Is Dyssynergic Defecation an Unrecognized Cause of Chronic Constipation in Patients Using Opioids?

OBJECTIVES: The impact of opioids on anorectal function is poorly understood but potentially relevant to the pathogenesis of opioid-induced constipation (OIC). To evaluate anorectal function testing (AFT) characteristics, symptom burden, and quality of life in chronically constipated patients prescribed an opioid (OIC) in comparison with constipated patients who are not on an opioid (NOIC). METHODS: Retrospective analysis of prospectively collected data on 3,452 (OIC = 588 and NOIC = 2,864) chronically constipated patients (Rome 3) who completed AFT. AFT variables included anal sphincter pressure and response during simulated defecation, balloon expulsion test (BET), and rectal sensation. Dyssynergic defecation (DD) was defined as an inability to relax the anal sphincter during simulated defecation and an abnormal BET. Patients completed Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. RESULTS: The mean age of the study cohort was 49 years. Most patients were women (82%) and whites (83%). Patients with OIC were older than NOIC patients (50.7 vs 48.3, P = 0.001). OIC patients were significantly more likely to have DD (28.6% vs 21.4%, P < 0.001), an abnormal simulated defecation response on anorectal manometry (59% vs 43.8%, P < 0.001), and an abnormal BET (48% vs 42.5%, P = 0.02) than NOIC patients. OIC patients reported more severe constipation symptoms (P < 0.02) and worse quality of life (P < 0.05) than NOIC patients. DISCUSSION: Chronically constipated patients who use opioids are more likely to have DD and more severe constipation symptoms than NOIC.

The importance of calprotectin for differentiating organic inflammatory disease and avoiding unnecessary procedures in paediatrics / Importancia de la calprotectina para la diferenciación de la enfermedad inflamatoria orgánica y la evitación de procedimientos innecesarios en pediatría

Background and objective: The objective of the study was to determine the ability of faecal calprotectin to differentiate functional and organic intestinal diseases in paediatric patients, and to evaluate the correlation between inflammatory parameters and levels of faecal calprotectin. Patients and methods: This retrospective study involved clinical data from 129 paediatric patients with symptoms of intestinal pathology. Faecal calprotectin was determined by quantitative immunoassay. Patients were classified into three groups: functional (32.8% of patients); organic non-inflammatory bowel disease (IBD, 53.9%); and organic IBD (13.3%). Results: Calprotectin levels were significantly different among the three groups; between patients with IBD and the others, and also between patients with non-organic IBD and functional. Positive associations were found between high levels of calprotectin and higher erythrocyte sedimentation rate (rho=0.497), C-reactive protein (rho=0.460), and platelet count (rho=0.232). Nevertheless, an inverse correlation was found between high levels of calprotectin and transferrin saturation (rho=−0.310), albumin (rho=−0.412), and haemoglobin levels (rho=−0.309). Discussion: Determination of faecal calprotectin is a complementary tool in clinical practice for discriminating between functional and organic IBD, avoiding, according to the levels of calprotectin, unnecessary invasive procedures in paediatric patients

Antecedentes y objetivo: El objetivo de este estudio fue determinar la capacidad de la calprotectina fecal para diferenciar las enfermedades funcionales y orgánicas en los pacientes pediátricos, y evaluar la correlación entre los parámetros inflamatorios y los niveles de calprotectina fecal. Pacientes y métodos: Este estudio retrospectivo incluyó los datos clínicos de 129 pacientes pediátricos con síntomas de enfermedad intestinal. Se determinaron los valores de calprotectina fecal mediante inmunoensayo cuantitativo. Se clasificaron los pacientes en 3 grupos: funcionales (32,8% de pacientes), enfermedad intestinal inflamatoria no orgánica (EII, 53,9%) e EII orgánica (13,3%). Resultados: Los niveles de calprotectina fueron significativamente diferentes entre los 3 grupos; entre los pacientes con EII y el resto, y también entre los pacientes con EII no orgánica e EII funcional. Se encontraron asociaciones positivas entre los niveles altos de calprotectina y la tasa de sedimentación eritrocítica alta (Rho=0,497), proteína C reactiva (Rho=0,460) y recuento plaquetario (Rho=0,232). Sin embargo, se encontró una correlación inversa entre los niveles altos de calprotectina y la saturación de transferrina (Rho=−0,310), albúmina (Rho=−0,412) y niveles de hemoglobina (Rho=−0,309). Discusión: La determinación de la calprotectina fecal es una herramienta complementara en la práctica clínica para discriminar entre EII funcional y EII orgánica, y evitar con arreglo a los niveles de calprotectina, los procedimientos invasivos innecesarios en pacientes pediátricos

