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Guts in IBS

Background. IBS affects 17 - 25% of general populationApprox. 50% IBS patients seek health care (predictors are age, female gender, abdominal pain, psychological distress)IBS accounts for 30

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Guts in IBS

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    1. Guts in IBS Dr Sameer Zar Consultant Gastroenterologist Epsom & St Helier NHS Trust

    2. Background IBS affects 17 - 25% of general population Approx. 50% IBS patients seek health care (predictors are age, female gender, abdominal pain, psychological distress) IBS accounts for 30 – 50% referrals to gastroenterology clinics Controversy whether IBS is a distinct disease entity or represents several different disease processes

    3. What’s new in IBS ? Definitions Epidemiology Pathophysiology Infection and Inflammation Food hypersensitivity Gut Flora Treatment 5HT4 agonists 5HT3 antagonists

    4. Definitions for IBS Defining the true phenotype or phenotypes is important in studying disease aetiology and identifying appropriate therapy Traditionally divided into three phenotypes: Diarrhoea predominant (D-IBS) Constipation predominant (C-IBS) ‘Alternators’ (A-IBS) No universal agreement on how best to define IBS and its subgroups Third point, Up until recently, there has been no universal agreement……. IBS was considered as a diagnosis of exclusion.Third point, Up until recently, there has been no universal agreement……. IBS was considered as a diagnosis of exclusion.

    5. Defining IBS – Road to Rome Manning Criteria 1989 Rome I Criteria 1994 Rome II Criteria 1999 Rome III criteria 2006 Over the years Various symptom base criteria have been proposed to define and diagnose IBS This started with the work by Manning and colleagues in 1989. Subsequently, an international working committee met in Rome and proposed a consensus definition of IBS and other functional disorders which were published in 1994. These were revised in 1999 and a further revision is set to come out in 2006. This, in essence, reflects recent advances in this field and our increasing understanding of this common yet complex disorder.Over the years Various symptom base criteria have been proposed to define and diagnose IBS This started with the work by Manning and colleagues in 1989. Subsequently, an international working committee met in Rome and proposed a consensus definition of IBS and other functional disorders which were published in 1994. These were revised in 1999 and a further revision is set to come out in 2006. This, in essence, reflects recent advances in this field and our increasing understanding of this common yet complex disorder.

    6. Manning Criteria Manning identified 6 symptoms which These symptom-based criteria have been introduced to encourage the clinicians to make a positive clinical diagnosis. However, none of these symptoms on its own is sufficient to make a diagnosis of IBS. It is usually the presence of a combination of symptoms which helps the physicians in making a positive diagnosis. Although these symptoms are significantly correlated to the diagnosis of IBS in female patients, the correlation in men is poor Manning identified 6 symptoms which These symptom-based criteria have been introduced to encourage the clinicians to make a positive clinical diagnosis. However, none of these symptoms on its own is sufficient to make a diagnosis of IBS. It is usually the presence of a combination of symptoms which helps the physicians in making a positive diagnosis. Although these symptoms are significantly correlated to the diagnosis of IBS in female patients, the correlation in men is poor

    7. Rome II Criteria

    8. Rome II – IBS subgroups Predominant stool pattern Abnormal stool frequency (a) >3/day (b) <3/day Abnormal stool form (c) loose/watery (d) lumpy/hard Abnormal passage (e) straining (f) urgency (g) incomplete evacuation Rome II criteria also attempted to classify the IBS subgroups based on predominant stool patternRome II criteria also attempted to classify the IBS subgroups based on predominant stool pattern

    9. Prevalence of IBS – Effect of definitions Lets look at the effect these various definitions has had on estimation of IBS prevalence in general population. As we can see from this study carried out by Saito and colleagues that as we use more precise definitions the population prevalence appears to be less. Some of these patients excluded from the diagnosis will fall under other functional gut disorders as defined by Rome committee. The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates. Saito YA, Talley NJ, J Melton L, Fett S, Zinsmeister AR, Locke GR. Division of Gastroenterology and Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN 55905, USA. saito.yuri@mayo.edu The 'Rome' criteria for irritable bowel syndrome (IBS) have evolved over 15 years with four published versions. The impact of these changes on community prevalence rates is not known. Study aims were to estimate the prevalence of IBS using the four Rome criteria and agreement between Rome II and previous criteria. Questionnaires were mailed to a random sample of Olmsted County, Minnesota residents in 1992. Age- and gender-adjusted prevalence estimates were calculated for Rome II (1999), Rome I (1992), Rome (1990), and Rome (1989) criteria. Per cent agreement and kappa values were calculated to assess agreement. Of 892 eligible subjects, 643 (72%) responded. The age- and gender-adjusted prevalence of IBS was 5.1% [95% confidence interval (CI): 3.1, 7.0], 6.8% (95% CI: 4.7, 8.9), 5.1% (95% CI: 3.2, 7.1) and 27.6% (95% CI: 23.6, 31.5), respectively. In comparison with Rome II criteria, per cent agreement and kappa values were 97.2% and 0.78 (95% CI: 0.69, 0.88), 96.4% and 0.68 (95% CI: 0.55, 0.80), and 79.0% and 0.29 (95% CI: 0.19, 0.40), respectively. Thus, although differences were seen with the older criteria, compared with the Rome I criteria, good agreement was seen and community prevalence estimates were similar with the Rome II criteria. Lets look at the effect these various definitions has had on estimation of IBS prevalence in general population. As we can see from this study carried out by Saito and colleagues that as we use more precise definitions the population prevalence appears to be less. Some of these patients excluded from the diagnosis will fall under other functional gut disorders as defined by Rome committee. The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates.

