Viola Andresen

Effects of 5-Hydroxytryptamine (Serotonin) Type 3 Antagonists on Symptom Relief and Constipation in Nonconstipated Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BACKGROUND & AIMS We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT(3)) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)-irritable bowel syndrome (IBS). METHODS Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT(3) antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently. RESULTS We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT(3) antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49-1.72; I(2) = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-1.39; I(2) = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28-5.60, I(2) = 65%); there was less constipation with 5-HT(3) antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41-0.99). Nine patients (0.2%) using 5-HT(3) antagonists had possible ischemic colitis versus none in control groups. CONCLUSIONS 5-HT(3) antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT(3) antagonists, although the risk is lower in those with D-IBS.

Inspection of the human stomach using remote-controlled capsule endoscopy: a feasibility study in healthy volunteers (with videos)

BACKGROUND Remote control of capsule endoscopes might allow reliable inspection of the human stomach. OBJECTIVE To assess the safety and efficacy of manipulation of a modified capsule endoscope with magnetic material (magnetic maneuverable capsule [MMC]) in the human stomach by using a handheld external magnet. DESIGN Open clinical trial. SETTING Academic hospital. PATIENTS Ten healthy volunteers. INTERVENTIONS Subjects swallowed the MMC and sherbet powder for gastric distention. An external magnetic paddle (EMP-2) was used to manipulate the MMC within the stomach. MMC responsiveness was evaluated on a screen showing the MMC film in real time. MAIN OUTCOME MEASUREMENTS Safety and tolerability (questionnaire), gastric residence time of the MMC, its responsiveness to the EMP-2, area of gastric mucosa visualized. RESULTS There were no adverse events. The MMC was always clearly attracted by the EMP-2 and responded to its movements. It remained in the stomach for 39 ± 24 minutes. In 7 subjects, both the cardia and the pylorus were inspected and 75% or more of the gastric mucosa was visualized (≥50% in all of the remaining subjects). A learning curve was clearly recognizable (identification of MMC localization, intended movements). LIMITATIONS Small amounts of fluid blocked the view of apical parts of the fundus; gastric distention was not sufficient to flatten all gastric folds. CONCLUSIONS Remote control of the MMC in the stomach of healthy volunteers using a handheld magnet is safe and feasible. Responsiveness of the MMC was excellent, and visualization of the gastric mucosa was good, although not yet complete, in the majority of subjects. The system appeared to be clinically valuable and should be developed further. ( CLINICAL TRIAL REGISTRATION NUMBER DE/CA05/2009031008.).

Irritable bowel syndrome: recent and novel therapeutic approaches.

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder affecting up to 3–15% of the general population in Western countries. It is characterised by unexplained abdominal pain, discomfort and bloating in association with altered bowel habits. The pathophysiology of IBS is considered to be multifactorial, involving disturbances of the brain-gut-axis: IBS has been associated with abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction and mucosal inflammation. Traditional IBS therapy is mainly symptom oriented and often unsatisfactory. Hence, there is a need for new treatment strategies. Increasing knowledge of brain-gut physiology, mechanisms, and neurotransmitters and receptors involved in gastrointestinal motor and sensory function have led to the development of several new therapeutic approaches. This article provides a systematic overview of recently approved or novel medications that show promise for the treatment of IBS; classification is based on the physiological systems targeted by the medication. The article includes agents acting on the serotonin receptor or serotonin transporter system, novel selective anticholinergics, α-adrenergic agonists, opioid agents, cholecystokinin antagonists, neurokinin antagonists, somatostatin receptor agonists, neurotrophin-3, corticotropin releasing factor antagonists, chloride channel activators, guanylate cyclase-c agonists, melatonin and atypical benzodiazepines. Finally, the role of probiotics and antibacterials in the treatment of IBS is summarised.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder affecting up to 3–15% of the general population in Western countries. It is characterised by unexplained abdominal pain, discomfort and bloating in association with altered bowel habits. The pathophysiology of IBS is considered to be multifactorial, involving disturbances of the brain-gut-axis: IBS has been associated with abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction and mucosal inflammation. Traditional IBS therapy is mainly symptom oriented and often unsatisfactory. Hence, there is a need for new treatment strategies. Increasing knowledge of brain-gut physiology, mechanisms, and neurotransmitters and receptors involved in gastrointestinal motor and sensory function have led to the development of several new therapeutic approaches. This article provides a systematic overview of recently approved or novel medications that show promise for the treatment of IBS; classification is based on the physiological systems targeted by the medication. The article includes agents acting on the serotonin receptor or serotonin transporter system, novel selective anticholinergics, α-adrenergic agonists, opioid agents, cholecystokinin antagonists, neurokinin antagonists, somatostatin receptor agonists, neurotrophin-3, corticotropin releasing factor antagonists, chloride channel activators, guanylate cyclase-c agonists, melatonin and atypical benzodiazepines. Finally, the role of probiotics and antibacterials in the treatment of IBS is summarised.

