drug development task: Topics by Science.gov

Sample records for drug development task

Working memory subsystems are impaired in chronic drug dependents.

PubMed

Soliman, Abdrabo Moghazy; Gadelrab, Hesham Fathy; Elfar, Rania Mohamed

2013-06-01

A large body of research that has investigated substance dependence and working memory (WM) resources, yet no prior study has used a comprehensive test battery to examine the impact of chronic drug dependence on WM as a multi-component system. This study examined the efficiency of several WM components in participants who were chronic drug dependents. In addition, the functioning of the four WM components was compared among dependents of various types of drugs. In total, 128 chronic drug dependents participated in this study. Their average age was 38.48 years, and they were classified into four drug-dependence groups. Chronic drug dependents were compared with a 36-participant control group that had a mean age of 37.6 years. A WM test battery that comprised eight tests and that assessed each of four WM components was administered to each participant. Compared with the control group, all four groups of drug dependents had significantly poorer test performance on all of the WM tasks. Among the four groups of drug users, the polydrug group had the poorest performance scores on each of the eight tasks, and the performance scores of the marijuana group were the least affected. Finally, the forward digit span task and the logical memory tasks were less sensitive than other tasks when differentiating between marijuana users and the normal participants. The four components of WM are impaired among chronic drug dependents. These results have implications for the development of tools, classification methods and therapeutic strategies for drug dependents.
Good research practices for measuring drug costs in cost effectiveness analyses: issues and recommendations: the ISPOR Drug Cost Task Force report--Part I.

PubMed

Hay, Joel W; Smeeding, Jim; Carroll, Norman V; Drummond, Michael; Garrison, Louis P; Mansley, Edward C; Mullins, C Daniel; Mycka, Jack M; Seal, Brian; Shi, Lizheng

2010-01-01

The assignment of prices or costs to pharmaceuticals can be crucial to results and conclusions that are derived from pharmacoeconomic cost effectiveness analyses (CEAs). Although numerous pharmacoeconomic practice guidelines are available in the literature and have been promulgated in many countries, these guidelines are either vague or silent about how drug costs should be established or measured. This is particularly problematic in pharmacoeconomic studies performed from the "societal" perspective, because typically the measured cost of a brand name pharmaceutical is not a true economic cost but also includes transfer payments from some members of society (patients and third party payers) to other members of society (pharmaceutical manufacturer stockholders) in large part as a reward for biomedical innovation. Moreover, there are numerous and complex institutional factors that influence how drug costs should be measured from other CEA perspectives, both internationally and within the domestic US context. The objective of this report is to provide guidance and recommendations on how drug costs should be measured for CEAs performed from a number of key analytic perspectives. ISPOR Task Force on Good Research Practices-Use of Drug Costs for Cost Effectiveness Analysis (Drug Cost Task Force [DCTF]) was appointed with the advice and consent of the ISPOR Board of Directors. Members were experienced developers or users of CEA models, worked in academia, industry, and as advisors to governments, and came from several countries. Because how drug costs should be measured for CEAs depend on the perspectives, five Task Force subgroups were created to develop drug cost standards from the societal, managed care, US government, industry, and international perspective. The ISPOR Task Force on Good Research Practices-Use of Drug Costs for Cost Effectiveness Analysis (DCTF) subgroups met to develop core assumptions and an outline before preparing six draft reports. They solicited comments on the outline and drafts from a core group of 174 external reviewers and more broadly from the membership of ISPOR at two ISPOR meetings and via the ISPOR web site. Drug cost measurements should be fully transparent and reflect the net payment most relevant to the user's perspective. The Task Force recommends that for CEAs of brand name drugs performed from a societal perspective, either 1) CEA analysts use a cost that more accurately reflects true societal drug costs (e.g., 20-60% of average sales price), or when that is too unrealistic to be meaningful for decision-makers, 2) refer to their analyses as from a "limited societal perspective." CEAs performed from a payer perspective should use drug prices actually paid by the relevant payer net of all rebates, copays, or other adjustments. When such price adjustments are confidential, the analyst should apply a typical or average discount that preserves this confidentiality. Drug transaction prices not only ration current use of medication but also ration future biomedical research and development. CEA researchers should tailor the appropriate measure of drug costs to the analytic perspective, maintain clarity and transparency on drug cost measurement, and report the sensitivity of CEA results to reasonable drug cost measurement alternatives.
Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study

PubMed Central

Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

2016-01-01

Background Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Objective Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Methods Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. Results One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). Conclusions The results suggest that nonexpert annotation might be a feasible option for comprehensive labeling of annotated PDDIs across a broader range of drug product labels. Preannotation of drug mentions may ease the annotation task. However, preannotation of PDDIs, as operationalized in this study, presented the participants with difficulties. Future work should test if these issues can be addressed by the use of better performing NLP and a different approach to presenting the PDDI preannotations to users during the annotation workflow. PMID:27066806
Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study.

PubMed

Hochheiser, Harry; Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

2016-04-11

Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). The results suggest that nonexpert annotation might be a feasible option for comprehensive labeling of annotated PDDIs across a broader range of drug product labels. Preannotation of drug mentions may ease the annotation task. However, preannotation of PDDIs, as operationalized in this study, presented the participants with difficulties. Future work should test if these issues can be addressed by the use of better performing NLP and a different approach to presenting the PDDI preannotations to users during the annotation workflow.
Risky decision making and the anterior cingulate cortex in abstinent drug abusers and nonusers.

PubMed

Fishbein, Diana H; Eldreth, Diana L; Hyde, Christopher; Matochik, John A; London, Edythe D; Contoreggi, Carlo; Kurian, Varughese; Kimes, Alane S; Breeden, Andrew; Grant, Steven

2005-04-01

Risky decision making is a hallmark behavioral phenotype of drug abuse; thus, an understanding of its biological bases may inform efforts to develop therapies for addictive disorders. A neurocognitive task that measures this function (Rogers Decision-Making Task; RDMT) was paired with measures of regional cerebral perfusion to identify brain regions that may underlie deficits in risky decision making in drug abusers. Subjects were abstinent drug abusers (> or =3 months) and healthy controls who underwent positron emission tomography scans with H(2)(15)O. Drug abusers showed greater risk taking and heightened sensitivity to rewards than control subjects. Both drug abusers and controls exhibited significant activations in a widespread network of brain regions, primarily in the frontal cortex, previously implicated in decision-making tasks. The only significant group difference in brain activation, however, was found in the left pregenual anterior cingulate cortex, with drug abusers exhibiting less task-related activation than control subjects. There were no significant correlations between neural activity and task performance within the control group. In the drug abuse group, on the other hand, increased risky choices on the RDMT negatively correlated with activation in the right hippocampus, left anterior cingulate gyrus, left medial orbitofrontal cortex, and left parietal lobule, and positively correlated with activation in the right insula. Drug abuse severity was related positively to right medial orbitofrontal activity. Attenuated activation of the pregenual ACC in the drug abusers relative to the controls during performance on the RDMT may underlie the abusers' tendency to choose risky outcomes.
Prediction of Human Cytochrome P450 Inhibition Using a Multitask Deep Autoencoder Neural Network.

PubMed

Li, Xiang; Xu, Youjun; Lai, Luhua; Pei, Jianfeng

2018-05-30

Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multitask model for concurrent inhibition prediction of five major CYP450 isoforms, namely, 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training a multitask autoencoder deep neural network (DNN) on a large dataset containing more than 13 000 compounds, extracted from the PubChem BioAssay Database. We demonstrate that the multitask model gave better prediction results than that of single-task models, previous reported classifiers, and traditional machine learning methods on an average of five prediction tasks. Our multitask DNN model gave average prediction accuracies of 86.4% for the 10-fold cross-validation and 88.7% for the external test datasets. In addition, we built linear regression models to quantify how the other tasks contributed to the prediction difference of a given task between single-task and multitask models, and we explained under what conditions the multitask model will outperform the single-task model, which suggested how to use multitask DNN models more effectively. We applied sensitivity analysis to extract useful knowledge about CYP450 inhibition, which may shed light on the structural features of these isoforms and give hints about how to avoid side effects during drug development. Our models are freely available at http://repharma.pku.edu.cn/deepcyp/home.php or http://www.pkumdl.cn/deepcyp/home.php .
Putative cognitive enhancers in preclinical models related to schizophrenia: the search for an elusive target.

PubMed

Barak, Segev; Weiner, Ina

2011-08-01

Several developments have converged to drive what may be called "the cognitive revolution" in drug discovery in schizophrenia (SCZ), including the emphasis on cognitive deficits as a core disabling aspect of SCZ, the increasing consensus that cognitive deficits are not treated satisfactorily by the available antipsychotic drugs (APDs), and the failure of animal models to predict drug efficacy for cognitive deficits in clinical trials. Consequently, in recent years, a paradigm shift has been encouraged in animal modeling, triggered by the NIMH sponsored Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, and intended to promote the development and use of behavioral measures in animals that can generate valid (clinically relevant) measures of cognition and thus promote the identification of cognition enhancers for SCZ. Here, we provide a non-exhaustive survey of the effects of putative cognition enhancers (PCEs) representing 10 pharmacological targets as well as antipsychotic drugs (APDs), on SCZ-mimetic drugs (NMDA antagonists, muscarinic antagonist scopolamine and dopaminergic agonist amphetamine), in several tasks considered to measure cognitive processes/domains that are disrupted in SCZ (the five choice serial reaction time task, sustain attention task, working and/or recognition memory (delayed (non)matching to sample, delayed alternation task, radial arm maze, novel object recognition), reversal learning, attentional set shifting, latent inhibition and spatial learning and memory). We conclude that most of the available models have no capacity to distinguish between PCEs and APDs and that there is a need to establish models based on tasks whose perturbations lead to performance impairments that are resistant to APDs, and/or to accept APDs as a "weak gold standard". Several directions derived from the surveyed data are suggested. Copyright © 2011 Elsevier Inc. All rights reserved.
Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

PubMed

Ravens, Ursula

2017-11-01

In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K + ) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting I Kur , the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I K,ACh , the Ca 2+ -activated K + channels of small conductance (SK) conducting I SK , and the two-pore domain K + (K2P) channels (tandem of P domains, weak inward-rectifying K + channels (TWIK-1), TWIK-related acid-sensitive K + channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents I TWIK-1 , I TASK-1 , and I TASK-3 . Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.
Maine: Cooperation between the Division of Special Education and Division of Alcohol and Drug Education Services.

ERIC Educational Resources Information Center

Rice, Sharon C.

1989-01-01

In 1984, Maine established the Task Force on Special Education and Chemical Dependency, which developed a report recommending, in part: collaboration between special education and local alcohol and drug abuse prevention programs; training for general and special education staff; and development of a vehicle for identification, assessment,…
Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee

PubMed Central

Paller, Channing J.; Bradbury, Penelope A.; Ivy, S. Percy; Seymour, Lesley; LoRusso, Patricia M.; Baker, Laurence; Rubinstein, Larry; Huang, Erich; Collyar, Deborah; Groshen, Susan; Reeves, Steven; Ellis, Lee M.; Sargent, Daniel J.; Rosner, Gary L.; LeBlanc, Michael L.; Ratain, Mark J.

2014-01-01

Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistical and regulatory challenges. The phase 1 trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee developed a set of recommendations for the phase 1 development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biological or pharmacological rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase 1 clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamic (i.e., biomarker). PMID:25125258
Nanomaterials in cancer-therapy drug delivery system.

PubMed

Zhang, Gen; Zeng, Xin; Li, Ping

2013-05-01

Nanomaterials can enhance the delivery and treatment efficiency of anti-cancer drugs, and the mechanisms of the tumor-reducing activity of nanomaterials with cancer drug have been investigated. The task for drug to reach pathological areas has facilitated rapid advances in nanomedicine. Herein, we summarize promising findings with respect to cancer therapeutics based on nano-drug delivery vectors. Relatively high toxicity of uncoated nanoparticles restricts the use of these materials in humans. In order to reduce toxicity, many approaches have focused on the encapsulation of nanoparticles with biocompatible materials. Efficient delivery systems have been developed that utilized nanoparticles loaded with high dose of cancer drug in the presence of bilayer molecules. Well-established nanotechnologies have been designed for drug delivery with specific bonding. Surface-modified nanoparticles as vehicles for drug delivery system that contains multiple nano-components, each specially designed to achieve aimed task for the emerging application delivery of therapeutics. Drug-coated polymer nanoparticles could efficiently increase the intracellular accumulation of anti-cancer drugs. This review also introduces the nanomaterials with drug on the induction of apoptosis in cancer cells in vitro and in vivo. Direct interactions between the particles and cellular molecules to cause adverse biological responses are also discussed.
Linked open drug data for pharmaceutical research and development

PubMed Central

2011-01-01

There is an abundance of information about drugs available on the Web. Data sources range from medicinal chemistry results, over the impact of drugs on gene expression, to the outcomes of drugs in clinical trials. These data are typically not connected together, which reduces the ease with which insights can be gained. Linking Open Drug Data (LODD) is a task force within the World Wide Web Consortium's (W3C) Health Care and Life Sciences Interest Group (HCLS IG). LODD has surveyed publicly available data about drugs, created Linked Data representations of the data sets, and identified interesting scientific and business questions that can be answered once the data sets are connected. The task force provides recommendations for the best practices of exposing data in a Linked Data representation. In this paper, we present past and ongoing work of LODD and discuss the growing importance of Linked Data as a foundation for pharmaceutical R&D data sharing. PMID:21575203
The ability for cocaine and cocaine-associated cues to compete for attention

PubMed Central

Pitchers, Kyle K.; Wood, Taylor R.; Skrzynski, Cari J.; Robinson, Terry E.; Sarter, Martin

2017-01-01

In humans, reward cues, including drug cues in addicts, are especially effective in biasing attention towards them, so much so they can disrupt ongoing task performance. It is not known, however, whether this happens in rats. To address this question, we developed a behavioral paradigm to assess the capacity of an auditory drug (cocaine) cue to evoke cocaine-seeking behavior, thus distracting thirsty rats from performing a well-learned sustained attention task (SAT) to obtain a water reward. First, it was determined that an auditory cocaine cue (tone-CS) reinstated drug-seeking equally in sign-trackers (STs) and goal-trackers (GTs), which otherwise vary in the propensity to attribute incentive salience to a localizable drug cue. Next, we tested the ability of an auditory cocaine cue to disrupt performance on the SAT in STs and GTs. Rats were trained to self-administer cocaine intravenously using an Intermittent Access self-administration procedure known to produce a progressive increase in motivation for cocaine, escalation of intake, and strong discriminative stimulus control over drug-seeking behavior. When presented alone, the auditory discriminative stimulus elicited cocaine-seeking behavior while rats were performing the SAT, but it was not sufficiently disruptive to impair SAT performance. In contrast, if cocaine was available in the presence of the cue, or when administered non-contingently, SAT performance was severely disrupted. We suggest that performance on a relatively automatic, stimulus-driven task, such as the basic version of the SAT used here, may be difficult to disrupt with a drug cue alone. A task that requires more top-down cognitive control may be needed. PMID:27890441
Good research practices for measuring drug costs in cost-effectiveness analyses: an international perspective: the ISPOR Drug Cost Task Force report--Part VI.

PubMed

Shi, Lizheng; Hodges, Meredith; Drummond, Michael; Ahn, Jeonghoon; Li, Shu Chuen; Hu, Shanlian; Augustovski, Federico; Hay, Joel W; Smeeding, Jim

2010-01-01

The pharmacoeconomic guidelines available in the literature or promulgated in many countries are either vague or silent about how drug costs should be established or measured so an international comparison of cost-effectiveness analysis (CEA) results can be made. The objective of this report is to provide guidance and recommendations on how drug costs should be measured for CEAs done from an internationally comparative perspective. Members of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force on Good Research Practices-Use of Drug Costs for Cost Effectiveness Analysis (Drug Cost Task Force [DCTF]) subgroup from several countries were experienced developers or users of CEA models, and worked in academia, industry, and as advisors to governments. They solicited comments on drafts from a core group of 174 external reviewers and more broadly, from the members of the ISPOR at the ISPOR 12th Annual International meeting and via the ISPOR Web site. Drug units should be standardized in terms of volume of active ingredient, regardless of packaging and dosing strength variations across countries. Drug costs should be measured in local currency per unit of active ingredient and should be converted to other currencies using sensitivity analyses of purchasing power parities (PPP) and exchange rates, whichever is more appropriate. When using drug prices from different years, the consumer price index for the local currency should be applied before the PPP and/or exchange rate conversion. CEA researchers conducting international pharmacoeconomic analysis should tailor the appropriate measure of drug costs to the international perspective, to maintain clarity and transparency on drug cost measurement in the context of international drug comparison and report the sensitivity of CEA results to reasonable cost conversions.
Mirtazapine and ketanserin alter preference for gambling-like schedules of reinforcement in rats.

PubMed

Persons, Amanda L; Tedford, Stephanie E; Celeste Napier, T

2017-07-03

Drug and behavioral addictions have overlapping features, e.g., both manifest preference for larger, albeit costlier, reinforcement options in cost/benefit decision-making tasks. Our prior work revealed that the mixed-function serotonergic compound, mirtazapine, attenuates behaviors by rats motivated by abused drugs. To extend this work to behavioral addictions, here we determined if mirtazapine and/or ketanserin, another mixed-function serotonin-acting compound, can alter decision-making in rats that is independent of drug (or food)-motivated reward. Accordingly, we developed a novel variable-ratio task in rats wherein intracranial self-stimulation was used as the positive reinforcer. Using lever pressing for various levels of brain stimulation, the operant task provided choices between a small brain stimulation current delivered on a fixed-ratio schedule (i.e., a predictable reward) and a large brain stimulation delivered following an unpredictable number of responses (i.e., a variable-ratio schedule). This task allowed for demonstration of individualized preference and detection of shifts in motivational influences during a pharmacological treatment. Once baseline preference was established, we determined that pretreatment with mirtazapine or ketanserin significantly decreased preference for the large reinforcer presented after gambling-like schedules of reinforcement. When the rats were tested the next day without drug, preference for the unpredictable large reinforcer option was restored. These data demonstrate that mirtazapine and ketanserin can reduce preference for larger, costlier reinforcement options, and illustrate the potential for these drugs to alter behavior. Copyright © 2017 Elsevier Inc. All rights reserved.
78 FR 9928 - Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0124] Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments AGENCY: Food and Drug Administration, HHS. ACTION: Notice; request for comments. SUMMARY: To assist the Food...
The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

PubMed

Hvoslef-Eide, M; Mar, A C; Nilsson, S R O; Alsiö, J; Heath, C J; Saksida, L M; Robbins, T W; Bussey, T J

2015-11-01

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. 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. 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. 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. This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.
Attention tasks as skills performance measures of drug effects.

PubMed

Moskowitz, H

1984-01-01

Both empirical epidemiological data on the causes of traffic accidents and conceptual models of skilled human performance stress the central role of perception and cognition. This paper examines the effects of drugs on two major components of cognitive perceptual performance, namely, concentrated attention or vigilance and divided attention. It is demonstrated that these two types of attention tasks are differentially affected by various drugs, so that sometimes one and sometimes another of these tasks is impaired. Various experimental paradigms to investigate these two attention functions are presented. It is demonstrated that attention tasks are frequently highly sensitive to drug effects, suggesting the importance of examining these functions when investigating the effects of drugs on skills performance.
Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat

PubMed Central

Beckmann, Joshua S.; Marusich, Julie A.; Gipson, Cassandra D.; Bardo, Michael T.

2010-01-01

It has been suggested that incentive salience plays a major role in drug abuse and the development of addiction. Additionally, novelty seeking has been identified as a significant risk factor for drug abuse. However, how differences in the readiness to attribute incentive salience relate to novelty seeking and drug abuse vulnerability has not been explored. The present experiments examined how individual differences in incentive salience attribution relate to novelty seeking and acquisition of cocaine self-administration in a preclinical model. Rats were first assessed in an inescapable novelty task and a novelty place preference task (measures of novelty seeking), followed by a Pavlovian conditioned approach task for food (a measure of incentive salience attribution). Rats then were trained to self-administer cocaine (0.3 or 1.0 mg/kg/infusion) using an autoshaping procedure. The results demonstrate that animals that attributed incentive salience to a food-associated cue were higher novelty seekers and acquired cocaine self-administration more quickly at the lower dose. The results suggest that novelty-seeking behavior may be a mediator of incentive salience attribution and that incentive salience magnitude may be an indicator of drug reward. PMID:20655954
Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

DTIC Science & Technology

2012-06-01

freezing in a Pavlovian cue- conditioned fear task in rats. In Stage II, we will evaluate the ability of candidate drugs to reverse fear conditioning ...disorder (PTSD). The underlying theory is that candidate drugs , when given following the reactivation of a conditioned fear response in animals, or a...traumatic memory in humans, will reduce the strength of the conditioned response or traumatic memory. We plan to test such drugs , either alone or in

Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals.

PubMed

Passamonti, Luca; Luijten, M; Ziauddeen, H; Coyle-Gilchrist, I T S; Rittman, T; Brain, S A E; Regenthal, R; Franken, I H A; Sahakian, B J; Bullmore, E T; Robbins, T W; Ersche, K D

2017-08-01

Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F 26 = 6.73, P = 0.01). During the go/no-go task, there was a treatment × trial × group interaction, although this finding only showed a trend towards statistical significance (F 26 = 3.38, P = 0.07). Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine's modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials.
Individual and combined effects of cannabis and tobacco on drug reward processing in non-dependent users.

PubMed

Hindocha, Chandni; Lawn, Will; Freeman, Tom P; Curran, H Valerie

2017-11-01

Cannabis and tobacco are often smoked simultaneously in joints, and this practice may increase the risks of developing tobacco and/or cannabis use disorders. Currently, there is no human experimental research on how these drugs interact on addiction-related measures. This study aimed to investigate how cannabis and tobacco, each alone and combined together in joints, affected individuals' demand for cannabis puffs and cigarettes, explicit liking of drug and non-drug-related stimuli and craving. A double-blind, 2 (active cannabis, placebo cannabis) × 2 (active tobacco, placebo tobacco) crossover design was used with 24 non-dependent cannabis and tobacco smokers. They completed a pleasantness rating task (PRT), a marijuana purchase task (MPT) and a cigarette purchase task (CPT) alongside measures of craving pre- and post-drug administration. Relative to placebo cannabis, active cannabis reduced liking of cannabis-associated stimuli and increased response time to all stimuli except cigarette-related stimuli. Relative to placebo cannabis, active cannabis decreased demand for cannabis puffs (trends for breakpoint and elasticity) and cigarettes (breakpoint, P max , O max ) on several characteristics of the purchase tasks. We found no evidence that active tobacco, both alone or combined with cannabis, had an effect on liking, demand or craving. Acutely, cannabis reduced liking of cannabis-related stimuli and demand for cannabis itself. Acute cannabis also reduced demand for cigarettes on the CPT. Acute tobacco administration did not affect demand or pleasantness ratings for cigarettes themselves or cannabis. In non-dependent cannabis and tobacco co-users, tobacco did not influence the rewarding effects of cannabis.
Cognitive and affective determinants of generic drug acceptance and use: cross-sectional and experimental findings

PubMed Central

Dohle, Simone; Siegrist, Michael

2013-01-01

An increase in generic substitution could be a viable approach to reduce global healthcare expenditures. In many countries, however, generic drug use is rather low. This study examines cognitive predictors (knowledge and beliefs) and affective predictors (general affect and sacred values) to explain generic drug acceptance and use. Data for the study come from a random postal survey conducted in Switzerland (N = 668). A detailed knowledge scale about generic drugs was developed. In addition, an experimental choice task was constructed in which respondents chose between branded and generic drugs. Generic drug acceptance as well as drug choices were influenced by knowledge, beliefs, and affect. It was also found that generic substitution is chosen less frequently for a more severe illness. Key insights could be used for developing information material or interventions aimed at increasing the substitution of generic drugs in order to make health care more affordable. PMID:25632372
SOCIAL MEDIA MINING SHARED TASK WORKSHOP.

PubMed

Sarker, Abeed; Nikfarjam, Azadeh; Gonzalez, Graciela

2016-01-01

Social media has evolved into a crucial resource for obtaining large volumes of real-time information. The promise of social media has been realized by the public health domain, and recent research has addressed some important challenges in that domain by utilizing social media data. Tasks such as monitoring flu trends, viral disease outbreaks, medication abuse, and adverse drug reactions are some examples of studies where data from social media have been exploited. The focus of this workshop is to explore solutions to three important natural language processing challenges for domain-specific social media text: (i) text classification, (ii) information extraction, and (iii) concept normalization. To explore different approaches to solving these problems on social media data, we designed a shared task which was open to participants globally. We designed three tasks using our in-house annotated Twitter data on adverse drug reactions. Task 1 involved automatic classification of adverse drug reaction assertive user posts; Task 2 focused on extracting specific adverse drug reaction mentions from user posts; and Task 3, which was slightly ill-defined due to the complex nature of the problem, involved normalizing user mentions of adverse drug reactions to standardized concept IDs. A total of 11 teams participated, and a total of 24 (18 for Task 1, and 6 for Task 2) system runs were submitted. Following the evaluation of the systems, and an assessment of their innovation/novelty, we accepted 7 descriptive manuscripts for publication--5 for Task 1 and 2 for Task 2. We provide descriptions of the tasks, data, and participating systems in this paper.
Recommendations from the Investigational New Drug/Investigational Device Exemption Task Force of the clInical and Translational Science Award Consortium: developing and implementing a sponsor-investigators training program.

PubMed

Holbein, M E Blair; Berglund, Jelena Petrovic; O'Reilly, Erin K; Hartman, Karen; Speicher, Lisa A; Adamo, Joan E; O'Riordan, Gerri; Brown, Jennifer Swanton; Schuff, Kathryn G

2014-06-01

The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration-regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.
Solid Phase Microextraction and Related Techniques for Drugs in Biological Samples

PubMed Central

Moein, Mohammad Mahdi; Said, Rana; Bassyouni, Fatma

2014-01-01

In drug discovery and development, the quantification of drugs in biological samples is an important task for the determination of the physiological performance of the investigated drugs. After sampling, the next step in the analytical process is sample preparation. Because of the low concentration levels of drug in plasma and the variety of the metabolites, the selected extraction technique should be virtually exhaustive. Recent developments of sample handling techniques are directed, from one side, toward automatization and online coupling of sample preparation units. The primary objective of this review is to present the recent developments in microextraction sample preparation methods for analysis of drugs in biological fluids. Microextraction techniques allow for less consumption of solvent, reagents, and packing materials, and small sample volumes can be used. In this review the use of solid phase microextraction (SPME), microextraction in packed sorbent (MEPS), and stir-bar sorbtive extraction (SBSE) in drug analysis will be discussed. In addition, the use of new sorbents such as monoliths and molecularly imprinted polymers will be presented. PMID:24688797
Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice.

PubMed

Johansson, Emily M; García-Gutiérrez, María S; Moscoso-Castro, María; Manzanares, Jorge; Valverde, Olga

2015-01-01

The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.
Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice

PubMed Central

Johansson, Emily M.; García-Gutiérrez, María S.; Moscoso-Castro, María; Manzanares, Jorge; Valverde, Olga

2015-01-01

The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders. PMID:26566284
Influence of Pharmacological Manipulations of NMDA and Cholinergic Receptors on Working versus Reference Memory in a Dual Component Odor Span Task

ERIC Educational Resources Information Center

MacQueen, David A.; Dalrymple, Savannah R.; Drobes, David J.; Diamond, David M.

2016-01-01

Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-D-aspartate receptor (NMDA-r) antagonists and is sensitive to…
Comparing errors in ED computer-assisted vs conventional pediatric drug dosing and administration.

PubMed

Yamamoto, Loren; Kanemori, Joan

2010-06-01

Compared to fixed-dose single-vial drug administration in adults, pediatric drug dosing and administration requires a series of calculations, all of which are potentially error prone. The purpose of this study is to compare error rates and task completion times for common pediatric medication scenarios using computer program assistance vs conventional methods. Two versions of a 4-part paper-based test were developed. Each part consisted of a set of medication administration and/or dosing tasks. Emergency department and pediatric intensive care unit nurse volunteers completed these tasks using both methods (sequence assigned to start with a conventional or a computer-assisted approach). Completion times, errors, and the reason for the error were recorded. Thirty-eight nurses completed the study. Summing the completion of all 4 parts, the mean conventional total time was 1243 seconds vs the mean computer program total time of 879 seconds (P < .001). The conventional manual method had a mean of 1.8 errors vs the computer program with a mean of 0.7 errors (P < .001). Of the 97 total errors, 36 were due to misreading the drug concentration on the label, 34 were due to calculation errors, and 8 were due to misplaced decimals. Of the 36 label interpretation errors, 18 (50%) occurred with digoxin or insulin. Computerized assistance reduced errors and the time required for drug administration calculations. A pattern of errors emerged, noting that reading/interpreting certain drug labels were more error prone. Optimizing the layout of drug labels could reduce the error rate for error-prone labels. Copyright (c) 2010 Elsevier Inc. All rights reserved.
Open Drug Discovery Toolkit (ODDT): a new open-source player in the drug discovery field.

PubMed

Wójcikowski, Maciej; Zielenkiewicz, Piotr; Siedlecki, Pawel

2015-01-01

There has been huge progress in the open cheminformatics field in both methods and software development. Unfortunately, there has been little effort to unite those methods and software into one package. We here describe the Open Drug Discovery Toolkit (ODDT), which aims to fulfill the need for comprehensive and open source drug discovery software. The Open Drug Discovery Toolkit was developed as a free and open source tool for both computer aided drug discovery (CADD) developers and researchers. ODDT reimplements many state-of-the-art methods, such as machine learning scoring functions (RF-Score and NNScore) and wraps other external software to ease the process of developing CADD pipelines. ODDT is an out-of-the-box solution designed to be easily customizable and extensible. Therefore, users are strongly encouraged to extend it and develop new methods. We here present three use cases for ODDT in common tasks in computer-aided drug discovery. Open Drug Discovery Toolkit is released on a permissive 3-clause BSD license for both academic and industrial use. ODDT's source code, additional examples and documentation are available on GitHub (https://github.com/oddt/oddt).
Developing new drugs for ovarian cancer: a challenging task in a changing reality.

PubMed

Canetta, R M; Carter, S K

1984-01-01

Recent therapeutic and technological advances have profoundly modified the parameters of new drug testing in ovarian cancer. The potential of compounds tested today in this disease therefore needs to be assessed according to this changing reality. Previous treatment with or without cisplatin is the criterion we have applied in our review of the single agent clinical data. Results obtained with older compounds have also been, when possible, reassessed in order to facilitate a comparative interpretation of recent trials. A brief overview of the most recently developed laboratory screening models has been conducted in order to stress their close relationship and their crucial role in future new drug development.
Demand curves for hypothetical cocaine in cocaine-dependent individuals.

PubMed

Bruner, Natalie R; Johnson, Matthew W

2014-03-01

Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks, drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and O max (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, P max, were significantly correlated with real-world cocaine use. Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use.
Developments in Neuropsychological and Neurophysiological Assessment: An Overview of Progress and Products of the JWGD3 (Joint Working Group on Drug Dependent Degradation) Level I Neuropsychology Task Area Group

DTIC Science & Technology

1986-01-01

995AB.081 IDA303502 11. TITLE (Indclude Security Classafication) Developments in Neuropsychological and Neurophysiological Assessment: An overview of...progress and products of the JWGD3 Level I Neuropsychology Task Area Group 12. PERSONAL AU1TOR(S) Reeves, D.L.; Taube, S.L. 13a. TYPE OF REPORT I13b...Phone: (301) 588-0058 7 Developments in Neuropsychological and Neurophysiological Assessment An Overview of Progress and Products of the JWGD3 Level I
Development of magnetic resonance technology for noninvasive boron quantification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradshaw, K.M.

1990-11-01

Boron magnetic resonance imaging (MRI) and spectroscopy (MRS) were developed in support of the noninvasive boron quantification task of the Idaho National Engineering Laboratory (INEL) Power Burst Facility/Boron Neutron Capture Therapy (PBF/BNCT) program. The hardware and software described in this report are modifications specific to a GE Signa{trademark} MRI system, release 3.X and are necessary for boron magnetic resonance operation. The technology developed in this task has been applied to obtaining animal pharmacokinetic data of boron compounds (drug time response) and the in-vivo localization of boron in animal tissue noninvasively. 9 refs., 21 figs.
Neuropsychological predictors of clinical outcome in opiate addiction.

PubMed

Passetti, F; Clark, L; Mehta, M A; Joyce, E; King, M

2008-04-01

A growing literature supports a role for neurocognitive deficits such as impaired decision-making in the development and maintenance of addictive behaviour. On the basis of these findings, it has been suggested that measures of neurocognitive functioning may be applied to the task of predicting clinical outcome in drug addiction. This in turn may have relevance for differentiating treatment based on individual patient needs. To explore this hypothesis we obtained neurocognitive measures of planning, impulsivity and decision-making from 37 opiate dependent individuals within 6 weeks of starting a community drug treatment programme and we followed them up 3 months into the programme. Performance on two tests of decision-making, but not on tests of planning, motor inhibition, reflection impulsivity or delay discounting, was found to predict abstinence from illicit drugs at 3 months with high specificity and moderate sensitivity. In particular, two thirds of the participants performing normally on the Cambridge Gamble Task and the Iowa Gambling Task, but none of those impaired on both, were abstinent from illicit drugs at follow up. Other neuropsychological, psychiatric or psychosocial factors measured in this sample did not explain this finding. The results are discussed in terms of the brain circuitry involved and the potential implications for the planning of treatment services for opiate dependence.
Process Pharmacology: A Pharmacological Data Science Approach to Drug Development and Therapy.

PubMed

Lötsch, Jörn; Ultsch, Alfred

2016-04-01

A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates.

PubMed

Buccafusco, Jerry J; Terry, Alvin V; Webster, Scott J; Martin, Daniel; Hohnadel, Elizabeth J; Bouchard, Kristy A; Warner, Samantha E

2008-08-01

The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task. The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.
Inhibition of the cancer-associated TASK 3 channels by magnetically induced thermal release of Tetrandrine from a polymeric drug carrier.

PubMed

Shi, Chen; Thum, Carolin; Zhang, Qian; Tu, Wei; Pelaz, Beatriz; Parak, Wolfgang J; Zhang, Yu; Schneider, Marc

2016-09-10

Two-pore domain (K2P) potassium channels have recently attracted growing interest in the field of cancer research. These channels play an important role in cancer biology specifically for cancer progression, including proliferation, migration, and apoptosis, which makes them an attractive target for novel cancer therapies. Here, we examined the effect of Tetrandrine (Tet), a natural compound known as a channel modulator, which is associated with anticancer activities, as potential drug in this regard. Xenopus oocyte with overexpression of K2P 9.1 (TASK 3) channels has been chosen as model system for this purpose. In order to release Tet and trigger the channels we developed a polymeric magnetic delivery system: Tetrandrine-Magnetite co-loaded poly (lactic-co-glycolic) acid particles. The embedded iron oxide magnetite (Fe3O4) nanoparticles (NPs) allow to inductively heat the particles by applying a high frequency alternating magnetic field, and thus trigger the release of the co-encapsulated Tet. As a proof of concept the nanoparticulate drug delivery system was heated by raising the suspension's temperature proving the temperature dependent release behaviour. Both heating approaches were then successfully applied for measuring the TASK 3 channels current in response to the released drug. It was found that the released Tet amount is sufficient to inhibit the TASK 3 channels in a dose dependent manner. Thus, such a stimulus responsive drug delivery system holds great promise as a novel approach for the treatment of various cancer types such as for the interaction with the two-pore domain potassium channels K2P 9.1. Copyright © 2016 Elsevier B.V. All rights reserved.
Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective.

PubMed

Landis, Margaret S; Boyden, Tracey; Pegg, Simon

2012-02-01

Delivery of drug therapeutics across the blood-brain barrier is a challenging task for pharmaceutical scientists. Nasal-to-CNS drug delivery has shown promising results in preclinical efficacy models and investigatory human clinical trials. The further development of this technology with respect to the establishment of valid, predictable preclinical species models, translatable pharmacokinetic-pharmacodynamic relationships and definition of toxicology impact will help attract additional pharmaceutical investment in this drug-delivery approach. Further discoveries in nasal nanotechnology, targeted delivery devices and diagnostic olfactory imaging will serve to fuel the advancements in this area of drug delivery.

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

DTIC Science & Technology

2009-06-01

for posttraumatic stress disorder (PTSD). The underlying theory is that candidate drugs , when given following the reactivation of a conditioned ...freezing in a Pavlovian cue- conditioned fear task in rats, as well as to reduce associated retrieval-induced activation of immediate early genes in the...amygdala. In Stage II, we will evaluate the ability of candidate drugs to reverse fear conditioning -induced synaptic enhancement in rat amygdala
Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

DTIC Science & Technology

2013-08-01

This project is to use cutting-edge technologies to characterize novel RSR genes and their functions in tumor suppression; identify gene signature...and membrane proteins associated with defective RSR; identify drugs that target these defects; and develop RSR-defect-targeting nanoparticles for...screening and validation of drugs that target RSR-defect cells. The progress of our third year research is described below. BODY The tasks
Intraseptal infusion of oxotremorine impairs memory in a delayed-non-match-to-sample radial maze task.

PubMed

Bunce, J G; Sabolek, H R; Chrobak, J J

2003-01-01

The medial septal nucleus is part of the forebrain circuitry that supports memory. This nucleus is rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive-enhancing drugs. Septal neurons, primarily cholinergic and GABAergic, innervate the entire hippocampal formation and regulate hippocampal formation physiology and emergent function. Direct intraseptal drug infusions can produce amnestic or promnestic effects depending upon the type of drug administered. However, intraseptal infusion of the cholinomimetic oxotremorine has been reported to produce both promnestic and amnestic effects when administered prior to task performance. The present study examined whether post-acquisition intraseptal infusion of oxotremorine would be promnestic or amnestic in a delayed-non-match-to-sample radial maze task. In this task rats must remember information about spatial locations visited during a daily sample session and maintain that information over extended retention intervals (hours) in order to perform accurately on the daily test session. Treatments may then be administered during the retention interval. Alterations in maze performance during the test session an hour or more after treatment evidences effects on memory. In the present study, intraseptal infusion of oxotremorine (1.0-10.0 microg) produced a linear dose-related impairment of memory performance. Importantly, we also observed disrupted performance on the day after treatment. This persistent deficit was related only to memory over the retention interval and did not affect indices of short-term memory (ability to avoid repetitive or proactive errors during both the pre- and post-delay sessions). The persistent deficit contrasts with the acute amnestic effects of other intraseptally administered drugs including the cholinomimetics carbachol and tacrine. Thus, intraseptal oxotremorine produced a preferential disruption of memory consolidation as well as a persistent alteration of medial septal circuits. These findings are discussed with regards to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related decline and Alzheimer's dementia.
Stimulus selectivity of drug purchase tasks: A preliminary study evaluating alcohol and cigarette demand.

PubMed

Strickland, Justin C; Stoops, William W

2017-06-01

The use of drug purchase tasks to measure drug demand in human behavioral pharmacology and addiction research has proliferated in recent years. Few studies have systematically evaluated the stimulus selectivity of drug purchase tasks to demonstrate that demand metrics are specific to valuation of or demand for the commodity under study. Stimulus selectivity is broadly defined for this purpose as a condition under which a specific stimulus input or target (e.g., alcohol, cigarettes) is the primary determinant of behavior (e.g., demand). The overall goal of the present study was to evaluate the stimulus selectivity of drug purchase tasks. Participants were sampled from the Amazon.com's crowdsourcing platform Mechanical Turk. Participants completed either alcohol and soda purchase tasks (Experiment 1; N = 139) or cigarette and chocolate purchase tasks (Experiment 2; N = 46), and demand metrics were compared to self-reported use behaviors. Demand metrics for alcohol and soda were closely associated with commodity-similar (e.g., alcohol demand and weekly alcohol use) but not commodity-different (e.g., alcohol demand and weekly soda use) variables. A similar pattern was observed for cigarette and chocolate demand, but selectivity was not as consistent as for alcohol and soda. Collectively, we observed robust selectivity for alcohol and soda purchase tasks and modest selectivity for cigarette and chocolate purchase tasks. These preliminary outcomes suggest that demand metrics adequately reflect the specific commodity under study and support the continued use of purchase tasks in substance use research. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Demand Curves for Hypothetical Cocaine in Cocaine-Dependent Individuals

PubMed Central

Bruner, Natalie R.; Johnson, Matthew W.

2013-01-01

Rationale Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. Objectives This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Methods Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Results Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and Omax (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, Pmax, were significantly correlated with real-world cocaine use. Conclusions Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use. PMID:24217899
C3 generic workstation: Performance metrics and applications

NASA Technical Reports Server (NTRS)

Eddy, Douglas R.

1988-01-01

The large number of integrated dependent measures available on a command, control, and communications (C3) generic workstation under development are described. In this system, embedded communications tasks will manipulate workload to assess the effects of performance-enhancing drugs (sleep aids and decongestants), work/rest cycles, biocybernetics, and decision support systems on performance. Task performance accuracy and latency will be event coded for correlation with other measures of voice stress and physiological functioning. Sessions will be videotaped to score non-verbal communications. Physiological recordings include spectral analysis of EEG, ECG, vagal tone, and EOG. Subjective measurements include SWAT, fatigue, POMS and specialized self-report scales. The system will be used primarily to evaluate the effects on performance of drugs, work/rest cycles, and biocybernetic concepts. Performance assessment algorithms will also be developed, including those used with small teams. This system provides a tool for integrating and synchronizing behavioral and psychophysiological measures in a complex decision-making environment.
Response requirement and increases in accuracy produced by stimulant drugs in a 5-choice serial reaction-time task in rats.

PubMed

Koffarnus, Mikhail N; Katz, Jonathan L

2011-02-01

Increased signal-detection accuracy on the 5-choice serial reaction time (5-CSRT) task has been shown with drugs that are useful clinically in treating attention deficit hyperactivity disorder (ADHD), but these increases are often small and/or unreliable. By reducing the reinforcer frequency, it may be possible to increase the sensitivity of this task to pharmacologically induced improvements in accuracy. Rats were trained to respond on the 5-CSRT task on a fixed ratio (FR) 1, FR 3, or FR 10 schedule of reinforcement. Drugs that were and were not expected to enhance performance were then administered before experimental sessions. Significant increases in accuracy of signal detection were not typically obtained under the FR 1 schedule with any drug. However, d-amphetamine, methylphenidate, and nicotine typically increased accuracy under the FR 3 and FR 10 schedules. Increasing the FR requirement in the 5-CSRT task increases the likelihood of a positive result with clinically effective drugs, and may more closely resemble conditions in children with attention deficits.
Professional Development: A Six-Year Data Evaluation of HIDTA Law Enforcement Task Force Training Programs

ERIC Educational Resources Information Center

Burnett, Larry D.

2012-01-01

This is a nationwide six-year data study of law enforcement training and professional development in relationship to workplace productivity. Why do we care about law enforcement training and professional development? Because the law enforcement environment is not standing still. Unlawful activity, and in particular drug trafficking strategies,…
The effects of heroin administration and drug cues on impulsivity.

PubMed

Jones, Jermaine D; Vadhan, Nehal P; Luba, Rachel R; Comer, Sandra D

2016-08-01

Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and continued use despite negative consequences. Behavioral impulsivity is a strong predictor of the initiation and maintenance of drug addiction. Preclinical data suggest that heroin may exacerbate impulsive characteristics in an individual but this has yet to be assessed in clinical samples. The current secondary data analysis sought to investigate the effects of heroin on impulsivity along with the effects of exposure to drug cues. Using the current data set, we also tentatively assessed the etiological relationship between impulsivity and heroin abuse. Sixteen heroin-dependent participants were recruited to complete Immediate Memory Task/Delayed Memory Task (IMT/DMT) and GoStop tasks following repeated heroin administration, following acute heroin administration, and following a drug cue exposure session. Four preceding days of active heroin availability, compared to four preceding days of placebo drug availability, increased impulsivity assessed using the IMT and DMT. Presentation of drug cues similarly acted to increase impulsivity assessments on all three tasks. It also appears that heavier users were more susceptible to the influence of drug cues on impulsivity. The present study represents a step toward a more comprehensive understanding of the interaction between opioid abuse and impulsivity. A better understanding of these factors could provide critical insight into the maintenance of heroin use and relapse.
Enhancing of chemical compound and drug name recognition using representative tag scheme and fine-grained tokenization.

PubMed

Dai, Hong-Jie; Lai, Po-Ting; Chang, Yung-Chun; Tsai, Richard Tzong-Han

2015-01-01

The functions of chemical compounds and drugs that affect biological processes and their particular effect on the onset and treatment of diseases have attracted increasing interest with the advancement of research in the life sciences. To extract knowledge from the extensive literatures on such compounds and drugs, the organizers of BioCreative IV administered the CHEMical Compound and Drug Named Entity Recognition (CHEMDNER) task to establish a standard dataset for evaluating state-of-the-art chemical entity recognition methods. This study introduces the approach of our CHEMDNER system. Instead of emphasizing the development of novel feature sets for machine learning, this study investigates the effect of various tag schemes on the recognition of the names of chemicals and drugs by using conditional random fields. Experiments were conducted using combinations of different tokenization strategies and tag schemes to investigate the effects of tag set selection and tokenization method on the CHEMDNER task. This study presents the performance of CHEMDNER of three more representative tag schemes-IOBE, IOBES, and IOB12E-when applied to a widely utilized IOB tag set and combined with the coarse-/fine-grained tokenization methods. The experimental results thus reveal that the fine-grained tokenization strategy performance best in terms of precision, recall and F-scores when the IOBES tag set was utilized. The IOBES model with fine-grained tokenization yielded the best-F-scores in the six chemical entity categories other than the "Multiple" entity category. Nonetheless, no significant improvement was observed when a more representative tag schemes was used with the coarse or fine-grained tokenization rules. The best F-scores that were achieved using the developed system on the test dataset of the CHEMDNER task were 0.833 and 0.815 for the chemical documents indexing and the chemical entity mention recognition tasks, respectively. The results herein highlight the importance of tag set selection and the use of different tokenization strategies. Fine-grained tokenization combined with the tag set IOBES most effectively recognizes chemical and drug names. To the best of the authors' knowledge, this investigation is the first comprehensive investigation use of various tag set schemes combined with different tokenization strategies for the recognition of chemical entities.
Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery.

PubMed

Hay, Justin L; Okkerse, Pieter; van Amerongen, Guido; Groeneveld, Geert Jan

2016-04-14

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug's pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action.
Current and emerging lipid-based systems for transdermal drug delivery.

PubMed

Singla, Sumeet K; Sachdeva, Vishal

2015-01-01

Developing a transdermal drug delivery system is a challenging task considering the selective permeability of the skin and the physicochemical properties the drug must possess to permeate through the skin. Lipid-based drug delivery systems have contributed a great deal in this direction in the last few decades, and thereby have helped to expand the range of therapeutic molecules that can be delivered through the skin in a safe and effective manner. Additionally, vesicular delivery systems such as nanoparticles and emulsions have also played important roles in providing alternative novel approaches for drug delivery. In this article, we will discuss some of the current and future lipid-based systems for transdermal drug delivery along with the associated challenges.
Position-aware deep multi-task learning for drug-drug interaction extraction.

PubMed

Zhou, Deyu; Miao, Lei; He, Yulan

2018-05-01

A drug-drug interaction (DDI) is a situation in which a drug affects the activity of another drug synergistically or antagonistically when being administered together. The information of DDIs is crucial for healthcare professionals to prevent adverse drug events. Although some known DDIs can be found in purposely-built databases such as DrugBank, most information is still buried in scientific publications. Therefore, automatically extracting DDIs from biomedical texts is sorely needed. In this paper, we propose a novel position-aware deep multi-task learning approach for extracting DDIs from biomedical texts. In particular, sentences are represented as a sequence of word embeddings and position embeddings. An attention-based bidirectional long short-term memory (BiLSTM) network is used to encode each sentence. The relative position information of words with the target drugs in text is combined with the hidden states of BiLSTM to generate the position-aware attention weights. Moreover, the tasks of predicting whether or not two drugs interact with each other and further distinguishing the types of interactions are learned jointly in multi-task learning framework. The proposed approach has been evaluated on the DDIExtraction challenge 2013 corpus and the results show that with the position-aware attention only, our proposed approach outperforms the state-of-the-art method by 0.99% for binary DDI classification, and with both position-aware attention and multi-task learning, our approach achieves a micro F-score of 72.99% on interaction type identification, outperforming the state-of-the-art approach by 1.51%, which demonstrates the effectiveness of the proposed approach. Copyright © 2018 Elsevier B.V. All rights reserved.
Health Education Program. Kanawha County Schools.

ERIC Educational Resources Information Center

Kanawha County Schools, Charleston, WV.

A task force, after a 2-year study, recommended a curriculum on health education which would meet the specific needs of both teachers and students. This teacher developed curriculum guide is comprised of five units on: human growth and development, diseases, nutrition, personal hygiene, drug education, safety and first aid. Each unit contains a…
Good research practices for measuring drug costs in cost-effectiveness analyses: a societal perspective: the ISPOR Drug Cost Task Force report--Part II.

PubMed

Garrison, Louis P; Mansley, Edward C; Abbott, Thomas A; Bresnahan, Brian W; Hay, Joel W; Smeeding, James

2010-01-01

Major guidelines regarding the application of cost-effectiveness analysis (CEA) have recommended the common and widespread use of the "societal perspective" for purposes of consistency and comparability. The objective of this Task Force subgroup report (one of six reports from the International Society for Pharmacoeconomics and Outcomes Research [ISPOR] Task Force on Good Research Practices-Use of Drug Costs for Cost Effectiveness Analysis [Drug Cost Task Force (DCTF)]) was to review the definition of this perspective, assess its specific application in measuring drug costs, identify any limitations in theory or practice, and make recommendations regarding potential improvements. Key articles, books, and reports in the methodological literature were reviewed, summarized, and integrated into a draft review and report. This draft report was posted for review and comment by ISPOR membership. Numerous comments and suggestions were received, and the report was revised in response to them. The societal perspective can be defined by three conditions: 1) the inclusion of time costs, 2) the use of opportunity costs, and 3) the use of community preferences. In practice, very few, if any, published CEAs have met all of these conditions, though many claim to have taken a societal perspective. Branded drug costs have typically used actual acquisition cost rather than the much lower social opportunity costs that would reflect only short-run manufacturing and distribution costs. This practice is understandable, pragmatic, and useful to current decision-makers. Nevertheless, this use of CEA focuses on static rather than dynamic efficacy and overlooks the related incentives for innovation. Our key recommendation is that current CEA practice acknowledge and embrace this limitation by adopting a new standard for the reference case as one of a "limited societal" or "health systems" perspective, using acquisition drug prices while including indirect costs and community preferences. The field of pharmacoeconomics also needs to acknowledge the limitations of this perspective when it comes to important questions of research and development costs, and incentives for innovation.
When more of the same is better

NASA Astrophysics Data System (ADS)

Fontanari, José F.

2016-01-01

Problem solving (e.g., drug design, traffic engineering, software development) by task forces represents a substantial portion of the economy of developed countries. Here we use an agent-based model of cooperative problem-solving systems to study the influence of diversity on the performance of a task force. We assume that agents cooperate by exchanging information on their partial success and use that information to imitate the more successful agent in the system —the model. The agents differ only in their propensities to copy the model. We find that, for easy tasks, the optimal organization is a homogeneous system composed of agents with the highest possible copy propensities. For difficult tasks, we find that diversity can prevent the system from being trapped in sub-optimal solutions. However, when the system size is adjusted to maximize the performance the homogeneous systems outperform the heterogeneous systems, i.e., for optimal performance, sameness should be preferred to diversity.
A Specific Two-pore Domain Potassium Channel Blocker Defines the Structure of the TASK-1 Open Pore*

PubMed Central

Streit, Anne K.; Netter, Michael F.; Kempf, Franca; Walecki, Magdalena; Rinné, Susanne; Bollepalli, Murali K.; Preisig-Müller, Regina; Renigunta, Vijay; Daut, Jürgen; Baukrowitz, Thomas; Sansom, Mark S. P.; Stansfeld, Phillip J.; Decher, Niels

2011-01-01

Two-pore domain potassium (K2P) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K2P channels. We describe A1899 as a potent and highly selective blocker of the K2P channel TASK-1. As A1899 acts as an open-channel blocker and binds to residues forming the wall of the central cavity, the drug was used to further our understanding of the channel pore. Using alanine mutagenesis screens, we have identified residues in both pore loops, the M2 and M4 segments, and the halothane response element to form the drug binding site of TASK-1. Our experimental data were used to validate a K2P open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K2P channels. PMID:21362619
Acute radiation sickness amelioration analysis. Technical report, 20 July 1990-19 July 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinson, S.I.; Feister, A.J.; Bareis, D.L.

1994-05-01

Three tasks were conducted under the Acute Radiation Sickness Amelioration Analysis in support of the Defense Nuclear Agency (DNA) and NATO Army Armaments Group (NAAG) Project Group 29 (PG-29) on drugs for the prevention of radiation-induced nausea and vomiting: (1) documents were collected and entered into a data base, (2) data reviews and analyses were performed, and (3) PG-29 and Triservice meetings involving anti-emetic drug development were supported and documented. Approximately 2000 documents were collected, with 1424 complete bibliographic citations entered into a WordPerfect 5.1 data base. Eight reviews and analyses addressing different aspects of the safety and efficacy ofmore » the candidate anti-emetic drugs ondansetron and granistron were prepared. Support was provided for seven international PG-29 meetings and two U.S. Triservice meetings in which the efforts of PG-29 were discussed. These tasks have enabled the DNA and PG-29 to make good progress toward the goal of recommending a serotonin type-3 (5-HT3) receptor antagonist anti-emetic drug for use in military personnel.« less
Selective attention moderates the relationship between attentional capture by signals of nondrug reward and illicit drug use.

PubMed

Albertella, Lucy; Copeland, Jan; Pearson, Daniel; Watson, Poppy; Wiers, Reinout W; Le Pelley, Mike E

2017-06-01

The current study examined whether cognitive control moderates the association between (non-drug) reward-modulated attentional capture and use of alcohol and other drugs (AOD). Participants were 66 university students who completed an assessment including questions about AOD use, a visual search task to measure value-modulated attentional capture, and a goal-directed selective attention task as a measure of cognitive control. The association between the effect of value-modulated attentional capture and illicit drug use was moderated by level of cognitive control. Among participants with lower levels of cognitive control, value-modulated attentional capture was associated with illicit drug use. This was not the case among participants with higher levels of cognitive control, who instead showed a significant association between illicit drug use and self-reported impulsivity, as well as alcohol use. These results provide support for models that view addictive behaviours as resulting from interaction and competition between automatic and more reflective processes. That is, the mechanisms that ultimately drive addictive behaviour may differ between people low or high in cognitive control. This has important implications for understanding the development and maintenance of substance use disorders and potentially their treatment and prevention. Copyright © 2017 Elsevier B.V. All rights reserved.
Fragment-based design of kinase inhibitors: a practical guide.

PubMed

Erickson, Jon A

2015-01-01

Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

Improving specialist drug prescribing in primary care using task and error analysis: an observational study.