    10. Prevalence of IBS – Effect of definitions Lets look at the effect these various definitions has had on estimation of IBS prevalence in general population. As we can see from this study carried out by Saito and colleagues that as we use more precise definitions the population prevalence appears to be less. Some of these patients excluded from the diagnosis will fall under other functional gut disorders as defined by Rome committee. The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates. Saito YA, Talley NJ, J Melton L, Fett S, Zinsmeister AR, Locke GR. Division of Gastroenterology and Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN 55905, USA. saito.yuri@mayo.edu The 'Rome' criteria for irritable bowel syndrome (IBS) have evolved over 15 years with four published versions. The impact of these changes on community prevalence rates is not known. Study aims were to estimate the prevalence of IBS using the four Rome criteria and agreement between Rome II and previous criteria. Questionnaires were mailed to a random sample of Olmsted County, Minnesota residents in 1992. Age- and gender-adjusted prevalence estimates were calculated for Rome II (1999), Rome I (1992), Rome (1990), and Rome (1989) criteria. Per cent agreement and kappa values were calculated to assess agreement. Of 892 eligible subjects, 643 (72%) responded. The age- and gender-adjusted prevalence of IBS was 5.1% [95% confidence interval (CI): 3.1, 7.0], 6.8% (95% CI: 4.7, 8.9), 5.1% (95% CI: 3.2, 7.1) and 27.6% (95% CI: 23.6, 31.5), respectively. In comparison with Rome II criteria, per cent agreement and kappa values were 97.2% and 0.78 (95% CI: 0.69, 0.88), 96.4% and 0.68 (95% CI: 0.55, 0.80), and 79.0% and 0.29 (95% CI: 0.19, 0.40), respectively. Thus, although differences were seen with the older criteria, compared with the Rome I criteria, good agreement was seen and community prevalence estimates were similar with the Rome II criteria. Lets look at the effect these various definitions has had on estimation of IBS prevalence in general population. As we can see from this study carried out by Saito and colleagues that as we use more precise definitions the population prevalence appears to be less. Some of these patients excluded from the diagnosis will fall under other functional gut disorders as defined by Rome committee. The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates.

    11. Incidence of IBS: Olmsted County,MN This study looks at the incidence of IBS in population over time. The overall incidence is 196/100,000 person-years. The incidence increases with age and across all age groups is higher in women than menThis study looks at the incidence of IBS in population over time. The overall incidence is 196/100,000 person-years. The incidence increases with age and across all age groups is higher in women than men

    12. Challenging the Definitions 69% of general population report at least 1 of the functional GI syndromes in preceding 3 months Up to 34% of IBS patients appear to transition to another functional disorder Defining the correct chronicity of symptoms is difficult in clinical practice (12 weeks in last 12 months) Organic abnormalities are starting to be identified in some patients with ‘gold standard’ functional disorders Some have challenged the validity of these criteria. There are several reasons for this: (after first point) In other words if two thirds of people report symptom complexes, It may be abnormal not to have at least one symptom complex! (Locke et al neurogastro motili 2005) (after 2nd point) It can be questioned that whether these indeed do represent multiple discrete disordersSome have challenged the validity of these criteria. There are several reasons for this: (after first point) In other words if two thirds of people report symptom complexes, It may be abnormal not to have at least one symptom complex! (Locke et al neurogastro motili 2005) (after 2nd point) It can be questioned that whether these indeed do represent multiple discrete disorders

    13. Natural History of IBS – systematic review 14 studies met study selection criteria 1-9% had an alternative organic disorder after 30 years of follow-up Long term follow-up: 2-18% worse, 30-50% unchanged Factors predicting worse symptoms long-term Prior surgery (one study) Higher somatic scores (one study) Higher baseline anxiety (two studies) Depression (one study) Good outcome Short duration Constipation

    14. Genetics - IBS clusters in families Familial aggregation of irritable bowel syndrome: a prospective study. Kalantar JS, Locke GR 3rd, Zinsmeister AR, Beighley CM, Talley NJ. Department of Medicine, University of Sydney, Australia. BACKGROUND: Patients with irritable bowel syndrome (IBS) often report family members with similar symptoms, but family studies are lacking. We hypothesised that if there is familial aggregation, there would be an increased frequency of IBS in first degree relatives of IBS patients compared with relatives of controls (the patient's spouse). METHODS: A valid self report bowel disease questionnaire (BDQ) that recorded symptoms, the somatic symptom checklist (a measure of somatisation), and a family information form (FIF) to collect the names and addresses of all first degree relatives were mailed to two groups of patients and their spouses (patients attending an IBS educational programme and residents of Olmsted County, Minnesota, who had been coded as IBS on a database). A BDQ was then mailed to all first degree relatives of subjects identified from the FIF. IBS diagnosis in the relatives was based on the Manning criteria. RESULTS: The BDQ was sent to a total of 355 eligible relatives; 71% responded (73% relatives of patients, 67% relatives of spouses). Relatives were comparable in mean age, sex distribution, and somatisation score. IBS prevalence was 17% in patients' relatives versus 7% in spouses' relatives (odds ratio adjusted for age and sex 2.7 (95% confidence interval (CI) 1.2, 6.3)). When also adjusted for somatisation score, the odds ratio was reduced to 2.5 (95% CI 0.9, 6.7). CONCLUSIONS: Familial aggregation of IBS occurs, supporting a genetic or intrafamilial environment component, but this may be explained in part by familial aggregation of somatisation.Familial aggregation of irritable bowel syndrome: a prospective study.

    15. IBS – A Diagnosis of Exclusion In the absence of any objective criteria, doctors managing these patients are faced with the dilemma of making a diagnosis of IBS while accepting a certain degree of uncertainty. In order to help avoid misdiagnosis, certain red flags have been identified which should alert the physician regarding the possibility of an underlying organic pathology. These include h/o weight loss…., fever, pos occult blood and abnormal physical signs. In addition, most physicians perform routine hematology and biochemistry testing including…….. Some physicians as a routine will perform a colonoscopy or a flexible sigmoidoscopy and a Ba enema when symptoms are vague and/or patient is older than 55 years of age. In the absence of any objective criteria, doctors managing these patients are faced with the dilemma of making a diagnosis of IBS while accepting a certain degree of uncertainty. In order to help avoid misdiagnosis, certain red flags have been identified which should alert the physician regarding the possibility of an underlying organic pathology. These include h/o weight loss…., fever, pos occult blood and abnormal physical signs. In addition, most physicians perform routine hematology and biochemistry testing including…….. Some physicians as a routine will perform a colonoscopy or a flexible sigmoidoscopy and a Ba enema when symptoms are vague and/or patient is older than 55 years of age.

    16. Diagnosis of IBS – What Tests? In the absence of any objective criteria, doctors managing these patients are faced with the dilemma of making a diagnosis of IBS while accepting a certain degree of uncertainty. In order to help avoid misdiagnosis, certain red flags have been identified which should alert the physician regarding the possibility of an underlying organic pathology. These include h/o weight loss…., fever, pos occult blood and abnormal physical signs. In addition, most physicians perform routine hematology and biochemistry testing including…….. Some physicians as a routine will perform a colonoscopy or a flexible sigmoidoscopy and a Ba enema when symptoms are vague and/or patient is older than 55 years of age. In the absence of any objective criteria, doctors managing these patients are faced with the dilemma of making a diagnosis of IBS while accepting a certain degree of uncertainty. In order to help avoid misdiagnosis, certain red flags have been identified which should alert the physician regarding the possibility of an underlying organic pathology. These include h/o weight loss…., fever, pos occult blood and abnormal physical signs. In addition, most physicians perform routine hematology and biochemistry testing including…….. Some physicians as a routine will perform a colonoscopy or a flexible sigmoidoscopy and a Ba enema when symptoms are vague and/or patient is older than 55 years of age.

