Camilleri, Michael

Abstract Background Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase ( HO 1) leads to loss of interstitial cells of Cajal and delayed gastric emptying ( GE ) in non‐obese diabetic mice. Our hypothesis was that hemin upregulation of HO 1 would restore normal GE in humans with gastroparesis. Aims To compare effects of hemin and placebo infusions on HO 1 activity and protein, GE , autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. Methods In a single‐center, double‐blind, placebo‐controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 ( SEM ) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO 1 protein and enzyme activity levels, GE with 13 C‐spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Key Results Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO 1 protein on days 3 ( p = 0.0002) and 7 ( p = 0.008) and HO 1 activity on day 3 ( p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Conclusions & Inferences Hemin failed to sustain increased HO 1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO 1 and improve GE .

AbstractBackgroundThis study compared prucalopride, a selective, prokinetic, 5‐HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high‐amplitude propagating contractions (HAPCs) in patients with chronic constipation.MethodsThis randomized, cross‐over, reader‐blinded study was conducted at a single site in the USA. The study was open to men and women aged 18–75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co‐primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity.Key ResultsThirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12‐h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2) and mean AUC, force, and amplitude (HAPC3) compared with PEG3350. Adverse events were mild or moderate.Conclusions & InferencesPrucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation.ClinicalTrials.gov number NCT01707667.

AbstractMost drug–drug interactions involve overlap or competition in drug metabolic pathways. However, there are medications, typically resins, whose function is to bind injurious substances such as bile acids or potassium within the digestive tract. The objective of this article is to review the functions of the stomach and the kinetics of emptying of different food forms or formulations to make recommendations on timing of medication administration in order to avoid intragastric drug interactions. Based on the profiles and kinetics of emptying of liquid nutrients and homogenized solids, a window of 3 h between administration of a resin drug and another ‘target’ medication would be expected to allow a median of 80% of medications with particle size <1 mm to empty from the stomach and, hence, avoid potential interaction such as binding of the ‘target’ medication within the stomach.

AbstractBackgroundGastrointestinal (GI) and non‐GI disorders are associated with altered intestinal permeability, which can be measured in vivo by urinary excretion after oral lactulose and mannitol ingestion. Inadvertent dietary consumption of 12Carbon (12C, regular) mannitol in food or from other sources may interfere with the test's interpretation. 13Carbon (13C) constitutes 1% of carbon in nature and 13C mannitol is a stable isotope. Our aim was to determine the performance of 13C mannitol for measurement of intestinal permeability.MethodsTen healthy volunteers underwent intestinal permeability assay using coadministered 12C mannitol, 13C mannitol and lactulose, followed by timed urine collections. Urinary sugar concentrations were measured using tandem high performance liquid chromatography–mass spectrometry.Key resultsWe found that 13C mannitol can be distinguishable from 12C mannitol on tandem mass spectrometry. In addition, 13C mannitol had ~20‐fold lower baseline contamination compared to 12C mannitol. We describe here the 13C mannitol assay method for the measurement of intestinal permeability.Conclusions & InferencesIn conclusion, 13C mannitol is superior to 12C mannitol for measurement of intestinal permeability. It avoids issues with baseline contamination and erratic excretions during the testing period.

AbstractBackgroundNeostigmine, an acetyl cholinesterase inhibitor, stimulates colonic motor activity and may induce vagally mediated cardiovascular effects. Our aim was to evaluate effects of i.v. neostigmine on colonic compliance and its safety in patients with chronic constipation.MethodsWe retrospectively reviewed medical records of a selected group of 144 outpatients with chronic constipation who were refractory to treatment. These patients had undergone intracolonic motility and compliance measurements with an infinitely compliant balloon linked to a barostat. Data abstracted included barostat balloon mean volumes with increases in pressure (4 mmHg steps from 0 to 44 mmHg) before and after i.v. neostigmine. Vital signs and oxygen saturation before and after neostigmine were recorded.Key ResultsOf the 144 patients, 133 were female, mean age was 41.0 ± 15.4 years (SD), and duration of constipation was 12.9 ± 13.8 years. Among patients who had undergone colonic transit measurement by scintigraphy, the overall colonic transit at 24 h (geometric center, GC24 [n = 115]) was 1.5 ± 0.7 (normal >1.3), and at 48 h (GC48 [n = 75]) it was 2.3 ± 0.9 (normal >1.9). Neostigmine decreased colonic compliance at lower distension pressures (e.g., 12 and 20 mmHg [both p < 0.001]), but not at 40 mmHg. There were expected minor changes in vital signs in response to neostigmine in 144 patients; however, one patient developed unresponsiveness, significant bradycardia, hypotension, and muscular rigidity that responded to 400 mcg i.v. atropine.Conclusions & InferencesNeostigmine significantly decreases colonic compliance in patients with refractory chronic constipation. Symptomatic bradycardia in response to neostigmine should be promptly reversed with atropine.

Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain.

AbstractBackgroundThe pemphigus group is characterized by the presence of circulating immunoglobulins against desmosomes. IgG/IgA pemphigus is defined by the presence of IgG and IgA cell surface deposits upon direct immunofluorescence (DIF) and/or circulating IgG and IgA autoantibodies upon indirect immunofluorescence. Previous reports of patients with IgG/IgA pemphigus are sparse. Whether IgG/IgA pemphigus is best classified as a subtype of IgG (classic) pemphigus or IgA pemphigus, or as a distinct entity, has yet to be determined.ObjectivesWe compared the features of patients with IgG/IgA pemphigus to those of IgG pemphigus and IgA pemphigus.MethodsRetrospective clinicopathologic study of patients with IgG, IgG/IgA, and IgA pemphigus evaluated at our clinic (1993–2013).ResultsWe included 26, 13, and seven patients with IgG, IgG/IgA, and IgA pemphigus, respectively. Patients with IgG/IgA pemphigus did not differ significantly from patients with IgG pemphigus in terms of clinical and microscopic features, DIF findings, anti‐desmoglein antibody values, and treatments required. However, patients with IgG/IgA pemphigus were significantly different from patients with IgA pemphigus regarding intertriginous distribution (P = 0.038) and pustular lesions (P < 0.001), acantholysis (P = 0.043), and presence of intercellular C3 deposits on DIF (P < 0.001).ConclusionComparative clinicopathologic data imply that IgG/IgA pemphigus may best be regarded as a variant of IgG pemphigus and distinct from IgA pemphigus.