Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?

Background: Abnormalities of gut motility and visceral pain perception are both thought to be involved in the pathogenesis of irritable bowel syndrome and may be susceptible to modulation by drugs affecting the various 5-HT receptor subtypes. The aim of this study was to investigate the therapeutic potential of a 5-HT₃ antagonist in irritable bowel syndrome.
Methods: Fifty patients with irritable bowel syndrome were treated with ondansetron, a highly selective 5-HT₃ antagonist, in a double-blind, placebo-controlled cross-over study. In addition to assessing its effect on the classical symptoms of irritable bowel syndrome (abdominal pain, distension and disordered bowel habit) its effect on symptoms often seen in irritable bowel syndrome, but more commonly associated with functional dyspepsia, was also examined.
Results: Ondansetron reduced bowel frequency ( P =0.035) and improved stool consistency ( P =0.002) in diarrhoea predominant irritable bowel syndrome and did not cause a deterioration of bowel habit in constipation predominant subjects. No statistically significant improvement was seen for abdominal pain or distension, although those patients who did respond were approximately twice as likely to be taking ondansetron than placebo. It was also found that ondansetron significantly improved the upper gastrointestinal symptoms of post-prandial epigastric discomfort ( P =0.008), flatulence ( P =0.022) and heartburn ( P =0.003).
Conclusion: The results of this study justify evaluation of the therapeutic potential of selective 5-HT antagonists in both functional dyspepsia and irritable bowel syndrome.     

Calcium polycarbophil compared with placebo in irritable bowel syndrome

Calcium polycarbophil was compared with placebo in 23 patients with irritable bowel syndrome in a six-month, randomized double-blind crossover study. Patients received polycarbophil tablets at a dosage of 6 g/day (twelve 0.5-g tablets) or matching placebo tablets. At study end, among patients expressing a preference, 15 of 21 (71%) chose polycarbophil over placebo for relief of the symptoms of irritable bowel syndrome. Statistically significant differences favouring polycarbophil were found among the following patient subgroups: 15 (79%) of 19 with constipation; all six with alternating diarrhoea and constipation; 13 (87%) of 15 with bloating; and 11 (92%) of 12 with two or more symptoms. Polycarbophil was rated better than placebo in monthly global responses to therapy. Patient diary entries showed statistically significant improvement for ease of passage with polycarbophil. Polycarbophil was rated better than placebo for relief of nausea, pain, and bloating. The data suggest that calcium polycarbophil can benefit irritable bowel syndrome patients with constipation or alternating diarrhoea and constipation and may be particularly useful in patients with bloating as a major complaint.     

Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation

AIM: To investigate the efficacy and safety of tegaserod, a novel 5-HT(4) receptor partial agonist, in a randomized, double-blind, placebo-controlled, 12-week treatment, multicentre study. METHODS: Eight hundred and eighty-one patients with irritable bowel syndrome, characterized by abdominal pain, bloating and constipation, received tegaserod, 2 mg b.d. or 6 mg b.d., or placebo for 12 weeks. RESULTS: Tegaserod, 2 mg b.d. and 6 mg b.d., showed a statistically significant relief of overall irritable bowel syndrome symptoms, measured by a weekly, self-administered questionnaire. At end-point, treatment differences from placebo were 12.7% and 11.8% for 2 mg b.d. and 6 mg b.d., respectively. The effect of tegaserod was noted as early as week 1, and was sustained over the 12-week treatment period. Individual irritable bowel syndrome symptoms assessed daily also showed a statistically significant improvement of abdominal discomfort/pain, number of bowel movements and stool consistency, and a favourable trend for reducing days with significant bloating. Adverse events were similar in all groups, with transient diarrhoea being the only adverse event seen more frequently with tegaserod than placebo. CONCLUSIONS: Based upon the results of this study, tegaserod offers rapid and sustained relief of the abdominal pain and constipation associated with irritable bowel syndrome. Tegaserod is also well tolerated.     

Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173 010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation

Background  A sensation of abdominal swelling (bloating) and actual increase in girth (distension) are troublesome features of irritable bowel syndrome (IBS), which is more common in patients with constipation, especially those with delayed transit.
Aim  To establish whether a fermented dairy product containing Bifidobacterium lactis DN-173 010 reduces distension in association with acceleration of gastrointestinal transit and improvement of symptoms in IBS with constipation.
Methods  A single centre, randomized, double-blind, controlled, parallel group study in which patients consumed the test product or control product for 4 weeks. Distension, orocaecal and colonic transit and IBS symptoms were assessed on an intention-to-treat population of 34 patients.
Results  Compared with control product, the test product resulted in a significant reduction in the percentage change in maximal distension [median difference – 39%, 95% CI (−78, −5); P  = 0.02] and a trend towards reduced mean distension during the day [−1.52 cm (−3.33, 0.39); P  = 0.096]. An acceleration of orocaecal [−1.2 h (−2.3,0); P  = 0.049] as well as colonic [−12.2 h (−22.8, −1.6); P  = 0.026] transit was observed and overall symptom severity [−0.5 (−1.0, −0.05); P  = 0.032] also improved.
Conclusions  This probiotic resulted in improvements in objectively measured abdominal girth and gastrointestinal transit, as well as reduced symptomatology. These data support the concept that accelerating transit is a useful strategy for treating distension.     

New therapeutical approaches for treatment of irritable bowel syndrome

Irritable bowel syndrome is a common functional disorder of the gut. The cause is not known. Symptoms can be quite variable and include abdominal pain, bloating, and sometimes bouts of diarrhea and/or constipation. It causes a great deal of discomfort and distress, but it does not permanently harm the intestine and does not lead to a serious disease, such as cancer. There are numerous treatment options in functional gastrointestinal disorders acting peripherally by influencing motility and visceral sensitivity. However, older 5-HT4 receptor agonists had limited clinical success because they were associated with changes in the cardiac function. New generation 5-HT4 receptor agonists, 5-HT, antagonists or partial antagonists are promising approaches to treat gastrointestinal dysmotility, particularly colonic diseases. A further new approach is the activation of chloride cannels within the gastrointestinal wall by the prostaglandin E metabolite lubiprostone. In patients with chronic constipation, lubiprostone produced a bowel movement, with sustained improvement in frequency as well as other constipation symptoms. Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase C (GC-C) receptor agonist and intestinal secretagogue is also an effective treatment for chronic constipation. The pharmacological profile suggests that orally administered linaclotide may be capable of improving the abdominal symptoms and bowel habits of patients suffering from of constipation-predominant irritable bowel syndrome and chronic constipation. Data are emerging, but the efficacy and safety profile of these agents in the treatment irritable bowel disease appears encouraging. Further randomized controlled trials are warranted.     

Review article: gender-related differences in functional gastrointestinal disorders

Many functional gastrointestinal disorders and other chronic visceral pain disorders such as interstitial cystitis and chronic pelvic pain are more common in women than in men. In irritable bowel syndrome (IBS) there is a 2 : 1 female to male ratio in prevalence of symptoms in community samples. Female irritable bowel syndrome patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms.
While animal studies have clearly demonstrated gender-related differences in pain perception and antinociceptive mechanisms, unequivocal evidence for gender-related differences in human pain perception or modulation has only been provided recently. Gender-related differences may be related to constant differences in the physiology of pain perception, such as structural or functional differences in the visceral afferent pathways involved in pain transmission or modulation, and/or they may be related to fluctuations in female sex hormones.
Preliminary evidence suggests that female irritable bowel syndrome patients show specific perceptual alterations in regards to rectosigmoid balloon distension and that they show differences in regional brain activation measured by positron emission tomography. This preliminary evidence suggests that gender-related differences in symptoms and in the perceptual responses to visceral stimuli exist in IBS patients and can be detected using specific stimulation paradigms and neuroimaging techniques.     

A randomized controlled trial of a probiotic,VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome

AIM: To investigate the effects of a probiotic formulation, VSL#3, on gastrointestinal transit and symptoms of patients with Rome II irritable bowel syndrome with predominant diarrhoea. METHODS: Twenty-five patients with diarrhoea-predominant irritable bowel syndrome were randomly assigned to receive VSL#3 powder (450 billion lyophilized bacteria/day) or matching placebo twice daily for 8 weeks after a 2-week run-in period. Pre- and post-treatment gastrointestinal transit measurements were performed in all patients. Patients recorded their bowel function and symptoms daily in a diary during the 10-week study, which was powered to detect a 50% change in the primary colonic transit end-point. RESULTS: There were no significant differences in mean gastrointestinal transit measurements, bowel function scores or satisfactory global symptom relief between the two treatment groups, pre- or post-therapy. Differences in abdominal bloating scores between treatments were borderline significant (P = 0.09, analysis of covariance). Further analysis revealed that abdominal bloating was reduced (P = 0.046) with VSL#3 [mean post- minus pre-treatment score, - 13.7; 95% confidence interval (CI), - 2.5 to - 24.9], but not with placebo (P = 0.54) (mean post- minus pre-treatment score, - 1.7; 95% CI, 7.1 to - 10.4). With the exception of changes in abdominal bloating, VSL#3 had no effect on other individual symptoms: abdominal pain, gas and urgency. All patients tolerated VSL#3 well. CONCLUSION: VSL#3 appears to be promising in the relief of abdominal bloating in patients with diarrhoea-predominant irritable bowel syndrome. This is unrelated to an alteration in gastrointestinal or colonic transit.     