    17. IBS Red Flags In the absence of any objective criteria, doctors managing these patients are faced with the dilemma of making a diagnosis of IBS while accepting a certain degree of uncertainty. In order to help avoid misdiagnosis, certain red flags have been identified which should alert the physician regarding the possibility of an underlying organic pathology. These include h/o weight loss…., fever, pos occult blood and abnormal physical signs. In addition, most physicians perform routine hematology and biochemistry testing including…….. Some physicians as a routine will perform a colonoscopy or a flexible sigmoidoscopy and a Ba enema when symptoms are vague and/or patient is older than 55 years of age. In the absence of any objective criteria, doctors managing these patients are faced with the dilemma of making a diagnosis of IBS while accepting a certain degree of uncertainty. In order to help avoid misdiagnosis, certain red flags have been identified which should alert the physician regarding the possibility of an underlying organic pathology. These include h/o weight loss…., fever, pos occult blood and abnormal physical signs. In addition, most physicians perform routine hematology and biochemistry testing including…….. Some physicians as a routine will perform a colonoscopy or a flexible sigmoidoscopy and a Ba enema when symptoms are vague and/or patient is older than 55 years of age.

    18. What Tests ? Diseases Tests IBD Colonoscopy/FS Infectious Diarrhoea Stool O & P, Stool Culture Colon Cancer Colonoscopy/FS Lactose Intolerance Breath Tests Thyroid disease TFTs Cholelithiasis U/S Coeliac Disease Antibody testing +/- D2 Bx

    19. What Radiological/Endoscopic Studies do IBS Patients Get at Their Initial Visit?

    20. Prevalence of Organic Disease among IBS patients

    21. Prevalence of Organic Disease among IBS patients

    22. Testing in IBS? “Current best evidence does not support the routine use of blood tests, stool studies, breath tests, abdominal imaging or lower endoscopy in order to exclude organic GI disease in patients with ‘typical’ IBS symptoms without alarm features” Cash &Chey. AP&T 2004;19:1235-45 However, the truth is that the current …….. Thyroid disorders, liver disease, disorder of Ca metabolism, liver disease, IBD and CRC occur at the same rate as in general population. Many argue that routine testing for these conditions, unless supported by patients symptomatology, is not indicated. The only exception is testing for coeliac disease . However, the truth is that the current …….. Thyroid disorders, liver disease, disorder of Ca metabolism, liver disease, IBD and CRC occur at the same rate as in general population. Many argue that routine testing for these conditions, unless supported by patients symptomatology, is not indicated. The only exception is testing for coeliac disease .

    23. Is screening for coeliac disease justified in IBS patients?

    24. Testing for Coeliac in IBS UK study: 14/300 (5%) IBS patients positive for coeliac on duodenal biopsy vs. 2/300 controls Sanders, Lancet 2001; 358: 1504 Irish Study: 30/150 (20%) patients with coeliac disease met Rome criteria vs. 8/162 (5%) controls O’Leary AJG 2002; 97: 1463 German Study: 102 D-IBS patients, 0 had serum antibodies but 30% had abnormality in duodenal aspirate Wahnschaffe, Gastroenetrol 2001; 121: 1329 US population study: 4% IBS vs. 2.6% controls TTG +ve Locke, Mayo Clin Proc. 2004; 79: 476 Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Department of Gastroenterology and Infectious Diseases, Universitatsklinikum Benjamin Franklin, Freie Universitat Berlin, D-12200 Berlin, Germany. ulliwahn@zedat.fu-berlin.de BACKGROUND & AIMS: Abdominal symptoms in the absence of mucosal abnormalities are features of both the irritable bowel syndrome (IBS) and latent/potential celiac disease (cd). To identify a possible subgroup of IBS patients with latent/potential cd, surrogate markers of cd were investigated in IBS patients. METHODS: IBS patients suffering from diarrhea (n = 102), and patients with active cd (n = 10), treated cd (n = 26), and latent cd (n = 5) were included in the study. We measured serum immunoglobulin (Ig) A against gliadin and tissue-transglutaminase, and IgA and IgM against gliadin, tissue-transglutaminase (intestinal cd-associated antibodies), and the dietary proteins beta-lactoglobulin and ovalbumin in duodenal aspirate by enzyme-linked immunosorbent assay. Intraepithelial lymphocytes (IELs) were counted in histology sections, and the expression of HLA-DQ2 (A1*0501/B1*0201) was investigated by polymerase chain reaction. In 26 IBS patients, the effect of 6 months of gluten withdrawal was examined. RESULTS: Most cd patients expressed HLA-DQ2 and had increased intestinal cd-associated antibodies, whereas cd-associated serum IgA and IEL counts were increased in active cd in contrast to treated or latent cd. In IBS patients, 35% were HLA-DQ2-positive, 23% had increased IEL counts, and 0% and 30% had increased cd-associated antibodies in serum and duodenal aspirate, respectively. Furthermore, stool frequency and intestinal IgA decreased significantly under a gluten-free diet in the subgroups of HLA-DQ2-positive and intestinal antibody-positive IBS patients when compared with IBS patients without these markers. CONCLUSIONS: HLA-DQ2 expression and increased intestinal cd-associated antibodies are markers that can identify latent/potential cd in a subgroup of IBS patients who consequently appear to profit from a gluten-free diet. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome.

    25. Pathophysiology of IBS Moving on to the pathophysiology of IBS now. The previous simplified model of interaction between patients’ psyche with environmental stressors leading to dysmotility and visceral hypersensitivity has been challenged as well. There is increasing evidence that there is an organic component involved in the pathophysiology of this condition. The model has become more complex……Moving on to the pathophysiology of IBS now. The previous simplified model of interaction between patients’ psyche with environmental stressors leading to dysmotility and visceral hypersensitivity has been challenged as well. There is increasing evidence that there is an organic component involved in the pathophysiology of this condition. The model has become more complex……

    26. Pathophysiology of IBS Recent evidence suggests that IBS may not be purely a functional disorder. It is increasingly being recognised that it has an organic component to it in the form of a low grade inflammation. This inflammatory component may be triggered by microbial or dietary factors. The brain-gut axis on the other hand is likely to condition this response through various neurohormonal mediators. Recent evidence suggests that IBS may not be purely a functional disorder. It is increasingly being recognised that it has an organic component to it in the form of a low grade inflammation. This inflammatory component may be triggered by microbial or dietary factors. The brain-gut axis on the other hand is likely to condition this response through various neurohormonal mediators.

