Alcohol Interventions for Trauma Patients Treated in Emergency Departments and Hospitals: A Cost Benefit Analysis

Summarizes a study of whether screening for problem drinking and interventions to reduce alcohol intake in hospital trauma centers reduce the direct cost of injury-related health care. Compares the costs of injury recidivism with and without intervention

Design and SAR Analysis of Covalent Inhibitors Driven by Hybrid QM/MM Simulations

Quantum mechanics/molecular mechanics (QM/MM) hybrid technique is emerging as a reliable computational method to investigate and characterize chemical reactions occurring in enzymes. From a drug discovery perspective, a thorough understanding of enzyme catalysis appears pivotal to assist the design of inhibitors able to covalently bind one of the residues belonging to the enzyme catalytic machinery. Thanks to the current advances in computer power, and the availability of more efficient algorithms for QM-based simulations, the use of QM/MM methodology is becoming a viable option in the field of covalent inhibitor design. In the present review, we summarized our experience in the field of QM/MM simulations applied to drug design problems which involved the optimization of agents working on two well-known drug targets, namely fatty acid amide hydrolase (FAAH) and epidermal growth factor receptor (EGFR). In this context, QM/MM simulations gave valuable information in terms of geometry (i.e., of transition states and metastable intermediates) and reaction energetics that allowed to correctly predict inhibitor binding orientation and substituent effect on enzyme inhibition. What is more, enzyme reaction modelling with QM/MM provided insights that were translated into the synthesis of new covalent inhibitor featured by a unique combination of intrinsic reactivity, on-target activity, and selectivity

Vascular access-specific health-related quality of life impacts among hemodialysis patients: qualitative development of the hemodialysis access-related quality of life (HARQ) instrument.

BackgroundEnd stage kidney disease and hemodialysis dependence are associated with impairments in health-related quality of life (HRQOL), which may be related to vascular access (VA). Few HRQOL measures are VA-specific and none differentiate HRQOL impact by VA type. We developed a VA-targeted HRQOL measure to distinguish the impact of fistulas, grafts and catheters.MethodsWe created an initial item pool based on literature review and then conducted focus groups at 4 US sites with 37 adults and interviews with nine dialysis clinicians about VA's impact on HRQOL. We then drafted the Hemodialysis Access-Related Quality of Life (HARQ) measure and cognitively tested it with 17 hemodialysis patients. Focus group and cognitive interview participants were diverse in age, gender, years on dialysis, and VA.ResultsWe identified six domains for the HARQ: symptoms, physical functioning, emotional impacts, social and role functioning, sleep, and care-related burdens. Cognitive interviews indicated that items were easily understood and supported content validity. Attributing HRQOL impact to VA as opposed to other hemodialysis burden was challenging for some items. Some items were dropped that were considered redundant by patients, limitations while dressing was added, and reference to VA-specific impact was included for each item. The average Flesch-Kincaid reading grade level for the revised 47-item HARQ was 5.3.ConclusionsThe HARQ features VA-specific content not addressed in other HRQOL measures, making it ideal for comparisons of different VA types and new VA technologies. The psychometric properties of the HARQ will be evaluated in future research

N-Acylethanolamine Acid Amidase (NAAA): Mechanism of Palmitoylethanolamide Hydrolysis Revealed by Mechanistic Simulations

The N-terminal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) catalyzes the hydrolytic deactivation of the lipid messenger palmitoylethanolamide (PEA), with optimal activity at acidic pH. Using the crystal structure of human NAAA as a starting point, we investigated the catalytic mechanism of PEA hydrolysis with a multiscale approach based on classic molecular dynamics (MD) and quantum mechanical/molecular mechanics (QM/MM) simulations coupled with enhanced sampling and path-collective variables (PCVs). The proton configuration of the catalytic nucleophile, Cys126, and of the surrounding carboxylates was critical to preserve the active site architecture. A stable Michaelis complex was then used to reconstruct the free-energy surfaces of NAAA acylation and deacylation during PEA hydrolysis. Acylation emerged as the critical step, with Cys126 acting both as an acid, to protonate the ethanolamine leaving group, and as a nucleophile, to attack the PEA carbonyl carbon. The ethanol fragment of PEA did not appear to play an indispensable role in acylation, a result further supported by kinetic experiments showing that NAAA hydrolyzes palmitoyl methyl amide (PMA) with high catalytic efficiency. Our multiscale approach identified a distinctive protonation state and catalytic mechanism for NAAA which accounts for pH-dependent activity, mutagenesis data, and mechanism of covalent inhibitors

Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8.

The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times

Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats

Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats

New Coumarin derivatives as cholinergic and cannabinoid system modulators

In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ42) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ42 self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation

N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

The MT2-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT1 and MT2 binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation

A Toy Model for Testing Finite Element Methods to Simulate Extreme-Mass-Ratio Binary Systems

Extreme mass ratio binary systems, binaries involving stellar mass objects orbiting massive black holes, are considered to be a primary source of gravitational radiation to be detected by the space-based interferometer LISA. The numerical modelling of these binary systems is extremely challenging because the scales involved expand over several orders of magnitude. One needs to handle large wavelength scales comparable to the size of the massive black hole and, at the same time, to resolve the scales in the vicinity of the small companion where radiation reaction effects play a crucial role. Adaptive finite element methods, in which quantitative control of errors is achieved automatically by finite element mesh adaptivity based on posteriori error estimation, are a natural choice that has great potential for achieving the high level of adaptivity required in these simulations. To demonstrate this, we present the results of simulations of a toy model, consisting of a point-like source orbiting a black hole under the action of a scalar gravitational field.Comment: 29 pages, 37 figures. RevTeX 4.0. Minor changes to match the published versio