Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4 butanediol (1,4-BD; BDO) : a literature review with a focus on UK fatalities related to non-medical use

Misuse of gamma hydroxybutrate (GHB) and gamma butyrolactone (GBL) has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on GHB and derivatives, and explores the largest series of deaths associated with their non-medical use. Descriptive analyses of cases associated with GHB/GBL and 1,4 butanediol (1,4-BD) use extracted from the UK’s National Programme on Substance Abuse Deaths database. From 1995 to September 2013, 159 GHB/GBL-associated fatalities were reported. Typical victims: White (92%), young (mean age 32 years); male (82%); with a drug misuse history (70%). Most deaths (79%) were accidental or related to drug use, the remainder (potential) suicides. GHB/GBL alone was implicated in 37%; alcohol 14%; other drugs 28%; other drugs and alcohol 15%. Its endogenous nature and rapid elimination limit toxicological detection. Post-mortem blood levels: mean 482 (range 0 - 6500; S.D. 758) mg/L. Results suggest significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, opiates, stimulants, and ketamine. More awareness is needed about risks associated with consumption.Peer reviewe

Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline

Sterile endophthalmitis rates and particle size analyses of different formulations of triamcinolone acetonide

David G Dodwell,1 Darrel A Krimmel,1 Christopher M de Fiebre2 1Illinois Retina Center, Springfield, IL, USA; 2CMdeF Consulting, Upper Saint Clair, PA, USA Purpose: To evaluate the rate of sterile endophthalmitis (SE) following intravitreal injection of three different formulations of triamcinolone acetonide (TA) in a single physician practice and also to assess the mean diameter and concentration of particles of the two TA formulations currently available commercially in the USA. It was hypothesized that TA formulations with smaller particles and/or greater concentrations would have a higher incidence of SE.Methods: Single-site, interventional case series in which the medical records of 392 consecutive eyes receiving intravitreal TA as Triesence®, Kenalog®-40, or preservative-free TA between September 2008 and October 2013 were retrospectively reviewed for the incidence of SE. Particle sizing of TA formulations was conducted by an independent commercial laboratory.Results: Five cases of SE were identified. The four cases of SE following Triesence® (4.6%) represented a rate significantly higher than the one case of SE following preservative-free TA (0.6%; P=0.049) and the 0% incidence rate of SE following Kenalog®-40 (P=0.0210). Triesence® had significantly smaller particles than Kenalog®-40 (P<0.0001).Conclusion: The rate of SE was the highest with the formulation of TA that had the smallest particle size and highest particle load (number of particles injected). The lowest rate of SE was seen with Kenalog®-40, the only TA formulation that contained a benzyl alcohol preservative. The data do not support a principal causative role of benzyl alcohol in the development of TA-induced SE. Instead, the data support the particle theory of TA-induced SE; however, larger-scale, multicenter studies are needed to confirm and expand on these findings. Keywords: sterile endophthalmitis, benzyl alcohol, Triesence®, Kenalog®-40, preservative-free triamcinolone acetonide, particle size, frustrated phagocytosi

Swine fevers hemispheric surveillance: annual report

108 páginas. Series Publicación Miscelánea A4/BR (IICA) no. 88-004. Este documento se encuentra en español y en inglésContiene el informe anual, correspondiente al período 1986-1987, del Sistema Hemisférico de Vigilancia de Pestes Suinas establecido entre el IICA y el Centro Panamericano de Fiebre Aftosa en 1986. La información analítica y numérica que se presenta en este documento, se basa en los reportes de los países que participaron en dicho sistema durante el período señalado, a saber: Bolivia, Colombia, Ecuador, Perú, Venezuela, Chile, Paraguay, Uruguay, Brasil, El Salvador, Guatemala, Honduras y México. El contenido informativo está organizado bajo la siguiente estructura: (1) antecedentes generales sobre la situación de las pestes suinas en los países del hemisferio; (2) resúmenes y análisis de los informes por país; y (3) anexos. La información es presentada con cuadros y gráficosContains the annual report, corresponding to the 1986-1987 period, of the Hemispheric Swiss Pest Surveillance System established between IICA and the Pan American Foot-and-Mouth Disease Center in 1986. The analytical and numerical information presented in this document is based on the reports from the countries that participated in said system during the indicated period, namely: Bolivia, Colombia, Ecuador, Peru, Venezuela, Chile, Paraguay, Uruguay, Brazil, El Salvador, Guatemala, Honduras and Mexico. The informative content is organized under the following structure: (1) general background on the situation of swine pests in the countries of the hemisphere; (2) summaries and analysis of country reports; and (3) annexes. The information is presented with charts and graph

Mechanistically Guided Predictive Models for Ligand and Initiator Effects in Copper-Catalyzed Atom Transfer Radical Polymerization (Cu-ATRP)

Copper-catalyzed atom transfer radical polymerization (Cu-ATRP) is one of the most widely used controlled radical polymerization techniques. Notwithstanding the extensive mechanistic studies in the literature, the transition states of the activation/deactivation of the growing polymer chain, a key equilibrium in Cu-ATRP, have not been investigated computationally. Therefore, the understanding of the origin of ligand and initiator effects on the rates of activation/deactivation is still limited. Here, we present the first computational analysis of Cu-ATRP activation transition states to reveal factors that affect the rates of activation and deactivation. The Br atom transfer between the polymer chain and the Cu catalyst occurs through an unusual bent geometry that involves pronounced interactions between the polymer chain end and the ancillary ligand on the Cu catalyst. Therefore, the rates of activation/deactivation are determined by both the electronic properties of the Cu catalyst and the ligand-initiator steric repulsions. In addition, our calculations revealed the important role of ligand backbone flexibility on the activation. These theoretical analyses led to the identification of three chemically meaningful descriptors, namely HOMO energy of the catalyst (EHOMO), percent buried volume (Vbur%), and distortion energy of the catalyst (ΔEdist), to describe the electronic, steric, and flexibility effects on reactivity, respectively. A robust and simple predictive model for ligand effect on reactivity is thereby established by correlating these three descriptors with experimental activation rate constants using multivariate linear regression. Validation using a structurally diverse set of ligands revealed the average error is less than ±2 kcal/mol compared to the experimentally derived activation energies. The same approach was also applied to develop a predictive model for reactivity of different alkyl halide initiators using R–X bond dissociation energy (BDE) and Cu–X halogenophilicity as descriptors.We thank the NIH (GM128779) and NSF(CHE1707490) for financial support for this work. M.L.C. gratefully acknowledges a Georgina Sweet ARC Laureate Fellowship (FL170100041) and generous allocations of supercomputing time on the National Facility of the Australian National Computational Infrastructur