    27. CNS Contribution to GI Pain Chronic abdominal pain Functional GI disorders IBS Functional dyspepsia Chronic GI disorders GERD IBD Acute GI episodes Bowel obstruction Cholecystitis W all recognise the role of central modulation of pain in various GI conditions with an increasing contribution of central component to pain perception with chronic conditions and functional gut disorders.W all recognise the role of central modulation of pain in various GI conditions with an increasing contribution of central component to pain perception with chronic conditions and functional gut disorders.

    28. Brain-Gut influences on severity & treatment in IBS This CNS conditioning of pain perception involves both excitatory and inhibitory psychosocial and environmental factors and a cumulative effect of these factors is likely to determine the severity of symptoms experienced by the patients. Based on this model, antidepressants and behavioural therapies have been used to mange patients who are at the severe end of this spectrum. This CNS conditioning of pain perception involves both excitatory and inhibitory psychosocial and environmental factors and a cumulative effect of these factors is likely to determine the severity of symptoms experienced by the patients. Based on this model, antidepressants and behavioural therapies have been used to mange patients who are at the severe end of this spectrum.

    29. Tri-cyclic anti-depressants for IBS RCTs for tricyclics published in English Studies of low quality 1 TCAs appear to be effective at low doses Improvement in global symptoms (OR=4.2) and pain 2 NNT=3 Efficacious even if low quality studies are excluded 3 Can exacerbate constipation; sedation & weight gain also problematic

    30. SSRIs for treatment of IBS Mixed results to date Fluoxetine did not significantly alter rectal threshold for discomfort/pain relative to placebo; 53% of fluoxetine treated pts & 76% of placebo-treated pts reported significant abdominal pain scores after 6 wks (NS). Global symptom relief not altered1 NNT=3 Over-all well being improved more with paroxetine than with placebo (63% vs. 26%; p=0.01), but abdominal pain, bloating, and social functioning did not 2

    31. Psychological Therapies for IBS Cognitive-behavioural therapy Hypnotherapy Relaxation/Stress management Interpersonal therapy Available studies suggest benefit: 17 provided data suitable for meta-analysis 50% reduction of symptoms: OR = 12 (95% CI 5.56-25.96) ?heterogeneity NNT = 2

    32. Post-infectious IBS One third of IBS patients have a h/o acute gastroenteritis at the onset of IBS Chaudhry et al . Quart J Med 1962; 31:307-322 Incidence is higher in individuals who had severe infection & were hospitalised Most common organisms responsible were Salmonella and Campylobacter RR of post-infectious IBS 11.9 (6.7-21.0) Rodriguez et al. BMJ 1999; 318(7183): 565-566

    33. Post-infectious IBS

    34. Post-infectious IBS

    35. Risk Factors for Post-infectious IBS <60 years of age Females Absence of vomiting Prolonged diarrhoeal illness Hypochondriasis Stressful life events in year preceding infection

    36. Bacterial Overgrowth and IBS? May explain Bloating and Gas In Support Greater hydrogen excretion after lactulose ingestion Increased prevalence of abnormal lactulose breath test in IBS Improvement of IBS symptoms after antibiotics Against Lack of culture positive studies Lin JAMA, 2004; 292: 852-8 Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. Lin HC. Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA. henry.c.lin@usc.edu CONTEXT: Irritable bowel syndrome (IBS), which affects 11% to 14% of the population, is a puzzling condition with multiple models of pathophysiology including altered motility, visceral hypersensitivity, abnormal brain-gut interaction, autonomic dysfunction, and immune activation. Although no conceptual framework accounts for all the symptoms and observations in IBS, a unifying explanation may exist since 92% of these patients share the symptom of bloating regardless of their predominant complaint. EVIDENCE ACQUISITION: Ovid MEDLINE was searched through May 2004 for relevant English-language articles beginning with those related to bloating, gas, and IBS. Bibliographies of pertinent articles and books were also scanned for additional suitable citations. EVIDENCE SYNTHESIS: The possibility that small intestinal bacterial overgrowth (SIBO) may explain bloating in IBS is supported by greater total hydrogen excretion after lactulose ingestion, a correlation between the pattern of bowel movement and the type of excreted gas, a prevalence of abnormal lactulose breath test in 84% of IBS patients, and a 75% improvement of IBS symptoms after eradication of SIBO. Altered gastrointestinal motility and sensation, changed activity of the central nervous system, and increased sympathetic drive and immune activation may be understood as consequences of the host response to SIBO. CONCLUSIONS: The gastrointestinal and immune effects of SIBO provide a possible unifying framework for understanding frequent observations in IBS, including postprandial bloating and distension, altered motility, visceral hypersensitivity, abnormal brain-gut interaction, autonomic dysfunction, and immune activation. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome.

    37. Antibiotics in IBS Randomised 55 Neomycin 56 placebo Composite IBS score reduction >49% (0-15) Neomycin 43% vs. placebo 23% Response males = females Methane excretors in C-IBS but not in D-IBS Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Pimentel M, Chow EJ, Lin HC. GI Motility Program, Department of Medicine, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. OBJECTIVE: We have recently found an association between abnormal lactulose breath test (LBT) findings and irritable bowel syndrome (IBS). The current study was designed to test the effect of antibiotic treatment for IBS in a double-blind fashion. METHODS: Consecutive IBS subjects underwent an LBT with the results blinded. All subjects were subsequently randomized into two treatment groups (neomycin or placebo). The prevalence of abnormal LBT was compared with a gender-matched control group. Seven days after completion of treatment, subjects returned for repeat LBT. A symptom questionnaire was administered on both days. RESULTS: After exclusion criteria were met, 111 IBS subjects (55 neomycin, 56 placebo) entered the study, with 84% having an abnormal LBT, compared with 20% in healthy controls (p < 0.01). In an intention-to-treat analysis of all 111 subjects, neomycin resulted in a 35.0% improvement in a composite score, compared with 11.4% for placebo (p < 0.05). Additionally, patients reported a percent bowel normalization of 35.3% after neomycin, compared with 13.9% for placebo (p < 0.001). There was a graded response to treatment, such that the best outcome was observed if neomycin was successful in normalizing the LBT (75% improvement) (one-way ANOVA, p < 0.0001). LBT gas production was associated with IBS subgroup, such that methane excretion was 100% associated with constipation-predominant IBS. Methane excretors had a mean constipation severity of 4.1, compared with 2.3 in all other subjects (p < 0.001). CONCLUSIONS: An abnormal LBT is common in subjects with IBS. Normalization of LBT with neomycin leads to a significant reduction in IBS symptoms. The type of gas seen on LBT is also associated with IBS subgroup.Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study.

