Investigation of the impact of urine handling procedures on interpretation of urinalysis findings and product safety in subjects treated with ezogabine

Neil Brickel,1 Sarah DeRossett,2 Mauro Buraglio,3 Christopher Evans,4 Si&ocirc;n Jones51Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, Middlesex, UK; 2Neurosciences Therapy Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Neurosciences Therapy Area Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK; 4Bioanalytical Science and Toxicokinetics, PTS-DMPK, GlaxoSmithKline, King of Prussia, PA, USA; 5Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Uxbridge, Middlesex, UKBackground: Ezogabine (also known by the international nonproprietary name of retigabine) is an antiepileptic drug codeveloped and comarketed by Valeant Pharmaceuticals North America and GlaxoSmithKline, which reduces neuronal excitability by enhancing the activity of potassium channels and has the potential to have effects on the urinary system through a pharmacologic action on bladder smooth muscle. In a single post-herpetic neuralgia trial, but not in an extensive epilepsy development program, proteinuria was unexpectedly reported in patients receiving ezogabine. Consequently, investigations were conducted to determine whether the reported proteinuria represented a true or false-positive finding.Methods: Patients receiving ezogabine 900&ndash;1200 mg/day in an open-label extension (Study 303) of a Phase III epilepsy trial voluntarily provided urine samples. Fresh samples were analyzed immediately at the study site, and stabilized aliquots were analyzed 1&ndash;3 days after collection at two central laboratories. In an open-label study in healthy volunteers receiving ezogabine 600&ndash;900 mg/day (Study RTG114137), urine samples were analyzed fresh (<2 hours after collection) and, using two different stabilizers and storage at room temperature, after 24 and 72 hours. Fluid intake was restricted prior to one sample point. Albumin:creatinine ratios were assessed in both studies.Results: In Study 303, there was notable variation in clarity, color, and proteinuria between fresh and stored urine samples, and between samples analyzed at different laboratories. In RTG114137, reporting rates of proteinuria were elevated following storage using one stabilizer, and the frequency of color change from fresh to stored samples differed between the stabilizers and between 24 and 72 hours with one stabilizer. Following fluid restriction, proteinuria rates were elevated with both stabilizers. Poor tolerability of ezogabine 750&ndash;900 mg/day resulted in limited titration beyond 750 mg/day and early termination of RTG114137.Conclusion: Hydration status, interval between urine collection and analysis, and the type of stabilizer used are all factors that may lead to false-positive proteinuria findings in patients receiving ezogabine and should be borne in mind if abnormalities are reported.Keywords: antiepileptic drugs, ezogabine, retigabine, urinary safety, urinalysi

Machine learning-based analysis of COVID-19 pandemic impact on US research networks

This study explores how fallout from the changing public health policy around COVID-19 has changed how researchers access and process their science experiments. Using a combination of techniques from statistical analysis and machine learning, we conduct a retrospective analysis of historical network data for a period around the stay-At-home orders that took place in March 2020. Our analysis takes data from the entire ESnet infrastructure to explore DOE high-performance computing (HPC) resources at OLCF, ALCF, and NERSC, as well as User sites such as PNNL and JLAB. We look at detecting and quantifying changes in site activity using a combination of t-Distributed Stochastic Neighbor Embedding (t-SNE) and decision tree analysis. Our findings bring insights into the working patterns and impact on data volume movements, particularly during late-night hours and weekends

Changes of lymphocyte beta-adrenergic receptors after surgical stress

In this study the authors' purpose was to observe the effects of surgical stress on the number of lymphocyte beta-adrenergic receptors in hypertensive and normotensive subjects. It was noticed that after surgery a significant reduction occurred in the number of binding sites of lymphocytes of both hypertensive and normotensive subjects. The time course of recovery to the pre-operative values of binding sites varied between the two groups, being slower in normotensive than in hypertensive patients. This might suggest a different pattern of regulation of the beta-adrenergic receptor between hypertensive and normotensive subjects

I-129 in Swedish rivers: distribution and sources

We analyzed the concentration of I-129 in the water of 26 rivers covering most of the runoff from Sweden, with the aim of assessing current contamination levels, distribution patterns and potential sources in freshwater systems of northern Europe. The results show relatively high values (up to 1.4 x 10(9) atoms 1(-1)), steeply decreasing levels with increasing latitude and a positive correlation with Cl concentration and other chemical parameters. The I-129 concentrations observed in south Sweden are probably the highest ever recorded in rivers without any direct discharge from a nuclear installation. The strong latitudinal dependence suggests a northward dilution and possibly depletion of the isotope and a transport from a source located to the south. The most plausible source of the I-129 in the studied rivers is atmospheric fallout of I-129 emitted either by atmospheric discharges from the nuclear reprocessing facilities at Sellafield (England) and La Hague (France) or by volatilization from seawater contaminated by the same sources. The question is now whether and at what rate the I-129 concentration in Nordic watersheds will increase further if discharges from nuclear reprocessing continue. (C) 2003 Elsevier Science B.V. All rights reserved