Calprotectina fecal, marcador eficaz en la diferenciación de enfermedades inflamatorias intestinales y trastornos funcionales gastrointestinales / Faecal calprotectin, an useful marker in discriminating between inflammatory bowel disease and functional gastrointestinal disorders

INTRODUCCIÓN: La discriminación entre enfermedades inflamatorias intestinales (EII) y trastornos funcionales gastrointestinales es compleja debido a que pueden presentar cuadros clínicos similares. La calprotectina fecal (CPF) es un marcador inflamatorio útil para este fin y permite seleccionar a los pacientes que más se pueden beneficiar de someterse a una colonoscopia. El objetivo fundamental de este estudio fue valorar la utilidad de la CPF para diferenciar entre enfermedades orgánicas y funcionales. MATERIAL Y MÉTODOS: Se determinó la concentración de CPF de 264 pacientes que presentaban signos o síntomas gastrointestinales indicativos de enfermedad orgánica, y se calculó su precisión diagnóstica mediante el área bajo la curva a partir del diagnóstico final. RESULTADOS: Los pacientes con enfermedad orgánica presentaron valores de CPF mayores (mediana 254 μg/g; intervalo de confianza [IC] 95%, rango intercuartil 105-588,5) que el grupo con enfermedad funcional (95 μg/g; IC 95%, 47,25-243,92; p < 0,0001), así como el grupo con EII (270,85 μg/g; IC 95%, 96,85-674,00) obtuvo valores más elevados que el grupo con síndrome del intestino irritable (79,70; IC 95%, 36,50-117,25; p < 0,0001). Para un valor de corte de 150 μg/g se obtuvo un valor del área bajo la curva de 0,718 para discriminar entre enfermedad orgánica y funcional, y de 0,872 para discriminar entre síndrome del intestino irritable y EII. CONCLUSIÓN: En este estudio se corrobora el alto valor de la CPF en la evaluación de pacientes con sospecha de EII. La mejor eficacia diagnóstica se consigue con un cut-off de 150μg/g para la discriminación entre EII y síndrome del intestino irritable

INTRODUCTION: Diagnostic discrimination between inflammatory bowel disease (IBD) and functional gastrointestinal disorders is complex, as they cause similar signs and symptoms. Faecal calprotectin (FC) is a useful marker in this context, and can be used to select patients who will most benefit from colonoscopy. The aim of this study was to evaluate the utility of FC in discriminating between organic disease and functional disorders. MATERIAL AND METHODS: The study included 264 patients presenting with gastrointestinal complaints consistent with an organic pathology. FC levels were determined and diagnostic accuracy was assessed using the area under the curve obtained from the final diagnosis. RESULTS: Calprotectin levels in organic bowel disease patients were significantly higher (median 254 μ g/g; 95% confidence interval [CI], interquartile range 105-588.5) than in functional disease patients (95 μ g/g; 95% CI, 47.25-243.92) (P < .0001). Similarly, in patients with IBD, the values obtained were higher (270.85 μg/g; 95% CI, 96.85-674.00) than in those with irritable bowel syndrome (79.70μ g/g; 95% CI, 36.50-117.25) (P<.0001). For a cut-off of 150 μ g/g, FC had an area under the ROC curve to discriminate between organic and functional disease of 0.718, and 0.872 to discriminate between irritable bowel syndrome and IBD. CONCLUSION: Our study supports the importance of FC as a marker in the evaluation of patients with IBD. The best diagnostic accuracy is obtained at a cut-off value of 150μ g/g

Colonic and anorectal motility testing in the high-resolution era.