    38. Rifaximin in IBS Semi-synthetic non-systemic anti-microbial agent (derivative of rifamycin) Efficacious in traveller's diarrhoea Used for bacterial overgrowth Promising in IBS! E. coli shown to develop resistance to rifaximin in vitro, but probably less of a problem than with other antibiotics Antibiotics for inflammatory bowel disease: do they work? Guslandi M. Gastroenterology Unit, S. Raffaele University Hospital, Milan, Italy. guslandi.mario@hsr.it A growing amount of evidence indicates that the intestinal flora plays a pathogenic role in inflammatory bowel disease (IBD): hence, the use of anti-bacterial agents as ancillary treatment in patients with ulcerative colitis, or Crohn's disease. While the results with anti-tubercular agents remain inconclusive, antibiotic treatment in IBD is usually carried out with either metronidazole or ciprofloxacin, or both. Controlled trials are scarce and, although both antibiotics appear to provide clinical benefit, definitive conclusions cannot be drawn and precise therapeutic guidelines cannot be suggested. The best results are achieved in the long-term treatment of Crohn's disease and in the management of pouchitis, or of perianal Crohn's disease. Long-term tolerability of antibiotic treatment may be poor due to the appearance of systemic side-effects. The use of non-absorbable anti-bacterial agents such as rifaximin deserves further investigation Minerva Gastroenterol Dietol. 2006 Mar;52(1):89-95. Related Articles, Links Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with rifaximin. Cuoco L, Salvagnini M. Gastroenterology Unit, S. Bortolo Hospital, Vicenza, Italy. AIM: Irritable bowel syndrome (IBS) is a frequent diagnosis in gastroenterology, but it is now clear that an altered dynamic equilibrium and bacterial overgrowth in the small intestine may mimic an IBS-like syndrome. METHODS: We have, therefore, evaluated the real prevalence of small intestinal bacterial overgrowth (SIBO) by retrospectively examining the glucose hydrogen (H(2)) breath test in 96 patients with a previous symptoms-based IBS diagnosis. Moreover, we wished to evaluate the efficacy of the locally acting antibiotic rifaximin in eradicating a SIBO syndrome. RESULTS: The breath test showed a SIBO syndrome in 44 out 96 IBS patients (45.8%), who had H(2) peaks in the expired air higher than 10 ppm over the baseline value (mean: 36.2+/-18.7 ppm). All these patients were treated with rifaximin (1 200 mg/day for 14 days) followed by a twenty-day cycle of probiotics. Twenty-three of them returned to a control visit within 4-5 months: the glucose breath test became negative in 19 cases (82.6%; P<0.01) and mean peak value of H(2) significantly decreased from 40.9+/-20.4 to 4.78+/-8.42 ppm (P<0.001). Patients reported also a substantial improvement of the IBS symptoms. No adverse effect was observed. CONCLUSIONS: These data indicate a SIBO syndrome is present in about half of patients with an IBS diagnosis and, therefore, it should always be suspected in these patients. Moreover, the use of broad-spectrum non absorbable antibiotics, such as rifaximin, represents a safe and effective approach to SIBO with a low risk of causing microbial resistance A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Sharara AI, Aoun E, Abdul-Baki H, Mounzer R, Sidani S, Elhajj I. Gastroenterology Division, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. AIMS: To study the efficacy of rifaximin, a nonabsorbable antibiotic, in relieving chronic functional symptoms of bloating and flatulence. METHODS: Randomized double-blind placebo-controlled trial consisting of three 10-day phases: baseline (phase 1), treatment with rifaximin 400 mg b.i.d. or placebo (phase 2), and post-treatment period (phase 3). Primary efficacy variable was subjective global symptom relief at the end of each phase. A symptom score was calculated from a symptom diary. Lactulose H2-breath test (LHBT) was performed at baseline and end of study. RESULTS: One hundred and twenty-four patients were enrolled (63 rifaximin and 61 placebo). Baseline characteristics were comparable and none had an abnormal baseline LHBT. Rome II criteria were met in 58.7% and 54.1%, respectively. At the end of phase 2, there was a significant difference in global symptom relief with rifaximin versus placebo (41.3% vs 22.9%, p = 0.03). This improvement was maintained at the end of phase 3 (28.6% vs 11.5%, p = 0.02). Mean cumulative and bloating-specific scores dropped significantly in the rifaximin group (p < 0.05). Among patients with IBS, a favorable response to rifaximin was noted (40.5% vs 18.2%; p = 0.04) persisting by the end of phase 3 (27% vs 9.1%; p = 0.05). H2-breath excretion dropped significantly among rifaximin responders and correlated with improvement in bloating and overall symptom scores (p = 0.01). No adverse events were reported. CONCLUSIONS: Rifaximin is a safe and effective treatment for abdominal bloating and flatulence, including in IBS patients. Symptom improvement correlates with reduction in H2-breath excretion. Future trials are needed to examine the efficacy of long-term or cyclic rifaximin in functional colonic disorders. Antibiotics for inflammatory bowel disease: do they work?

