Benzodiazepine Use and Misuse Among Patients in a Methadone Program

<p>Abstract</p> <p>Background</p> <p>Benzodiazepines (BZD) misuse is a serious public health problem, especially among opiate-dependent patients with anxiety enrolled in methadone program because it puts patients at higher risk of life-threatening multiple drug overdoses. Both elevated anxiety and BZD misuse increase the risk for ex-addicts to relapse. However, there is no recent study to assess how serious the problem is and what factors are associated with BZD misuse. This study estimates the prevalence of BZD misuse in a methadone program, and provides information on the characteristics of BZD users compared to non-users.</p> <p>Methods</p> <p>An anonymous survey was carried out at a methadone program in Baltimore, MD, and all patients were invited to participate through group meetings and fliers around the clinic on a voluntary basis. Of the 205 returned questionnaires, 194 were complete and entered into final data analysis. Those who completed the questionnaire were offered a $5 gift card as an appreciation.</p> <p>Results</p> <p>47% of the respondents had a history of BZD use, and 39.8% used BZD without a prescription. Half of the BZD users (54%) started using BZD after entering the methadone program, and 61% of previous BZD users reported increased or resumed use after entering methadone program. Compared to the non-users, BZD users were more likely to be White, have prescribed medication for mental problems, have preexistent anxiety problems before opiate use, and had anxiety problems before entering methadone program. They reported more mental health problems in the past month, and had higher scores in anxiety state, depression and perceived stress (p < .05).</p> <p>Conclusions</p> <p>Important information on epidemiology of BZD misuse among methadone-maintenance patients suggests that most methadone programs do not address co-occurring anxiety problems, and methadone treatment may trigger onset or worsening of BZD misuse. Further study is needed to explore how to curb misuse and abuse of BZD in the addiction population, and provide effective treatments targeting simultaneously addiction symptoms, anxiety disorders and BZD misuse.</p

Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling

Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118–310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.National Science Foundation (U.S.) (DB1-0821391)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-GM089903)National Institutes of Health (U.S.) (P30-ES002109

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Detection of Total UDP-Glucuronosyltransferase (UGT) Activity in Melanoma Cells.

The UDP-glucuronosyltransferases (UGTs) are integrally involved in the clearance of a wide range of drugs used to combat human diseases. UGT expression levels and activity can be induced by drug addition to cells and has been proposed as a potential intratumoral drug resistance mechanism. Traditional methods of assaying UGT activity are drug-centric and require HPLCs with multiple detectors (dependent on individual drug). Here, we describe a generalized method to detect total UGT activity (intrinsic or induced) via the UGT-Glo assay which utilizes a general UGT substrate with luminescence as the readout eliminating the need for multiple HPLC detectors to detect total UGT activity in a given sample. The method detailed here can be applied for any UGT containing sample, allowing for the efficient detection of total UGT activity to be the functional endpoint using a plate reader. In this manner, global changes in UGT activity can be monitored in response to a wide variety of stimuli