PURPOSE OF REVIEW: The past few years have seen an increase in the number of research and clinical groups around the world using high-resolution manometry (HRM) to record contractile activity in the anorectum and colon. Yet despite the uptake and growing number of publications, the clinical utility and potential advantages over traditional manometry remain undetermined. RECENT FINDINGS: Nearly all of the publications in the field of anorectal and colonic HRM have been published within the last 3 years. These studies have included some data on normal ranges in healthy adults, and abnormalities in patient groups with constipation or fecal incontinence, anal fissure, perineal descent, rectal cancer, and Hirschsprung's disease. Most of the studies have been conducted on adults, with only three published studies in pediatric populations. Very few studies have attempted to show advantages of HRM over traditional manometry SUMMARY: High-resolution anorectal and colonic manometry provide a more comprehensive characterization of motility patterns and coordinated activity; this may help to improve our understanding of the normal physiology and pathophysiology in these regions. To date, however, no published study has conclusively demonstrated a clinical, diagnostic, or interventional advantage over conventional manometry.

Pediatric Functional Constipation Gastrointestinal Symptom Profile Compared With Healthy Controls.

OBJECTIVES: Patient-reported outcomes are necessary to evaluate the gastrointestinal symptom profile of patients with functional constipation. Study objectives were to compare the gastrointestinal symptom profile of pediatric patients with functional constipation with matched healthy controls with the Pediatric Quality of Life Inventory Gastrointestinal Symptoms and Gastrointestinal Worry Scales and to establish clinical interpretability in functional constipation through identification of minimal important difference (MID) scores. The secondary objective compared the symptom profile of patients with functional constipation with patients with irritable bowel syndrome (IBS). METHODS: Gastrointestinal Symptoms and Worry Scales were completed in a 9-site study by 116 pediatric patients with functional constipation and 188 parents. Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were administered along with Gastrointestinal Worry Scales. A total of 341 families with healthy children and 43 families with patients with IBS completed the scales. RESULTS: A broad profile of gastrointestinal symptoms and worry were reported by patients with functional constipation in comparison with healthy controls (P < 0.001) with large effect sizes (>0.80) across the majority of symptom domains. Patients with IBS manifested a broader symptom profile than functional constipation, with differences for stomach pain, stomach discomfort when eating, and worry about stomachaches, with similar constipation scores. CONCLUSIONS: Pediatric patients with functional constipation report a broad gastrointestinal symptom profile in comparison with healthy controls and only somewhat fewer symptoms than patients with IBS, highlighting the critical need for more efficacious interventions to achieve healthy functioning.

[Functional diarrhea - pathophysiology, investigation and treatment]. / Funktionelle Diarrhoe - Pathophysiologie, Abklärung und Therapie.

The most important reason for functional diarrhea in clinical practice is diarrhea-predominant irritable bowel syndrome (IBS) which is characterized by chronic intermittent diarrhea and abdominal pain. The pathophysiology underlying IBS is complex and includes visceral hypersensitivity, abnormal gut motility and autonomous nervous system dysfunction as well as genetic and psychosocial factors. Treatment should be tailored to the individual's symptoms and involves general measures, pharmacological treatments, dietary interventions, psychotherapy and complementary and alternative approaches. The following manuscript will give an overview over pathophysiology, reasonable investigations and treatment of IBS.

Prevalence of colonic motor or evacuation disorders in patients presenting with chronic nausea and vomiting evaluated by a single gastroenterologist in a tertiary referral practice.