PubMed

Chana, Narinder; Porat, Talya; Whittlesea, Cate; Delaney, Brendan

2017-03-01

Electronic prescribing has benefited from computerised clinical decision support systems (CDSSs); however, no published studies have evaluated the potential for a CDSS to support GPs in prescribing specialist drugs. To identify potential weaknesses and errors in the existing process of prescribing specialist drugs that could be addressed in the development of a CDSS. Semi-structured interviews with key informants followed by an observational study involving GPs in the UK. Twelve key informants were interviewed to investigate the use of CDSSs in the UK. Nine GPs were observed while performing case scenarios depicting requests from hospitals or patients to prescribe a specialist drug. Activity diagrams, hierarchical task analysis, and systematic human error reduction and prediction approach analyses were performed. The current process of prescribing specialist drugs by GPs is prone to error. Errors of omission due to lack of information were the most common errors, which could potentially result in a GP prescribing a specialist drug that should only be prescribed in hospitals, or prescribing a specialist drug without reference to a shared care protocol. Half of all possible errors in the prescribing process had a high probability of occurrence. A CDSS supporting GPs during the process of prescribing specialist drugs is needed. This could, first, support the decision making of whether or not to undertake prescribing, and, second, provide drug-specific parameters linked to shared care protocols, which could reduce the errors identified and increase patient safety. © British Journal of General Practice 2017.
Professional ideologies and the development of syringe exchange: Wales as a case study.

PubMed

Keene, J M; Stimson, G V

1997-12-01

This paper is derived from an evaluative study of HIV prevention programs for drug injectors across Wales. It considers how different professional territories and ideologies, concepts of drug misuse and models of HIV prevention may influence policy development. The research involved monitoring the introduction and development of agency and community based syringe exchange schemes and initiatives taken by community pharmacists. Interviews with staff, managers and administrators, and descriptions of service history, development and delivery inform the discussion. HIV prevention varied in different areas of Wales depending on the particular professional group involved, local ideologies regarding drug use treatment, and the extent to which HIV prevention was seen either as a specialist area of expertise and specific remit of drug workers or a generic health care task. Drug agencies with an abstinence policy rejected syringe exchange; instead, prevention in those areas developed in ad hoc ways as health care workers and pharmacists attempted to develop a community based service. Drug agencies with a pre-existing harm minimisation model easily integrated syringe exchange into their work and played the major part in establishing the service, but there was difficulty in extending it beyond their professional caseloads. As there were disincentives to use treatment agencies, and their catchment areas were limited, these factors influenced effective service provision.
New perspectives and lessons learned in the identification of impurities in drug development.

PubMed

Sasaki, Ryan R; McGibbon, Graham; Lee, Mike S; Murray, Clare L; Pharr, Bruce

2014-11-01

Within the pharmaceutical industry, the rapid identification, elucidation and characterization of synthetic or process impurities or degradants form an intense and a comprehensive undertaking. Advances in laboratory hardware and software are changing the way in which scientists work together to help resolve impurities in a quick and efficient manner. Although the industry trend toward externalization and outsourcing of development tasks provides a cost-effective method, the demand for improved productivity in laboratory workflows in drug development continues to be a high priority. This brings a need for new approaches for communication, collaboration and data management. Copyright © 2014 Elsevier Ltd. All rights reserved.
Predicting Drug-Target Interactions for New Drug Compounds Using a Weighted Nearest Neighbor Profile.

PubMed

van Laarhoven, Twan; Marchiori, Elena

2013-01-01

In silico discovery of interactions between drug compounds and target proteins is of core importance for improving the efficiency of the laborious and costly experimental determination of drug-target interaction. Drug-target interaction data are available for many classes of pharmaceutically useful target proteins including enzymes, ion channels, GPCRs and nuclear receptors. However, current drug-target interaction databases contain a small number of drug-target pairs which are experimentally validated interactions. In particular, for some drug compounds (or targets) there is no available interaction. This motivates the need for developing methods that predict interacting pairs with high accuracy also for these 'new' drug compounds (or targets). We show that a simple weighted nearest neighbor procedure is highly effective for this task. We integrate this procedure into a recent machine learning method for drug-target interaction we developed in previous work. Results of experiments indicate that the resulting method predicts true interactions with high accuracy also for new drug compounds and achieves results comparable or better than those of recent state-of-the-art algorithms. Software is publicly available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2013/.
Macrophages with cellular backpacks for targeted drug delivery to the brain.

PubMed

Klyachko, Natalia L; Polak, Roberta; Haney, Matthew J; Zhao, Yuling; Gomes Neto, Reginaldo J; Hill, Michael C; Kabanov, Alexander V; Cohen, Robert E; Rubner, Michael F; Batrakova, Elena V

2017-09-01

Most potent therapeutics are unable to cross the blood-brain barrier following systemic administration, which necessitates the development of unconventional, clinically applicable drug delivery systems. With the given challenges, biologically active vehicles are crucial to accomplishing this task. We now report a new method for drug delivery that utilizes living cells as vehicles for drug carriage across the blood brain barrier. Cellular backpacks, 7-10 μm diameter polymer patches of a few hundred nanometers in thickness, are a potentially interesting approach, because they can act as drug depots that travel with the cell-carrier, without being phagocytized. Backpacks loaded with a potent antioxidant, catalase, were attached to autologous macrophages and systemically administered into mice with brain inflammation. Using inflammatory response cells enabled targeted drug transport to the inflamed brain. Furthermore, catalase-loaded backpacks demonstrated potent therapeutic effects deactivating free radicals released by activated microglia in vitro. This approach for drug carriage and release can accelerate the development of new drug formulations for all the neurodegenerative disorders. Copyright © 2017. Published by Elsevier Ltd.
Targeting TMPRSS2 ERG in Prostate Cancer

DTIC Science & Technology

2016-09-01

Assay development for surface Plasmon resonance with purified ERG protein (months 31-36, completed July 2016) 7c. Perform thermal shift and...surface Plasmon resonance on compounds and determine binding constants (months 37-42, completed July 2016) Task 8. Identify FDA approved drugs that
New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics.

PubMed

Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Ma, Dik-Lung; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

2013-01-01

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is "experience driven," the search for a therapeutically useful synthetic drug, like "looking for a needle in a haystack," is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.
Sustainability: Building Program and Coalition Support. A Prevention 101 Series Publication

ERIC Educational Resources Information Center

Glider, Peggy

2010-01-01

Given the prevalence of alcohol and other drug abuse and violence on campuses and in communities, programs and coalitions developed to prevent or intervene in these problems are faced with a challenging and long-term task. While the development of coalitions or campus-based prevention programs is a healthy start, these efforts must be sustained…
Variable activation in striatal subregions across components of a social influence task in young adult cannabis users.

PubMed

Gilman, Jodi M; Lee, Sang; Kuster, John K; Lee, Myung Joo; Kim, Byoung Woo; van der Kouwe, Andre; Blood, Anne J; Breiter, Hans C

2016-05-01

Decades of research have demonstrated the importance of social influence in initiation and maintenance of drug use, but little is known about neural mechanisms underlying social influence in young adults who use recreational drugs. To better understand whether the neural and/or behavioral response to social influence differs in young adults using illicit drugs, 20 marijuana-using young adults (MJ) aged 18-25, and 20 controls (CON) performed a decision-making task in the context of social influence, while they underwent functional magnetic resonance imaging scans. A priori analyses focused on the nucleus accumbens (NAc), with post hoc analyses in the rest of the striatum. In this task, participants could choose to either follow or go against group influence. When subjects applied social information to response choice selection (independent of following or going against group influence), we observed activation in the middle striatum (caudate), in the MJ group only, that extended ventrally into the NAc. MJ users but not CON showed greater activation in the NAc but not the caudate while making choices congruent with group influence as opposed to choices going against group influence. Activation in the NAc when following social influence was associated with amount of drug use reported. In contrast, during the feedback phase of the task we observed significant NAc activation in both MJ and CON, along with dorsal caudate activation only in MJ participants. This NAc activation did not correlate with drug use. This study shows that MJ users, but not CON, show differential brain activation across striatal subregions when applying social information to make a decision, following versus going against a group of peers, or receiving positive feedback. The current work suggests that differential neural sensitivity to social influence in regions such as the striatum may contribute to the development and/or maintenance of marijuana use.
A University Community Approach to Alcohol and Other Drugs. Phase One Report of The University of Michitan Task Force on Alcohol and Other Drugs: The "Rollicking Crew" Revisited.

ERIC Educational Resources Information Center

Michigan Univ., Ann Arbor.

This report discusses the need for an alcohol and drug use prevention program at the University of Michigan and presents findings from a task force that was established to investigate the problem of student alcohol and other drug use and identify areas where priority should be given for action. The opening section of the report presents the…
Development of Specific Inhibitors for Breast Cancer-Associated Variants of ErbB2

DTIC Science & Technology

2015-10-01

activity measurements (Months 9-15) Specific Aim 3: Identifying inhibitors of ErbB2 mutants.* Major Task 5: Produce ErbB2 structures for drug -lead...identified the activated cancer- associated ErbB2 mutants that will be used for drug screening, and we have established enzyme assays that will be suitable...during protein expression and purification. We measured enzyme activity using two assays: (1) a continuous spectrophotometric assay. In this assay
Novel Compounds Line up to Combat Drug Resistance in Cancer Cells | Center for Cancer Research

Cancer.gov

As the war on cancer has intensified and new molecular attacks on cancer cells have been developed, cancer cells have devised innovative ways of defending themselves. Many drugs have been designed or discovered and used to kill cancer cells; in response, these cells are staging new mechanisms to resist the effects of a variety of drugs, a phenomenon called multidrug resistance (MDR). One way cancer cells accomplish this is by catching the intruding drug and throwing it out of the cell before it can act. The arsenal that the cancer cell uses to accomplish this task is a collection of specialized proteins on its membrane called ATP-binding cassette (ABC) transporters.
Adapting Cognitive Task Analysis to Investigate Clinical Decision Making and Medication Safety Incidents.

PubMed

Russ, Alissa L; Militello, Laura G; Glassman, Peter A; Arthur, Karen J; Zillich, Alan J; Weiner, Michael

2017-05-03

Cognitive task analysis (CTA) can yield valuable insights into healthcare professionals' cognition and inform system design to promote safe, quality care. Our objective was to adapt CTA-the critical decision method, specifically-to investigate patient safety incidents, overcome barriers to implementing this method, and facilitate more widespread use of cognitive task analysis in healthcare. We adapted CTA to facilitate recruitment of healthcare professionals and developed a data collection tool to capture incidents as they occurred. We also leveraged the electronic health record (EHR) to expand data capture and used EHR-stimulated recall to aid reconstruction of safety incidents. We investigated 3 categories of medication-related incidents: adverse drug reactions, drug-drug interactions, and drug-disease interactions. Healthcare professionals submitted incidents, and a subset of incidents was selected for CTA. We analyzed several outcomes to characterize incident capture and completed CTA interviews. We captured 101 incidents. Eighty incidents (79%) met eligibility criteria. We completed 60 CTA interviews, 20 for each incident category. Capturing incidents before interviews allowed us to shorten the interview duration and reduced reliance on healthcare professionals' recall. Incorporating the EHR into CTA enriched data collection. The adapted CTA technique was successful in capturing specific categories of safety incidents. Our approach may be especially useful for investigating safety incidents that healthcare professionals "fix and forget." Our innovations to CTA are expected to expand the application of this method in healthcare and inform a wide range of studies on clinical decision making and patient safety.
Laboratory-Induced Stress and Craving among Individuals with Prescription Opioid Dependence

PubMed Central

Back, Sudie E.; Gros, Daniel F.; Price, Matthew; LaRowe, Steve; Flanagan, Julianne; Brady, Kathleen T.; Davis, Charles; Jaconis, Maryanne; McCauley, Jenna L.

2015-01-01

Background Stress and conditioned drug cues have been implicated in the initiation, maintenance and relapse to substances of abuse. Although stress and drug cues are often encountered together, little research exists on whether stress potentiates the response to drug cues. Method Participants (N = 75) were 39 community recruited individuals with current prescription opioid (PO) dependence and 36 healthy controls. Participants stayed overnight in the hospital for one night and then completed laboratory testing the following morning. During laboratory testing, participants were randomly assigned to a stress task (Trier Social Stress Task; TSST) or a no-stress condition. Following the stress manipulation, all participants completed a PO cue paradigm. Immediately before and after the stress and cue tasks, the following were assessed: subjective (stress, craving, anger, sadness, happiness), physiological (heart rate, blood pressure, galvanic skin response), and neuroendocrine responses (cortisol and dehydroepiandrosterone). Results Internal validity of the stress task was demonstrated, as evidenced by significantly higher subjective stress, as well as cortisol, heart rate and blood pressure in the TSST compared to the no-stress group. Individuals with PO dependence evidenced significantly greater reactivity to the stress task than controls. Craving increased significantly in response to the drug cue task among PO participants. No stress × cue interaction was observed. Conclusions In this study, heightened stress reactivity was observed among individuals with PO dependence. Exposure to acute stress, however, did not potentiate craving in response to conditioned drug cues. PMID:26342626
Consideration of species differences in developing novel molecules as cognition enhancers.

PubMed

Young, Jared W; Jentsch, J David; Bussey, Timothy J; Wallace, Tanya L; Hutcheson, Daniel M

2013-11-01

The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of novel procognitive molecules from testing in mice, rats and non-human primates, to clinical efficacy in patients with schizophrenia. CNTRICS highlighted improving construct validation of tasks across species to increase the likelihood that the translation of a candidate molecule to humans will be successful. Other aspects of cross-species behaviors remain important however. This review describes cognitive tasks utilized across species, providing examples of differences and similarities of innate behavior between species, as well as convergent construct and predictive validity. Tests of attention, olfactory discrimination, reversal learning, and paired associate learning are discussed. Moreover, information on the practical implication of species differences in drug development research is also provided. The issues covered here will aid in task development and utilization across species as well as reinforcing the positive role preclinical research can have in developing procognitive treatments for psychiatric disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.
Learning to think like a user: using cognitive task analysis to meet today's health care design challenges.

PubMed

Militello, L G

1998-01-01

The growing role of information technology in our society has changed the very nature of many of the tasks that workers are called on to perform. Technology has resulted in a dramatic reduction in the number of proceduralized, rote tasks that workers must face. The impact of technology on many tasks and functions has been to greatly increase demands on the cognitive skills of workers. More procedural or predictable tasks are now handled by smart machines, while workers are responsible for tasks that require inference, diagnosis, judgment, and decision making. The increase in the cognitive demands placed on workers and the redistribution of tasks have created a need for a better understanding of the cognitive components of many tasks. This need has been recognized by many in the health care domain, including the U.S. Food and Drug Administration (FDA). Recent FDA regulations encourage the use of human factors in the development of medical devices, instruments, and systems. One promising set of methods for filling this need is cognitive task analysis.
Annual banned-substance review: Analytical approaches in human sports drug testing.

PubMed

Thevis, Mario; Kuuranne, Tiia; Geyer, Hans

2018-01-01

Several high-profile revelations concerning anti-doping rule violations over the past 12 months have outlined the importance of tackling prevailing challenges and reducing the limitations of the current anti-doping system. At this time, the necessity to enhance, expand, and improve analytical test methods in response to the substances outlined in the World Anti-Doping Agency's (WADA) Prohibited List represents an increasingly crucial task for modern sports drug-testing programs. The ability to improve analytical testing methods often relies on the expedient application of novel information regarding superior target analytes for sports drug-testing assays, drug elimination profiles, alternative test matrices, together with recent advances in instrumental developments. This annual banned-substance review evaluates literature published between October 2016 and September 2017 offering an in-depth evaluation of developments in these arenas and their potential application to substances reported in WADA's 2017 Prohibited List. Copyright © 2017 John Wiley & Sons, Ltd.
Participatory design for drug-drug interaction alerts.

PubMed

Luna, Daniel; Otero, Carlos; Almerares, Alfredo; Stanziola, Enrique; Risk, Marcelo; González Bernaldo de Quirós, Fernán

2015-01-01

The utilization of decision support systems, in the point of care, to alert drug-drug interactions has been shown to improve quality of care. Still, the use of these systems has not been as expected, it is believed, because of the difficulties in their knowledge databases; errors in the generation of the alerts and the lack of a suitable design. This study expands on the development of alerts using participatory design techniques based on user centered design process. This work was undertaken in three stages (inquiry, participatory design and usability testing) it showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction in the system.
Trace Contraband Detection Field-Test by the South Texas Specialized Crimes and Narcotics Task Force

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hannum, David W.; Shannon, Gary W.

This report describes the collaboration between the South Texas Specialized Crimes and Narcotics Task Force (STSCNTF) and Sandia National Laboratories (SNL) in a field test that provided prototype hand-held trace detection technology for use in counter-drug operations. The National Institute of Justice (NIJ)/National Law Enforcement and Corrections Technology Center (NLECTC)/Border Research and Technology Center (BRTC) was contacted by STSCNTF for assistance in obtaining cutting-edge technology. The BRTC created a pilot project for Sandia National Laboratories (SNL) and the STSCNTF for the use of SNL’s Hound, a hand-held sample collection and preconcentration system that, when combined with a commercial chemical detector,more » can be used for the trace detection of illicit drugs and explosives. The STSCNTF operates in an area of high narcotics trafficking where methods of concealment make the detection of narcotics challenging. Sandia National Laboratories’ (SNL) Contraband Detection Department personnel provided the Hound system hardware and operational training. The Hound system combines the GE VaporTracer2, a hand-held commercial chemical detector, with an SNL-developed sample collection and preconcentration system. The South Texas Task force reported a variety of successes, including identification of a major shipment of methamphetamines, the discovery of hidden compartments in vehicles that contained illegal drugs and currency used in drug deals, and the identification of a suspect in a nightclub shooting. The main advantage of the hand-held trace detection unit is its ability to quickly identify the type of chemical (drugs or explosives) without a long lag time for laboratory analysis, which is the most common analysis method for current law enforcement procedures.« less
New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics

PubMed Central

Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

2013-01-01

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development. PMID:23634172

Interventions to improve the use of antimalarials in south-east Asia: an overview.

PubMed Central

Gomes, M.; Wayling, S.; Pang, L.

1998-01-01

There are few drugs for malaria, and those which are available for use are subject to rapid development of resistance. Curiously, little effort has been made to improve drug use in malaria-endemic countries and to assess the benefits of such improvements. Advances can be made in public understanding of the value of ingesting a full regimen of antimalarials, in order to achieve complete cure, and in improving simple technologies (blister packaging) to achieve the same result. Better efforts can be made to reduce the availability of fake or substandard drugs in the marketplace. In this article, we describe the outcome of a concerted effort to improve drug compliance and drug quality in an area of multidrug resistance for malaria. These research efforts, guided by the Task Force for Improved Use of Antimalarials, characterized the problems in drug compliance in South-East Asia, and developed interventions to improve drug use in the various countries. Interventions involved drug packaging, public information campaigns, and assessments of drug quality. Results show that blister packaging worked best to improve drug compliance and that the increased cost of packaged medication did not limit its use. Drug quality was a major problem in unregulated countries and should be improved. PMID:9763718
Interventions to improve the use of antimalarials in south-east Asia: an overview.

PubMed

Gomes, M; Wayling, S; Pang, L

1998-01-01

There are few drugs for malaria, and those which are available for use are subject to rapid development of resistance. Curiously, little effort has been made to improve drug use in malaria-endemic countries and to assess the benefits of such improvements. Advances can be made in public understanding of the value of ingesting a full regimen of antimalarials, in order to achieve complete cure, and in improving simple technologies (blister packaging) to achieve the same result. Better efforts can be made to reduce the availability of fake or substandard drugs in the marketplace. In this article, we describe the outcome of a concerted effort to improve drug compliance and drug quality in an area of multidrug resistance for malaria. These research efforts, guided by the Task Force for Improved Use of Antimalarials, characterized the problems in drug compliance in South-East Asia, and developed interventions to improve drug use in the various countries. Interventions involved drug packaging, public information campaigns, and assessments of drug quality. Results show that blister packaging worked best to improve drug compliance and that the increased cost of packaged medication did not limit its use. Drug quality was a major problem in unregulated countries and should be improved.
Evolution of Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

PubMed

Andersson, Tommy B

2017-10-01

The pharmaceutical industry urgently needs reliable pre-clinical models to evaluate the efficacy and safety of new chemical entities before they enter the clinical trials. Development of in vitro model systems that emulate the functions of the human liver organ has been an elusive task. Cell lines exhibit a low drug-metabolizing capacity and primary liver cells rapidly dedifferentiate in culture, which restrict their usefulness substantially. Recently, the development of hepatocyte spheroid cultures has shown promising results. The proteome and transcriptome in the spheroids were similar to the liver tissue, and hepatotoxicity of selected substances was detected at in vivo-relevant concentrations. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
78 FR 56852 - Exemption of Records Systems Under the Privacy Act

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-16

... Crime Drug Enforcement Task Forces Management Information System (OCDETF MIS).'' JUSTICE/CRM-028 is... Management Information System'' (last published at 57 FR 8473 (March 10, 1992)). Previously, when these...), and (8); (f); and (g): (1) The Organized Crime Drug Enforcement Task Forces Management Information...
Development and tuning of an original search engine for patent libraries in medicinal chemistry.

PubMed

Pasche, Emilie; Gobeill, Julien; Kreim, Olivier; Oezdemir-Zaech, Fatma; Vachon, Therese; Lovis, Christian; Ruch, Patrick

2014-01-01

The large increase in the size of patent collections has led to the need of efficient search strategies. But the development of advanced text-mining applications dedicated to patents of the biomedical field remains rare, in particular to address the needs of the pharmaceutical & biotech industry, which intensively uses patent libraries for competitive intelligence and drug development. We describe here the development of an advanced retrieval engine to search information in patent collections in the field of medicinal chemistry. We investigate and combine different strategies and evaluate their respective impact on the performance of the search engine applied to various search tasks, which covers the putatively most frequent search behaviours of intellectual property officers in medical chemistry: 1) a prior art search task; 2) a technical survey task; and 3) a variant of the technical survey task, sometimes called known-item search task, where a single patent is targeted. The optimal tuning of our engine resulted in a top-precision of 6.76% for the prior art search task, 23.28% for the technical survey task and 46.02% for the variant of the technical survey task. We observed that co-citation boosting was an appropriate strategy to improve prior art search tasks, while IPC classification of queries was improving retrieval effectiveness for technical survey tasks. Surprisingly, the use of the full body of the patent was always detrimental for search effectiveness. It was also observed that normalizing biomedical entities using curated dictionaries had simply no impact on the search tasks we evaluate. The search engine was finally implemented as a web-application within Novartis Pharma. The application is briefly described in the report. We have presented the development of a search engine dedicated to patent search, based on state of the art methods applied to patent corpora. We have shown that a proper tuning of the system to adapt to the various search tasks clearly increases the effectiveness of the system. We conclude that different search tasks demand different information retrieval engines' settings in order to yield optimal end-user retrieval.
Development and tuning of an original search engine for patent libraries in medicinal chemistry

PubMed Central

2014-01-01

Background The large increase in the size of patent collections has led to the need of efficient search strategies. But the development of advanced text-mining applications dedicated to patents of the biomedical field remains rare, in particular to address the needs of the pharmaceutical & biotech industry, which intensively uses patent libraries for competitive intelligence and drug development. Methods We describe here the development of an advanced retrieval engine to search information in patent collections in the field of medicinal chemistry. We investigate and combine different strategies and evaluate their respective impact on the performance of the search engine applied to various search tasks, which covers the putatively most frequent search behaviours of intellectual property officers in medical chemistry: 1) a prior art search task; 2) a technical survey task; and 3) a variant of the technical survey task, sometimes called known-item search task, where a single patent is targeted. Results The optimal tuning of our engine resulted in a top-precision of 6.76% for the prior art search task, 23.28% for the technical survey task and 46.02% for the variant of the technical survey task. We observed that co-citation boosting was an appropriate strategy to improve prior art search tasks, while IPC classification of queries was improving retrieval effectiveness for technical survey tasks. Surprisingly, the use of the full body of the patent was always detrimental for search effectiveness. It was also observed that normalizing biomedical entities using curated dictionaries had simply no impact on the search tasks we evaluate. The search engine was finally implemented as a web-application within Novartis Pharma. The application is briefly described in the report. Conclusions We have presented the development of a search engine dedicated to patent search, based on state of the art methods applied to patent corpora. We have shown that a proper tuning of the system to adapt to the various search tasks clearly increases the effectiveness of the system. We conclude that different search tasks demand different information retrieval engines' settings in order to yield optimal end-user retrieval. PMID:24564220
Planning deficits in polysubstance dependent users: Differential associations with severity of drug use and intelligence.

PubMed

Valls-Serrano, C; Verdejo-García, A; Caracuel, A

2016-05-01

Polysubstance use is associated with alterations in different components of executive functioning such as working memory and response inhibition. Nevertheless, less attention has been given to executive planning skills, which are required to benefit of low structured interventions. This study examines the association between severity of use of cocaine, heroin, alcohol, fluid and crystallized intelligence and planning tasks varying on degree of structure. Data were collected from 60 polysubstance users and 30 healthy controls. Cognitive assessment consisted of three planning tasks with different structure levels: Stockings of Cambridge, Zoo Map test, and Multiple Errands Test. Polysubstance users had significant planning deficits across the three tasks compared to healthy controls. Hierarchical regression models showed that severity of drug use and fluid and crystallized intelligence significantly explained performance in all the planning tasks. However, these associations were higher for low-structured real world tasks. These low-structured tasks also showed a unique association with crystallized but not fluid intelligence. Drug abuse is negatively associated with planning abilities, and intelligence is positively associated with planning performance in real-world tasks. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
76 FR 63927 - Interagency Task Force on Antimicrobial Resistance (ITFAR): An Update on A Public Health Action...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-14

... items are organized into four focus areas: Surveillance, Prevention and Control, Research, and Product... of the Action Plan: Surveillance, Prevention and Control, Research, and Product Development. Written... for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), and National Institutes...
Computational Chemistry in the Pharmaceutical Industry: From Childhood to Adolescence.

PubMed

Hillisch, Alexander; Heinrich, Nikolaus; Wild, Hanno

2015-12-01

Computational chemistry within the pharmaceutical industry has grown into a field that proactively contributes to many aspects of drug design, including target selection and lead identification and optimization. While methodological advancements have been key to this development, organizational developments have been crucial to our success as well. In particular, the interaction between computational and medicinal chemistry and the integration of computational chemistry into the entire drug discovery process have been invaluable. Over the past ten years we have shaped and developed a highly efficient computational chemistry group for small-molecule drug discovery at Bayer HealthCare that has significantly impacted the clinical development pipeline. In this article we describe the setup and tasks of the computational group and discuss external collaborations. We explain what we have found to be the most valuable and productive methods and discuss future directions for computational chemistry method development. We share this information with the hope of igniting interesting discussions around this topic. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Developing therapeutic microRNAs for cancer

PubMed Central

Bader, AG; Brown, D; Stoudemire, J; Lammers, P

2014-01-01

Despite substantial progress in understanding the cancer-signaling network, effective therapies remain scarce due to insufficient disruption of oncogenic pathways, drug resistance and drug-induced toxicity. This complexity of cancer defines an urgent goal for researchers and clinicians to develop novel therapeutic strategies. The discovery of microRNAs (miRNAs) provides new hope for accomplishing this task. Supported by solid evidence for a critical role in cancer and bolstered by a unique mechanism of action, miRNAs are likely to yield a new class of targeted therapeutics. In contrast to current cancer medicines, miRNA-based therapies function by subtle repression of gene expression on a yet large number of oncogenic factors and are, therefore, anticipated to be highly efficacious. After the completion of target validation for several candidates, the development of therapeutic miRNAs is now moving to a new stage that involves pharmacological drug delivery, preclinical toxicology and regulatory guidelines. PMID:21633392
Identification of Direct Protein Targets of Small Molecules

PubMed Central

2010-01-01

Small-molecule target identification is a vital and daunting task for the chemical biology community as well as for researchers interested in applying the power of chemical genetics to impact biology and medicine. To overcome this “target ID” bottleneck, new technologies are being developed that analyze protein–drug interactions, such as drug affinity responsive target stability (DARTS), which aims to discover the direct binding targets (and off targets) of small molecules on a proteome scale without requiring chemical modification of the compound. Here, we review the DARTS method, discuss why it works, and provide new perspectives for future development in this area. PMID:21077692
Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

PubMed

Marugán, Carlos; Torres, Raquel; Lallena, María José

2015-01-01

Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.
78 FR 69753 - Exemption of Records Systems Under the Privacy Act

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-21

... Drug Enforcement Task Forces Management Information System (OCDETF MIS) (JUSTICE/OCDETF-001); and (2... to JUSTICE/OCDETF- 001 and renamed as the ``Organized Crime Drug Enforcement Task Forces Management Information System (OCDETF MIS),'' and JUSTICE/CRM-028 has been renumbered to JUSTICE/OCDETF-002 while...
Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.
GalenOWL: Ontology-based drug recommendations discovery

PubMed Central

2012-01-01

Background Identification of drug-drug and drug-diseases interactions can pose a difficult problem to cope with, as the increasingly large number of available drugs coupled with the ongoing research activities in the pharmaceutical domain, make the task of discovering relevant information difficult. Although international standards, such as the ICD-10 classification and the UNII registration, have been developed in order to enable efficient knowledge sharing, medical staff needs to be constantly updated in order to effectively discover drug interactions before prescription. The use of Semantic Web technologies has been proposed in earlier works, in order to tackle this problem. Results This work presents a semantic-enabled online service, named GalenOWL, capable of offering real time drug-drug and drug-diseases interaction discovery. For enabling this kind of service, medical information and terminology had to be translated to ontological terms and be appropriately coupled with medical knowledge of the field. International standards such as the aforementioned ICD-10 and UNII, provide the backbone of the common representation of medical data, while the medical knowledge of drug interactions is represented by a rule base which makes use of the aforementioned standards. Details of the system architecture are presented while also giving an outline of the difficulties that had to be overcome. A comparison of the developed ontology-based system with a similar system developed using a traditional business logic rule engine is performed, giving insights on the advantages and drawbacks of both implementations. Conclusions The use of Semantic Web technologies has been found to be a good match for developing drug recommendation systems. Ontologies can effectively encapsulate medical knowledge and rule-based reasoning can capture and encode the drug interactions knowledge. PMID:23256945
A behavioral economic analysis of the nonmedical use of prescription drugs among young adults.

PubMed

Pickover, Alison M; Messina, Bryan G; Correia, Christopher J; Garza, Kimberly B; Murphy, James G

2016-02-01

The nonmedical use of prescription drugs is a widely recognized public health issue, and young adults are particularly vulnerable to their use. Behavioral economic drug purchase tasks capture an individual's strength of desire and motivation for a particular drug. We examined young adult prescription drug purchase and consumption patterns using hypothetical behavioral economic purchase tasks for prescription sedatives/tranquilizers, stimulants, and opiate pain relievers. We also examined relations between demand, use frequency, and Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) substance use disorder (SUD) symptoms, and sex differences in these relations. Undergraduate students who endorsed past-year prescription drug use (N = 393) completed an online questionnaire for course credit. Measures assessed substance use frequency and DSM-5 SUD symptoms. Hypothetical purchase tasks for sedatives, stimulants, and pain relievers assessed participants' consumption and expenditure patterns for these substances across 25 prices. Past-year prescription sedative, stimulant, and pain reliever use was endorsed by 138, 258, and 189 participants, respectively. Among these users, consumption for their respective substance decreased as a function of ascending price, as expected. Demand indices for a prescription drug were associated with each other and with use frequency and SUD symptoms, with variability across substances but largely not by sex. In addition, demand for prescription pain relievers differentially predicted symptoms independent of use, with differences for females and males. In conclusion, hypothetical consumption and expenditure patterns for prescription drugs were generally well described by behavioral economic demand curves, and the observed associations with use and SUD symptoms provide support for the utility of prescription drug purchase tasks. PsycINFO Database Record (c) 2016 APA, all rights reserved.
Automation of Technology for Cancer Research.

PubMed

van der Ent, Wietske; Veneman, Wouter J; Groenewoud, Arwin; Chen, Lanpeng; Tulotta, Claudia; Hogendoorn, Pancras C W; Spaink, Herman P; Snaar-Jagalska, B Ewa

2016-01-01

Zebrafish embryos can be obtained for research purposes in large numbers at low cost and embryos develop externally in limited space, making them highly suitable for high-throughput cancer studies and drug screens. Non-invasive live imaging of various processes within the larvae is possible due to their transparency during development, and a multitude of available fluorescent transgenic reporter lines.To perform high-throughput studies, handling large amounts of embryos and larvae is required. With such high number of individuals, even minute tasks may become time-consuming and arduous. In this chapter, an overview is given of the developments in the automation of various steps of large scale zebrafish cancer research for discovering important cancer pathways and drugs for the treatment of human disease. The focus lies on various tools developed for cancer cell implantation, embryo handling and sorting, microfluidic systems for imaging and drug treatment, and image acquisition and analysis. Examples will be given of employment of these technologies within the fields of toxicology research and cancer research.
Making America Work. Productive People, Productive Policies. Follow-up Report 1988.

ERIC Educational Resources Information Center

National Governors' Association, Washington, DC.

The National Governors' Association's Making America Work initiative had a dual focus. Five task forces spent a year developing action agendas to address five barriers to self-sufficiency and productivity: teenage pregnancy, adult illiteracy, welfare dependency, alcohol and drug abuse, and dropping out of school. The second phase of the initiative…
Student Task Force: An Experiment in Interdisciplinary Education.

ERIC Educational Resources Information Center

Weiner, Harry

During the first semester of the 1971-72 academic year, students at 7 universities located in urban areas across the U.S. participated in an interdisciplinary program that was designed to help the students develop problem-solving techniques. The particular problem that the students attacked was that of drug addiction. This problem incorporated the…
Identifying adverse drug event information in clinical notes with distributional semantic representations of context.

PubMed

Henriksson, Aron; Kvist, Maria; Dalianis, Hercules; Duneld, Martin

2015-10-01

For the purpose of post-marketing drug safety surveillance, which has traditionally relied on the voluntary reporting of individual cases of adverse drug events (ADEs), other sources of information are now being explored, including electronic health records (EHRs), which give us access to enormous amounts of longitudinal observations of the treatment of patients and their drug use. Adverse drug events, which can be encoded in EHRs with certain diagnosis codes, are, however, heavily underreported. It is therefore important to develop capabilities to process, by means of computational methods, the more unstructured EHR data in the form of clinical notes, where clinicians may describe and reason around suspected ADEs. In this study, we report on the creation of an annotated corpus of Swedish health records for the purpose of learning to identify information pertaining to ADEs present in clinical notes. To this end, three key tasks are tackled: recognizing relevant named entities (disorders, symptoms, drugs), labeling attributes of the recognized entities (negation, speculation, temporality), and relationships between them (indication, adverse drug event). For each of the three tasks, leveraging models of distributional semantics - i.e., unsupervised methods that exploit co-occurrence information to model, typically in vector space, the meaning of words - and, in particular, combinations of such models, is shown to improve the predictive performance. The ability to make use of such unsupervised methods is critical when faced with large amounts of sparse and high-dimensional data, especially in domains where annotated resources are scarce. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Perceptions of Health-Related Community Reentry Challenges among Incarcerated Drug Users in Azerbaijan, Kyrgyzstan, and Ukraine.

PubMed

Rozanova, Julia; Morozova, Olga; Azbel, Lyuba; Bachireddy, Chethan; Izenberg, Jacob M; Kiriazova, Tetiana; Dvoryak, Sergiy; Altice, Frederick L

2018-05-04

Facing competing demands with limited resources following release from prison, people who inject drugs (PWID) may neglect health needs, with grave implications including relapse, overdose, and non-continuous care. We examined the relative importance of health-related tasks after release compared to tasks of everyday life among a total sample of 577 drug users incarcerated in Ukraine, Azerbaijan, and Kyrgyzstan. A proxy measure of whether participants identified a task as applicable (easy or hard) versus not applicable was used to determine the importance of each task. Correlates of the importance of health-related reentry tasks were analyzed using logistic regression, with a parsimonious model being derived using Bayesian lasso method. Despite all participants having substance use disorders and high prevalence of comorbidities, participants in all three countries prioritized finding a source of income, reconnecting with family, and staying out of prison over receiving treatment for substance use disorders, general health conditions, and initiating methadone treatment. Participants with poorer general health were more likely to prioritize treatment for substance use disorders. While prior drug injection and opioid agonist treatment (OAT) correlated with any interest in methadone in all countries, only in Ukraine did a small number of participants prioritize getting methadone as the most important post-release task. While community-based OAT is available in all three countries and prison-based OAT only in Kyrgyzstan, Kyrgyz prisoners were less likely to choose help staying off drugs and getting methadone. Overall, prisoners consider methadone treatment inapplicable to their pre-release planning. Future studies that involve patient decision-making and scale-up of OAT within prison settings are needed to better improve individual and public health.
Device for Investigation of Mechanical Tension of Isolated Smooth Muscle Vessels and Airway Segments of Animals

NASA Astrophysics Data System (ADS)

Aleinik, A.; Karpovich, N.; Turgunova, N.; Nosarev, A.

2016-11-01

For the purpose of testing and the search for new drug compounds, designed to heal many human diseases, it is necessary to investigate the deformation of experimental tissue samples under influence of these drugs. For this task a precision force sensor for measuring the mechanical tension, produced by isolated ring segments of blood vessels and airways was created. The hardware and software systems for the study of changes in contractile responses of the airway smooth muscles and blood vessels of experimental animals was developed.
Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research

PubMed Central

Salamone, John D.; Correa, Merce; Yang, Jen-Hau; Rotolo, Renee; Presby, Rose

2018-01-01

Operant behavior is not only regulated by factors related to the quality or quantity of reinforcement, but also by the work requirements inherent in performing instrumental actions. Moreover, organisms often make effort-related decisions involving economic choices such as cost/benefit analyses. Effort-based decision making is studied using behavioral procedures that offer choices between high-effort options leading to relatively preferred reinforcers vs. low effort/low reward choices. Several neural systems, including the mesolimbic dopamine (DA) system and other brain circuits, are involved in regulating effort-related aspects of motivation. Considerable evidence indicates that mesolimbic DA transmission exerts a bi-directional control over exertion of effort on instrumental behavior tasks. Interference with DA transmission produces a low-effort bias in animals tested on effort-based choice tasks, while increasing DA transmission with drugs such as DA transport blockers tends to enhance selection of high-effort options. The results from these pharmacology studies are corroborated by the findings from recent articles using optogenetic, chemogenetic and physiological techniques. In addition to providing important information about the neural regulation of motivated behavior, effort-based choice tasks are useful for developing animal models of some of the motivational symptoms that are seen in people with various psychiatric and neurological disorders (e.g., depression, schizophrenia, Parkinson’s disease). Studies of effort-based decision making may ultimately contribute to the development of novel drug treatments for motivational dysfunction. PMID:29628879
Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research.

PubMed

Salamone, John D; Correa, Merce; Yang, Jen-Hau; Rotolo, Renee; Presby, Rose

2018-01-01

Operant behavior is not only regulated by factors related to the quality or quantity of reinforcement, but also by the work requirements inherent in performing instrumental actions. Moreover, organisms often make effort-related decisions involving economic choices such as cost/benefit analyses. Effort-based decision making is studied using behavioral procedures that offer choices between high-effort options leading to relatively preferred reinforcers vs. low effort/low reward choices. Several neural systems, including the mesolimbic dopamine (DA) system and other brain circuits, are involved in regulating effort-related aspects of motivation. Considerable evidence indicates that mesolimbic DA transmission exerts a bi-directional control over exertion of effort on instrumental behavior tasks. Interference with DA transmission produces a low-effort bias in animals tested on effort-based choice tasks, while increasing DA transmission with drugs such as DA transport blockers tends to enhance selection of high-effort options. The results from these pharmacology studies are corroborated by the findings from recent articles using optogenetic, chemogenetic and physiological techniques. In addition to providing important information about the neural regulation of motivated behavior, effort-based choice tasks are useful for developing animal models of some of the motivational symptoms that are seen in people with various psychiatric and neurological disorders (e.g., depression, schizophrenia, Parkinson's disease). Studies of effort-based decision making may ultimately contribute to the development of novel drug treatments for motivational dysfunction.
Virtual screening for development of new effective compounds against Staphylococcus aureus.

PubMed

Diniz, Roseane Costa; Soares, Lucas Weba; da Silva, Luis Claudio Nascimento

2018-03-26

Staphylococcus aureus is a notorious pathogenic bacterium causing a wide range of diseases from soft-tissue contamination, to more serious and deep-seated infections. This species is highlighted by its ability to express several kinds of virulence factors and to acquire genes related to drug resistance. Target this number of factors to design any drug is not an easy task. In this review we discuss the importance of computational methods to impulse the development of new drugs against S. aureus. The application of docking methods to screen large library of natural or synthetic compounds and to provide insights into action mechanisms is demonstrated. Particularly, highlighted the studies that validated in silico results with biochemical and microbiological assays. We also comment the computer-aided design of new molecules using some known inhibitors. The confirmation of in silico results with biochemical and microbiological assays allowed the identification of lead molecules that could be used for drug design such as rhodomyrtone, quinuclidine, berberine (and their derivative compounds). The fast development in the computational methods is essential to improve our ability to discovery new drugs, as well as to expand understanding about drug-target interactions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Identification of G-Protein-Coupled Receptors (GPCRs) in Pulmonary Artery Smooth Muscle Cells as Novel Therapeutic Targets

DTIC Science & Technology

2017-10-01

available pharmacological agents (in particular, for which FDA-approved drugs exist) and that we predict have a pathophysiological impact. The Sub-tasks...on the responses to a known receptor agonist. To be completed by 8/2018. 3e. Pending results of studies in Sub-tasks 2-4, test ability of drugs ...cardiac and lung fibroblasts as possible drug targets for tissue fibrosis. R21AG053568 (PI: P. Insel) 9/30/2016-4/30/2018
Relating Human Genetic Variation to Variation in Drug Responses

PubMed Central

Madian, Ashraf G.; Wheeler, Heather E.; Jones, Richard Baker; Dolan, M. Eileen

2012-01-01

Although sequencing a single human genome was a monumental effort a decade ago, more than one thousand genomes have now been sequenced. The task ahead lies in transforming this information into personalized treatment strategies that are tailored to the unique genetics of each individual. One important aspect of personalized medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses. Additionally, we discuss the major challenges in translating this knowledge into a systems-level understanding of drug physiology with the ultimate goal of developing more effective personalized clinical treatment strategies. PMID:22840197
Development and Testing of a Smartphone-Based Cognitive/Neuropsychological Evaluation System for Substance Abusers.

PubMed

Pal, Reshmi; Mendelson, John; Clavier, Odile; Baggott, Mathew J; Coyle, Jeremy; Galloway, Gantt P

2016-01-01

In methamphetamine (MA) users, drug-induced neurocognitive deficits may help to determine treatment, monitor adherence, and predict relapse. To measure these relationships, we developed an iPhone app (Neurophone) to compare lab and field performance of N-Back, Stop Signal, and Stroop tasks that are sensitive to MA-induced deficits. Twenty healthy controls and 16 MA-dependent participants performed the tasks in-lab using a validated computerized platform and the Neurophone before taking the latter home and performing the tasks twice daily for two weeks. N-Back task: there were no clear differences in performance between computer-based vs. phone-based in-lab tests and phone-based in-lab vs. phone-based in-field tests. Stop-Signal task: difference in parameters prevented comparison of computer-based and phone-based versions. There was significant difference in phone performance between field and lab. Stroop task: response time measured by the speech recognition engine lacked precision to yield quantifiable results. There was no learning effect over time. On an average, each participant completed 84.3% of the in-field NBack tasks and 90.4% of the in-field Stop Signal tasks (MA-dependent participants: 74.8% and 84.3%; healthy controls: 91.4% and 95.0%, respectively). Participants rated Neurophone easy to use. Cognitive tasks performed in-field using Neurophone have the potential to yield results comparable to those obtained in a laboratory setting. Tasks need to be modified for use as the app's voice recognition system is not yet adequate for timed tests.
Developmental Changes in the Mother-Child Interactions of Hyperactive Boys: Effects of Two Dose Levels of Ritalin.

ERIC Educational Resources Information Center

Barkley, Russell A.; And Others

1985-01-01

Mother/child interactions of 60 hyperactive children 5, 6, 7, 8 and 9 years of age were studied during free play and task periods. Significant age effects and several drug effects were found in the task period. Drug effects were essentially the same across all five age levels. (Author/RH)
The subtype-selective nicotinic acetylcholine receptor agonist SIB-1553A improves both attention and memory components of a spatial working memory task in chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys.

PubMed

Schneider, J S; Tinker, J P; Menzaghi, F; Lloyd, G K

2003-07-01

Monkeys that receive chronic low dose (CLD) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration develop deficits in spatial delayed-response task performance. The present study examined the extent to which SIB-1553A [(+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride], a novel neuronal nicotinic acetylcholine receptor (nAChR) agonist with selectivity for beta4 subunit-containing nAChRs, could counteract this cognitive deficit produced by CLD MPTP exposure. Prior to MPTP treatment, monkeys displayed a delay-dependent decrement in performance on a variable delayed response task. CLD MPTP treatment caused a shift to a delay-independent pattern of responding on this task, such that short-delay trials were performed as poorly as long-delay trials. At lower doses (e.g., 0.025 mg/kg), SIB-1553A significantly improved performance on short-delay trials but only at 24 h after drug administration. At higher doses (e.g., 0.50 mg/kg), SIB-1553A significantly improved performance on both short- and long-delay trials at both 20 min and 24 h after drug administration. When tested 24 h after drug administration, monkeys performed long-delay trials with greater accuracy than they did under normal (pre-MPTP) conditions. These results suggest that at lower doses, SIB-1553A may be more effective in improving attentional deficits associated with CLD MPTP exposure, whereas at higher doses, SIB-1553A may effectively improve both attentional and memory performance.
Prescription opioid misusing chronic pain patients exhibit dysregulated context-dependent associations: Investigating associative learning in addiction with the cue-primed reactivity task.

PubMed

Garland, Eric L; Bryan, Craig J; Kreighbaum, Lydia; Nakamura, Yoshio; Howard, Matthew O; Froeliger, Brett

2018-06-01

Associative learning undergirds the development of addiction, such that drug-related cues serve as conditioned stimuli to elicit drug-seeking responses. Plausibly, among opioid misusing chronic pain patients, pain-related information may serve as a conditioned stimulus to magnify opioid cue-elicited autonomic and craving responses through a process of second-order conditioning. We utilized a novel psychophysiological probe of pain-opioid conditioned associations, the Cue-Primed Reactivity (CPR) task. In this task, participants were presented with images as primes (200 ms) and cues (6000 ms) in pairs organized in four task blocks: "control-opioid," "pain-opioid," "control-pain," and "opioid-pain." Opioid-treated chronic pain patients (N = 30) recruited from an Army base in the Western United States were classified as opioid misusers (n = 17) or non-misusers (n = 13) via a validated cutpoint on the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 2008). Opioid misuse status was examined as a predictor of HRV, craving, and mood responses on the CPR task. HRV increased to a greater extent during the pain-opioid block compared to the control-opioid block for non-misusers compared to misusers (p = .003, η 2 partial  = 0.27). In contrast, craving increased to a greater extent from baseline to the pain-opioid block for misusers than for non-misusers (p = .03, η 2 partial  = .16). Findings suggest that opioid-treated chronic pain patients exhibit Pavlovian conditioned responses to opioid cues strengthened by an associative learning process of second-order conditioning when primed by pain-related images. This pain-opioid contingency appears to become disrupted among individuals who engage in opioid misuse, such that opioid-related stimuli elicit motivational responses irrespective of pain-related contextual stimuli. Copyright © 2018 Elsevier B.V. All rights reserved.
New Developments in the Field of Reaction Technology: The Multiparallel Reactor HPMR 50-96

PubMed Central

Allwardt, Arne; Wendler, Christian; Thurow, Kerstin

2005-01-01

Catalytic high-pressure reactions play an important role in classic bulk chemistry. The optimization of common reactions, the search for new and more effective catalysts, and the increasing use of catalytic pressure reactions in the field of drug development call for high-parallel reaction systems. A crucial task of current developments, apart from the parameters of pressure, temperature, and number of reaction chambers, is, in this respect, the systems' integration into complex laboratory automation environments. PMID:18924722
Driving Neurofibroma Formation in Mice

DTIC Science & Technology

2006-08-01

pirfenidone . Ratner, Nancy DAMD17-02-1-0679 5 BODY Task 1: Analysis of EGFR-expressing mouse. a. Define abnormalities in...EGFR-overexpressing mouse nerves (Year 1). b. Evaluate effects of: a specific EGFR receptor antagonist and c. an anti-fibrotic drug, pirfenidone ...considered significant. Task 1c, In Progress: Evaluate effects of an anti-fibrotic drug, pirfenidone . Our move to the Children’s Hospital Research
Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task.

PubMed

Goldstein, Rita Z; Woicik, Patricia A; Maloney, Thomas; Tomasi, Dardo; Alia-Klein, Nelly; Shan, Juntian; Honorio, Jean; Samaras, Dimitris; Wang, Ruiliang; Telang, Frank; Wang, Gene-Jack; Volkow, Nora D

2010-09-21

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.
Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldstein, R.Z.; Goldstein, R.Z.; Woicik, P.A.

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function)more » in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.« less
Probabilistic Reward- and Punishment-based Learning in Opioid Addiction: Experimental and Computational Data

PubMed Central

Myers, Catherine E.; Sheynin, Jony; Baldson, Tarryn; Luzardo, Andre; Beck, Kevin D.; Hogarth, Lee; Haber, Paul; Moustafa, Ahmed A.

2016-01-01

Addiction is the continuation of a habit in spite of negative consequences. A vast literature gives evidence that this poor decision-making behavior in individuals addicted to drugs also generalizes to laboratory decision making tasks, suggesting that the impairment in decision-making is not limited to decisions about taking drugs. In the current experiment, opioid-addicted individuals and matched controls with no history of illicit drug use were administered a probabilistic classification task that embeds both reward-based and punishment-based learning trials, and a computational model of decision making was applied to understand the mechanisms describing individuals’ performance on the task. Although behavioral results showed thatopioid-addicted individuals performed as well as controls on both reward- and punishment-based learning, the modeling results suggested subtle differences in how decisions were made between the two groups. Specifically, the opioid-addicted group showed decreased tendency to repeat prior responses, meaning that they were more likely to “chase reward” when expectancies were violated, whereas controls were more likely to stick with a previously-successful response rule, despite occasional expectancy violations. This tendency to chase short-term reward, potentially at the expense of developing rules that maximize reward over the long term, may be a contributing factor to opioid addiction. Further work is indicated to better understand whether this tendency arises as a result of brain changes in the wake of continued opioid use/abuse, or might be a pre-existing factor that may contribute to risk for addiction. PMID:26381438
Prefrontal activation during inhibitory control measured by near-infrared spectroscopy for differentiating between autism spectrum disorders and attention deficit hyperactivity disorder in adults.

PubMed

Ishii-Takahashi, Ayaka; Takizawa, Ryu; Nishimura, Yukika; Kawakubo, Yuki; Kuwabara, Hitoshi; Matsubayashi, Junko; Hamada, Kasumi; Okuhata, Shiho; Yahata, Noriaki; Igarashi, Takashi; Kawasaki, Shingo; Yamasue, Hidenori; Kato, Nobumasa; Kasai, Kiyoto; Kano, Yukiko

2014-01-01

The differential diagnosis of autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) based solely on symptomatic and behavioral assessments can be difficult, even for experts. Thus, the development of a neuroimaging marker that differentiates ASDs from ADHD would be an important contribution to this field. We assessed the differences in prefrontal activation between adults with ASDs and ADHD using an entirely non-invasive and portable neuroimaging tool, near-infrared spectroscopy. This study included 21 drug-naïve adults with ASDs, 19 drug-naïve adults with ADHD, and 21 healthy subjects matched for age, sex, and IQ. Oxygenated hemoglobin concentration changes in the prefrontal cortex were assessed during a stop signal task and a verbal fluency task. During the stop signal task, compared to the control group, the ASDs group exhibited lower activation in a broad prefrontal area, whereas the ADHD group showed underactivation of the right premotor area, right presupplementary motor area, and bilateral dorsolateral prefrontal cortices. Significant differences were observed in the left ventrolateral prefrontal cortex between the ASDs and ADHD groups during the stop signal task. The leave-one-out cross-validation method using mean oxygenated hemoglobin changes yielded a classification accuracy of 81.4% during inhibitory control. These results were task specific, as the brain activation pattern observed during the verbal fluency task did not differentiate the ASDs and ADHD groups significantly. This study therefore provides evidence of a difference in left ventrolateral prefrontal activation during inhibitory control between adults with ASDs and ADHD. Thus, near-infrared spectroscopy may be useful as an auxiliary tool for the differential diagnosis of such developmental disorders.
Ad hoc versus standardized admixtures for continuous infusion drugs in neonatal intensive care: cognitive task analysis of safety at the bedside.

PubMed

Brannon, Timothy S

2006-01-01

Continuous infusion intravenous (IV) drugs in neonatal intensive care are usually prepared based on patient weight so that the dose is readable as a simple multiple of the infusion pump rate. New safety guidelines propose that hospitals switch to using standardized admixtures of these drugs to prevent calculation errors during ad hoc preparation. Extended hierarchical task analysis suggests that switching to standardized admixtures may lead to more errors in programming the pump at the bedside.
Ad Hoc versus Standardized Admixtures for Continuous Infusion Drugs in Neonatal Intensive Care: Cognitive Task Analysis of Safety at the Bedside

PubMed Central

Brannon, Timothy S.

2006-01-01

Continuous infusion intravenous (IV) drugs in neonatal intensive care are usually prepared based on patient weight so that the dose is readable as a simple multiple of the infusion pump rate. New safety guidelines propose that hospitals switch to using standardized admixtures of these drugs to prevent calculation errors during ad hoc preparation. Extended hierarchical task analysis suggests that switching to standardized admixtures may lead to more errors in programming the pump at the bedside. PMID:17238482
Sex differences in guanfacine effects on stress-induced stroop performance in cocaine dependence.

PubMed

Milivojevic, Verica; Fox, Helen C; Jayaram-Lindstrom, Nitya; Hermes, Gretchen; Sinha, Rajita

2017-10-01

Chronic drug abuse leads to sex-specific changes in drug cue and stress physiologic and neuroendocrine reactivity as well as in neural responses to stress and cue-related challenges and in executive function such as inhibitory control, cognitive flexibility and self control. Importantly, these functions have been associated with high risk of relapse and treatment. Alpha-2 agonism may enhance inhibitory cognitive processes in the face of stress with sex-specific effects, however this has not been previously assessed in cocaine dependence. Forty inpatient treatment-seeking cocaine dependent individuals (13F/27M) were randomly assigned to receive either placebo or up to 3mgs of Guanfacine. Three laboratory sessions were conducted following 3-4 weeks of abstinence, where patients were exposed to three 10-min personalized guided imagery conditions (stress, drug cue, combined stress/cue), one per day, on consecutive days in a random, counterbalanced order. The Stroop task was administered at baseline and immediately following imagery exposure. Guanfacine treated women improved their performance on the Stroop task following exposure to all 3 imagery conditions compared with placebo women (p=0.02). This improvement in cognitive inhibitory performance was not observed in the men. Enhancing the ability to cognitively regulate in the face of stress, drug cues and combined stress and drug cue reactivity may be key targets for medications development in cocaine dependent women. Copyright © 2017 Elsevier B.V. All rights reserved.

