control study involving more than 18,000 patients from the Inter-mountain Healthcare database in Utah identified 12 cardiovascular events in 2603patients receiving tegaserod versus 54 cardiovascular events in 15,618 matchedThis finding yielded an incidence rate of 0.46% in tegaserod users versusan incidence rate of 0.35% in controls (odds ratio 5 1.27, 95% CI 0.68–2.38, P 5 .46).
Investigators cardiovascular events was identified in their study. An observational cohort study wasalso performed on more than 100,000 patients using the Ingenix Research DatabaseMart, a US health insurance claims database.In this study researchers found noincrease in cardiovascular ischemic events in those taking tegaserod versus matchedcontrols over a period of 6 months (cardiovascular RR 5 1.14 [95% CI 0.83–1.56],stroke RR 5 1.09 [95% CI 0.49–2.02]). Despite the results of these retrospective data-base studies, no clear conclusions have been reached regarding the cardiovascularsafety profile of tegaserod. Tegaserod remained available in the United States fora short time through a restrictive compassionate program. Tegaserod was completelyremoved from the market in 2009 and is no longer available in the United States orCanada. There are no plans by the manufacturer to reintroduce tegaserod to themarket.
Lubiprostone is the only chloride channel activator with FDA approval for the manage-ment of IBS-C (see Lubiprostone is an oral bicyclic fatty acid derivative ofprostaglandin E1. It is a potent and highly selective activator of the type-2 chloridechannel (ClC-2) located on the apical side of human intestinal epithelial ClC-2 is a voltage-gated transmembrane chloride channel that regulates chlorideion transport across the cellular membrane.ClC-2 is found in cells throughoutthe body and throughout the gastrointestinal tract.Primary functions of ClC-2channels include maintenance of the membrane potential of the cell, regulation ofpH and cell volume, and regulation of chloride ion channel transport and fluid secre-tion. Through dose-dependent ClC-2 activation, lubiprostone promotes a net flow ofchloride ions across the apical membrane of epithelial cells. This process leads topassive paracellular movement of sodium ions and water and a resultant net increasein fluid secretion into the lumen of the These physiologic effects are feltto underlie the clinical benefits of lubiprostone.
Initial studies investigating the effects of lubiprostone in healthy adults reported an acceleration of small bowel transit and colonic transit and an increase in frequency ofbowel movement.Three RCTs involving a total of 688 adults reported the effi-cacy of lubiprostone in the treatment of chronic idiopathic constipation.In thesetrials, lubiprostone was consistently found to be superior to placebo at increasing thenumber of weekly spontaneous bowel movements. Lubiprostone was also effective inimproving stool consistency, straining, constipation severity, bloating, and treatmenteffectiveness. The most commonly reported side effects included nausea, headache,and diarrhea. A pooled analysis of 91 patients meeting diagnostic criteria for IBS-Cfrom the 2 phase III constipation trials revealed significant improvements in constipa-tion symptoms as well as abdominal symptoms with lubiprostone compared withplacebo.This observation led to further evaluation of lubiprostone in the treatmentof IBS-C.
The efficacy and tolerability of lubiprostone have been assessed in several high- quality RCTs. A phase II, dose-ranging, double-blind, placebo-controlled trial was per-formed in 194 adults meeting Rome II criteria for IBS (92% female, 83% Inthis trial, participants were randomized to 1 of 4 12-week treatment arms: placebo,lubiprostone 8 mg twice daily, lubiprostone 16 mg twice daily, or lubiprostone 24 mgtwice daily. All 3 doses of lubiprostone were superior to placebo with regard tofrequency of spontaneous bowel movement (P.0499), constipation severity(P.0056), stool consistency (P<.0001), and straining (P.0094) in each of the 3 months of treatment. Those randomized to lubiprostone also experienced signifi-cantly less abdominal discomfort/pain than those receiving placebo at months 1and 2 (P 5 .0431 and P 5 .0336, respectively). Bloating was significantly improvedwith lubiprostone versus placebo at months 1 and 2 (P 5 .0298 and P 5 .0398, respec-tively). Adverse events were greatest in those taking 16 mg twice daily or 24 mg twicedaily. The 8-mg dose taken twice daily had the best efficacy and safety profile, and wastherefore the dose selected for further study in subsequent phase III clinical trials.