    39. Probiotics for IBS Probiotic bacteria may have anti-inflammatory effects on GI mucosa 2 four wk studies found that L. plantarum is better than placebo for IBS Abd pain1,2, flatulence2 VSL #3 improved bloating but not global symptoms, pain, urgency or transit in IBS with diarrhoea3 Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Nobaek S, Johansson ML, Molin G, Ahrne S, Jeppsson B. Department of Surgery, Lund University, Lund University Hospital, Sweden. OBJECTIVE: The influence of the gastrointestinal (GI) microflora in patients with irritable bowel syndrome (IBS) has not been clearly elucidated. This study was undertaken to see if patients with IBS have an imbalance in their normal colonic flora, as some bacterial taxa are more prone to gas production than others. We also wanted to study whether the flora could be altered by exogenous supplementation. In a previous study we have characterized the mucosa-associated lactobacilli in healthy individuals and found some strains with good colonizing ability. Upon colonization, they seemed to reduce gas formation. METHODS: The study comprised 60 patients with IBS and a normal colonoscopy or barium enema. Patients fulfilling the Rome criteria, without a history of malabsorption, and with normal blood tests underwent a sigmoidoscopy with biopsy. They were randomized into two groups, one receiving 400 ml per day of a rose-hip drink containing 5 x 10(7) cfu/ml of Lactobacillus plantarum (DSM 9843) and 0.009 g/ml oat flour, and the other group receiving a plain rose-hip drink, comparable in color, texture, and taste. The administration lasted for 4 wk. The patients recorded their own GI function, starting 2 wk before the study and continuing throughout the study period. Twelve months after the end of the study all patients were asked to complete the same questionnaire regarding their symptomatology as at the start of the study. RESULTS: All patients tolerated the products well. The patients receiving Lb. plantarum had these bacteria on rectal biopsies. There were no major changes of Enterobacteriaceae in either group, before or after the study, but the Enterococci increased in the placebo group and remained unchanged in the test group. Flatulence was rapidly and significantly reduced in the test group compared with the placebo group (number of days with abundant gas production, test group 6.5 before, 3.1 after vs 7.4 before and 5.6 after for the placebo group). Abdominal pain was reduced in both groups. At the 12-month follow-up, patients in the test group maintained a better overall GI function than control patients. There was no difference between the groups regarding bloating. Fifty-nine percent of the test group patients had a continuous intake of fermented products, whereas the corresponding figure for the control patients was 73%. CONCLUSIONS: The results of the study indicate that the administration of Lb. plantarum with known probiotic properties decreased pain and flatulence in patients with IBS. The fiber content of the test solution was minimal and it is unlikely that the fiber content could have had any effect. This type of probiotic therapy warrants further studies in IBS patients. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Kim HJ, Vazquez Roque MI, Camilleri M, Stephens D, Burton DD, Baxter K, Thomforde G, Zinsmeister AR. Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Group, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. AIM: To evaluate the effects of a combination probiotic on symptoms and colonic transit in patients with irritable bowel syndrome (IBS) and significant bloating. METHODS: Forty-eight patients with Rome II IBS were randomized in a parallel group, double-blind design to placebo or VSL# 3 twice daily (31 patients received 4 weeks and 17 patients 8 weeks of treatment). Pre- and post-treatment colonic transit measurements were performed using scintigraphy with (111)In charcoal. Symptoms were summarized as an average daily score for the entire period of treatment and separately for the first 4 weeks of treatment. Weekly satisfactory relief of abdominal bloating was assessed. RESULTS: Treatment with VSL# 3 was associated with reduced flatulence over the entire treatment period (placebo 39.5 +/- 2.6 vs VSL# 3 29.7 +/- 2.6, P = 0.011); similarly, during the first 4 weeks of treatment, flatulence scores were reduced (placebo 40.1 +/- 2.5 vs VSL# 3 30.8 +/- 2.5, P = 0.014). Proportions of responders for satisfactory relief of bloating, stool-related symptoms, abdominal pain and bloating scores were not different. Colonic transit was retarded with VSL# 3 relative to placebo (colon geometric center 2.27 +/- 0.20 vs 2.83 +/- 0.19, P = 0.05 respectively). CONCLUSION: VSL# 3 reduces flatulence scores and retards colonic transit without altering bowel function in patients with IBS and bloating.Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome.

    40. Food Hypersensitivity in IBS 20 – 65% of IBS patients attribute symptoms to adverse food reactions Estimated prevalence of food hypersensitivity is 1.4 – 1.8% in general population Young et al, Lancet 1994; 343: 1127-30 Exclusion diets may be beneficial in IBS patients

    41. Exclusion Diets in IBS In 1982, Jones et al first evaluated the usefulness of exclusion diet in 25 IBS One week of exclusion diet (single meat, fruit and water) Symptom improved in 14/21 (67%) Double-blind provocation in 6 patients Patients correctly identified 10/12 test days and 11/12 control days

    42. Exclusion Diets in IBS

    43. Exclusion Diets in IBS

    44. Food hypersensitivity in extra-intestinal allergic disorders IgE mediated food hypersensitivity has been demonstrated in atopic dermatitis, allergic rhinitis,urticaria and asthma Pelikan 1998, Yunginger1988 Michaelsson 1973, Sampson 1985 Food specific IgG4 abs are elevated in atopic eczema and respiratory allergic disorders Merrett et al 1984, Shakib et al 1986 Food specific abs of either IgG4 or IgE class may predominate in an individual with food allergy El-rafie et al 1989, Awazuhara et al 1997

    45. IgE mediated food hypersensitivity in IBS Total serum IgE & RAST but not skin prick tests predict response to food elimination in atopic IBS but not in non-atopic IBS Petitpierre 1985, Zwetchkenbaum 1988 Paediatric IBS with elevated total IgE and/or h/o allergy have increased intestinal permeability (9/17) Barau et al 1990 75% (236/312) patients with food hypersensitivity have increased IgE Fc fragment in faecal extracts (22/32 or 68% IBS) Andre et al 1995

    46. Serum IgG4 and IgE in IBS IgE & IgG4 titres to 16 common foods using FEIA 108 IBS (52 D-IBS, 32 C-IBS & 24 A-IBS) & 43 controls Foods tested included milk, eggs, cheese, wheat, red meats, chicken, fish, potatoes, rice, tomatoes & shrimps No significant difference in IgE titres in IBS vs. controls IgG4 titres to common foods are significantly elevated in IBS vs. controls

    47. Food specific IgG4 antibodies in IBS

    49. Disodium Cromoglycate (DSCG) in IBS DSCG inhibits release of inflammatory mediators from mast cells 428 IBS patients were randomised to receive DSCG or exclusion diet DSCG was as effective as elimination diet (67% vs. 60%) Response was greater in patients with a positive skin prick test to food allergens in both groups (75% vs. 54% in elimination diet gp and 81% vs. 58% in DSCG gp)

    50. ‘Colonoscopic allergen provocation test’ 70 pts with suspected food hypersensitivity Sub-mucosal inj of suspected foods ‘extracts’ in caecum Weal and flare response Positive test in 77% (54/70) of which 74% (39/53) IBS Response to exclusion diet in 83% (29/35) at 3/12 Poor relationship with skin prick test and specific IgE 5 Controls had no response to any antigen tested

    51. Effect of IgG4 Guided exclusion diet in IBS 25 IBS (3M/22F; mean age 42) IgG4 titres to 16 common foods (FEIA) Foods with titres =250 ľg/L excluded x 6/12 On average 8 foods excluded (range 3-13) Symptoms assessed at baseline, 3- & 6-months Rectal compliance & sensitivity measured at baseline & 6-months using barostat

    52. Effect of exclusion diet in IBS

    53. Effect of exclusion diet on Rectal Compliance in IBS

    54. IgG4 guided exclusion diet in IBS Double blind, randomised controlled trial Specific IgG4 ab titres to a panel of 29 foods tested A cut off value of 3 x background signal of the sample was taken as ‘positive test’ Patients were randomised to ‘true’ diet or sham diet x 12 weeks Symptom severity was assessed using visual analogue scale