Facilitating adverse drug event detection in pharmacovigilance databases using molecular structure similarity: application to rhabdomyolysis

PubMed Central

Vilar, Santiago; Harpaz, Rave; Chase, Herbert S; Costanzi, Stefano; Rabadan, Raul

2011-01-01

Background Adverse drug events (ADE) cause considerable harm to patients, and consequently their detection is critical for patient safety. The US Food and Drug Administration maintains an adverse event reporting system (AERS) to facilitate the detection of ADE in drugs. Various data mining approaches have been developed that use AERS to detect signals identifying associations between drugs and ADE. The signals must then be monitored further by domain experts, which is a time-consuming task. Objective To develop a new methodology that combines existing data mining algorithms with chemical information by analysis of molecular fingerprints to enhance initial ADE signals generated from AERS, and to provide a decision support mechanism to facilitate the identification of novel adverse events. Results The method achieved a significant improvement in precision in identifying known ADE, and a more than twofold signal enhancement when applied to the ADE rhabdomyolysis. The simplicity of the method assists in highlighting the etiology of the ADE by identifying structurally similar drugs. A set of drugs with strong evidence from both AERS and molecular fingerprint-based modeling is constructed for further analysis. Conclusion The results demonstrate that the proposed methodology could be used as a pharmacovigilance decision support tool to facilitate ADE detection. PMID:21946238
Rational drug therapy education in clinical phase carried out by task-based learning

PubMed Central

Bilge, S. Sırrı; Akyüz, Bahar; Ağrı, Arzu Erdal; Özlem, Mıdık

2017-01-01

Objectives: Irrational drug use results in drug interactions, treatment noncompliance, and drug resistance. Rational pharmacotherapy education is being implemented in many faculties of medicine. Our aim is to introduce rational pharmacotherapy education by clinicians and to evaluate task-based rational drug therapy education in the clinical context. Methods: The Kirkpatrick's evaluation model was used for the evaluation of the program. The participants evaluated the program in terms of constituents of the program, utilization, and contribution to learning. Voluntary participants responded to the evaluation forms after the educational program. Data are evaluated using both quantitative and qualitative tools. SPSS (version 21) used for quantitative data for determining mean and standard deviation values. Descriptive qualitative analysis approach is used for the analysis of open-ended questions. Results: It was revealed that the program and its components have been favorable. A total 95.9% of the students consider the education to be beneficial. Simulated patients practice and personal drug choice/problem-based learning sessions were appreciated by the students in particular. 93.9% of the students stated that all students of medicine should undergo this educational program. Among the five presentations contained in the program, “The Principles of Prescribing” received the highest points (9 ± 1.00) from participating students in general evaluation of the educational program. Conclusion: This study was carried out to improve task-based rational drug therapy education. According to feedback from the students concerning content, method, resource, assessment, and program design; some important changes, especially in number of facilitators and indications, are made in rational pharmacotherapy education in clinical task-based learning program. PMID:28458432
The development of biomarkers to reduce attrition rate in drug discovery focused on oncology and central nervous system.

PubMed

Safavi, Maliheh; Sabourian, Reyhaneh; Abdollahi, Mohammad

2016-10-01

The task of discovery and development of novel therapeutic agents remains an expensive, uncertain, time-consuming, competitive, and inefficient enterprise. Due to a steady increase in the cost and time of drug development and the considerable amount of resources required, a predictive tool is needed for assessing the safety and efficacy of a new chemical entity. This study is focused on the high attrition rate in discovery and development of oncology and central nervous system (CNS) medicines, because the failure rate of these medicines is higher than others. Some approaches valuable in reducing attrition rates are proposed and the judicious use of biomarkers is discussed. Unlike the significant progress made in identifying and characterizing novel mechanisms of disease processes and targeted therapies, the process of novel drug development is associated with an unacceptably high attrition rate. The application of clinically qualified predictive biomarkers holds great promise for further development of therapeutic targets, improved survival, and ultimately personalized medicine sets for patients. Decisions such as candidate selection, development risks, dose ranging, early proof of concept/principle, and patient stratification are based on the measurements of biologically and/or clinically validated biomarkers.
Delivery of Cancer Therapeutics Using Nanotechnology

PubMed Central

Lim, Eun-Kyung; Jang, Eunji; Lee, Kwangyeol; Haam, Seungjoo; Huh, Yong-Min

2013-01-01

Nanoparticles have been investigated as drug carriers, because they provide a great opportunity due to their advantageous features: (i) various formulations using organic/inorganic materials, (ii) easy modification of targeting molecules, drugs or other molecules on them, (iii) effective delivery to target sites, resulting in high therapeutic efficacy and (iv) controlling drug release by external/internal stimuli. Because of these features, therapeutic efficacy can be improved and unwanted side effects can be reduced. Theranostic nanoparticles have been developed by incorporating imaging agents in drug carriers as all-in-one system, which makes it possible to diagnose and treat cancer by monitoring drug delivery behavior simultaneously. Recently, stimuli-responsive, activatable nanomaterials are being applied that are capable of producing chemical or physical changes by external stimuli. By using these nanoparticles, multiple tasks can be carried out simultaneously, e.g., early and accurate diagnosis, efficient cataloguing of patient groups of personalized therapy and real-time monitoring of disease progress. In this paper, we describe various types of nanoparticles for drug delivery systems, as well as theranostic systems. PMID:24300452
Drug-Target Interaction Prediction through Label Propagation with Linear Neighborhood Information.

PubMed

Zhang, Wen; Chen, Yanlin; Li, Dingfang

2017-11-25

Interactions between drugs and target proteins provide important information for the drug discovery. Currently, experiments identified only a small number of drug-target interactions. Therefore, the development of computational methods for drug-target interaction prediction is an urgent task of theoretical interest and practical significance. In this paper, we propose a label propagation method with linear neighborhood information (LPLNI) for predicting unobserved drug-target interactions. Firstly, we calculate drug-drug linear neighborhood similarity in the feature spaces, by considering how to reconstruct data points from neighbors. Then, we take similarities as the manifold of drugs, and assume the manifold unchanged in the interaction space. At last, we predict unobserved interactions between known drugs and targets by using drug-drug linear neighborhood similarity and known drug-target interactions. The experiments show that LPLNI can utilize only known drug-target interactions to make high-accuracy predictions on four benchmark datasets. Furthermore, we consider incorporating chemical structures into LPLNI models. Experimental results demonstrate that the model with integrated information (LPLNI-II) can produce improved performances, better than other state-of-the-art methods. The known drug-target interactions are an important information source for computational predictions. The usefulness of the proposed method is demonstrated by cross validation and the case study.
Profile of Executive and Memory Function Associated with Amphetamine and Opiate Dependence

PubMed Central

Ersche, Karen D; Clark, Luke; London, Mervyn; Robbins, Trevor W; Sahakian, Barbara J

2007-01-01

Cognitive function was assessed in chronic drug users on neurocognitive measures of executive and memory function. Current amphetamine users were contrasted with current opiate users, and these two groups were compared with former users of these substances (abstinent for at least one year). Four groups of participants were recruited: amphetamine-dependent individuals, opiate-dependent individuals, former users of amphetamines, and/or opiates and healthy non-drug taking controls. Participants were administered the Tower of London (TOL) planning task and the 3D-IDED attentional set-shifting task to assess executive function, and Paired Associates Learning and Delayed Pattern Recognition Memory tasks to assess visual memory function. The three groups of substance users showed significant impairments on TOL planning, Pattern Recognition Memory and Paired Associates Learning. Current amphetamine users displayed a greater degree of impairment than current opiate users. Consistent with previous research showing that healthy men are performing better on visuo-spatial tests than women, our male controls remembered significantly more paired associates than their female counterparts. This relationship was reversed in drug users. While performance of female drug users was normal, male drug users showed significant impairment compared to both their female counterparts and male controls. There was no difference in performance between current and former drug users. Neither years of drug abuse nor years of drug abstinence were associated with performance. Chronic drug users display pronounced neuropsychological impairment in the domains of executive and memory function. Impairment persists after several years of drug abstinence and may reflect neuropathology in frontal and temporal cortices. PMID:16160707
Recent developments of functional magnetic resonance imaging research for drug development in Alzheimer's disease.

PubMed

Hampel, Harald; Prvulovic, David; Teipel, Stefan J; Bokde, Arun L W

2011-12-01

The objective of this review is to evaluate recent advances in functional magnetic resonance imaging (fMRI) research in Alzheimer's disease for the development of therapeutic agents. The basic building block underpinning cognition is a brain network. The measured brain activity serves as an integrator of the various components, from genes to structural integrity, that impact the function of networks underpinning cognition. Specific networks can be interrogated using cognitive paradigms such as a learning task or a working memory task. In addition, recent advances in our understanding of neural networks allow one to investigate the function of a brain network by investigating the inherent coherency of the brain networks that can be measured during resting state. The coherent resting state networks allow testing in cognitively impaired patients that may not be possible with the use of cognitive paradigms. In particular the default mode network (DMN) includes the medial temporal lobe and posterior cingulate, two key regions that support episodic memory function and are impaired in the earliest stages of Alzheimer's disease (AD). By investigating the effects of a prospective drug compound on this network, it could illuminate the specificity of the compound with a network supporting memory function. This could provide valuable information on the methods of action at physiological and behaviourally relevant levels. Utilizing fMRI opens up new areas of research and a new approach for drug development, as it is an integrative tool to investigate entire networks within the brain. The network based approach provides a new independent method from previous ones to translate preclinical knowledge into the clinical domain. Copyright © 2011 Elsevier Ltd. All rights reserved.
[Pulmonary hypertension: the future has begun].

PubMed

Olschewski, Horst

2006-04-15

In recent years, pulmonary hypertension got into the focus of research due to the development of efficacious medications and the discovery of important pathologic mechanisms of disease. Currently, prostanoids, endothelin receptor antagonists and phosphodiesterase 5 inhibitors are the most important substance groups used for treatment. Substances that are emerging in tumor therapy (tyrosine kinase inhibitors, epidermal growth factor [EGF] und platelet-derived growth factor [PDGF] receptor blockers), vasoactive intestinal peptide (VIP), rho-kinase inhibitors and targeted drugs for endothelial dysfunction will be evaluated as future drugs for pulmonary hypertension. Improving early diagnosis of pulmonary hypertension will be an important task in the future. Both the development of diagnostic methods with increased sensitivity and specificity and a broad awareness program will be necessary to achieve this goal.
Effects of low to moderate acute doses of pramipexole on impulsivity and cognition in healthy volunteers.

PubMed

Hamidovic, Ajna; Kang, Un Jung; de Wit, Harriet

2008-02-01

The neurotransmitter dopamine is integrally involved in the rewarding effects of drugs, and it has also been thought to mediate impulsive behaviors in animal models. Most of the studies of drug effects on impulsive behaviors in humans have involved drugs with complex actions on different transmitter systems and different receptor subtypes. The present study was designed to characterize the effect of single doses of pramipexole, a D2/D3 agonist, on measures of cognitive and impulsive behavior, as well as on mood in healthy volunteers. Healthy men and women (N = 10) received placebo and 2 doses of pramipexole, 0.25 and 0.50 mg, in a within-subject, double-blinded study. Outcome measures included changes in cognitive performance, assessed by the Automated Neuropsychological Assessment Metrics, several behavioral measures related to impulsive behavior, including the Balloon Analogue Risk Task, Delay Discounting Task, Go/No-Go Task, Card Perseveration Task, and subjective ratings of mood assessed by Addiction Research Center Inventory, Profile of Mood States, and Drug Effects Questionnaire. Pramipexole decreased positive ratings of mood (euphoria, intellectual efficiency, and energy) and increased both subjectively reported sedation and behavioral sedation indicated by impaired cognitive performance on several measures of the Automated Neuropsychological Assessment Metrics. Single low to medium doses of this drug did not produce a decrease in impulsive responding on behavioral measures included in this study. The sedative-like effects observed in this study may reflect presynaptic actions of the drug. Higher doses with postsynaptic actions may be needed to produce either behavioral or subjective stimulant-like effects.
Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs.

PubMed

Gualtieri, Fulvio; Manetti, Dina; Romanelli, Maria Novella; Ghelardini, Carla

2002-01-01

Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies. Development of cognition enhancers is still a difficult task because of complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. After the early serendipitous discovery of first generation cognition enhancers, current research is based on a variety of working hypotheses, derived from the progress of knowledge in the neurobiopathology of cognitive processes. Among other classes of drugs, piracetam-like cognition enhancers (nootropics) have never reached general acceptance, in spite of their excellent tolerability and safety. In the present review, after a general discussion of the problems connected with the design and development of cognition enhancers, the class is examined in more detail. Reasons for the problems encountered by nootropics, compounds therapeutically available and those in development, their structure activity relationships and mechanisms of action are discussed. Recent developments which hopefully will lead to a revival of the class are reviewed.
Initial Development of an E-cigarette Purchase Task: A Mixed Methods Study

PubMed Central

Cassidy, Rachel N.; Tidey, Jennifer W.; Colby, Suzanne M.; Long, Victoria; Higgins, Stephen T.

2017-01-01

Objectives Behavioral economic purchase tasks, which estimate demand for drugs, have been successfully developed for cigarettes and are widely used. However, a validated purchase task does not yet exist for e-cigarettes. The aim of this project was to identify the relevant units for an e-cigarette purchase task (E-CPT). Methods Focus groups (N=28 participants in 7 groups, 2-7 participants per group) consisting of current e-cigarette users were conducted. Participants discussed their daily use patterns, completed a preliminary E-CPT which asked how many puffs of their e-cigarette they would consume per day at escalating prices, and discussed the extent to which the task accurately reflected their real-world behavior. Groups were recorded and transcribed; analysis focused on statements related to daily consumption and the E-CPT. Results Participants were unlikely to quantify their daily use in terms of puffs, and perceptions about the appropriate unit for an E-CPT varied across device type. Users of first-generation devices (eg, cigalikes) reported that the relevant unit was the individual device/cartridge; however, participants who purchased nicotine liquid for their device emphasized that e-liquid volume in milliliters would better reflect their use. Conclusions Multiple versions of the E-CPT may be necessary to provide valid measures of e-cigarette demand. PMID:28824938
Low Striatal Dopamine D2-type Receptor Availability is Linked to Simulated Drug Choice in Methamphetamine Users.

PubMed

Moeller, Scott J; Okita, Kyoji; Robertson, Chelsea L; Ballard, Michael E; Konova, Anna B; Goldstein, Rita Z; Mandelkern, Mark A; London, Edythe D

2018-03-01

Individuals with drug use disorders seek drugs over other rewarding activities, and exhibit neurochemical deficits related to dopamine, which is involved in value-based learning and decision-making. Thus, a dopaminergic disturbance may underpin drug-biased choice in addiction. Classical drug-choice assessments, which offer drug-consumption opportunities, are inappropriate for addicted individuals seeking treatment or abstaining. Fifteen recently abstinent methamphetamine users and 15 healthy controls completed two laboratory paradigms of 'simulated' drug choice (choice for drug-related vs affectively pleasant, unpleasant, and neutral images), and underwent positron emission tomography measurements of dopamine D2-type receptor availability, indicated by binding potential (BP ND ) for [ 18 F]fallypride. Thirteen of the methamphetamine users and 10 controls also underwent [ 11 C]NNC112 PET scans to measure dopamine D1-type receptor availability. Group analyses showed that, compared with controls, methamphetamine users chose to view more methamphetamine-related images on one task, with a similar trend on the second task. Regression analyses showed that, on both tasks, the more methamphetamine users chose to view methamphetamine images, specifically vs pleasant images (the most frequently chosen images across all participants), the lower was their D2-type BP ND in the lateral orbitofrontal cortex, an important region in value-based choice. No associations were observed with D2-type BP ND in striatal regions, or with D1-type BP ND in any region. These results identify a neurochemical correlate for a laboratory drug-seeking paradigm that can be administered to treatment-seeking and abstaining drug-addicted individuals. More broadly, these results refine the central hypothesis that dopamine-system deficits contribute to drug-biased decision-making in addiction, here showing a role for the orbitofrontal cortex.
A day in the life of a pharmacovigilance case processor.

PubMed

Bhangale, Ritesh; Vaity, Sayali; Kulkarni, Niranjan

2017-01-01

Pharmacovigilance (PV) has grown significantly in India in the last couple of decades. The etymological roots for the word "pharmacovigilance" are "Pharmakon" (Greek for drug) and "Vigilare" (Latin for to keep watch). It relies on information gathered from the collection of individual case safety reports and other pharmacoepidemiological data. The PV data processing cycle starts with data collection in computerized systems followed by complete data entry which includes adverse event coding, drug coding, causality and expectedness assessment, narrative writing, quality control, and report submissions followed by data storage and maintenance. A case processor plays an important role in conducting these various tasks. The case processor should also manage drug safety information, possess updated knowledge about global drug safety regulations, summarize clinical safety data, participate in meetings, write narratives with medical input from a physician, report serious adverse events to the regulatory authorities, participate in the training of operational staff on drug safety issues, quality control work of other staff in the department, and take on any other task as assigned by the manager or medical director within the capabilities of the drug safety associate. There can be challenges while handling all these tasks at a time, hence the associate will have to maintain a balance to overcome them and keep on updating their knowledge on drug safety regulations, which in turn, would help in increasing their learning curve.
Deficits of long-term memory in ecstasy users are related to cognitive complexity of the task.

PubMed

Brown, John; McKone, Elinor; Ward, Jeff

2010-03-01

Despite animal evidence that methylenedioxymethamphetamine (ecstasy) causes lasting damage in brain regions related to long-term memory, results regarding human memory performance have been variable. This variability may reflect the cognitive complexity of the memory tasks. However, previous studies have tested only a limited range of cognitive complexity. Furthermore, comparisons across different studies are made difficult by regional variations in ecstasy composition and patterns of use. The objective of this study is to evaluate ecstasy-related deficits in human verbal memory over a wide range of cognitive complexity using subjects drawn from a single geographical population. Ecstasy users were compared to non-drug using controls on verbal tasks with low cognitive complexity (stem completion), moderate cognitive complexity (stem-cued recall and word list learning) and high cognitive complexity (California Verbal Learning Test, Verbal Paired Associates and a novel Verbal Triplet Associates test). Where significant differences were found, both groups were also compared to cannabis users. More cognitively complex memory tasks were associated with clearer ecstasy-related deficits than low complexity tasks. In the most cognitively demanding task, ecstasy-related deficits remained even after multiple learning opportunities, whereas the performance of cannabis users approached that of non-drug using controls. Ecstasy users also had weaker deliberate strategy use than both non-drug and cannabis controls. Results were consistent with the proposal that ecstasy-related memory deficits are more reliable on tasks with greater cognitive complexity. This could arise either because such tasks require a greater contribution from the frontal lobe or because they require greater interaction between multiple brain regions.
Dopaminergic modulation of multi-muscle synergies in postural tasks performed by patients with Parkinson’s disease

PubMed Central

Falaki, Ali; Huang, Xuemei; Lewis, Mechelle M.; Latash, Mark L.

2017-01-01

Background Postural instability is one of most disabling motor symptoms in Parkinson’s disease. Indices of multi-muscle synergies are new measurements of postural stability. Objectives We explored the effects of dopamine-replacement drugs on multi-muscle synergies stabilizing center of pressure coordinate and their adjustments prior to a self-triggered perturbation in patients with Parkinson’s disease. We hypothesized that both synergy indices and synergy adjustments would be improved on dopaminergic drugs. Methods Patients at Hoehn-Yahr stages II and III performed whole-body tasks both off- and on-drugs while standing. Muscle modes were identified as factors in the muscle activation space. Synergy indices stabilizing center of pressure in the anterior-posterior direction were quantified in the muscle mode space during a load-release task. Results Dopamine-replacement drugs led to more consistent organization of muscles in stable groups (muscle modes). On-drugs patients showed larger indices of synergies and anticipatory synergy adjustments. In contrast, no medication effects were seen on anticipatory postural adjustments or other performance indices. Conclusions Dopamine-replacement drugs lead to significant changes in characteristics of multi-muscle synergies in Parkinson’s disease. Studies of synergies may provide a biomarker sensitive to problems with postural stability and agility and to efficacy of dopamine-replacement therapy. PMID:28110044
Drugs for rare disorders.

PubMed

Cremers, Serge; Aronson, Jeffrey K

2017-08-01

Estimates of the frequencies of rare disorders vary from country to country; the global average defined prevalence is 40 per 100 000 (0.04%). Some occur in only one or a few patients. However, collectively rare disorders are fairly common, affecting 6-8% of the US population, or about 30 million people, and a similar number in the European Union. Most of them affect children and most are genetically determined. Diagnosis can be difficult, partly because of variable presentations and partly because few clinicians have experience of individual rare disorders, although they may be assisted by searching databases. Relatively few rare disorders have specific pharmacological treatments (so-called orphan drugs), partly because of difficulties in designing trials large enough to determine benefits and harms alike. Incentives have been introduced to encourage the development of orphan drugs, including tax credits and research aids, simplification of marketing authorization procedures and exemption from fees, and extended market exclusivity. Consequently, the number of applications for orphan drugs has grown, as have the costs of using them, so much so that treatments may not be cost-effective. It has therefore been suggested that not-for-profit organizations that are socially motivated to reduce those costs should be tasked with producing them. A growing role for patient organizations, improved clinical and translational infrastructures, and developments in genetics have also contributed to successful drug development. The translational discipline of clinical pharmacology is an essential component in drug development, including orphan drugs. Clinical pharmacologists, skilled in basic pharmacology and its links to clinical medicine, can be involved at all stages. They can contribute to the delineation of genetic factors that determine clinical outcomes of pharmacological interventions, develop biomarkers, design and perform clinical trials, assist regulatory decision making, and conduct postmarketing surveillance and pharmacoepidemiological and pharmacoeconomic assessments. © 2017 The British Pharmacological Society.
BEHAVIORAL PHARMACOLOGY OF THE ODOR SPAN TASK: EFFECTS OF FLUNITRAZEPAM, KETAMINE, METHAMPHETAMINE AND METHYLPHENIDATE

PubMed Central

Galizio, Mark; April, Brooke; Deal, Melissa; Hawkey, Andrew; Panoz-Brown, Danielle; Prichard, Ashley; Bruce, Katherine

2018-01-01

The Odor Span Task is an incrementing non-matching-to-sample procedure that permits the study of behavior under the control of multiple stimuli. Rats are exposed to a series of odor stimuli and selection of new stimuli is reinforced. Successful performance thus requires remembering which stimuli have previously been presented during a given session. This procedure has been frequently used in neurobiological studies as a rodent model of working memory; however, only a few studies have examined the effects of drugs on performance in this task. The present experiments explored the behavioral pharmacology of a modified version of the Odor Span Task by determining the effects of stimulant drugs methylphenidate and methamphetamine, NMDA antagonist ketamine, and positive GABAA modulator flunitrazepam. All four drugs produced dose-dependent impairment of performances on the Odor Span Task, but for methylphenidate and methamphetamine, these occurred only at doses that had similar effects on performance of a simple odor discrimination. Generally, these disruptions were based on omission of responding at the effective doses. The effects of ketamine and flunitrazepam were more selective in some rats. That is, some rats tested under flunitrazepam and ketamine showed decreases in accuracy on the Odor Span Task at doses that did not affect simple discrimination performance. These selective effects indicate disruption of within-session stimulus control. Overall, these findings support the potential of the Odor Span Task as a baseline for the behavioral pharmacological analysis of remembering. PMID:27747877
Task analysis of Air Force pharmacy practice.

PubMed

Bartholomew, A; Sawyer, W T; Coats, L

1995-01-15

The frequency with which United States Air Force pharmacists perform specific professional tasks and the pharmacists' views as to the importance of those tasks were studied. A questionnaire was prepared that asked recipients to rate each of 36 tasks selected as representing the spectrum of practice activities. There were four categories of tasks: managerial tasks, dispensing tasks, drug information tasks, and patient care tasks. Recipients rated the tasks with respect to frequency of performance and importance on separate 6-point scales. The questionnaire was mailed in May 1991 to the 225 pharmacists then serving in the Air Force worldwide. Of the 225 questionnaires, 150 usable questionnaires were returned (response rate, 67%). All the tasks in the survey were performed by at least one Air Force pharmacy officer, although the frequency of task performance varied. In particular, the frequency of many patient care tasks was low. All the tasks were perceived to have some importance, but drug information tasks were rated as being significantly more important than tasks in the other categories; patient care tasks were rated lowest in importance. The results varied with the respondents' demographic characteristics. Pharmacy officers with more years of service, more senior positions, higher rank, or an advanced degree in a field other than pharmacy tended to give responses that diverged from those of the population. A 1991 survey showed an awareness among Air Force pharmacists of the need to orient practice around patient care; however, they were not spending substantial time on patient care and tended to view it as less important than more traditional pharmacy tasks.
Safety-oriented usability test of a semi-automated unit dose system: role of task allocation between human and machine.

PubMed

Pelayo, Sylvia; Hassler, Sylvain; Bernonville, Stéphanie; Aldegheri, Julien; Beuscart-Zephir, Marie-Catherine

2013-01-01

The distribution of tasks between humans and machines in the design of healthcare systems is an important issue for patient safety. This paper presents a usability test performed to compare a semi-automated unit dose system (UDS) with the usual/manual preparation procedure for preparing and administering drugs. The results show that the UDS prevents the frequent administration errors encountered with the usual cabinets and produces a better performance in terms of time for filling the pill dispensers (6.52 sec ± 1.1 vs. 8.5 sec ± 1.5 (t(9, 16) = 3.12, p <.007)). But the results also stress that the UDS takes entire control of the preparation and administration tasks, thus leading to a loss of control of the process by nurses (difficulties experienced by them in resuming their actions, difficulties in memorizing drugs, lack of confidence in the UDS while they "blindly" rely on it). The distribution of tasks between the nurses and the UDS should be modified to give back control to the nurses. Design suggestions were provided in this way. For instance, the UDS may guide the nurses for the drugs localization in the cabinet but leaves the validation of the drugs to the nurses.
Atrial fibrillation: Therapeutic potential of atrial K+ channel blockers.

PubMed

Ravens, Ursula; Odening, Katja E

2017-08-01

Despite the epidemiological scale of atrial fibrillation, current treatment strategies are of limited efficacy and safety. Ideally, novel drugs should specifically correct the pathophysiological mechanisms responsible for atrial fibrillation with no other cardiac or extracardiac actions. Atrial-selective drugs are directed toward cellular targets with sufficiently different characteristics in atria and ventricles to modify only atrial function. Several potassium (K + ) channels with either predominant expression in atria or distinct electrophysiological properties in atria and ventricles can serve as atrial-selective drug targets. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting I Kur , the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I K,ACh , the Ca 2+ -activated K + channels of small conductance (SK) conducting I SK , and the two pore domain K + (K2P) channels TWIK-1, TASK-1 and TASK-3 that are responsible for voltage-independent background currents I TWIK-1 , I TASK-1 , and I TASK-3 . Here, we briefly review the characteristics of these K + channels and their roles in atrial fibrillation. The antiarrhythmic potential of drugs targeting the described channels is discussed as well as their putative value in treatment of atrial fibrillation. Copyright © 2016 Elsevier Inc. All rights reserved.

To Determine if a Combined U.S. and Afghanistan Military-Civilian Counter-Narcotics Joint Task Force Should Be Created to Support the Fight Against Counterinsurgencies in the Afghan Theater of War

DTIC Science & Technology

2011-06-10

AFGHAN THEATER OF WAR, by Major Keith W. Alfeiri, 88 pages. The opium trade is a major funding source for the insurgency in Afghanistan. The Afghan...joint task force should be created to support the fight against counterinsurgencies in the Afghan theater of war. The drug trade has often been used to...remains that drugs fund terrorism and insurgents as the money flows between the drug trade and insurgents. According to a United Nations (UN
Organized Crime and Drug Enforcement Task Force. Hearing before the Committee on the Judiciary. United States Senate, Ninety-Eighth Congress, First Session on the Organized Crime and Drug Enforcement Task Force in the Mid-Atlantic Region Which Would Coordinate Government Agencies, Including U.S. Attorneys, the FBI, DEA, Customs Service, BATF, and the IRS. Dover, Delaware.

ERIC Educational Resources Information Center

Congress of the U.S., Washington, DC. Senate Committee on the Judiciary.

This document presents testimony and proceedings from the Congressional hearings on organized crime and drug enforcement in the Mid-Atlantic region, and government efforts to solve these problems. Opening statements are presented from Senators Strom Thurmond and Joseph Biden. Testimony is also presented from the United States attorneys for the…
Recent Perspectives in Ocular Drug Delivery

PubMed Central

Gaudana, Ripal; Jwala, J.; Boddu, Sai H. S.; Mitra, Ashim K.

2015-01-01

Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. PMID:18758924
DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina.

PubMed

Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

2017-02-01

Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.
DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina

NASA Astrophysics Data System (ADS)

Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

2017-02-01

Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.
Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

PubMed

Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

2016-07-05

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.
In silico and in vitro methods to optimize the performance of experimental gastroretentive floating mini-tablets.

PubMed

Eberle, Veronika A; Häring, Armella; Schoelkopf, Joachim; Gane, Patrick A C; Huwyler, Jörg; Puchkov, Maxim

2016-01-01

Development of floating drug delivery systems (FDDS) is challenging. To facilitate this task, an evaluation method was proposed, which allows for a combined investigation of drug release and flotation. It was the aim of the study to use functionalized calcium carbonate (FCC)-based lipophilic mini-tablet formulations as a model system to design FDDS with a floating behavior characterized by no floating lag time, prolonged flotation and loss of floating capability after complete drug release. Release of the model drug caffeine from the mini-tablets was assessed in vitro by a custom-built stomach model. A cellular automata-based model was used to simulate tablet dissolution. Based on the in silico data, floating forces were calculated and analyzed as a function of caffeine release. Two floating behaviors were identified for mini-tablets: linear decrease of the floating force and maintaining of the floating capability until complete caffeine release. An optimal mini-tablet formulation with desired drug release time and floating behavior was developed and tested. A classification system for a range of varied floating behavior of FDDS was proposed. The FCC-based mini-tablets had an ideal floating behavior: duration of flotation is defined and floating capability decreases after completion of drug release.
Consensus Recommendations on Sulfonylurea and Sulfonylurea Combinations in the Management of Type 2 Diabetes Mellitus – International Task Force

PubMed Central

Kalra, Sanjay; Bahendeka, Silver; Sahay, Rakesh; Ghosh, Sujoy; Md, Fariduddin; Orabi, Abbas; Ramaiya, Kaushik; Al Shammari, Sameer; Shrestha, Dina; Shaikh, Khalid; Abhayaratna, Sachitha; Shrestha, Pradeep K.; Mahalingam, Aravinthan; Askheta, Mazen; A. Rahim, Aly Ahmed; Eliana, Fatimah; Shrestha, Hari K.; Chaudhary, Sandeep; Ngugi, Nancy; Mbanya, Jean Claude; Aye, Than Than; Latt, Tint Swe; Akanov, Zhanay A.; Syed, Abbas Raza; Tandon, Nikhil; Unnikrishnan, A. G.; Madhu, S. V.; Jawa, Ali; Chowdhury, Subhankar; Bajaj, Sarita; Das, Ashok Kumar

2018-01-01

For decades, sulfonylureas (SUs) have been important drugs in the antidiabetic therapeutic armamentarium. They have been used as monotherapy as well as combination therapy. Focus on newer drugs and concerns about the risk of severe hypoglycemia and weight gain with some SUs have led to discussion on their safety and utility. It has to be borne in mind that the adverse events associated with SUs should not be ascribed to the whole class, as many modern SUs, such as glimepiride and gliclazide modified release, are associated with better safety profiles. Furthermore, individualization of treatment, using SUs in combination with other drugs, backed with careful monitoring and patient education, ensures maximum benefits with minimal side effects. The current guidelines, developed by experts from Africa, Asia, and the Middle East, promote the safe and smart use of SUs in combination with other glucose-lowering drugs. PMID:29535952
The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation.

PubMed

Götestam Skorpen, Carina; Hoeltzenbein, Maria; Tincani, Angela; Fischer-Betz, Rebecca; Elefant, Elisabeth; Chambers, Christina; da Silva, Josè; Nelson-Piercy, Catherine; Cetin, Irene; Costedoat-Chalumeau, Nathalie; Dolhain, Radboud; Förger, Frauke; Khamashta, Munther; Ruiz-Irastorza, Guillermo; Zink, Angela; Vencovsky, Jiri; Cutolo, Maurizio; Caeyers, Nele; Zumbühl, Claudia; Østensen, Monika

2016-05-01

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Probabilistic reward- and punishment-based learning in opioid addiction: Experimental and computational data.

PubMed

Myers, Catherine E; Sheynin, Jony; Balsdon, Tarryn; Luzardo, Andre; Beck, Kevin D; Hogarth, Lee; Haber, Paul; Moustafa, Ahmed A

2016-01-01

Addiction is the continuation of a habit in spite of negative consequences. A vast literature gives evidence that this poor decision-making behavior in individuals addicted to drugs also generalizes to laboratory decision making tasks, suggesting that the impairment in decision-making is not limited to decisions about taking drugs. In the current experiment, opioid-addicted individuals and matched controls with no history of illicit drug use were administered a probabilistic classification task that embeds both reward-based and punishment-based learning trials, and a computational model of decision making was applied to understand the mechanisms describing individuals' performance on the task. Although behavioral results showed that opioid-addicted individuals performed as well as controls on both reward- and punishment-based learning, the modeling results suggested subtle differences in how decisions were made between the two groups. Specifically, the opioid-addicted group showed decreased tendency to repeat prior responses, meaning that they were more likely to "chase reward" when expectancies were violated, whereas controls were more likely to stick with a previously-successful response rule, despite occasional expectancy violations. This tendency to chase short-term reward, potentially at the expense of developing rules that maximize reward over the long term, may be a contributing factor to opioid addiction. Further work is indicated to better understand whether this tendency arises as a result of brain changes in the wake of continued opioid use/abuse, or might be a pre-existing factor that may contribute to risk for addiction. Copyright © 2015 Elsevier B.V. All rights reserved.
iDrug: a web-accessible and interactive drug discovery and design platform

PubMed Central

2014-01-01

Background The progress in computer-aided drug design (CADD) approaches over the past decades accelerated the early-stage pharmaceutical research. Many powerful standalone tools for CADD have been developed in academia. As programs are developed by various research groups, a consistent user-friendly online graphical working environment, combining computational techniques such as pharmacophore mapping, similarity calculation, scoring, and target identification is needed. Results We presented a versatile, user-friendly, and efficient online tool for computer-aided drug design based on pharmacophore and 3D molecular similarity searching. The web interface enables binding sites detection, virtual screening hits identification, and drug targets prediction in an interactive manner through a seamless interface to all adapted packages (e.g., Cavity, PocketV.2, PharmMapper, SHAFTS). Several commercially available compound databases for hit identification and a well-annotated pharmacophore database for drug targets prediction were integrated in iDrug as well. The web interface provides tools for real-time molecular building/editing, converting, displaying, and analyzing. All the customized configurations of the functional modules can be accessed through featured session files provided, which can be saved to the local disk and uploaded to resume or update the history work. Conclusions iDrug is easy to use, and provides a novel, fast and reliable tool for conducting drug design experiments. By using iDrug, various molecular design processing tasks can be submitted and visualized simply in one browser without installing locally any standalone modeling softwares. iDrug is accessible free of charge at http://lilab.ecust.edu.cn/idrug. PMID:24955134
Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats.

PubMed

Frankel, Sari; Medvedeva, Natalia; Gutherz, Samuel; Kulick, Catherine; Kondratyev, Alexei; Forcelli, Patrick A

2016-04-01

Anticonvulsant drugs, when given during vulnerable periods of brain development, can have long-lasting consequences on nervous system function. In rats, the second postnatal week approximately corresponds to the late third trimester of gestation/early infancy in humans. Exposure to phenobarbital during this period has been associated with deficits in learning and memory, anxiety-like behavior, and social behavior, among other domains. Phenobarbital is the most common anticonvulsant drug used in neonatology. Several other drugs, such as lamotrigine, phenytoin, and clonazepam, have also been reported to trigger behavioral changes. A new generation anticonvulsant drug, retigabine, has not previously been evaluated for long-term effects on behavior. Retigabine acts as an activator of KCNQ channels, a mechanism that is unique among anticonvulsants. Here, we examined the effects retigabine exposure from postnatal day (P)7 to P14 on behavior in adult rats. We compared these effects with those produced by phenobarbital (as a positive control) and saline (as a negative control). Motor behavior was assessed by using the open field and rotarod, anxiety-like behavior by the open field, elevated plus maze, and light-dark transition task, and learning/memory by the passive avoidance task; social interactions were assessed in same-treatment pairs, and nociceptive sensitivity was assessed via the tail-flick assay. Motor behavior was unaltered by exposure to either drug. We found that retigabine exposure and phenobarbital exposure both induced increased anxiety-like behavior in adult animals. Phenobarbital, but not retigabine, exposure impaired learning and memory. These drugs also differed in their effects on social behavior, with retigabine-exposed animals displaying greater social interaction than phenobarbital-exposed animals. These results indicate that neonatal retigabine induces a subset of behavioral alterations previously described for other anticonvulsant drugs and extend our knowledge of drug-induced behavioral teratogenesis to a new mechanism of anticonvulsant action. Copyright © 2016 Elsevier Inc. All rights reserved.
Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

PubMed Central

Frankel, Sari; Medvedeva, Natalia; Gutherz, Samuel; Kulick, Catherine; Kondratyev, Alexei; Forcelli, Patrick A.

2016-01-01

Anticonvulsant drugs, when given during vulnerable periods of brain development, can have long-lasting consequences on nervous system function. In rats, the second postnatal week approximately corresponds to the late third trimester of gestation/early infancy in humans. Exposure to phenobarbital during this period has been associated with deficits in learning and memory, anxiety-like behavior, and social behavior, among other domains. Phenobarbital is the most common anticonvulsant drug used in neonatology. Several other drugs, such as lamotrigine, phenytoin, and clonazepam have also been reported to trigger behavioral changes. A new generation anticonvulsant drug, retigabine, has not previously been evaluated for long-term effects on behavior. Retigabine acts as an activator of KCNQ channels, a mechanism that is unique among anticonvulsants. Here, we examined the effects retigabine exposure from postnatal day (P)7 to P14 on behavior in adult rats. We compared these effects to those produced by phenobarbital (as a positive control) and saline (as a negative control). Motor behavior was assessed using the open field and rotarod, anxiety-like behavior by the open field, elevated plus maze, and light-dark transition task, and learning/memory by the passive avoidance task; social interactions were assessed in same-treatment pairs and nociceptive sensitivity was assessed via the tail-flick assay. Motor behavior was unaltered by exposure to either drug. We found that retigabine and phenobarbital exposure both induced increased anxiety-like behavior in adult animals. Phenobarbital, but not retigabine exposure impaired learning and memory. These drugs also differed in their effects on social behavior, with retigabine-exposed animals displaying greater social interaction than phenobarbital-exposed animals. These results indicate that neonatal retigabine induces a subset of behavioral alterations previously described for other anticonvulsant drugs, and extend our knowledge of drug-induced behavioral teratogenesis to a new mechanism of anticonvulsant action. PMID:26921596
Joint Interagency Task Forces; the Right Model to Combat Transnational Organized Crime

DTIC Science & Technology

2015-05-18

of predicting drug movements with incredible accuracy. 8 JIATF-South started life as one of three Department of Defense (DOD) Joint Task...on terrorism, human trafficking, drug smuggling; a JIATF Africa /Middle East focused on terrorism, arms smuggling, infectious diseases; and, a JIATF...narco terrorist threats within the prescribed JOA.” 72 As previously mentioned, JIATF-South has by necessity already started to widen its focus to TCO
The use of mechanistic evidence in drug approval.

PubMed

Aronson, Jeffrey K; La Caze, Adam; Kelly, Michael P; Parkkinen, Veli-Pekka; Williamson, Jon

2018-06-11

The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies. © 2018 The Authors Journal of Evaluation in Clinical Practice Published by John Wiley & Sons Ltd.
3D-Lab: a collaborative web-based platform for molecular modeling.

PubMed

Grebner, Christoph; Norrby, Magnus; Enström, Jonatan; Nilsson, Ingemar; Hogner, Anders; Henriksson, Jonas; Westin, Johan; Faramarzi, Farzad; Werner, Philip; Boström, Jonas

2016-09-01

The use of 3D information has shown impact in numerous applications in drug design. However, it is often under-utilized and traditionally limited to specialists. We want to change that, and present an approach making 3D information and molecular modeling accessible and easy-to-use 'for the people'. A user-friendly and collaborative web-based platform (3D-Lab) for 3D modeling, including a blazingly fast virtual screening capability, was developed. 3D-Lab provides an interface to automatic molecular modeling, like conformer generation, ligand alignments, molecular dockings and simple quantum chemistry protocols. 3D-Lab is designed to be modular, and to facilitate sharing of 3D-information to promote interactions between drug designers. Recent enhancements to our open-source virtual reality tool Molecular Rift are described. The integrated drug-design platform allows drug designers to instantaneously access 3D information and readily apply advanced and automated 3D molecular modeling tasks, with the aim to improve decision-making in drug design projects.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Hannum, David W.; Shannon, Gary W.

This report describes the collaboration between the South Texas Specialized Crimes and Narcotics Task Force (STSCNTF) and Sandia National Laboratories (SNL) in a field test that provided prototype hand-held trace detection technology for use in counter-drug operations. The National Institute of Justice (NIJ)/National Law Enforcement and Corrections Technology Center (NLECTC)/Border Research and Technology Center (BRTC) was contacted by STSCNTF for assistance in obtaining cutting-edge technology. The BRTC created a pilot project for Sandia National Laboratories (SNL) and the STSCNTF for the use of SNL’s Hound, a hand-held sample collection and preconcentration system that, when combined with a commercial chemical detector,more » can be used for the trace detection of illicit drugs and explosives. The STSCNTF operates in an area of high narcotics trafficking where methods of concealment make the detection of narcotics challenging. Sandia National Laboratories’ (SNL) Contraband Detection Department personnel provided the Hound system hardware and operational training. The Hound system combines the GE VaporTracer2, a hand-held commercial chemical detector, with an SNL-developed sample collection and preconcentration system. The South Texas Task force reported a variety of successes, including identification of a major shipment of methamphetamines, the discovery of hidden compartments in vehicles that contained illegal drugs and currency used in drug deals, and the identification of a suspect in a nightclub shooting. The main advantage of the hand-held trace detection unit is its ability to quickly identify the type of chemical (drugs or explosives) without a long lag time for laboratory analysis, which is the most common analysis method for current law enforcement procedures.« less
Caffeine Use and Extroversion.

ERIC Educational Resources Information Center

Landrum, R. Eric; Meliska, Charles J.

Some research on the stimulant effect of caffeine suggests that the amount of behavioral enhancement produced by caffeine may depend on subjects' prior experience with the task and the drug. A study was undertaken to test whether prior experience with a task while under the influence of caffeine would facilitate performance of that task. Male…
Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

PubMed Central

Pierce, Christopher G.; Lopez-Ribot, Jose L.

2014-01-01

Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751
Exploring Spanish health social media for detecting drug effects.

PubMed

Segura-Bedmar, Isabel; Martínez, Paloma; Revert, Ricardo; Moreno-Schneider, Julián

2015-01-01

Adverse Drug reactions (ADR) cause a high number of deaths among hospitalized patients in developed countries. Major drug agencies have devoted a great interest in the early detection of ADRs due to their high incidence and increasing health care costs. Reporting systems are available in order for both healthcare professionals and patients to alert about possible ADRs. However, several studies have shown that these adverse events are underestimated. Our hypothesis is that health social networks could be a significant information source for the early detection of ADRs as well as of new drug indications. In this work we present a system for detecting drug effects (which include both adverse drug reactions as well as drug indications) from user posts extracted from a Spanish health forum. Texts were processed using MeaningCloud, a multilingual text analysis engine, to identify drugs and effects. In addition, we developed the first Spanish database storing drugs as well as their effects automatically built from drug package inserts gathered from online websites. We then applied a distant-supervision method using the database on a collection of 84,000 messages in order to extract the relations between drugs and their effects. To classify the relation instances, we used a kernel method based only on shallow linguistic information of the sentences. Regarding Relation Extraction of drugs and their effects, the distant supervision approach achieved a recall of 0.59 and a precision of 0.48. The task of extracting relations between drugs and their effects from social media is a complex challenge due to the characteristics of social media texts. These texts, typically posts or tweets, usually contain many grammatical errors and spelling mistakes. Moreover, patients use lay terminology to refer to diseases, symptoms and indications that is not usually included in lexical resources in languages other than English.

Graph-based similarity concepts in virtual screening.

PubMed

Hutter, Michael C

2011-03-01

Applying similarity for finding new promising compounds is a key issue in drug design. Conversely, quantifying similarity between molecules has remained a difficult task despite the numerous approaches. Here, some general aspects along with recent developments regarding similarity criteria are collected. For the purpose of virtual screening, the compounds have to be encoded into a computer-readable format that permits a comparison, according to given similarity criteria, comprising the use of the 3D structure, fingerprints, graph-based and alignment-based approaches. Whereas finding the most common substructures is the most obvious method, more recent approaches take into account chemical modifications that appear throughout existing drugs, from various therapeutic categories and targets.
The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description

PubMed Central

McGonigle, John; Murphy, Anna; Paterson, Louise M; Reed, Laurence J; Nestor, Liam; Nash, Jonathan; Elliott, Rebecca; Ersche, Karen D; Flechais, Remy SA; Newbould, Rexford; Orban, Csaba; Smith, Dana G; Taylor, Eleanor M; Waldman, Adam D; Robbins, Trevor W; Deakin, JF William; Nutt, David J; Lingford-Hughes, Anne R; Suckling, John

2016-01-01

Objectives: We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction – reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants. Experimental design: Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. Principle observations: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. Conclusions: In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres. PMID:27703042
The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description.

PubMed

McGonigle, John; Murphy, Anna; Paterson, Louise M; Reed, Laurence J; Nestor, Liam; Nash, Jonathan; Elliott, Rebecca; Ersche, Karen D; Flechais, Remy Sa; Newbould, Rexford; Orban, Csaba; Smith, Dana G; Taylor, Eleanor M; Waldman, Adam D; Robbins, Trevor W; Deakin, Jf William; Nutt, David J; Lingford-Hughes, Anne R; Suckling, John

2017-01-01

We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction - reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants. Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. Principle observations: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres.
Functional evaluation of out-of-the-box text-mining tools for data-mining tasks.

PubMed

Jung, Kenneth; LePendu, Paea; Iyer, Srinivasan; Bauer-Mehren, Anna; Percha, Bethany; Shah, Nigam H

2015-01-01

The trade-off between the speed and simplicity of dictionary-based term recognition and the richer linguistic information provided by more advanced natural language processing (NLP) is an area of active discussion in clinical informatics. In this paper, we quantify this trade-off among text processing systems that make different trade-offs between speed and linguistic understanding. We tested both types of systems in three clinical research tasks: phase IV safety profiling of a drug, learning adverse drug-drug interactions, and learning used-to-treat relationships between drugs and indications. We first benchmarked the accuracy of the NCBO Annotator and REVEAL in a manually annotated, publically available dataset from the 2008 i2b2 Obesity Challenge. We then applied the NCBO Annotator and REVEAL to 9 million clinical notes from the Stanford Translational Research Integrated Database Environment (STRIDE) and used the resulting data for three research tasks. There is no significant difference between using the NCBO Annotator and REVEAL in the results of the three research tasks when using large datasets. In one subtask, REVEAL achieved higher sensitivity with smaller datasets. For a variety of tasks, employing simple term recognition methods instead of advanced NLP methods results in little or no impact on accuracy when using large datasets. Simpler dictionary-based methods have the advantage of scaling well to very large datasets. Promoting the use of simple, dictionary-based methods for population level analyses can advance adoption of NLP in practice. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association.
Influence of pharmacological manipulations of NMDA and cholinergic receptors on working versus reference memory in a dual component odor span task.

PubMed

MacQueen, David A; Dalrymple, Savannah R; Drobes, David J; Diamond, David M

2016-06-01

Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-d-aspartate receptor (NMDA-r) antagonists and is sensitive to cholinergic manipulations. The present study sought to determine whether an impairment in OST performance can be produced by systemic administration of the competitive NMDA-r antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP; 3, 10, 17 mg/kg i.p.) in a unique dual-component variant of the OST, and whether this impairment is ameliorated by nicotine (0.75 mg/kg i.p.). Male Sprague-Dawley rats were trained to asymptotic level of performance on a 24-trial two-comparison incrementing nonmatching to sample OST. In addition, rats were administered a two-comparison olfactory reference memory (RM) task, which was integrated into the OST. The RM task provided an assessment of the effects of drug administration on global behavioral measures, long-term memory and motivation. Several measures of working memory (span, longest run, and accuracy) were dose dependently impaired by CPP without adversely affecting RM. Analysis of drug effects across trial blocks demonstrated a significant impairment of performance even at low memory loads, suggesting a CPP-induced deficit of olfactory short-term memory that is not load-dependent. Although nicotine did not ameliorate CPP-induced impairments in span or accuracy, it did block the impairment in longest run produced by the 10 mg/kg dose of CPP. Overall, our results indicate that performance in our 24 odor two-comparison OST is capacity dependent and that CPP impaired OST working, but not reference, memory. © 2016 MacQueen et al.; Published by Cold Spring Harbor Laboratory Press.
Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

PubMed

Gallant, S; Welch, L; Martone, P; Shalev, U

2017-06-15

Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.
Effects of modafinil on attention performance, short-term memory and executive function in university students: a randomized trial.

PubMed

Fernández, Alejandro; Mascayano, Franco; Lips, Walter; Painel, Andrés; Norambuena, Jonathan; Madrid, Eva

2015-06-30

Modafinil is a drug developed and used for the treatment of excessive lethargy. Even though very effective for sleep disorders, it is still controversial whether modafinil can improve performance in high-order cognitive processes such as memory and executive function. This randomized, double-blind, placebo-controlled, crossover trial was designed to evaluate the effect of modafinil (compared to placebo) on the cognitive functions of healthy students. 160 volunteers were recruited and allocated randomly to modafinil or placebo group, and were assessed using the Stroop Test, BCET test and Digit span test. We found a significant difference in favor of modafinil compared to placebo in the proportion of correct answers of Stroop Test in congruent situation. A significant shorter latency of modafinil group in the incongruent situation of Stroop test was also found. No differences were found in Digit Span, or BCET tests. The study demonstrated that modafinil does not enhance the global cognitive performance of healthy non-sleep deprived students, except regarding non-demanding tasks. In particular, this drug does not seem to have positive effects on mental processes that sustain studying tasks in the college population under normal conditions. We expect these findings to demystify the use of this drug and help decision making concerning pharmacological public policies.
Advanced drug and gene delivery systems based on functional biodegradable polycarbonates and copolymers.

PubMed

Chen, Wei; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan

2014-09-28

Biodegradable polymeric nanocarriers are one of the most promising systems for targeted and controlled drug and gene delivery. They have shown several unique advantages such as excellent biocompatibility, prolonged circulation time, passive tumor targeting via the enhanced permeability and retention (EPR) effect, and degradation in vivo into nontoxic products after completing their tasks. The current biodegradable drug and gene delivery systems exhibit, however, typically low in vivo therapeutic efficacy, due to issues of low loading capacity, inadequate in vivo stability, premature cargo release, poor uptake by target cells, and slow release of therapeutics inside tumor cells. To overcome these problems, a variety of advanced drug and gene delivery systems has recently been designed and developed based on functional biodegradable polycarbonates and copolymers. Notably, polycarbonates and copolymers with diverse functionalities such as hydroxyl, carboxyl, amine, alkene, alkyne, halogen, azido, acryloyl, vinyl sulfone, pyridyldisulfide, and saccharide, could be readily obtained by controlled ring-opening polymerization. In this paper, we give an overview on design concepts and recent developments of functional polycarbonate-based nanocarriers including stimuli-sensitive, photo-crosslinkable, or active targeting polymeric micelles, polymersomes and polyplexes for enhanced drug and gene delivery in vitro and in vivo. These multifunctional biodegradable nanosystems might be eventually developed for safe and efficient cancer chemotherapy and gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.
Lipid nanoparticles for the delivery of poorly water-soluble drugs.

PubMed

Bunjes, Heike

2010-11-01

This review discusses important aspects of lipid nanoparticles such as colloidal lipid emulsions and, in particular, solid lipid nanoparticles as carrier systems for poorly water-soluble drugs, with a main focus on the parenteral and peroral use of these carriers. A short historical background of the development of colloidal lipid emulsions and solid lipid nanoparticles is provided and their similarities and differences are highlighted. With regard to drug incorporation, parameters such as the chemical nature of the particle matrix and the physicochemical nature of the drug, effects of drug partition and the role of the particle interface are discussed. Since, because of the crystalline nature of their lipid core, solid lipid nanoparticles display some additional important features compared to emulsions, their specificities are introduced in more detail. This mainly includes their solid state behaviour (crystallinity, polymorphism and thermal behaviour) and the consequences of their usually non-spherical particle shape. Since lipid nanoemulsions and -suspensions are also considered as potential means to alter the pharmacokinetics of incorporated drug substances, some underlying basic considerations, in particular concerning the drug-release behaviour of such lipid nanodispersions on dilution, are addressed as well. Colloidal lipid emulsions and solid lipid nanoparticles are interesting options for the delivery of poorly water-soluble drug substances. Their specific physicochemical properties need, however, to be carefully considered to provide a rational basis for their development into effective carrier systems for a given delivery task. © 2010 The Author. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.
Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia

PubMed Central

YOUNG, Jared W; POWELL, Susan; RISBROUGH, Victoria; MARSTON, Hugh M; GEYER, Mark A

2009-01-01

Cognitive deficits in schizophrenia are among the core symptoms of the disease, correlate with functional outcome, and are not well treated with current antipsychotic therapies. In order to bring together academic, industrial, and governmental bodies to address this great ‘unmet therapeutic need’, the NIMH sponsored the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Through careful factor analysis and consensus of expert opinion, MATRICS identified seven domains of cognition that are deficient in schizophrenia (attention/vigilance, working memory, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition) and recommended a specific neuropsychological test battery to probe these domains. In order to move the field forward and outline an approach for translational research, there is a need for a “preclinical MATRICS” to develop a rodent test battery that is appropriate for drug development. In this review, we outline such an approach and review current rodent tasks that target these seven domains of cognition. The rodent tasks are discussed in terms of their validity for probing each cognitive domain as well as a brief overview of the pharmacology and manipulations relevant to schizophrenia for each task. PMID:19269307
Using Stimulant Drugs in the Classroom.

ERIC Educational Resources Information Center

Barkley, Russell A.