Irritable bowel syndrome and other gastrointestinal disorders: evaluating self-medication in an Asian community setting

Background Gastrointestinal disorders frequently present symptoms which are often self-treated. Objective To record demographic profile of patients visiting community pharmacies for self-treatment with medications for gastrointestinal disorders, the number of these patients who fulfilled irritable bowel syndrome diagnostic criteria, and to judge the appropriateness of their treatment requests. Setting Singapore community pharmacies. Method The multicentre study was conducted using ROME III adapted criteria on adults above 18?years who have self-selected medicinal products for treatment of irritable bowel syndrome or gastrointestinal symptoms in the community pharmacy. Results Among those seeking self-medication, 36.8?% fulfilled criteria for irritable bowel syndrome, with irritable bowel syndrome-mixed (16.3?%) being the most prevalent subtype. For patients not fulfilling criteria for irritable bowel syndrome diagnosis, rates for other functional gastrointestinal disorders were constipation (20.5?%), dyspepsia (16.3?%), gastroesophageal reflux disease (12.1?%), diarrhoea (8.9?%), bloating (4.2?%), and heartburn (3.2?%). There were more females with gastrointestinal complaints. Overall, 21.6?% of the total participants had recently sought medical attention for their gastrointestinal complaint. 20?% of patients selected inappropriate medication for their gastrointestinal complaints, and the antacids class had the highest incidence of inappropriate medication use. Possible co-existing relationships were seen between gastroesophageal reflux disease with dyspepsia, irritable bowel syndrome with gastroesophageal reflux disease, irritable bowel syndrome with dyspepsia, and diarrhoea with constipation. Conclusion Patients who fulfilled criteria for irritable bowel syndrome had a high tendency to self-treat their gastrointestinal symptoms. Constipation complaints were also common. Around one in five patients self-medicated gastrointestinal symptoms inappropriately, with antacids being the most common.     

The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study

BACKGROUND: Irritable bowel syndrome has been treated with selective serotonin reuptake inhibitors but there is not enough evidence from controlled trials to prove their effectiveness. AIM: To compare the effects of fluoxetine and placebo in the treatment of pain and constipation-predominant irritable bowel syndrome in a double-blind randomized-controlled trial. METHODS: Forty-four cases meeting Rome II criteria for irritable bowel syndrome with predominance of pain and constipation were included in this study. Organic causes were ruled out by detailed history, physical examination, laboratory tests and colonoscopy. Participants were then randomly assigned to receive either fluoxetine or placebo for 12 weeks. Symptoms addressed by the Rome II criteria were recorded during treatment and 4 weeks after termination of treatment. RESULTS: Fluoxetine was significantly more effective than placebo in decreasing abdominal discomfort, relieving feeling and sense of bloating, increasing frequency of bowel movements and decreasing consistency of stool. Mean number of symptoms per patient decreased from 4.6 to 0.7 in the fluoxetine group vs. 4.5 to 2.9 in controls (P < 0.001). CONCLUSIONS: Fluoxetine is an effective and well-tolerated short-term treatment for pain and constipation-predominant irritable bowel syndrome.     

Review article: bloating in functional bowel disorders

Bloating is a frequently reported symptom in functional bowel disorders. It usually occurs in combination with other symptoms, but may also occur in isolation. The severity of bloating tends to worsen during the course of the day and improves overnight. Although frequently considered to be a subjective phenomenon, recent studies have shown that bloating is associated with a measurable increase in abdominal girth. The pathophysiology of bloating remains elusive, but the evidence supports a sensorimotor dysfunction of the bowel. The possible mechanisms include abnormal gas trapping, fluid retention, food intolerance and altered gut microbial flora. Further studies are needed to define the sensorimotor abnormalities associated with bloating, which might be segmental and transient rather than generalized and persistent. The lack of understanding of this symptom is paralleled by a limited availability of therapeutic options. Conventional medications used in functional bowel disorders are not helpful and may indeed worsen the symptoms. In future, new drugs with activity against serotonin and kappa receptors, or novel approaches such as the use of exclusion diets, probiotics and hypnotherapy, may prove to be useful.     

Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome

Introduction: Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction. Areas covered: This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages. Expert opinion: Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.     

Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation

Background Analyses of a trial in constipated patients indicated that lubiprostone may be an effective treatment for irritable bowel syndrome with constipation. Aim To assess the efficacy and safety of three lubiprostone doses for irritable bowel syndrome with constipation. Methods 195 irritable bowel syndrome with constipation patients received daily doses of 16 [8 μg twice daily (b.d.)], 32 (16 μg b.d.) or 48 μg (24 μg b.d.) lubiprostone or placebo b.d. for 3 months. Gastrointestinal parameters were recorded in diaries daily by patients. Results After 1 month, lubiprostone showed significantly greater improvements in mean abdominal discomfort/pain scores vs. placebo (P = 0.023). After 2 months, all lubiprostone groups showed significantly greater improvements in mean abdominal discomfort/pain scores (P ≤ 0.039). After 3 months of treatment, the improvement in each lubiprostone arm was greater than placebo, but the test for trend was no longer significant. Treatment with lubiprostone showed significantly higher rates of gastrointestinal adverse events (P = 0.020), especially diarrhoea and nausea. Conclusion Lubiprostone significantly improved gastrointestinal symptoms of irritable bowel syndrome with constipation at all doses. Higher doses of lubiprostone, especially the 48 μg/day group, were associated with more gastrointestinal adverse events. From these data, the 16 μg/day dose demonstrated the optimal combination of efficacy and safety. These results warrant further study of lubiprostone for treatment of irritable bowel syndrome with constipation patients.     

Tegaserod: a serotonin 5-HT4 receptor agonist for treatment of constipation-predominant irritable bowel syndrome

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.     

The usual medical care for irritable bowel syndrome

AIMS: To determine what constitutes usual medical care for irritable bowel syndrome, which patient characteristics influence choice of treatment and how satisfied patients are with care. METHODS: Patient encounters in a health maintenance organization were prospectively monitored to identify visits coded irritable bowel syndrome, abdominal pain, constipation or diarrhoea. Within 2 weeks these patients were sent postal questionnaires (n = 1770, 59% participation) to assess patient characteristics and treatment recommendations. Responders were sent follow-up questionnaires 6 months later (77% participation) to assess adherence and satisfaction with treatment. RESULTS: Treatments employed most frequently were dietary advice, explanation, exercise advice, reassurance, advice to reduce stress and antispasmodic medications. Primary care physicians and gastroenterologists provided similar treatments. Patient confidence was higher for lifestyle advice (63-67, 100-point scale) than for medications (46-59). However, adherence was greater for medications (62-79 vs. 59-69, 100-point scale). Satisfactory relief was reported by 57%, but only 22% reported that symptom severity was reduced by half. Usual medical treatment was less effective for irritable bowel syndrome than for constipation, diarrhoea, or abdominal pain. CONCLUSIONS: Usual medical care for irritable bowel syndrome emphasizes education and lifestyle modification more than drugs; patients have a greater expectation of benefit from lifestyle modification than drugs. Overall 57% of irritable bowel syndrome patients report satisfactory relief.     

Utility of red flag symptom exclusions in the diagnosis of irritable bowel syndrome

BACKGROUND: Studies suggest that the positive predictive value of the Rome II criteria for diagnosing irritable bowel syndrome can be enhanced by excluding red flag symptoms suggestive of organic diseases. AIM: We assessed the utility of red flags for detecting organic diseases in patients diagnosed irritable bowel syndrome by their physicians. METHODS: Systematic chart reviews were completed in 1434 patients with clinical diagnoses of irritable bowel syndrome, abdominal pain, diarrhoea or constipation, who also completed questionnaires to identify Rome II criteria for irritable bowel syndrome and red flag symptoms. RESULTS: The overall incidence of gastrointestinal cancer was 2.5% (but 1.0% in those with irritable bowel syndrome), for inflammatory bowel disease 2.0% (1.2% in irritable bowel syndrome), and for malabsorption 1.3% (0.7% in irritable bowel syndrome). Red flags were reported by 84% of the sample. The positive predictive value of individual red flags for identifying organic disease was 7-9%. Excluding any patient with a red flag improved the agreement between Rome II and clinical diagnosis by a modest 5%, but left 84% of patients who were diagnosed with irritable bowel syndrome by their physicians, without a diagnosis. CONCLUSIONS: Red flags may be useful for identifying patients who require additional diagnostic evaluation, but incorporating them into the Rome criteria would not improve sensitivity and would result in too many missed irritable bowel syndrome diagnoses.     

