Citations

Background The relationship between delayed gastric emptying and upper GI symptoms (UGI Sx) is controversial. Objective To assess association between gastric emptying and UGI Sx, independent of treatment. Design We performed a systematic review and meta-analysis of the literature from 2007 to 2017, review of references and additional papers identified by content expert. We included studies evaluating the association between gastric emptying and nausea, vomiting, early satiety/postprandial fullness, abdominal pain and bloating. Covariate analyses included optimal gastric emptying test method, gastric emptying type (breath test or scintigraphy) and patient category. Meta-regression compared the differences based on type of gastric emptying tests. Results Systematic review included 92 gastric emptying studies (26 breath test, 62 scintigraphy, 1 ultrasound and 3 wireless motility capsule); 25 of these studies provided quantitative data for meta-analysis (15 scintigraphy studies enrolling 4056 participants and 10 breath test studies enrolling 2231 participants). Meta-regression demonstrated a significant difference between optimal and suboptimal gastric emptying test methods when comparing delayed gastric emptying with nausea and vomiting. On evaluating studies using optimal gastric emptying test methodology, there were significant associations between gastric emptying and nausea (OR 1.6, 95% CI 1.4 to 1.8), vomiting (OR 2.0, 95% CI 1.6 to 2.7), abdominal pain (OR 1.5, 95% CI 1.0 to 2.2 ) and early satiety/fullness (OR 1.8, 95% CI 1.2 to 2.6) for patients with UGI Sx; gastric emptying and early satiety/fullness in patients with diabetes; gastric emptying and nausea in patients with gastroparesis. Conclusions The systematic review and meta-analysis supports an association between optimally measured delayed gastric emptying and UGI Sx.

AbstractBackgroundCannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms.PurposeThe objective of this article is to increase the awareness of gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms. The non‐selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity. In addition to the well‐recognized manifestations of cannabinoid hyperemesis, cannabinoid mechanisms result in human and animal models of gastrointestinal and colonic dysmotility. Decreased enteric FAAH activity is associated with colonic inertia in slow transit constipation and, conversely, the orphan G protein‐coupled receptor, GPR55, is overexpressed in streptozotocin‐induced gastroparesis, suggesting it is involved in inhibition of antral motility. Experimental therapies in gastrointestinal motility and functional disorders are focused predominantly on pain relief mediated through cannabinoid 2 receptors or inhibition of DAGLα to normalize colonic transit. In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.

AbstractBackgroundThe reproducibility of gastric emptying (GE) measured with scintigraphy in patients is poorly understood. Our aims were to assess the intra and inter‐individual reproducibility of these parameters in patients with upper gastrointestinal symptoms.MethodsSixty patients (21 diabetics, 39 non‐diabetics) with upper gastrointestinal symptoms underwent scintigraphic‐assessment of GE of a solid meal (296 kcal, 30% fat) over 4 hours on two occasions at an average interval of 15 days. The concordance correlation coefficient (CCC), intra and inter‐individual coefficients of variation (COV) of GE endpoints were analyzed.ResultsThe GE t1/2 was 134 ± 8 minutes (mean ± SEM) for the first and 128 ± 6 minutes for the second study. The mean (95% CI) CCC between the two studies was 0.79 (0.67, 0.87) for GE at 1 hour, 0.83 (0.75, 0.9) for GE at 2 hours, 0.54 (0.34, 0.7) for GE at 4 hours, and 0.79 (0.68, 0.86) for GE t1/2. However, in 18 of 60 patients (30%), the characterization of GE as normal, delayed, or rapid differed between the first and second studies. For gastric empting t1/2, the inter‐individual coefficients of variation was 40%; the intra‐individual COV was 20%, comparable in diabetics and non‐diabetics, and greater in patients with rapid (28%) than delayed (18%) or normal GE (12%).Conclusions & InferencesAmong patients with upper gastrointestinal symptoms, GE measured with scintigraphy is relatively reproducible. In 30% of cases, the interpretation was different between the two assessments. Hence, a diagnosis of gastroparesis based on a single study may occasionally be inaccurate.