Two phase III 12-week, multicenter, double-blind, randomized, placebo-controlled trials further evaluated lubiprostone in a total of 1167 patients (92% female) meetingthe Rome II criteria for IBS-C.In these trials, participants were randomized in 2:1fashion to receive lubiprostone 8 mg twice a day (n 5 780) or placebo (n 5 387).
The studies used a rigorous and previously untested primary end point. For this endpoint, participants used a 7-point balanced Likert scale to answer the following ques-tion: “How would you rate your relief of IBS symptoms (abdominal pain/discomfort,bowel habits, and other IBS symptoms) over the past week compared with how youfelt before you entered the study?” Those reporting at least moderate relief in 4 of 4weeks or significant relief in 2 of 4 weeks were considered monthly responders. Anoverall responder had to be a monthly responder in 2 of the 3 months of the clinicaltrial. This rigorous end point was designed to minimize the placebo effect. In these2 phase III trials, those on lubiprostone were nearly twice as likely to be respondersas those on placebo (18% vs 10%, P 5 .001). Lubiprostone was also superior toplacebo in improving individual IBS symptoms, including abdominal discomfort/pain, stool consistency, straining, constipation severity, and QOL. The most commontreatment-related side effects were nausea (8%), diarrhea (6%), and abdominal pain(5%). There was no difference in serious side effects between those taking lubipro-stone and placebo (1% in both groups). The results of these 2 large well-designed clin-ical trials led to the FDA’s approval in April 2008 for the use of lubiprostone in thetreatment of women aged 18 years and older suffering from IBS-C.
Since the FDA’s approval of lubiprostone in the treatment of IBS-C, several addi- tional studies reported in abstract form have further characterized the effects of lubi-prostone on IBS-C symptoms. A 36-week open-labeled extension trial usinglubiprostone 8 mg twice daily was performed in 476 participants from the 2 initial phaseIII clinical Using the same primary end point as in the initial phase III trials,those receiving lubiprostone during the initial 12-week phase III trial experienced anincrease in response from 15% to 37% and those initially receiving placebo experi-enced an increase in response from 8% to 31% at the conclusion of the 36-weekextension period. Diarrhea (4.8%) and nausea (3.5%) were the most commonlyreported side effects in this extension trial. No treatment-related serious side effectswere reported during the 48 weeks of therapy. A withdrawal trial was also performedon selected participants from 1 of the pivotal phase III clinical trials.Those receivinglubiprostone for the initial 12 weeks were randomly assigned to continue on lubipro-stone 8 mg twice daily for an additional 4 weeks or given placebo. The responserate at 16 weeks was 38% in those continued on lubiprostone and 40% in thoseswitched to placebo. This curious finding might be explained by residual benefits oflubiprostone extending beyond its discontinuation or regression to the mean in theplacebo group. A retrospective analysis of data from the 2 phase III trials was per-formed to determine which individual IBS symptoms were most responsible for theglobal improvement in IBS.The findings of this study suggested that the beneficialeffects of lubiprostone on multiple IBS symptoms were responsible for its efficacy forglobal IBS-C symptoms. The effects of lubiprostone on QOL measures were assessedthrough a retrospective analysis of data from the initial 2 phase III clinical trials.This analysis revealed significant improvement in the QOL domains of health worry(P 5 .025) and body image (P 5 .015), with a trend for improvement in overall IBS-QOL score and domains of social reaction, food avoidance, and dysphoria in thosereceiving lubiprostone compared with those receiving placebo.
The efficacy of lubiprostone in the treatment of IBS-C was critically evaluated by the ACG IBS Task An evidence-based systematic review was performed, withthe Task Force concluding that “Lubiprostone in a dose of 8mg twice daily is moreeffective than placebo in relieving global IBS symptoms in women with IBC-S (Grade1B rating).” Lubiprostone is contraindicated in patients with mechanical bowelobstruction and should be avoided in patients with preexisting diarrhea. In additionto the side effects of nausea, diarrhea, and headache, there have been postmarketingreports of dyspnea. This side effect has been specifically described as “chest tight-ness” or “difficulty taking a breath” occurring within an hour of taking the first dose.