曲美布汀治疗肠易激综合征的临床疗效

目的 :观察曲美布汀治疗肠易激综合征(IBS)的临床疗效。方法 :参照罗马Ⅱ标准 ,选择 60例IBS病人 ,随机分成治疗组和对照组 ,每组 30例。对照组男性 12例 ,女性 18例 ,年龄 (33±s 16)a。治疗组男性 13例 ,女性 17例 ,年龄 (31± 12 )a。 2组均给予谷维素 (2 0mg ,po ,tid)、维生素B1(2 0mg ,po ,tid)、维生素C (0 .2 g ,po ,tid)。治疗组加用曲美布汀 2 0 0mg ,po ,tid ,疗程 2wk。观察治疗前后IBS腹痛、腹泻、便秘、腹胀的情况。结果 :治疗组wk 1总有效率 67% ,wk 2总有效率 83%。wk 2腹痛缓解率 90 % ,腹泻缓解率 89% ,便秘缓解率77% ,腹胀缓解率 81%。无明显不良反应。结论 :曲美布汀是治疗IBS安全有效的药物     

Drug treatment of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) is defined as a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit, and with features of disordered defecation and distension. The irritable bowel syndrome occurs in 10 to 20% of people worldwide and is very commonly encountered in clinical practice. This has encouraged the pharmaceutical industry to search for effective drug therapy. So far, a universally effective agent has not been found, and since this is a chronic, benign disorder, beginning in youth, long term drug use should be avoided. Nevertheless, if a specific IBS symptom, such as constipation or abdominal pain dominates, a specific drug may be helpful. However, tests and treatment should be minimised or even avoided in order to do no harm. A largely nonpharmaceutical approach to IBS should be taken. This approach employs drugs sparingly and then only targeted at specific and resistant symptoms.     

Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist

BACKGROUND: No currently available treatment provides consistent relief of irritable bowel syndrome. Colonic sensory and motor function are modulated partly through 5HT3-receptors. AIM: To evaluate effects of the 5HT3-receptor antagonist, alosetron, in irritable bowel syndrome. METHODS: Randomized, double-blind, placebo-controlled, dose-ranging (1, 2, 4, 8 mg b.d. alosetron), 12-week trial in 370 patients with diarrhoea-predominant or alternating constipation and diarrhoea irritable bowel syndrome. Weekly measurement of adequate relief was the key end-point; other irritable bowel syndrome symptoms were collected daily using an electronic phone system. RESULTS: Alosetron (1 mg or 2 mg b.d.) significantly (P < 0.05 vs. placebo) increased the proportion of females, but not males, reporting adequate relief. Stool consistency, frequency and percentage days with urgency improved over placebo (P < 0.05) within the first month with all doses of alosetron, and persisted throughout the trial with all doses in female patients. With 1 mg b.d. alosetron, females had improved stool consistency and urgency within the first week, and adequate relief and improved stool frequency within the first 2 weeks. There was no consistent improvement in bowel function among male patients. CONCLUSION: In female irritable bowel syndrome patients with predominant diarrhoea or alternating constipation and diarrhoea, alosetron is effective in treatment of abdominal pain and discomfort and bowel-related symptoms.     

援生力维和小剂量抗抑郁药治疗难治性肠易激综合征的临床疗效

目的 观察援生力维和小剂量抗抑郁药治疗难治性肠易激综合征（IBS）的临床疗效。方法64例IBS患者，在谷雏素、维生素B1、维生素C等治疗基础上，治疗组加用援生力维200mg，3次／d，疗程4周。观察治疗前后患者腹痛、腹泻、便秘、腹胀的情况。结果治疗组4周末总有效率71．9％，8周末总有效率84、4％，均显著高于对照组（P＜0、01）；8周末腹痛缓解率86．7％，腹泻缓解率81．0％，便秘缓解率78、6％，腹胀缓解率81．3％，均明显高于对照组（P＜．05或0．01）。均无明显不良反应发生。结论援生力维和小剂量抗抑郁药治疗难治性IBS安全有效。