Seated anorectal manometry during simulated evacuation. A physiological exercise or a new clinically useful diagnostic test?

Symptoms such as a feeling of incomplete evacuation, straining, absence of the call to stool, anal blockage or digitation suggest the presence a functional defecation disorder. As symptoms do not distinguish between patients with and without functional defecation diosrder, Rome IV criteria recommend that this disorder is diagnosed when two of three tests are positive: balloon expulsion test (BET), anorectal manometry (ARM) and defecography. However previous studies have demonstrated that the agreement among these tests is limited. In this issue of Neurogastroenterology and Motility, Sharma et al tested the hypothesis that conducting the ARM in a seated position would increase the diagnostic accuracy of the test in discriminating between patients with normal and prolonged BET. This minireview discusses the current knowledge on the role of the techniques to diagnose defecation disorder and the potential role of the ARM in a seated position

The management of functional dyspepsia in clinical practice: what lessons can be learnt from recent literature?

Functional dyspepsia is a prevalent functional gastrointestinal disorder that can significantly erode the quality of life of sufferers and places a major cost burden on healthcare services. In this article, we review the recent literature, selecting the information we consider relevant since it has changed our clinical management of patients with functional dyspepsia

Targeting mu opioid receptors to modulate gastrointestinal function: what have we learnt so far from the studies in functional bowel disorders?

Opioids have recently received much attention because of the epidemic in their use in some countries such as the USA and the UK. Concerns have been raised about the possibility that they can increase mortality in patients when used on a long-term basis. Moreover, they are known to induce paradoxical hyperalgesia as well as alterations of gut function. The analgesic properties of opioids are mediated by receptors located in the brain, but as opioid receptors are also expressed in the gastrointestinal tract, new drugs acting on these receptors have recently been developed to treat two functional disorders, namely irritable bowel syndrome with diarrhoea and opioid-induced constipation. The aim of this article is to highlight some interesting observations resulting from the development of these drugs in the field of functional gastrointestinal disorders

Hyoscine butylbromide mode of action on bowel motility: From pharmacology to clinical practice

Background: Hyoscine butylbromide (HBB) has been available for use as an antispasmodic since 1951 and is indicated for the treatment of abdominal pain associated with cramps. A previous review in 2007 summarized the evidence on the mode of action of HBB in vitro and in vivo in both animal and human studies. However, since then, novel publications have appeared within the literature and also our knowledge of what represents normal motility in humans has evolved. Purpose: This review is the result of the collaboration between a basic scientist and clinicians with the aim of providing an updated overview of the mechanisms of action of HBB and its clinical efficacy to guide not only use in clinical practice, but also future research

Bisacodyl: A review of pharmacology and clinical evidence to guide use in clinical practice in patients with constipation

Background: Bisacodyl is a member of the diphenylmethane family and is considered to be a stimulant laxative. It has a dual prokinetic and secretory action and needs to be converted into the active metabolite bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) in the gut to achieve the desired laxative effect. Bisacodyl acts locally in the large bowel by directly enhancing the motility, reducing transit time and increasing the water content of the stool. A recent network meta-analysis concluded that bisacodyl showed similar efficacy to prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat and sodium picosulfate for the primary endpoint of ≥3 complete spontaneous bowel movements (CSBM)/week and an increase of ≥1 CSBM/week over baseline. The meta-analysis also found that bisacodyl may be superior to the other laxatives for the secondary endpoint of change from baseline in the number of spontaneous bowel movements per week in patients with chronic constipation. This observation stimulated the authors to review the available literature on bisacodyl, which has been available on the market since the 1950s. Purpose: The aim of the current review was to provide an overview of the historic background, structure, function and mechanism of action of bisacodyl. Additionally, we discuss the important features and studies for bisacodyl to understand its peculiar characteristics and guide its use in clinical practice, but also stimulate research on open questions

Pan-colonic pressurizations associated with relaxation of the anal sphincter in health and disease: a new colonic motor pattern identified using high-resolution manometry

Background: Only few studies have applied high-resolution manometry (HRM) to the study of colonic motility in adults and none of them have concurrently evaluated colonic and anal motor activity. Aims: To evaluate colonic and anal motor activity by means of HRM in healthy subjects. As the present study revealed the presence of a new colonic motor pattern (pan-colonic pressurizations) in healthy subjects, three additional studies were conducted: the first and the second to exclude that this motor event results from an artefact due to abdominal wall contraction and to confirm its modulation by cholinergic stimulation and the third, as pilot study, to test the hypothesis that this colonic pattern is defective in patients with chronic constipation refractory to current pharmacological treatments. Methods: In both volunteers and patients the HRM catheter was advanced proximally during colonoscopy. Results: In all subjects, pressure increases of 15±3 mmHg and 24±4s simultaneously occurring in all colonic sensors (pan-colonic pressurizations), associated with anal sphincter relaxation were identified. Subjects had 85±38 pan-colonic pressurizations which increased significantly during meal (p=0.007) and decreased afterward (p=0.01), and were correlated with feelings of and desire to evacuate gas. The mean number of propagating sequences was 47±39, and only retrograde increased significantly postprandially (p=0.01). Pan-colonic pressurizations differed from strain artifacts and significantly increased after prostigmine. In patients pan-colonic pressurizations were significantly reduced as compared to volunteers. Conclusions: Pan-colonic pressurizations associated with relaxations of the anal sphincter represent a new colonic motor pattern which seems to be defective in patients with treatment-refractory chronic constipation and may play a role in the transport of colonic gas and in the facilitation of the propagating sequences-induced colonic transport

