Citations

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.

ABSTRACTPreservation of osteochondral allografts used for transplantation is critical to ensure favorable outcomes for patients after surgical treatment of cartilage defects. To study the biological effects of protocols currently used for cartilage storage, we investigated differences in gene expression between stored allograft cartilage and fresh cartilage from living donors using high throughput molecular screening strategies. We applied next generation RNA sequencing (RNA‐seq) and real‐time reverse transcription quantitative polymerase chain reaction (RT‐qPCR) to assess genome‐wide differences in mRNA expression between stored allograft cartilage and fresh cartilage tissue from living donors. Gene ontology analysis was used to characterize biological pathways associated with differentially expressed genes. Our studies establish reduced levels of mRNAs encoding cartilage related extracellular matrix (ECM) proteins (i.e., COL1A1, COL2A1, COL10A1, ACAN, DCN, HAPLN1, TNC, and COMP) in stored cartilage. These changes occur concomitantly with increased expression of “early response genes” that encode transcription factors mediating stress/cytoprotective responses (i.e., EGR1, EGR2, EGR3, MYC, FOS, FOSB, FOSL1, FOSL2, JUN, JUNB, and JUND). The elevated expression of “early response genes” and reduced levels of ECM‐related mRNAs in stored cartilage allografts suggests that tissue viability may be maintained by a cytoprotective program that reduces cell metabolic activity. These findings have potential implications for future studies focused on quality assessment and clinical optimization of osteochondral allografts used for cartilage transplantation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1950–1959, 2016.

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.