1979-01-01

Research is reviewed on the effects of stimulant drugs on the classroom behavior and academic achievement of hyperactive children. Results indicate that stimulant drugs do not appreciably improve academic achievement, but are effective in improving attention span, on-task behavior, activity level, and disruptive behavior. (Author/MH)
Rodent Versions of the Iowa Gambling Task: Opportunities and Challenges for the Understanding of Decision-Making

PubMed Central

de Visser, Leonie; Homberg, Judith R.; Mitsogiannis, Manuela; Zeeb, Fiona D.; Rivalan, Marion; Fitoussi, Aurélie; Galhardo, Vasco; van den Bos, Ruud; Winstanley, Catherine A.; Dellu-Hagedorn, Françoise

2011-01-01

Impaired decision-making is a core problem in several psychiatric disorders including attention-deficit/hyperactivity disorder, schizophrenia, obsessive–compulsive disorder, mania, drug addiction, eating disorders, and substance abuse as well as in chronic pain. To ensure progress in the understanding of the neuropathophysiology of these disorders, animal models with good construct and predictive validity are indispensable. Many human studies aimed at measuring decision-making capacities use the Iowa gambling task (IGT), a task designed to model everyday life choices through a conflict between immediate gratification and long-term outcomes. Recently, new rodent models based on the same principle have been developed to investigate the neurobiological mechanisms underlying IGT-like decision-making on behavioral, neural, and pharmacological levels. The comparative strengths, as well as the similarities and differences between these paradigms are discussed. The contribution of these models to elucidate the neurobehavioral factors that lead to poor decision-making and to the development of better treatments for psychiatric illness is considered, along with important future directions and potential limitations. PMID:22013406
Effects of buprenorphine on responses to social stimuli in healthy adults

PubMed Central

Bershad, Anya K.; Seiden, Jacob A.; de Wit, Harriet

2015-01-01

In addition to its classical role in mediating responses to pain, the opioid system is strongly implicated in the regulation of social behavior. In young laboratory animals, low doses of opioid analgesic drugs reduce responses to isolation distress and increase play behavior. However, little is known about how opioid drugs affect responses to social stimuli in humans. Here we examined the effects of buprenorphine, a mu-opioid partial agonist and kappa-antagonist, on three dimensions of social processing; i) responses to simulated social rejection, ii) attention to emotional facial expressions, and iii) emotional responses to images with and without social content. Healthy adults (N = 36) attended two sessions during which they received either placebo or 0.2mg sublingual buprenorphine in randomized order, under double-blind conditions. Ninety minutes after drug administration, they completed three behavioral tasks: i) a virtual ball-toss game in which they were first included and then excluded by the other players; ii) an attention task in which they were shown pairs of faces (one emotional and one neutral), while the direction of their gazes was recorded using electrooculography, and iii) a picture-viewing task, in which they rated standardized images with and without social content. During the ball-toss game, buprenorphine decreased perceived social rejection. During the attention task, the drug reduced initial attention to fearful facial expressions, without influencing attention to angry, happy, and sad faces. Finally, during the picture-viewing task, buprenorphine increased ratings of positivity of images with social content, without affecting ratings of nonsocial images. These results suggest that even at low doses, opioid analgesic drugs reduce responses to some types of negative social stimuli, while enhancing positive responses to social stimuli. This provides further support for the role of the opioid system in mediating responses to social rejection and social reward. PMID:26409030
Regulation and Device Development: Tips for Optimizing Your Experience With the Food and Drug Administration.

PubMed

Brooks, Steven S

2017-06-01

Physician-inventors are in a unique position to identify unserved patient needs, and innovate solutions to clinical problems. These solutions may also have associated commercial opportunities. The logistics of developing these medical products, however, can seem a daunting task. One of the primary barriers in the United States is the regulatory process of the Food and Drug Administration (FDA). In this article, we will explore the risk-based approach used by the FDA which forms a framework to consider the regulatory pathway and the process to gain regulatory clearance or approval for medical devices. Inherent device properties and the procedural risk of the devices will determine the rigor with which they are scrutinized by FDA, and the evidentiary requirements to legally market them. Data and evidentiary development will vary depending on risk and regulatory precedent and may or may not require clinical data This regulatory paradigm will determine into which risk-based device class they fit, and whether they are regulated under the 510(k) or premarket approval application pathways. The FDA, although gatekeeper of the US market and tasked with determining which products are safe and effective, can be a powerful ally for product development. They have significant scientific and medical expertise, and mechanisms to both provide guidance, and also to consider novel approaches to product development and evidence development. Early interaction for routine and novel products alike can result in expedited and efficient development. This collaborative approach can be best practice to most expeditiously develop the next generation of products, getting them into the hands of US doctors and into the treatment of US patients. Copyright © 2017. Published by Elsevier Inc.
A neural joint model for entity and relation extraction from biomedical text.

PubMed

Li, Fei; Zhang, Meishan; Fu, Guohong; Ji, Donghong

2017-03-31

Extracting biomedical entities and their relations from text has important applications on biomedical research. Previous work primarily utilized feature-based pipeline models to process this task. Many efforts need to be made on feature engineering when feature-based models are employed. Moreover, pipeline models may suffer error propagation and are not able to utilize the interactions between subtasks. Therefore, we propose a neural joint model to extract biomedical entities as well as their relations simultaneously, and it can alleviate the problems above. Our model was evaluated on two tasks, i.e., the task of extracting adverse drug events between drug and disease entities, and the task of extracting resident relations between bacteria and location entities. Compared with the state-of-the-art systems in these tasks, our model improved the F1 scores of the first task by 5.1% in entity recognition and 8.0% in relation extraction, and that of the second task by 9.2% in relation extraction. The proposed model achieves competitive performances with less work on feature engineering. We demonstrate that the model based on neural networks is effective for biomedical entity and relation extraction. In addition, parameter sharing is an alternative method for neural models to jointly process this task. Our work can facilitate the research on biomedical text mining.
The Defense Science Board 2001 Summer Study on Defense Science and Technology

DTIC Science & Technology

2002-05-01

SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10 . SPONSOR/MONITOR’S ACRONYM(S) 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION...Today, it takes roughly 10 to 15 years to develop a safe drug for a specific purpose. The task force believes that it is possible for the United...performance in later screens. DSB Summer Study on Defense Science and Technology ___________________________________________ 10 The
Cortical activation deficits during facial emotion processing in youth at high risk for the development of substance use disorders.

PubMed

Hulvershorn, Leslie A; Finn, Peter; Hummer, Tom A; Leibenluft, Ellen; Ball, Brandon; Gichina, Victoria; Anand, Amit

2013-08-01

Recent longitudinal studies demonstrate that addiction risk may be influenced by a cognitive, affective and behavioral phenotype that emerges during childhood. Relatively little research has focused on the affective or emotional risk components of this high-risk phenotype, including the relevant neurobiology. Non-substance abusing youth (N=19; mean age=12.2) with externalizing psychopathology and paternal history of a substance use disorder and demographically matched healthy comparisons (N=18; mean age=11.9) were tested on a facial emotion matching task during functional MRI. This task involved matching faces by emotions (angry, anxious) or matching shape orientation. High-risk youth exhibited increased medial prefrontal, precuneus and occipital cortex activation compared to the healthy comparison group during the face matching condition, relative to the control shape condition. The occipital activation correlated positively with parent-rated emotion regulation impairments in the high-risk group. These findings suggest a preexisting abnormality in cortical activation in response to facial emotion matching in youth at high risk for the development of problem drug or alcohol use. These cortical deficits may underlie impaired affective processing and regulation, which in turn may contribute to escalating drug use in adolescence. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Cortical Activation Deficits During Facial Emotion Processing in Youth at High Risk for the Development of Substance Use Disorders*

PubMed Central

Hulvershorn, Leslie A.; Finn, Peter; Hummer, Tom A.; Leibenluft, Ellen; Ball, Brandon; Gichina, Victoria; Anand, Amit

2013-01-01

Background Recent longitudinal studies demonstrate that addiction risk may be influenced by a cognitive, affective and behavioral phenotype that emerges during childhood. Relatively little research has focused on the affective or emotional risk components of this high-risk phenotype, including the relevant neurobiology. Methods Non-substance abusing youth (N = 19; mean age = 12.2) with externalizing psychopathology and paternal history of a substance use disorder and demographically matched healthy comparisons (N=18; mean age = 11.9) were tested on a facial emotion matching task during functional MRI. This task involved matching faces by emotions (angry, anxious) or matching shape orientation. Results High-risk youth exhibited increased medial prefrontal, precuneus and occipital cortex activation compared to the healthy comparison group during the face matching condition, relative to the control shape condition. The occipital activation correlated positively with parent-rated emotion regulation impairments in the high-risk group. Conclusions These findings suggest a preexisting abnormality in cortical activation in response to facial emotion matching in youth at high risk for the development of problem drug or alcohol use. These cortical deficits may underlie impaired affective processing and regulation, which in turn may contribute to escalating drug use in adolescence. PMID:23768841
Drug repurposing in kidney disease.

PubMed

Panchapakesan, Usha; Pollock, Carol

2018-07-01

Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Hence, we have included CV endpoints for the drugs. This review begins with candidates in acute kidney injury: vasodilators levosimendan and vitamin D, followed by candidates in CKD, with particular focus on diabetic kidney disease, autosomal dominant polycystic kidney disease, and focal segmental glomerulosclerosis. Examples include glucose-lowering drugs (sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 agonists, and metformin), which have mechanistic potential for cardiac and/or renal protection beyond glucose lowering, with broader applicability to the nondiabetic population; xanthine oxidase inhibitors (allopurinol, febuxostat), selective endothelin receptor A antagonist (atrasentan), Janus kinase inhibitor (baricitinib), selective costimulation modulator (abatacept), pentoxyfylline, and the DNA demethylating agent/vasodilator (hydralazine). Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
A side-effect free method for identifying cancer drug targets.

PubMed

Ashraf, Md Izhar; Ong, Seng-Kai; Mujawar, Shama; Pawar, Shrikant; More, Pallavi; Paul, Somnath; Lahiri, Chandrajit

2018-04-27

Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3.

PubMed

Wright, Paul D; Veale, Emma L; McCoull, David; Tickle, David C; Large, Jonathan M; Ococks, Emma; Gothard, Gemma; Kettleborough, Catherine; Mathie, Alistair; Jerman, Jeffrey

2017-11-04

Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K + channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( ±0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafine's activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3. Copyright © 2017 Elsevier Inc. All rights reserved.
Measuring the construct of executive control in schizophrenia: defining and validating translational animal paradigms for discovery research.

PubMed

Gilmour, Gary; Arguello, Alexander; Bari, Andrea; Brown, Verity J; Carter, Cameron; Floresco, Stan B; Jentsch, David J; Tait, David S; Young, Jared W; Robbins, Trevor W

2013-11-01

Executive control is an aspect of cognitive function known to be impaired in schizophrenia. Previous meetings of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group have more precisely defined executive control in terms of two constructs: "rule generation and selection", and "dynamic adjustments of control". Next, human cognitive tasks that may effectively measure performance with regard to these constructs were identified to be developed into practical and reliable measures for use in treatment development. The aim of this round of CNTRICS meetings was to define animal paradigms that have sufficient promise to warrant further investigation for their utility in measuring these constructs. Accordingly, "reversal learning" and the "attentional set-shifting task" were nominated to assess the construct of rule generation and selection, and the "stop signal task" for the construct of dynamic adjustments of control. These tasks are described in more detail here, with a particular focus on their utility for drug discovery efforts. Presently, each assay has strengths and weaknesses with regard to this point and increased emphasis on improving practical aspects of testing, understanding predictive validity, and defining biomarkers of performance represent important objectives in attaining confidence in translational validity here. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.
Conformational Analysis of Drug Molecules: A Practical Exercise in the Medicinal Chemistry Course

ERIC Educational Resources Information Center

Yuriev, Elizabeth; Chalmers, David; Capuano, Ben

2009-01-01

Medicinal chemistry is a specialized, scientific discipline. Computational chemistry and structure-based drug design constitute important themes in the education of medicinal chemists. This problem-based task is associated with structure-based drug design lectures. It requires students to use computational techniques to investigate conformational…
Analysis of cigarette purchase task instrument data with a left-censored mixed effects model.

PubMed

Liao, Wenjie; Luo, Xianghua; Le, Chap T; Chu, Haitao; Epstein, Leonard H; Yu, Jihnhee; Ahluwalia, Jasjit S; Thomas, Janet L

2013-04-01

The drug purchase task is a frequently used instrument for measuring the relative reinforcing efficacy (RRE) of a substance, a central concept in psychopharmacological research. Although a purchase task instrument, such as the cigarette purchase task (CPT), provides a comprehensive and inexpensive way to assess various aspects of a drug's RRE, the application of conventional statistical methods to data generated from such an instrument may not be adequate by simply ignoring or replacing the extra zeros or missing values in the data with arbitrary small consumption values, for example, 0.001. We applied the left-censored mixed effects model to CPT data from a smoking cessation study of college students and demonstrated its superiority over the existing methods with simulation studies. Theoretical implications of the findings, limitations of the proposed method, and future directions of research are also discussed.
Development of novel in silico model for developmental toxicity assessment by using naïve Bayes classifier method.

PubMed

Zhang, Hui; Ren, Ji-Xia; Kang, Yan-Li; Bo, Peng; Liang, Jun-Yu; Ding, Lan; Kong, Wei-Bao; Zhang, Ji

2017-08-01

Toxicological testing associated with developmental toxicity endpoints are very expensive, time consuming and labor intensive. Thus, developing alternative approaches for developmental toxicity testing is an important and urgent task in the drug development filed. In this investigation, the naïve Bayes classifier was applied to develop a novel prediction model for developmental toxicity. The established prediction model was evaluated by the internal 5-fold cross validation and external test set. The overall prediction results for the internal 5-fold cross validation of the training set and external test set were 96.6% and 82.8%, respectively. In addition, four simple descriptors and some representative substructures of developmental toxicants were identified. Thus, we hope the established in silico prediction model could be used as alternative method for toxicological assessment. And these obtained molecular information could afford a deeper understanding on the developmental toxicants, and provide guidance for medicinal chemists working in drug discovery and lead optimization. Copyright © 2017 Elsevier Inc. All rights reserved.
Exploring the associations between drug side-effects and therapeutic indications.

PubMed

Wang, Fei; Zhang, Ping; Cao, Nan; Hu, Jianying; Sorrentino, Robert

2014-10-01

Drug therapeutic indications and side-effects are both measurable patient phenotype changes in response to the treatment. Inferring potential drug therapeutic indications and identifying clinically interesting drug side-effects are both important and challenging tasks. Previous studies have utilized either chemical structures or protein targets to predict indications and side-effects. In this study, we compared drug therapeutic indication prediction using various information including chemical structures, protein targets and side-effects. We also compared drug side-effect prediction with various information sources including chemical structures, protein targets and therapeutic indication. Prediction performance based on 10-fold cross-validation demonstrates that drug side-effects and therapeutic indications are the most predictive information source for each other. In addition, we extracted 6706 statistically significant indication-side-effect associations from all known drug-disease and drug-side-effect relationships. We further developed a novel user interface that allows the user to interactively explore these associations in the form of a dynamic bipartitie graph. Many relationship pairs provide explicit repositioning hypotheses (e.g., drugs causing postural hypotension are potential candidates for hypertension) and clear adverse-reaction watch lists (e.g., drugs for heart failure possibly cause impotence). All data sets and highly correlated disease-side-effect relationships are available at http://astro.temple.edu/∼tua87106/druganalysis.html. Copyright © 2014 Elsevier Inc. All rights reserved.
Addiction research centres and the nurturing of creativity. The Chinese National Institute on Drug Dependence, Peking University: past, present and future.

PubMed

Wang, Xi; Zhao, Dong; Shi, Jie; Zhao, Chengzheng; Liu, Zhimin; Lu, Lin

2010-09-01

In the 25 years since drug abuse re-emerged in China in the 1980s, the National Institute of Drug Dependence (NIDD) has made many contributions to China's antidrug campaign. This present paper offers an account of the history, current status and future of drug dependence research at NIDD. NIDD was originally a research centre at Beijing Medical University, founded by the Chinese Ministry of Health to address the rapid spread of drug abuse in China. Originally, the main task of NIDD was to complete the commissions assigned by the government and university. Further developments transformed NIDD into a national research institute in the field of drug addiction that began to conduct its own research. NIDD has now created a professional team spread across several independent departments involved in neurobiological mechanisms, epidemiological surveys and monitoring, pre-clinical and clinical evaluation of new drugs (mainly analgesic drugs and detoxification drugs) and informatics and data analysis. As a university-based research institute, NIDD's funding derives mainly from grants provided by the government and financial support from international organizations. Its past and present research has a gained NIDD a reputation with both practitioners and policy makers in the field of drug addiction. In the future, NIDD will continue to engage in various aspects of drug addiction research and will enter the field of brain function.
Propofol and midazolam inhibit conscious memory processes very soon after encoding: an event-related potential study of familiarity and recollection in volunteers.

PubMed

Veselis, Robert A; Pryor, Kane O; Reinsel, Ruth A; Li, Yuelin; Mehta, Meghana; Johnson, Ray

2009-02-01

Intravenous drugs active via gamma-aminobutyric acid receptors to produce memory impairment during conscious sedation. Memory function was assessed using event-related potentials (ERPs) while drug was present. The continuous recognition task measured recognition of photographs from working (6 s) and long-term (27 s) memory while ERPs were recorded from Cz (familiarity recognition) and Pz electrodes (recollection recognition). Volunteer participants received sequential doses of one of placebo (n = 11), 0.45 and 0.9 microg/ml propofol (n = 10), 20 and 40 ng/ml midazolam (n = 12), 1.5 and 3 microg/ml thiopental (n = 11), or 0.25 and 0.4 ng/ml dexmedetomidine (n = 11). End-of-day yes/no recognition 225 min after the end of drug infusion tested memory retention of pictures encoded on the continuous recognition tasks. Active drugs increased reaction times and impaired memory on the continuous recognition task equally, except for a greater effect of midazolam (P < 0.04). Forgetting from continuous recognition tasks to end of day was similar for all drugs (P = 0.40), greater than placebo (P < 0.001). Propofol and midazolam decreased the area between first presentation (new) and recognized (old, 27 s later) ERP waveforms from long-term memory for familiarity (P = 0.03) and possibly for recollection processes (P = 0.12). Propofol shifted ERP amplitudes to smaller voltages (P < 0.002). Dexmedetomidine may have impaired familiarity more than recollection processes (P = 0.10). Thiopental had no effect on ERPs. Propofol and midazolam impaired recognition ERPs from long-term memory but not working memory. ERP measures of memory revealed different pathways to end-of-day memory loss as early as 27 s after encoding.
FDA marketing claims, and the practitioner.

PubMed

Runner, Susan

2006-03-01

The Food and Drug Administration (FDA) is the federal agency that is tasked with regulating market entry for medical devices. The laws that govern this process are codified in the Federal Food Drug and Cosmetic Act (the Act) and the regulations are based on this law. The medical device amendments to the Act were instituted in 1976, instituting the methods for classification of medical devices and the format for the premarket review of devices. Information for practitioners on how medical devices come to market, what data are required, how specific claims are cleared, and how the practitioner can give input to the system are critical for the further development of safe and effective medical devices.
Cognitive control dysfunction and abnormal frontal cortex activation in stimulant drug users and their biological siblings.

PubMed

Smith, D G; Jones, P S; Bullmore, E T; Robbins, T W; Ersche, K D

2013-05-14

Cognitive and neural abnormalities are known to accompany chronic drug abuse, with impairments in cognition and changes in cortical structure seen in stimulant-dependent individuals. However, premorbid differences have also been observed in the brains and behavior of individuals at risk for substance abuse, before they develop dependence. Endophenotype research has emerged as a useful method for assessing preclinical traits that may be risk factors for pathology by studying patient populations and their undiagnosed first-degree relatives. This study used the color-word Stroop task to assess executive functioning in stimulant-dependent individuals, their unaffected biological siblings and unrelated healthy control volunteers using a functional magnetic resonance imaging paradigm. Both the stimulant-dependent and sibling participants demonstrated impairments in cognitive control and processing speed on the task, registering significantly longer response latencies. However, the two groups generated very different neural responses, with the sibling participants exhibiting a significant decrease in activation in the inferior frontal gyrus compared with both stimulant-dependent individuals and control participants. Both target groups also demonstrated a decrease in hemispheric laterality throughout the task, exhibiting a disproportionate increase in right hemispheric activation, which was associated with their behavioral inefficiencies. These findings not only suggest a possible risk factor for stimulant abuse of poor inhibitory control and cortical inefficiency but they also demonstrate possible adaptations in the brains of stimulant users.
Memory for Drug Related Visual Stimuli in Young Adult, Cocaine Dependent Polydrug Users

PubMed Central

Ray, Suchismita; Pandina, Robert; Bates, Marsha E.

2015-01-01

Background and Objectives Implicit (unconscious) and explicit (conscious) memory associations with drugs have been examined primarily using verbal cues. However, drug seeking, drug use behaviors, and relapse in chronic cocaine and other drug users are frequently triggered by viewing substance related visual cues in the environment. We thus examined implicit and explicit memory for drug picture cues to understand the relative extent to which conscious and unconscious memory facilitation of visual drug cues occurs during cocaine dependence. Methods Memory for drug related and neutral picture cues was assessed in 14 inpatient cocaine dependent polydrug users and a comparison group of 21 young adults with limited drug experience (N = 35). Participants completed picture cue exposure, free recall and recognition tasks to assess explicit memory, and a repetition priming task to assess implicit memory. Results Drug cues, compared to neutral cues were better explicitly recalled and implicitly primed, and especially so in the cocaine group. In contrast, neutral cues were better explicitly recognized, and especially in the control group. Conclusion Certain forms of explicit and implicit memory for drug cues were enhanced in cocaine users compared to controls when memory was tested a short time following cue exposure. Enhanced unconscious memory processing of drug cues in chronic cocaine users may be a behavioral manifestation of heightened drug cue salience that supports drug seeking and taking. There may be value in expanding intervention techniques to utilize cocaine users’ implicit memory system. PMID:24588421
Levetiracetam reduces abnormal network activations in temporal lobe epilepsy.

PubMed

Wandschneider, Britta; Stretton, Jason; Sidhu, Meneka; Centeno, Maria; Kozák, Lajos R; Symms, Mark; Thompson, Pamela J; Duncan, John S; Koepp, Matthias J

2014-10-21

We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE). In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose. We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left. Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response. This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures. © 2014 American Academy of Neurology.
Risk-prone individuals prefer the wrong options on a rat version of the Iowa Gambling Task.

PubMed

Rivalan, Marion; Ahmed, Serge H; Dellu-Hagedorn, Françoise

2009-10-15

Decision making in complex and conflicting situations, as measured in the widely used Iowa Gambling Task (IGT), can be profoundly impaired in psychiatric disorders, such as attention-deficit/hyperactivity disorder, drug addiction, and also in healthy individuals for whom immediate gratification prevails over long-term gain. The cognitive processes underlying these deficits are poorly understood, in part due to a lack of suitable animal models assessing complex decision making with good construct validity. We developed a rat gambling task analogous to the IGT that tracks, for the first time, the ongoing decision process within a single session in an operant cage. Rats could choose between various options. Disadvantageous options, as opposed to advantageous ones, offered bigger immediate food reward but were followed by longer, unpredictable penalties (time-out). The majority of rats can evaluate and deduce favorable options more or less rapidly according to task complexity, whereas others systematically choose disadvantageously. These interindividual differences are stable over time and do not depend on task difficulty or on the level of food restriction. We find that poor decision making does not result from a failure to acquire relevant information but from hypersensitivity to reward and higher risk taking in anxiogenic situations. These results suggest that rats, as well as human poor performers, share similar traits to those observed in decision-making related psychiatric disorders. These traits could constitute risk factors of developing such disorders. The rapid identification of poor decision makers using the rat gambling task should promote the discovery of the specific brain dysfunctions that cause maladapted decision making.
The Adolescent Who Does Not Finish Anything.

ERIC Educational Resources Information Center

Breiner, Sander J.

1985-01-01

Practical information for therapists who deal with adolescents who do not finish tasks is presented. The relationship of task incompletion to neurosis, psychosis, depression, homosexuality, and drug abuse is described, and techniques and guidelines for treatment are provided. (Author)
Differential effects of MDMA and methylphenidate on social cognition.

PubMed

Schmid, Yasmin; Hysek, Cédric M; Simmler, Linda D; Crockett, Molly J; Quednow, Boris B; Liechti, Matthias E

2014-09-01

Social cognition is important in everyday-life social interactions. The social cognitive effects of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate (both used for neuroenhancement and as party drugs) are largely unknown. We investigated the acute effects of MDMA (75 mg), methylphenidate (40 mg) and placebo using the Facial Emotion Recognition Task, Multifaceted Empathy Test, Movie for the Assessment of Social Cognition, Social Value Orientation Test and the Moral Judgment Task in a cross-over study in 30 healthy subjects. Additionally, subjective, autonomic, pharmacokinetic, endocrine and adverse drug effects were measured. MDMA enhanced emotional empathy for positive emotionally charged situations in the MET and tended to reduce the recognition of sad faces in the Facial Emotion Recognition Task. MDMA had no effects on cognitive empathy in the Multifaceted Empathy Test or social cognitive inferences in the Movie for the Assessment of Social Cognition. MDMA produced subjective 'empathogenic' effects, such as drug liking, closeness to others, openness and trust. In contrast, methylphenidate lacked such subjective effects and did not alter emotional processing, empathy or mental perspective-taking. MDMA but not methylphenidate increased the plasma levels of oxytocin and prolactin. None of the drugs influenced moral judgment. Effects on emotion recognition and emotional empathy were evident at a low dose of MDMA and likely contribute to the popularity of the drug. © The Author(s) 2014.
Implicit processing of heroin and emotional cues in abstinent heroin users: early and late event-related potential effects.

PubMed

Yang, Ling; Zhang, Jianxun; Zhao, Xin

2015-05-01

The abnormal cognitive processing of drug cues is a core characteristic of drug dependence. Previous research has suggested that the late positive potential (LPP) of heroin users is increased by heroin-related stimuli because of the attention-grabbing nature of such stimuli. The present research used a modified emotional Stroop (eStroop) task to examine whether there was an early posterior negativity (EPN) modulation to heroin cues compared with emotional or neutral stimuli in heroin dependent subjects. Fifteen former heroin users and 15 matched controls performed the eStroop task, which was composed of positive, negative, heroin-related, and neutral pictures with superimposed color squares. Participants responded to the color of the square and not to the picture while behavioral data and event-related potentials were recorded. There were no significant differences of EPN amplitudes to emotional and neutral stimuli between heroin users and controls. However, heroin users displayed increased EPN modulation for heroin cues, whereas this modulation was absent in controls. Drug-related cues acquire motivational salience and automatically capture the attention of heroin users at early processing stages, even when engaged in a non-drug-related task. The EPN to heroin cues could represent a novel electrophysiological index with clinical implications for selecting abstinent drug users who are at increased risk of relapse or to evaluate treatment interventions.
Measuring Attention in Rodents: Comparison of a Modified Signal Detection Task and the 5-Choice Serial Reaction Time Task

PubMed Central

Turner, Karly M.; Peak, James; Burne, Thomas H. J.

2016-01-01

Neuropsychiatric research has utilized cognitive testing in rodents to improve our understanding of cognitive deficits and for preclinical drug development. However, more sophisticated cognitive tasks have not been as widely exploited due to low throughput and the extensive training time required. We developed a modified signal detection task (SDT) based on the growing body of literature aimed at improving cognitive testing in rodents. This study directly compares performance on the modified SDT with a traditional test for measuring attention, the 5-choice serial reaction time task (5CSRTT). Adult male Sprague-Dawley rats were trained on either the 5CSRTT or the SDT. Briefly, the 5CSRTT required rodents to pay attention to a spatial array of five apertures and respond with a nose poke when an aperture was illuminated. The SDT required the rat to attend to a light panel and respond either left or right to indicate the presence of a signal. In addition, modifications were made to the reward delivery, timing, control of body positioning, and the self-initiation of trials. It was found that less training time was required for the SDT, with both sessions to criteria and daily session duration significantly reduced. Rats performed with a high level of accuracy (>87%) on both tasks, however omissions were far more frequent on the 5CSRTT. The signal duration was reduced on both tasks as a manipulation of task difficulty relevant to attention and a similar pattern of decreasing accuracy was observed on both tasks. These results demonstrate some of the advantages of the SDT over the traditional 5CSRTT as being higher throughput with reduced training time, fewer omission responses and their body position was controlled at stimulus onset. In addition, rats performing the SDT had comparable high levels of accuracy. These results highlight the differences and similarities between the 5CSRTT and a modified SDT as tools for assessing attention in preclinical animal models. PMID:26834597
Fractured families: parental perspectives of the effects of adolescent drug abuse on family life.

PubMed

Jackson, Debra; Usher, Kim; O'Brien, Louise

Drug use in young people has serious ramifications for health and well-being of young people and their families and continues to be an area of major concern for health workers. Though the task of dealing with drug-related problems falls on families, particularly parents, very little literature has explored parental experiences of managing drug use within the context of family life. Eighteen parents of drug-abusing young people were recruited into this qualitative study that aimed to develop understandings into the effects of adolescent drug use on family life. Findings revealed that the experience of having a drug-abusing adolescent family member had a profound effect on other members of the immediate family. Family relationships were fractured and split as a result of the on-going destructive and damaging behaviour of the drug-abusing young person. Five themes were identified that captured the concept of fractured families. These are: betrayal and loss of trust: 'You had to have the doors locked'; abuse, threats and violence: 'there were holes in the wall'; sibling anger and resentment: 'Better off now with him gone'; isolated, disgraced and humiliated: 'You are on your own with it'; and, feeling blamed: 'You are not a good parent'. Implications for practice and further research are drawn from the findings of this paper.
The runway model of drug self-administration

PubMed Central

Ettenberg, Aaron

2009-01-01

Behavioral scientists have employed operant runways as a means of investigating the motivational impact of incentive stimuli for the better part of the past 100 years. In this task, the speed with which a trained animal traverses a long straight alley for positive incentive stimuli, like food or water, provides a reliable index of the subject’s motivation to seek those stimuli. The runway is therefore a particularly appropriate tool for investigating the drug-seeking behavior of animals working for drugs of abuse. The current review describes our laboratory’s work over the past twenty years developing and implementing an operant runway model of drug self-administration. Procedures are described that methodologically dissociate the antecedent motivational processes that induce an animal to seek a drug, from the positive reinforcing consequences of actually earning the drug. Additional work is reviewed on the use of the runway method as a means of modeling the factors that often result in a “relapse” of drug self-administration after a period of abstinence (i.e., a response reinstatement test), as are runway studies that revealed the presence of opposing positive and negative consequences of self-administered cocaine. This body of work suggests that the runway method has served as a powerful behavioral tool for the study of the behavioral and neurobiological basis of drug self-administration. PMID:19032964
BOKP: A DNA Barcode Reference Library for Monitoring Herbal Drugs in the Korean Pharmacopeia

PubMed Central

Liu, Jinxin; Shi, Linchun; Song, Jingyuan; Sun, Wei; Han, Jianping; Liu, Xia; Hou, Dianyun; Yao, Hui; Li, Mingyue; Chen, Shilin

2017-01-01

Herbal drug authentication is an important task in traditional medicine; however, it is challenged by the limitations of traditional authentication methods and the lack of trained experts. DNA barcoding is conspicuous in almost all areas of the biological sciences and has already been added to the British pharmacopeia and Chinese pharmacopeia for routine herbal drug authentication. However, DNA barcoding for the Korean pharmacopeia still requires significant improvements. Here, we present a DNA barcode reference library for herbal drugs in the Korean pharmacopeia and developed a species identification engine named KP-IDE to facilitate the adoption of this DNA reference library for the herbal drug authentication. Using taxonomy records, specimen records, sequence records, and reference records, KP-IDE can identify an unknown specimen. Currently, there are 6,777 taxonomy records, 1,054 specimen records, 30,744 sequence records (ITS2 and psbA-trnH) and 285 reference records. Moreover, 27 herbal drug materials were collected from the Seoul Yangnyeongsi herbal medicine market to give an example for real herbal drugs authentications. Our study demonstrates the prospects of the DNA barcode reference library for the Korean pharmacopeia and provides future directions for the use of DNA barcoding for authenticating herbal drugs listed in other modern pharmacopeias. PMID:29326593

How Do Clinical Information Systems Affect the Cognitive Demands of General Practitioners?: Usability Study with a Focus on Cognitive Workload.

PubMed

Ariza, Ferran; Kalra, Dipak; Potts, Henry Ww

2015-11-20

Clinical information systems in the National Health Service do not need to conform to any explicit usability requirements. Poor usability can increase the mental workload experienced by clinicians and cause fatigue, increase error rates and impact the overall patient safety. Mental workload can be used as a measure of usability. To assess the subjective cognitive workload experienced by general practitioners (GPs) with their systems. To raise awareness of the importance of usability in system design among users, designers, developers and policymakers. We used a modified version of the NASA Task Load Index, adapted for web. We developed a set of common clinical scenarios and computer tasks on an online survey. We emailed the study link to 199 clinical commissioning groups and 1,646 GP practices in England. Sixty-seven responders completed the survey. The respondents had spent an average of 17 years in general practice, had experience of using a mean of 1.5 GP computer systems and had used their current system for a mean time of 6.7 years. The mental workload score was not different among systems. There were significant differences among the task scores, but these differences were not specific to particular systems. The overall score and task scores were related to the length of experience with their present system. Four tasks imposed a higher mental workload on GPs: 'repeat prescribing', 'find episode', 'drug management' and 'overview records'. Further usability studies on GP systems should focus on these tasks. Users, policymakers, designers and developers should remain aware of the importance of usability in system design.What does this study add?• Current GP systems in England do not need to conform to explicit usability requirements. Poor usability can increase the mental workload of clinicians and lead to errors.• Some clinical computer tasks incur more cognitive workload than others and should be considered carefully during the design of a system.• GPs did not report overall very high levels of subjective cognitive workload when undertaking common clinical tasks with their systems.• Further usability studies on GP systems should focus on the tasks incurring higher cognitive workload.• Users, policymakers, and designers and developers should remain aware of the importance of usability in system design.
Responsible pricing in value-based assessment of cancer drugs: real-world data are an inevitable addition to select meaningful new cancer treatments

PubMed Central

van Harten, Wim; IJzerman, Maarten J

2017-01-01

Recently, NICE was given the task of governing the Cancer Drug Fund (CDF) in the UK as the latter was criticized for allowing too many insufficiently tested drugs to be covered [1, 2]. The CDF was initiated in 2012, but immediately received criticism from several health economists because of the rather strict coverage criteria that are commonly used by NICE for most other health services in the NHS. This led to questions about the use of different reimbursement criteria (why have a different fund otherwise?) for expensive cancer drugs. Such a separate fund would potentially take away large amounts of the collective health budget. This led to questions about the use of different reimbursement criteria (why have a different fund otherwise?) for expensive cancer drugs compared to other technologies. This is just one example of discussions that are taking place in many countries on the issue of drug coverage policies. This development takes place against a background of increasingly intense discussion on pricing and affordability of (new) cancer drugs, the responsible behavior of pharmaceutical companies that spend public resources for R&D, and the lack of transparency in pricing and R&D expenditure in combination with profit margins of sometimes up to 20%. We argue that Real-World Evidence (RWE) may play a much greater and, on occasion, pivotal role in developing sustainable cancer care, because it allows much better estimates of actual drug use and costs and increases transparency in health outcomes. PMID:28955404
Responsible pricing in value-based assessment of cancer drugs: real-world data are an inevitable addition to select meaningful new cancer treatments.

PubMed

van Harten, Wim; IJzerman, Maarten J

2017-01-01

Recently, NICE was given the task of governing the Cancer Drug Fund (CDF) in the UK as the latter was criticized for allowing too many insufficiently tested drugs to be covered [1, 2]. The CDF was initiated in 2012, but immediately received criticism from several health economists because of the rather strict coverage criteria that are commonly used by NICE for most other health services in the NHS. This led to questions about the use of different reimbursement criteria (why have a different fund otherwise?) for expensive cancer drugs. Such a separate fund would potentially take away large amounts of the collective health budget. This led to questions about the use of different reimbursement criteria (why have a different fund otherwise?) for expensive cancer drugs compared to other technologies. This is just one example of discussions that are taking place in many countries on the issue of drug coverage policies. This development takes place against a background of increasingly intense discussion on pricing and affordability of (new) cancer drugs, the responsible behavior of pharmaceutical companies that spend public resources for R&D, and the lack of transparency in pricing and R&D expenditure in combination with profit margins of sometimes up to 20%. We argue that Real-World Evidence (RWE) may play a much greater and, on occasion, pivotal role in developing sustainable cancer care, because it allows much better estimates of actual drug use and costs and increases transparency in health outcomes.
High-Performance Signal Detection for Adverse Drug Events using MapReduce Paradigm.

PubMed

Fan, Kai; Sun, Xingzhi; Tao, Ying; Xu, Linhao; Wang, Chen; Mao, Xianling; Peng, Bo; Pan, Yue

2010-11-13

Post-marketing pharmacovigilance is important for public health, as many Adverse Drug Events (ADEs) are unknown when those drugs were approved for marketing. However, due to the large number of reported drugs and drug combinations, detecting ADE signals by mining these reports is becoming a challenging task in terms of computational complexity. Recently, a parallel programming model, MapReduce has been introduced by Google to support large-scale data intensive applications. In this study, we proposed a MapReduce-based algorithm, for common ADE detection approach, Proportional Reporting Ratio (PRR), and tested it in mining spontaneous ADE reports from FDA. The purpose is to investigate the possibility of using MapReduce principle to speed up biomedical data mining tasks using this pharmacovigilance case as one specific example. The results demonstrated that MapReduce programming model could improve the performance of common signal detection algorithm for pharmacovigilance in a distributed computation environment at approximately liner speedup rates.
Identifying interactions between chemical entities in biomedical text.

PubMed

Lamurias, Andre; Ferreira, João D; Couto, Francisco M

2014-10-23

Interactions between chemical compounds described in biomedical text can be of great importance to drug discovery and design, as well as pharmacovigilance. We developed a novel system, \\"Identifying Interactions between Chemical Entities\\" (IICE), to identify chemical interactions described in text. Kernel-based Support Vector Machines first identify the interactions and then an ensemble classifier validates and classifies the type of each interaction. This relation extraction module was evaluated with the corpus released for the DDI Extraction task of SemEval 2013, obtaining results comparable to state-of-the-art methods for this type of task. We integrated this module with our chemical named entity recognition module and made the whole system available as a web tool at www.lasige.di.fc.ul.pt/webtools/iice.
Identifying interactions between chemical entities in biomedical text.

PubMed

Lamurias, Andre; Ferreira, João D; Couto, Francisco M

2014-12-01

Interactions between chemical compounds described in biomedical text can be of great importance to drug discovery and design, as well as pharmacovigilance. We developed a novel system, "Identifying Interactions between Chemical Entities" (IICE), to identify chemical interactions described in text. Kernel-based Support Vector Machines first identify the interactions and then an ensemble classifier validates and classifies the type of each interaction. This relation extraction module was evaluated with the corpus released for the DDI Extraction task of SemEval 2013, obtaining results comparable to stateof- the-art methods for this type of task. We integrated this module with our chemical named entity recognition module and made the whole system available as a web tool at www.lasige.di.fc.ul.pt/webtools/iice.
An Approach for Casual Drug Users. Technical Paper.

ERIC Educational Resources Information Center

Bloom, Erwin S., Ed.

This publication was written to respond to the fact that many drug treatment centers receive inappropriate referrals of casual or recreational marihuana users from the courts for "treatment" as an alternative to jail. A drug abuse task force recommended that agencies give priority to abusers of the high-risk categories and to compulsive users of…
A Framework for Addressing the Needs of Students Prenatally Exposed to Alcohol and Other Drugs

ERIC Educational Resources Information Center

Watson, Silvana M. R.; Westby, Carol E.; Gable, Robert A.

2007-01-01

In this article, the authors review learning and behavioral problems of children exposed prenatally to alcohol and other drugs, focusing on executive-function deficits such as difficulty shifting tasks, maintaining attention, and manipulating information in working memory. They discuss various risk factors associated with prenatal drug exposure so…
75 FR 11893 - Food and Drug Administration Transparency Task Force; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2009-N-0247... Administration, HHS. ACTION: Notice; request for comments. SUMMARY: The Food and Drug Administration (FDA) is soliciting comments from interested persons on ways in which FDA can increase transparency between FDA and...
Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.

PubMed

Kwan, Patrick; Arzimanoglou, Alexis; Berg, Anne T; Brodie, Martin J; Allen Hauser, W; Mathern, Gary; Moshé, Solomon L; Perucca, Emilio; Wiebe, Samuel; French, Jacqueline

2010-06-01

To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.
Animal models of schizophrenia

PubMed Central

Jones, CA; Watson, DJG; Fone, KCF

2011-01-01

Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble ‘positive-like’ symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21449915
Gene Expression Changes in the Motor Cortex Mediating Motor Skill Learning

PubMed Central

Cheung, Vincent C. K.; DeBoer, Caroline; Hanson, Elizabeth; Tunesi, Marta; D'Onofrio, Mara; Arisi, Ivan; Brandi, Rossella; Cattaneo, Antonino; Goosens, Ki A.

2013-01-01

The primary motor cortex (M1) supports motor skill learning, yet little is known about the genes that contribute to motor cortical plasticity. Such knowledge could identify candidate molecules whose targeting might enable a new understanding of motor cortical functions, and provide new drug targets for the treatment of diseases which impair motor function, such as ischemic stroke. Here, we assess changes in the motor-cortical transcriptome across different stages of motor skill acquisition. Adult rats were trained on a gradually acquired appetitive reach and grasp task that required different strategies for successful pellet retrieval, or a sham version of the task in which the rats received pellet reward without needing to develop the reach and grasp skill. Tissue was harvested from the forelimb motor-cortical area either before training commenced, prior to the initial rise in task performance, or at peak performance. Differential classes of gene expression were observed at the time point immediately preceding motor task improvement. Functional clustering revealed that gene expression changes were related to the synapse, development, intracellular signaling, and the fibroblast growth factor (FGF) family, with many modulated genes known to regulate synaptic plasticity, synaptogenesis, and cytoskeletal dynamics. The modulated expression of synaptic genes likely reflects ongoing network reorganization from commencement of training till the point of task improvement, suggesting that motor performance improves only after sufficient modifications in the cortical circuitry have accumulated. The regulated FGF-related genes may together contribute to M1 remodeling through their roles in synaptic growth and maturation. PMID:23637843
Multimodal system designed to reduce errors in recording and administration of drugs in anaesthesia: prospective randomised clinical evaluation.

PubMed

Merry, Alan F; Webster, Craig S; Hannam, Jacqueline; Mitchell, Simon J; Henderson, Robert; Reid, Papaarangi; Edwards, Kylie-Ellen; Jardim, Anisoara; Pak, Nick; Cooper, Jeremy; Hopley, Lara; Frampton, Chris; Short, Timothy G

2011-09-22

To clinically evaluate a new patented multimodal system (SAFERSleep) designed to reduce errors in the recording and administration of drugs in anaesthesia. Prospective randomised open label clinical trial. Five designated operating theatres in a major tertiary referral hospital. Eighty nine consenting anaesthetists managing 1075 cases in which there were 10,764 drug administrations. Use of the new system (which includes customised drug trays and purpose designed drug trolley drawers to promote a well organised anaesthetic workspace and aseptic technique; pre-filled syringes for commonly used anaesthetic drugs; large legible colour coded drug labels; a barcode reader linked to a computer, speakers, and touch screen to provide automatic auditory and visual verification of selected drugs immediately before each administration; automatic compilation of an anaesthetic record; an on-screen and audible warning if an antibiotic has not been administered within 15 minutes of the start of anaesthesia; and certain procedural rules-notably, scanning the label before each drug administration) versus conventional practice in drug administration with a manually compiled anaesthetic record. Primary: composite of errors in the recording and administration of intravenous drugs detected by direct observation and by detailed reconciliation of the contents of used drug vials against recorded administrations; and lapses in responding to an intermittent visual stimulus (vigilance latency task). Secondary: outcomes in patients; analyses of anaesthetists' tasks and assessments of workload; evaluation of the legibility of anaesthetic records; evaluation of compliance with the procedural rules of the new system; and questionnaire based ratings of the respective systems by participants. The overall mean rate of drug errors per 100 administrations was 9.1 (95% confidence interval 6.9 to 11.4) with the new system (one in 11 administrations) and 11.6 (9.3 to 13.9) with conventional methods (one in nine administrations) (P = 0.045 for difference). Most were recording errors, and, though fewer drug administration errors occurred with the new system, the comparison with conventional methods did not reach significance. Rates of errors in drug administration were lower when anaesthetists consistently applied two key principles of the new system (scanning the drug barcode before administering each drug and keeping the voice prompt active) than when they did not: mean 6.0 (3.1 to 8.8) errors per 100 administrations v 9.7 (8.4 to 11.1) respectively (P = 0.004). Lapses in the vigilance latency task occurred in 12% (58/471) of cases with the new system and 9% (40/473) with conventional methods (P = 0.052). The records generated by the new system were more legible, and anaesthetists preferred the new system, particularly in relation to long, complex, and emergency cases. There were no differences between new and conventional systems in respect of outcomes in patients or anaesthetists' workload. The new system was associated with a reduction in errors in the recording and administration of drugs in anaesthesia, attributable mainly to a reduction in recording errors. Automatic compilation of the anaesthetic record increased legibility but also increased lapses in a vigilance latency task and decreased time spent watching monitors. Trial registration Australian New Zealand Clinical Trials Registry No 12608000068369.
Deep learning for pharmacovigilance: recurrent neural network architectures for labeling adverse drug reactions in Twitter posts.

PubMed

Cocos, Anne; Fiks, Alexander G; Masino, Aaron J

2017-07-01

Social media is an important pharmacovigilance data source for adverse drug reaction (ADR) identification. Human review of social media data is infeasible due to data quantity, thus natural language processing techniques are necessary. Social media includes informal vocabulary and irregular grammar, which challenge natural language processing methods. Our objective is to develop a scalable, deep-learning approach that exceeds state-of-the-art ADR detection performance in social media. We developed a recurrent neural network (RNN) model that labels words in an input sequence with ADR membership tags. The only input features are word-embedding vectors, which can be formed through task-independent pretraining or during ADR detection training. Our best-performing RNN model used pretrained word embeddings created from a large, non-domain-specific Twitter dataset. It achieved an approximate match F-measure of 0.755 for ADR identification on the dataset, compared to 0.631 for a baseline lexicon system and 0.65 for the state-of-the-art conditional random field model. Feature analysis indicated that semantic information in pretrained word embeddings boosted sensitivity and, combined with contextual awareness captured in the RNN, precision. Our model required no task-specific feature engineering, suggesting generalizability to additional sequence-labeling tasks. Learning curve analysis showed that our model reached optimal performance with fewer training examples than the other models. ADR detection performance in social media is significantly improved by using a contextually aware model and word embeddings formed from large, unlabeled datasets. The approach reduces manual data-labeling requirements and is scalable to large social media datasets. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1

PubMed Central

Chabernaud, Camille; Mennes, Maarten; Kardel, Peter G.; Gaillard, William D.; Kalbfleisch, M. Layne; VanMeter, John W.; Packer, Roger J.; Milham, Michael P.; Castellanos, Francisco X.; Acosta, Maria T.

2012-01-01

In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as “continuous resting-state data” for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model. PMID:22433254
Harm reduction and “Clean” community: can Viet Nam have both?

PubMed Central

2012-01-01

The findings of our research show that while police play multiple roles in the fight against drug-related crime, they often perceived their tasks – especially preventing and controlling drug use on the one hand, and supporting harm reduction on the other – as contradictory, and this creates tensions in their work and relations with their communities. Although they are leaders and implementers of harm reduction, not all police know about it, and some remain skeptical or perceive it as contradictory to their main task of fighting drugs. Methadone treatment is seen by some as in competition with their main task of coordinating conventional drug treatment in the rehabilitation center. The history of drug use and the evolution of discourses on drug use in Viet Nam have created these conflicting pressures on police, and thus created contradictory expectations and led to different views and attitudes of police regarding various harm reduction measures. This might aid understanding why, despite the comprehensive and progressive policies on HIV/AIDS and harm reduction in Viet Nam, it is not easy for police to actively and effectively support and be involved in harm reduction at the ground level. To promote the wider acceptance of harm reduction the concept of community safety must be expanded to include community health; harm reduction must be integrated into the “new society” movement; and laws and policies need further revision to reduce contradiction between current drug laws and HIV laws. Harm reduction guidelines for police and other actors need to be disseminated and supported, embodying better ways of working between sectors, and all sectors in the partnership require support for building capacity to contribute to the overall goal. PMID:22769430
Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper.

PubMed

Brockow, K; Aberer, W; Atanaskovic-Markovic, M; Bavbek, S; Bircher, A; Bilo, B; Blanca, M; Bonadonna, P; Burbach, G; Calogiuri, G; Caruso, C; Celik, G; Cernadas, J; Chiriac, A; Demoly, P; Oude Elberink, J N G; Fernandez, J; Gomes, E; Garvey, L H; Gooi, J; Gotua, M; Grosber, M; Kauppi, P; Kvedariene, V; Laguna, J J; Makowska, J S; Mosbech, H; Nakonechna, A; Papadopolous, N G; Ring, J; Romano, A; Rockmann, H; Sargur, R; Sedlackova, L; Sigurdardottir, S; Schnyder, B; Storaas, T; Torres, M; Zidarn, M; Terreehorst, I

2016-11-01

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Endophytic fungi: a reservoir of antibacterials

PubMed Central

Deshmukh, Sunil K.; Verekar, Shilpa A.; Bhave, Sarita V.

2015-01-01

Multidrug drug resistant bacteria are becoming increasingly problematic particularly in the under developed countries of the world. The most important microorganisms that have seen a geometric rise in numbers are Methicillin resistant Staphylococcus aureus, Vancomycin resistant Enterococcus faecium, Penicillin resistant Streptococcus pneumonia and multiple drug resistant tubercule bacteria to name a just few. New drug scaffolds are essential to tackle this every increasing problem. These scaffolds can be sourced from nature itself. Endophytic fungi are an important reservoir of therapeutically active compounds. This review attempts to present some data relevant to the problem. New, very specific and effective antibiotics are needed but also at an affordable price! A Herculean task for researchers all over the world! In the Asian subcontinent indigenous therapeutics that has been practiced over the centuries such as Ayurveda have been effective as “handed down data” in family generations. May need a second, third and more “in-depth investigations?” PMID:25620957
Modeling the effect of dynamic surfaces on membrane penetration

NASA Astrophysics Data System (ADS)

van Lehn, Reid; Alexander-Katz, Alfredo

2011-03-01

The development of nanoscale materials for targeted drug delivery is an important current pursuit in materials science. One task of drug carriers is to release therapeutic agents within cells by bypassing the cell membrane to maximize the effectiveness of their payload and minimize bodily exposure. In this work, we use coarse-grained simulations to study nanoparticles (NPs) grafted with hydrophobic and hydrophilic ligands that rearrange in response to the amphiphilic lipid bilayer. We demonstrate that this dynamic surface permits the NP to spontaneously penetrate to the bilayer midplane when the surface ligands are near an order-disorder transition. We believe that this work will lead to the design of new drug carriers capable of non-specifically accessing cell interiors based solely on their dynamic surface properties. Our work is motivated by existing nanoscale systems such as micelles, or NPs grafted with highly mobile ligands or polymer brushes.
Functional evaluation of out-of-the-box text-mining tools for data-mining tasks

PubMed Central

Jung, Kenneth; LePendu, Paea; Iyer, Srinivasan; Bauer-Mehren, Anna; Percha, Bethany; Shah, Nigam H

2015-01-01

Objective The trade-off between the speed and simplicity of dictionary-based term recognition and the richer linguistic information provided by more advanced natural language processing (NLP) is an area of active discussion in clinical informatics. In this paper, we quantify this trade-off among text processing systems that make different trade-offs between speed and linguistic understanding. We tested both types of systems in three clinical research tasks: phase IV safety profiling of a drug, learning adverse drug–drug interactions, and learning used-to-treat relationships between drugs and indications. Materials We first benchmarked the accuracy of the NCBO Annotator and REVEAL in a manually annotated, publically available dataset from the 2008 i2b2 Obesity Challenge. We then applied the NCBO Annotator and REVEAL to 9 million clinical notes from the Stanford Translational Research Integrated Database Environment (STRIDE) and used the resulting data for three research tasks. Results There is no significant difference between using the NCBO Annotator and REVEAL in the results of the three research tasks when using large datasets. In one subtask, REVEAL achieved higher sensitivity with smaller datasets. Conclusions For a variety of tasks, employing simple term recognition methods instead of advanced NLP methods results in little or no impact on accuracy when using large datasets. Simpler dictionary-based methods have the advantage of scaling well to very large datasets. Promoting the use of simple, dictionary-based methods for population level analyses can advance adoption of NLP in practice. PMID:25336595

Exploring Spanish health social media for detecting drug effects

PubMed Central

2015-01-01

Background Adverse Drug reactions (ADR) cause a high number of deaths among hospitalized patients in developed countries. Major drug agencies have devoted a great interest in the early detection of ADRs due to their high incidence and increasing health care costs. Reporting systems are available in order for both healthcare professionals and patients to alert about possible ADRs. However, several studies have shown that these adverse events are underestimated. Our hypothesis is that health social networks could be a significant information source for the early detection of ADRs as well as of new drug indications. Methods In this work we present a system for detecting drug effects (which include both adverse drug reactions as well as drug indications) from user posts extracted from a Spanish health forum. Texts were processed using MeaningCloud, a multilingual text analysis engine, to identify drugs and effects. In addition, we developed the first Spanish database storing drugs as well as their effects automatically built from drug package inserts gathered from online websites. We then applied a distant-supervision method using the database on a collection of 84,000 messages in order to extract the relations between drugs and their effects. To classify the relation instances, we used a kernel method based only on shallow linguistic information of the sentences. Results Regarding Relation Extraction of drugs and their effects, the distant supervision approach achieved a recall of 0.59 and a precision of 0.48. Conclusions The task of extracting relations between drugs and their effects from social media is a complex challenge due to the characteristics of social media texts. These texts, typically posts or tweets, usually contain many grammatical errors and spelling mistakes. Moreover, patients use lay terminology to refer to diseases, symptoms and indications that is not usually included in lexical resources in languages other than English. PMID:26100267
NO-SSRIs: Nitric Oxide Chimera Drugs Incorporating a Selective Serotonin Reuptake Inhibitor

PubMed Central

2011-01-01

Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 h. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter; however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061) were made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide cotherapy of neuropathologies concomitant with depression. PMID:21927645
Reward-Based Learning as a Function of Severity of Substance Abuse Risk in Drug-Naïve Youth with ADHD.

PubMed

Parvaz, Muhammad A; Kim, Kristen; Froudist-Walsh, Sean; Newcorn, Jeffrey H; Ivanov, Iliyan

2018-06-20

Attention-deficit/hyperactivity disorder (ADHD) is associated with elevated risk for later development of substance use disorders (SUD), specifically because youth with ADHD, similar to individuals with SUD, exhibit deficits in learning abilities and reward processing. Another known risk factor for SUD is familial history of substance dependence. Youth with familial SUD history show reward processing deficits, higher prevalence of externalizing disorders, and higher impulsivity scores. Thus, the main objective of this proof-of-concept study is to investigate whether risk loading (ADHD and parental substance use) for developing SUD in drug-naïve youth impacts reward-related learning. Forty-one drug-naïve youth, stratified into three groups: Healthy Controls (HC, n = 13; neither ADHD nor parental SUD), Low Risk (LR, n = 13; ADHD only), and High Risk (HR, n = 15; ADHD and parental SUD), performed a novel Anticipation, Conflict, and Reward (ACR) task. In addition to conventional reaction time (RT) and accuracy analyses, we analyzed computational variables including learning rates and assessed the influence of learned predictions of reward probability and stimulus congruency on RT. The multivariate ANOVA on learning rate, congruence, and prediction revealed a significant main Group effect across these variables [F(3, 37) = 3.79, p = 0.018]. There were significant linear effects for learning rate (Contrast Estimate = 0.181, p = 0.038) and the influence of stimulus congruency on RTs (Contrast Estimate = 1.16, p = 0.017). Post hoc comparisons revealed that HR youth showed the most significant deficits in accuracy and learning rates, while stimulus congruency had a lower impact on RTs in this group. LR youth showed scores between those of the HC and HR youth. These preliminary results suggest that deficits in learning and in adjusting to task difficulty are a function of increasing risk loading for SUD in drug-naïve youth. These results also highlight the importance of developing and applying computational models to study intricate details in behavior that typical analytic methodology may not be sensitive to.
Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.
Chemical proteomics for target discovery of head-to-tail cyclized mini-proteins

NASA Astrophysics Data System (ADS)

Hellinger, Roland; Thell, Kathrin; Vasileva, Mina; Muhammad, Taj; Gunasekera, Sunithi; Kümmel, Daniel; Göransson, Ulf; Becker, Christian W.; Gruber, Christian W.

