Discovery of Tenapanor: A First-in-Class Minimally Systemic Inhibitor of Intestinal Na/H Exchanger Isoform 3.

We present herein the design, synthesis, and optimization of gut-restricted inhibitors of Na/H exchanger isoform 3 (NHE3). NHE3 is predominantly expressed in the kidney and gastrointestinal tract where it acts as the major absorptive sodium transporter. We desired minimally systemic agents that would block sodium absorption in the gastrointestinal tract but avoid exposure in the kidney.

Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice.

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance.

Development and Characterization of a Human and Mouse Intestinal Epithelial Cell Monolayer Platform.

We describe the development and characterization of a mouse and human epithelial cell monolayer platform of the small and large intestines, with a broad range of potential applications including the discovery and development of minimally systemic drug candidates. Culture conditions for each intestinal segment were optimized by correlating monolayer global gene expression with the corresponding tissue segment. The monolayers polarized, formed tight junctions, and contained a diversity of intestinal epithelial cell lineages.

Determination of trans-resveratrol and its metabolites in rat serum using liquid chromatography with high-resolution time of flight mass spectrometry.

In this study we developed a sensitive method using high performance liquid chromatography (HPLC) coupled to electrospray ionization (ESI) with high resolution time of flight (TOF) mass spectrometry (MS) for the determination of naturally occurring antioxidant trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene, RES). This method enabled an investigation of a relationship between tumor growth in rats and concentration of RES and its primary metabolites, trans-resveratrol-3-O-sulfate-3-O-sulfate (R3S) and trans-resveratrol-3-O-β-d-glucuronide (R3G), in rat serum after RES exposure (5 or 25mg/kg/day). RES levels in rat serum were near the limit of detection, showing concentrations of 4±1 and 12±4ng/mL for low and high-dose exposure, respectively.

Is post-pneumonia chest X-ray for lung malignancy useful? Results of an audit of current practice.

Background/aim: Patients with community-acquired pneumonia (CAP) are often screened with repeat chest X-ray within 6-12 weeks following an admission. This practice is aimed to detect underlying lung malignancy, which can be difficult to identify initially when an acute infiltrate is present on X-ray. We conducted a study on the use of follow-up chest X-rays after an admission with CAP to determine the yield of suspected or diagnosed cancer.