Current and Novel Therapeutic Options for Irritable Bowel Syndrome Management

Irritable bowel syndrome is a functional gastrointestinal disorder affecting up to 3-15% of the general population in western countries. It is characterised by unexplained abdominal pain, discomfort, and bloating in association with altered bowel habits. The pathophysiology of irritable bowel syndrome is multifactorial involving disturbances of the brain-gut axis. The pathophysiology provides the rationale for pharmacotherapy: abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction, and mucosal immune activation. Understanding the mechanisms, and their mediators or modulators including neurotransmitters and receptors have led to several therapeutic approaches including agents acting on the serotonin receptor or serotonin transporter system, antidepressants, novel selective anticholinergics, alpha-adrenergic agonists, opioid agents, cholecystokinin-antagonists, neurokinin-antagonists, somatostatin receptor agonists, corticotropin releasing factor antagonists, chloride channel activators, guanylate cyclase-c agonists, melatonin, atypical benzodiazepines, antibiotics, immune modulators and probiotics. The mechanisms and current evidence regarding efficacy of these agents are reviewed.

Influence of clinical parameters on the results of 13C-octanoic acid breath tests: Examination of different mathematical models in a large patient cohort

Abstract  It is assumed, although not proven, that 13CO2‐excretion following ingestion of 13C‐octanoic acid (13C‐OA) does not only depend on gastric emptying (GE) but also on absorption and metabolism of 13C‐OA and endogenous CO2‐production. Our aims were (i) to test the effects of patient characteristics and of diseases that may impair 13C‐OA‐metabolism on GE parameters. (ii) To compare different GE endpoints. Therefore, we investigated effects of age, gender, BMI and diseases with potential impact on 13C‐OA‐metabolism (including pancreatic, liver and lung disease, diabetes, IBD) on cumulative 4h‐13CO2‐excretion (4h‐CUM) and T½ calculated by non‐linear regression model (NL, determined by shape of breath test curve) and generalized linear regression model (GLR, reflects absolute 13CO2‐excretion) in 1279 patients and 19 healthy controls who underwent a standardized 13C‐OA‐breath test. Digestive and metabolic disturbances hardly influenced 4h‐CUM or T½ calculated by NL or GLR models. In the multivariate linear regression models, 4h‐CUM was significantly predicted by diabetes adjusted for age, gender and IBD but influence of these parameters was small (R2 = 0.028, P < 0.0001). T½NL and 4h‐CUM were weakly correlated, even after exclusion of tests with unrealistically high estimates for T½NL (n = 1095, R2 = 0.029, P < 0.0001). Conversely, 4h‐CUM was closely associated with T½GLR (exponential correlation, R2 = 0.774, P < 0.00001, n = 1279). We conclude that influences of digestive and metabolic disturbances on 13CO2‐excretion following 13C‐OA‐application are generally low. Thus, our findings resolve an important criticism of methods using absolute 13CO2‐excretion for evaluation of 13C‐OA‐breath tests and suggest that such models may correctly identify T½ in a mixed patient population.

Irritable Bowel Syndrome—The Main Recommendations

BACKGROUND Irritable bowel syndrome is characterized by chronic abdominal symptoms and irregular bowel movements without any cause than can be revealed by routine diagnostic assessment. In recent years, its pathophysiology has come to be much better understood, and new therapeutic approaches have been developed. These advances were taken into consideration and assessed for their relevance to clinical practice in the framework of a new interdisciplinary S3 guideline. METHODS A systematic search of the literature retrieved a total 5573 articles, from which 243 were selected on the basis of criteria relating to their form and content, individually assessed, and summarized in evidence tables. The recommendations formulated in this way were discussed in a Delphi procedure and a consensus conference, then accordingly modified and finalized. RESULTS Variable symptom constellations are caused by disturbances of gastrointestinal regulation at multiple levels. The diagnosis of irritable bowel syndrome requires both chronic bowel symptoms that interfere with everyday life and the exclusion of relevant differential diagnoses. Its treatment is based on general therapeutic principles, dietary recommendations, psychological components, and symptomatic medication. Bulking agents, laxatives, spasmolytics, loperamide, and probiotic agents are recommended (with variable recommendation strengths), as are--for selected patients--antidepressants, 5-HT4 agonists, 5-HT3 antagonists, and topical antibiotics. CONCLUSION The first German S3 guideline on irritable bowel syndrome translates up-to-date scientific knowledge as represented in current publications into concrete recommendations for diagnosis and treatment in clinical practice. In the future, it is likely that further causative pathophysiological mechanisms will be discovered; this should lead, in turn, to the development of new, causally directed treatments, which will supplement or replace the traditional, purely symptomatic treatments that are still in use today.