2017-10-01

Target deconvolution is one of the most challenging tasks in drug discovery, but a key step in drug development. In contrast to small molecules, there is a lack of validated and robust methodologies for target elucidation of peptides. In particular, it is difficult to apply these methods to cyclic and cysteine-stabilized peptides since they exhibit reduced amenability to chemical modification and affinity capture; however, such ribosomal synthesized and post-translationally modified peptide natural products are rich sources of promising drug candidates. For example, plant-derived circular peptides called cyclotides have recently attracted much attention due to their immunosuppressive effects and oral activity in the treatment of multiple sclerosis in mice, but their molecular target has hitherto not been reported. In this study a chemical proteomics approach using photo-affinity crosslinking was developed to determine a target of the circular peptide [T20K]kalata B1. Using this prototypic nature-derived peptide enabled the identification of a possible modulation of 14-3-3 proteins. This biochemical interaction was validated via competition pull down assays as well as a cellular reporter assay indicating an effect on 14-3-3-dependent transcriptional activity. As proof of concept, the presented approach may be applicable for target elucidation of various cyclic peptides and mini-proteins, in particular cyclotides, which represent a promising class of molecules in drug discovery and development.
Spotlight on valsartan-sacubitril fixed-dose combination for heart failure: the evidence to date.

PubMed

Vilela-Martin, José Fernando

2016-01-01

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin-angiotensin-aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.
Spotlight on valsartan–sacubitril fixed-dose combination for heart failure: the evidence to date

PubMed Central

Vilela-Martin, José Fernando

2016-01-01

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin–angiotensin–aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease. PMID:27274196
Living on pyrrolic foundations - Advances in natural and artificial bioactive pyrrole derivatives.

PubMed

Domagala, Anna; Jarosz, Tomasz; Lapkowski, Mieczyslaw

2015-07-15

Pyrrole, a simple heterocyclic system, is an important building block for numerous biologically active compounds both natural and synthetic in origin, which boast an immense array of qualities, baleful and beneficial alike. The latter have given rise to a bountiful variety of pyrrole-based drugs, with many more being designed, developed and applied each year, as evidenced by the amount of entries in the Cambridge Structural Database skyrocketing from about six hundred in 2004 to more than a thousand over the course of the last decade. Particularly important in light of the ever-encroaching menace of drug-resistant bacteria, the vast progress in the field necessitates a sound organisational framework and summary - a task, to which we contribute this summary and checklist of the most recent developments, indicating the classes of compounds, which have attracted the most significant research attention. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Report of the ASHP Task Force on Caring for Patients Served by Specialty Suppliers.

PubMed

Caselnova, Dominick; Donley, Kathy; Ehlers, Diane; Hyduk, Amy E; Koontz, Susannah E; Nowobilski-Vasilios, Anna; Pawlicki, Kathleen S; Poikonen, John C; Poremba, Art C; Sasser, Cathy L; Schell, Kenneth H; Schwab, Jay L; Swinarski, Dave; Chen, David; Kirschenbaum, Bonnie; Armitstead, John

2010-10-01

Task Force recommendations are discussed in more detail in eAppendix A (available at www.ajhp.org). What follows is a brief summary of those recommendations. In very abbreviated terms, the Task Force suggested that ASHP: 1. Consider creating and maintaining a Web resource center on ASHP's website to provide information about restricted drug distributions systems (RDDSs), risk evaluation and mitigation strategies (REMSs), risk assessment and minimization plans (RiskMAPs), and specialty suppliers and products. 2. Provide comprehensive education to members, other health professionals, regulators, third-party payers, patients, and other stakeholders about RDDSs, REMSs, RiskMAPs, and specialty suppliers and products. 3. Develop policies to advocate that a. Pharmacists serve as the institutional leaders in compliance and utilization challenges of safely managing externally supplied medications and related drug administration devices, b. Agencies, organizations, and associations that influence the distribution, sale, and dispensing of medications under these alternative distribution models address issues these models create in continuity of care, reimbursement, and patient safety, c. The Centers for Medicare and Medicaid Services and the Joint Commission develop standards and interpretations that accommodate hospital use of these products and devices when currently available technology (e.g., cold-chain storage, e-pedigree) is used to ensure patient safety, d. Group purchasing organizations negotiate contractual arrangements for specialty pharmaceuticals for both acquisition costs and distribution arrangements, and e. Information technology (IT) be used to resolve issues created by alternative distribution models and that ASHP work with IT vendors to ensure that programs are designed to meet the needs of these evolving models. 4. Quantify through research, perhaps in cooperation with entities such as the Agency for Healthcare Research and Quality, the Institute of Medicine, and the Institute for Safe Medication Practices, the impact of alternative distribution models on financial, safety, clinical, and humanistic patient outcomes. 5. Develop multidisciplinary tools and best practices that assist health care practitioners address the challenges created by alternative distribution models, from patient intake and referral to hospital discharge.
Illicit Drugs and African American Youth in Summit University. A Summit University Anti-Drug Initiative Task Force Report.

ERIC Educational Resources Information Center

Minnesota State Dept. of Human Services, St. Paul. Chemical Dependency Program Div.

This report addresses the legislation passed by the 1990 Minnesota Legislature concerning the African American Youth Treatment Planning effort for providing five recommendations on prevention, treatment, and aftercare of drug abuse for this population. Based on a literature review and needs assessment that entailed a demographic and socioeconomic…
Anticipatory reward processing in addicted populations: a focus on the monetary incentive delay task.

PubMed

Balodis, Iris M; Potenza, Marc N

2015-03-01

Advances in brain imaging techniques have allowed neurobiological research to temporally analyze signals coding for the anticipation of reward. In addicted populations, both hyporesponsiveness and hyperresponsiveness of brain regions (e.g., ventral striatum) implicated in drug effects and reward system processing have been reported during anticipation of generalized reward. We discuss the current state of knowledge of reward processing in addictive disorders from a widely used and validated task: the monetary incentive delay task. Only studies applying the monetary incentive delay task in addicted and at-risk adult populations are reviewed, with a focus on anticipatory processing and striatal regions activated during task performance as well as the relationship of these regions with individual difference (e.g., impulsivity) and treatment outcome variables. We further review drug influences in challenge studies as a means to examine acute influences on reward processing in abstinent, recreationally using, and addicted populations. Generalized reward processing in addicted and at-risk populations is often characterized by divergent anticipatory signaling in the ventral striatum. Although methodologic and task variations may underlie some discrepant findings, anticipatory signaling in the ventral striatum may also be influenced by smoking status, drug metabolites, and treatment status in addicted populations. Divergent results across abstinent, recreationally using, and addicted populations demonstrate complexities in interpreting findings. Future studies would benefit from focusing on characterizing how impulsivity and other addiction-related features relate to anticipatory striatal signaling over time. Additionally, identifying how anticipatory signals recover or adjust after protracted abstinence will be important in understanding recovery processes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
How to develop a proactive formulary system.

PubMed

Crane, V S; Gonzalez, E R; Hull, B L

1994-10-01

To develop a quality formulary system, a proactive approach is necessary. This approach incorporates a prospective product and concurrent product analyses. A prospective product analysis, in turn, involves a review of current formulary agents, those likely to enter the marketplace shortly, and the formation of an expert review panel. This panel's tasks are to examine therapeutic, economic, and humanistic aspects of therapy and to set initial parameters for appropriate and cost-effective use of accepted products. Keys to a successful formulary system are to continuously monitor drug use and compliance with criteria and to work collaboratively with all institutional professionals in the development, implementation, and monitoring of the system.
Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans.

PubMed

Laczó, Jan; Markova, Hana; Lobellova, Veronika; Gazova, Ivana; Parizkova, Martina; Cerman, Jiri; Nekovarova, Tereza; Vales, Karel; Klovrzova, Sylva; Harrison, John; Windisch, Manfred; Vlcek, Kamil; Svoboda, Jan; Hort, Jakub; Stuchlik, Ales

2017-02-01

Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.
Unified Tri-service Cognitive Performance Assessment Battery (UTC-PAB). Part 1: Design and specification of the battery

NASA Astrophysics Data System (ADS)

Englund, C. E.; Reeves, D. L.; Shingledecker, C. A.; Thorne, D. R.; Wilson, K. P.

1987-02-01

The Unified Tri-Service Cognitive Performance Assessment Battery (UTC-PAB) represents the primary metric for a Level 2 evaluation of cognitive performance in the JWGD3 MILPERF chemical defense biomedical drug screening program. Emphasis for UTC-PAB development has been on the standardization of test batteries across participating laboratories with respect to content, computer-based administration, test scoring, and data formatting. This effort has produced a 25-test UTC-PAB that represents the consolidation and unification of independent developments by the Tri-service membership. Test selection was based on established test validity and relevance of military performance. Sensitivity to effects of hostile environments and sustained operations were also considerations involved in test selection. Information processing, decision making, perception, and mental workload capacity are among the processes and abilities addressed in the battery. The UTC-PAB represents a dynamic approach to battery development. The nature of the biomedical drugs screened and information from performance centered task analyses will direct the form of future versions of the battery.
Testing New Drugs for Treatment of Melanoma Patients Applying Connectivity Map Database Analysis with Melanoma Gene Signatures

DTIC Science & Technology

2012-10-01

use of R packages implemented in Bioconductor. Each dataset was normalized from raw data using the Frozen RMA (fRMA) algorithm . We applied the same...because development of the specific algorithms and fine tuning of the analytic strategy to accomplish this task was not immediately straightforward. We...express firefly luciferase using a retrovirus that encodes a fusion of luciferase and neomycin phosphotransferase (LucNeo), will be implanted and followed
78 FR 56737 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-13

... system as the ``Organized Crime Drug Enforcement Task Forces Management Information System'' (OCDETF MIS... Task Forces Management Information System (OCDETF MIS). SECURITY CLASSIFICATION: Unclassified. SYSTEM... Office of Management and Budget (OMB) Circular No. A-130, notice is hereby given that the Department of...
A Manual Control Test for the Detection and Deterrence of Impaired Drivers

NASA Technical Reports Server (NTRS)

Stein, A. C.; Allen, R. W.; Jex, H. R.

1984-01-01

A brief manual control test and a decision strategy were developed, laboratory tested, and field validated which provide a means for detecting human operator impairment from alcohol or other drugs. The test requires the operator to stabilize progressively unstable controlled element dynamics. Control theory and experimental data verify that the human operator's control ability on this task is constrained by basic cybernetic characteristics, and that task performance is reliably affected by impairment effects on these characteristics. Assessment of human operator control ability is determined by a statistically based decision strategy. The operator is allowed several chances to exceed a preset pass criterion. Procedures are described for setting the pass criterion based on individual ability and a desired unimpaired failure rate. These procedures were field tested with apparatus installed in automobiles that were designed to discourage drunk drivers from operating their vehicles. This test program demonstrated that the control task and detection strategy could be applied in a practical setting to screen human operators for impairment in their basic cybernetic skills.
Neurocognitive Characterizations of Russian Heroin Addicts without a Significant History of Other Drug Use

PubMed Central

Fishbein, Diana H.; Krupitsky, Evgeny; Flannery, Barbara A.; Langevin, Doris J.; Bobashev, Georgiy; Verbitskaya, Elena; Augustine, Cynthia B.; Bolla, Karen I.; Zvartau, Edwin; Schech, Barry; Egorova, Valentina; Bushara, Natali; Tsoy, Marina

2007-01-01

Research on the neurocognitive characteristics of heroin addiction is sparse and studies that do exist include polydrug abusers; thus, they are unable to distinguish neurocognitive effects of heroin from those of other drugs. To identify neurocognitive correlates specific to heroin addiction, the present study was conducted in St. Petersburg, Russia where individuals typically abuse and/or become addicted to only one substance, generally alcohol or heroin. Heroin addicts were recruited from an inpatient treatment facility in St. Petersburg. Three comparison groups included alcoholics, addicts who used both alcohol and heroin, and non-abusers. Psychiatric, background, and drug history evaluations were administered after detoxification to screen for exclusion criteria and characterize the sample. Executive Cognitive Functions (ECF) that largely activate areas of the prefrontal cortex and its circuitry measured include complex visual pattern recognition (Paired Associates Learning), working memory (Delayed Matching to Sample), problem solving (Stockings of Cambridge), executive decision making (Cambridge Decision Making Task), cognitive flexibility (Stroop Color-Word Task) and response shifting (Stop Change Task). In many respects, the heroin addicts were similar to alcohol and alcohol\\heroin dependent groups in neurocognitive deficits relative to controls. The primary finding was that heroin addicts exhibited significantly more disadvantageous decision making and longer deliberation times while making risky decisions than the other groups. Because the nature and degree of recovery from drug abuse are likely a function of the type or pattern of neurocognitive impairment, differential drug effects must be considered. PMID:17382488
Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance.

PubMed

Weed, M R; Taffe, M A; Polis, I; Roberts, A C; Robbins, T W; Koob, G F; Bloom, F E; Gold, L H

1999-10-25

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.
Nuclear Drug Delivery for Breast Cancer Chemotherapy

DTIC Science & Technology

2008-09-01

similar results were obtained. 10.;)UI:SJI:IJI Il:l1lVl;) Polymer -drug conjugate, nuclear drug delivery, drug resistance, breast cancer 10...conjugates (5 Months): a. Synthesize linear polyethyleneimine (pEl, Mn ~5-10kDa) by ring-opening polymerization . b. React the PEl with proper 5-membered...functionalized CR-PEI. Milestone 1: Obtaining the FA- or LHRH-functionalized TCRC with optimal charge-reversal kinetics. TASK 2. To in vitro and in vivo evaluate

Modafinil improves rapid shifts of attention.

PubMed

Marchant, Natalie L; Kamel, Faddy; Echlin, Kezia; Grice, John; Lewis, Mark; Rusted, Jennifer M

2009-01-01

The majority of studies investigating the cognitive effects of modafinil, a wake-promoting compound, demonstrate some improvements in attention. The potential of the drug to selectively benefit distinct components of attention has yet to be fully explored in healthy adults. The present study was conducted to investigate modafinil's effect on specific cognitive tasks that tax components of attention switching. One required the rapid switching of attention between stimuli, and another contained an embedded working memory component on top of the attentional shift requirements. Additionally, prospective memory was examined, which requires the interruption of an ongoing activity to retrieve and act upon a previously formed intention. Healthy non-smoking volunteers, matched on age, intelligence, and baseline cognitive ability, received either a capsule that contained 200 mg modafinil or placebo. Subjective measures of mood and physiological response were taken throughout the experimental session, and the tasks were completed between 2 and 3 h post-dosing. Two hundred milligrams modafinil improved accuracy without a reaction time trade-off, in both conditions of the attention-shifting task, but only when resources were most challenged. In contrast, the drug afforded no improvement in prospective remembering or in the ongoing task that was interrupted. Modafinil appears to promote rapid switching of attention in conditions that are most demanding, whilst it offers no benefits in a task that requires unpredictable and infrequent disengagement of attention from an ongoing task in order to act upon an alternative task.
Deficits in complex motor functions, despite no evidence of procedural learning deficits, among HIV+ individuals with history of substance dependence

PubMed Central

Gonzalez, Raul; Jacobus, Joanna; Amatya, Anup K.; Quartana, Phillip J.; Vassileva, Jasmin; Martin, Eileen M.

2008-01-01

HIV and drugs of abuse affect common neural systems underlying procedural memory, including the striatum. We compared performance of 48 HIV seropositive (HIV+) and 48 HIV seronegative (HIV−) participants with history of cocaine and/or heroin dependence across multiple Trial Blocks of three procedural learning (PL) tasks: Rotary Pursuit (RPT), Mirror Star Tracing (MST), and Weather Prediction (WPT). Groups were well matched on demographic, psychiatric, and substance use parameters, and all participants were verified abstinent from drugs. Mixed model ANOVAs revealed that the HIV+ group performed more poorly across all tasks, with a significant main effect of HIV serostatus observed on the MST and a trend toward significance obtained for the RPT. No significant differences were observed on the WPT. Both groups demonstrated significant improvements in performance across all three PL tasks. Importantly, no significant Serostatus X Trial Block interactions were observed on any task. Thus, the HIV+ group tended to perform worse than the HIV− group across all trial blocks of PL tasks with motor demands, but showed no differences in their rate of improvement across all tasks. These findings are consistent with HIV-associated deficits in complex motor skills, but not in procedural learning. PMID:18999351
A relational learning approach to Structure-Activity Relationships in drug design toxicity studies.

PubMed

Camacho, Rui; Pereira, Max; Costa, Vítor Santos; Fonseca, Nuno A; Adriano, Carlos; Simões, Carlos J V; Brito, Rui M M

2011-09-16

It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current "target-rich, lead-poor" scenario. Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal--iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms. Copyright 2011 The Author(s). Published by Journal of Integrative Bioinformatics.
Pavlovian-to-instrumental transfer in alcohol dependence: a pilot study.

PubMed

Garbusow, Maria; Schad, Daniel J; Sommer, Christian; Jünger, Elisabeth; Sebold, Miriam; Friedel, Eva; Wendt, Jean; Kathmann, Norbert; Schlagenhauf, Florian; Zimmermann, Ulrich S; Heinz, Andreas; Huys, Quentin J M; Rapp, Michael A

2014-01-01

Pavlovian processes are thought to play an important role in the development, maintenance and relapse of alcohol dependence, possibly by influencing and usurping ongoing thought and behavior. The influence of pavlovian stimuli on ongoing behavior is paradigmatically measured by pavlovian-to-instrumental transfer (PIT) tasks. These involve multiple stages and are complex. Whether increased PIT is involved in human alcohol dependence is uncertain. We therefore aimed to establish and validate a modified PIT paradigm that would be robust, consistent and tolerated by healthy controls as well as by patients suffering from alcohol dependence, and to explore whether alcohol dependence is associated with enhanced PIT. Thirty-two recently detoxified alcohol-dependent patients and 32 age- and gender-matched healthy controls performed a PIT task with instrumental go/no-go approach behaviors. The task involved both pavlovian stimuli associated with monetary rewards and losses, and images of drinks. Both patients and healthy controls showed a robust and temporally stable PIT effect. Strengths of PIT effects to drug-related and monetary conditioned stimuli were highly correlated. Patients more frequently showed a PIT effect, and the effect was stronger in response to aversively conditioned CSs (conditioned suppression), but there was no group difference in response to appetitive CSs. The implementation of PIT has favorably robust properties in chronic alcohol-dependent patients and in healthy controls. It shows internal consistency between monetary and drug-related cues. The findings support an association of alcohol dependence with an increased propensity towards PIT. © 2014 S. Karger AG, Basel.
ZK DrugResist 2.0: A TextMiner to extract semantic relations of drug resistance from PubMed.

PubMed

Khalid, Zoya; Sezerman, Osman Ugur

2017-05-01

Extracting useful knowledge from an unstructured textual data is a challenging task for biologists, since biomedical literature is growing exponentially on a daily basis. Building an automated method for such tasks is gaining much attention of researchers. ZK DrugResist is an online tool that automatically extracts mutations and expression changes associated with drug resistance from PubMed. In this study we have extended our tool to include semantic relations extracted from biomedical text covering drug resistance and established a server including both of these features. Our system was tested for three relations, Resistance (R), Intermediate (I) and Susceptible (S) by applying hybrid feature set. From the last few decades the focus has changed to hybrid approaches as it provides better results. In our case this approach combines rule-based methods with machine learning techniques. The results showed 97.67% accuracy with 96% precision, recall and F-measure. The results have outperformed the previously existing relation extraction systems thus can facilitate computational analysis of drug resistance against complex diseases and further can be implemented on other areas of biomedicine. Copyright © 2017 Elsevier Inc. All rights reserved.
Highlights in Endocytosis of Nanostructured Systems.

PubMed

Voltan, Aline R; Alarcon, Kaila M; Fusco-Almeida, Ana M; Soares, Christiane P; Mendes-Giannini, Maria J S; Chorilli, Marlus

2017-01-01

The focus of this review is the cellular internalisation mechanism of nanostructured systems (NSs) and their endosomal escape for targeted drug delivery. Endocytosis is a cellular process of internalisation of different molecules and foreign microorganisms. It is currently being studied for drug delivery through nanostructured systems. The most commonly studied routes of cellular uptake are phagocytosis, macro-pinocytosis, clathrinmediated endocytosis, caveolin-mediated endocytosis, and clathrin and caveolinindependent endocytosis. The mechanism utilised by NSs for cellular entry depends on factors such as cell type and its physicochemical properties. Currently, with the development of drugs-loaded onto NSs, it has been possible to increase the therapeutic index against few diseases. The NSs can deliver the active drug at locations that conventional drugs cannot, thereby minimising unwanted side effects. On cellular entry of NSs, there is a possibility of an endosomal escape of the contents into the cytoplasm, a mechanism that can be exploited so that NSs can migrate intra-cellularly and deliver the drug to the target of interest. Designing endolysosomal escape strategy is not an easy task, but it is critical for the optimal pharmacological action on the target tissue. The cellular uptake of drugs is a very important factor in therapy. Although NSs have emerged as effective drug delivery vehicle for treatment of diseases, it is crucial to understand the mechanism of NSs endocytosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Relationship between ecstasy use and depression: a study controlling for poly-drug use

PubMed Central

Roiser, Jonathan P.; Sahakian, Barbara J.

2008-01-01

Rationale 3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) causes serotonin neuron damage in laboratory animals. The serotonin system is known to be important in the regulation of mood. Previous research has shown that MDMA users score higher on self-report ratings of depression than controls. However, MDMA users commonly take other illicit substances and many studies do not fully control for poly-drug use. Objectives The aim of this study was to examine the relationship between MDMA use and affective disturbance, while fully controlling for poly-drug use. Methods Participants were 30 current MDMA users, 30 poly-drug controls who had never used MDMA, 30 drug-naïve controls with no history of illicit drug use and 20 ex-MDMA users. The current MDMA users and poly-drug controls were well matched on all indices of non-MDMA drug use. All participants were administered the Beck Depression Inventory (BDI) and the Affective Go/No-go task, which has been shown to be sensitive to depression. Results The current and ex-MDMA users scored significantly higher on the BDI than the drug-naive controls, but were not significantly different from the poly-drug controls. There were no differences between the groups in terms of affective bias scores on the Affective Go/No-go task. Conclusions Increased scores on self-report depression scales in MDMA users are not entirely attributable to MDMA use. MDMA users do not show the same attentional bias towards negatively toned material as depressed patients. PMID:14652710
The impact of the legal regime of intellectual property protection in the pharmaceutical market.

PubMed

Pashkov, Vitaliy M; Golovanova, Iryna A; Olefir, Andrii A

the functioning of the healthcare industry in any country is impossible without providing enough medicines for patient care. This problem can best be resolved only when the majority of drugs, especially vital, will be made at national plants (industry). In this context, competition from generic drugs is the most optimal strategy to reduce drug's prices. the paper should examine how the legal regime of intellectual property affects the availability of medicines for people and identify ways of supporting breakthrough inventions and counter ≪unreal innovations≫. for the purpose of study were generalized information from the scientific journals of medical and legal perspective, monographs by using a set of scientific methods. Namely under systematic approach have been analyzed the problems of pharmaceutical market, ways of producing generic and original drugs. Comparative legal method was useful for learning features of flexible mechanisms of the TRIPS Agreement and market regulation of medicines in the world. based on the research was found that developed countries with strong pharmaceutical industry are interested in maximizing the protection of intellectual property rights, including importing countries. Flexible mechanisms of the TRIPS Agreement can be useful for developing countries. thus, successful development of pharmaceutical industry and health care should be accompanied by the following measures: - improvement of public health must be recognized as a main task of government policy; - substantial state support aimed at increasing the availability of drugs in the domestic market and the strengthening of export potential; - decrease patent protection of medicines and stimulate market launch of generic copies.
The impact of the legal regime of intellectual property protection in the pharmaceutical market.

PubMed

Pashkov, Vitaliy M; Golovanova, Iryna A; Olefir, Andrii A

2016-01-01

the functioning of the healthcare industry in any country is impossible without providing enough medicines for patient care. This problem can best be resolved only when the majority of drugs, especially vital, will be made at national plants (industry). In this context, competition from generic drugs is the most optimal strategy to reduce drug's prices. the paper should examine how the legal regime of intellectual property affects the availability of medicines for people and identify ways of supporting breakthrough inventions and counter ≪unreal innovations≫. for the purpose of study were generalized information from the scientific journals of medical and legal perspective, monographs by using a set of scientific methods. Namely under systematic approach have been analyzed the problems of pharmaceutical market, ways of producing generic and original drugs. Comparative legal method was useful for learning features of flexible mechanisms of the TRIPS Agreement and market regulation of medicines in the world. based on the research was found that developed countries with strong pharmaceutical industry are interested in maximizing the protection of intellectual property rights, including importing countries. Flexible mechanisms of the TRIPS Agreement can be useful for developing countries. thus, successful development of pharmaceutical industry and health care should be accompanied by the following measures: - improvement of public health must be recognized as a main task of government policy; - substantial state support aimed at increasing the availability of drugs in the domestic market and the strengthening of export potential; - decrease patent protection of medicines and stimulate market launch of generic copies.
A probabilistic approach to identify putative drug targets in biochemical networks.

PubMed

Murabito, Ettore; Smallbone, Kieran; Swinton, Jonathan; Westerhoff, Hans V; Steuer, Ralf

2011-06-06

Network-based drug design holds great promise in clinical research as a way to overcome the limitations of traditional approaches in the development of drugs with high efficacy and low toxicity. This novel strategy aims to study how a biochemical network as a whole, rather than its individual components, responds to specific perturbations in different physiological conditions. Proteins exerting little control over normal cells and larger control over altered cells may be considered as good candidates for drug targets. The application of network-based drug design would greatly benefit from using an explicit computational model describing the dynamics of the system under investigation. However, creating a fully characterized kinetic model is not an easy task, even for relatively small networks, as it is still significantly hampered by the lack of data about kinetic mechanisms and parameters values. Here, we propose a Monte Carlo approach to identify the differences between flux control profiles of a metabolic network in different physiological states, when information about the kinetics of the system is partially or totally missing. Based on experimentally accessible information on metabolic phenotypes, we develop a novel method to determine probabilistic differences in the flux control coefficients between the two observable phenotypes. Knowledge of how differences in flux control are distributed among the different enzymatic steps is exploited to identify points of fragility in one of the phenotypes. Using a prototypical cancerous phenotype as an example, we demonstrate how our approach can assist researchers in developing compounds with high efficacy and low toxicity. © 2010 The Royal Society
Drug Information Services Today: Current Role and Future Perspectives in Rational Drug Therapy.

PubMed

Amundstuen Reppe, Linda; Spigset, Olav; Schjøtt, Jan

2016-02-01

Polypharmacy and complex drug treatment regimens are becoming increasingly common, which may lead to adverse drug reactions, drug interactions, medication nonadherence, and increasing costs and thus challenge the rational use of drugs. At the same time, the accessibility of drug information increases, and health care professionals may have limited opportunities and capabilities to search and critically evaluate drug information. Clinicians have reported difficulties in searching the best evidence and translating study findings into clinically meaningful information applicable to specific patients. Consequently, it remains a challenge to ensure the rational use of drugs in the years to come. Drug information centers (DICs) have been established to promote the rational use of drugs. One of the most important tasks of DICs is the question and answer services for health care professionals posing drug-related questions. DICs staffed by pharmacists and clinical pharmacologists hold expertise in searching for drug information and critical evaluation of the literature. The uniqueness in this service lies not only in the identification and interpretation of the scientific literature but also in the adaptation of the findings into specific clinical situations and the discussion of possible solutions with the enquirer. Thus, DICs could provide valuable decision support to the clinic. Taking into account the increasing number of possible drug-related questions that will arise today and in the future, the DICs will remain highly relevant in the years to come. However, the DICs must follow the developments in health information technology to disseminate relevant, unbiased drug information to old and new users of the service. Moreover, the DICs are important tools to counterbalance the drug information published by the pharmaceutical industry. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.
Anticipatory Reward Processing in Addicted Populations: A Focus on the Monetary Incentive Delay Task

PubMed Central

Balodis, Iris M.; Potenza, Marc N.

2014-01-01

Advances in brain imaging techniques have allowed neurobiological research to temporally analyze signals coding for the anticipation of rewards. In addicted populations, both hypo- and hyper-responsiveness of brain regions (e.g., ventral striatum) implicated in drug effects and reward system processing have been reported during anticipation of generalized reward. Here, we discuss the current state of knowledge of reward processing in addictive disorders from a widely used and validated task: the Monetary Incentive Delay Task (MIDT). The current paper constrains review to those studies applying the MIDT in addicted and at-risk adult populations, with a focus on anticipatory processing and striatal regions activated during task performance, as well as the relationship of these regions with individual difference (e.g., impulsivity) and treatment outcome variables. We further review drug influences in challenge studies as a means to examine acute influences on reward processing in abstinent, recreationally using and addicted populations. Here, we discuss that generalized reward processing in addicted and at-risk populations is often characterized by divergent anticipatory signaling in the ventral striatum. Although methodological/task variations may underlie some discrepant findings, anticipatory signaling in the ventral striatum may also be influenced by smoking status, drug metabolites and treatment status in addicted populations. Divergent results across abstinent, recreationally using and addicted populations demonstrate complexities in interpreting findings. Future studies will benefit from focusing on characterizing how impulsivity and other addiction-related features relate to anticipatory striatal signaling over time. Additionally, identifying how anticipatory signals recover/adjust following protracted abstinence will be important in understanding recovery processes. PMID:25481621
Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain.

PubMed

Rodriguez, Pavel; Zhou, Wei; Barrett, Douglas W; Altmeyer, Wilson; Gutierrez, Juan E; Li, Jinqi; Lancaster, Jack L; Gonzalez-Lima, Francisco; Duong, Timothy Q

2016-11-01

Purpose To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain. Materials and Methods The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebo-controlled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22-62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 × 2 repeated-measures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug × time between group interactions. Multiple comparison correction was applied, with cluster-corrected P < .05 indicating a significant difference. Results Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9-3.4, P = .01-.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9-4.2, P = .03-.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01). Conclusion Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval. © RSNA, 2016 Online supplemental material is available for this article.
The Iowa Gambling Task in Parkinson's disease: A meta-analysis on effects of disease and medication.

PubMed

Evens, Ricarda; Hoefler, Michael; Biber, Karolina; Lueken, Ulrike

2016-10-01

Decision-making under uncertainty as measured by the Iowa Gambling Task has frequently been studied in Parkinson's disease. The dopamine overdose hypothesis assumes that dopaminergic effects follow an inverted U-shaped function, restoring some cognitive functions while overdosing others. The present work quantitatively summarizes disease and medication effects on task performance and evaluates evidence for the dopamine overdose hypothesis of impaired decision-making in Parkinson's disease. A systematic literature search was performed to identify studies examining the Iowa Gambling Task in patients with Parkinson's disease. Outcomes were quantitatively combined, with separate estimates for the clinical (patients ON medication vs. healthy controls), disease (patients OFF medication vs. healthy controls), and medication effects (patients ON vs. OFF medication). Furthermore, using meta-regression analysis it was explored whether the study characteristics drug level, disease duration, and motor symptoms explained heterogeneous performance between studies. Patients with Parkinson's disease ON dopaminergic medication showed significantly impaired Iowa Gambling Task performance compared to healthy controls. This impairment was not normalized by short-term withdrawal of medication. Heterogeneity across studies was not explained by dopaminergic drug levels, disease durations or motor symptoms. While this meta-analysis showed significantly impaired decision-making performance in Parkinson's disease, there was no evidence that this impairment was related to dopamine overdosing. However, only very few studies assessed patients OFF medication and future studies are needed to concentrate on the modulation of dopaminergic drug levels and pay particular attention to problems related to repeated testing. Furthermore, short- vs. long-term medication effects demand further in-depth investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.
K+ channel TASK-1 knockout mice show enhanced sensitivities to ataxic and hypnotic effects of GABA(A) receptor ligands.

PubMed

Linden, Anni-Maija; Aller, M Isabel; Leppä, Elli; Rosenberg, Per H; Wisden, William; Korpi, Esa R

2008-10-01

TASK two-pore-domain leak K(+) channels occur throughout the brain. However, TASK-1 and TASK-3 knockout (KO) mice have few neurological impairments and only mildly reduced sensitivities to inhalational anesthetics, contrasting with the anticipated functions and importance of these channels. TASK-1/-3 channel expression can compensate for the absence of GABA(A) receptors in GABA(A) alpha6 KO mice. To investigate the converse, we analyzed the behavior of TASK-1 and -3 KO mice after administering drugs with preferential efficacies at GABA(A) receptor subtypes: benzodiazepines (diazepam and flurazepam, active at alpha1betagamma2, alpha2betagamma2, alpha3betagamma2, and alpha5betagamma2 subtypes), zolpidem (alpha1betagamma2 subtype), propofol (beta2-3-containing receptors), gaboxadol (alpha4betadelta and alpha6betadelta subtypes), pregnanolone, and pentobarbital (many subtypes). TASK-1 KO mice showed increased motor impairment in rotarod and beam-walking tests after diazepam and flurazepam administration but not after zolpidem. They also showed prolonged loss of righting reflex induced by propofol and pentobarbital. Autoradiography indicated no change in GABA(A) receptor ligand binding levels. These altered behavioral responses to GABAergic drugs suggest functional up-regulation of alpha2beta2/3gamma2 and alpha3beta2/3gamma2 receptor subtypes in TASK-1 KO mice. In addition, female, but not male, TASK-1 KO mice were more sensitive to gaboxadol, suggesting an increased influence of alpha4betadelta or alpha6betadelta subtypes. The benzodiazepine sensitivity of TASK-3 KO mice was marginally increased. Our results underline that TASK-1 channels perform such key functions in the brain that compensation is needed for their absence. Furthermore, because inhalation anesthetics act partially through GABA(A) receptors, the up-regulation of GABA(A) receptor function in TASK-1 KO mice might mask TASK-1 channel's significance as a target for inhalation anesthetics.
Amphetamine Challenge: A Marker of Brain Function that Mediates Risk for Drug and Alcohol Abuse

DTIC Science & Technology

2008-05-01

drugs. We record the effects of the drug on their mood , and select a group of people who experience strong, positive feelings from the drug...in other research projects), we identified the task parameters that would reliably elicit in young adults (i.e., in the age range we planned to test...manuscript, University of Minnesota, Minneapolis, MN. Tellegen, A. (1985). Structure of mood and personality and their relevance to assessing anxiety
Reasons for Use, Abstention, and Quitting Illicit Drug Use by American Adolescents: A Report Commissioned by the Drugs-Violence Task Force of the National Sentencing Commission. Monitoring the Future Occasional Paper No. 44.

ERIC Educational Resources Information Center

Johnston, Lloyd D.

The data for this report were obtained from the Monitoring the Future study. Surveys from eighth, tenth, and twelfth grade respondents were used to examine adolescents' reasons for use, abstention, and quitting illicit drug use. Many reasons were found for drug use. Abstainers provided more reasons for their abstention than quitters gave for their…
Drug drug interaction extraction from the literature using a recursive neural network

PubMed Central

Lim, Sangrak; Lee, Kyubum

2018-01-01

Detecting drug-drug interactions (DDI) is important because information on DDIs can help prevent adverse effects from drug combinations. Since there are many new DDI-related papers published in the biomedical domain, manually extracting DDI information from the literature is a laborious task. However, text mining can be used to find DDIs in the biomedical literature. Among the recently developed neural networks, we use a Recursive Neural Network to improve the performance of DDI extraction. Our recursive neural network model uses a position feature, a subtree containment feature, and an ensemble method to improve the performance of DDI extraction. Compared with the state-of-the-art models, the DDI detection and type classifiers of our model performed 4.4% and 2.8% better, respectively, on the DDIExtraction Challenge’13 test data. We also validated our model on the PK DDI corpus that consists of two types of DDIs data: in vivo DDI and in vitro DDI. Compared with the existing model, our detection classifier performed 2.3% and 6.7% better on in vivo and in vitro data respectively. The results of our validation demonstrate that our model can automatically extract DDIs better than existing models. PMID:29373599
Development of Less Toxic Treatment Strategies for Metastatic and Drug-Resistant Breast Cancer Using Noninvasive Optical Monitoring

DTIC Science & Technology

2017-09-01

models has been evaluated, with one good option, the Py230 cell lines, as our choice for use in future studies . We have conducted the first study ... Study of Progressive Resistance Major Task 6: dDOS fabrication Subtask 15: Design /Fabricate dDOS system and new custom dDOS probe 6-24 Dr...until year 3 of the study , based on current accrual trends with our clinical collaborators at the Boston Medical Center for different projects, the
Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology.

PubMed

Mula, Marco; Kanner, Andres M; Schmitz, Bettina; Schachter, Steven

2013-01-01

In 2008, the U.S. Food and Drug Administration (FDA) issued an alert to health care professionals about an increased risk of suicide ideation and suicide behavior in people treated with antiepileptic drugs (AEDs). Since then, a number of retrospective cohort and case-control studies have been published that are trying to address this issue, but gathered results are contradictory. This report represents an expert consensus statement developed by an ad hoc task force of the Commission on Neuropsychobiology of the International League Against Epilepsy (ILAE). Although some (but not all) AEDs can be associated with treatment-emergent psychiatric problems that can lead to suicidal ideation and behavior, the actual suicidal risk is yet to be established, but it seems to be very low. The risk of stopping AEDs or refusing to start AEDs is significantly worse and can actually result in serious harm including death to the patient. Suicidality in epilepsy is multifactorial, and different variables are operant. Clinicians should investigate the existence of such risk factors and adopt appropriate screening instruments. If necessary, patients should be referred for a psychiatric evaluation, but AED treatment should not be withheld, even in patients with positive suicidal risks. When starting an AED or switching from one to other AEDs, patients should be advised to report to their treating physician any change in mood and suicidal ideation. Data on treatment-emergent psychiatric adverse events need to be collected, in addition to general safety information, during controlled studies in order to have meaningful information for patients and their relatives when a new drug is marketed. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Impaired psychomotor function and plasma methadone and levo-alpha-acetylmethadol (LAAM) concentrations in opioid-substitution patients.

PubMed

Newcombe, David A L; Somogyi, Andrew A; Bochner, Felix; White, Jason M

2017-06-01

Tolerance to the psychomotor impairing effects of opioid drugs is expected to develop with repeated dosing, but may be incomplete. The relationship between plasma opioid concentration and psychomotor function in opioid-dependent patients was examined to determine whether impairment was more likely at the time of highest plasma drug concentration. Sixteen patients participating in a cross-over trial comparing methadone and LAAM completed a tracking task (OSPAT) 11 times over the dosing-interval for methadone (24-hrs) and LAAM (48-hrs). Venous blood was collected for the quantification of plasma (R)-(-)-methadone, LAAM, and nor-LAAM concentrations. The Digit Symbol Substitution Test (DSST) and Trail-Making Test were administered at the time of peak plasma concentration. Ten healthy controls (HCs) also participated. OSPAT scores (obtained for 15 patients) fluctuated significantly across the dosing-interval for both drugs and were lower in patients than HCs at the times of peak concentrations of (R)-(-)-methadone (1 hr: (mean difference; 95% CI) (2.13; 0.18-4.08); 2 hrs: (2.38; 0.48-4.28) postdosing) and LAAM (2 hrs: (1.81; 0.09-3.53), and 4 hrs (1.90: 0.9-3.71) postdosing). Within-participant analysis of the peak-change from baseline for OSPAT scores found that 10 of the 15 patients could be categorized as impaired on methadone and 9 on LAAM. No HCs were impaired. Patients performed worse on the DSST and Trails-A than HCs, but not on Trails-B. Results suggest that some patients receiving opioids long term may exhibit impairment at the time of highest plasma drug concentration. These patients should be made aware that their ability to undertake complex tasks may be affected. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth.

PubMed

Ivanov, Iliyan; Liu, Xun; Shulz, Kurt; Fan, Jin; London, Edythe; Friston, Karl; Halperin, Jeffrey M; Newcorn, Jeffrey H

2012-02-28

It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Large-scale extraction of accurate drug-disease treatment pairs from biomedical literature for drug repurposing

PubMed Central

2013-01-01

Background A large-scale, highly accurate, machine-understandable drug-disease treatment relationship knowledge base is important for computational approaches to drug repurposing. The large body of published biomedical research articles and clinical case reports available on MEDLINE is a rich source of FDA-approved drug-disease indication as well as drug-repurposing knowledge that is crucial for applying FDA-approved drugs for new diseases. However, much of this information is buried in free text and not captured in any existing databases. The goal of this study is to extract a large number of accurate drug-disease treatment pairs from published literature. Results In this study, we developed a simple but highly accurate pattern-learning approach to extract treatment-specific drug-disease pairs from 20 million biomedical abstracts available on MEDLINE. We extracted a total of 34,305 unique drug-disease treatment pairs, the majority of which are not included in existing structured databases. Our algorithm achieved a precision of 0.904 and a recall of 0.131 in extracting all pairs, and a precision of 0.904 and a recall of 0.842 in extracting frequent pairs. In addition, we have shown that the extracted pairs strongly correlate with both drug target genes and therapeutic classes, therefore may have high potential in drug discovery. Conclusions We demonstrated that our simple pattern-learning relationship extraction algorithm is able to accurately extract many drug-disease pairs from the free text of biomedical literature that are not captured in structured databases. The large-scale, accurate, machine-understandable drug-disease treatment knowledge base that is resultant of our study, in combination with pairs from structured databases, will have high potential in computational drug repurposing tasks. PMID:23742147
Measuring reinforcement learning and motivation constructs in experimental animals: relevance to the negative symptoms of schizophrenia.

PubMed

Markou, Athina; Salamone, John D; Bussey, Timothy J; Mar, Adam C; Brunner, Daniela; Gilmour, Gary; Balsam, Peter

2013-11-01

The present review article summarizes and expands upon the discussions that were initiated during a meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu) meeting. A major goal of the CNTRICS meeting was to identify experimental procedures and measures that can be used in laboratory animals to assess psychological constructs that are related to the psychopathology of schizophrenia. The issues discussed in this review reflect the deliberations of the Motivation Working Group of the CNTRICS meeting, which included most of the authors of this article as well as additional participants. After receiving task nominations from the general research community, this working group was asked to identify experimental procedures in laboratory animals that can assess aspects of reinforcement learning and motivation that may be relevant for research on the negative symptoms of schizophrenia, as well as other disorders characterized by deficits in reinforcement learning and motivation. The tasks described here that assess reinforcement learning are the Autoshaping Task, Probabilistic Reward Learning Tasks, and the Response Bias Probabilistic Reward Task. The tasks described here that assess motivation are Outcome Devaluation and Contingency Degradation Tasks and Effort-Based Tasks. In addition to describing such methods and procedures, the present article provides a working vocabulary for research and theory in this field, as well as an industry perspective about how such tasks may be used in drug discovery. It is hoped that this review can aid investigators who are conducting research in this complex area, promote translational studies by highlighting shared research goals and fostering a common vocabulary across basic and clinical fields, and facilitate the development of medications for the treatment of symptoms mediated by reinforcement learning and motivational deficits. Copyright © 2013 Elsevier Ltd. All rights reserved.
Measuring reinforcement learning and motivation constructs in experimental animals: relevance to the negative symptoms of schizophrenia

PubMed Central

Markou, Athina; Salamone, John D.; Bussey, Timothy; Mar, Adam; Brunner, Daniela; Gilmour, Gary; Balsam, Peter

2013-01-01

The present review article summarizes and expands upon the discussions that were initiated during a meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu). A major goal of the CNTRICS meeting was to identify experimental procedures and measures that can be used in laboratory animals to assess psychological constructs that are related to the psychopathology of schizophrenia. The issues discussed in this review reflect the deliberations of the Motivation Working Group of the CNTRICS meeting, which included most of the authors of this article as well as additional participants. After receiving task nominations from the general research community, this working group was asked to identify experimental procedures in laboratory animals that can assess aspects of reinforcement learning and motivation that may be relevant for research on the negative symptoms of schizophrenia, as well as other disorders characterized by deficits in reinforcement learning and motivation. The tasks described here that assess reinforcement learning are the Autoshaping Task, Probabilistic Reward Learning Tasks, and the Response Bias Probabilistic Reward Task. The tasks described here that assess motivation are Outcome Devaluation and Contingency Degradation Tasks and Effort-Based Tasks. In addition to describing such methods and procedures, the present article provides a working vocabulary for research and theory in this field, as well as an industry perspective about how such tasks may be used in drug discovery. It is hoped that this review can aid investigators who are conducting research in this complex area, promote translational studies by highlighting shared research goals and fostering a common vocabulary across basic and clinical fields, and facilitate the development of medications for the treatment of symptoms mediated by reinforcement learning and motivational deficits. PMID:23994273
Preparation of human drug metabolites using fungal peroxygenases

Treesearch

Marzena Poraj-Kobielska; Matthias Kinne; René Ullrich; Katrin Scheibner; Gernot Kayser; Kenneth E. Hammel; Martin Hofrichter

2011-01-01

The synthesis of hydroxylated and O- or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi Agrocybe aegerita and Coprinellus...
Effects of Experimental Unemployment, Employment and Punishment Analogs on Opioid Seeking and Consumption in Heroin-Dependent Volunteers

PubMed Central

Greenwald, Mark K.

2010-01-01

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only + Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24 mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8-mg/day) volunteers first sampled two HYD doses (0 and 24 mg IM in randomized, counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2 mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3 hr after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only + Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased Pmax (i.e., lower “essential value” of HYD) and Omax (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability. PMID:20537815
A comparison of the central nervous system effects of haloperidol, chlorpromazine and sulpiride in normal volunteers.

PubMed Central

McClelland, G R; Cooper, S M; Pilgrim, A J

1990-01-01

1. Twelve healthy male volunteers participated in four experimental occasions during each of which they were dosed with one of the following anti-psychotic drugs: chlorpromazine (50 mg), haloperidol (3 mg), sulpiride (400 mg) and placebo. Drugs were allocated to subjects in a double-blind, crossover fashion. 2. The subject's mood state, psychometric performance and electroencephalogram (EEG) were assessed pre-dose, and at 2, 4, 6, 8, 24 and 48 h post-dose. Mood states were assessed using 16 visual analogue scales and psychomotor performance was measured using the following tests: elapsed time estimation, tapping rate, choice reaction times, a rapid information processing task, flash fusion threshold, a manipulative motor task, digit span, body sway and tremor. 3. Chlorpromazine and haloperidol significantly reduced subjective ratings of 'alertness' and 'contentedness', and haloperidol significantly reduced feelings of 'calmness'. Sulpiride did not significantly affect any of the visual analogue scales. 4. All three anti-psychotic drugs had similar EEG effects with peak effect 2 to 4 h postdose. The profile was characterised by an increase in the proportion of slow wave activity (delta and theta) as well as decreased alpha (8-14 Hz) and faster (beta) wave activity. 5. Chlorpromazine reduced tapping rate and increased choice reaction movement times. Haloperidol reduced the flash fusion threshold frequency at 6 h post-dose. Sulpiride prolonged the duration of the manipulative motor task, particularly at 48 h post-dose. 6. All three anti-psychotic drugs impaired performance on the rapid information processing task. Chlorpromazine significantly reduced the number of correct letter pair identifications at 2, 4 and 6 h post-dose, haloperidol at 4, 6, 8, 24 and 48 h post-dose, and sulpiride at 24 h post-dose.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2288826
Anticonvulsant medications attenuate amphetamine-induced deficits in behavioral inhibition but not decision making under risk on a rat gambling task.

PubMed

Tremblay, Melanie; Winstanley, Catharine A

2016-11-01

Impulsivity is a major component of mania in bipolar disorder (BD), and patients also show impairments in decision-making involving risk on the Iowa Gambling Task (IGT). Similar deficits are observed in some patients with temporal lobe epilepsy (TLE), and incidence of problem gambling is higher in both these populations. Anticonvulsant drugs are widely used in the treatment of epilepsy, but also as mood stabilizers and prophylaxis for the management of BD. Unfortunately, little is still known about the precise mechanisms of action underlying their efficacy, and the specific behavioral aspect targeted by these drugs. This project explored the effect of the three anticonvulsant drugs currently also used as mood stabilizers- carbamazepine, valproate and lamotrigine on aspects of decision-making using a rat analogue of the IGT, the rat Gambling Task (rGT). In this task, rats choose between four distinct, probabilistic reinforcement schedules. Sugar pellet profits are maximized by adopting a conservative strategy, avoiding tempting high-risk, high-reward options. Effects of the anticonvulsant agents were assessed on baseline performance and also in conjunction with amphetamine administration, in order to approximate a "mania-like" state. Carbamazepine appeared to slow processing speed, decreasing premature responses and increasing choice latency, whereas valproate and lamotrigine had no effect. When administered prior to amphetamine, lamotrigine was the only drug that failed to attenuate the pro-impulsive effect of the psychostimulant. Further studies looking at chronic administration of anticonvulsants may help us understand the impact of this medication class on decision-making and impulsivity in healthy rats and disease models. Copyright © 2016 Elsevier B.V. All rights reserved.
Bio-hybrid cell-based actuators for microsystems.

PubMed

Carlsen, Rika Wright; Sitti, Metin

2014-10-15

As we move towards the miniaturization of devices to perform tasks at the nano and microscale, it has become increasingly important to develop new methods for actuation, sensing, and control. Over the past decade, bio-hybrid methods have been investigated as a promising new approach to overcome the challenges of scaling down robotic and other functional devices. These methods integrate biological cells with artificial components and therefore, can take advantage of the intrinsic actuation and sensing functionalities of biological cells. Here, the recent advancements in bio-hybrid actuation are reviewed, and the challenges associated with the design, fabrication, and control of bio-hybrid microsystems are discussed. As a case study, focus is put on the development of bacteria-driven microswimmers, which has been investigated as a targeted drug delivery carrier. Finally, a future outlook for the development of these systems is provided. The continued integration of biological and artificial components is envisioned to enable the performance of tasks at a smaller and smaller scale in the future, leading to the parallel and distributed operation of functional systems at the microscale. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer’s Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force

PubMed Central

Soto, M.; Abushakra, S.; Cummings, J.; Siffert, J.; Robert, P.; Vellas, B.; Lyketsos, C.G.

2015-01-01

BACKGROUND The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes. PMID:26413494
Plan to combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force.

PubMed

2009-02-13

An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and nearly 9 million persons develop disease caused by M. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited countries, it also occurs in the United States. During 1985-1992, the United States was confronted with an unprecedented TB resurgence. This resurgence was accompanied by a rise in multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin. In addition, virtually untreatable strains of M. tuberculosis are emerging globally. Extensively drug-resistant (XDR) TB is defined as MDR TB that also is resistant to the most effective second-line therapeutic drugs used commonly to treat MDR TB: fluoroquinolones and at least one of three injectable second-line drugs used to treat TB (amikacin, kanamycin, or capreomycin). XDR TB has been identified in all regions of the world, including the United States. In the United States, the cost of hospitalization for one XDR TB patient is estimated to average $483,000, approximately twice the cost for MDR TB patients. Because of the limited responsiveness of XDR TB to available antibiotics, mortality rates among patients with XDR TB are similar to those of TB patients in the preantibiotic era. In January 1992, CDC convened a Federal TB Task Force to draft an action plan to improve prevention and control of drug-resistant TB in the United States (CDC. National action plan to combat multidrug-resistant tuberculosis. MMWR 1992;41([No. RR-11]). In November 2006, CDC reconvened the Task Force to draft an updated action plan to address the issue of MDR TB and XDR TB. Task Force members were divided into nine response areas and charged with articulating the most pressing problems, identifying barriers to improvement, and recommending specific action steps to improve prevention and control of XDR TB within their respective areas. Although the first priority of the Federal TB Task Force convened in 2006 was to delineate objectives and action steps to address MDR TB and XDR TB domestically, members recognized the necessity for TB experts in the United States to work with the international community to help strengthen TB control efforts globally. TB represents a substantial public health problem in low- and middle-income countries, many of which might benefit from assistance by the United States. In addition, the global TB epidemic directly affects the United States because the majority of all cases of TB and 80% of cases of MDR TB reported in the United States occur among foreign-born persons. For these reasons, the Action Plan also outlines potential steps that U.S. government agencies can take to help solve global XDR TB problems. Unless the fundamental causes of MDR TB and XDR TB are addressed in the United States and internationally, the United States is likely to experience a growing number of cases of MDR TB and XDR TB that will be difficult, if not impossible, to treat or prevent. The recommendations provided in this report include specific action steps and new activities that will require additional funding and a renewed commitment by government and nongovernment organizations involved in domestic and international TB control efforts to be implemented effectively. The Federal TB Task Force will coordinate activities of various federal agencies and partner with state and local health departments, nonprofit and TB advocacy organizations in implementing this plan to control and prevent XDR TB in the United States and to contribute to global efforts in the fight against this emerging public health crisis.
Development of classification models for identifying "true" P-glycoprotein (P-gp) inhibitors through inhibition, ATPase activation and monolayer efflux assays.

PubMed

Rapposelli, Simona; Coi, Alessio; Imbriani, Marcello; Bianucci, Anna Maria

2012-01-01

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as "true" P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function.
Smokers exhibit biased neural processing of smoking and affective images.

PubMed

Oliver, Jason A; Jentink, Kade G; Drobes, David J; Evans, David E

2016-08-01

There has been growing interest in the role that implicit processing of drug cues can play in motivating drug use behavior. However, the extent to which drug cue processing biases relate to the processing biases exhibited to other types of evocative stimuli is largely unknown. The goal of the present study was to determine how the implicit cognitive processing of smoking cues relates to the processing of affective cues using a novel paradigm. Smokers (n = 50) and nonsmokers (n = 38) completed a picture-viewing task, in which participants were presented with a series of smoking, pleasant, unpleasant, and neutral images while engaging in a distractor task designed to direct controlled resources away from conscious processing of image content. Electroencephalogram recordings were obtained throughout the task for extraction of event-related potentials (ERPs). Smokers exhibited differential processing of smoking cues across 3 different ERP indices compared with nonsmokers. Comparable effects were found for pleasant cues on 2 of these indices. Late cognitive processing of smoking and pleasant cues was associated with nicotine dependence and cigarette use. Results suggest that cognitive biases may extend across classes of stimuli among smokers. This raises important questions about the fundamental meaning of cognitive biases, and suggests the need to consider generalized cognitive biases in theories of drug use behavior and interventions based on cognitive bias modification. (PsycINFO Database Record (c) 2016 APA, all rights reserved).
Disentangling the nature of the nicotine stimulus.

PubMed

Bevins, Rick A; Barrett, Scott T; Polewan, Robert J; Pittenger, Steven T; Swalve, Natashia; Charntikov, Sergios

2012-05-01

Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using "standard" testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more "standard" testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli. Copyright © 2011 Elsevier B.V. All rights reserved.
NEONATAL VISUAL INFORMATION PROCESSING IN COCAINE-EXPOSED AND NON-EXPOSED INFANTS

PubMed Central

Singer, Lynn T.; Arendt, Robert; Fagan, Joseph; Minnes, Sonia; Salvator, Ann; Bolek, Tina; Becker, Michael

2014-01-01

This study investigated early neonatal visual preferences in 267 poly drug exposed neonates (131 cocaine-exposed and 136 non-cocaine exposed) whose drug exposure was documented through interviews and urine and meconium drug screens. Infants were given four visual recognition memory tasks comparing looking time to familiarized stimuli of lattices and rectangular shapes to novel stimuli of a schematic face and curved hourglass and bull’s eye forms. Cocaine-exposed infants performed more poorly, after consideration of confounding factors, with a relationship of severity of cocaine exposure to lower novelty score found for both self-report and biologic measures of exposure, Findings support theories which link prenatal cocaine exposure to deficits in information processing entailing attentional and arousal organizational systems. Neonatal visual discrimination and attention tasks should be further explored as potentially sensitive behavioral indicators of teratologic effects. PMID:25717215
Prenatal Drug Exposure and Adolescent Cortisol Reactivity: Association with Behavioral Concerns.