Tolerability, gastric emptying patterns, and symptoms during Nottingham Test Meal in 330 secondary care non-diabetic dyspeptic patients

Scintigraphy is used for overall assessment of gastric emptying. Adherence to an international consensus protocol is recommended to ensure quality; however, this has not been widely adopted because preparation of the “egg-beater” meal is inconvenient in clinical practice. In this report, we audit the tolerability and the results of gastric emptying scintigraphy with the 400ml Tc-99m-labelled liquid nutrient Nottingham Test Meal (NTM). Methods: Results from 330 consecutive adult, non-diabetic patients with dyspeptic symptoms referred for gastric scintigraphy were analysed. Gastric half-emptying time (T50) and validated measurements of early- and late-phase gastric emptying were acquired. Postprandial sensations of fullness, bloating, heartburn, nausea and epigastric pain were recorded using 100mm visual analogue scales (VAS) before and 0, 30 and 90 minutes after NTM ingestion. Results were compared with those previously obtained in healthy subjects.Key Results: Almost all (98%) of the patients were able to consume the 400ml NTM. Considering early- and late-phase gastric emptying, frequently observed patterns included normal early- with slow late-phase (25%) and fast early- with slow late-phase emptying (27%). Abnormal score of fullness and/ or dyspeptic symptoms were observed in 88% of dyspeptic patients. Abnormal fullness at T0 (after completed drink ingestion) was associated with slow late-phase of gastric emptying, especially in women. Conclusions: Gastric scintigraphy with the NTM is simple to perform and well tolerated. Whether the identified abnormal gastric emptying patterns could predict different treatment outcome in patients with functional dyspepsia is the subject of ongoing prospective studies

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose symptoms include abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals in the community at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but IBS is also more common in people with psychological co-morbidity, and in young adult females. The pathophysiology of IBS remains incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered central nervous system processing. Other less reproducible mechanisms may include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people the diagnosis can be made based on the clinical history, with limited, judicious, use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key, and can improve quality of life and symptoms, and reduce health care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for those with more severe symptoms; these include central neuromodulators, intestinal secretagogues, drugs acting on 5-hydroxytryptamine or opioid receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), and psychological therapies. The increased understanding of the pathophysiology of IBS in the last 10 years has led to a healthy pipeline of novel drugs in development

“Development of Fixed Dose Combination Products” Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy

The gastrointestinal (GI) tract is one of the most popular and used routes of drug product administration due to the convenience for better patient compliance and reduced costs to the patient compared to other routes. However, its complex nature poses a great challenge for formulation scientists when developing more complex dosage forms such as those combining two or more drugs. Fixed dose combination (FDC) products are two or more single active ingredients combined in a single dosage form. This formulation strategy represents a novel formulation which is as safe and effective compared to every mono-product separately. A complex drug product, to be dosed through a complex route, requires judicious considerations for formulation development. Additionally, it represents a challenge from a regulatory perspective at the time of demonstrating bioequivalence (BE) for generic versions of such drug products. This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenues for successfully developing FDC products and their generic versions

High-resolution manometry reveals different effect of polyethylene glycol, bisacodyl and prucalopride on colonic motility in healthy subjects: an acute, open label, randomised, crossover, reader blinded study with potential clinical implications

PEG, bisacodyl and prucalopride have been reported to be more effective than placebo in treating patients with constipation but about 50% of the patients still do not respond to these medications. Only bisacodyl and pucalopride are expected to directly stimulate the colonic motility in humans in vivo. As no previous study has done this, the aim of the study was to investigate the effect of PEG, bysacodyl and prucalopride as compared to placebo on colonic motility assessed by means of the high-resolution manometry (HRM) in healthy subjects.Methods: 10 healthy subjects have been enrolled in an acute, open-label, randomized, reader-blinded, cross-over study and requested to undergo a colonoscopy-assisted HRM measuring their colonic motility before and after administration of 13.8 g (two doses) PEG, 10 mg bisacodyl, 2 mg prucalopride and placebo. Results: in the human prepared colon, oral administration of PEG significantly increases the number of low amplitude long distance propagating contractions (P= 0.007 vs placebo) while bisacodyl significantly increases the number of high amplitude propagating contractions (HAPCs) (all P[less than]0.01 vs PEG, prucalopride and placebo). Prucalopride has no major effect on the number of propagating contractions but increases HAPCs amplitude (P= 0.01) and seems to increase the number of simultaneous pressure increases.Conclusions: In humans, PEG, prucalopride and bisacodyl have distinct effects on colonic motility in humans. This information has clinical implication, as it indicates that the combination of prucalopride and bisacodyl, normally not considered in clinical practice, could be effective in treating patients with constipation refractory to single medications