Summary
Background
Irritable bowel syndrome with constipation (IBS‐C) represents a significant burden to patients and healthcare systems due to its prevalence and lack of successful symptomatic ...resolution with established treatment options. Linaclotide 290 μg has recently been approved by the European Medicines Agency (EMA) for moderate‐to‐severe IBS‐C and by the US Food and Drug Administration for IBS‐C (290 μg dose) and for chronic constipation (145 μg dose).
Aim
To summarise data leading to the approval of linaclotide for IBS‐C, with focus on EMA‐pre‐specified outcome measures.
Methods
Literature search of a peer‐review database (PubMed) and review of congress s on linaclotide preclinical and clinical trial data in IBS‐C.
Results
Preclinical studies suggest that the guanylate cyclase C agonist (GCCA) linaclotide acts through elevation of cyclic guanosine monophosphate (cGMP) levels, leading to accelerated gastrointestinal (GI) transit through increased fluid secretion and reduced visceral hypersensitivity. Clinical trial data demonstrate that linaclotide improves abdominal symptoms (pain, bloating) and bowel symptoms (constipation) compared with placebo in patients with IBS‐C. The most frequent side effect, diarrhoea, results from the therapeutic action of linaclotide. Linaclotide acts locally in the GI tract with minimal systemic exposure, resulting in low oral bioavailability and thus a low risk of relevant systemic adverse effects.
Conclusion
Linaclotide, a first‐in‐class GCCA, is a promising new drug with a novel, dual mechanism of action that, unlike more well‐established agents, can relieve the abdominal pain, bloating and constipation associated with IBS‐C and has a low propensity for systemic side effects.
Background
Chronic intestinal pseudo‐obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be ...non‐specific, and result in this condition being diagnosed incorrectly or too late with consequences for morbidity and even mortality.
Purpose
The present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis and therapeutic options for CIPO. Although pediatric and adult CIPO share many clinical aspects distinctive features can be identified. There is no single diagnostic test or pathognomonic finding of CIPO, thus a stepwise approach including radiology, endoscopy, laboratory, manometry, and histopathology should be considered in the diagnostic work‐up. Treatment of patients with CIPO is challenging and requires a multidisciplinary effort with participation of appropriately experienced gastroenterologists, pathologists, dieticians, surgeons, psychologists, and other subspecialists based on the presence of comorbidities. Current treatment options invariably involve surgery and specialized nutritional support, especially in children. Medical therapies are mainly aimed to avoid complications such as sepsis or intestinal bacterial overgrowth and, where possible, restore intestinal propulsion. More efficacious therapeutic options are eagerly awaited for such difficult patients.
Chronic intestinal pseudo‐obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be non‐specific, and result in an incorrect or too late diagnosis with consequences in terms of morbidity and even mortality. Thus, the present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis, and therapeutic options for CIPO.
Growing evidence suggests that patients with irritable bowel syndrome (IBS) have increased intestinal permeability. In addition, mucosal soluble mediators are involved in the pathophysiology of pain ...in IBS. We aimed to investigate (1) paracellular permeability in colonic biopsies of patients with IBS; and (2) the ability of soluble factors from colonic biopsies to reproduce these alterations in vitro.
Paracellular permeability in colonic biopsies of healthy subjects and patients with IBS was measured by mounting the biopsies in Ussing chambers. Cleared supernatant (SUP) of the culture from colonic biopsies was collected and applied to Caco-2 cells for 48 h. Paracellular permeability and transepithelial resistance (TER) were evaluated. mRNA expression of the tight junction proteins, zonula occludens (ZO)-1 and occludin, was assessed in colonic biopsies. Abdominal pain was assessed using a validated questionnaire.
Permeability of colonic biopsies was significantly higher in patients with IBS compared to healthy subjects. These changes were associated with significantly lower expression of ZO-1 mRNA in biopsies of IBS as compared to healthy subjects. Compared to healthy subjects, SUP of IBS markedly reduced TER and significantly increased permeability in Caco-2 cells. SUP of IBS patients induced a significant decrease of ZO-1 mRNA in Caco-2 as compared to healthy subjects. SUP-induced increased paracellular permeability correlated with the severity of abdominal pain.
Our study shows that colonic soluble mediators are able to reproduce functional (permeability) and molecular (ZO-1 mRNA expression) alterations observed in IBS patients. These findings might pave the way both to identify novel biomarkers as well as new therapeutic targets in IBS.
Polyethylene glycol (PEG) 3350 plus electrolytes (PEG 3350+E) is an established treatment for constipation and has been proposed as a treatment option for constipation associated with irritable bowel ...syndrome (IBS-C). This study aimed to compare the efficacy and safety of PEG 3350+E vs. placebo in adult patients with IBS-C.
Following a 14-day run-in period without study medication, patients with confirmed IBS-C were randomized to receive PEG 3350+E (N=68) or placebo (N=71) for 28 days. The primary endpoint was the mean number of spontaneous bowel movements (SBMs) per day in the last treatment week.