The dyspnea typically resolves over several hours but sometimes reoccurs withsubsequent dosing. Similar symptoms were reported in the clinical trials. This adverseevent occurred more frequently in those with chronic constipation receiving 24 mgtwice daily than those with IBS-C receiving 8 mg twice daily (>2.5% vs 0.4%, respec-tively). Although not considered a serious event, the potential for dyspnea has beenadded in safety labeling under “warnings and precautions.” Lubiprostone carriesa pregnancy category C rating because of fetal demise in guinea pig studies. Themanufacturer recommends documentation of a negative pregnancy test before initia-tion of therapy and use of contraception while taking lubiprostone in women capableof childbearing. The ACG Task Force also concluded a need for further studies in menwith IBS-C before a recommendation for use in this population.
A variety of peripheral acting agents, including fiber supplements, laxatives, antidiar-rheals, antispasmodics, the serotonergic antagonist alosetron, and the chloridechannel activator lubiprostone, are used in the treatment of IBS. Fiber supplements,laxatives, antidiarrheals, and antispasmodics are most effective on specific individualsymptoms associated with this syndrome. The evidence supporting the use of theseagents in IBS is largely anecdotal, although they are generally safe and well tolerated.
On the other hand, alosetron and lubiprostone have shown efficacy in the global aswell as individual symptoms of IBS in high-quality clinical trials. Alosetron hasa restricted FDA indication for treatment of women with severe IBS-D refractory totraditional therapy. For safety purposes, alosetron can be prescribed only througha specific risk management program. Lubiprostone is approved only for the treatmentof women aged 18 years or older suffering from IBS-C. Because of safety related tothe fetus, lubiprostone cannot be taken during pregnancy.
1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders.
2. Sadik R, Bjornsson E, Simren M. The relationship between symptoms, body mass index, gastrointestinal transit and stool frequency in patients with irritablebowel syndrome. Eur J Gastroenterol Hepatol 2010;22(1):102–8.
3. Camilleri M. Motor function in irritable bowel syndrome. Can J Gastroenterol 4. Manabe N, Wong BS, Camilleri M, et al. Lower functional gastrointestinal disor- ders: evidence of abnormal colonic transit in a 287 patient cohort. Neurogas-troenterol Motil 2010;22(3):293, e82.
5. Deiteren A, Camilleri M, Burton D, et al. Effect of meal ingestion on ileocolonic and colonic transit in health and irritable bowel syndrome. Dig Dis Sci 2010;55(2):384–91.
6. Cann PA, Read NW, Brown C, et al. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 1983;24(5):405–11.
7. Stevens J, VanSoest PJ, Robertson JB, et al. Comparison of the effects of psyl- lium and wheat bran on gastrointestinal transit time and stool characteristics.
J Am Diet Assoc 1988;88(3):323–6.
8. Ford AC, Talley NJ, Spiegel BM, et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic reviewand meta-analysis. BMJ 2008;337:a2313.
9. Parisi GC, Zilli M, Miani MP, et al. High-fiber diet supplementation in patients with irritable bowel syndrome (IBS): a multicenter, randomized, open trial compar-ison between wheat bran diet and partially hydrolyzed guar gum (PHGG). DigDis Sci 2002;47(8):1697–704.
10. Parisi G, Bottona E, Carrara M, et al. Treatment effects of partially hydrolyzed guar gum on symptoms and quality of life of patients with irritable bowelsyndrome. A multicenter randomized open trial. Dig Dis Sci 2005;50(6):1107–12.
11. Toskes PP, Connery KL, Ritchey TW. Calcium polycarbophil compared with placebo in irritable bowel syndrome. Aliment Pharmacol Ther 1993;7(1):87–92.
12. Chiba T, Kudara N, Sato M, et al. Colonic transit, bowel movements, stool form, and abdominal pain in irritable bowel syndrome by treatments with calcium pol-ycarbophil. Hepatogastroenterology 2005;52(65):1416–20.
13. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol2009;104(Suppl 1):S1–35.
14. Quartero AO, Meineche-Schmidt V, Muris J, et al. Bulking agents, antispas- modic and antidepressant medication for the treatment of irritable bowelsyndrome. Cochrane Database Syst Rev 2005;2:CD003460.
15. American College of Gastroenterology Functional Gastrointestinal Disorders Task Force. Evidence-based position statement on the management of irritablebowel syndrome in North America. Am J Gastroenterol 2002;97(11 Suppl):S1–5.
