Camilleri, M

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.

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.

Linked ContentThis article is linked to Yiannakou et al paper. To view this article visit https://doi.org/10.1111/apt.14349.

AbstractBackgroundOpioid‐induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu‐opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid‐naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid‐naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.MethodsA PubMed search of μ‐opioid antagonists to counter μ‐opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.Key ResultsThe approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid‐naïve subjects. Trials investigating the required dose of alvimopan showed 0.5‐1 mg dose was efficacious in treating OIC; a 10‐fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid‐naïve subjects compared to chronic opioid users. Opioid‐naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.Conclusions & InferencesOpioid‐naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ‐opioid antagonist effect.

SummaryBackgroundThe serum biomarkers, elevated 7αC4 (C4) and decreased FGF19, have been proposed as screening tests for bile acid diarrhoea.AimTo analyse prevalence, specificity and reproducibility of fasting C4 and FGF19 in identifying bile acid diarrhoea in patients with irritable bowel syndrome with predominant diarrhoea or functional diarrhoea (summarised as IBS‐D).MethodsWe prospectively studied fasting serum C4 and FGF19 in 101 IBS‐D patients; we reviewed data from 37 of the 101 patients with prior fasting serum C4 and FGF19 and from 30 of the 101 patients with prior faecal bile acids per 48 hours. We compared results with normal values (C4 ≥52.5 ng/mL [n=184], FGF‐19 ≤61.7 pg/mL [n=50]). We used Spearman correlation and Bland‐Altman plots to appraise reproducibility.ResultsAmong the 101 patients, there was a negative correlation between serum C4 and FGF19 (Rs=−.342, P=.0005). Bile acid diarrhoea was diagnosed in 10 patients based on elevated serum C4 levels (mean 23.5±23.1 [SD] ng/mL) and 21 patients based on decreased FGF19 levels (121.6±84.2 pg/mL). With replicate tests in patients with stable IBS‐D, 78% of C4 and 70% of FGF19 measurements remained concordant, with 3% and 11% respectively consistently positive for bile acid diarrhoea in the 101 patients. Compared to 48 hours faecal bile acids, specificity for C4 and FGF19 was 83% and 78%, respectively. Bland‐Altman plots demonstrated greater reliability of C4 than FGF19.ConclusionsAmong 101 patents with IBS‐D, fasting FGF19 and C4 levels had good specificity and negative predictive value, suggesting utility as screening tests to exclude bile acid diarrhoea.

AbstractBackgroundColonic pseudo‐obstruction (CPO) is characterized by colonic distention in the absence of mechanical obstruction or toxic megacolon. Concomitant secretory diarrhea (SD) with hypokalemia (SD‐CPO) due to gastrointestinal (GI) loss requires further characterization.AimTo perform a systematic review of SD‐CPO, report a case study, and compare SD‐CPO with classical CPO (C‐CPO).MethodsWe performed a search of MEDLINE, EMBASE, Cochrane, and Scopus for reports based on a priori criteria for CPO, SD and GI loss of potassium. An additional case at Mayo Clinic was included.ResultsNine publications met inclusion criteria, with a total of 14 cases. Six studies had high, three moderate, and our case high methodological quality. Median age was 74 years (66‐97), with 2:1 male/female ratio. Kidney disease was present in 6/14 patients. Diarrhea was described as profuse, watery, or viscous in 10 patients. Median serum, stool, and urine potassium concentrations (mmol/L) were 2.4 (range: 1.9‐3.1), 137 (100‐180), and 17 (8‐40), respectively. Maximal diameter of colon and cecum (median) were 10.2 cm and 10.5 cm, respectively. Conservative therapy alone was effective in five out of 14 patients. Median potassium supplementation was 124 mEq/d (40‐300). Colonic decompression was effective in three out of six patients; one had a total colectomy; three out of 14 had died. The main differences between SD‐CPO and C‐CPO were lower responses to treatments: conservative measures (35.7% vs 73.6%, P=.01), neostigmine (17% vs 89.2%, P<.001), and colonic decompression (50% vs 82.4%, P=.02).ConclusionSD‐CPO is a rare phenotype associated with increased fecal potassium and is more difficult to treat than C‐CPO.

