[Show abstract][Hide abstract] ABSTRACT: To determine if the observed paracellular sucrose leak in Barrett's esophagus patients is due to their proton pump inhibitor (PPI) use.
The in vivo sucrose permeability test was administered to healthy controls, to Barrett's patients and to non-Barrett's patients on continuous PPI therapy. Degree of leak was tested for correlation with presence of Barrett's, use of PPIs, and length of Barrett's segment and duration of PPI use.
Barrett's patients manifested a near 3-fold greater, upper gastrointestinal sucrose leak than healthy controls. A decrease of sucrose leak was observed in Barrett's patients who ceased PPI use for 7 d. Although initial introduction of PPI use (in a PPI-naïve population) results in dramatic increase in sucrose leak, long-term, continuous PPI use manifested a slow spontaneous decline in leak. The sucrose leak observed in Barrett's patients showed no correlation to the amount of Barrett's tissue present in the esophagus.
Although future research is needed to determine the degree of paracellular leak in actual Barrett's mucosa, the relatively high degree of leak observed with in vivo sucrose permeability measurement of Barrett's patients reflects their PPI use and not their Barrett's tissue per se.
Full-text · Article · Jun 2012 · World Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Inflammatory Bowel Disease--comprised of Crohn's Disease and Ulcerative Colitis (UC)--is a complex, multi-factorial inflammatory disorder of the gastrointestinal tract. In this study we have explored the utility of naturally occurring circulating miRNAs as potential blood-based biomarkers for non-invasive prediction of UC incidences. Whole genome maps of circulating miRNAs in micro-vesicles, Peripheral Blood Mononuclear Cells and platelets have been constructed from a cohort of 20 UC patients and 20 normal individuals. Through Significance Analysis of Microarrays, a signature of 31 differentially expressed platelet-derived miRNAs has been identified and biomarker performance estimated through a non-probabilistic binary linear classification using Support Vector Machines. Through this approach, classifier measurements reveal a predictive score of 92.8% accuracy, 96.2% specificity and 89.5% sensitivity in distinguishing UC patients from normal individuals. Additionally, the platelet-derived biomarker signature can be validated at 88% accuracy through qPCR assays, and a majority of the miRNAs in this panel can be demonstrated to sub-stratify into 4 highly correlated intensity based clusters. Analysis of predicted targets of these biomarkers reveal an enrichment of pathways associated with cytoskeleton assembly, transport, membrane permeability and regulation of transcription factors engaged in a variety of regulatory cascades that are consistent with a cell-mediated immune response model of intestinal inflammation. Interestingly, comparison of the miRNA biomarker panel and genetic loci implicated in IBD through genome-wide association studies identifies a physical linkage between hsa-miR-941 and a UC susceptibility loci located on Chr 20. Taken together, analysis of these expression maps outlines a promising catalog of novel platelet-derived miRNA biomarkers of clinical utility and provides insight into the potential biological function of these candidates in disease pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Proton pump inhibitors are the second most commonly prescribed drug class in the United States. The increased utilization of PPIs parallels the rising incidence of reflux disease. Owing to their clinical efficacy and relative lack of tachyphylaxis, PPIs have largely displaced H-2 receptor antagonists in the treatment of acid peptic disorders. The elevation of intragastric pH and subsequent alterations of gastric physiology induced by PPIs may yield undesired effects within the upper GI tract. The ubiquity of the various types of H(+), K(+)-ATPase could also contribute to non-gastric effects. PPIs may influence physiology in other ways, such as inducing transepithelial leak.
Full-text · Article · May 2009 · Drug discovery today
[Show abstract][Hide abstract] ABSTRACT: The current standard therapy for chronic hepatitis C virus (HCV), combination therapy with pegylated interferon and ribavirin, is plagued by a number of side effects, most notably anemia. This anemia is typically managed with a reduction of ribavirin dosing, which may lead to reduced efficacy. Taribavirin, an oral prodrug of ribavirin, which has been shown to induce a lesser degree of anemia, is being investigated for the treatment of chronic HCV.
To summarize the clinical trials involving taribavirin and its potential role in the treatment of chronic HCV.
Information was obtained via searches for data related to taribavirin, as well as other current and investigational therapies for chronic HCV. Press releases discussing otherwise unpublished trial outcomes were obtained from the website of Valeant Pharmaceuticals, the producer of Viramidine (taribavirin).
Taribavirin may increase adherence to therapy for chronic HCV by reducing the need for dose reduction due to anemia. A recent Phase II trial investigating early and sustained virological response showed no statistically significant differences between ribavirin 1000/1200 mg and taribavirin at 800-, 1200-, or 1600-mg dosing, while illustrating a lesser degree of anemia in 800- and 1200-mg dosing of taribavirin. Ongoing studies will continue to examine the efficacy of combination therapy with taribavirin in the place of ribavirin.
No preview · Article · Jan 2009 · Expert Opinion on Pharmacotherapy
[Show abstract][Hide abstract] ABSTRACT: Proton pump inhibitors (PPIs) are one of the most widely used drug classes in the US and are now frontline medications for gastro-oesophageal reflux disease (GERD) and dyspepsia. In a previous work, we observed that a transmucosal, upper gastrointestinal (GI) leak exists in Barrett's oesophagus (BO) patients. PPI medications are commonly used by Barrett's patients.
To examine if the PPI, esomeprazole, affects the barrier function of the upper GI tract.
The sucrose permeability test (SPT) was used to assess the possible effect of the PPI, esomeprazole, on upper GI leak in 37 first-time-presenting GERD patients and 25 healthy controls.
Esomeprazole induced a significant transmucosal leak in the upper GI tract of patients taking the drug for the first time. The leak occurred quickly, within days of first taking the drug. The leak was also reversed within days of stopping the medication.
This is the first patient-based study showing that a PPI compromises upper GI barrier function. There are potential implications for transmucosal leak of other medications that a patient on a PPI may be taking, as well as possible leak of endogenous peptides/proteins. The clinical consequences of this phenomenon are currently unknown, but are potentially important.
[Show abstract][Hide abstract] ABSTRACT: Background: Our group has recently published that proton pump inhibitors (PPIs) induce transmucosal, paracellular, bidirectional leakage in the gastric corpus epithelium to a wide range of molecules. Aim: This study was undertaken to determine if H-2 blocker medications also induce such leakage, or whether it is a result of specific inhibition of H + ,K + -ATPase. Methods: At the beginning and end of a dosage regimen of omeprazole or famotidine, healthy volunteers with no history of gastrointestinal disease consumed a (probe) solution of 100 gms of sucrose in 200 cc of water. Subsequently an 8 hr urine specimen was collected. The sucrose concentration in the urine specimen (mg/ml) multiplied by the total urine vol-ume equaled the amount of sucrose (mg) which leaked from the gastric lumen into the bloodstream. Results: Like omeprazole, famotidine was also able to induce significant transmucosal leakage across the mucosal barrier of the upper gastrointestinal tract. Famotidine-induced leakage exhibited a narrower time course than was observed with omeprazole. Conclusions: The fact that both classes of acid suppressive medications induce leak implies that leak results not from di-rect inhibition of the H + ,K + -ATPase, or from a side effect of omeprazole-like molecules, but is more generally related to the overall inhibition of acid secretion. The medical significance of such gastric leak is discussed.