16. Khoshoo V, Armstead C, Landry L. Effect of a laxative with and without tegaser- od in adolescents with constipation predominant irritable bowel syndrome.
Aliment Pharmacol Ther 2006;23(1):191–6.
17. Lee OY. Asian motility studies in irritable bowel syndrome. J Neurogastroenterol 18. Chey WY, Jin HO, Lee MH, et al. Colonic motility abnormality in patients with irri- table bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroen-terol 2001;96(5):1499–506.
19. Cann PA, Read NW, Holdsworth CD, et al. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig Dis Sci 1984;29(3):239–47.
20. Hovdenak N. Loperamide treatment of the irritable bowel syndrome. Scand J Gastroenterol Suppl 1987;130:81–4.
21. Lavo B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome–a double-blind placebo controlled study. Scand J GastroenterolSuppl 1987;130:77–80.
22. Efskind PS, Bernklev T, Vatn MH. A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996;31(5):463–8.
23. Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the manage- ment of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97(11 Suppl):S7–26.
24. Drossman DA, Camilleri M, Mayer EA, et al. AGA technical review on irritable bowel syndrome. Gastroenterology 2002;123(6):2108–31.
25. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987;92(6):1885–93.
26. Clemens CH, Samsom M, Roelofs JM, et al. Association between pain episodes and high amplitude propagated pressure waves in patients with irritable bowelsyndrome. Am J Gastroenterol 2003;98(8):1838–43.
27. Fukudo S, Kanazawa M, Kano M, et al. Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritablebowel syndrome. J Gastroenterol 2002;37(Suppl 14):145–50.
28. Talley NJ. Pharmacologic therapy for the irritable bowel syndrome. Am J Gastro- 29. Irritable colon syndrome treated with an antispasmodic drug. Practitioner 1976; 30. Page JG, Dirnberger GM. Treatment of the irritable bowel syndrome with Bentyl (dicyclomine hydrochloride). J Clin Gastroenterol 1981;3(2):153–6.
31. Ritchie JA, Truelove SC. Treatment of irritable bowel syndrome with loraze- pam, hyoscine butylbromide, and ispaghula husk. Br Med J 1979;1(6160):376–8.
32. Nigam P, Kapoor KK, Rastog CK, et al. Different therapeutic regimens in irritable bowel syndrome. J Assoc Physicians India 1984;32(12):1041–4.
33. Schafer E, Ewe K. [The treatment of irritable colon. Efficacy and tolerance of buscopan plus, buscopan, paracetamol and placebo in ambulatory patientswith irritable colon]. Fortschr Med 1990;108(25):488–92 [in German].
34. Glende M, Morselli-Labate AM, Battaglia G, et al. Extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide in irri-table bowel syndrome. Eur J Gastroenterol Hepatol 2002;14(12):1331–8.
35. Baldi F, Corinaldesi R, Ferrarini F. Clinical and functional evaluation of octilonium bromide in irritable bowel syndrome. A double blind controlled trial. Clin Trials J1983;20:77–88.
36. Castiglione F, Daniele B, Mazzacca G. Therapeutic strategy for the irritable bowel syndrome. Ital J Gastroenterol 1991;23(8 Suppl 1):53–5.
37. Centonze V, Imbimbo BP, Campanozzi F, et al. Oral cimetropium bromide, a new antimuscarinic drug, for long-term treatment of irritable bowel syndrome. AmJ Gastroenterol 1988;83(11):1262–6.
38. Passaretti S, Guslandi M, Imbimbo BP, et al. Effects of cimetropium bromide on gastrointestinal transit time in patients with irritable bowel syndrome. AlimentPharmacol Ther 1989;3(3):267–76.
39. Levy C, Charbonnier A, Cachin M. [Pinaverium bromide and functional colonic disease (double-blind study)]. Sem Hop Ther 1977;53(7–8):372–4 [in French].
40. Delmont J. [The value of adding an antispasmodic musculotropic agent in the treatment of painful constipation in functional colopathies with bran. Double-blind study]. Med Chir Dig 1981;10(4):365–70 [in French].
