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.

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption.

Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans.

The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake.

Characterization of the differentiation and leptin secretion profile of adult stem cells on patterned polylactide films.

Several issues need to be better understood before breast tissue engineering becomes a clinically viable option. One of the most important aspects is the interaction between cells and the microtopography of the implant surface. The aim of this study was to evaluate the efficacy of D1 cells, multipotent mouse bone marrow stromal precursors, in differentiating to adipocytes and to characterize their metabolic activity (lactic acid released and glucose consumed), leptin secretion and lipid production when cultured on patterned poly(L-lactide) (PLLA) films.

Exploring the positional attachment of glycopeptide/beta-lactam heterodimers.

Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams.

Fingerprint evidence in England and Wales--the revised standard.

Evidence of personal identity, often based solely on the comparison of a single finger impression, or fragment of an impression, has been accepted by courts of law at all levels in England and Wales since 1901, when the fingerprint system of identification was first adopted by police forces. Fingerprint identification is used by police forces world-wide, not only for the identification of latent fingermarks left at crime scenes, but also as the basis for ensuring accuracy in the criminal record system. For more than a century fingerprint evidence has been shown without doubt to be the best form of personal identification yet devised and millions of comparisons and subsequent identifications have been effected world-wide without any flaw in the system having been detected.

Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424).

Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci.

Internet support for people who are affected by breast cancer.

People of all ages now use the internet as a fast and easy way of gaining access to health information. It would seem logical, therefore, to use the internet as a resource when someone is affected by breast cancer. However, the quality of information available on the web can vary from excellent to appalling and an internet search on the subject of breast cancer can result in nearly two million possible websites to view: a daunting prospect for many people.

Liquid chromatographic determination of tilmicosin in swine feed at 200-400 mg/kg level: interlaboratory study.

An analytical method for the determination of tilmicosin at 200-400 mg/kg, the intended use concentration range, was evaluated in an interlaboratory study involving 5 laboratories, including the sponsor. The interlaboratory study evaluated the intra- and interlaboratory precision and accuracy of a tilmicosin feed method. The method procedure involved extracting tilmicosin from feed by adding 200 mL extractant to 20 g feed and shaking for 1 h.

Liquid chromatographic determination and liquid chromatographic-thermospray mass spectrometric confirmation of nicarbazin in chicken tissues: interlaboratory study.

The U.S. Food and Drug Administration sponsored an interlaboratory study of a liquid chromatographic determination with ultraviolet detection of nicarbazin in chicken liver and muscle tissues.

Confirmation of oxytetracycline, tetracycline and chlortetracycline residues in milk by particle beam liquid chromatography/mass spectrometry.

A method using particle beam liquid chromatography/mass spectrometry was developed for the confirmation of oxytetracycline, tetracycline and chlortetracycline residues in bovine milk. This method is one of the first to apply particle beam technology to the confirmation of animal drug residues in food products for regulatory purposes. The milk is centrifuged, using molecular weight cut-off filters to remove components of 25,000 daltons and above from the milk.

Nonradioactive nucleic acid detection by enhanced chemiluminescence using probes directly labeled with horseradish peroxidase.

The use of nucleic acid probes directly labeled with horseradish peroxidase for detection of single copy sequences on Southern blots of human genomic DNA by enhanced chemiluminescence is described. Of the target sequences, 6 x 10(5) molecules (1 amol) have been detected on blue sensitive film using exposures of up to 60 min and probes of 0.3-5.

Serotonin as a facilitatory neurotransmitter in the anticonvulsant activity of methaqualone.

The neuromodulatory role of serotonin in the anticonvulsant activity of methaqualone was investigated. A dose-dependent increase in the ability of methaqualone to provide protection against pentylenetetrazol (90 mg/kg SC)-induced convulsions in mice was observed. The ED50 value for the anticonvulsant activity of methaqualone was calculated and found to be 60 mg/kg, IP.

The use of a tissue expander to enlarge a graft for surgical treatment of a pressure ulcer in a quadriplegic. Case report.

This case reports the use of a tissue expander to facilitate the surgical closure of a decubitus ulcer in a spinal cord injured quadriplegic. The patient is a 42-year-old man with chronic nonhealing of a right ischial pressure ulcer. It had required a flap rotation and partial ischiectomy in the remote past that had been problem-free for many years.

Salvage of chronically exposed Gore-Tex vascular access grafts in the hemodialysis patient.

Exposure and infection of a Gore-Tex vascular access graft often results in removal of the graft. Salvage of the graft is possible, however, with the use of well-vascularized muscle flaps. In 1982, Hodgkinson was the first to use a sublimis muscle flap to cover an exposed vascular access graft.

Preparation and antiarthritic and analgesic activity of 4,5-diaryl-2-(substituted thio)-1H-imidazoles and their sulfoxides and sulfones.

A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles was synthesized and evaluated as antiinflammatory and analgesic agents in the rat adjuvant induced arthritis assay and the mouse phenyl-p-benzoquinone writhing (PQW) assay. Several analogues were found to be more potent than phenylbutazone and indomethacin. Structure-activity relationships are discussed.

Orbital rim trauma causing a blowout fracture.

A case report is presented that supports the theory that traumatic deformation of the bony orbital rims, without concomitant orbital soft-tissue injury, can cause an orbital blowout fracture.

Isolation and characterization of the cytosolic and chloroplast forms of spinach leaf fructose diphosphate aldolase.

Two different isoenzymes of fructose-P2 aldolase can be resolved by chromatography of crude spinach leaf extracts on DEAE-cellulose columns. The acidic isoenzyme comprises about 85% of the total leaf aldolase activity. The two forms differ in primary structure as judged by their distinctive amino acid compositions, tryptic peptide patterns, and immunological properties.