Perspective on high-throughput bioanalysis to support assays in early drug discovery.

As the desire for a shortened design/make/test/learn cycle increases in early drug discovery, the pressure to rapidly deliver drug metabolism pharmacokinetic data continues to rise. From a bioanalytical standpoint, assays are challenging because they are amenable to automation and thus capable of generating a high number of samples for analysis. To keep up with analysis demands, automated method development workflows, rapid sample analysis approaches and efficient data analysis software must be utilized.

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster.

Rapid Detection of Bacillus anthracis Spores Using Immunomagnetic Separation and Amperometry.

Portable detection and quantitation methods for (anthrax) spores in pure culture or in environmental samples are lacking. Here, an amperometric immunoassay has been developed utilizing immunomagnetic separation to capture the spores and remove potential interferents from test samples followed by amperometric measurement on a field-portable instrument. Antibody-conjugated magnetic beads and antibody-conjugated glucose oxidase were used in a sandwich format for the capture and detection of target spores.

From framework to the frontline: designing a structure and process for drug supply shortage planning.

Drug shortages are not new; they have been managed through conservation, procurement of alternatives, and redistribution of stock The Sandoz shortage in 2012 has caused a radical reduction of generic injectables. In Newfoundland and Labrador, our response has led to the development of the framework, structure, and process outlined in this paper. The efforts have eased the concerns of clinicians and leaders, as they are aware of the decision-making resource for situations of drug and technology shortage.

Discovery of 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists.

GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent.

Specificity of monoclonal antibodies to strains of Dickeya sp. that cause bacterial heart rot of pineapple.

During a severe outbreak of bacterial heart rot that occurred in pineapple plantations on Oahu, Hawaii, in 2003 and years following, 43 bacterial strains were isolated from diseased plants or irrigation water and identified as Erwinia chrysanthemi (now Dickeya sp.) by phenotypic, molecular, and pathogenicity assays. Rep-PCR fingerprint patterns grouped strains from pineapple plants and irrigation water into five genotypes (A-E) that differed from representatives of other Dickeya species, Pectobacterium carotovorum and other enteric saprophytes isolated from pineapple.

The identification of pyrazolo[1,5-a]pyridines as potent p38 kinase inhibitors.

A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.

Novel benzimidazole-based MCH R1 antagonists.

The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

Implantation of a biventricular pacing and defibrillator device via a persistent left superior vena cava.

A persistent left superior vena cava was discovered in a 66-year-old man with heart failure undergoing implantation of a biventricular pacing and defibrillator device. An active fixation right ventricular defibrillator lead was placed through a curved guiding catheter. A sub-selection catheter and a guidewire allowed the engagement of a posterior-lateral branch of the coronary sinus, performance of an angiogram without an occlusive balloon, and optimal lead placement.

Purification of GFP fusion proteins from transgenic plant cell cultures.

Green fluorescence protein (GFP) has become a widely used reporter in many areas of life science. Monitoring foreign protein expression via GFP fusion is also very appealing for bioprocess applications. GFP itself has been purified from recombinant organisms by several methods, often involving unfavorable conditions (e.

Pyrazolo[1,5-a]pyridines as p38 kinase inhibitors.

[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.

Interhemispheric Differences in Polar Stratospheric HNO3, H2O, CIO, and O3.

Simultaneous global measurements of nitric acid (HNO(3)), water (H(2)O), chlorine monoxide (CIO), and ozone (O(3)) in the stratosphere have been obtained over complete annual cycles in both hemispheres by the Microwave Limb Sounder on the Upper Atmosphere Research Satellite. A sizeable decrease in gas-phase HNO(3) was evident in the lower stratospheric vortex over Antarctica by early June 1992, followed by a significant reduction in gas-phase H(2)O after mid-July. By mid-August, near the time of peak CIO, abundances of gas-phase HNO(3) and H(2)O were extremely low.

Maternal rating of child health at school age: does the vulnerable child syndrome persist?

Objectives: To assess the extent to which parental ratings of child health, including perceived vulnerability to illness, are associated with current and past health events and sociodemographic characteristics of the family and the child.

Design: Prospective cohort study of children aged 8 to 10 years previously assessed in infancy in two multi-site studies.

Setting: Thirteen sites largely in eastern United States.