41. Moshal MG, Herron M. A clinical trial of trimebutine (Mebutin) in spastic colon.
42. Fielding JF. Double blind trial of trimebutine in the irritable bowel syndrome. Ir 43. Mitchell SA, Mee AS, Smith GD, et al. Alverine citrate fails to relieve the symp- toms of irritable bowel syndrome: results of a double-blind, randomized,placebo-controlled trial. Aliment Pharmacol Ther 2002;16(6):1187–95.
44. Kruis W, Weinzierl M, Schussler P, et al. Comparison of the therapeutic effect of wheat bran, mebeverine and placebo in patients with the irritable bowelsyndrome. Digestion 1986;34(3):196–201.
45. Gilvarry J, Kenny A, Fielding JF. The non-effect of pirenzepine in dietary resis- tant irritable bowel syndrome. Ir J Med Sci 1989;158(10):262.
46. Piai G, Mazzacca G. Prifinium bromide in the treatment of the irritable colon syndrome. Gastroenterology 1979;77(3):500–2.
47. Di Girolamo G, de los Santos AR, Marti ML, et al. Propinox in intestinal colic: multicenter randomized prospective double-blind study of three doses of propi-nox vs. placebo in acute intestinal colic pain. Int J Clin Pharmacol Res 2000;20(1–2):31–40.
48. Ghidini O, Zenari L, Guilarte N, et al. Effects of short-term treatment with coen- zyme A or sulodexide on plasma lipids in patients with hypertriglyceridemia(type IV) or mixed hyperlipemia (type IIb). Int J Clin Pharmacol Ther Toxicol1986;24(7):390–6.
49. Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome. World J Gastroenterol2010;16(5):547–53.
50. Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of smooth muscle relax- ants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2001;15(3):355–61.
51. Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. AnnIntern Med 2000;133(2):136–47.
52. Keszthelyi D, Troost FJ, Masclee AA. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol Motil2009;21(12):1239–49.
53. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132(1):397–414.
54. Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal sero- tonin content and decreased serotonin reuptake transporter in ulcerative colitisand irritable bowel syndrome. Gastroenterology 2004;126(7):1657–64.
55. Bearcroft CP, Perrett D, Farthing MJ. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998;42(1):42–6.
56. Houghton LA, Atkinson W, Whitaker RP, et al. Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symp-tomatic female subjects with diarrhoea predominant irritable bowel syndrome.
57. Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of 5-hydroxytrypta- mine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 2005;3(4):349–57.
58. Atkinson W, Lockhart S, Whorwell PJ, et al. Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowelsyndrome. Gastroenterology 2006;130(1):34–43.
59. Zuo XL, Li YQ, Yang XZ, et al. Plasma and gastric mucosal 5-hydroxytrypta- mine concentrations following cold water intake in patients with diarrhea-predominant irritable bowel syndrome. J Gastroenterol Hepatol 2007;22(12):2330–7.
60. Coulie B, Tack J, Sifrim D, et al. Role of nitric oxide in fasting gastric fundus tone and in 5-HT1 receptor-mediated relaxation of gastric fundus. Am J Physiol 1999;276(2 Pt 1):G373–7.
61. Coulie B, Tack J, Maes B, et al. Sumatriptan, a selective 5-HT1 receptor agonist, induces a lag phase for gastric emptying of liquids in humans. Am J Physiol1997;272(4 Pt 1):G902–8.
62. Tack J, Coulie B, Wilmer A, et al. Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man. Gut 1998;42(1):36–41.
63. Talley NJ, Phillips SF, Haddad A, et al. GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci1990;35(4):477–80.
64. Zighelboim J, Talley NJ, Phillips SF, et al. Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3antagonism. Dig Dis Sci 1995;40(4):819–27.
65. Delvaux M, Louvel D, Mamet JP, et al. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment PharmacolTher 1998;12(9):849–55.
66. Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthyvolunteers. Aliment Pharmacol Ther 2000;14(6):775–82.
67. Baeyens R, Reyntjens A, Verlinden M. Cisapride accelerates gastric emptying and mouth-to-caecum transit of a barium meal. Eur J Clin Pharmacol 1984;27(3):315–8.
68. Staniforth DH, Pennick M. Human pharmacology of renzapride: a new gastroki- netic benzamide without dopamine antagonist properties. Eur J Clin Pharmacol1990;38(2):161–4.
69. Degen L, Petrig C, Studer D, et al. Effect of tegaserod on gut transit in male and female subjects. Neurogastroenterol Motil 2005;17(6):821–6.