    55. IgG4 guided exclusion diet in IBS

    56. Randomised controlled trial of IgG food elimination

    57. Mast Cells

    59. Mast Cells in IBS In 1962, Hiatt and Katz reported increased mast cells in the muscle layer of 4 surgical specimens of ‘spastic colitis’ IBS patients have increased mast cells in terminal ileum Weston et al Dig Dis Sci 1993; 38: 38: 1590-5 Yang et al demonstrated increased mast cells in close proximity to unmyelinated nerve fibres in IBS Yang et al 1997 Gradient of mast cells is seen from terminal ileum, caecum to rectum in IBS patients unpublished data

    60. Inflammatory Cells in IBS

    61. Mast Cells in IBS

    62. Pathogenetic model for food hypersensitivity in IBS

    63. Serotonin (5HT) in the GI Tract

    64. Mucosal 5-HT and SERT in IBS: a molecular defect? 5-HT, tryptophan hydroxylase 1 mRNA, SERT mRNA & SERT immunoreactivity all significantly ? in UC, C-IBS & D-IBS Enterochromaffin cells ? in severe UC but unchanged in C-IBS & D-IBS No change in 5-HT release Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM, Moses PL. Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT 05405, USA. BACKGROUND & AIMS: Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. METHODS: Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. RESULTS: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. CONCLUSIONS: These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.

    65. Role of Serotonin in IBS Increased plasma post-prandial 5HT levels in D-IBS Bearcroft et al. Gut 1998;42:42-46 Increased number of EC cells in post-infectious IBS Spiller et al. Gut 2000; 47:804 Clinical differences in IBS may be related to genetic polymorphisms in the transporter gene for 5-HT reuptake (SERT) Camilleri et al Gastroenterology 2002; 123:425-432 Moses et al. AJG 2003; 98: S262-263

    66. Pharmacological effects of Tegaserod Stimulates 5-HT4 receptors Stimulates the peristaltic reflex Induces chloride secretion in the intestine* Reduces visceral sensitivity* *Animal data

    67. Tegaserod (5HT4 agonist)

    68. Clinical trials of Tegaserod for C-IBS

    69. Clinical trials of Tegaserod for C-IBS RR of being a responder (global relief) higher on 12mg (RR 1.19, 95%CI 1.09, 1.29) vs. placebo NNT =14 Tegaserod for the treatment of irritable bowel syndrome. Evans BW, Clark WK, Moore DJ, Whorwell PJ. Department of Medicines Management, Keele University, Newcastle-under-Lyme, Staffordshire, UK, ST5 5BG. BACKGROUND: IBS is a complex disorder that encompasses a wide profile of symptoms. Current drug treatments for irritable bowel syndrome (IBS) are of limited value. Many target specific symptoms only. Tegaserod, a 5HT(4) partial agonist, represents a novel mechanism of action in the treatment of IBS. OBJECTIVES: The objective of this review was to evaluate the efficacy and tolerability of tegaserod for the treatment of IBS in adults and adolescents aged 12 years and above. SEARCH STRATEGY: MEDLINE 1966-November 2002 and EMBASE 1980-November 2002 were searched. The text and key words used included "tegaserod", "HTF 919", "irritable bowel", and "colonic diseases, functional". The Cochrane Central Register of Controlled Trials, the Inflammatory Bowel Disease Review Group Specialized Trials Register, and Science Citation Index were also searched. Proceedings from the British Society of Gastroenterology Annual Meeting, and Digestive Disease Week (1998-2002) were hand searched. The manufacturer of tegaserod was contacted. Relevant articles were retrieved, and their reference lists were also reviewed. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing tegaserod with placebo, no treatment or any other intervention (pharmacological or non-pharmacological) in subjects aged 12 years and above with a diagnosis of IBS, focusing on clinical endpoints were considered for review. DATA COLLECTION AND ANALYSIS: Study inclusion and exclusion, data extraction and quality assessment was undertaken by two reviewers independently. Meta-analysis was performed where study populations, designs, outcomes, and statistical reporting allowed combination of data in a valid way, using the summary statistic relative risk with 95% CI.Eight short-term placebo-controlled studies fulfilled our inclusion criteria. These were predominantly conducted in women. Seven studies evaluated the efficacy of tegaserod on global gastrointestinal (GI) symptoms in patients with constipation-predominant IBS (C-IBS). One small study evaluated safety in patients with diarrhoea-predominant IBS. MAIN RESULTS: The relative risk (RR) of being a responder in terms of global relief of GI symptoms was significantly higher with tegaserod 12 mg (RR 1.19, 95% CI 1.09, 1.29) and tegaserod 4 mg (RR 1.15, 95% CI 1.02, 1.31) compared with placebo, with a number needed to treat (NNT) of 14 and 20 respectively. When all tegaserod doses were combined and compared with placebo (n=4040), the RR of being a responder was 1.17 (95% CI 1.08, 1.27), with a NNT of 17. Although the pooled results indicate statistically significant benefit with tegaserod, the a priori minimal clinically important differences set in two of the four pooled studies were not reached. Tegaserod did not significantly improve the patients' individual symptoms of abdominal pain and discomfort although bowel habit showed a statistically significant improvement with tegaserod 4 mg and there was a non-significant trend in favour of tegaserod 12 mg. When GI symptoms were assessed separately, those indicative of GI motility such as number of bowel movements and days without bowel movements were generally improved with tegaserod although the proportion of patients experiencing diarrhoea was significantly higher in the tegaserod 12 mg group compared with placebo (RR 2.75, 95% CI 1.90, 3.97), with a number needed to harm (NNH) of 20. Effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies. REVIEWER'S CONCLUSIONS: Tegaserod appears to improve the overall symptomatology of IBS but there are currently few data on its effect on quality of life. In addition, more information is needed about its efficacy in men. It would also be of interest to know whether treatment with tegaserod leads either directly, or indirectly, to changes in visceral sensitivity or psychopathology, which are also considered important in the pathophysiology of this condition.Tegaserod for the treatment of irritable bowel syndrome.