In both groups, mean weekly number of SBMs (±s.d.) increased from run-in. The difference between the groups in week 4 (PEG 3350+E, 4.40±2.581; placebo, 3.11±1.937) was statistically significant (95% confidence interval: 1.17, 1.95; P<0.0001). Although mean severity score for abdominal discomfort/pain was significantly reduced compared with run-in with PEG 3350+E, there was no difference vs. placebo. Spontaneous complete bowel movements, responder rates, stool consistency, and severity of straining also showed superior improvement in the PEG 3350+E group over placebo in week 4. The most common drug related treatment-emergent adverse events were abdominal pain (PEG 3350+E, 4.5%; placebo, 0%) and diarrhoea (PEG 3350+E, 4.5%; placebo, 4.3%).
In IBS-C, PEG 3350+E was superior to placebo for relief of constipation, and although a statistically significant improvement in abdominal discomfort/pain was observed compared with baseline, there was no associated improvement compared with placebo. PEG 3350+E is a well-established and effective treatment that should be considered suitable for use in IBS-C.
Summary
Background
The nonselective 5‐HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs).
Aim
To perform a systematic review of the safety ...profile, particularly cardiovascular, of 5‐HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy.
Methods
Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD‐5108 (velusetrag) and ATI‐7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. s from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.
Results
Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5‐HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically.
Two nonselective 5‐HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5‐HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5‐HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5‐HT4 agonists with no hERG or 5‐HT1 affinity (renzapride, clebopride, mosapride).
Conclusions
5‐HT4 agonists for GI disorders differ in chemical structure and selectivity for 5‐HT4 receptors. Selectivity for 5‐HT4 over non‐5‐HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5‐HT4 agonists may offer improved safety to treat patients with impaired GI motility.
Background Although constipation can be a chronic and severe problem, it is largely treated empirically. Evidence for the efficacy of some of the older laxatives from well‐designed trials is ...limited. Patients often report high levels of dissatisfaction with their treatment, which is attributed to a lack of efficacy or unpleasant side‐effects. Management guidelines and recommendations are limited and are not sufficiently current to include treatments that became available more recently, such as prokinetic agents in Europe.
Purpose We present an overview of the pathophysiology, diagnosis, current management and available guidelines for the treatment of chronic constipation, and include recent data on the efficacy and potential clinical use of the more newly available therapeutic agents. Based on published algorithms and guidelines on the management of chronic constipation, secondary pathologies and causes are first excluded and then diet, lifestyle, and, if available, behavioral measures adopted. If these fail, bulk‐forming, osmotic, and stimulant laxatives can be used. If symptoms are not satisfactorily resolved, a prokinetic agent such as prucalopride can be prescribed. Biofeedback is recommended as a treatment for chronic constipation in patients with disordered defecation. Surgery should only be considered once all other treatment options have been exhausted.
Background
Prucalopride is a 5‐HT4 receptor agonist with gastrointestinal prokinetic activities. This integrated analysis of data from three 12‐week, double‐blind trials evaluated the effect of ...prucalopride 2 mg q.d. on common constipation symptoms in women in whom laxatives had failed to provide adequate relief. The effect of prucalopride on bowel function was outside the scope of the analysis and has been described elsewhere.
Methods
Women with self‐reported inadequate relief from laxatives and included in the prucalopride 2 mg or placebo arm of the trials were selected for analysis. Symptom severity was determined with the Patient Assessment of Constipation Symptoms (PAC–SYM) questionnaire. Observed changes from baseline in individual item scores were also evaluated by calculating Cohen's D effect sizes using baseline standard deviation (SD) (>0.2–0.5, >0.5–0.8 and >0.8 for small, moderate and large effects, respectively).
Key Results
Data were analyzed for 936 women. The proportion of women with a PAC‐SYM severity score >2 at baseline was 50.0% for abdominal symptoms, 71.4% for stool symptoms, and 15.5% for rectal symptoms. Excluding the women without presence of a symptom at baseline from the effect size calculations showed that prucalopride 2 mg had a large effect (>0.8) on all PAC‐SYM items, including abdominal pain, abdominal discomfort, bloating, straining, and painful bowel movements. For abdominal symptoms and stool symptoms, effect sizes with prucalopride 2 mg were 1.3–2.3 times larger than those with placebo.
Conclusions & Inferences
Prucalopride 2 mg q.d. for 12 weeks alleviates common constipation symptoms in women in whom laxatives had failed to provide adequate relief.
This integrated analysis of three 12‐week clinical trials assessed the effect on symptoms of prucalopride 2 mg once daily, compared with placebo, in 936 women with self‐reported inadequate relief from laxatives. For women with symptoms at baseline, treatment with prucalopride 2 mg had a large effect (>0.8) on all items in the Patient Assessment of Constipation Symptoms (PAC‐SYM) questionnaire, including abdominal pain, abdominal discomfort, bloating, straining, and painful bowel movements. Prucalopride 2 mg once daily for 12 weeks alleviates common constipation symptoms in women in whom laxatives have failed to provide adequate relief.