70. Tack J, Broeckaert D, Coulie B, et al. The influence of cisapride on gastric tone and the perception of gastric distension. Aliment Pharmacol Ther 1998;12(8):761–6.
71. Tack J, Vos R, Janssens J, et al. Influence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment Pharmacol Ther 2003;18(10):1031–7.
72. Coffin B, Farmachidi JP, Rueegg P, et al. Tegaserod, a 5-HT4 receptor partial agonist, decreases sensitivity to rectal distension in healthy subjects. AlimentPharmacol Ther 2003;17(4):577–85.
73. Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.
74. Camilleri M, Chey WY, Mayer EA, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001;161(14):1733–40.
75. Watson ME, Lacey L, Kong S, et al. Alosetron improves quality of life in women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2001;96(2):455–9.
76. Lembo T, Wright RA, Bagby B, et al. Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irri-table bowel syndrome. Am J Gastroenterol 2001;96(9):2662–70.
77. Olden K, DeGarmo RG, Jhingran P, et al. Patient satisfaction with alosetron for the treatment of women with diarrhea-predominant irritable bowel syndrome.
Am J Gastroenterol 2002;97(12):3139–46.
78. Chey WD, Chey WY, Heath AT, et al. Long-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. AmJ Gastroenterol 2004;99(11):2195–203.
79. Krause R, Ameen V, Gordon SH, et al. A randomized, double-blind, placebo- controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetronin women with severe diarrhea-predominant IBS. Am J Gastroenterol 2007;102(8):1709–19.
80. Chang L, Ameen VZ, Dukes GE, et al. A dose-ranging, phase II study of the effi- cacy and safety of alosetron in men with diarrhea-predominant IBS. Am J Gas-troenterol 2005;100(1):115–23.
81. Ford AC, Brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis.
Am J Gastroenterol 2009;104(7):1831–43 [quiz: 1844].
82. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematicreview of clinical trials and post-marketing surveillance data. Am J Gastroenterol2006;101(5):1069–79.
83. Chang L, Tong K, Ameen V. Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinicalcharacteristics, outcomes, and incidences. Am J Gastroenterol 2010;105(4):866–75.
84. Muller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients withabdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001;15(10):1655–66.
85. Novick J, Miner P, Krause R, et al. A randomized, double-blind, placebo- controlled trial of tegaserod in female patients suffering from irritable bowelsyndrome with constipation. Aliment Pharmacol Ther 2002;16(11):1877–88.
86. Lefkowitz M, Shi Y, Heggland J, et al. Tegaserod rapidly improves abdominal pain, bloating and bowel function in patients with C-IBS [abstract]. Gut 2000;47(Suppl 3):A217.
87. Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenter-ology 1998;115(2):370–80.
88. Nguyen A, Camilleri M, Kost LJ, et al. SDZ HTF 919 stimulates canine colonic motility and transit in vivo. J Pharmacol Exp Ther 1997;280(3):1270–6.
89. Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthymale subjects. Aliment Pharmacol Ther 2001;15(11):1745–51.
90. Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome.
91. Jiao HM, Xie PY. Tegaserod inhibits noxious rectal distention induced responses and limbic system c-Fos expression in rats with visceral hypersensitivity. WorldJ Gastroenterol 2004;10(19):2836–41.
92. Schikowski A, Thewissen M, Mathis C, et al. Serotonin type-4 receptors modu- late the sensitivity of intramural mechanoreceptive afferents of the cat rectum.
Neurogastroenterol Motil 2002;14(3):221–7.
93. Sabate JM, Bouhassira D, Poupardin C, et al. Sensory signalling effects of tega- serod in patients with irritable bowel syndrome with constipation. Neurogas-troenterol Motil 2008;20(2):134–41.
94. Chey WD, Pare P, Viegas A, et al. Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial. Am JGastroenterol 2008;103(5):1217–25.
95. Kellow J, Lee OY, Chang FY, et al. An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerabilityof tegaserod in patients with irritable bowel syndrome. Gut 2003;52(5):671–6.
96. Nyhlin H, Bang C, Elsborg L, et al. A double-blind, placebo-controlled, random- ized study to evaluate the efficacy, safety and tolerability of tegaserod inpatients with irritable bowel syndrome. Scand J Gastroenterol 2004;39(2):119–26.