BACKGROUND: Nausea and vomiting are thought to result from upper gastrointestinal dysfunctions. Our clinical observations led to the hypothesis that colonic motor dysfunction is associated with nausea and vomiting. METHODS: We reviewed electronic medical records (EMR) of 149 patients presenting with complaints of nausea and/or vomiting in a tertiary gastroenterology practice to investigate the association with disorders of colonic motor or evacuation disorders. We extracted demographics, gastric emptying (GE in 149) and colonic transit (CT in 138) of solids, ascending colon emptying half-time (AC t1/2 ), rectal evacuation by anorectal manometry (ARM) in 91 and balloon expulsion test (BE) in 55 patients. We estimated the proportions with delayed GE or CT, based on the 5th percentile of GE (in 319) and CT in 220 healthy volunteers using same method. KEY RESULTS: Among 11 patients with nausea and/or vomiting with only GE measured, five had delayed and six normal GE. Among the 149 patients, 77 (52%) patients had evacuation disorders, confirmed by objective tests in 68 patients, and clinical examination in nine patients. In the 138 patients with both GE and CT measured, 106 (76%) had both normal GE and CT, 11 (8%) only delayed GE, 16 (11%) normal GE with delayed CT, and five (3%) delayed GE and CT. Among 21 patients (15%) with delayed CT, nine had slow AC t1/2 and 12 evacuation disorder. CONCLUSIONS & INFERENCES: In patients with chronic nausea and/or vomiting in gastroenterology practice, evaluation of colonic motility and rectal evacuation should be considered, since about half the patients have abnormal functions that conceivably contribute to the presenting nausea and/or vomiting.

Exploring the benefits of of anal irrigation.

This article discusses the prevalence, causes and impact of bowel dysfunction among adults, and suggests that anal irrigation may be considered as a viable alternative for selected patients who experience long-standing problems, where previous treatments have proved ineffective. Two case studies demonstrate the positive benefits of anal irrigation, and discuss some of the incidental findings such as fewer urinary tract.

Pathogenesis of colonic diverticular disease.

PURPOSE: This paper aims to review the current evidence regarding pathogenesis of colonic diverticular disease and its complications, which are a major health problem in the Western world. METHODS: Based on selective Medline searches, relevant literature was indentified regarding pathogenesis of (1) diverticulosis/formation of diverticula, (2) diverticulitis/inflammation of diverticula, (3) complicated diverticulitis/perforation, and (4) diverticular bleeding. RESULTS: Pathogenesis of colonic diverticula is regarded as a multifactorial process, involving dietary factors (Western low-fiber diet), structural changes of the colonic wall (altered musculature, collagen, elastin, etc.) and functional changes (motility disorder, increased intraluminal pressure). Genetic changes are also discussed and aging is also a key factor. Pathogenesis of inflammation (diverticulosis) is regarded as a result of "microperforations" at the fundus of the diverticulum, and not an "abscessed diverticulum" due to an impacted fecolith. Histamine and its receptors do also seem to play a role, corresponding with the promising prophylactic approach with probiotics. Pathogenesis of complicated diverticulitis is characterized by perforation, which is the cardinal feature. Furthermore, an intensive inflammatory infiltrate with macrophages is found in surgical specimens, even after antibiotic pretreatment. Steroid intake and immunosuppression are risk factors and only recently a glucocorticoid-induced tumor necrosis factor-receptor has been suggested to resemble the molecular link. Diverticular bleeding is a distinct disease process-which does usually take place without diverticulitis-and is due to eccentric rupture of the vas rectum. CONCLUSIONS: The pathophysiology of diverticular disease is multifactorial. Some of the current evidence has important implications for clinical practice, e.g., the suggested role of steroid intake and immunosuppression for complicated diverticulitis.

Food choice as a key management strategy for functional gastrointestinal symptoms.