AbstractBackgroundFollowing ablation therapy for cardiac arrhythmias, patients may develop upper gastrointestinal (UGI) symptoms. The vagus nerve is close to the atria and may be affected by ablating energy.AimTo identify structural or functional complications in UGI tract following ablation for atrial fibrillation (AF) and clinical outcomes and association with vagal dysfunction.MethodsUsing natural language processing of electronic medical records and an AF ablation database of 5380 patients treated during 17 years, we identified 40 patients with UGI complications. We evaluated vagal dysfunction by electrocardiogram (ECG) showing lack of sinus arrhythmia (variation in R‐R interval by ≥120 milliseconds, in presence of normal sinus P waves and constant P‐R interval).Key ResultsAmong 40 patients: (A) eight had structural GI complications confirmed by diagnostic tests: seven with esophageal ulcer/erosions and no signs of UGI bleeding and one developed esophagopericardial fistula (and survived with treatment); (B) 15 had functional UGI complications confirmed by objective motility tests. Nine had newly developed symptoms and six had aggravated symptoms; and (C) the remaining 17 had GI symptoms without relevant diagnostic results. Most UGI issues resolved spontaneously or with conservative treatment. However, 2 died several weeks after ablation procedure; cause of death was suspected atrioesophageal fistula or esophageal rupture. Vagal dysfunction persisted for 3 months in 13 and was transient in 8.Conclusions/InferencesAlthough most GI issues resolved spontaneously, there should be a high index of clinical suspicion in patients with persistent symptoms. Vagal dysfunction may serve as a marker of more extensive tissue damage.

Abstract Background Diagnosis of rectal evacuation disorders ( RED ) is currently based on anorectal manometry ( ARM ) and evacuation tests in specialized laboratories; we recently showed higher rectal gas volume ( RGV ) and maximum rectal gas transaxial area ( MRGTA ) measured on abdominal and pelvic computed tomography ( CT ) in patients with documented RED .The aim of this study was to obtain cut‐off values of RGV , MRGTA , and rectal area on scout film ( RASF ) to differentiate constipated patients with RED from those without RED , based on ARM , balloon expulsion test ( BET ), and colon transit test. Methods We identified 118 constipated patients (65 with RED ) with prior record of CT . Using standard CT software, we used a variable region of interest ( ROI ) program to measure RGV , MRTGA , and RASF , as previously described. We constructed receiver operating characteristics curves based on different values, and we estimated AUC , specificity, and positive predictive value ( PPV ) to detect RED in patients with constipation. Key Results Receiver operating characteristics of the models to predict RED showed AUC 0.751 for RGV and 0.737 for MRGTA (both P <.001), and 0.623 for RASF ( P =.029). At specificity of 90%, RGV of 30 mL had a PPV 77.3%, MRGTA of 10 cm 2 had a PPV 75.0%, and RFAS of 9 cm 2 had a PPV of 68.8% for identifying constipated patients with RED . Conclusions & Inferences Rectal gas measurements on abdominal imaging may indicate RED in patients with constipation. At ~90% specificity for RED , RGV of 20 or 30 mL or MRGTA of 10 cm 2 on CT has PPV ~75%, and RASF of >9 cm 2 has PPV of ~69%.

AbstractBackgroundIn an open‐label study of 26 patients with IBS‐C and chronic constipation, treatment with a vibrating (VIBRANT) capsule twice a week for 7.5 weeks resulted in 88.5% responders. Effects on colonic transit are unclear. We aimed to compare effects of VIBRANT and sham capsule treatment on colonic transit in patients with functional constipation.MethodsPatients with functional constipation (Rome III criteria) were randomized to VIBRANT or sham capsule treatment for 8 weeks and underwent scintigraphic colonic transit measurements during week 8. We estimated the overall rate of colonic transit from the slope of progression of colonic geometric center over 48 hours. The capsule was activated 8 hours after ingestion, and the vibration sequence included 240 cycles.Key ResultsThere were no significant group differences in overall colonic transit [GC48, 2.76 (IQR 2.42‐4.03) for sham group and 3.46 (2.55‐4.61) for active treatment group (P=.13)]. Additionally, the progression of the isotope through the colon was numerically faster, though not significantly different (slope, P=.14) in the VIBRANT capsule group compared to the sham group. Three participants in the VIBRANT capsule group had accelerated colonic transit at 32 hours and faster colonic transit slope compared to the 95th percentile of the sham group.Conclusions and InferencesAlthough there were no group differences between VIBRANT and sham capsule treatment on colonic transit, at least one (and possibly three) of 12 patients receiving the VIBRANT capsule had faster colonic transit. The vibration parameters to accelerate colonic transit in patients with functional constipation require further optimization.