Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double-blind, placebo-controlled pharmacodynamic study.

BACKGROUND: Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. METHODS: Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. KEY RESULTS: A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%). CONCLUSIONS & INFERENCES: In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period.

Biliary interleukin-6 and tumor necrosis factor-alpha in patients undergoing endoscopic retrograde cholangiopancreatography.

Cytokines are low-molecular-weight protein mediators that possess a wide spectrum of inflammatory, metabolic, and immunomodulatory properties. Cytokines have been shown to be produced by monocytes/macrophages, lymphocytes, fibroblasts, endothelial cells, and more recently, hepatocytes and biliary epithelium. The aim of this study was to define biliary levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) in various disease states. Fifty-four patients undergoing ERCP comprised the study group. IL-6 and TNF-alpha were measured in aspirated bile using an ELISA technique. Levels of both TNF-alpha and IL-6 were significantly higher in patients with cholangitis (P < 0.00001). Moreover, IL-6 was 100% specific for cholangitis since none of the patients without bacterial cholangitis-including patients with biliary obstruction secondary to cholangiocarcinoma or pancreatic carcinoma-had measurable IL-6 in their bile. Low levels of biliary TNF-alpha were detectable in five patients without cholangitis; the sensitivity and specificity of TNF-alpha for cholangitis were 100% and 82%, respectively. There was a strong statistical correlation between biliary IL-6 and TNF-alpha levels (r = 0.819, P < 0.0001). In contrast, the correlations between biliary cytokines and serum biochemical parameters were weak. These results suggest that IL-6 and TNF-alpha are sensitive markers for cholangitis and may differentiate it from other types of biliary tract disease.