PubMed

Buckingham-Howes, Stacy; Mazza, Dayna; Wang, Yan; Granger, Douglas A; Black, Maureen M

2016-09-01

To examine stress reactivity in a sample of adolescents with prenatal drug exposure (PDE) by examining the consequences of PDE on stress-related adrenocortical reactivity, behavioral problems, and drug experimentation during adolescence. Participants (76 PDE, 61 non-drug exposed [NE]; 99% African-American; 50% male; mean age = 14.17 yr, SD = 1.17) provided a urine sample, completed a drug use questionnaire, and provided saliva samples (later assayed for cortisol) before and after a mild laboratory stress task. Caregivers completed the Behavior Assessment System for Children, Second Edition (BASC II) and reported their relationship to the adolescent. The NE group was more likely to exhibit task-related cortisol reactivity compared to the PDE group. Overall behavior problems and drug experimentation were comparable across groups with no differences between PDE and NE groups. In unadjusted mediation analyses, cortisol reactivity mediated the association between PDE and BASC II aggression scores (95% bootstrap confidence interval [CI], 0.04-4.28), externalizing problems scores (95% bootstrap CI, 0.03-4.50), and drug experimentation (95% bootstrap CI, 0.001-0.54). The associations remain with the inclusion of gender as a covariate but not when age is included. Findings support and expand current research in cortisol reactivity and PDE by demonstrating that cortisol reactivity attenuates the association between PDE and behavioral problems (aggression) and drug experimentation. If replicated, PDE may have long-lasting effects on stress-sensitive physiological mechanisms associated with behavioral problems (aggression) and drug experimentation in adolescence.
Impact of drug shortages on U.S. health systems.

PubMed

Kaakeh, Rola; Sweet, Burgunda V; Reilly, Cynthia; Bush, Colleen; DeLoach, Sherry; Higgins, Barb; Clark, Angela M; Stevenson, James

2011-10-01

A study was performed to quantify the personnel resources required to manage drug shortages, define the impact of drug shortages on health systems nationwide, and assess the adequacy of information resources available to manage drug shortages. An online survey was sent to the 1322 members of the American Society of Health-System Pharmacists who were identified as directors of pharmacy. Survey recipients were asked to identify which of the 30 most recent drug shortages listed affected their health system, to identify actions taken to manage the shortage, and to rate the impact of each shortage. Employees responsible for completing predefined tasks were identified, and the average time spent by each type of employee completing these tasks was estimated. Labor costs associated with managing shortages were calculated. A total of 353 respondents completed the survey, yielding a response rate of 27%. Pharmacists and pharmacy technicians spent more time managing drug shortages than did physicians and nurses. There was a significant association between the time spent managing shortages and the size of the institution, the number of shortages managed, and the institution's level of automation. Overall, 70% of the respondents felt that the information resources available to manage drug shortages were not good. The labor costs associated with managing shortages in the United States is an estimated $216 million annually. A survey of directors of pharmacy revealed that labor costs and the time required to manage drug shortages are significant and that current information available to manage drug shortages is considered suboptimal.
Extinction of Conditioned Responses to Methamphetamine-Associated Stimuli in Healthy Humans.

PubMed

Cavallo, Joel S; Ruiz, Nicholas A; de Wit, Harriet

2016-07-01

Contextual stimuli present during drug experiences become associated with the drug through Pavlovian conditioning and are thought to sustain drug-seeking behavior. Thus, extinction of conditioned responses is an important target for treatment. To date, acquisition and extinction to drug-paired cues have been studied in animal models or drug-dependent individuals, but rarely in non-drug users. We have recently developed a procedure to study acquisition of conditioned responses after single doses of methamphetamine (MA) in healthy volunteers. Here, we examined extinction of these responses and their persistence after conditioning. Healthy adults (18-35 years; N = 20) received two pairings of audio-visual stimuli with MA (20 mg oral) or placebo. Responses to stimuli were assessed before and after conditioning, using three tasks: behavioral preference, attentional bias, and subjective "liking." Subjects exhibited behavioral preference for the drug-paired stimuli at the first post-conditioning test, but this declined rapidly on subsequent extinction tests. They also exhibited a bias to initially look towards the drug-paired stimuli at the first post-test session, but not thereafter. Subjects who experienced more positive subjective drug effects during conditioning exhibited a smaller decline in preference during the extinction phase. Further, longer inter-session intervals during the extinction phase were associated with less extinction of the behavioral preference measure. Conditioned responses after two pairings with MA extinguish quickly, and are influenced by both subjective drug effects and the extinction interval. Characterizing and refining this conditioning procedure will aid in understanding the acquisition and extinction processes of drug-related conditioned responses in humans.
Extinction of Conditioned Responses to Methamphetamine-Associated Stimuli in Healthy Humans

PubMed Central

Cavallo, Joel S.; Ruiz, Nicholas A.; de Wit, Harriet

2016-01-01

Rationale Contextual stimuli present during drug experiences become associated with the drug through Pavlovian conditioning, and are thought to sustain drug-seeking behavior. Thus, extinction of conditioned responses is an important target for treatment. To date, acquisition and extinction to drug-paired cues have been studied in animal models or drug-dependent individuals, but rarely in non drug-users. Objective We have recently developed a procedure to study acquisition of conditioned responses after single doses of methamphetamine (MA) in healthy volunteers. Here we examined extinction of these responses and their persistence after conditioning. Methods Healthy adults (18–35 yrs; N=20) received two pairings of audio-visual stimuli with MA (20 mg oral) or placebo. Responses to stimuli were assessed before and after conditioning, using three tasks: behavioral preference, attentional bias, and subjective ‘liking.’ Results Subjects exhibited behavioral preference for the drug-paired stimuli at the first post-conditioning test, but this declined rapidly on subsequent extinction tests. They also exhibited a bias to initially look towards the drug-paired stimuli at the first post-test session, but not thereafter. Subjects who experienced more positive subjective drug effects during conditioning exhibited a smaller decline in preference during the extinction phase. Further, longer inter-session intervals during the extinction phase were associated with less extinction of the behavioral preference measure. Conclusions Conditioned responses after two pairings with MA extinguish quickly, and are influenced by both subjective drug effects and the extinction interval. Characterizing and refining this conditioning procedure will aid in understanding the acquisition and extinction processes of drug-related conditioned responses in humans. PMID:27113223

Stimulus properties of nicotine, amphetamine, and chlordiazepoxide as positive features in a pavlovian appetitive discrimination task in rats.

PubMed

Palmatier, Matthew I; Wilkinson, Jamie L; Metschke, Dawn M; Bevins, Rick A

2005-04-01

Recent experiments from our laboratory have demonstrated that drug states can signal when environmental cues will be followed by rewarding outcomes (ie Pavlovian conditioning). However, little is known about the generality of this approach and whether it can be used for studying the pharmacological properties of drug states. Accordingly, the present experiments tested the pharmacological specificity of nicotine (0.4 mg/kg), amphetamine (1 mg/kg), and chlordiazepoxide (CDP, 5 mg/kg) in this Pavlovian drug discrimination procedure. Following drug administration, presentation of a conditional stimulus (CS) was followed by brief access to sucrose. When saline was administered, the same CS was presented but sucrose was withheld. In substitution tests, rats in each condition received varying doses of all training drugs and caffeine. Anticipatory food seeking developed during the CS on drug sessions but not on saline sessions for all drug features (ie drug state-specific conditional response (CR)). In generalization tests, this CR decreased as a function of decreases in the training dose. Median effective doses (ED50s) were calculated for nicotine (0.054 mg/kg), amphetamine (0.26 mg/kg), and CDP (2.48 mg/kg). No compound tested substituted for the CDP training drug. Partial substitution was evident between nicotine and amphetamine; CDP did not substitute for either of these drug features. Caffeine fully substituted for nicotine (ED50 = 15.45 mg/kg) and amphetamine (ED50 = 3.70 mg/kg), but not for CDP. These results are consistent with the hypothesis that drug states can occasion appetitive Pavlovian CRs in a pharmacologically specific manner.
Impaired flexibility in decision making in rats after administration of the pharmacological stressor yohimbine.

PubMed

Schwager, Andrea L; Haack, Andrew K; Taha, Sharif A

2014-10-01

Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized. To characterize changes in decision making caused by acute pharmacological stress, the effects of yohimbine (an α2-adrenergic antagonist) were examined in a delay discounting task. Noradrenergic contributions to decision making were further characterized by examining the effects of propranolol (a β antagonist), prazosin (an α1 antagonist), and guanfacine (an α2 agonist). Sprague-Dawley rats were administered drugs prior to performance on a delay discounting task, in which the delay preceding the large reward increased within each session (ascending delays). To dissociate drug-induced changes in delay sensitivity from behavioral inflexibility, drug effects were subsequently tested in a modified version of the discounting task, in which the delay preceding the large reward decreased within each session (descending delays). Yohimbine increased choice of the large reward when tested with ascending delays but decreased choice of the same large reward when tested with descending delays, suggesting that drug effects could be attributed to perseverative choice of the lever preferred at the beginning of the session. Propranolol increased choice of the large reward when tested with ascending delays. Prazosin and guanfacine had no effect on reward choice. The stress-like effects of yohimbine administration may impair decision making by causing inflexible, perseverative behavior.
Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans

PubMed Central

Roiser, Jonathan P.; Robbins, Trevor W.; Sahakian, Barbara J.

2013-01-01

Rationale Chronic drug use has been associated with increased impulsivity and maladaptive behaviour, but the underlying mechanisms of this impairment remain unclear. We investigated the ability to adapt behaviour according to changes in reward contingencies, using a probabilistic reversal-learning task, in chronic drug users and controls. Materials and methods Five groups were compared: chronic amphetamine users (n = 30); chronic cocaine users (n = 27); chronic opiate users (n = 42); former drug users of psychostimulants and opiates (n = 26); and healthy non-drug-taking control volunteers (n = 25). Participants had to make a forced choice between two alternative stimuli on each trial to acquire a stimulus–reward association on the basis of degraded feedback and subsequently to reverse their responses when the reward contingencies changed. Results Chronic cocaine users demonstrated little behavioural change in response to the change in reward contingencies, as reflected by perseverative responding to the previously rewarded stimulus. Perseverative responding was observed in cocaine users regardless of whether they completed the reversal stage successfully. Task performance in chronic users of amphetamines and opiates, as well as in former drug users, was not measurably impaired. Conclusion Our findings provide convincing evidence for response perseveration in cocaine users during probabilistic reversal-learning. Pharmacological differences between amphetamine and cocaine, in particular their respective effects on the 5-HT system, may account for the divergent task performance between the two psychostimulant user groups. The inability to reverse responses according to changes in reinforcement contingencies may underlie the maladaptive behaviour patterns observed in chronic cocaine users but not in chronic users of amphetamines or opiates. PMID:18214445
Alcohol and Drug Use and the Developing Brain

PubMed Central

Gray, Kevin M.

2016-01-01

Adolescence is an important neurodevelopmental period marked by rapidly escalating rates of alcohol and drug use. Over the past decade, research has attempted to disentangle pre- and post-substance use effects on brain development by using sophisticated longitudinal designs. This review focuses on recent, prospective studies and addresses the following important questions: (1) what neuropsychological and neural features predate adolescent substance use, making youth more vulnerable to engage in heavy alcohol or drug use, and (2) how does heavy alcohol and drug use affect normal neural development and cognitive functioning? Findings suggest that pre-existing neural features that relate to increased substance use during adolescence include poorer neuropsychological functioning on tests of inhibition and working memory, smaller gray and white matter volume, changes in white matter integrity, and altered brain activation during inhibition, working memory, reward, and resting state. After substance use is initiated, alcohol and marijuana use are associated with poorer cognitive functioning on tests of verbal memory, visuospatial functioning, psychomotor speed, working memory, attention, cognitive control, and overall IQ. Heavy alcohol use during adolescence is related to accelerated decreases in gray matter and attenuated increases in white matter volume, as well as increased brain activation during tasks of inhibition and working memory, relative to controls. Larger longitudinal studies with more diverse samples are needed to better understand the interactive effects of alcohol, marijuana, and other substances, as well as the role of sex, co-occurring psychopathology, genetics, sleep, and age of initiation on substance use. PMID:26984684
[GP medication prioritisation in older patients with multiple comorbidities recently discharged from hospital: a case-based bottom-up approach].

PubMed

Herrmann, M L H; von Waldegg, G H; Kip, M; Lehmann, B; Andrusch, S; Straub, H; Robra, B-P

2015-01-01

After the hospital discharge of older patients with multiple morbidities, GPs are often faced with the task of prioritising the patients' drug regimens so as to reduce the risk of overmedication. How do GPs prioritise such medications in multimorbid elderly patients at the transition between inpatient and home care? The experience by the GPs is documented in typical case vignettes. 44 GPs in Sachsen-Anhalt were recruited--they were engaged in focus group discussions and interviewed using semi-standardised questionnaires. Typical case vignettes were developed, relevant to the everyday care that elderly patients would typically receive from their GPs with respect to their drug optimisation. According to the results of the focus groups, the following issues affect GPs' decisions: drug and patient safety, their own competence in the health system, patient health literacy, evidence base, communication between secondary and primary care (and their respective influences on each other). When considering individual cases, patient safety, patient wishes, and quality of life were central. This is demonstrated by the drug dispositions of one exemplary case vignette. GPs do prioritise drug regimens with rational criteria. Initial problem delineation, process documentation and the design of a transferable product are interlinking steps in the development of case vignettes. Care issues of drug therapy in elderly patients with multiple morbidities should be investigated further with larger representative samples in order to clarify whether the criteria used here are applied contextually or consistently. Embedding case vignettes into further education concepts is also likely to be useful. © Georg Thieme Verlag KG Stuttgart · New York.
Drug Program Report: Credentialing.

ERIC Educational Resources Information Center

Contee, Jerome A., Ed.

This report contains several articles on drug abuse worker credentialing, and provides an update on information about credentialing policies and reciprocity efforts of the states. The first article reports on a meeting of the credentialing/reciprocity task force comprised of representatives from 10 states which have exhibited leadership in the…
Effects of nicotine on response inhibition and interference control.

PubMed

Ettinger, Ulrich; Faiola, Eliana; Kasparbauer, Anna-Maria; Petrovsky, Nadine; Chan, Raymond C K; Liepelt, Roman; Kumari, Veena

2017-04-01

Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.
DNA Nanostructures as Smart Drug-Delivery Vehicles and Molecular Devices.

PubMed

Linko, Veikko; Ora, Ari; Kostiainen, Mauri A

2015-10-01

DNA molecules can be assembled into custom predesigned shapes via hybridization of sequence-complementary domains. The folded structures have high spatial addressability and a tremendous potential to serve as platforms and active components in a plethora of bionanotechnological applications. DNA is a truly programmable material, and its nanoscale engineering thus opens up numerous attractive possibilities to develop novel methods for therapeutics. The tailored molecular devices could be used in targeting cells and triggering the cellular actions in the biological environment. In this review we focus on the DNA-based assemblies - primarily DNA origami nanostructures - that could perform complex tasks in cells and serve as smart drug-delivery vehicles in, for example, cancer therapy, prodrug medication, and enzyme replacement therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.
Addiction research centres and the nurturing of creativity: the Department of Alcohol, Drugs and Addiction at the National Institute for Health and Welfare in Finland: diverse problems, diverse perspectives.

PubMed

Hakkarainen, Pekka; Kiianmaa, Kalervo; Kuoppasalmi, Kimmo; Tigerstedt, Christoffer

2012-10-01

The Department of Alcohol, Drugs and Addiction started operations on 1 January 2009, when the National Institute of Public Health (KTL) and the National Research and Development Centre for Welfare and Health (STAKES) were merged. The newly formed institute, called the National Institute for Health and Welfare (THL), operates under the Finnish Ministry of Social Affairs and Health. The scope of the research and preventive work conducted in the Department covers alcohol, drugs, tobacco and gambling issues. The two main tasks of the Department are (i) to research, produce and disseminate information on alcohol and drugs, substance use, addictions and their social and health-related effects and (ii) to develop prevention and good practices with a view to counteracting the onset and development of alcohol and drug problems and the damaging effects of smoking and other addictions. The number of staff hovers at approximately 60 people. The Department is organized into three units, one specialized in social sciences (the Alcohol and Drug Research Unit), another in laboratory analytics (the Alcohol and Drug Analytics Unit) and the third primarily in preventive work (the Addiction Prevention Unit). These units incorporate a rich variety and long traditions of both research and preventive work. The mixture of different disciplines creates good opportunities for interdisciplinary research projects and collaboration within the Department. Also, the fact that in the same administrative context there are both researchers and people specialized in preventive work opens up interesting possibilities for combining efforts from these two branches. Nationally, the Department is a key player in all its fields of interest. It engages in a great deal of cooperation both nationally and internationally, and among its strengths are the high-quality, regularly collected long-term data sets. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.
49 CFR 40.343 - What tasks may a service agent perform for an employer?

Code of Federal Regulations, 2010 CFR

2010-10-01

... employer? 40.343 Section 40.343 Transportation Office of the Secretary of Transportation PROCEDURES FOR TRANSPORTATION WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Roles and Responsibilities of Service Agents § 40.343 What tasks may a service agent perform for an employer? As a service agent, you may perform for...
Response to the Task Force on School Governance.

ERIC Educational Resources Information Center

Denoyer, Richard A.

Although the Task Force on School Governance report claims that restructuring of school boards is essential to save the nation's failing schools, the real failure is society itself. Societal problems such as the nation's $4 trillion debt, air and water pollution, crime, drug abuse, and special interest lobbies abound, and legislators'…
Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs.

PubMed

Liu, Mei; Wu, Yonghui; Chen, Yukun; Sun, Jingchun; Zhao, Zhongming; Chen, Xue-wen; Matheny, Michael Edwin; Xu, Hua

2012-06-01

Adverse drug reaction (ADR) is one of the major causes of failure in drug development. Severe ADRs that go undetected until the post-marketing phase of a drug often lead to patient morbidity. Accurate prediction of potential ADRs is required in the entire life cycle of a drug, including early stages of drug design, different phases of clinical trials, and post-marketing surveillance. Many studies have utilized either chemical structures or molecular pathways of the drugs to predict ADRs. Here, the authors propose a machine-learning-based approach for ADR prediction by integrating the phenotypic characteristics of a drug, including indications and other known ADRs, with the drug's chemical structures and biological properties, including protein targets and pathway information. A large-scale study was conducted to predict 1385 known ADRs of 832 approved drugs, and five machine-learning algorithms for this task were compared. This evaluation, based on a fivefold cross-validation, showed that the support vector machine algorithm outperformed the others. Of the three types of information, phenotypic data were the most informative for ADR prediction. When biological and phenotypic features were added to the baseline chemical information, the ADR prediction model achieved significant improvements in area under the curve (from 0.9054 to 0.9524), precision (from 43.37% to 66.17%), and recall (from 49.25% to 63.06%). Most importantly, the proposed model successfully predicted the ADRs associated with withdrawal of rofecoxib and cerivastatin. The results suggest that phenotypic information on drugs is valuable for ADR prediction. Moreover, they demonstrate that different models that combine chemical, biological, or phenotypic information can be built from approved drugs, and they have the potential to detect clinically important ADRs in both preclinical and post-marketing phases.
Recent Advances in Laser-Ablative Synthesis of Bare Au and Si Nanoparticles and Assessment of Their Prospects for Tissue Engineering Applications.

PubMed

Al-Kattan, Ahmed; Nirwan, Viraj P; Popov, Anton; Ryabchikov, Yury V; Tselikov, Gleb; Sentis, Marc; Fahmi, Amir; Kabashin, Andrei V

2018-05-24

Driven by surface cleanness and unique physical, optical and chemical properties, bare (ligand-free) laser-synthesized nanoparticles (NPs) are now in the focus of interest as promising materials for the development of advanced biomedical platforms related to biosensing, bioimaging and therapeutic drug delivery. We recently achieved significant progress in the synthesis of bare gold (Au) and silicon (Si) NPs and their testing in biomedical tasks, including cancer imaging and therapy, biofuel cells, etc. We also showed that these nanomaterials can be excellent candidates for tissue engineering applications. This review is aimed at the description of our recent progress in laser synthesis of bare Si and Au NPs and their testing as functional modules (additives) in innovative scaffold platforms intended for tissue engineering tasks.
The Role of the Military in the War on Drugs

DTIC Science & Technology

1990-02-10

duty and other tasks. To transport the Blackhawks, the Army needed an Air Force Galaxy airlifter.4 Despite the logistical support required for BLAST...as Fort Benning, Ga., Ranger instructors train federal drug enforcement agents to operate and survive in a jungle environment.8 Army helicopters have
Individual differences in the influence of task-irrelevant Pavlovian cues on human behavior.

PubMed

Garofalo, Sara; di Pellegrino, Giuseppe

2015-01-01

Pavlovian-to-instrumental transfer (PIT) refers to the process of a Pavlovian reward-paired cue acquiring incentive motivational proprieties that drive choices. It represents a crucial phenomenon for understanding cue-controlled behavior, and it has both adaptive and maladaptive implications (i.e., drug-taking). In animals, individual differences in the degree to which such cues bias performance have been identified in two types of individuals that exhibit distinct Conditioned Responses (CR) during Pavlovian conditioning: Sign-Trackers (ST) and Goal-Trackers (GT). Using an appetitive PIT procedure with a monetary reward, the present study investigated, for the first time, the extent to which such individual differences might affect the influence of reward-paired cues in humans. In a first task, participants learned an instrumental response leading to reward; then, in a second task, a visual Pavlovian cue was associated with the same reward; finally, in a third task, PIT was tested by measuring the preference for the reward-paired instrumental response when the task-irrelevant reward-paired cue was presented, in the absence of the reward itself. In ST individuals, but not in GT individuals, reward-related cues biased behavior, resulting in an increased likelihood to perform the instrumental response independently paired with the same reward when presented with the task-irrelevant reward-paired cue, even if the reward itself was no longer available (i.e., stronger PIT effect). This finding has important implications for developing individualized treatment for maladaptive behaviors, such as addiction.
Individual differences in the influence of task-irrelevant Pavlovian cues on human behavior

PubMed Central

Garofalo, Sara; di Pellegrino, Giuseppe

2015-01-01

Pavlovian-to-instrumental transfer (PIT) refers to the process of a Pavlovian reward-paired cue acquiring incentive motivational proprieties that drive choices. It represents a crucial phenomenon for understanding cue-controlled behavior, and it has both adaptive and maladaptive implications (i.e., drug-taking). In animals, individual differences in the degree to which such cues bias performance have been identified in two types of individuals that exhibit distinct Conditioned Responses (CR) during Pavlovian conditioning: Sign-Trackers (ST) and Goal-Trackers (GT). Using an appetitive PIT procedure with a monetary reward, the present study investigated, for the first time, the extent to which such individual differences might affect the influence of reward-paired cues in humans. In a first task, participants learned an instrumental response leading to reward; then, in a second task, a visual Pavlovian cue was associated with the same reward; finally, in a third task, PIT was tested by measuring the preference for the reward-paired instrumental response when the task-irrelevant reward-paired cue was presented, in the absence of the reward itself. In ST individuals, but not in GT individuals, reward-related cues biased behavior, resulting in an increased likelihood to perform the instrumental response independently paired with the same reward when presented with the task-irrelevant reward-paired cue, even if the reward itself was no longer available (i.e., stronger PIT effect). This finding has important implications for developing individualized treatment for maladaptive behaviors, such as addiction. PMID:26157371
Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain

PubMed Central

Rodriguez, Pavel; Zhou, Wei; Barrett, Douglas W.; Altmeyer, Wilson; Gutierrez, Juan E.; Li, Jinqi; Lancaster, Jack L.; Gonzalez-Lima, Francisco

2016-01-01

Purpose To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain. Materials and Methods The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebo-controlled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22–62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 × 2 repeated-measures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug × time between group interactions. Multiple comparison correction was applied, with cluster-corrected P < .05 indicating a significant difference. Results Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9–3.4, P = .01–.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9–4.2, P = .03–.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01). Conclusion Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval. © RSNA, 2016 Online supplemental material is available for this article. PMID:27351678
Long-term effects of exposure to methamphetamine in adolescent rats.

PubMed

Ye, Tony; Pozos, Hilda; Phillips, Tamara J; Izquierdo, Alicia

2014-05-01

Flexible cognition is a set of processes mediated by the prefrontal cortex (PFC), an area of the brain that continues to develop during adolescence and into adulthood. Adult rodents exhibit impairments specific to reversal learning across various dosing regimens of methamphetamine (mAMPH). For adolescent rodents, ongoing PFC development can be assessed by discrimination reversal learning, a task dependent on frontostriatal integrity. The task may also index an increased vulnerability for mAMPH sampling in adulthood. The purpose of the present study was to investigate the long-term effects of escalating, adolescent mAMPH exposure on reversal learning, a PFC-dependent task (Experiment 1) and the likelihood of later sampling of mAMPH in adulthood (Experiment 2). Unlike previous research in adult-treated rats, our results show more generalized learning impairments after adolescent mAMPH exposure to include both attenuated visual discrimination as well as reversal learning. Additionally, we found that rats pre-exposed to mAMPH during adolescence consumed significantly more drug in adulthood. Intake of mAMPH was positively correlated with this learning. Taken together, these findings show that even modest exposure to mAMPH during adolescence may induce general learning impairments in adulthood, and an enduring sensitivity to the effects of mAMPH. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Long-term effects of exposure to methamphetamine in adolescent rats

PubMed Central

Ye, Tony; Pozos, Hilda; Phillips, Tamara J.; Izquierdo, Alicia

2014-01-01

Background Flexible cognition is a set of processes mediated by the prefrontal cortex (PFC), an area of the brain that continues to develop during adolescence and into adulthood. Adult rodents exhibit impairments specific to reversal learning across various dosing regimens of methamphetamine (mAMPH). For adolescent rodents, ongoing PFC development can be assessed by discrimination reversal learning, a task dependent on frontostriatal integrity. The task may also index an increased vulnerability for mAMPH sampling in adulthood. Methods The purpose of the present study was to investigate the long-term effects of escalating, adolescent mAMPH exposure on reversal learning, a PFC-dependent task (Experiment 1) and the likelihood of later sampling of mAMPH in adulthood (Experiment 2). Results Unlike previous research in adult-treated rats, our results show more generalized learning impairments after adolescent mAMPH exposure to include both attenuated visual discrimination as well as reversal learning. Additionally, we found that rats pre-exposed to mAMPH during adolescence consumed significantly more drug in adulthood. Intake of mAMPH was positively correlated with this learning. Conculsion Taken together, these findings show that even modest exposure to mAMPH during adolescence may induce general learning impairments in adulthood, and an enduring sensitivity to the effects of mAMPH. PMID:24629630
The pharmacology of effort-related choice behavior: Dopamine, depression, and individual differences.

PubMed

Salamone, John D; Correa, Merce; Yohn, Samantha; Lopez Cruz, Laura; San Miguel, Noemi; Alatorre, Luisa

2016-06-01

This review paper is focused upon the involvement of mesolimbic dopamine (DA) and related brain systems in effort-based processes. Interference with DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task, such that rats with impaired DA transmission show a heightened sensitivity to ratio requirements. Impaired DA transmission also affects effort-related choice behavior, which is assessed by tasks that offer a choice between a preferred reinforcer that has a high work requirement vs. less preferred reinforcer that can be obtained with minimal effort. Rats and mice with impaired DA transmission reallocate instrumental behavior away from food-reinforced tasks with high response costs, and show increased selection of low reinforcement/low cost options. Tests of effort-related choice have been developed into models of pathological symptoms of motivation that are seen in disorders such as depression and schizophrenia. These models are being employed to explore the effects of conditions associated with various psychopathologies, and to assess drugs for their potential utility as treatments for effort-related symptoms. Studies of the pharmacology of effort-based choice may contribute to the development of treatments for symptoms such as psychomotor slowing, fatigue or anergia, which are seen in depression and other disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Relating drug–protein interaction network with drug side effects

PubMed Central

Mizutani, Sayaka; Pauwels, Edouard; Stoven, Véronique; Goto, Susumu; Yamanishi, Yoshihiro

2012-01-01

Motivation: Identifying the emergence and underlying mechanisms of drug side effects is a challenging task in the drug development process. This underscores the importance of system–wide approaches for linking different scales of drug actions; namely drug-protein interactions (molecular scale) and side effects (phenotypic scale) toward side effect prediction for uncharacterized drugs. Results: We performed a large-scale analysis to extract correlated sets of targeted proteins and side effects, based on the co-occurrence of drugs in protein-binding profiles and side effect profiles, using sparse canonical correlation analysis. The analysis of 658 drugs with the two profiles for 1368 proteins and 1339 side effects led to the extraction of 80 correlated sets. Enrichment analyses using KEGG and Gene Ontology showed that most of the correlated sets were significantly enriched with proteins that are involved in the same biological pathways, even if their molecular functions are different. This allowed for a biologically relevant interpretation regarding the relationship between drug–targeted proteins and side effects. The extracted side effects can be regarded as possible phenotypic outcomes by drugs targeting the proteins that appear in the same correlated set. The proposed method is expected to be useful for predicting potential side effects of new drug candidate compounds based on their protein-binding profiles. Supplementary information: Datasets and all results are available at http://web.kuicr.kyoto-u.ac.jp/supp/smizutan/target-effect/. Availability: Software is available at the above supplementary website. Contact: yamanishi@bioreg.kyushu-u.ac.jp, or goto@kuicr.kyoto-u.ac.jp PMID:22962476
Perspectives on bioanalytical mass spectrometry and automation in drug discovery.

PubMed

Janiszewski, John S; Liston, Theodore E; Cole, Mark J

2008-11-01

The use of high speed synthesis technologies has resulted in a steady increase in the number of new chemical entities active in the drug discovery research stream. Large organizations can have thousands of chemical entities in various stages of testing and evaluation across numerous projects on a weekly basis. Qualitative and quantitative measurements made using LC/MS are integrated throughout this process from early stage lead generation through candidate nomination. Nearly all analytical processes and procedures in modern research organizations are automated to some degree. This includes both hardware and software automation. In this review we discuss bioanalytical mass spectrometry and automation as components of the analytical chemistry infrastructure in pharma. Analytical chemists are presented as members of distinct groups with similar skillsets that build automated systems, manage test compounds, assays and reagents, and deliver data to project teams. The ADME-screening process in drug discovery is used as a model to highlight the relationships between analytical tasks in drug discovery. Emerging software and process automation tools are described that can potentially address gaps and link analytical chemistry related tasks. The role of analytical chemists and groups in modern 'industrialized' drug discovery is also discussed.
A pilot study of loss aversion for drug and non-drug commodities in cocaine users.

PubMed

Strickland, Justin C; Beckmann, Joshua S; Rush, Craig R; Stoops, William W

2017-11-01

Numerous studies in behavioral economics have demonstrated that individuals are more sensitive to the prospect of a loss than a gain (i.e., loss aversion). Although loss aversion has been well described in "healthy" populations, little research exists in individuals with substance use disorders. This gap is notable considering the prominent role that choice and decision-making play in drug use. The purpose of this pilot study was to evaluate loss aversion in active cocaine users. Current cocaine users (N=38; 42% female) participated in this within-subjects laboratory pilot study. Subjects completed a battery of tasks designed to assess loss aversion for drug and non-drug commodities under varying risk conditions. Standardized loss aversion coefficients (λ) were compared to theoretically and empirically relevant normative values (i.e., λ=2). Compared to normative loss aversion coefficient values, a precise and consistent decrease in loss aversion was observed in cocaine users (sample λ≈1). These values were observed across drug and non-drug commodities as well as under certain and risky conditions. These data represent the first systematic study of loss aversion in cocaine-using populations and provide evidence for equal sensitivity to losses and gains or loss equivalence. Futures studies should evaluate the specificity of these effects to a history of cocaine use as well as the impact of manipulations of loss aversion on drug use to determine how this phenomenon may contribute to intervention development efforts. Copyright © 2017 Elsevier B.V. All rights reserved.
Drug Stroop: Mechanisms of response to computerized cognitive behavioral therapy for cocaine dependence in a randomized clinical trial.

PubMed

DeVito, Elise E; Kiluk, Brian D; Nich, Charla; Mouratidis, Maria; Carroll, Kathleen M

2018-02-01

Poor performance on Drug Stroop tasks, which could indicate attentional bias to drug-related cues, craving, poor cognitive control (including poor response inhibition), has been associated with substance use severity, treatment retention and substance use treatment outcomes. Cognitive Behavioral Therapy (CBT) focuses on training in appraisal and coping strategies, including strategies to minimize the negative impact of triggers and coping with drug-cue-induced craving. One mechanism of action of CBT may be the strengthening of cognitive control processes and reduction of attentional bias to drug-related stimuli. Methadone-maintained individuals with cocaine-use disorders, participating in a randomized controlled trial of treatment as usual (TAU) versus TAU plus access to computer-based CBT (CBT4CBT), completed a computerized Drug Stroop task at pre- and post-treatment. Analyses determined whether attentional bias toward drug-related stimuli changed differentially by treatment group or cocaine use outcomes across the treatment period and whether engagement in components of CBT4CBT or TAU treatment related to changes in attentional bias toward drug-related stimuli at post- versus pre-treatment. Participants achieving a longer duration of cocaine abstinence during treatment (3+ weeks) showed greater reductions in Drug Stroop Effect than those with shorter maximum continuous abstinence. Reductions in Drug Stroop Effect across treatment were associated with greater engagement with CBT4CBT-specific treatment components, but not TAU-specific treatment components. Reduction in attentional bias to drug-related cues and craving and/or improved executive cognitive control and response inhibition may contribute to the mechanism of action of CBT4CBT. Copyright © 2017 Elsevier B.V. All rights reserved.
Medicine and pharmacy--facts and myths about the development of an innovative pharmaceutical industry in Poland.

PubMed

Kubiak, Włodzimierz

2005-01-01

Innovation is fundamental to the pharmaceutical industry and a key to improvements in healthcare. Its effectiveness depends on huge, constant investments in research. This innovative industry directly affects the course of studies in healthcare and medicine. Its efforts translate directly into the length and quality of our lives. For several years now, the progress underway in pharmaceutical industry has produced measurable benefits. Doctors have new pharmaceuticals at their disposal, including many types of antibiotics and anti-viral drugs, vaccines and a wide range of drugs which save lives or make them more comfortable. In the near future, ever more efficient cures for neoplastic, rheumatic, neurological, psychic, metabolic, circulatory or respiratory diseases can be expected. Innovation is necessary. The human population is ageing, and the task of an innovative pharmaceutical industry is to keep it in a good condition. The use of innovative drugs can translate directly into lowering the costs of illness. A continuous reduction in spending on healthcare has been observed. The costs of inventing an innovative drug are enormous though (US dollar 800 million), and studies on a new drug last between 10 and 13 years. An essential element in recovering the incurred costs and ensuring funds needed for new research is protection by patent. Innovative pharmaceutical companies in Poland are committed to increasing the competitiveness and sustaining the development of not only the market, but also the entire pharmaceutical sector. It is a group of companies of crucial importance to the Polish healthcare system, as it influences improvement in the quality of medical services. Through their investments and spending on research and development, innovative companies accelerate economic growth. In Poland, the innovative pharmaceutical industry is represented by the Association of Pharmaceutical Companies Representatives in Poland (SPFFwP).
Integration of drug dosing data with physiological data streams using a cloud computing paradigm.

PubMed

Bressan, Nadja; James, Andrew; McGregor, Carolyn

2013-01-01

Many drugs are used during the provision of intensive care for the preterm newborn infant. Recommendations for drug dosing in newborns depend upon data from population based pharmacokinetic research. There is a need to be able to modify drug dosing in response to the preterm infant's response to the standard dosing recommendations. The real-time integration of physiological data with drug dosing data would facilitate individualised drug dosing for these immature infants. This paper proposes the use of a novel computational framework that employs real-time, temporal data analysis for this task. Deployment of the framework within the cloud computing paradigm will enable widespread distribution of individualized drug dosing for newborn infants.
Behavioral and neuroimaging evidence for overreliance on habit learning in alcohol-dependent patients

PubMed Central

Sjoerds, Z; de Wit, S; van den Brink, W; Robbins, T W; Beekman, A T F; Penninx, B W J H; Veltman, D J

2013-01-01

Substance dependence is characterized by compulsive drug-taking despite negative consequences. Animal research suggests an underlying imbalance between goal-directed and habitual action control with chronic drug use. However, this imbalance, and its associated neurophysiological mechanisms, has not yet been experimentally investigated in human drug abusers. The aim of the present study therefore was to assess the balance between goal-directed and habit-based learning and its neural correlates in abstinent alcohol-dependent (AD) patients. A total of 31 AD patients and 19 age, gender and education matched healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during completion of an instrumental learning task designed to study the balance between goal-directed and habit learning. Task performance and task-related blood oxygen level-dependent activations in the brain were compared between AD patients and healthy matched controls. Findings were additionally associated with duration and severity of alcohol dependence. The results of this study provide evidence for an overreliance on stimulus-response habit learning in AD compared with HC, which was accompanied by decreased engagement of brain areas implicated in goal-directed action (ventromedial prefrontal cortex and anterior putamen) and increased recruitment of brain areas implicated in habit learning (posterior putamen) in AD patients. In conclusion, this is the first human study to provide experimental evidence for a disturbed balance between goal-directed and habitual control by use of an instrumental learning task, and to directly implicate cortical dysfunction to overreliance on inflexible habits in AD patients. PMID:24346135
Behavioral and neuroimaging evidence for overreliance on habit learning in alcohol-dependent patients.

PubMed

Sjoerds, Z; de Wit, S; van den Brink, W; Robbins, T W; Beekman, A T F; Penninx, B W J H; Veltman, D J

2013-12-17

Substance dependence is characterized by compulsive drug-taking despite negative consequences. Animal research suggests an underlying imbalance between goal-directed and habitual action control with chronic drug use. However, this imbalance, and its associated neurophysiological mechanisms, has not yet been experimentally investigated in human drug abusers. The aim of the present study therefore was to assess the balance between goal-directed and habit-based learning and its neural correlates in abstinent alcohol-dependent (AD) patients. A total of 31 AD patients and 19 age, gender and education matched healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during completion of an instrumental learning task designed to study the balance between goal-directed and habit learning. Task performance and task-related blood oxygen level-dependent activations in the brain were compared between AD patients and healthy matched controls. Findings were additionally associated with duration and severity of alcohol dependence. The results of this study provide evidence for an overreliance on stimulus-response habit learning in AD compared with HC, which was accompanied by decreased engagement of brain areas implicated in goal-directed action (ventromedial prefrontal cortex and anterior putamen) and increased recruitment of brain areas implicated in habit learning (posterior putamen) in AD patients. In conclusion, this is the first human study to provide experimental evidence for a disturbed balance between goal-directed and habitual control by use of an instrumental learning task, and to directly implicate cortical dysfunction to overreliance on inflexible habits in AD patients.
Elucidating the role of D4 receptors in mediating attributions of salience to incentive stimuli on Pavlovian conditioned approach and conditioned reinforcement paradigms.

PubMed

Cocker, P J; Vonder Haar, C; Winstanley, C A

2016-10-01

The power of drug-associated cues to instigate drug 'wanting' and consequently promote drug seeking is a corner stone of contemporary theories of addiction. Gambling disorder has recently been added to the pantheon of addictive disorders due to the phenomenological similarities between the diseases. However, the neurobiological mechanism that may mediate increased sensitivity towards conditioned stimuli in addictive disorders is unclear. We have previously demonstrated using a rodent analogue of a simple slot machine that the dopamine D4 receptor is critically engaged in controlling animals' attribution of salience to stimuli associated with reward in this paradigm, and consequently may represent a target for the treatment of gambling disorder. Here, we investigated the role of acute administration of a D4 receptor agonist on animals' responsivity to conditioned stimuli on both a Pavlovian conditioned approach (autoshaping) and a conditioned reinforcement paradigm. Following training on one of the two tasks, separate cohorts of rats (male and female) were administered a dose of PD168077 shown to be maximally effective at precipitating errors in reward expectancy on the rat slot machine task (10mg/kg). However, augmenting the activity of the D4 receptors in this manner did not alter behaviour on either task. These data therefore provide novel evidence that the D4 receptor does not alter incentive motivation in response to cues on simple behavioural tasks. Copyright © 2016 Elsevier B.V. All rights reserved.
Co-delivery of docetaxel and gemcitabine using PEGylated self-assembled stealth nanoparticles for improved breast cancer therapy.

PubMed

Kushwah, Varun; Katiyar, Sameer S; Agrawal, Ashish Kumar; Gupta, Ramesh C; Jain, Sanyog

2018-04-20

The present report deals with conjugation of dual drug; docetaxel (DTX) and gemcitabine (GEM) with linker poly-ethylene-glycol (PEG) to develop amphiphilic molecule having self-assembled property. The synthesized conjugate (DTX-PEG-GEM) demonstrated critical micelle concentration (CMC) in the range of 5-10μg/ml which self-assembled to form NPs with size 124.2±5.7. Remarkably higher coumarin-6 (C-6) fluorescence signals observed in case of C-6 loaded NPs, suggested enhanced cellular uptake via clathrin mediated endocytosis. Developed NPs demonstrated 4.8-fold higher AUC (0-∞) value of GEM in comparison with Gemzar®. Tumor growth inhibition study demonstrated significant reduction in tumor volume and higher survival rate with NPs. Moreover, NPs demonstrated significantly lower hepato- and nephro-toxicity, evident from both histopathological sections and biochemical markers level estimation, and hemolytic toxicity. Data in hand suggest enhanced therapeutic efficacy and reduced toxicity of developed NPs over conventional drugs, resulting in efficient combinatorial chemotherapeutic-regimen and patient compliance, which is still an unmet task. Copyright © 2018 Elsevier Inc. All rights reserved.
Using In-vivo Fluorescence Imaging in Personalized Cancer Diagnostics and Therapy, an Image and Treat Paradigm

PubMed Central

Ardeshirpour, Yasaman; Chernomordik, Victor; Capala, Jacek; Hassan, Moinuddin; Zielinsky, Rafal; Griffiths, Gary; Achilefu, Samuel; Smith, Paul; Gandjbakhckhe, Amir

2013-01-01

The major goal in developing drugs targeting specific tumor receptors, such as Monoclonal AntiBodies (MAB), is to make a drug compound that targets selectively the cancer-causing biomarkers, inhibits their functionality, and/or delivers the toxin specifically to the malignant cells. Recent advances in MABs show that their efficacy depends strongly on characterization of tumor biomarkers. Therefore, one of the main tasks in cancer diagnostics and treatment is to develop non-invasive in-vivo imaging techniques for detection of cancer biomarkers and monitoring their down regulation during the treatment. Such methods can potentially result in a new imaging and treatment paradigm for cancer therapy. In this article we have reviewed fluorescence imaging approaches, including those developed in our group, to detect and monitor Human Epidermal Growth Factor 2 (HER2) receptors before and during therapy. Transition of these techniques from the bench to bedside is the ultimate goal of our project. Similar approaches can be used potentially for characterization of other cancer related cell biomarkers. PMID:22066595
Metabolomics Guides Rational Development of a Simplified Cell Culture Medium for Drug Screening against Trypanosoma brucei

PubMed Central

Creek, Darren J.; Nijagal, Brunda; Kim, Dong-Hyun; Rojas, Federico; Matthews, Keith R.

2013-01-01

In vitro culture methods underpin many experimental approaches to biology and drug discovery. The modification of established cell culture methods to make them more biologically relevant or to optimize growth is traditionally a laborious task. Emerging metabolomic technology enables the rapid evaluation of intra- and extracellular metabolites and can be applied to the rational development of cell culture media. In this study, untargeted semiquantitative and targeted quantitative metabolomic analyses of fresh and spent media revealed the major nutritional requirements for the growth of bloodstream form Trypanosoma brucei. The standard culture medium (HMI11) contained unnecessarily high concentrations of 32 nutrients that were subsequently removed to make the concentrations more closely resemble those normally found in blood. Our new medium, Creek's minimal medium (CMM), supports in vitro growth equivalent to that in HMI11 and causes no significant perturbation of metabolite levels for 94% of the detected metabolome (<3-fold change; α = 0.05). Importantly, improved sensitivity was observed for drug activity studies in whole-cell phenotypic screenings and in the metabolomic mode of action assays. Four-hundred-fold 50% inhibitory concentration decreases were observed for pentamidine and methotrexate, suggesting inhibition of activity by nutrients present in HMI11. CMM is suitable for routine cell culture and offers important advantages for metabolomic studies and drug activity screening. PMID:23571546
Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases

PubMed Central

Patel, Sulabh P.; Vaishya, Ravi; Patel, Ashaben; Agrahari, Vibhuti; Pal, Dhananjay; Mitra, Ashim K.

2016-01-01

This manuscript is focused on the development of pentablock (PB) copolymer based sustained release formulation for the treatment of posterior segment ocular diseases. We have successfully synthesized biodegradable and biocompatible PB copolymers for the preparation of nanoparticles (NPs) and thermosensitive gel. Achieving high drug loading with hydrophilic biotherapeutics (peptides /proteins) is a challenging task. Moreover, small intravitreal injection volume (≤100 μL) requires high loading to develop a long term (6 months) sustained release formulation. We have successfully investigated various formulation parameters to achieve maximum peptide/protein (octreotide, insulin, lysozyme, IgG-Fab, IgG, and catalase) loading in PB NPs. Improvement in drug loading can facilitate delivery of larger doses of therapeutic proteins via limited injection volume. A composite formulation comprised of NPs in gel system exhibited sustained release (without burst effect) of peptides and proteins, may serve as a platform technology for the treatment of posterior segment ocular diseases. PMID:26964498
Assessing pharmacokinetics of indocyanine green-loaded nanoparticle in tumor with a dynamic diffuse fluorescence tomography system

NASA Astrophysics Data System (ADS)

Zhang, Yanqi; Yin, Guoyan; Zhao, Huijuan; Ma, Wenjuan; Gao, Feng; Zhang, Limin

2018-02-01

Real-time and continuous monitoring of drug release in vivo is an important task in pharmaceutical development. Here, we devoted to explore a real-time continuous study of the pharmacokinetics of free indocyanine green (ICG) and ICG loaded in the shell-sheddable nanoparticles in tumor based on a dynamic diffuse fluorescence tomography (DFT) system: A highly-sensitive dynamic DFT system of CT-scanning mode generates informative and instantaneous sampling datasets; An analysis procedure extracts the pharmacokinetic parameters from the reconstructed time curves of the mean ICG concentration in tumor, using the Gauss-Newton scheme based on two-compartment model. Compared with the pharmacokinetic parameters of free ICG in tumor, the ICG loaded in the shell-sheddable nanoparticles shows efficient accumulation in tumor. The results demonstrate our proposed dynamic-DFT can provide an integrated and continuous view of the drug delivery of the injected agents in different formulations, which is helpful for the development of diagnosis and therapy for tumors.
New guidelines for health care for alcohol and drug users and the real work: possible contributions of ergonomics to the restructuring of work and competence development.

PubMed

de Almeida, Daniela Tonizza; de Oliveira Echternacht, E Eliza Helena

2012-01-01

The study investigated, through a literature review, how the research community has addressed the difficulties experiences by the teams in front of new prescriptions for the treatment of alcohol and drug users in Centers of Psyco-social Attention and discusses the relevance of the conceptual and methodological references of Ergonomics for understand and transform work situations. Such studies tend to do an analysis that does not account for variability present in both the workers and work organization and prioritize the analysis of final results of the, disqualifying local inventions due to tasks imposed by policy guidelines. It is estimated that the Ergonomics, considering the diversity of training, learning and experience, contributes to the implementation of media to promote the continued development of competences that can meet the demands of production and expands knowledge about the problems experienced and the possibilities of overcoming them.
Finding Relational Associations in HIV Resistance Mutation Data

NASA Astrophysics Data System (ADS)

Richter, Lothar; Augustin, Regina; Kramer, Stefan

HIV therapy optimization is a hard task due to rapidly evolving mutations leading to drug resistance. Over the past five years, several machine learning approaches have been developed for decision support, mostly to predict therapy failure from the genotypic sequence of viral proteins and additional factors. In this paper, we define a relational representation for an important part of the data, namely the sequences of a viral protein (reverse transcriptase), their mutations, and the drug resistance(s) associated with those mutations. The data were retrieved from the Los Alamos National Laboratories' (LANL) HIV databases. In contrast to existing work in this area, we do not aim directly for predictive modeling, but take one step back and apply descriptive mining methods to develop a better understanding of the correlations and associations between mutations and resistances. In our particular application, we use the Warmr algorithm to detect non-trivial patterns connecting mutations and resistances. Our findings suggest that well-known facts can be rediscovered, but also hint at the potential of discovering yet unknown associations.
Selective processing of smoking-related cues in smokers: manipulation of deprivation level and comparison of three measures of processing bias.

PubMed

Mogg, Karin; Bradley, Brendan P

2002-12-01

Recent theories of addiction suggest that an attentional bias for drug-related cues plays an important role in maintaining drug-taking behaviours. A key feature of the present study is that it used three different measures of processing bias for linguistic and pictorial smoking-related cues: masked and unmasked conditions of the modified Stroop task, and a pictorial version of the visual probe task. Participants were smokers (n = 27), who were tested twice, with deprivation level manipulated as a within-subjects variable. They were asked to abstain from smoking for 12 h before one session, and to smoke normally before the other. Results were consistent with an attentional bias for smoking-related pictures on the visual probe task, and for smoking-related words in the unmasked condition of the modified Stroop task. The latter bias was most strongly predicted by self-reported urge to smoke, rather than by the deprivation manipulation. There was no evidence of a preconscious bias for smoking cues. The three measures of cognitive bias (from masked and unmasked Stroop and visual probe tasks) were not significantly correlated with each other, which suggests they may tap different underlying mechanisms. We discuss the results with respect to conceptualizations of selective attention, addiction and motivational states in general.
Expecting innovation: psychoactive drug primes and the generation of creative solutions.

PubMed

Hicks, Joshua A; Pedersen, Sarah L; Pederson, Sarah L; Friedman, Ronald S; McCarthy, Denis M

2011-08-01

Many individuals expect that alcohol and drug consumption will enhance creativity. The present studies tested whether substance related primes would influence creative performance for individuals who possessed creativity-related substance expectancies. Participants (n = 566) were briefly exposed to stimuli related to psychoactive substances (alcohol, for Study 1, Sample 1, and Study 2; and marijuana, for Study 1, Sample 2) or neutral stimuli. Participants in Study 1 then completed a creative problem-solving task, while participants in Study 2 completed a divergent thinking task or a task unrelated to creative problem solving. The results of Study 1 revealed that exposure to the experimental stimuli enhanced performance on the creative problem-solving task for those who expected the corresponding substance would trigger creative functioning. In a conceptual replication, Study 2 showed that participants exposed to alcohol cues performed better on a divergent thinking task if they expected alcohol to enhance creativity. It is important to note that this same interaction did not influence performance on measures unrelated to creative problem solving, suggesting that the activation of creativity-related expectancies influenced creative performance, specifically. These findings highlight the importance of assessing expectancies when examining pharmacological effects of alcohol and marijuana. Future directions and implications for substance-related interventions are discussed. (c) 2011 APA, all rights reserved.
Utilizing data consortia to monitor safety and effectiveness of biosimilars and their innovator products.

PubMed

Baldziki, Mike; Brown, Jeff; Chan, Hungching; Cheetham, T Craig; Conn, Thomas; Daniel, Gregory W; Hendrickson, Mark; Hilbrich, Lutz; Johnson, Ayanna; Miller, Steven B; Moore, Tom; Motheral, Brenda; Priddy, Sarah A; Raebel, Marsha A; Randhawa, Gurvaneet; Surratt, Penny; Walraven, Cheryl; White, T Jeff; Bruns, Kevin; Carden, Mary Jo; Dragovich, Charlie; Eichelberger, Bernadette; Rosato, Edith; Sega, Todd

2015-01-01

The Biologics Price Competition and Innovation Act, introduced as part of the Affordable Care Act, directed the FDA to create an approval pathway for biologic products shown to be biosimilar or interchangeable with an FDA-approved innovator drug. These biosimilars will not be chemically identical to the reference agent. Investigational studies conducted with biosimilar agents will likely provide limited real-world evidence of their effectiveness and safety. How do we best monitor effectiveness and safety of biosimilar products once approved by the FDA and used more extensively by patients? To determine the feasibility of developing a distributed research network that will use health insurance plan and health delivery system data to detect biosimilar safety and effectiveness signals early and be able to answer important managed care pharmacy questions from both the government and managed care organizations. Twenty-one members of the AMCP Task Force on Biosimilar Collective Intelligence Systems met November 12, 2013, to discuss issues involved in designing this consortium and to explore next steps. The task force concluded that a managed care biosimilars research consortium would be of significant value. Task force members agreed that it is best to use a distributed research network structurally similar to existing DARTNet, HMO Research Network, and Mini-Sentinel consortia. However, for some surveillance projects that it undertakes, the task force recognizes it may need supplemental data from managed care and other sources (i.e., a "hybrid" structure model). The task force believes that AMCP is well positioned to lead the biosimilar-monitoring effort and that the next step to developing a biosimilar-innovator collective intelligence system is to convene an advisory council to address organizational governance.
Behavioral Economic Analysis of Opioid Consumption In Heroin-Dependent Individuals: Effects of Alternative Reinforcer Magnitude and Post-Session Drug Supply

PubMed Central

Greenwald, Mark K; Steinmiller, Caren L

2009-01-01

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand were influenced by HYD unit price (UP), alternative money reinforcement magnitude and post-session HYD supply. Heroin dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day first sampled two HYD doses (12 and 24 mg IM, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could earn a HYD unit dose (2 mg, fixed) or money ($2 or $4, varied across sessions), administered immediately after the work session. Before the PR task, volunteers were told which HYD supplemental dose (none, Drug A or B) would be available 3 hr after receiving the PR-contingent dose. PR-contingent HYD choice significantly decreased when $4 relative to $2 was concurrently available. Information about the post-session HYD supplement moderated this effect: when subjects were told a supplemental dose was available, HYD-seeking behavior decreased when the money alternative was smaller ($2), but this information did not further attenuate HYD choice, which was already low, when the money alternative was higher ($4). HYD demand elasticity was only increased by the $4 relative to $2 alternative without the HYD supplement. In summary, opioid-seeking behavior is influenced by the availability of concurrent non-drug and drug alternatives. These findings show that drug availability and non-drug alternatives interact to modulate drug-seeking behavior. PMID:19464125

Evaluating psychological markers for human nicotine dependence: tobacco choice, extinction, and Pavlovian-to-instrumental transfer.

PubMed

Hogarth, Lee; Chase, Henry W

2012-06-01

Individual differences in drug dependence may be mediated by several abnormalities in associative learning, including perseveration of drug-seeking following contingency change, greater control over drug-seeking by Pavlovian stimuli, or greater sensitivity to drug reinforcement establishing higher rates of drug-seeking. To evaluate these three candidate markers for nicotine dependence, Experiment 1 contrasted daily (N = 22) and nondaily smoker groups (N = 22) on a novel instrumental learning task, where one S+ was first trained as a predictor of tobacco reward before being extinguished. Experiment 2 compared daily (N = 18) and nondaily smoker groups (N = 18) on a concurrent-choice task for tobacco and chocolate reward before an extinction test in which the tobacco response was extinguished, followed by a Pavlovian-to-instrumental transfer test, wherein the impact of tobacco and chocolate cues on concurrent choice was measured (gender was balanced within each smoker group). The results showed no group difference in sensitivity to extinction of either the stimulus-drug or response-drug contingency in Experiments 1 and 2, respectively, nor did groups show a difference in Pavlovian-to-instrumental transfer of control over tobacco choice. By contrast, nicotine-dependence status was marked by a higher frequency of tobacco choice in the concurrent-choice procedure, and this choice preference was associated with subjective craving (gender did not affect any behavioral measure). These results favor the view that nicotine dependence in this sample is not determined by individual predilection for perseveration or stimulus-control over drug-seeking, but by greater sensitivity to reinforcement of instrumental drug choice. Value-based decision theories of dependence are discussed.
Individual differences in decision making and reward processing predict changes in cannabis use: a prospective functional magnetic resonance imaging study.