Background: This paper reports the 3-month prevalence rates of gastrointestinal (GI) symptoms from the Domestic/International Gastroenterology Surveillance Study (DIGEST), and their relationship with ...demographic factors; namely age, gender and body mass index (BMI). Methods: Subjects were recruited from 10 international sites by a total of 5581 face-to-face interviews conducted with randomly selected members of the general population aged 18 years and over (50.6% female; mean age 44 years). The sample was divided according to whether subjects reported 1 or more of 14 GI symptoms, or no GI symptoms. Those with any of 11 upper GI symptoms were then subdivided according to their most bothersome symptom: gastro-oesophageal reflux (GORD)-like symptoms, ulcer-like symptoms or dysmotility-like symptoms. Symptoms were classified as relevant if they were of at least moderate severity and/or occurred at least once a week. Results: A mean of 46.4% of subjects reported experiencing one or more of the 14 GI symptoms, with 28.1% experiencing upper GI symptoms classified as relevant. Significant differences between the prevalences of relevant symptoms were evident between sampling sites. The estimated prevalence of GORD-like symptoms for the pooled sample was 7.7%. For ulcer-like symptoms, prevalence was 4.1%, and for dysmotility-like symptoms 15.5%. Significant differences were observed in the prevalence rates of symptom groups between countries. Women were significantly more likely than men to experience relevant symptoms, with gender differences also observed in the rates of GORD-like and dysmotility-like symptoms. The proportion of those with relevant symptoms experiencing GORD-like symptoms increased significantly with age; ulcer-like symptoms showed no significant relationship with age; and dysmotility-like symptoms decreased significantly with age. The prevalence of relevant symptoms increased with increasing BMI. Conclusions: In conclusion, the DIGEST has provided valuable data on the cross-country prevalence of upper GI symptoms, and their association with biological factors.
Summary
Background
Intestinal immune activation is involved in irritable bowel syndrome (IBS) pathophysiology. While most dietary approaches in IBS involve food avoidance, there are fewer indications ...on food supplementation. Palmithoylethanolamide, structurally related to the endocannabinoid anandamide, and polydatin are dietary compounds which act synergistically to reduce mast cell activation.
Aim
To assess the effect on mast cell count and the efficacy of palmithoylethanolamide/polydatin in patients with IBS.
Methods
We conducted a pilot, 12‐week, randomised, double‐blind, placebo‐controlled, multicentre study assessing the effect of palmithoylethanolamide/polydatin 200 mg/20 mg or placebo b.d. on low‐grade immune activation, endocannabinoid system and symptoms in IBS patients. Biopsy samples, obtained at screening visit and at the end of the study, were analysed by immunohistochemistry, enzyme‐linked immunoassay, liquid chromatography and Western blot.
Results
A total of 54 patients with IBS and 12 healthy controls were enrolled from five European centres. Compared with controls, IBS patients showed higher mucosal mast cell counts (3.2 ± 1.3 vs. 5.3 ± 2.7%, P = 0.013), reduced fatty acid amide oleoylethanolamide (12.7 ± 9.8 vs. 45.8 ± 55.6 pmol/mg, P = 0.002) and increased expression of cannabinoid receptor 2 (0.7 ± 0.1 vs. 1.0 ± 0.8, P = 0.012). The treatment did not significantly modify IBS biological profile, including mast cell count. Compared with placebo, palmithoylethanolamide/polydatin markedly improved abdominal pain severity (P < 0.05).
Conclusions
The marked effect of the dietary supplement palmithoylethanolamide/polydatin on abdominal pain in patients with IBS suggests that this is a promising natural approach for pain management in this condition. Further studies are now required to elucidate the mechanism of action of palmithoylethanolamide/polydatin in IBS. ClinicalTrials.gov number, NCT01370720.
Linked ContentThis article is linked to Quigley paper. To view this article visit https://doi.org/10.1111/apt.14014.
Summary
Background
The Rome criteria are currently required by health authorities for the inclusion of patients affected by functional dyspepsia in therapeutic trials. However, the degree of ...adherence to these criteria has not been formally verified.
Aim
To review adherence to the Rome criteria for inclusion criteria, outcome measures and endpoints in therapeutic trials on functional dyspepsia and the potential impact on the conclusions that can be drawn from these studies.
Methods
A total of 1818 articles were screened. Fifty‐eight trials claiming to include adults affected by functional dyspepsia as defined by the Rome criteria published as full articles in English between 2000 and 2013 were considered.
Results
Lack of full adherence to the Rome criteria of inclusion criteria was found in 54% of the studies, due to inclusion of patients with symptoms not reported in the Rome criteria or definitions of dyspeptic symptom that varied from those proposed by the Rome criteria. Ninety‐five per cent of clinical trials adopted therapeutic outcome measures that were not adherent to the Rome criteria, using questionnaires that did not include all dyspeptic symptoms or including symptoms other than those proposed by the Rome criteria.
Conclusions
Stringent criteria have not been adopted for inclusion criteria and outcome measures in the vast majority of published studies on functional dyspepsia that claim to have been carried out according to the Rome criteria. Appropriate questionnaires should be developed to promote adherence to internationally accepted definitions of the syndrome in future studies.
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