Brandler, Justin

SummaryBackgroundGastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction.AimTo evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5‐HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids.MethodsSingle‐centre, placebo‐controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99mTc‐egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111In‐charcoal delivered in methacrylate‐coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2. Statistical analysis used baseline parameters as covariates (ANCOVA).ResultsPatients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying T1/2, colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG.ConclusionI.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short‐term treatment of gastric and intestinal motility disorders.ClinicalTrials.gov #NCT03281577

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [−11% (−16, −4), P = 0.004]; and FD [−8% (−9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying. NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.

INTRODUCTION: Reduced gastric accommodation (GA) or accelerated or delayed gastric emptying (GE) contributes to pathophysiology in functional dyspepsia (FD). Secretin is an endogenous hormone secreted postprandially from the duodenal mucosa. Our objective was to determine the effects of secretin in human gastric motor functions and satiation in health and FD. METHODS: We conducted a double-blind, randomized, placebo-controlled, cross-over trial in 10 healthy participants and 10 patients with FD by Rome IV criteria. Subjects were randomized to IV secretin or normal saline with a 1-4 week washout period. We measured GA using validated 99m Tc-single photon emission computed tomography with a standardized 300 mL meal of 111 In radiolabeled Ensure®. We measured GE using scintigraphy of the same meal and symptoms 30 minutes post meal based on 100 mm visualized analog scale (VAS). To measure volume to fullness (VTF) and maximum tolerated volume (MTV), we performed Ensure® nutrient drink test (NDT) and recorded symptoms 30 min post-MTV. Wilcoxon Signed-Rank Test was used for comparison within healthy and FD groups and ANCOVA modeling was used for intention to treat comparison between groups, adjusting for age, sex, and treatment arm (secretin vs. placebo). Study drug was provided by ChiroClin, Inc. RESULTS: The median age for healthy volunteers (HV) was 45.0 years [IQR: 38.0, 49.0 (80% female)] and for FD was 50.5 years [42.0, 55.0 (70% female)]. There was no statistical difference in either group for secretin vs. placebo for GA. Secretin delayed GE in both HV and FD (Table 1). There was decrease in GE for secretin vs. placebo in HV at 20 minutes [-10% (-13, -7), P = 0.008] and 30 minutes [-11% (-16, -4), P = 0.004]. This finding was also seen in the FD group for GE at 25 minutes [-5% (-9, 0), P = 0.047] and 30 minutes [-8% (-9, 0), P = 0.03]. There were no statistically significant differences between treatment arms for VTF or MTV in either HV or FD. On ANCOVA analysis, there were statistically significant increases in nausea at 30 minutes ( P = 0.0016) and fullness at 30 minutes ( P = 0.0002) for secretin vs. placebo in FD compared to HV. CONCLUSION: Secretin delayed GE in both healthy volunteers and FD without significantly altering GA, VTF, or MTV. Secretin receptor stimulation deserves further study in FD patients with accelerated GE.

INTRODUCTION: There is still controversy surrounding the use of symptoms, history, and tests for diagnosis of rectal evacuation disorders (RED) and slow transit constipation (STC). We performed a comprehensive literature-based analysis to ascertain pooled prevalence, sensitivity (SN), specificity (SP), and likelihood ratios (LR) for clinical parameters to determine pre- and post-test probabilities of diagnosing RED and STC without RED. METHODS: Using MEDLINE and PUBMED, we examined systematic and clinical reviews, meta-analyses, primers, guidelines, and consensus statements since 1999 to determine the diagnostic utility of history, symptoms, and testing for RED and STC. Studies were included if binary data were available to assess true/false positives or negatives to pool and calculate SN/SP/LR. Given there are no “gold standard” diagnostic criteria for RED or STC, designation of “true” RED or STC was based on confirmation by at least one objective anorectal or colonic transit test. Controls varied across studies; all had normal anorectal and/or transit tests by the specific protocol used in each study. We assessed STC alone (associated with normal anorectal testing). RESULTS: We reviewed 97 articles involving studies from many different countries, and 63 articles for RED and 61 articles for STC met inclusion/exclusion criteria. The prevalence of disease phenotypes among 4160 patients with chronic constipation based on objective testing was RED alone 23.3%, normal transit constipation (NTC) alone 31.9%, STC alone 16.2%, and RED + STC 14.3%. To diagnose RED (Figure 1, Table 1), the most clinically significant symptoms included hard/lumpy stools (+LR 269.6, n = 1583) and urinary symptoms (100% specificity, n = 58). The strongest digital rectal exam (DRE) findings were poor anal relaxation (+LR 5.3, n = 529) or increased anal squeeze (+LR 8.4, n = 395). The most predictive anorectal tests were balloon expulsion time >120 s (+LR 5.5, n = 551) and rectoanal pressure gradient < −40 mmHg with high anal pressure on straining on anorectal manometry (100% specificity, n = 101). For STC alone, the most predictive symptom was a call to stool (+LR 10.5, n = 75). Patients without abdominal distension/fullness/bloating were less likely to have RED (−LR 0.2, n = 324) or STC alone (−LR 0.2, n = 93). CONCLUSION: Symptom assessments and DREs are critical in the evaluation for RED and STC. RED is highly prevalent in patients presenting with chronic idiopathic constipation.