PubMed

Cousijn, Janna; Wiers, Reinout W; Ridderinkhof, K Richard; van den Brink, Wim; Veltman, Dick J; Porrino, Linda J; Goudriaan, Anna E

2013-11-01

Decision-making deficits are thought to play an important role in the development and persistence of substance use disorders. Individual differences in decision-making abilities and their underlying neurocircuitry may, therefore, constitute an important predictor for the course of substance use and the development of substance use disorders. Here, we investigate the predictive value of decision making and neural mechanisms underlying decision making for future cannabis use and problem severity in a sample of heavy cannabis users. Brain activity during a monetary decision-making task (Iowa gambling task) was compared between 32 heavy cannabis users and 41 matched non-using controls using functional magnetic resonance imaging. In addition, within the group of heavy cannabis users, associations were examined between task-related brain activations, cannabis use and cannabis use-related problems at baseline, and change in cannabis use and problem severity after a 6-month follow-up. Despite normal task performance, heavy cannabis users compared with controls showed higher activation during wins in core areas associated with decision making. Moreover, within the group of heavy cannabis users, win-related activity and activity anticipating loss outcomes in areas generally involved in executive functions predicted change in cannabis use after 6 months. These findings are consistent with previous studies and point to abnormal processing of motivational information in heavy cannabis users. A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.
Environment-Mediated Drug Resistance in Neuroblastoma

DTIC Science & Technology

2014-10-01

AD_________________ Award Number: W81XWH-12-1-0572 TITLE: Environment-Mediated Drug Resistance in Neuroblastoma PRINCIPAL INVESTIGATOR: Yu...Resistance in Neuroblastoma 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0572 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Yu, Hua E 5d. PROJECT...collaborative experiments have demonstrated that monocytes collaborate with MSC in inducing STAT3-dependent drug resistance in neuroblastoma (Task 1), that S1P
Approaches to Drug Abuse Prevention at Colleges and Universities. A Collection of Presentations Made at the National Collegiate Drug Awareness Week Kick-Off Conference (Washington, D.C., February 1988).

ERIC Educational Resources Information Center

Office of Educational Research and Improvement (ED), Washington, DC.

The National Collegiate Drug Awareness Week 1988 (conceived and initiated by the Inter-Association Task Force on Alcohol and Other Substance Issues) began with a Kick-Off Conference of educators that provided students and professionals an opportunity to share ideas and experiences. One-page abstracts of 17 conference presentations are as follows:…
Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

PubMed Central

Maloney, Thomas; Parvaz, Muhammad A.; Alia-Klein, Nelly; Woicik, Patricia A.; Telang, Frank; Wang, Gene-Jack; Volkow, Nora D.; Goldstein, Rita Z.

2010-01-01

Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects’ self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes. PMID:20395264
TU-EF-210-04: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less
Extracting Drug-Drug Interactions with Word and Character-Level Recurrent Neural Networks

PubMed Central

Kavuluru, Ramakanth; Rios, Anthony; Tran, Tung

2017-01-01

Drug-drug interactions (DDIs) are known to be responsible for nearly a third of all adverse drug reactions. Hence several current efforts focus on extracting signal from EMRs to prioritize DDIs that need further exploration. To this end, being able to extract explicit mentions of DDIs in free text narratives is an important task. In this paper, we explore recurrent neural network (RNN) architectures to detect and classify DDIs from unstructured text using the DDIExtraction dataset from the SemEval 2013 (task 9) shared task. Our methods are in line with those used in other recent deep learning efforts for relation extraction including DDI extraction. However, to our knowledge, we are the first to investigate the potential of character-level RNNs (Char-RNNs) for DDI extraction (and relation extraction in general). Furthermore, we explore a simple but effective model bootstrapping method to (a). build model averaging ensembles, (b). derive confidence intervals around mean micro-F scores (MMF), and (c). assess the average behavior of our methods. Without any rule based filtering of negative examples, a popular heuristic used by most earlier efforts, we achieve an MMF of 69.13. By adding simple replicable heuristics to filter negative instances we are able to achieve an MMF of 70.38. Furthermore, our best ensembles produce micro F-scores of 70.81 (without filtering) and 72.13 (with filtering), which are superior to metrics reported in published results. Although Char-RNNs turnout to be inferior to regular word based RNN models in overall comparisons, we find that ensembling models from both architectures results in nontrivial gains over simply using either alone, indicating that they complement each other. PMID:29034375
Effects of amphetamine exposure in adolescence or young adulthood on inhibitory control in adult male and female rats

PubMed Central

Hammerslag, Lindsey R.; Waldman, Alex J.; Gulley, Joshua M.

2014-01-01

Heightened impulsivity is a feature of some psychiatric disorders, including addiction, that also have sex-specific patterns of expression. The relationship between addiction and impulsivity may be driven by drug-induced changes in behavior caused by long term adaptations in signaling within the medial prefrontal cortex (mPFC). Here, we used a response inhibition task that is sensitive to changes in mPFC function to examine the effects of sex and exposure to amphetamine (AMPH) on impulsive action and vigilance. We also examined drug-induced alterations in glutamatergic and dopaminergic signaling through challenge injections with the NMDA receptor antagonist MK-801 (dizocilpine) and AMPH. Male and female Sprague Dawley rats were injected (i.p.) with saline or 3 mg/kg AMPH every other day during adolescence (postnatal day (P) 27–45) or adulthood (P85–103). Starting on P125–135, rats were tested for their ability to lever press for a food reward during periods of signaled availability and withhold responding during a “premature response” phase. In experiment 1, rats received challenge injections (i.p.) of MK-801 and AMPH followed by tests of task performance and locomotor activity. In experiment 2, rats received intra-mPFC infusion of MK-801. We found that females had better inhibitory control and poorer vigilance than males and that AMPH exposure had both sex- and age-of-exposure dependent effects on impulsivity. Systemic drug challenges disrupted task performance, particularly in females, and increased impulsivity while intra-mPFC infusions had modest effects. AMPH exposure did not affect responses to drug challenges. Together, these results suggest that sex mediates both trait and drug-induced impulsivity. PMID:24462963
Prime Drug Interplay in Dental Practice

PubMed Central

Govila, Vivek; Saini, Ashish; Verma, Sunil Chandra

2016-01-01

Drug interaction is a negative representation of pharmacotherapy. In order to provide the best patient care possible, a thorough knowledge of how the drug interactions occur is needed for proper application in practice. Possible interactions among current medication and drugs being prescribed should be considered always. A thorough understanding of the mechanism of interactions among drugs is a must for the health care practitioner. Considering the astounding number of drugs patients may be taking, this task seems discouraging. The count of possible interactions in dental practice are less due to few number of drugs utilized and brief period of therapy, but still notable number are to be considered. The aim of present preview is to consider the manifold and multiplex nature of pharmacological drug-drug interaction in the general dental practice setting. PMID:27135021
Quantitative prediction of drug side effects based on drug-related features.

PubMed

Niu, Yanqing; Zhang, Wen

2017-09-01

Unexpected side effects of drugs are great concern in the drug development, and the identification of side effects is an important task. Recently, machine learning methods are proposed to predict the presence or absence of interested side effects for drugs, but it is difficult to make the accurate prediction for all of them. In this paper, we transform side effect profiles of drugs as their quantitative scores, by summing up their side effects with weights. The quantitative scores may measure the dangers of drugs, and thus help to compare the risk of different drugs. Here, we attempt to predict quantitative scores of drugs, namely the quantitative prediction. Specifically, we explore a variety of drug-related features and evaluate their discriminative powers for the quantitative prediction. Then, we consider several feature combination strategies (direct combination, average scoring ensemble combination) to integrate three informative features: chemical substructures, targets, and treatment indications. Finally, the average scoring ensemble model which produces the better performances is used as the final quantitative prediction model. Since weights for side effects are empirical values, we randomly generate different weights in the simulation experiments. The experimental results show that the quantitative method is robust to different weights, and produces satisfying results. Although other state-of-the-art methods cannot make the quantitative prediction directly, the prediction results can be transformed as the quantitative scores. By indirect comparison, the proposed method produces much better results than benchmark methods in the quantitative prediction. In conclusion, the proposed method is promising for the quantitative prediction of side effects, which may work cooperatively with existing state-of-the-art methods to reveal dangers of drugs.
A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

PubMed

Schadt, Simone; Bister, Bojan; Chowdhury, Swapan K; Funk, Christoph; Hop, Cornelis E C A; Humphreys, W Griffith; Igarashi, Fumihiko; James, Alexander D; Kagan, Mark; Khojasteh, S Cyrus; Nedderman, Angus N R; Prakash, Chandra; Runge, Frank; Scheible, Holger; Spracklin, Douglas K; Swart, Piet; Tse, Susanna; Yuan, Josh; Obach, R Scott

2018-06-01

Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
Estimating HIV-1 Fitness Characteristics from Cross-Sectional Genotype Data

PubMed Central

Gopalakrishnan, Sathej; Montazeri, Hesam; Menz, Stephan; Beerenwinkel, Niko; Huisinga, Wilhelm

2014-01-01

Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure. PMID:25375675
Multiple Animal Studies for Medical Chemical Defense Program in Soldier/ Patient Decontamination and Drug Development on Task Order 84-6: Pyruvate Dehydrogenase System for Determining the Effectiveness of Arsenic Antidotes

DTIC Science & Technology

1988-03-11

adenine dinucleotide FAD = flavin-adenine dinucleotide iipS2 = lipoic acid lip(SH)2 = dihydrolipoic acid CoA = coenzyme A. SHepatic PDH complex activity...tissues has yet to be fully characterized, but it probably involves arsenic binding to the lipoic acid and dithiol moieties of the complex (Fluharty...covalently bound lipoic acid substrate of dihydrolipoyl transacetylase is greater per mole of L and CVAA than for sodium arsenite. This is possible
Integrating in silico prediction methods, molecular docking, and molecular dynamics simulation to predict the impact of ALK missense mutations in structural perspective.

PubMed

Doss, C George Priya; Chakraborty, Chiranjib; Chen, Luonan; Zhu, Hailong

2014-01-01

Over the past decade, advancements in next generation sequencing technology have placed personalized genomic medicine upon horizon. Understanding the likelihood of disease causing mutations in complex diseases as pathogenic or neutral remains as a major task and even impossible in the structural context because of its time consuming and expensive experiments. Among the various diseases causing mutations, single nucleotide polymorphisms (SNPs) play a vital role in defining individual's susceptibility to disease and drug response. Understanding the genotype-phenotype relationship through SNPs is the first and most important step in drug research and development. Detailed understanding of the effect of SNPs on patient drug response is a key factor in the establishment of personalized medicine. In this paper, we represent a computational pipeline in anaplastic lymphoma kinase (ALK) for SNP-centred study by the application of in silico prediction methods, molecular docking, and molecular dynamics simulation approaches. Combination of computational methods provides a way in understanding the impact of deleterious mutations in altering the protein drug targets and eventually leading to variable patient's drug response. We hope this rapid and cost effective pipeline will also serve as a bridge to connect the clinicians and in silico resources in tailoring treatments to the patients' specific genotype.
[Hospital pharmaceutical practice in prison].

PubMed

Harcouët, L

2010-09-01

Since 1994, hospital pharmaceutical teams have been in charge of pharmaceutical tasks in "unités de consultation et de soins ambulatoires" (UCSA), which are hospital consulting care units in French prisons. In 2008, pharmaceutical team in Parisian prisons received 6500 prescriptions and prepared 85,000 nominative bags containing drugs. Prisoners were 1.3% to receive treatments against HIV, 8.2% cardiovascular drugs, 7.2% opioid substitution treatments, and 52.9% psychoactive drugs, including 39.3% hypnotics, 40.5% anxiolytics, 11.3% antidepressants and 12.2% neuroleptics. In prison, the dichotomy between somatic and mental care is marked, attitudes of prisoners about their medicines are complex (important claims, embezzlement, etc.) and it is difficult for law defendants to maintain treatment confidentiality and to prepare prison outing in terms of health. To attenuate the heterogeneity of drug distribution systems in French prisons, we propose pharmaceutical analysis of prescriptions and nominative dispensation, computerization in UCSA in coordination with hospitals, a better contribution of prison medical and pharmaceutical staff in hospital "drug committees" and the redaction of pharmaceutical guidelines. Acting in concert with multidisciplinary medical staff in UCSA, pharmaceutical teams have to develop epidemiological studies to improve knowledge in prisoner's health and also prevention and health care in prison. Copyright © 2010 Elsevier Masson SAS. All rights reserved.
Age and sex effects levels of choline compounds in the anterior cingulate cortex of adolescent methamphetamine users.

PubMed

Cloak, Christine C; Alicata, Daniel; Chang, Linda; Andrews-Shigaki, Brian; Ernst, Thomas

2011-12-15

Methamphetamine can be neurotoxic to the adult brain; however, many individuals first use methamphetamine during adolescence, and the drug's impact on this period of brain development is unknown. Therefore, we evaluated young methamphetamine users for possible abnormalities in brain metabolite concentrations. Anterior cingulate cortex (ACC), frontal white matter (FWM), basal ganglia, and thalamus were studied with localized proton magnetic resonance spectroscopy in 54 periadolescent (ages 13-23 years) methamphetamine users and 53 comparison subjects. The concentrations of major brain metabolites and their associations with age, sex and cognition were assessed. FWM total-creatine correlated with age in methamphetamine-using males and comparison females, but not comparison males or methamphetamine-using females, leading to a drug by sex by age interaction (p=0.003) and ACC choline-containing compounds (CHO) correlated with age only in comparison males leading to a drug by sex by age interaction (p=0.03). Higher ACC CHO was associated with faster performance on the Stroop Interference task in the control males. Male methamphetamine users had slowest performance on the Stroop Interference task and did not show age-appropriate levels of ACC CHO. The altered age-appropriate levels of ACC CHO and poorer executive function in male methamphetamine users suggest methamphetamine abuse may interfere with brain maturation. These periadolescents did not have the abnormal neuronal markers previously reported in adult methamphetamine users, suggesting that neuronal abnormalities may be the result of long-term use or interference in normal cortical maturation, emphasizing the need for early intervention for young methamphetamine users. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease.

PubMed

McClean, Paula L; Hölscher, Christian

2014-11-01

Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. We have previously shown that liraglutide showed neuroprotective effects in the APPswe/PS1ΔE9 mouse model of AD. Here, we test the GLP-1 receptor agonist lixisenatide in the same mouse model and compare the effects to liraglutide. After ten weeks of daily i.p. injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed, performance in an object recognition task was improved in APP/PS1 mice by both drugs at all doses tested. When analysing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug. Lixisenatide (1 nmol/kg) was most effective. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex was reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured. Copyright © 2014 Elsevier Ltd. All rights reserved.
Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective.

PubMed

Cifaldi, Loredana; Locatelli, Franco; Marasco, Emiliano; Moretta, Lorenzo; Pistoia, Vito

2017-12-01

Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.
The effect of methylphenidate on postural stability under single and dual task conditions in children with attention deficit hyperactivity disorder - a double blind randomized control trial.

PubMed

Jacobi-Polishook, Talia; Shorer, Zamir; Melzer, Itshak

2009-05-15

To investigate the effects of Methylphenidate (MPH) on postural stability in attention deficit hyperactivity disorder (ADHD) children in single and dual task conditions. A randomized controlled double-blind study analyzing postural stability in 24 ADHD children before and after MPH vs. placebo treatments, in three task conditions: (1) Single task, standing still; (2) dual task, standing still performing a memory-attention demanding task; (3) standing still listening to music. MPH resulted in a significant improvement in postural stability during the dual task condition and while listening to music, with no equivalent improvement in placebo controls. MPH improves postural stability in ADHD, especially when an additional task is performed. This is probably due to enhanced attention abilities, thus contributing to improved balance control during performance of tasks that require attention. MPH remains to be studied as a potential drug treatment to improve balance control and physical functioning in other clinical populations.
SSEL-ADE: A semi-supervised ensemble learning framework for extracting adverse drug events from social media.

PubMed

Liu, Jing; Zhao, Songzheng; Wang, Gang

2018-01-01

With the development of Web 2.0 technology, social media websites have become lucrative but under-explored data sources for extracting adverse drug events (ADEs), which is a serious health problem. Besides ADE, other semantic relation types (e.g., drug indication and beneficial effect) could hold between the drug and adverse event mentions, making ADE relation extraction - distinguishing ADE relationship from other relation types - necessary. However, conducting ADE relation extraction in social media environment is not a trivial task because of the expertise-dependent, time-consuming and costly annotation process, and the feature space's high-dimensionality attributed to intrinsic characteristics of social media data. This study aims to develop a framework for ADE relation extraction using patient-generated content in social media with better performance than that delivered by previous efforts. To achieve the objective, a general semi-supervised ensemble learning framework, SSEL-ADE, was developed. The framework exploited various lexical, semantic, and syntactic features, and integrated ensemble learning and semi-supervised learning. A series of experiments were conducted to verify the effectiveness of the proposed framework. Empirical results demonstrate the effectiveness of each component of SSEL-ADE and reveal that our proposed framework outperforms most of existing ADE relation extraction methods The SSEL-ADE can facilitate enhanced ADE relation extraction performance, thereby providing more reliable support for pharmacovigilance. Moreover, the proposed semi-supervised ensemble methods have the potential of being applied to effectively deal with other social media-based problems. Copyright © 2017 Elsevier B.V. All rights reserved.

Semantic Web Ontology and Data Integration: a Case Study in Aiding Psychiatric Drug Repurposing.

PubMed

Liang, Chen; Sun, Jingchun; Tao, Cui

2015-01-01

There remain significant difficulties selecting probable candidate drugs from existing databases. We describe an ontology-oriented approach to represent the nexus between genes, drugs, phenotypes, symptoms, and diseases from multiple information sources. We also report a case study in which we attempted to explore candidate drugs effective for bipolar disorder and epilepsy. We constructed an ontology incorporating knowledge between the two diseases and performed semantic reasoning tasks with the ontology. The results suggested 48 candidate drugs that hold promise for further breakthrough. The evaluation demonstrated the validity our approach. Our approach prioritizes the candidate drugs that have potential associations among genes, phenotypes and symptoms, and thus facilitates the data integration and drug repurposing in psychiatric disorders.
The Neurotensin NTS1 Receptor Agonist PD149163 Produces Antidepressant-Like Effects in the Forced Swim Test: Further Support for Neurotensin as a Novel Pharmacologic Strategy for Antidepressant Drugs.

PubMed

Carey, Lawrence M; Rice, Remington J; Prus, Adam J

2017-08-01

Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS 1 receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS 1 receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.

PubMed

Bahn Chair, Rebecca S; Burch, Henry B; Cooper, David S; Garber, Jeffrey R; Greenlee, M Carol; Klein, Irwin; Laurberg, Peter; McDougall, I Ross; Montori, Victor M; Rivkees, Scott A; Ross, Douglas S; Sosa, Julie Ann; Stan, Marius N

2011-06-01

Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This article describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspeciality physicians and others providing care for patients with this condition. The development of these guidelines was commissioned by the American Thyroid Association in association with the American Association of Clinical Endocrinologists. The American Thyroid Association and American Association of Clinical Endocrinologists assembled a task force of expert clinicians who authored this report. The task force examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to develop the text and a series of specific recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' ophthalmopathy; and management of other miscellaneous causes of thyrotoxicosis. One hundred evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.

PubMed

Bahn, Rebecca S; Burch, Henry B; Cooper, David S; Garber, Jeffrey R; Greenlee, M Carol; Klein, Irwin; Laurberg, Peter; McDougall, I Ross; Montori, Victor M; Rivkees, Scott A; Ross, Douglas S; Sosa, Julie Ann; Stan, Marius N

2011-01-01

Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This article describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspeciality physicians and others providing care for patients with this condition. The development of these guidelines was commissioned by the American Thyroid Association in association with the American Association of Clinical Endocrinologists. The American Thyroid Association and American Association of Clinical Endocrinologists assembled a task force of expert clinicians who authored this report. The task force examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to develop the text and a series of specific recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' ophthalmopathy; and management of other miscellaneous causes of thyrotoxicosis. One hundred evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
Building gold standard corpora for medical natural language processing tasks.

PubMed

Deleger, Louise; Li, Qi; Lingren, Todd; Kaiser, Megan; Molnar, Katalin; Stoutenborough, Laura; Kouril, Michal; Marsolo, Keith; Solti, Imre

2012-01-01

We present the construction of three annotated corpora to serve as gold standards for medical natural language processing (NLP) tasks. Clinical notes from the medical record, clinical trial announcements, and FDA drug labels are annotated. We report high inter-annotator agreements (overall F-measures between 0.8467 and 0.9176) for the annotation of Personal Health Information (PHI) elements for a de-identification task and of medications, diseases/disorders, and signs/symptoms for information extraction (IE) task. The annotated corpora of clinical trials and FDA labels will be publicly released and to facilitate translational NLP tasks that require cross-corpora interoperability (e.g. clinical trial eligibility screening) their annotation schemas are aligned with a large scale, NIH-funded clinical text annotation project.
Neuropsychology and neuropharmacology of P3a and P3b.

PubMed

Polich, John; Criado, José R

2006-05-01

Perspectives on the P300 event-related brain potential (ERP) are reviewed by outlining the distinction between the P3a and P3b subcomponents. The critical factor for eliciting P3a is how target/standard discrimination difficulty rather than novelty modulates task processing. The neural loci of P3a and P3b generation are sketched and a theoretical model is developed. P3a originates from stimulus-driven disruption of frontal attention engagement during task processing. P3b originates when temporal-parietal mechanisms process the stimulus information for memory storage. The neuropharmacological implications of this view are then outlined by evaluating how acute and chronic use of ethanol, marijuana, and nicotine affect P3a and P3b. The findings suggest that the circuit underlying ERP generation is influenced in a different ways for acute intake and varies between chronic use levels across drugs. Theoretical implications are assessed.
Coincidence of role expectations between staff and volunteer members of drug free community coalitions.

PubMed

Goldstein, Marc B; Sapere, Heather; Daviau, John

2017-08-01

Community coalitions have proliferated as a means of addressing a range of complex community problems. Such coalitions often consist of a small paid staff and volunteer members. The present study examines one likely contributor to coalition effectiveness: the degree of agreement on role expectations between paid staff and volunteer members. Role confusion occurs when paid staff and volunteers differ in their expectations of who is responsible for accomplishing specific tasks. Staff and volunteer members from 69 randomly selected Drug Free Coalitions in the United States as well as 21 Drug Free Coalitions in Connecticut were asked to respond to an online survey asking about 37 specific coalition tasks critical for effective coalition functioning and the degree to which paid staff and/or voluntary members should be responsible for accomplishing each. Our final sample consisted of 476 individuals from 35 coalitions. Using coalitions as the unit of analysis, we found significant differences between paid staff and volunteer coalition members on nine tasks reflecting four domains: meeting leadership and participation, (2) planning and implementation leadership, (3) publicity/media relations, and (4) logistical functions. Implications of these differences and ways that evaluators could help coalitions deal with differing role expectations were discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.
Design and validation of a microfluidic device for blood-brain barrier monitoring and transport studies

NASA Astrophysics Data System (ADS)

Ugolini, Giovanni Stefano; Occhetta, Paola; Saccani, Alessandra; Re, Francesca; Krol, Silke; Rasponi, Marco; Redaelli, Alberto

2018-04-01

In vitro blood-brain barrier models are highly relevant for drug screening and drug development studies, due to the challenging task of understanding the transport mechanism of drug molecules through the blood-brain barrier towards the brain tissue. In this respect, microfluidics holds potential for providing microsystems that require low amounts of cells and reagent and can be potentially multiplexed for increasing the ease and throughput of the drug screening process. We here describe the design, development and validation of a microfluidic device for endothelial blood-brain barrier cell transport studies. The device comprises of two microstructured layers (top culture chamber and bottom collection chamber) sandwiching a porous membrane for the cell culture. Microstructured layers include two pairs of physical electrodes, embedded into the device layers by geometrically defined guiding channels with computationally optimized positions. These electrodes allow the use of commercial electrical measurement systems for monitoring trans-endothelial electrical resistance (TEER). We employed the designed device for performing preliminary assessment of endothelial barrier formation with murine brain endothelial cells (Br-bEnd5). Results demonstrate that cellular junctional complexes effectively form in the cultures (expression of VE-Cadherin and ZO-1) and that the TEER monitoring systems effectively detects an increase of resistance of the cultured cell layers indicative of tight junction formation. Finally, we validate the use of the described microsystem for drug transport studies demonstrating that Br-bEnd5 cells significantly hinder the transport of molecules (40 kDa and 4 kDa dextran) from the top culture chamber to the bottom collection chamber.
Neural mechanisms underlying ecstasy-related attentional bias.

PubMed

Roberts, Gloria M P; Garavan, Hugh

2013-08-30

Conditioned responses to cues associated with drug taking play a pivotal role in a number of theories of drug addiction. This study examined whether attentional biases towards drug-related cues exist in recreational drug users who predominantly used ecstasy (3,4-methylenedioxymethamphetamine). Experiment 1 compared 30 ecstasy users, 25 cannabis users, and 30 controls in an attentional distraction task in which neutral, evocative, and ecstasy-related pictures were presented within a coloured border, requiring participants to respond as quickly as possible to the border colour. Experiment 2 employed functional magnetic resonance imaging (fMRI) and the attentional distraction task and tested 20 ecstasy users and 20 controls. Experiment 1 revealed significant response speed interference by the ecstasy-related pictures in the ecstasy users only. Experiment 2 revealed increased prefrontal and occipital activity in ecstasy users in all conditions. Activations in response to the ecstasy stimuli in these regions showed an apparent antagonism whereby ecstasy users, relative to controls, showed increased occipital but decreased right prefrontal activation. These results are interpreted to reflect increased visual processing of, and decreased prefrontal control over, the irrelevant but salient ecstasy-related stimuli. These results suggest that right inferior frontal cortex may play an important role in controlling drug-related attentional biases and may thus play an important role in mediating control over drug usage. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: A cross-sectional ERP study

PubMed Central

Parvaz, Muhammad A.; Maloney, Thomas; Moeller, Scott J.; Woicik, Patricia A.; Alia-Klein, Nelly; Telang, Frank; Wang, Gene-Jack; Squires, Nancy K.; Volkow, Nora D.; Goldstein, Rita Z.

2012-01-01

Recent studies suggest that drug addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD−) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0¢, 1¢ and 45¢). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD− showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self-administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward. PMID:22841343
Dopamine, urges to smoke, and the relative salience of drug versus non-drug reward.

PubMed

Freeman, Tom P; Das, Ravi K; Kamboj, Sunjeev K; Curran, H Valerie

2015-01-01

When addicted individuals are exposed to drug-related stimuli, dopamine release is thought to mediate incentive salience attribution, increasing attentional bias, craving and drug seeking. It is unclear whether dopamine acts specifically on drug cues versus other rewards, and if these effects correspond with craving and other forms of cognitive bias. Here, we administered the dopamine D2/D3 agonist pramipexole (0.5 mg) to 16 tobacco smokers in a double-blind placebo-controlled crossover design. Visual fixations on smoking and money images were recorded alongside smoking urges and fluency tasks. Pramipexole attenuated a marked bias in initial orienting towards smoking relative to money but did not alter a maintained attentional bias towards smoking. Pramipexole decreased urges to smoke retrospectively after the task but not on a state scale. Fewer smoking words were generated after pramipexole but phonological and semantic fluency were preserved. Although these treatment effects did not correlate with each other, changes in initial orienting towards smoking and money were inversely related to baseline scores. In conclusion, pramipexole can reduce the salience of an addictive drug compared with other rewards and elicit corresponding changes in smoking urges and cognitive bias. These reward-specific and baseline-dependent effects support an 'inverted-U' shaped profile of dopamine in addiction. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
A validation of event-related FMRI comparisons between users of cocaine, nicotine, or cannabis and control subjects.

PubMed

Murphy, Kevin; Dixon, Veronica; LaGrave, Kathleen; Kaufman, Jacqueline; Risinger, Robert; Bloom, Alan; Garavan, Hugh

2006-07-01

Noninvasive brain imaging techniques are a powerful tool for researching the effects of drug abuse on brain activation measures. However, because many drugs have direct vascular effects, the validity of techniques that depend on blood flow measures as a reflection of neuronal activity may be called into question. This may be of particular concern in event-related functional magnetic resonance imaging (fMRI), where current analytic techniques search for a specific shape in the hemodynamic response to neuronal activity. To investigate possible alterations in task-related activation as a result of drug abuse, fMRI scans were conducted on subjects in four groups as they performed a simple event-related finger-tapping task: users of cocaine, nicotine, or cannabis and control subjects. Activation measures, as determined by two different analytic methods, did not differ between the groups. A comparison between an intravenous saline and an intravenous cocaine condition in cocaine users found a similar null result. Further in-depth analyses of the shape of the hemodynamic responses in each group also showed no differences. This study demonstrates that drug groups may be compared with control subjects using event-related fMRI without the need for any post hoc procedures to correct for possible drug-induced cardiovascular alterations. Thus, fMRI activation differences reported between these drug groups can be more confidently interpreted as reflecting neuronal differences.
Predicting drug-induced liver injury in human with Naïve Bayes classifier approach.

PubMed

Zhang, Hui; Ding, Lan; Zou, Yi; Hu, Shui-Qing; Huang, Hai-Guo; Kong, Wei-Bao; Zhang, Ji

2016-10-01

Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.
Risky Decision Making in a Laboratory Driving Task Is Associated with Health Risk Behaviors during Late Adolescence but Not Adulthood

ERIC Educational Resources Information Center

Kim-Spoon, Jungmeen; Kahn, Rachel; Deater-Deckard, Kirby; Chiu, Pearl; Steinberg, Laurence; King-Casas, Brooks

2016-01-01

Adolescence is characterized by increasing incidence of health risk behaviors, including experimentation with drugs and alcohol. To fill the gap in our understanding of the associations between risky decision-making and health risk behaviors, we investigated associations between laboratory-based risky decision-making using the Stoplight task and…
The effects of nicotine dependence and acute abstinence on the processing of drug and non-drug rewards.

PubMed

Lawn, W; Freeman, T P; Hindocha, C; Mokrysz, C; Das, R K; Morgan, C J A; Curran, H V

2015-07-01

Drug addiction may be characterised by a hypersensitivity to drug rewards and a hyposensitivity to non-drug rewards. This imbalance may become further polarised during acute abstinence. (i) Examine the differences between dependent and occasional smokers in choices for, motivation for and self-reported wanting and liking of cigarette and non-drug rewards. (ii) Examine the effects of 12-h nicotine abstinence on these metrics. Dependent (n = 20) and occasional, non-dependent smokers (n = 20) were tested after ad libitum smoking and ≥12-h of nicotine abstinence. A novel task was developed (Drug, Reward and Motivation-Choice (DReaM-Choice)) in which different rewards (cigarettes, music and chocolate) could be won. In each trial, participants chose between two rewards and then could earn the chosen reward via repeated button-pressing. Participants subsequently 'consumed' and rated subjective liking of the rewards they had won. Compared with occasional smokers, dependent smokers made more choices for (p < 0.001), pressed more for (p = 0.046) and reported more wanting (p = 0.007) and liking (p < 0.001) of cigarettes, and also made fewer choices for chocolate (p = 0.005). There were no differences between the groups on button-pressing for chocolate or music. However, the balance between drug and non-drug reward processing was different between the groups across all metrics. Twelve-hour nicotine abstinence led to more cigarette choices (p < 0.001) and fewer music choices (p = 0.042) in both groups. Nicotine dependence was associated with a hypersensitivity to cigarette rewards, but we found little evidence indicating a hyposensitivity to non-drug rewards. Our findings question the moderating influence of dependence on how acute nicotine abstinence affects reward processing.
Use and reimbursement of off-label drugs in pediatric anesthesia: the Italian experience.

PubMed

Salvo, Ida; Landoni, Giovanni; Mucchetti, Marta; Cabrini, Luca; Pani, Luca

2014-06-01

Most of the drugs used in anesthesia are off-label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market). Define a list of medicinal products commonly used off-label in pediatrics anesthesia to be reimbursed by Italian National Health System. We hereby describe the methodological framework used to allow reimbursed use of a list of medicinal products, widely used off-label in pediatric patients, ensuring the best therapeutic results with the lowest possible risk for children. A task force of pediatric anesthesiologists from Italy petitioned the Italian Medicines Agency (AIFA) to allow a number of commonly utilized but off-label drugs for pediatric anesthesia to be reimbursed for specific indications. For each drug, both the supporting literature and expert opinion were used, and the resulting list of drugs allowed to be used/reimbursed officially by AIFA was significantly expanded. This paper documents one approach to the problem of off-label use of drugs for pediatric patients that can be a model for future efforts. Continuous efforts are needed from government institutions and sponsors on drug development and on drug approval process in pediatrics, as research on drug effectiveness and safety is mandatory in children as in adults. At the same time, clinicians must become more familiar with the drug-approval process, participate to sponsored trials, and perform ztrials themselves. © 2014 John Wiley & Sons Ltd.
Effects of self-administered cocaine in adolescent and adult male rats on orbitofrontal cortex-related neurocognitive functioning

PubMed Central

Harvey, Roxann C.; Dembro, Kimberly A.; Rajagopalan, Kiran; Mutebi, Michael M.; Kantak, Kathleen M.

2010-01-01

Rationale Deficits in amygdala-related stimulus-reward learning are produced following 18 drug-free days of cocaine self-administration or its passive delivery in rats exposed during adulthood. No deficits in stimulus-reward learning are produced by cocaine exposure initiated during adolescence. Objectives To determine if age of initiating cocaine exposure differentially affects behavioral functioning of an additional memory system linked to cocaine addiction, the orbitofrontal cortex. Materials and methods A yoked-triad design (n=8) was used. One rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling drug delivery (1.0 mg/kg) self-administered cocaine from either P37–P59 or P77–P99, and then underwent 18 drug-free days (P60–P77 vs. P100–P117). Rats next were tested for acquisition of odor-delayed win-shift behavior conducted over 15 sessions (P78–P96 vs. P118–P136). Results Cocaine self-administration did not differ between adults and adolescents. During the test phase of the odor-delayed win-shift task (relatively difficult task demands), rats from both drug-onset ages showed learning deficits. Rats with cocaine self-administration experience committed more errors and had longer session latencies compared to rats passively receiving saline or cocaine. Rats with adolescent-onset cocaine self-administration experience showed an additional learning deficit by requiring more sessions to reach criterion levels for task acquisition compared to same-aged passive saline controls or rats with adult-onset cocaine self-administration experience. Rats passively receiving cocaine did not differ from the passive saline control from either age group. Conclusions Rats with adolescent-onset cocaine self-administration experience were more impaired in an orbitofrontal cortex-related learning task than rats with adult-onset cocaine self-administration experience. PMID:19513699
Procedural and declarative memory performance, and the memory consolidation function of sleep, in recent and abstinent Ecstasy/MDMA users

PubMed Central

Blagrove, Mark; Seddon, Jennifer; George, Sophie; Parrott, Andrew C.; Stickgold, Robert; Walker, Matthew; Jones, Katy; Morgan, Michael J.

2013-01-01

This study assessed the effects of ecstasy/MDMA on declarative memory (Rivermead Behavioral Memory task - RBMT), on procedural learning (Finger Tapping Task - FTT), and on the memory consolidation function of sleep for these two tasks. Testing occurred in 2 afternoon testing sessions, 24 hours apart so that a full period of sleep was allowed between them. Groups were: Non-drug taking Controls (n=24); Recent Ecstasy/MDMA users, who had taken ecstasy and/or MDMA 2–3 days before the first testing session (n=25), and Abstinent Ecstasy/MDMA users, who had not taken ecstasy/MDMA for at least 8 days before the first session (n=17). The recent ecstasy/MDMA users performed significantly worse than controls on the RBMT (mean recall 76.1% of control group recall), but did not differ from controls on FTT performance. Correspondingly there was a significant regression between the continuous variable of recency of ecstasy/MDMA use and RBMT performance. However, there was an interaction between ecstasy/MDMA use and subsequent other drug use. Controls had similar RBMT scores to recent ecstasy/MDMA users who did not take other drugs 48 – 24 hours before testing, but scored significantly better than recent ecstasy/MDMA users who took various other drugs (mainly cannabis) 48 – 24 hours before testing. For both tasks the control, recent ecstasy/MDMA and abstinent ecstasy/MDMA users did not differ in their change of performance across 24 hours; there was thus no evidence that ecstasy/MDMA impairs the memory consolidation function of sleep for either declarative or procedural memory. For participants in the two ecstasy/MDMA groups greater lifetime consumption of ecstasy tablets was associated with significantly more deficits in procedural memory. Furthermore, greater lifetime consumption of ecstasy tablets and of cocaine, were also associated with significantly more deficits in declarative memory. PMID:20615932
MDMA does not alter responses to the Trier Social Stress Test in humans.

PubMed

Bershad, Anya K; Miller, Melissa A; de Wit, Harriet

2017-07-01

±3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested. In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task. Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure. The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test. Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined.
MDMA does not alter responses to the Trier Social Stress Test in humans

PubMed Central

Bershad, Anya K.; Miller, Melissa A.; de Wit, Harriet

2018-01-01

Rationale ±3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested. Objectives In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task. Methods Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure. Results The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test. Conclusions Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined. PMID:28432376

Nicotine restores functional connectivity of the ventral attention network in schizophrenia.

PubMed

Smucny, Jason; Olincy, Ann; Tregellas, Jason R

2016-09-01

While previous work has suggested that nicotine may transiently improve attention deficits in schizophrenia, the neuronal mechanisms are poorly understood. This study is the first to examine the effects of nicotine on connectivity within the ventral attention network (VAN) during a selective attention task in schizophrenia. Using a crossover design, 17 nonsmoking patients with schizophrenia and 20 age/gender-matched nonsmoking healthy controls performed a go/no-go task with environmental noise distractors during application of a 7 mg nicotine or placebo patch. Psychophysiological interaction analysis was performed to analyze task-associated changes in connectivity between a ventral parietal cortex (VPC) seed and the inferior frontal gyrus (IFG), key components of the human VAN. Effects of nicotine on resting state VAN connectivity were also examined. A significant diagnosis × drug interaction was observed on task-associated connectivity between the VPC seed and the left IFG (F(1,35) = 8.03, p < 0.01). This effect was driven by decreased connectivity after placebo in patients and greater connectivity after nicotine. Resting state connectivity analysis showed a significant main effect of diagnosis between the seed and right IFG (F = 4.25, p = 0.023) due to increased connectivity in patients during placebo, but no drug × diagnosis interactions or main effects of drug. This study is the first to demonstrate that 1) the VAN is disconnected in schizophrenia during selective attention, and 2) nicotine may normalize this pathological state. Copyright © 2016 Elsevier Ltd. All rights reserved.
Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial.

PubMed

Gilleen, J; Michalopoulou, P G; Reichenberg, A; Drake, R; Wykes, T; Lewis, S W; Kapur, S

2014-04-01

Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
The effect of topiramate plasma concentration on linguistic behavior, verbal recall and working memory.

PubMed

Marino, S E; Pakhomov, S V S; Han, S; Anderson, K L; Ding, M; Eberly, L E; Loring, D W; Hawkins-Taylor, C; Rarick, J O; Leppik, I E; Cibula, J E; Birnbaum, A K

2012-07-01

This is the first study of the effect of topiramate on linguistic behavior and verbal recall using a computational linguistics system for automated language and speech analysis to detect and quantify drug-induced changes in speech recorded during discourse-level tasks. Healthy volunteers were administered a single, 100-mg oral dose of topiramate in two double-blind, randomized, placebo-controlled, crossover studies. Subjects' topiramate plasma levels ranged from 0.23 to 2.81 μg/mL. We found a significant association between topiramate levels and impairment on measures of verbal fluency elicited during a picture description task, correct number of words recalled on a paragraph recall test, and reaction time recorded during a working memory task. Using the tools of clinical pharmacology and computational linguistics, we elucidated the relationship between the determinants of a drug's disposition as reflected in plasma concentrations and their impact on cognitive functioning as reflected in spoken language discourse. Copyright © 2012 Elsevier Inc. All rights reserved.
An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0.

PubMed

Sullivan, Ryan J; Atkins, Michael B; Kirkwood, John M; Agarwala, Sanjiv S; Clark, Joseph I; Ernstoff, Marc S; Fecher, Leslie; Gajewski, Thomas F; Gastman, Brian; Lawson, David H; Lutzky, Jose; McDermott, David F; Margolin, Kim A; Mehnert, Janice M; Pavlick, Anna C; Richards, Jon M; Rubin, Krista M; Sharfman, William; Silverstein, Steven; Slingluff, Craig L; Sondak, Vernon K; Tarhini, Ahmad A; Thompson, John A; Urba, Walter J; White, Richard L; Whitman, Eric D; Hodi, F Stephen; Kaufman, Howard L

2018-05-30

Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.
GPs' opinions of public and industrial information regarding drugs: a cross-sectional study

PubMed Central

2011-01-01

Background General Practitioners {GP} in Sweden prescribe more than 50% of all prescriptions. Scientific knowledge on the opinions of GPs regarding drug information has been sparse. Such knowledge could be valuable when designing evidence-based drug information to GPs. GPs' opinions on public- and industry-provided drug information are presented in this article. Methods A cross-sectional study using a questionnaire was answered by 368 GPs at 97 primary-health care centres {PHCC}. The centres were invited to participate by eight out of 29 drug and therapeutic committees {DTCs}. A multilevel model was used to analyse associations between opinions of GPs regarding drug information and whether the GPs worked in public sector or in a private enterprise, their age, sex, and work experience. PHCC and geographical area were included as random effects. Results About 85% of the GPs perceived they received too much information from the industry, that the quality of public information was high and useful, and that the main task of public authorities was to increase the GPs' knowledge of drugs. Female GPs valued information from public authorities to a much greater extent than male GPs. Out of the GPs, 93% considered the main task of the industry was to promote sales. Differences between the GPs' opinions between PHCCs were generally more visible than differences between areas. Conclusions Some kind of incentives could be considered for PHCCs that actively reduce drug promotion from the industry. That female GPs valued information from public authorities to a much greater extent than male GPs should be taken into consideration when designing evidence-based drug information from public authorities to make implementation easier. PMID:21867497
Prediction of anti-cancer drug response by kernelized multi-task learning.

PubMed

Tan, Mehmet

2016-10-01

Chemotherapy or targeted therapy are two of the main treatment options for many types of cancer. Due to the heterogeneous nature of cancer, the success of the therapeutic agents differs among patients. In this sense, determination of chemotherapeutic response of the malign cells is essential for establishing a personalized treatment protocol and designing new drugs. With the recent technological advances in producing large amounts of pharmacogenomic data, in silico methods have become important tools to achieve this aim. Data produced by using cancer cell lines provide a test bed for machine learning algorithms that try to predict the response of cancer cells to different agents. The potential use of these algorithms in drug discovery/repositioning and personalized treatments motivated us in this study to work on predicting drug response by exploiting the recent pharmacogenomic databases. We aim to improve the prediction of drug response of cancer cell lines. We propose to use a method that employs multi-task learning to improve learning by transfer, and kernels to extract non-linear relationships to predict drug response. The method outperforms three state-of-the-art algorithms on three anti-cancer drug screen datasets. We achieved a mean squared error of 3.305 and 0.501 on two different large scale screen data sets. On a recent challenge dataset, we obtained an error of 0.556. We report the methodological comparison results as well as the performance of the proposed algorithm on each single drug. The results show that the proposed method is a strong candidate to predict drug response of cancer cell lines in silico for pre-clinical studies. The source code of the algorithm and data used can be obtained from http://mtan.etu.edu.tr/Supplementary/kMTrace/. Copyright © 2016 Elsevier B.V. All rights reserved.
A New Data Representation Based on Training Data Characteristics to Extract Drug Name Entity in Medical Text

PubMed Central

Basaruddin, T.

2016-01-01

One essential task in information extraction from the medical corpus is drug name recognition. Compared with text sources come from other domains, the medical text mining poses more challenges, for example, more unstructured text, the fast growing of new terms addition, a wide range of name variation for the same drug, the lack of labeled dataset sources and external knowledge, and the multiple token representations for a single drug name. Although many approaches have been proposed to overwhelm the task, some problems remained with poor F-score performance (less than 0.75). This paper presents a new treatment in data representation techniques to overcome some of those challenges. We propose three data representation techniques based on the characteristics of word distribution and word similarities as a result of word embedding training. The first technique is evaluated with the standard NN model, that is, MLP. The second technique involves two deep network classifiers, that is, DBN and SAE. The third technique represents the sentence as a sequence that is evaluated with a recurrent NN model, that is, LSTM. In extracting the drug name entities, the third technique gives the best F-score performance compared to the state of the art, with its average F-score being 0.8645. PMID:27843447
Text Mining for Drugs and Chemical Compounds: Methods, Tools and Applications.

PubMed

Vazquez, Miguel; Krallinger, Martin; Leitner, Florian; Valencia, Alfonso

2011-06-01

Providing prior knowledge about biological properties of chemicals, such as kinetic values, protein targets, or toxic effects, can facilitate many aspects of drug development. Chemical information is rapidly accumulating in all sorts of free text documents like patents, industry reports, or scientific articles, which has motivated the development of specifically tailored text mining applications. Despite the potential gains, chemical text mining still faces significant challenges. One of the most salient is the recognition of chemical entities mentioned in text. To help practitioners contribute to this area, a good portion of this review is devoted to this issue, and presents the basic concepts and principles underlying the main strategies. The technical details are introduced and accompanied by relevant bibliographic references. Other tasks discussed are retrieving relevant articles, identifying relationships between chemicals and other entities, or determining the chemical structures of chemicals mentioned in text. This review also introduces a number of published applications that can be used to build pipelines in topics like drug side effects, toxicity, and protein-disease-compound network analysis. We conclude the review with an outlook on how we expect the field to evolve, discussing its possibilities and its current limitations. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Functional network alterations and their structural substrate in drug-resistant epilepsy

PubMed Central

Caciagli, Lorenzo; Bernhardt, Boris C.; Hong, Seok-Jun; Bernasconi, Andrea; Bernasconi, Neda

2014-01-01

The advent of MRI has revolutionized the evaluation and management of drug-resistant epilepsy by allowing the detection of the lesion associated with the region that gives rise to seizures. Recent evidence indicates marked chronic alterations in the functional organization of lesional tissue and large-scale cortico-subcortical networks. In this review, we focus on recent methodological developments in functional MRI (fMRI) analysis techniques and their application to the two most common drug-resistant focal epilepsies, i.e., temporal lobe epilepsy related to mesial temporal sclerosis and extra-temporal lobe epilepsy related to focal cortical dysplasia. We put particular emphasis on methodological developments in the analysis of task-free or “resting-state” fMRI to probe the integrity of intrinsic networks on a regional, inter-regional, and connectome-wide level. In temporal lobe epilepsy, these techniques have revealed disrupted connectivity of the ipsilateral mesiotemporal lobe, together with contralateral compensatory reorganization and striking reconfigurations of large-scale networks. In cortical dysplasia, initial observations indicate functional alterations in lesional, peri-lesional, and remote neocortical regions. While future research is needed to critically evaluate the reliability, sensitivity, and specificity, fMRI mapping promises to lend distinct biomarkers for diagnosis, presurgical planning, and outcome prediction. PMID:25565942
Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress.

PubMed

Childs, Emma; Lutz, Joseph A; de Wit, Harriet

2017-08-01

Cannabis smokers often report that they use the drug to relax or to relieve emotional stress. However, few clinical studies have shown evidence of the stress-relieving effects of cannabis or cannabinoid agonists. In this study, we sought to assess the influence of delta-9-tetrahydrocannabinol (THC), a main active ingredient of cannabis, upon emotional responses to an acute psychosocial stressor among healthy young adults. Healthy volunteers (N=42) participated in two experimental sessions, one with psychosocial stress (Trier Social Stress Test, TSST) and another with a non-stressful task, after receiving 0 (N=13), 7.5mg (N=14) or 12.5mg (N=15) oral THC. Capsules were administered under randomized, double blind conditions, 2.5h before the tasks began. We measured subjective mood and drug effects, vital signs and salivary cortisol before and at repeated times after the capsule and tasks. Subjects also appraised the tasks, before and after completion. In comparison to placebo, 7.5mg THC significantly reduced self-reported subjective distress after the TSST and attenuated post-task appraisals of the TSST as threatening and challenging. By contrast, 12.5mg THC increased negative mood overall i.e., both before and throughout the tasks, and pre-task ratings of the TSST as threatening and challenging. It also impaired TSST performance and attenuated blood pressure reactivity to the stressor. Our findings suggest that a low dose of THC produces subjective stress-relieving effects in line with those commonly reported among cannabis users, but that higher doses may non-specifically increase negative mood. Copyright © 2017. Published by Elsevier B.V.
Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moeller, S.J.; Moeller, S.J.; Maloney, T.

Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessedmore » objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes.« less
Cue-elicited increases in incentive salience for marijuana: Craving, demand, and attentional bias.

PubMed

Metrik, Jane; Aston, Elizabeth R; Kahler, Christopher W; Rohsenow, Damaris J; McGeary, John E; Knopik, Valerie S; MacKillop, James

2016-10-01

Incentive salience is a multidimensional construct that includes craving, drug value relative to other reinforcers, and implicit motivation such as attentional bias to drug cues. Laboratory cue reactivity (CR) paradigms have been used to evaluate marijuana incentive salience with measures of craving, but not with behavioral economic measures of marijuana demand or implicit attentional processing tasks. This within-subjects study used a new CR paradigm to examine multiple dimensions of marijuana's incentive salience and to compare CR-induced increases in craving and demand. Frequent marijuana users (N=93, 34% female) underwent exposure to neutral cues then to lit marijuana cigarettes. Craving, marijuana demand via a marijuana purchase task, and heart rate were assessed after each cue set. A modified Stroop task with cannabis and control words was completed after the marijuana cues as a measure of attentional bias. Relative to neutral cues, marijuana cues significantly increased subjective craving and demand indices of intensity (i.e., drug consumed at $0) and Omax (i.e., peak drug expenditure). Elasticity significantly decreased following marijuana cues, reflecting sustained purchase despite price increases. Craving was correlated with demand indices (r's: 0.23-0.30). Marijuana users displayed significant attentional bias for cannabis-related words after marijuana cues. Cue-elicited increases in intensity were associated with greater attentional bias for marijuana words. Greater incentive salience indexed by subjective, behavioral economic, and implicit measures was observed after marijuana versus neutral cues, supporting multidimensional assessment. The study highlights the utility of a behavioral economic approach in detecting cue-elicited changes in marijuana incentive salience. Published by Elsevier Ireland Ltd.
Effects of marijuana on visuospatial working memory: an fMRI study in young adults.

PubMed

Smith, Andra M; Longo, Carmelinda A; Fried, Peter A; Hogan, Matthew J; Cameron, Ian

2010-06-01

The effects of marijuana use on visuospatial working memory were investigated in 19-21-year-olds using functional magnetic resonance imaging (fMRI). Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood including: prenatal drug history, detailed cognitive/behavioral performance, and current and past drug usage. This information allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana, nicotine, alcohol, and caffeine exposure and offspring alcohol, marijuana, and nicotine use. Ten marijuana users and 14 nonusing controls performed a visuospatial 2-back task while fMRI blood oxygen level-dependent response was examined. Despite similar task performance, marijuana users had significantly greater activation in the inferior and middle frontal gyri, regions of the brain normally associated with visuospatial working memory. Marijuana users also had greater activation in the right superior temporal gyrus, a region of the brain not typically associated with visuospatial working memory tasks. These results suggest that marijuana use leads to altered neural functioning during visuospatial working memory after controlling for other prenatal and current drug use. This alteration appears to be compensated for by the recruitment of blood flow in additional brain regions. It is possible that this compensation may not be sufficient in more real-life situations where this type of processing is required and thus deficits may be observed. Awareness of these neural physiological effects of marijuana in youth is critical.
Cue-Elicited Increases in Incentive Salience for Marijuana: Craving, Demand, and Attentional Bias

PubMed Central

Metrik, Jane; Aston, Elizabeth R.; Kahler, Christopher W.; Rohsenow, Damaris J.; McGeary, John E.; Knopik, Valerie S.; MacKillop, James

2016-01-01

Background Incentive salience is a multidimensional construct that includes craving, drug value relative to other reinforcers, and implicit motivation such as attentional bias to drug cues. Laboratory cue reactivity (CR) paradigms have been used to evaluate marijuana incentive salience with measures of craving, but not with behavioral economic measures of marijuana demand or implicit attentional processing tasks. Methods This within-subjects study used a new CR paradigm to examine multiple dimensions of marijuana’s incentive salience and to compare CR-induced increases in craving and demand. Frequent marijuana users (N=93, 34% female) underwent exposure to neutral cues then to lit marijuana cigarettes. Craving, marijuana demand via a marijuana purchase task, and heart rate were assessed after each cue set. A modified Stroop task with cannabis and control words was completed after the marijuana cues as a measure of attentional bias. Results Relative to neutral cues, marijuana cues significantly increased subjective craving and demand indices of intensity (i.e., drug consumed at $0) and Omax (i.e., peak drug expenditure). Elasticity significantly decreased following marijuana cues, reflecting sustained purchase despite price increases. Craving was correlated with demand indices (r’s: 0.23–0.30). Marijuana users displayed significant attentional bias for cannabis-related words after marijuana cues. Cue-elicited increases in intensity were associated with greater attentional bias for marijuana words. Conclusions Greater incentive salience indexed by subjective, behavioral economic, and implicit measures was observed after marijuana versus neutral cues, supporting multidimensional assessment. The study highlights the utility of a behavioral economic approach in detecting cue-elicited changes in marijuana incentive salience. PMID:27515723
Brain potentials measured during a Go/NoGo task predict completion of substance abuse treatment.

PubMed

Steele, Vaughn R; Fink, Brandi C; Maurer, J Michael; Arbabshirani, Mohammad R; Wilber, Charles H; Jaffe, Adam J; Sidz, Anna; Pearlson, Godfrey D; Calhoun, Vince D; Clark, Vincent P; Kiehl, Kent A

2014-07-01

U.S. nationwide estimates indicate that 50% to 80% of prisoners have a history of substance abuse or dependence. Tailoring substance abuse treatment to specific needs of incarcerated individuals could improve effectiveness of treating substance dependence and preventing drug abuse relapse. We tested whether pretreatment neural measures of a response inhibition (Go/NoGo) task would predict which individuals would or would not complete a 12-week cognitive behavioral substance abuse treatment program. Adult incarcerated participants (n = 89; women n = 55) who volunteered for substance abuse treatment performed a Go/NoGo task while event-related potentials (ERPs) were recorded. Stimulus- and response-locked ERPs were compared between participants who completed (n = 68; women = 45) and discontinued (n = 21; women = 10) treatment. As predicted, stimulus-locked P2, response-locked error-related negativity (ERN/Ne), and response-locked error positivity (Pe), measured with windowed time-domain and principal component analysis, differed between groups. Using logistic regression and support-vector machine (i.e., pattern classifiers) models, P2 and Pe predicted treatment completion above and beyond other measures (i.e., N2, P300, ERN/Ne, age, sex, IQ, impulsivity, depression, anxiety, motivation for change, and years of drug abuse). Participants who discontinued treatment exhibited deficiencies in sensory gating, as indexed by smaller P2; error-monitoring, as indexed by smaller ERN/Ne; and adjusting response strategy posterror, as indexed by larger Pe. The combination of P2 and Pe reliably predicted 83.33% of individuals who discontinued treatment. These results may help in the development of individualized therapies, which could lead to more favorable, long-term outcomes. © 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.
Brain Potentials Measured During a Go/NoGo Task Predict Completion of Substance Abuse Treatment

PubMed Central

Steele, Vaughn R.; Fink, Brandi C.; Maurer, J. Michael; Arbabshirani, Mohammad R.; Wilber, Charles H.; Jaffe, Adam J.; Sidz, Anna; Pearlson, Godfrey D.; Calhoun, Vince D.; Clark, Vincent P.; Kiehl, Kent A.