Recognition of food components that induce functional gut symptoms in patient's functional bowel disorders (FBD) has been challenging. Food directly or indirectly provides considerable afferent input into the enteric nervous system. There is an altered relationship between the afferent input and perception/efferent response in FBD. Defining the nature of food-related stimuli may provide a means of minimizing such an input and gut symptoms. Using this premise, reducing the intake of FODMAPs (fermentable oligo-, di-, and mono-saccharides and polyols)--poorly absorbed short-chain carbohydrates that, by virtue of their small molecular size and rapid fermentability, will distend the intestinal lumen with liquid and gas--improves symptoms in the majority of patients. Well-developed methodologies to deliver the diet via dietician-led education are available. Another abundant source of afferent input is natural and added food chemicals (such as salicylates, amines, and glutamates). Studies are needed to assess the efficacy of the low food chemical dietary approach. A recent placebo-controlled trial of FODMAP-poor gluten provided the first valid evidence that non-celiac gluten intolerance might actually exist, but its prevalence and underlying mechanisms require elucidation. Food choice via the low FODMAP and potentially other dietary strategies is now a realistic and efficacious therapeutic approach for functional gut symptoms.

Lactulose hydrogen breath test and functional symptoms in pediatric patients.

BACKGROUND: The role of small intestinal bacterial overgrowth (SIBO) in functional digestive disorders in the pediatric population is a matter of controversy, since methods currently used to establish this diagnosis are difficult to interpret. The aim of this work was to analyze the characteristics of the lactulose H(2) breath test (LHBT) in children with functional gastrointestinal symptoms according to more recent criteria. METHODS: Seventy-two patients and 17 controls were enrolled. A questionnaire was administered regarding digestive symptoms (abdominal pain, bloating, vomiting, and bowel-movement disorders). A lactose hydrogen breath test was performed to rule out lactose malabsorption and a LHBT was used to measure the time elapsed between lactulose oral ingestion and an increment of H(2) concentration of 20 ppm over basal. RESULTS: There were no differences of age and gender between patients and controls. Mean time to 20-ppm change was shorter in patients (56.3 ± 3 min) compared to healthy children (74.7 ± 5 min), p\0.05. In 39% of patients, rise of H(2) occurred during the first 40 min after lactulose ingestion, and in almost all controls, an increment was observed between 50 and 90 min (p\0.05). Symptoms were unrelated to time to 20-ppm change. CONCLUSIONS: An abnormal LHBT was found in children with functional symptoms of the digestive tract, but the exact mechanism involved, accelerated intestinal transit or SIBO, needs to be confirmed by an additional method.

Novel diagnostics and therapy of colonic motor disorders.

Colonic motor abnormalities are implicated in several gastrointestinal disorders including constipation, irritable bowel syndrome and functional diarrhoea. Defining the colonic abnormalities is difficult and several novel techniques including, high-resolution fibre optic manometry, wireless motility capsules, ultrasound and magnetic resonance imaging have emerged to help in the diagnosis of these conditions. Coupled with the developing techniques are the novel treatments that look to restore normal colonic motility. These treatments include pharmacological agents (pharmabiotics, serotonin agonist, secretagogues) and medical devices (sacral nerve stimulation, transcutaneous electrical stimulation and biofeedback). This review summarizes the novel techniques used to record and define colonic motor abnormalities and the current status of the emerging treatments used to treat them.

Isolated colonic inertia is not usually the cause of chronic constipation.

AIM: Chronic constipation is classified as outlet obstruction, colonic inertia or both. We aimed to determine the incidence of isolated colonic inertia in chronic constipation and to study symptom pattern in those with prolonged colonic transit time. METHODS: Chronic constipation patients were classified radiologically by surgeon-reported defaecating proctography and transit study into four groups: isolated outlet obstruction, isolated colonic inertia, outlet obstruction plus colonic inertia, or normal. Symptom patterns were defined as stool infrequency (twice weekly or less) or frequent unsuccessful evacuations (more than twice weekly). RESULTS: Of 541 patients with chronic constipation, 289 (53%) were classified as isolated outlet obstruction, 26 (5%) as isolated colonic inertia, 159 (29%) as outlet obstruction plus colonic inertia and 67 (12%) as normal. Of 448 patients (83%) with outlet obstruction, 35% had additional colonic inertia. Only 14% of those with prolonged colonic transit time had isolated colonic inertia. Frequent unsuccessful evacuations rather than stool infrequency was the commonest symptom pattern in all three disease groups (isolated outlet obstruction 86%, isolated colonic inertia 54% and outlet obstruction plus colonic inertia 63%). CONCLUSION: Isolated colonic inertia is an unusual cause of chronic constipation. Most patients with colonic inertia have associated outlet obstruction. These data question the clinical significance of isolated colonic inertia.