When you're only a phone call away: a comparison of the information in telephone and face-to-face interviews.

Telephone interviews offer an economical method of obtaining information, but little published experience addresses the use of telephone interviews for the sometimes lengthy questionnaires composed of scales with multiple-category items often required in developmental and behavioral research. In a study of the outcomes of very low birth weight infants, circumstances required that we administer a questionnaire, including seven scales composed of several Likert-type items each, to a substantial portion of the study population. Those contacted by telephone (n = 1067) differed from those responding face-to-face (n = 822) in being less likely to have a very low birth weight child and more likely to be white and of higher maternal education.

Hospitalization of very low birth weight children at school age.

Objective: To assess whether very low birth weight (VLBW) increases the risk of hospitalization at school age.

Design: Prospective, multisite cohort study.

Participants: Selected from a previous multisite, hospital-based trial, 611 VLBW children, and, from a prior representative sample, 724 children who weighed 1501 to 2500 gm and 533 who weighed > 2500 gm.

The health and developmental status of very low-birth-weight children at school age.

Objective: To assess the effect of improved survival of increasingly premature infants by examining the outcomes at school age of a large group of children born at different birth weights.

Design: Inception cohort.

Setting/participants: Participants were selected from two previously studied multisite cohorts: very low-birth-weight (less than or equal to 1500 g) children referred to participating intensive care units and heavier birth-weight children drawn from a stratified random sample of births in geographically defined regions.

Cohort reconstruction: which infants can be restudied at school age?

Longer-term follow-up of infants with specific health concerns, such as low birthweight, is critical to assessing the effect of medical interventions. This report examines the approach of reconstructing previously studied cohorts in terms of the factors discriminating between respondents and non-respondents. Follow-up was attempted during 1987-1988 for 1875 children born during a 6-month period in 1978 in three geographically defined regions in the United States, for whom 1-year assessments of health and developmental status were obtained at 1 year of age as part of a previous study.

Maternal cocaine abuse and necrotizing enterocolitis: outcome and survival.

Since 1987, multiple complications related to maternal cocaine abuse have been reported. Necrotizing enterocolitis-(NEC) of the newborn has been observed with increasing frequency. We report a comparative analysis of infants with NEC born to cocaine abusing mothers (n = 11) to a standard population of newborns with NEC (n = 50) treated in this institution from January 1987 to July 1989.

Beckwith-Wiedemann syndrome with unusual hepatic and pancreatic features: a case expanding the phenotype.

We describe an infant with Beckwith-Wiedemann syndrome (BWS) who had hepatic and pancreatic findings not previously described in BWS. These were biliary dysgenesis and enlargement and cystic dysplasia of the pancreas. The biliary dysgenesis was characterized by proliferation of abnormally shaped ducts in the portal tracts.

Effect of sustained pharmacologic vitamin E levels on incidence and severity of retinopathy of prematurity: a controlled clinical trial.

The incidence and severity of retinopathy of prematurity (ROP) as affected by vitamin E prophylaxis at pharmacologic serum levels (5 mg/dl) were evaluated in a double-masked clinical trial of infants with a birth weight less than or equal to 2000 gm or a gestational age less than or equal to 36 weeks. The infants were enrolled by age 5 days and randomly assigned to receive parenterally administered, and later orally administered, free alpha-tocopherol (vitamin E) or its placebo. Study medication was continued until retinal vascularization was complete or active ROP had subsided, except in infants with a diagnosis of severe disease, in whom vitamin E was substituted for study medication.

Perinatal events and necrotizing enterocolitis in premature infants.

Among 2123 premature infants monitored during a large multicenter study of patent ductus arteriosus, necrotizing enterocolitis (NEC) was diagnosed in 121 (5.7%) of these infants. Rates ranged from 13.

Relationship of prolonged pharmacologic serum levels of vitamin E to incidence of sepsis and necrotizing enterocolitis in infants with birth weight 1,500 grams or less.

The incidence of culture-proven neonatal sepsis and necrotizing enterocolitis (NEC) in preterm infants maintained at pharmacologic (mean 5.1 mg/dL +/- 1.45 SD) serum vitamin E levels for long periods was prospectively studied as part of a double-masked clinical trial of the effect of prophylactic vitamin E v placebo treatment on the development and course of retinopathy of prematurity (ROP).