OBJECTIVES: Although systemic sclerosis (SSc) is known to affect the gastrointestinal (GI) tract, most of the literature focuses on esophageal, small intestinal, or anorectal manifestations. There have been no reviews focused on large bowel SSc complications in over 30 years. The aim of this study is to perform a systematic review of colonic manifestations and complications of SSc. METHODS: An experienced librarian conducted a search of databases, including English and Spanish articles. The search used keywords including “systemic sclerosis,” “scleroderma,” and “colon.” A systematic review was performed using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Case reports/series were screened for validity by adapting from criteria published elsewhere. RESULTS: Of 1,890 articles, 74 met selection criteria. Fifty-nine of the 77 articles were case reports/series. The most common article topics on colonic SSc complications were constipation/dysmotility (15), colonic volvulus (8), inflammatory bowel disease (7), microscopic colitis (6), megacolon (6), and telangiectasia (6). Colonic manifestations constituted 24% of articles on GI complications of SSc. There were a total of 85 cases (84% women, with a median age of onset of colon complication of 52 years). Limited cutaneous SSc phenotype (65.6%) was more common than diffuse (26.2%). Patients frequently had poor outcomes with high mortality related to colonic complications (27%). Recent studies explore contemporary topics such as the microbiome in SSc and prucalopride for chronic constipation in SSc. DISCUSSION: Colonic complications comprise a large proportion of the published reports on GI symptoms afflicting patients with SSc and require raised diagnostic suspicion and deliberate action to avoid potentially serious complications including death.

AbstractObjectiveTo compare estimates of gastric accommodation (GA) with single photon emission computed tomography (SPECT) to measurements based on intragastric meal distribution immediately post‐meal ingestion (IMD0).MethodsWe evaluated 108 diabetics with upper gastrointestinal (UGI) symptoms who had undergone gastric emptying of solids (GE) by scintigraphy and GA measurements by SPECT. Immediately after ingestion of a 99mTc‐labeled egg meal (time 0), we estimated IMD0 as radioactive counts or area of the proximal half of the stomach on two‐dimensional images. Gastric volume (GV) during fasting and after 300 mL Ensure® was measured by SPECT to quantify accommodation volume (AV) or postprandial to fasting volume ratio (GVR). From the measured proximal gastric area, we estimated the volume of proximal stomach (4/3 × π × r3). We performed regression analyses to assess relationships between IMD0 and GA (AV) and GVR.ResultsThere was a significant correlation between area and radioactivity counts in the proximal stomach (r = 0.67, P < 0.001); however, there was considerable interpersonal variation [bias 0.20 (95% CI −0.07, 0.47)]. There were no significant correlations between total GV or AV or VR by SPECT and measurements using IMD0: proximal gastric counts, area, and estimated volume as continuous variables of dichotomized patient groups, based on published cutoff values. There were no significant differences in total gastric area or the IMD0 parameters (% area or % radioactive counts) between those with and without UGI symptoms except for fullness and satiety.ConclusionsIntragastric meal distribution immediately post‐meal ingestion is not significantly correlated with GA measurement by SPECT.

OBJECTIVES: Our aim was to characterize upper gastrointestinal (UGI) symptoms and associations in individuals with diabetes mellitus (DM) who had undergone evaluation of gastric emptying (GE) and accommodation (GA) at a referral center. METHODS: From the Mayo Clinic Rochester electronic medical records of adults with diabetes types 1 and 2 (DM1 and DM2) evaluated between January 1997 and December 2015, we extracted demographics, UGI symptoms, current medications, treatments for diabetes, GE solids by scintigraphy, GA by single photon emission computed tomography (SPECT), and diabetes complications. We compared subgroups with delayed (GE at 2 h <25% or GE at 4 h <75%), rapid (GE at 1 h > 35%), and normal GE, as well as reduced (<428 mL) and normal GA. RESULTS: We reviewed 108 patients (60.2% females, median age 49.0 years). Overall, 71.3% had DM2; one-third of these were insulin dependent and had fairly well-controlled diabetes (median HbA1c 6.7% (IQR 6.2; 7.9)). Manifestations of diabetic triopathy (peripheral neuropathy, nephropathy, and retinopathy) were uncommon at presentation with UGI symptoms. Nausea was the most common symptom (80.6%). There were single or combined GE (total 56%: rapid in 37%, slow in 19%) and GA (total 39%) abnormalities; there was normal GA and GE in 28%; 40.3% of the DM2 patients had accelerated GE at 1 h. GE at 1 h is associated with nausea/vomiting, and fasting gastric volume is associated with bloating. CONCLUSIONS: Among referred diabetic patients with UGI symptoms, GE and GA testing identifies potential targets for individualizing treatment and avoidance of empirical trials for the 28% with no disturbance of GE and GA.