Patient experience and satisfaction with sacral neuromodulation: results of a single-center sample survey.

PURPOSE: Sacral neuromodulation is a well researched and successful treatment for functional bowel disorders. Indications have expanded throughout the years and various studies have been published on clinical efficacy or on technique improvement. The main goal of this retrospective study was to systematically evaluate daily experiences with this treatment and measure the long-term satisfaction of sacral neuromodulation therapy for functional bowel disorders. METHODS: After institutional review board approval a new, self-designed postal questionnaire was sent to all patients in our center who were being treated with sacral neuromodulation. Only patients with a minimal follow-up of 1 year were included in the survey. Implantation years range from 2000 to 2007. RESULTS: A total of 174 patients received the questionnaire regarding patient satisfaction and experience with sacral neuromodulation therapy. The response rate after reminder letter was 71.8% (n = 125) including 114 (91.2%) females. Patient satisfaction was high: 81 patients (65.3%) reported their results as very satisfying, 30 patients (24.2%) were moderately satisfied, and 13 patients (10.4%) were not satisfied. Analysis showed that patient satisfaction can be explained by both patient perception of present bowel function and their evaluation of the quality of daily life. No significant relationship was found with patient demographics, self-ascribed (co)morbidity, behavioral habits, or therapy duration. A total of 47 patients (38.2%) reported having some concerns regarding the future with sacral neuromodulation treatment. Twenty-eight patients (23.1%) reported a temporary loss of effect at any time during sacral neuromodulation therapy. Pain at the implantation site was reported by 65 patients (52.4%). CONCLUSIONS: This study shows that patients treated with sacral neuromodulation, in general, are very satisfied. The main problems mentioned by patients are pain, loss of efficacy, and general concerns.

Psychosocial factors, psychiatric illness and functional gastrointestinal disorders: a historical perspective.

A new classification of functional gastrointestinal disorders (FGID) became available recently, based on consensus in expert committees ('Rome III process'). It is widely accepted that these frequent disorders, although their pathophysiology remains incompletely understood, result from a complex reciprocal interaction between biological, psychological and social factors that can be predisposing, precipitating and/or perpetuating. Comorbidity with psychiatric disorders, especially mood and anxiety disorders, is high. Modern epidemiologic, psychophysiological and functional neuroimaging studies have partially elucidated the mechanisms underlying the relation between cognitive-affective processes on the one hand and GI function and symptom reporting on the other. The aim of this article is to provide a noncomprehensive historical review of the literature on FGID up to the mid-20th century, with special emphasis on the role of psychosocial factors and psychiatric comorbidity. We can conclude from this review that a lot of the knowledge that became available recently through modern research methodology can also be found in the historical psychosomatic and neuroscience literature, though obviously less empirically grounded. This provides further support for an integrative, multidisciplinary biopsychosocial approach to FGID.

Lack of utility of abdominal x-rays in the evaluation of children with constipation: comparison of different scoring methods.