Functional gastrointestinal disorders (FGIDs) and IBDs are two of the most prevalent disorders of the GI tract and consume a significant proportion of healthcare resources. Recent studies have shown that membrane-bound guanylate cyclase-C (GC-C) receptors lining the GI tract may serve as novel therapeutic targets in the treatment of FGIDs and IBDs. GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH-dependent manner and modulates key physiological functions. These include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity and regulation of epithelial regeneration. Studies of the GC-C paracrine signalling axis have revealed the therapeutic potential of these receptors in treating GI disorders, including chronic idiopathic constipation and irritable bowel syndrome–constipation. This review focuses on the evolving understanding of GC-C function in health and disease, and strategies for translating these principles into new treatments for FGIDs and IBDs.

AbstractBackgroundWeight loss in response to the long‐acting GLP‐1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric‐emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short‐acting GLP‐1 agonist, exenatide.MethodsWe evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 μg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks. Data were analyzed using the dominant genetic model and intention‐to‐treat analysis.Key ResultsThere was a significant correlation between changes in weight and GE T1/2 (rs = −.382, P = .004). GLP1R rs6923761 minor allele A (AA_AG) carriers who received either exenatide or liraglutide had greater delay in GE T1/2 relative to baseline (117.9 ± 27.5 [SEM] minutes and 128.9 ± 38.32 minutes) compared to GG genotype (95.8 ± 30.4 minutes and 61.4 ± 21.4 minutes, respectively; P = .11). There was a non‐significant difference in weight loss based on GLP1R rs6923761 genotype after 5 weeks of treatment. There were no significant correlations with TCF7L2 (rs7903146) genotype.Conclusions & InferencesThe minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T1/2 in response to liraglutide and exenatide. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists.

This mini-review summarizes recent new developments in visceral analgesics. This promising field is important, as a new approach to address abdominal pain with peripheral visceral analgesics is considered a key approach to addressing the current opioid crisis. Some of the novel compounds address peripheral pain mechanisms through modulation of opioid receptors via biased ligands, nociceptin/orphanin FQ opioid peptide (NOP) receptor, or dual action on NOP and μ-opioid receptor, buprenorphine and morphiceptin analogs. Other compounds target nonopioid mechanisms, including cannabinoid (CB2), N-methyl-d-aspartate, calcitonin gene-related peptide, estrogen, and adenosine A2Breceptors and transient receptor potential (TRP) channels (TRPV1, TRPV4, and TRPM8). Although current evidence is based predominantly on animal models of visceral pain, early human studies also support the evidence from the basic and animal research. This augurs well for the development of nonaddictive, visceral analgesics for treatment of chronic abdominal pain, an unmet clinical need.

AbstractBackgroundGastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use.PurposeThe purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug‐induced cardiac arrhythmias, specifically drug‐induced longQTsyndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug‐induced cardiac arrhythmia associated with prokinetic agents and otherQTinterval prolonging medications can be mitigated successfully.

Abstract Background Nausea, vomiting, and constipation ( OIC ) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu‐opiate opioid receptor antagonist. Aim To compare the effects on pan‐gut transit of treatment with codeine, naloxegol, or combination in healthy volunteers. Methods We conducted a randomized, double‐blind, placebo‐controlled, single‐center, parallel‐group study in 72 healthy opioid‐naïve adults, randomized to: codeine (30 mg q.i.d.), naloxegol (25 mg daily), codeine and naloxegol, or matching placebo. During 3 days of treatment, we measured gastric emptying ( GE ) T 1/2 , colonic filling at 6 hours ( CF 6), colonic geometric center at 24 and 48 hours, and ascending colon emptying ( ACE ) T 1/2 . Key Results Participants were 59.7% women, median BMI 25.0 kg/m 2 , and median age 33.8 years. Codeine significantly retarded GE T 1/2, CF 6, overall colonic transit, and ACE T 1/2 . There was significant difference ( P = .026) in GE T 1/2 between codeine (144.0 min [ IQR 110.5‐238.6]) and naloxegol (95.5 min [89.1‐135.4]). There was a significant overall group difference in CF 6 ( P = .023), with significant difference ( P = .019) between codeine (11.0% [0.0‐45.0]) and naloxegol (51% [18.8‐76.2]). However, no significant differences were found between codeine‐treated participants concomitantly receiving placebo or naloxegol. Conclusions and Inferences Short‐term administration of naloxegol (25 mg) in healthy, opioid‐naïve volunteers does not reverse the retardation of gastric, small bowel, or colonic transit induced by acute administration of codeine. Further studies with naloxegol at higher dose are warranted to assess the ability to reverse the retardation of transit caused by acute administration of codeine in opioid‐naïve subjects.