    70. Tegaserod : Long-term Safety Multi-centre open-label, 12-month study of tegaserod in 579 C-IBS patients Dose 2mg bid x 1 month, then 2mg or 6mg bid for the following month 53% patients completed the trial AEs: Mild & transient (diarrhoea 10.1%; headache 8.3%; abdominal pain 7.4%; flatulence 5.5%) Tegaserod was well tolerated and data suggest that treatment is safe over 12-months Long-term safety of tegaserod in patients with constipation-predominant irritable bowel syndrome. Tougas G, Snape WJ Jr, Otten MH, Earnest DL, Langaker KE, Pruitt RE, Pecher E, Nault B, Rojavin MA. Medicine and Gastroenterology, McMaster University Medical Center, Hamilton, Canada. BACKGROUND: Tegaserod is a 5-hydroxytryptamine-4 receptor partial agonist. Oral administration causes gastrointestinal effects resulting in increased gastrointestinal motility and attenuation of visceral sensation. AIM: : To determine the long-term safety and tolerability of tegaserod in patients suffering from irritable bowel syndrome with constipation as the predominant symptom of altered bowel habits. METHOD: A multicentre, open-label study with flexible dose titration of tegaserod in out-patients suffering from constipation-predominant irritable bowel syndrome. RESULTS: A total of 579 patients with constipation-predominant irritable bowel syndrome were treated with tegaserod. Of these, 304 (53%) completed the trial. The most common adverse events, classified as related to tegaserod for any dose, were mild and transient diarrhoea (10.1%), headache (8.3%), abdominal pain (7.4%) and flatulence (5.5%). Forty serious adverse events were reported in 25 patients (4.4% of patients) leading to discontinuation in six patients. There was one serious adverse event, acute abdominal pain, classified as possibly related to tegaserod. There were no consistent differences in adverse events between patients previously exposed to tegaserod and those treated de novo. No pattern-forming tegaserod-related abnormalities in haematological and biochemical laboratory tests, urinalysis, blood pressure, pulse rate or electrocardiograms were found. CONCLUSIONS: Tegaserod appears to be well tolerated in the treatment of patients with constipation-predominant irritable bowel syndrome. The adverse event profile, clinical laboratory evaluations, vital signs and electrocardiogram recordings revealed no evidence of any unexpected adverse events, and suggest that treatment is safe over a 12-month period.Long-term safety of tegaserod in patients with constipation-predominant irritable bowel syndrome.

    71. Tegaserod (5HT4 agonist) in C-IBS The 5-HT4 receptor agonist tegaserod is more effective than placebo at relieving global IBS symptoms in female IBS patients with constipation (Grade A recommendation)

    72. 5-HT3 Antagonists for D-IBS Visceral afferent effects ENS effects Delays colonic transit Decreases colonic tone Inhibits Cl- secretion Blunts the gastro-colonic response Central effects Anti-emetic properties Benefits in anxious or neurotic?

    73. Alosetron for D-IBS in women 5HT3 antagonist NNT = 7 In USA approved only for women with severe D-IBS (<5% of IBS) Risk= ischaemic colitis 0.15% Start at 1mg od for 4 wks. If well tolerated and symptoms not controlled, can be increased to 1mg bd Safety and efficacy in men has not been established Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Cremonini F, Delgado-Aros S, Camilleri M. Clinical Enteric Neuroscience, Translational & Epidemiological Research Program, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. The 5HT3 receptor antagonist alosetron has been tested in several trials on irritable bowel syndrome (IBS) patients. The aim of the present meta-analysis was to determine its effect on adequate relief of pain or global improvement of symptoms in IBS patients. Six large, multicentre, randomized, placebo-controlled trials fulfilled pre-set criteria for high quality and were included in the meta-analysis; 1762 patients were randomized to alosetron treatment and 1356 to placebo. Seventy-five per cent of the patients experienced diarrhoea-predominant IBS and 93% were females. The pooled odds ratio for adequate relief of pain or global symptoms improvement was 1.81 [95% confidence interval (CI) 1.57-2.10). The average number of patients needed to treat with alosetron for one patient to achieve improvement over placebo treatment was seven (95% CI 5.74-9.43). The present analysis shows that alosetron 1 mg b.i.d. positively impacts global symptoms, and pain and discomfort in non-constipated IBS female patients. One in four patients treated with alosetron may develop constipation. The efficacy of alosetron is unclear in male patients.Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials.

    74. Alosetron for D-IBS in men 662 randomised to alosetron or placebo twice daily 12 weeks All doses of alosetron significantly reduced stool consistency scores (p<0.001) One subject taking 0.5mg bid developed ischaemic colitis A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS. Chang L, Ameen VZ, Dukes GE, McSorley DJ, Carter EG, Mayer EA. Center for Neurovisceral Sciences and Women's Health, UCLA Division of Digestive Diseases, Los Angeles, California, USA. BACKGROUND: A randomized, double blind, placebo-controlled dose-ranging study was conducted to assess the efficacy of alosetron in men with diarrhea-predominant irritable bowel syndrome (IBS). METHODS: Six hundred and sixty-two men were randomized to treatment with alosetron 0.5, 1.0, 2.0, 4.0 mg, or placebo twice daily for 12 wk, followed by a 4-wk posttreatment period. Adequate relief of IBS pain and discomfort during week 5-12 of the treatment phase was the primary endpoint; secondary endpoints included bowel urgency, stool frequency, and consistency, incomplete evacuation, bloating, and abdominal pain or discomfort. RESULTS: Subjects ranked urgency and abdominal pain as their most bothersome IBS symptoms. The average rate of adequate relief during week 5-12 was significantly higher in the alosetron 1.0 mg twice-daily group compared to placebo (53%vs 40%, p= 0.04), and all doses of alosetron significantly reduced stool consistency scores (p < 0.001) indicating firmer stools. No significant effects of alosetron were seen with regard to urgency, number of bowel movements, bloating, and incomplete evacuation. Constipation was the most common adverse event and occurred in a dose-related manner among subjects receiving alosetron, 9% (0.5 mg twice daily), 15% (1.0 mg twice daily), 11% (2.0 mg twice daily), and 21% (4.0 mg twice daily). No serious adverse events of constipation were reported. One subject in the 0.5 mg twice-daily group had an episode of rectal bleeding suggestive of a possible diagnosis of ischemic colitis. CONCLUSIONS: Alosetron 1 mg twice daily provided adequate relief of IBS pain and discomfort, and improved stool consistency in men with diarrhea-predominant IBS.A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS.

    75. Alosetron (5-HT3) Antagonists for D-IBS The 5 HT3-receptor antagonist alosetron is more effective than placebo at relieving global IBS symptoms in female IBS patients with diarrhoea (Grade A recommendation)

    76. Ischaemic colitis and IBS: Systematic Review Four studies reported the general population incidence of ischaemic colitis: range 4.5-44 cases per 100,000 person-years Two reported the disease-specific population incidence in IBS Risk increased 2-4 fold by prevalent IBS Risk higher in females and in those >64 years

    77. Ischaemic colitis and IBS: Systematic Review

    78. What’s new in IBS ? Consensus Definitions Epidemiology Pathophysiology Infection and Inflammation Food hypersensitivity Gut Flora New Treatments 5HT4 agonists 5HT3 antagonists

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