BACKGROUND AND AIM: Abdominal x-rays are used diagnostically in the evaluation of children with constipation. However, their clinical utility has not been established. The aim of the study was to assess the accuracy of different methods in identifying children with functional constipation (FC) or nonretentive fecal incontinence (NRFI). PATIENTS AND METHODS: Retrospective review of abdominal x-rays in which colonic transit (CT), Barr, Leech, and fecal loading (FL) scores were blindly measured by blinded pediatric gastroenterologists and a radiologist. Children were classified a priori as FC or NRFI. RESULTS: One hundred sixty patients (125 FC, 35 NRFI) were studied. There were significant differences (P < 0.05) when comparing those with FC and those with NRFI: CT: 51 +/- 18 vs 40 +/- 21 hours; Barr: 14 +/- 5 vs 11 +/- 4; Leech: 10 +/- 2 vs 8 +/- 2; FL: 2 +/- 0.5 vs 1.7 +/- 0.4. More than 20% of FC had normal Barr and Leech scores, whereas >50% of NRFI had abnormal scores. CT discriminated better between FC and NRFI. There was a significant correlation (P < 0.05) between CT and Barr (0.45), Leech (0.41) and FL scores (0.36), and between Barr and Leech scores (r = 0.94). There was good intraobserver correlation between Barr, Leech, and FL scores but poor interobserver reproducibility. CONCLUSIONS: Although significant differences in overall FC and NRFI scores exist, the discriminative value is low for all scores. There is poor interobserver reproducibility of the Barr, Leech, and FL scores. These findings confirm the limited value of the plain abdominal x-ray in the evaluation of children with constipation.

New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders.

IMPORTANCE OF THE FIELD: Gastrointestinal (GI) dysmotility is an important mechanism in functional GI disorders (FGIDs) including constipation, irritable bowel syndrome, functional dyspepsia, and gastroparesis. 5-hydroxytryptamine(4) (5-HT(4)) receptors are targets for the treatment of GI motility disorders. However, older 5-HT(4) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac HERG potassium channel. AREAS COVERED IN THIS REVIEW: We conducted a PubMed search using the following key words alone or in combination: 5-HT(4), safety, toxicity, pharmacokinetics, pharmacodynamics, clinical trial, cardiac, hERG, arrhythmia, potassium current, elderly, prucalopride, ATI-7505, and velusetrag (TD-5108), to review mechanisms of action, clinical efficacy, safety and tolerability of three new-generation 5-HT(4) receptor agonists. WHAT THE READER WILL GAIN: Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT(4) receptor agonists that are devoid of action on other receptors within their therapeutic range. Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and, to a variable degree, in clinical trials that significantly relieve chronic constipation. Currently available evidence shows that the new 5-HT(4) receptor agonists have safe cardiac profiles. TAKE HOME MESSAGE: New-generation 5-HT(4) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.

Functional constipation in children: a systematic review on prognosis and predictive factors.

BACKGROUND AND AIM: Knowledge regarding prognosis and factors influencing the clinical course of functional constipation in children is important to enable general practitioners and paediatricians to give accurate patient information, to compare treatment strategies, and identify children with high risk for unfavourable outcome. The objective of the study was to investigate and summarize the quantity and quality of evidence on prognosis of childhood constipation with and without treatment and its predictive factors. METHODS: An extensive literature search in MEDLINE and Embase was performed to identify prospective follow-up studies evaluating the prognosis or prognostic determinants of functional constipation. Methodological quality was assessed using a standardised list. Results on prognosis of constipation were statistically pooled, and the influence of prognostic factors was summarised in a best evidence synthesis. RESULTS: The search strategy resulted in a total of 2882 abstracts. Only 14 publications met our inclusion criteria, of which 21% scored high methodological quality. Included studies showed large heterogeneity in study populations and outcome measures. Without regard to these differences, 49.3% +/- 11.8% of all of the children followed for 6 to 12 months were found to recover and taken off laxatives. The percentage of children who were free from complaints, regardless of laxative use, after 6 to 12 months was 60.6% +/- 19.2%. There is substantial evidence that defecation frequency and a positive family history are not associated with recovery from constipation. CONCLUSIONS: The few studies published on prognosis of childhood functional constipation and predictive factors showed large heterogeneity and poor methodological quality. Overall, 60.6% of children are found to be free from symptoms after 6 to 12 months. Recovery rate showed no relation with defecation frequency or positive family history. Based on the present literature, we are unable to identify a group of children with high risk for poor prognosis.