Comparison of mathematical methods for calculating colonic compliance in humans: power exponential, computer-based and manual linear interpolation models

Abstract  Measuring compliance allows differentiation of sensory changes from changes in thresholds because of altered compliance. As compliance of the colorectum is sigmoidal, a power exponential analysis was recommended. We aimed to develop and validate simpler measurements of compliance. Forty subjects (23 female, 17 male) underwent colonic barostat procedures comparing dronabinol vs placebo. Results of the effects on compliance were reported elsewhere. Compliance was determined as volume response to pressures ranging from 0 to 36 mmHg. Pressures corresponding to 10%, 50% and 90% (Pr10, Pr50 and Pr90) of maximum volume at 36 mmHg were estimated using a power exponential model, computer‐based and manual linear interpolation. Data were compared and concordance evaluated. Pr50 and Pr90 were not significantly different by all methods for baseline and post‐treatment. Respectively, concordance correlation coefficients were: pretreatment, 0.879, 0.464 and post‐treatment, 0.879, 0.623. There is larger variation in Pr10 comparing all methods and manual calculations allow for the closest fit to the data. Concordance correlation coefficients were pretreatment = 0.189 and post‐treatment = 0.322. There were no gender differences in compliance measurements. Results of compliance are highly concordant amongst all models. However, computer‐based or manual interpolations appear superior to power exponential models for estimating Pr10.

Factors affecting satisfaction with treatment in European women with chronic constipation: An internet survey

Background Data on factors affecting treatment satisfaction in European women with chronic constipation are limited. Objective To assess factors associated with treatment satisfaction among European women with chronic constipation. Methods A 2011–2012 internet survey was conducted in men and women from 12 European countries. Respondents analysed were female with self-reported chronic constipation (≥1 symptoms for ≥6 months of lumpy/hard stools, feeling of incomplete evacuation, and pain during defecation, as well as <3 bowel movements/week). For laxative users, satisfaction with treatment, factors affecting satisfaction, and interactions with healthcare professionals were collected. Results and conclusions In total, 4805/50,319 participants fulfilled the inclusion criteria (female with chronic constipation). Of the laxative users (1575/4805), 57% (n = 896) were satisfied with their treatment, while 26% were neutral, and 17% dissatisfied. Dissatisfied respondents visited their GP less frequently in the past 12 months, were more likely to obtain over-the-counter laxatives, and took a dose higher than recommended more frequently than those satisfied. Respondents were most satisfied with ease of use of treatment and least satisfied with relief from bloating. Newer treatments aimed at alleviating symptoms, particularly bloating, are required for respondents neutral or dissatisfied with their current treatment.

Challenges in drug development for functional gastrointestinal disorders. Part II: Visceral pain

Abstract  There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders. The human pharmacodynamic models and biomarkers pertaining to two important conditions are reviewed in a two‐part article: functional dyspepsia (part I) and visceral pain (part II). With visceral pain models, the large coefficient of variation in sensation end points in human studies precludes definitive conclusions such as go/no go decisions or dose selection for phase IIb or III studies, unless very large numbers of patients are evaluated in phase IIA pharmacodynamic studies. This renders such pharmacological studies ambitious, or unachievable in a timely fashion. Moreover, the results of tests and clinical trials should be interpreted with greater knowledge of the drug pharmacokinetics, including the influence of CYP metabolism and potential drug interactions. Thus, it is important to identify valid biomarkers of visceral pain for the assessment of treatment response in pharmacodynamic studies. In this second part of a two‐part article, we shall discuss the special challenges in developing medications for visceral pain and the general importance of including pharmacokinetic and pharmacogenomic studies in drug development programmes.