97. Tougas G, Snape WJ Jr, Otten MH, et al. Long-term safety of tegaserod in patients with constipation-predominant irritable bowel syndrome. Aliment Phar-macol Ther 2002;16(10):1701–8.
98. Schoenfeld P. Review article: the safety profile of tegaserod. Aliment Pharmacol 99. Thompson CA. Novartis suspends tegaserod sales at FDA’s request. Am J 100. Serebruany VL, Mouelhi ME, Pfannkuche HJ, et al. Investigations on 5-HT4 receptor expression and effects of tegaserod on human platelet aggregationin vitro. Am J Ther 2010;17(6):543–52.
101. Anderson JL, May HT, Bair TL, et al. Lack of association of tegaserod with adverse cardiovascular outcomes in a matched case-control study. J Cardio-vasc Pharmacol Ther 2009;14(3):170–5.
102. Loughlin J, Quinn S, Rivero E, et al. Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study. J Cardiovasc Pharmacol Ther2010;15(2):151–7.
103. Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell chlo- ride transport and recombinant human ClC-2 chloride currents. Am J PhysiolCell Physiol 2004;287(5):C1173–83.
104. Suzuki M, Morita T, Iwamoto T. Diversity of Cl(-) channels. Cell Mol Life Sci 2006; 105. Lipecka J, Bali M, Thomas A, et al. Distribution of ClC-2 chloride channel in rat and human epithelial tissues. Am J Physiol Cell Physiol 2002;282(4):C805–16.
106. Ueno R. Multiple, escalating, oral-dose study to assess the safety, tolerance and pharmacodynamic profile of lubiprostone in normal healthy volunteers[abstract]. Neurogastroenterol Motil 2005;17(4):626.
107. Camilleri M, Bharucha AE, Ueno R, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motorfunctions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2006;290(5):G942–7.
108. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled,dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther2007;25(11):1351–61.
109. Johanson JF, Morton D, Geenen J, et al. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2chloride channel activator, in patients with chronic constipation. Am J Gastroen-terol 2008;103(1):170–7.
110. Barish CF, Drossman D, Johanson JF, et al. Efficacy and safety of lubiprostone in patients with chronic constipation. Dig Dis Sci 2010;55(4):1090–7.
111. Johanson J, Wahle A, Ueno R. Efficacy and safety of lubiprostone in a subgroup of constipation patients diagnosed with irritable bowel syndrome with constipa-tion (IBS-C) [abstract]. Am J Gastroenterol 2006;101:s491.
112. Johanson JF, Drossman DA, Panas R, et al. Clinical trial: phase 2 study of lubi- prostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther2008;27(8):685–96.
113. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome–results of tworandomized, placebo-controlled studies. Aliment Pharmacol Ther 2009;29(3):329–41.
114. Chey WD, Drossman D, Scott C, et al. Lubiprostone is effective and well toler- ated through 48 weeks of treatment in adults with irritable bowel syndromeand constipation [abstract]. Gastroenterology 2008;134(4 Suppl 1):A215.
115. Chey WD, Saad RJ, Panas R, et al. Discontinuation of lubiprostone treatment for irritable bowel syndrome with constipation is not associated with symptomincrease or recurrence: results from a randomized withdrawal study [abstract].
Gastroenterology 2008;134(4 Suppl 1):A401.
116. Chey WD, Drossman D, Scott C, et al. What symptoms drive global symptom improvement with lubiprostone in patients with irritable bowel syndrome andconstipation: data from two multicenter, randomized, placebo-controlled trials[abstract]. Gastroenterology 2008;134(4 Suppl 1):A28.
117. Drossman D, Chey WD, Scott C, et al. Health-related quality of life in adults with irritable bowel syndrome with constipation: results of a combined analysisof two phase 3 studies with lubiprostone [abstract]. Gastroenterology 2008;134(4 Suppl 1):A469.
Effect of joint injections in children with juvenile idiopathic arthritis:evaluation by 3D-gait analysisE Brostro¨m, S Hagelberg and Y Haglund-A Department of Woman and Child Health, Karolinska Institute, Astrid Lindgren Children’s Hospital, Stockholm, Sweden ˚ kerlind Y. Effect of joint injections in children with juvenileidiopathic arthritis: evaluation by 3D-gait analysis. Acta Pædiatr