Designing interactive newsprint

The possibility of linking paper to digital information is enhanced by recent developments in printed electronics. In this article we report the design and evaluation of a local newspaper augmented with capacitive touch regions and an embedded Bluetooth chip working with an adjunct device. These allowed the interactive playback of associated audio and the registration of manual voting actions on the web. Design conventions inherited from paper and the web were explored by showing four different versions of an interactive newspaper to 16 community residents. The diverse responses of residents are described, outlining the potential of the approach for local journalism and recommendations for the design of interactive newsprint

Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases

Gut Hormone Pharmacology of a Novel GPR119 Agonist (GSK1292263), Metformin, and Sitagliptin in Type 2 Diabetes Mellitus: Results from Two Randomized Studies

<div><p></p><p>GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25–800 mg; n = 45) or multiple doses (100–600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼five-fold compared with placebo, reaching peak concentrations of ∼50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.</p><p>Trial Registration:</p><p>Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01119846" target="_blank">NCT01119846</a> Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01128621" target="_blank">NCT01128621</a></p></div

Plasma concentrations of total PYY in Study 1 following 13 days of dosing GSK263, placebo or sitagliptin (A), and in Study 2 on Day 14 of co-dosing these study treatments with metformin (B).

<p>The vertical black lines indicate the times of the meals. Values are Means (pmol/L) ± SEM.</p

Disposition of the subjects in Studies 1 and 2.

†<p>Number of subjects included in PK and PD population (N (%)): 4 (67%). Samples from 2 subjects were unusable because they had thawed in transit to the analytical laboratory.</p><p><b>Abbreviations:</b> AE, Adverse Event.</p

Percent change from baseline WM-AUC_{(0–24 h)} for the gut peptides following repeat-dose administration in Studies 1 and 2.

<p><b>Abbreviations</b>: CI, Confidence Interval; GIP, Glucose-dependent Insulinotropic Peptide; GLP-1, Glucagon-Like Peptide-1; PYY, Peptide Tyrosine-Tyrosine; PD, Pharmacodynamics; WM-AUC_{(0–24 h)}, Weighted-Mean Area Under the plasma-Concentration time curve time zero to 24 h.</p

Pharmacokinetic parameters of GSK263 following single and repeat-dose administration in Studies 1 and 2^†.

†<p>All calculations of noncompartmental parameters were based on actual sampling times. The maximum plasma concentration (C_max) was estimated directly from the raw concentration-time data (C_max). The apparent terminal elimination half-life (t_1/2) obtained as the ratio of ln2/λz, where λz is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. The area under the plasma concentration-time curve to the last quantifiable concentration (AUC_(0–t)) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.</p><p><b>Abbreviations:</b> NA, Not Applicable.</p