Comprehensive evaluation of the pharmacological and toxicological effects of γ-valerolactone as compared to γ-hydroxybutyric acid: Insights from in vivo and in silico models

Γ-valerolactone (GVL), marketed online as "Tranquilli-G" and "excellent Valium", is used as a legal substitute for γ-hydroxybutyric acid (GHB); however, until now, GVL has only been connected to one Drug-Facilitated Sexual Assault (DFSA) case. Moreover, the pharmaco-toxicological effects of GVL are poorly studied. The aim of this study was to investigate the 1) in vivo effects of gavage administration of GVL (100-3000 mg/kg) on neurological (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, motor activity (bar, drag, and accelerod test) and cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in CD-1 male mice and the 2) in silico ADMET profile of GVL in comparison to GHB and the open active form γ-hydroxyvaleric acid (GHV). The present study demonstrates that GVL inhibits, in a dose-dependent manner, sensorimotor and motor responses and induces cardiorespiratory depression (at a dose of 3000 mg/kg) in mice. The determination of the ED50 in sensorimotor and motor responses revealed that GVL is about 4-5 times less potent than GHB. In silico prediction of ADMET profiles revealed toxicokinetic similarities between GHB and GHV, and differences with GVL. These results suggest that GVL could be used as a substitute for GHB and should be added to forensic toxicology screenings

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Timed written picture naming in 14 European languages

We describe the Multilanguage Written Picture Naming Dataset. This gives trial-level data and time and agreement norms for written naming of the 260 pictures of everyday objects that compose the colorized Snodgrass and Vanderwart picture set (Rossion & Pourtois in Perception, 33, 217-236, 2004). Adult participants gave keyboarded responses in their first language under controlled experimental conditions (N = 1,274, with subsamples responding in Bulgarian, Dutch, English, Finnish, French, German, Greek, Icelandic, Italian, Norwegian, Portuguese, Russian, Spanish, and Swedish). We measured the time to initiate a response (RT) and interkeypress intervals, and calculated measures of name and spelling agreement. There was a tendency across all languages for quicker RTs to pictures with higher familiarity, image agreement, and name frequency, and with higher name agreement. Effects of spelling agreement and effects on output rates after writing onset were present in some, but not all, languages. Written naming therefore shows name retrieval effects that are similar to those found in speech, but our findings suggest the need for cross-language comparisons as we seek to understand the orthographic retrieval and/or assembly processes that are specific to written output

Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: What size of data platforms and which study designs do we need to assess safety issues?

Background: Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.Methods: We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.Results: The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).Conclusions: Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project

OBJECTIVES: To estimate the risk of AMI for individual NSAIDs.METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) match

Evaluation for the removal efficiency of vocs and heavy metals by zeolites-based materials in the wastewater: A case study in the tito scalo industrial area

The current study was designed to demonstrate the efficiency of selected zeolites in the immobilization of heavy metals and volatile organic compounds from water in the industrial area of Tito Scalo (Basilicata Region in Southern Italy). The efficiency of zeolite materials has been evaluated by analyzing real water samples, by a multi-technique approach. Gas chromatography (GC) and inductively coupled plasma optical emission spectrometry (ICP-OES) were selected for the detection of volatile organic compounds (VOCs) and heavy metals respectively, and then by thermal analysis (TG, DTA) and X-ray powder diffraction (XRD) to verify the presence of contaminants in the structural channels of the adsorbents. ZSM-5 zeolite (MFI topology) was suitable for volatile organic compounds, showing removal efficiencies >87%. 13X (FAU topology) was more selective for in situ abatements of heavy metals, with efficiencies up to 100%. After VOCs and heavy metals removal, structure refinements of loaded zeolites highlighted variations of both lattice parameters and extraframework content confirming the pollutants immobilization in the framework microporosities. The occurrence of these species was also confirmed by DTA curves showing different phenomena explained on the basis of the nature and number of extraframework species hosted in the zeolite micropores

Time-Course of Grammatical Processing in Deaf Readers: An Eye-Movement Study

Twenty participants who were deaf and 20 chronological age-matched participants with typical hearing (TH) (mean age: 12\ua0years) were asked to judge the correctness of written sentences with or without a grammatically incongruent word while their eye movements were registered. TH participants outperformed deaf participants in grammaticality judgment accuracy. For both groups, First Pass and Total Fixation Times of target words in correct trials were significantly longer in the incongruent condition than in the congruent one. However, whereas TH students showed longer First Pass in the target area than deaf students across congruity conditions, deaf students made more fixations than their TH controls. Syntactic skills, vocabulary, and word reading speeds (measured with additional tests) were significantly lower in deaf students but only syntactic skills were systematically associated to the time-course of congruity processing. These results suggest that syntactic skills could have a cascading effect in sentence processing for deaf readers

Cancer mortality trend analysis in Italy, 1970-2007

To provide an updated review of cancer mortality trends in Italy, cancer mortality and census data, from 1970 to 2007, were extracted from the WHO mortality database and analyzed using age-specific and standardized rates, and joinpoint regression. Total cancer mortality rates in men have been declining by 1.8% yearly since 1994, reaching a rate of 147 per 100 000 residents (world standard) in 2007. In women, total cancer mortality rates have been decreasing by 1.1% yearly since 1991, resulting in a standardized mortality rate of 85 per 100 000 residents in 2007. Avoided deaths, compared with rates of 1988, from lung, intestinal, stomach, and breast cancers amount to 30 646. In men, trends were driven by cancers of the lung and other tobacco-related sites, intestines, and stomach. Favorable trends for cancers of the breast, intestines, stomach, and uterus contributed to falls in mortality rate in women. Downward trends were seen in both sexes for Hodgkin's lymphoma, bone cancer, and leukemias. Lung cancer in women showed an upward trend, with mortality rates increasing by 2.6% yearly since 1997, becoming the second cause of cancer mortality in middle-aged women. Rising trends were seen in women for oral and pancreatic cancers, as well. The favorable trends in cancer mortality are related to reduced tobacco smoking and alcohol consumption in men, advancements in treatment and management for colorectal cancer, breast cancer, leukemias, and a few other rare treatable cancers, and improved diagnosis of colorectal, breast, and cervical cancers. The greater role of tobacco-related deaths in women suggests the need for targeted strategies. © 2011 Wolters Kluwer Health. Lippincott Williams & Wilkins