2014-01-01

Background US nationwide estimates indicate 50–80% of prisoners have a history of substance abuse or dependence. Tailoring substance abuse treatment to specific needs of incarcerated individuals could improve effectiveness of treating substance dependence and preventing drug abuse relapse. The purpose of the present study was to test the hypothesis that pre-treatment neural measures of a Go/NoGo task would predict which individuals would or would not complete a 12-week cognitive behavioral substance abuse treatment program. Methods Adult incarcerated participants (N=89; Females=55) who volunteered for substance abuse treatment performed a response inhibition (Go/NoGo) task while event-related potentials (ERP) were recorded. Stimulus- and response-locked ERPs were compared between individuals who completed (N=68; Females=45) and discontinued (N=21; Females=10) treatment. Results As predicted, stimulus-locked P2, response-locked error-related negativity (ERN/Ne), and response-locked error positivity (Pe), measured with windowed time-domain and principal component analysis, differed between groups. Using logistic regression and support-vector machine (i.e., pattern classifiers) models, P2 and Pe predicted treatment completion above and beyond other measures (i.e., N2, P300, ERN/Ne, age, sex, IQ, impulsivity, and self-reported depression, anxiety, motivation for change, and years of drug abuse). Conclusions We conclude individuals who discontinue treatment exhibited deficiencies in sensory gating, as indexed by smaller P2, error-monitoring, as indexed by smaller ERN/Ne, and adjusting response strategy post-error, as indexed by larger Pe. However, the combination of P2 and Pe reliably predicted 83.33% of individuals who discontinued treatment. These results may help in the development of individualized therapies, which could lead to more favorable, long-term outcomes. PMID:24238783
Does the Drug Facts Label for nonprescription drugs meet its design objectives? A new procedure for assessing label effectiveness

PubMed Central

Ryan, Michael P; Costello-White, Reagan N

2017-01-01

We demonstrate an expanded procedure for assessing drug-label comprehension. Innovations include a pretest of drug preconceptions, verbal ability and label attentiveness measures, a label-scanning task, a free-recall test, category-clustering measures, and preconception-change scores. In total, 55 female and 39 male undergraduates read a facsimile Drug Facts Label for aspirin, a Cohesive-Prose Label, or a Scrambled-Prose Label. The Drug Facts Label outperformed the Scrambled-Prose Label, but not the Cohesive-Prose Label, in scanning effectiveness. The Drug Facts Label was no better than the Cohesive-Prose Label or the Scrambled-Prose Label in promoting attentiveness, recall and organization of drug facts, or misconception refutation. Discussion focuses on the need for refutational labels based on a sequence-of-events text schema. PMID:29379613
Quantum chemical approaches in structure-based virtual screening and lead optimization

NASA Astrophysics Data System (ADS)

Cavasotto, Claudio N.; Adler, Natalia S.; Aucar, Maria G.

2018-05-01

Today computational chemistry is a consolidated tool in drug lead discovery endeavors. Due to methodological developments and to the enormous advance in computer hardware, methods based on quantum mechanics (QM) have gained great attention in the last 10 years, and calculations on biomacromolecules are becoming increasingly explored, aiming to provide better accuracy in the description of protein-ligand interactions and the prediction of binding affinities. In principle, the QM formulation includes all contributions to the energy, accounting for terms usually missing in molecular mechanics force-fields, such as electronic polarization effects, metal coordination, and covalent binding; moreover, QM methods are systematically improvable, and provide a greater degree of transferability. In this mini-review we present recent applications of explicit QM-based methods in small-molecule docking and scoring, and in the calculation of binding free-energy in protein-ligand systems. Although the routine use of QM-based approaches in an industrial drug lead discovery setting remains a formidable challenging task, it is likely they will increasingly become active players within the drug discovery pipeline.
Synthetic Biology and Personalized Medicine

PubMed Central

Jain, K.K.

2013-01-01

Synthetic biology, application of synthetic chemistry to biology, is a broad term that covers the engineering of biological systems with structures and functions not found in nature to process information, manipulate chemicals, produce energy, maintain cell environment and enhance human health. Synthetic biology devices contribute not only to improve our understanding of disease mechanisms, but also provide novel diagnostic tools. Methods based on synthetic biology enable the design of novel strategies for the treatment of cancer, immune diseases metabolic disorders and infectious diseases as well as the production of cheap drugs. The potential of synthetic genome, using an expanded genetic code that is designed for specific drug synthesis as well as delivery and activation of the drug in vivo by a pathological signal, was already pointed out during a lecture delivered at Kuwait University in 2005. Of two approaches to synthetic biology, top-down and bottom-up, the latter is more relevant to the development of personalized medicines as it provides more flexibility in constructing a partially synthetic cell from basic building blocks for a desired task. PMID:22907209
Evaluation and analysis of non-intrusive techniques for detecting illicit substances

DOE Office of Scientific and Technical Information (OSTI.GOV)

Micklich, B.J.; Roche, C.T.; Fink, C.L.

1995-12-31

Argonne National Laboratory (ANL) and the Houston Advanced Research Center (HARC) have been tasked by the Counterdrug Technology Assessment Center of the Office of National Drug Control Policy to conduct evaluations and analyses of technologies for the non-intrusive inspection of containers for illicit substances. These technologies span the range of nuclear, X-ray, and chemical techniques used in nondestructive sample analysis. ANL has performed assessments of nuclear and X-ray inspection concepts and undertaken site visits with developers to understand the capabilities and the range of applicability of candidate systems. ANL and HARC have provided support to law enforcement agencies (LEAs), includingmore » participation in numerous field studies. Both labs have provided staff to assist in the Narcotics Detection Technology Assessment (NDTA) program for evaluating drug detection systems. Also, the two labs are performing studies of drug contamination of currency. HARC has directed technical evaluations of automated ballistics imaging and identification systems under consideration by law enforcement agencies. ANL and HARC have sponsored workshops and a symposium, and are participating in a Non-Intrusive Inspection Study being led by Dynamics Technology, Incorporated.« less

Anti-Emetic Drug Effects on Pilot Performance, Phase 2: Simulation Test.

DTIC Science & Technology

1996-04-01

The objectives of this study were to evaluate the effects of two anti-emetic drugs, granisetron (2 mg oral dose) and ondansetron (8 mg oral dose), on...and preduce no cognitive, psychomotor or subjective state changes. In this study, there was no evidence of performance degradation caused by either granisetron or ondansetron when tested in a complex military task environment.
Stimulant Drug Effects on Touchscreen Automated Paired-Associates Learning (PAL) in Rats

ERIC Educational Resources Information Center

Roschlau, Corinna; Votteler, Angeline; Hauber, Wolfgang

2016-01-01

Here we tested in rats effects of the procognitive drugs modafinil and methylphenidate on post-acquisition performance in an object-location paired-associates learning (PAL) task. Modafinil (32; 64 mg/kg) was without effect, while higher (9 mg/kg) but not lower (4.5 mg/kg) doses of methylphenidate impaired PAL performance. Likewise, higher but not…
Genetic networks and soft computing.

PubMed

Mitra, Sushmita; Das, Ranajit; Hayashi, Yoichi

2011-01-01

The analysis of gene regulatory networks provides enormous information on various fundamental cellular processes involving growth, development, hormone secretion, and cellular communication. Their extraction from available gene expression profiles is a challenging problem. Such reverse engineering of genetic networks offers insight into cellular activity toward prediction of adverse effects of new drugs or possible identification of new drug targets. Tasks such as classification, clustering, and feature selection enable efficient mining of knowledge about gene interactions in the form of networks. It is known that biological data is prone to different kinds of noise and ambiguity. Soft computing tools, such as fuzzy sets, evolutionary strategies, and neurocomputing, have been found to be helpful in providing low-cost, acceptable solutions in the presence of various types of uncertainties. In this paper, we survey the role of these soft methodologies and their hybridizations, for the purpose of generating genetic networks.
Comparing Exponential and Exponentiated Models of Drug Demand in Cocaine Users

PubMed Central

Strickland, Justin C.; Lile, Joshua A.; Rush, Craig R.; Stoops, William W.

2016-01-01

Drug purchase tasks provide rapid and efficient measurement of drug demand. Zero values (i.e., prices with zero consumption) present a quantitative challenge when using exponential demand models that exponentiated models may resolve. We aimed to replicate and advance the utility of using an exponentiated model by demonstrating construct validity (i.e., association with real-world drug use) and generalizability across drug commodities. Participants (N = 40 cocaine-using adults) completed Cocaine, Alcohol, and Cigarette Purchase Tasks evaluating hypothetical consumption across changes in price. Exponentiated and exponential models were fit to these data using different treatments of zero consumption values, including retaining zeros or replacing them with 0.1, 0.01, 0.001. Excellent model fits were observed with the exponentiated model. Means and precision fluctuated with different replacement values when using the exponential model, but were consistent for the exponentiated model. The exponentiated model provided the strongest correlation between derived demand intensity (Q0) and self-reported free consumption in all instances (Cocaine r = .88; Alcohol r = .97; Cigarette r = .91). Cocaine demand elasticity was positively correlated with alcohol and cigarette elasticity. Exponentiated parameters were associated with real-world drug use (e.g., weekly cocaine use), whereas these correlations were less consistent for exponential parameters. Our findings show that selection of zero replacement values impact demand parameters and their association with drug-use outcomes when using the exponential model, but not the exponentiated model. This work supports the adoption of the exponentiated demand model by replicating improved fit and consistency, in addition to demonstrating construct validity and generalizability. PMID:27929347
Comparing exponential and exponentiated models of drug demand in cocaine users.

PubMed

Strickland, Justin C; Lile, Joshua A; Rush, Craig R; Stoops, William W

2016-12-01

Drug purchase tasks provide rapid and efficient measurement of drug demand. Zero values (i.e., prices with zero consumption) present a quantitative challenge when using exponential demand models that exponentiated models may resolve. We aimed to replicate and advance the utility of using an exponentiated model by demonstrating construct validity (i.e., association with real-world drug use) and generalizability across drug commodities. Participants (N = 40 cocaine-using adults) completed Cocaine, Alcohol, and Cigarette Purchase Tasks evaluating hypothetical consumption across changes in price. Exponentiated and exponential models were fit to these data using different treatments of zero consumption values, including retaining zeros or replacing them with 0.1, 0.01, or 0.001. Excellent model fits were observed with the exponentiated model. Means and precision fluctuated with different replacement values when using the exponential model but were consistent for the exponentiated model. The exponentiated model provided the strongest correlation between derived demand intensity (Q0) and self-reported free consumption in all instances (Cocaine r = .88; Alcohol r = .97; Cigarette r = .91). Cocaine demand elasticity was positively correlated with alcohol and cigarette elasticity. Exponentiated parameters were associated with real-world drug use (e.g., weekly cocaine use) whereas these correlations were less consistent for exponential parameters. Our findings show that selection of zero replacement values affects demand parameters and their association with drug-use outcomes when using the exponential model but not the exponentiated model. This work supports the adoption of the exponentiated demand model by replicating improved fit and consistency and demonstrating construct validity and generalizability. (PsycINFO Database Record (c) 2016 APA, all rights reserved).
Is Neural Processing of Negative Stimuli Altered in Addiction Independent of Drug Effects? Findings From Drug-Naïve Youth with Internet Gaming Disorder.

PubMed

Yip, Sarah W; Gross, James J; Chawla, Megha; Ma, Shan-Shan; Shi, Xing-Hui; Liu, Lu; Yao, Yuan-Wei; Zhu, Lei; Worhunsky, Patrick D; Zhang, Jintao

2018-05-01

Difficulties in emotion regulation are commonly reported among individuals with alcohol and drug addictions and contribute to the acquisition and maintenance of addictive behaviors. Alterations in neural processing of negative affective stimuli have further been demonstrated among individuals with addictions. However, it is unclear whether these alterations are a general feature of addictions or are a result of prolonged exposure to drugs of abuse. To test the hypothesis of altered negative affect processing independent of drug effects, this study assessed neural function among drug-naïve youth with a behavioral addiction-Internet gaming disorder (IGD). Fifty-six young adults (28 with IGD, 28 matched controls) participated in fMRI scanning during performance of a well-validated emotion regulation task. Between-group differences in neural activity during task performance were assessed using a whole-brain, mixed-effects ANOVA with correction for multiple comparisons at currently recommended thresholds (voxel-level p<0.001, pFWE<0.05). Compared to controls, youth with IGD exhibited significantly blunted neural responses within distributed subcortical and cortical regions including the striatum, insula, lateral prefrontal cortex and anterior cingulate in response to negative affective cues, as well as during emotion regulation. Independent component analysis (ICA) further identified between-group differences in engagement of a fronto-cingulo-parietal network, involving decreased engagement in IGD youth relative to controls. Study findings are largely consistent with those from prior neuroimaging studies in substance-use disorders, thus raising the possibility that neural processing of negative affect may be blunted across drug and behavioral addictions independent of acute or chronic drug effects.
Neurocognitive and psychiatric dimensions of hot, but not cool, impulsivity predict HIV sexual risk behaviors among drug users in protracted abstinence.

PubMed

Wilson, Michael J; Vassileva, Jasmin

2016-03-01

Impulsivity is an important risk factor for HIV risky drug and sexual behaviors. Research identifies hot (i.e. affectively-mediated, reward-based) and cool (motoric, attentional, independent of context) neurocognitive and psychiatric dimensions of impulsivity, though the impact of specific drugs of abuse on these varieties of impulsivity remains an open question. The present study examined the associations of neurocognitive and psychiatric varieties of hot and cool impulsivity with measures of lifetime and recent sexual risk behaviors among users of different classes of drugs. The study sample was comprised of drug users in protracted (> 1 year) abstinence: heroin mono-dependent (n = 61), amphetamine mono-dependent (n = 44), and polysubstance dependent (n = 73). Hot impulsivity was operationalized via neurocognitive tasks of reward-based decision-making and symptoms of psychopathy. Cool impulsivity was operationalized via neurocognitive tasks of response inhibition and symptoms of attention deficit/hyperactivity disorder (ADHD). Hot impulsivity was associated with sexual risk behaviors among heroin and amphetamine users in protracted abstinence, whereas cool impulsivity was not associated with sexual risk behaviors among any drug-using group. Neurocognitive hot impulsivity was associated with recent (past 30-day) sexual risk behaviors, whereas psychopathy was associated with sexual risk behaviors during more remote time-periods (past 6 month and lifetime) and mediated the association between heroin dependence and past 6-month sexual risk behaviors. Assessments and interventions aimed at reducing sexual risk behaviors among drug users should focus on hot neurocognitive and psychiatric dimensions of impulsivity, such as decision-making and psychopathy. Cool dimensions of impulsivity such as response inhibition and ADHD were not related to sexual risk behaviors among drug users in protracted abstinence.
Neurocognitive and psychiatric dimensions of “hot” impulsivity, but not “cool” impulsivity, predict HIV sexual risk behaviors among drug users in protracted abstinence

PubMed Central

Wilson, Michael J.; Vassileva, Jasmin

2016-01-01

Background Impulsivity is an important risk factor for HIV risky drug and sexual behaviors. Research identifies “hot” (i.e., affectively-mediated, reward-based) and “cool” (motoric, attentional, independent of context) neurocognitive and psychiatric dimensions of impulsivity, though the impact of specific drugs of abuse on these varieties of impulsivity remains an open question. Objectives The present study examined the associations of neurocognitive and psychiatric varieties of “hot” and “cool” impulsivity with measures of lifetime and recent sexual risk behaviors among users of different classes of drugs. Methods The study sample was comprised drug users in protracted (>1yr) abstinence: heroin monodependent (n=61), amphetamine monodependent (n=44), and polysubstance dependent (n= 73). “Hot” impulsivity was operationalized via neurocognitive tasks of reward-based decision-making and symptoms of psychopathy. “Cool” impulsivity was operationalized via neurocognitive tasks of response inhibition and symptoms of ADHD. Results “Hot” impulsivity was associated with sexual risk behaviors among heroin and amphetamine users in protracted abstinence, whereas “cool” impulsivity was not associated with sexual risk behaviors among any drug-using group. Neurocognitive “hot” impulsivity was associated with recent (past 30-day) sexual risk behaviors, whereas psychopathy was associated with sexual risk behaviors during more remote time-periods (past 6 month and lifetime) and mediated the association between heroin dependence and past 6-month sexual risk behaviors. Conclusion Assessments and interventions aimed at reducing sexual risk behaviors among drug users should focus on “hot” neurocognitive and psychiatric dimensions of impulsivity, such as decision-making and psychopathy. “Cool” dimensions of impulsivity such as response inhibition and ADHD were not related to sexual risk behaviors among drug users in protracted abstinence. PMID:26837332
Attentional Bias for Non-drug Reward is Magnified in Addiction

PubMed Central

Anderson, Brian A.; Faulkner, Monica L.; Rilee, Jessica J.; Yantis, Steven; Marvel, Cherie L.

2014-01-01

Attentional biases for drug-related stimuli play a prominent role in addiction, predicting treatment outcome. Attentional biases also develop for stimuli that have been paired with non-drug reward in adults without a history of addiction, the magnitude of which is predicted by visual working memory capacity and impulsiveness. We tested the hypothesis that addiction is associated with an increased attentional bias for non-drug (monetary) reward relative to that of healthy controls, and that this bias is related to working memory impairments and increased impulsiveness. Seventeen patients receiving methadone maintenance treatment for opioid dependence and seventeen healthy controls participated. Impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11), visual working memory capacity was measured as the ability to recognize briefly presented color stimuli, and attentional bias was measured as the magnitude of response time slowing caused by irrelevant but previously reward-associated distractors in a visual search task. The results showed that attention was biased toward the distractors across all participants, replicating previous findings. Importantly, this bias was significantly greater in the patients than in the controls and was negatively correlated with visual working memory capacity. Patients were also significantly more impulsive than controls as a group. Our findings demonstrate that patients in treatment for addiction experience greater difficulty ignoring stimuli associated with non-drug reward. This non-specific reward-related bias could mediate the distracting quality of drug-related stimuli previously observed in addiction. PMID:24128148
The role of validated analytical methods in JECFA drug assessments and evaluation for recommending MRLs.

PubMed

Boison, Joe O

2016-05-01

The Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) is one of three Codex committees tasked with applying risk analysis and relying on independent scientific advice provided by expert bodies organized by FAO/WHO when developing standards. While not officially part of the Codex Alimentarius Commission structure, JECFA provides independent scientific advice to the Commission and its specialist committees such as the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) in setting maximum residue limits (MRLs) for veterinary drugs. Codex methods of analysis (Types I, II, III, and IV) are defined in the Codex Procedural Manual as are criteria to be used for selecting methods of analysis. However, if a method is to be used under a single laboratory condition to support regulatory work, it must be validated according to an internationally recognized protocol and the use of the method must be embedded in a quality assurance system in compliance with ISO/IEC 17025:2005. This paper examines the attributes of the methods used to generate residue depletion data for drug registration and/or licensing and for supporting regulatory enforcement initiatives that experts consider to be useful and appropriate in their assessment of methods of analysis. Copyright © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd. © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.
Are prescription drug insurance choices consistent with expected utility theory?

PubMed

Bundorf, M Kate; Mata, Rui; Schoenbaum, Michael; Bhattacharya, Jay

2013-09-01

To determine the extent to which people make choices inconsistent with expected utility theory when choosing among prescription drug insurance plans and whether tabular or graphical presentation format influences the consistency of their choices. Members of an Internet-enabled panel chose between two Medicare prescription drug plans. The "low variance" plan required higher out-of-pocket payments for the drugs respondents usually took but lower out-of-pocket payments for the drugs they might need if they developed a new health condition than the "high variance" plan. The probability of a change in health varied within subjects and the presentation format (text vs. graphical) and the affective salience of the clinical condition (abstract vs. risk related to specific clinical condition) varied between subjects. Respondents were classified based on whether they consistently chose either the low or high variance plan. Logistic regression models were estimated to examine the relationship between decision outcomes and task characteristics. The majority of respondents consistently chose either the low or high variance plan, consistent with expected utility theory. Half of respondents consistently chose the low variance plan. Respondents were less likely to make discrepant choices when information was presented in graphical format. Many people, although not all, make choices consistent with expected utility theory when they have information on differences among plans in the variance of out-of-pocket spending. Medicare beneficiaries would benefit from information on the extent to which prescription drug plans provide risk protection. PsycINFO Database Record (c) 2013 APA, all rights reserved.
GERIREX - growing a second generation medical expert system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kocur, J. Jr.; Suh, S.C.

This article describes GERIREX, a medical expert system as the core module of an integrated system for total management of a medical practice. GERIREX is currently a first-generation consultant in the domain of prescribing for the geriatric patient with multiple ailments. Employing rule and objective probabilistic knowledge representations, the system performs at the near-expert level, correctly ranking single and multiple drug therapy for hypertension and/or congestive heart failure in the presence of between two and seven of 18 common accompanying or underlying conditions. GERIREX creates permanent consultation records and can access patient information from existing databases. System requirements are metmore » by very modest PCs, yet power, speed, flexibility, and ease of use rival or exceed those of many other systems. GERIREX interfaces with a variety of configurations and applications, including text, spreadsheets, databases, and executables, to fit in with current plans to upgrade to a second generation system, providing a degree of self-maintenance through intelligent parsing of a drug data source such as the Physicians` Desk Reference (PDR - CDROM version). Another option under consideration is developing neural networks to both replace the current knowledge base, and to embody the rationale employed by the medical expert in evaluating drug data for treatment selection. In this version, the current drug database would be used as warning data for the network tasked with adding new drugs to the drug database, imitating the process whereby a physician determines their personal arsenal from among the wide range of available options.« less
Amphetamine as a social drug: Effects of d-amphetamine on social processing and behavior

PubMed Central

Wardle, Margaret C.; Garner, Matthew J.; Munafò, Marcus R.; de Wit, Harriet

2012-01-01

Rationale Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others. Objectives We examined effects of d-amphetamine on processing of emotional facial expressions, and on the social behavior of talking. We predicted amphetamine would enhance attention, identification and responsivity to positive expressions, and that this in turn would predict increased talkativeness. Methods Over three sessions, 36 healthy normal adults received placebo, 10mg, and 20mg d-amphetamine under counterbalanced double-blind conditions. At each session we measured processing of happy, fearful, sad and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking. Results Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine. Conclusions The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine. PMID:22526538
Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: a cross-sectional ERP study.

PubMed

Parvaz, Muhammad A; Maloney, Thomas; Moeller, Scott J; Woicik, Patricia A; Alia-Klein, Nelly; Telang, Frank; Wang, Gene-Jack; Squires, Nancy K; Volkow, Nora D; Goldstein, Rita Z

2012-07-30

Recent studies suggest that drug-addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this event-related potential study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD-) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0¢, 1¢ and 45¢). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD- showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self-administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Data mart construction based on semantic annotation of scientific articles: A case study for the prioritization of drug targets.

PubMed

Teixeira, Marlon Amaro Coelho; Belloze, Kele Teixeira; Cavalcanti, Maria Cláudia; Silva-Junior, Floriano P

2018-04-01

Semantic text annotation enables the association of semantic information (ontology concepts) to text expressions (terms), which are readable by software agents. In the scientific scenario, this is particularly useful because it reveals a lot of scientific discoveries that are hidden within academic articles. The Biomedical area has more than 300 ontologies, most of them composed of over 500 concepts. These ontologies can be used to annotate scientific papers and thus, facilitate data extraction. However, in the context of a scientific research, a simple keyword-based query using the interface of a digital scientific texts library can return more than a thousand hits. The analysis of such a large set of texts, annotated with such numerous and large ontologies, is not an easy task. Therefore, the main objective of this work is to provide a method that could facilitate this task. This work describes a method called Text and Ontology ETL (TOETL), to build an analytical view over such texts. First, a corpus of selected papers is semantically annotated using distinct ontologies. Then, the annotation data is extracted, organized and aggregated into the dimensional schema of a data mart. Besides the TOETL method, this work illustrates its application through the development of the TaP DM (Target Prioritization data mart). This data mart has focus on the research of gene essentiality, a key concept to be considered when searching for genes showing potential as anti-infective drug targets. This work reveals that the proposed approach is a relevant tool to support decision making in the prioritization of new drug targets, being more efficient than the keyword-based traditional tools. Copyright © 2018 Elsevier B.V. All rights reserved.
Medical Concept Normalization in Social Media Posts with Recurrent Neural Networks.

PubMed

Tutubalina, Elena; Miftahutdinov, Zulfat; Nikolenko, Sergey; Malykh, Valentin

2018-06-12

Text mining of scientific libraries and social media has already proven itself as a reliable tool for drug repurposing and hypothesis generation. The task of mapping a disease mention to a concept in a controlled vocabulary, typically to the standard thesaurus in the Unified Medical Language System (UMLS), is known as medical concept normalization. This task is challenging due to the differences in the use of medical terminology between health care professionals and social media texts coming from the lay public. To bridge this gap, we use sequence learning with recurrent neural networks and semantic representation of one- or multi-word expressions: we develop end-to-end architectures directly tailored to the task, including bidirectional Long Short-Term Memory, Gated Recurrent Units with an attention mechanism, and additional semantic similarity features based on UMLS. Our evaluation against a standard benchmark shows that recurrent neural networks improve results over an effective baseline for classification based on convolutional neural networks. A qualitative examination of mentions discovered in a dataset of user reviews collected from popular online health information platforms as well as a quantitative evaluation both show improvements in the semantic representation of health-related expressions in social media. Copyright © 2018. Published by Elsevier Inc.
Optimising experimental research in respiratory diseases: an ERS statement.

PubMed

Bonniaud, Philippe; Fabre, Aurélie; Frossard, Nelly; Guignabert, Christophe; Inman, Mark; Kuebler, Wolfgang M; Maes, Tania; Shi, Wei; Stampfli, Martin; Uhlig, Stefan; White, Eric; Witzenrath, Martin; Bellaye, Pierre-Simon; Crestani, Bruno; Eickelberg, Oliver; Fehrenbach, Heinz; Guenther, Andreas; Jenkins, Gisli; Joos, Guy; Magnan, Antoine; Maitre, Bernard; Maus, Ulrich A; Reinhold, Petra; Vernooy, Juanita H J; Richeldi, Luca; Kolb, Martin

2018-05-01

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models. Focus was put on their specific benefits and limitations. This will result in more efficient use of resources and greater reduction in the numbers of animals employed, thereby enhancing the ethical standards and translational capacity of experimental research.The task force statement addresses general issues of experimental research (ethics, species, sex, age, ex vivo and in vitro models, gene editing). The statement also includes research recommendations on modelling asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung infections, acute lung injury and pulmonary hypertension.The task force stressed the importance of using multiple models to strengthen validity of results, the need to increase the availability of human tissues and the importance of standard operating procedures and data quality. Copyright ©ERS 2018.
Stereoselective synthesis from a process research perspective.

PubMed

Hillier, Michael C; Reider, Paul J

2002-03-01

The process chemists' primary responsibility is to develop efficient and reproducible syntheses of pharmaceutically active compounds. This task is complicated when dealing with chiral molecules that often must be made as single isomers according to regulatory guidelines. The presence of any isomeric impurity in the final product, even in small amounts, is usually not acceptable. This requirement necessitates an exquisite understanding of the methods employed in the construction of chiral drugs. However, the chemistry available for this purpose is sometimes limited and often requires a significant amount of effort and creativity to be made both functional and consistent.
Ketamine Disrupts Frontal and Hippocampal Contribution to Encoding and Retrieval of Episodic Memory: An fMRI Study

PubMed Central

Honey, G.D.; Honey, R.A.E.; O’Loughlin, C.; Sharar, S.R.; Kumaran, D.; Suckling, J.; Menon, D.K.; Sleator, C.; Bullmore, E.T.; Fletcher, P.C.

2012-01-01

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance. PMID:15537676
Preference conditioning in healthy individuals: correlates with hazardous drinking.

PubMed

Balodis, Iris M; Lockwood, Kathleen P; Magrys, Sylvia A; Olmstead, Mary C

2010-06-01

Conditioned reward is a classic measure of drug-induced brain changes in animal models of addiction. The process can be examined in humans using the Conditioned Pattern Preference (CPP) task, in which participants associate nonverbal cues with reward but demonstrate low awareness of this conditioning. Previously, we reported that alcohol intoxication does not affect CPP acquisition in humans, but our data indicated that prior drug use may impact conditioning scores. To test this possibility, the current study examined the relationship between self-reported alcohol use and preference conditioning in the CPP task. Working memory was assessed during conditioning by asking participants to count the cues that appeared at each location on a computer screen. Participants (69 female and 23 male undergraduate students) completed the Alcohol Use Disorders Identification Test (AUDIT) and the Rutgers Alcohol Problem Index (RAPI) as measures of hazardous drinking. Self-reported hazardous drinking was significantly correlated with preference conditioning in that individuals who scored higher on these scales exhibited an increased preference for the reward-paired cues. In contrast, hazardous drinking did not affect working memory errors on the CPP task. These findings support evidence that repeated drug use sensitizes neural pathways mediating conditioned reward and point to a neurocognitive disposition linking substance misuse and responses to reward-paired stimuli. The relationship between hazardous drinking and conditioned reward is independent of changes in cognitive function, such as working memory.

Enhanced Flexible Tubular Microelectrode with Conducting Polymer for Multi-Functional Implantable Tissue-Machine Interface

NASA Astrophysics Data System (ADS)

Tian, Hong-Chang; Liu, Jing-Quan; Kang, Xiao-Yang; Tang, Long-Jun; Wang, Ming-Hao; Ji, Bo-Wen; Yang, Bin; Wang, Xiao-Lin; Chen, Xiang; Yang, Chun-Sheng

2016-05-01

Implantable biomedical microdevices enable the restoration of body function and improvement of health condition. As the interface between artificial machines and natural tissue, various kinds of microelectrodes with high density and tiny size were developed to undertake precise and complex medical tasks through electrical stimulation and electrophysiological recording. However, if only the electrical interaction existed between electrodes and muscle or nerve tissue without nutrition factor delivery, it would eventually lead to a significant symptom of denervation-induced skeletal muscle atrophy. In this paper, we developed a novel flexible tubular microelectrode integrated with fluidic drug delivery channel for dynamic tissue implant. First, the whole microelectrode was made of biocompatible polymers, which could avoid the drawbacks of the stiff microelectrodes that are easy to be broken and damage tissue. Moreover, the microelectrode sites were circumferentially distributed on the surface of polymer microtube in three dimensions, which would be beneficial to the spatial selectivity. Finally, the in vivo results confirmed that our implantable tubular microelectrodes were suitable for dynamic electrophysiological recording and simultaneous fluidic drug delivery, and the electrode performance was further enhanced by the conducting polymer modification.
Enhanced Flexible Tubular Microelectrode with Conducting Polymer for Multi-Functional Implantable Tissue-Machine Interface.

PubMed

Tian, Hong-Chang; Liu, Jing-Quan; Kang, Xiao-Yang; Tang, Long-Jun; Wang, Ming-Hao; Ji, Bo-Wen; Yang, Bin; Wang, Xiao-Lin; Chen, Xiang; Yang, Chun-Sheng

2016-05-27

Implantable biomedical microdevices enable the restoration of body function and improvement of health condition. As the interface between artificial machines and natural tissue, various kinds of microelectrodes with high density and tiny size were developed to undertake precise and complex medical tasks through electrical stimulation and electrophysiological recording. However, if only the electrical interaction existed between electrodes and muscle or nerve tissue without nutrition factor delivery, it would eventually lead to a significant symptom of denervation-induced skeletal muscle atrophy. In this paper, we developed a novel flexible tubular microelectrode integrated with fluidic drug delivery channel for dynamic tissue implant. First, the whole microelectrode was made of biocompatible polymers, which could avoid the drawbacks of the stiff microelectrodes that are easy to be broken and damage tissue. Moreover, the microelectrode sites were circumferentially distributed on the surface of polymer microtube in three dimensions, which would be beneficial to the spatial selectivity. Finally, the in vivo results confirmed that our implantable tubular microelectrodes were suitable for dynamic electrophysiological recording and simultaneous fluidic drug delivery, and the electrode performance was further enhanced by the conducting polymer modification.
Reforms: a quest for efficiency or an opportunity for vested interests'? A case study of pharmaceutical policy reforms in Tanzania.

PubMed

Mori, Amani Thomas; Kaale, Eliangiringa Amos; Risha, Peter

2013-07-13

Regulation of the pharmaceutical sector is a challenging task for most governments in the developing countries. In Tanzania, this task falls under the Food and Drugs Authority and the Pharmacy Council. In 2010, the Pharmacy Council spearheaded policy reforms in the pharmaceutical sector aimed at taking over the control of the regulation of the business of pharmacy from the Tanzania Food and Drugs Authority. This study provides a critical analysis of these reforms. The study employed a qualitative case-study design. Data was collected through in-depth interviews, focus group discussions and document reviews. Data was analyzed thematically using a policy triangle framework. The analysis was done manually. The reforms adopted an incremental model of public policy-making and the process was characterized by lobbying for political support, negotiations and bargaining between the interest groups. These negotiations were largely centred on vested interests and not on the impact of the reforms on the efficiency of pharmaceutical regulations in the country. Stakeholders from the micro and meso levels were minimally involved in the policy reforms. Recent pharmaceutical regulation reforms in Tanzania were overshadowed by vested interests, displacing a critical analysis of optimal policy options that have the potential to increase efficiency in the regulation of the business of pharmacy. Politics influenced decision-making at different levels of the reform process.
PRESENTATION--PPCPS: OVERVIEW OF SOURCES ...

EPA Pesticide Factsheets

This presentation briefly summarizes some of what is known and not known about the occurrence of drugs in the environment, the potential for chronic effects on wildlife (and some instances of acute effects), the relevance of drug residues in drinking water to consumer risk perception, and actions that can be taken to reduce environmental exposure. Efforts are underway at U.S. federal agencies such as the USGS, FDA, USDA, NOAA, NIEHS, and the CDC, as well as the EPA. This work is beginning to be coordinated under an Interagency Task Group (PiE: Pharmaceuticals in the Environment), which was chartered under a subcommittee of OSTP's (National Science and Technology Council) Committee on Environment and Natural Resources (http://www.ostp.gov/NSTC/html/committee/cenr.html). The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of analy
PPCPS: OVERVIEW OF SOURCES, ENVIRONMENTAL ...

EPA Pesticide Factsheets

This presentation briefly summarizes some of what is known and not known about the occurrence of drugs in the environment, the potential for chronic effects on wildlife (and some instances of acute effects), the relevance of drug residues in drinking water to consumer risk perception, and actions that can be taken to reduce environmental exposure. Efforts are underway at U.S. federal agencies such as the USGS, FDA, USDA, NOAA, NIEHS, and the CDC, as well as the EPA. This work is beginning to be coordinated under an Interagency Task Group (PiE: Pharmaceuticals in the Environment), which was chartered under a subcommittee of OSTP¿s (National Science and Technology Council) Committee on Environment and Natural Resources (http://www.ostp.gov/NSTC/html/committee/cenr.html). The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of an
Bioavailability and Pharmacodynamics of Promethazine in Human Subjects

NASA Technical Reports Server (NTRS)

Boyd, J. L.; Boster, B.; Wang, Z.; Shah, V.; Berens, K. L.; Sipes, W. E.; Anderson, K. E.; Putcha, L.

2004-01-01

The acute effects of exposure to microgravity include the development of space motion sickness, which usually requires therapeutic intervention. The current drug of choice, promethazine (PMZ), is available to astronauts in three different dosage forms during space flight; its side effects include nausea, dizziness, sedation and impaired psychomotor performance. This ground-based study is designed to validate flight-suitable methods for pharmacodynamic evaluation of PMZ and to estimate bioavailability and pharmacodynamics of PMZ. Experimental design consists of intramuscular administration of three doses of PMZ (12.5,25 and 50 mg) and placebo in a randomized double blind fashion to human subjects and collecting blood, urine and saliva samples for 72 h. Subjects also complete cognitive performance test batteries, WinSCAT (Windows based Space Cognitive Assessment Test) and ARES (ANAM Readiness Evaluation System). Preliminary results indicate a significant relationship (p=9.88e-05) between circulating PMZ levels and cognitive performance parameters. Time to accurately complete memory tasks increases significantly with concentrations; higher concentrations also increase response time and decrease accuracy of substitution and matching tasks. AUC and half-life estimates for PMZ ranged between 0.12 and 1.7 mg.h/L and 15 and 50 h, respectively. These preliminary results indicate that PMZ may exhibit dose-dependent pharmacokinetics in humans; also, WinSCAT and ARES are sensitive for pharmacodynamic assessment of PMZ, and may be applicable for assessing the pharmacodynamics of other neurocognitive drugs.
Method of synthesis of abstract images with high self-similarity

NASA Astrophysics Data System (ADS)

Matveev, Nikolay V.; Shcheglov, Sergey A.; Romanova, Galina E.; Koneva, Ð.¢atiana A.

2017-06-01

Abstract images with high self-similarity could be used for drug-free stress therapy. This based on the fact that a complex visual environment has a high affective appraisal. To create such an image we can use the setup based on the three laser sources of small power and different colors (Red, Green, Blue), the image is the pattern resulting from the reflecting and refracting by the complicated form object placed into the laser ray paths. The images were obtained experimentally which showed the good therapy effect. However, to find and to choose the object which gives needed image structure is very difficult and requires many trials. The goal of the work is to develop a method and a procedure of finding the object form which if placed into the ray paths can provide the necessary structure of the image In fact the task means obtaining the necessary irradiance distribution on the given surface. Traditionally such problems are solved using the non-imaging optics methods. In the given case this task is very complicated because of the complicated structure of the illuminance distribution and its high non-linearity. Alternative way is to use the projected image of a mask with a given structure. We consider both ways and discuss how they can help to speed up the synthesis procedure for the given abstract image of the high self-similarity for the setups of drug-free therapy.
PHARMACEUTICALS AND PERSONAL CARE PRODUCTS ...

EPA Pesticide Factsheets

This presentation briefly summarizes some of what is known and not known about the occurrence of drugs in the environment, the potential for chronic effects on wildlife (and some instances of acute effects), the relevance of drug residues in drinking water to consumer risk perception, and actions that can be taken to reduce environmental exposure. Efforts are underway at U.S. federal agencies such as the USGS, FDA, USDA, NOAA, NIEHS, and the CDC, as well as the EPA. This work is beginning to be coordinated under an Interagency Task Group (PiE: Pharmaceuticals in the Environment), which was chartered under a subcommittee of OSTP's (National Science and Technology Council) Committee on Environment and Natural Resources (http://www.ostp.gov/NSTC/html/committee/cenr. html). The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of an
PRESENTATION--PHARACEUTICALS AND PERSONAL ...

EPA Pesticide Factsheets

This presentation briefly summarizes some of what is known and not known about the occurrence of drugs in the environment, the potential for chronic effects on wildlife (and some instances of acute effects), the relevance of drug residues in drinking water to consumer risk perception, and actions that can be taken to reduce environmental exposure. Efforts are underway at U.S. federal agencies such as the USGS, FDA, USDA, NOAA, NIEHS, and the CDC, as well as the EPA. This work is beginning to be coordinated under an Interagency Task Group (PiE: Pharmaceuticals in the Environment), which was chartered under a subcommittee of OSTP's (National Science and Technology Council) Committee on Environment and Natural Resources (http://www.ostp.gov/NSTC/html/committee/cenr.html). The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of analy
MULTI-STAGE DELIVERY NANO-PARTICLE SYSTEMS FOR THERAPEUTIC APPLICATIONS

PubMed Central

Serda, Rita E.; Godin, Biana; Blanco, Elvin; Chiappini, Ciro; Ferrari, Mauro

2010-01-01

Background The daunting task for drug molecules to reach pathological lesions has fueled rapid advances in Nanomedicine. The progressive evolution of nanovectors has led to the development of multi-stage delivery systems aimed at overcoming the numerous obstacles encountered by nanovectors on their journey to the target site. Scope of Review This review summarizes major findings with respect to silicon-based drug delivery vectors for cancer therapeutics and imaging. Based on rational design, well established silicon technologies have been adapted for the fabrication of nanovectors with specific shapes, sizes, and porosities. These vectors are part of a multi-stage delivery system that contains multiple nano-components, each designed to achieve a specific task with the common goal of site-directed delivery of therapeutics. Major Conclusions Quasi-hemispherical and discoidal silicon microparticles are superior to spherical particles with respect to margination in the blood, with particles of different shapes and sizes having unique distributions in vivo. Cellular adhesion and internalization of silicon microparticles is influenced by microparticle shape and surface charge, with the latter dictating binding of serum opsonins. Based on in vitro cell studies, the internalization of porous silicon microparticles by endothelial cells and macrophages is compatible with cellular morphology, intracellular trafficking, mitosis, cell cycle progression, cytokine release, and cell viability. In vivo studies support superior therapeutic efficacy of liposomal encapsulated siRNA when delivered in multi-stage systems compared to free nanoparticles. PMID:20493927
PHARMACEUTICALS IN THE ENVIRONMENT: OVERVIEW ...

EPA Pesticide Factsheets

This presentation briefly summarizes some of what is known and not known about the occurrence of drugs in the environment, the potential for chronic effects on wildlife (and some instances of acute effects), the relevance of drug residues in drinking water to consumer risk perception, and actions that can be taken to reduce environmental exposure. Efforts are underway at U.S. federal agencies such as the USGS, FDA, USDA, NOAA, NIEHS, and the CDC, as well as the EPA. This work is beginning to be coordinated under an Interagency Task Force (PiE: Pharmaceuticals in the Environment), which was chartered under a subcommittee of OSTP's (National Science and Technology Council) Committee on Environment and Natural Resources (http://www.ostp.gov/NSTC/html/committee/cenr.html). The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of ana
Thioredoxin Glutathione Reductase as a Novel Drug Target: Evidence from Schistosoma japonicum

PubMed Central

Xie, ShuYing; Qian, ChunYan; Wang, Jie; Zhang, Wei; Yin, XuRen; Hua, ZiChun; Yu, ChuanXin

2012-01-01

Background Schistosomiasis remains a major public health concern affecting billions of people around the world. Currently, praziquantel is the only drug of choice for treatment of human schistosomiasis. The emergence of drug resistance to praziquantel in schistosomes makes the development of novel drugs an urgent task. Thioredoxin glutathione reductase (TGR) enzymes in Schistosoma mansoni and some other platyhelminths have been identified as alternative targets. The present study was designed to confirm the existense and the potential value of TGR as a target for development of novel antischistosomal agents in Schistosoma japonicum, a platyhelminth endemic in Asia. Methods and Findings After cloning the S. japonicum TGR (SjTGR) gene, the recombinant SjTGR selenoprotein was purified and characterized in enzymatic assays as a multifunctional enzyme with thioredoxin reductase (TrxR), glutathione reductase (GR) and glutaredoxin (Grx) activities. Immunological and bioinformatic analyses confirmed that instead of having separate TrxR and GR proteins in mammalian, S. japonicum only encodes TGR, which performs the functions of both enzymes and plays a critical role in maintaining the redox balance in this parasite. These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths. Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice. Conclusions Collectively, our study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate TrxR and GR enzymes, exists in S. japonicum. Furthermore, TGR may be a potential target for development of novel agents against schistosomes. This assumption is strengthened by our demonstration that the SjTGR is an essential enzyme for maintaining the thiol-disulfide redox homeostasis of S. japonicum. PMID:22384025
Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users.

PubMed

Curran, H Valerie; Brignell, Catherine; Fletcher, Sally; Middleton, Paul; Henry, John

2002-10-01

Although some aspects of memory functions are known to be acutely impaired by delta(9)-tetrahydrocannabinol (delta(9)-THC; the main active constituent of marijuana), effects on other aspects of memory are not known and the time course of functional impairments is unclear. The present study aimed to detail the acute and residual cognitive effects of delta(9)-THC in infrequent cannabis users. A balanced, double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg delta(9)-THC with matched placebo in 15 male volunteers. Participants were assessed pre and 1, 2, 4, 6, 8, 24 and 48 h post-drug. Delta(9)-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration (2 h post-drug). At the same time point, performance on an implicit memory task was preserved intact. The higher dose of delta(9)-THC resulted in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by delta(9)-THC. In several tasks, delta(9)-THC increased both speed and error rates, reflecting "riskier" speed-accuracy trade-offs. Subjective effects were also most marked at 2 h but often persisted longer, with participants rating themselves as "stoned" for 8 h. Participants experienced a strong drug effect, liked this effect and, until 4 h, wanted more oral delta(9)-THC. No effects of delta(9)-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral delta(9)-THC are minimal. These data demonstrate that oral delta(9)-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory.
Intranasal oxytocin impedes the ability to ignore task-irrelevant facial expressions of sadness in students with depressive symptoms.

PubMed

Ellenbogen, Mark A; Linnen, Anne-Marie; Cardoso, Christopher; Joober, Ridha

2013-03-01

The administration of oxytocin promotes prosocial behavior in humans. The mechanism by which this occurs is unknown, but it likely involves changes in social information processing. In a randomized placebo-controlled study, we examined the influence of intranasal oxytocin and placebo on the interference control component of inhibition (i.e. ability to ignore task-irrelevant information) in 102 participants using a negative affective priming task with sad, angry, and happy faces. In this task, participants are instructed to respond to a facial expression of emotion while simultaneously ignoring another emotional face. On the subsequent trial, the previously-ignored emotional valence may become the emotional valence of the target face. Inhibition is operationalized as the differential delay between responding to a previously-ignored emotional valence and responding to an emotional valence unrelated to the previous one. Although no main effect of drug administration on inhibition was observed, a drug × depressive symptom interaction (β = -0.25; t = -2.6, p < 0.05) predicted the inhibition of sad faces. Relative to placebo, participants with high depression scores who were administered oxytocin were unable to inhibit the processing of sad faces. There was no relationship between drug administration and inhibition among those with low depression scores. These findings are consistent with increasing evidence that oxytocin alters social information processing in ways that have both positive and negative social outcomes. Because elevated depression scores are associated with an increased risk for major depressive disorder, difficulties inhibiting mood-congruent stimuli following oxytocin administration may be associated with risk for depression. Copyright © 2012 Elsevier Ltd. All rights reserved.
Defining and redefining harm reduction in the Lao context

PubMed Central

2012-01-01

The response to drug use in Laos has focused on reducing opium supply (supply reduction) and rates of drug use (demand reduction). However, recently there is increased interest among government counterparts to discuss and develop broader responses to injecting drug use (IDU) including the introduction of harm reduction programs. The concept of harm reduction has just been introduced to Lao PDR and as yet there is no agreement on a definition of the concept. We highlight here a range of issues that remain controversial in Lao PDR in the HIV, drug use and harm reduction discourse, the definition of 'harm reduction' and related terms; and the scope of harm reduction. This was a qualitative study, consisting of in-depth interviews with 27 law enforcement and 8 health officers who work in the fields of HIV and/or drug control about their understanding of HIV related to drug use, and concepts of harm reduction. Content analysis was performed to identify the coding, categories and themes. We found that law enforcement officers in particular had limited understanding about harm reduction and the feasibility and appropriateness of harm reduction services in the Lao context. Harm reduction should be a core element of a public health response to HIV where drug use and IDU exists. Recommendations include the necessity of increasing the awareness of harm reduction among law enforcement officers and providing appropriate evidence to support the needs of harm reduction policy and programs. HIV prevention and treatment strategies should be integrated within existing social and cultural frameworks, working with the task force for HIV/IDU and other government counterparts. PMID:22769736
Addiction research centres and the nurturing of creativity. The Centre for Alcohol and Drug Research: social science alcohol and drug research in Denmark.

PubMed

Pedersen, Mads U; Elmeland, Karen; Frank, Vibeke A

2011-12-01

The purpose of this paper is to introduce the social science alcohol and drug research undertaken by the Centre for Alcohol and Drug Research (CRF) and at the same time offer an insight into the development in Danish alcohol and drug research throughout the past 15-20 years. A review of articles, books and reports published by researcher from CRF from the mid-1990s until today and an analysis of the policy-making in the Danish substance use and misuse area. CRF is a result of the discussions surrounding social, health and allocation policy questions since the mid-1980s. Among other things, these discussions led to the formal establishment of the Centre in 1991 under the Aarhus University, the Faculty of Social Science. Since 2001 the Centre has received a permanent basic allocation, which has made it possible to appoint tenured senior researchers; to work under a more long-term research strategy; to function as a milieu for educating PhD students; and to diversify from commissioned research tasks to initiating projects involving more fundamental research. Research at the Centre is today pivoted around four core areas: consumption, policy, prevention and treatment. The emergence, continuation, financing and character of the research taking place at CRF can be linked closely to the specific Danish drug and alcohol discourse and to the division of the responsibility for alcohol and drug research into separate Ministries. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.
In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.

PubMed

Mayorga, C; Celik, G; Rouzaire, P; Whitaker, P; Bonadonna, P; Rodrigues-Cernadas, J; Vultaggio, A; Brockow, K; Caubet, J C; Makowska, J; Nakonechna, A; Romano, A; Montañez, M I; Laguna, J J; Zanoni, G; Gueant, J L; Oude Elberink, H; Fernandez, J; Viel, S; Demoly, P; Torres, M J

2016-08-01

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Huperzine A: Behavioral and Pharmacological Evaluation in Rhesus Monkeys

DTIC Science & Technology

2008-06-01

challenged with 30 ug/kg scopolamine . Doses of 1 and 10 ug/kg HUP improved choice accuracy on a previously learned delayed spatial memory task in the...elderly subjects, and doses of 10 and 100 ug/kg reversed the scopolamine -induced deficits in the younger monkeys. Unfortunately, no data regarding...interval) in the spatial memory task differentially modulated the drug effects on performance. Specifically, scopolamine impaired accuracy
An Examination of Problems and Solutions Related to the Chronic "Revolving Door" Alcohol Abuser. DHSS Planning Guideline #1, Task Assignment #1.11. Long-Term Support, Chronic Alcoholism and Other Drug Abuse.

ERIC Educational Resources Information Center

Vick, John W.; Houden, Dorothy

This report contains recommendations of a Wisconsin Task Assignment Steering Committee created to explore solutions to some significant problems facing adult chronic "revolving-detox-door" alcohol abusers (CRA's), persons with repeated admissions for detoxification services; and to examine the system that serves and funds them. This…
Effects of chronic scopolamine administration on spatial working memory and hippocampal receptors related to learning.

PubMed

Doguc, Duygu K; Delibas, Namik; Vural, Huseyin; Altuntas, Irfan; Sutcu, Recep; Sonmez, Yonca

2012-12-01

Scopolamine has been used in neuropsychopharmacology as a standard drug that leads to symptoms mimicking cognitive deficits seen during the aging process in healthy humans and animals. Scopolamine is known to be a nonselective muscarinic receptor blocker, but its chronic effect on the expression of certain hippocampal receptors is not clear. The aim of the present study was to determine the effect of chronic scopolamine administration on hippocampal receptor expression and spatial working memory in two different learning tasks, the water maze and the eight-arm radial maze. Male rats (8-12 months) were trained in both tasks. Subsequently, different groups received physiological saline or 0.1, 0.8, or 2 mg/kg scopolamine hydrobromide, respectively, for 15 days. After drug administration, the rats were retested for both tasks, and hippocampal expressions of NR2A, NR2B, nAChRα7, and mAChRM1 receptors were assessed by western blotting analysis. In both tasks, the spatial working memory was decreased dose dependently in all groups compared with the control group. In terms of receptor expressions, 0.8 and 2 mg/kg scopolamine administration significantly decreased NR2A protein expression, which corroborates suggestions of an interaction between cholinergic and glutamatergic receptors in the hippocampus.

A conveyor belt task for assessing visuo-motor coordination in the marmoset (Callithrix jacchus): effects of diazepam, chlorpromazine, pentobarbital and d-amphetamine.

PubMed

D'Mello, G D; Duffy, E A; Miles, S S

1985-01-01

A conveyor belt task for assessing visuo-motor coordination in the marmoset is described. Animals are motivated by apple, a preferred food, under a state of minimal food deprivation. The apparatus used was designed to test animals within their home cages and not restrained in any way, thus avoiding possible confounding factors associated with restraint stress. Stable baseline levels of performance were reached by all animals in a median of 24 sessions. Performance was shown to be differentially sensitive to the effects of four psychoactive drugs. Moderate doses of diazepam, chlorpromazine and pentobarbital disrupted visuo-motor coordination in a dose-related manner. The possibility that disruption of performance observed at higher doses may have resulted from non-specific actions of these drugs such as decreases in feeding motivation were not supported by results from ancillary experiments. Changes in performance characteristic of high dose effects were similar in nature to changes observed when the degree of task difficulty was increased. Doses of d-amphetamine up to and including those reported to produce signs of stereotypy failed to influence performance. The potential of the conveyor belt task for measuring visuo-motor coordination in both primate and rodent species is discussed.
Adolescent fluoxetine exposure produces enduring, sex-specific alterations of visual discrimination and attention in rats.

PubMed

LaRoche, Ronee B; Morgan, Russell E

2007-01-01

Over the past two decades the use of selective serotonin reuptake inhibitors (SSRIs) to treat behavioral disorders in children has grown rapidly, despite little evidence regarding the safety and efficacy of these drugs for use in children. Utilizing a rat model, this study investigated whether post-weaning exposure to a prototype SSRI, fluoxetine (FLX), influenced performance on visual tasks designed to measure discrimination learning, sustained attention, inhibitory control, and reaction time. Additionally, sex differences in response to varying doses of fluoxetine were examined. In Experiment 1, female rats were administered (P.O.) fluoxetine (10 mg/kg ) or vehicle (apple juice) from PND 25 thru PND 49. After a 14 day washout period, subjects were trained to perform a simultaneous visual discrimination task. Subjects were then tested for 20 sessions on a visual attention task that consisted of varied stimulus delays (0, 3, 6, or 9 s) and cue durations (200, 400, or 700 ms). In Experiment 2, both male and female Long-Evans rats (24 F, 24 M) were administered fluoxetine (0, 5, 10, or 15 mg/kg) then tested in the same visual tasks used in Experiment 1, with the addition of open-field and elevated plus-maze testing. Few FLX-related differences were seen in the visual discrimination, open field, or plus-maze tasks. However, results from the visual attention task indicated a dose-dependent reduction in the performance of fluoxetine-treated males, whereas fluoxetine-treated females tended to improve over baseline. These findings indicate that enduring, behaviorally-relevant alterations of the CNS can occur following pharmacological manipulation of the serotonin system during postnatal development.
The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

PubMed Central

Pacchiarotti, Isabella; Bond, David J.; Baldessarini, Ross J.; Nolen, Willem A.; Grunze, Heinz; Licht, Rasmus W.; Post, Robert M.; Berk, Michael; Goodwin, Guy M.; Sachs, Gary S.; Tondo, Leonardo; Findling, Robert L.; Youngstrom, Eric A.; Tohen, Mauricio; Undurraga, Juan; González-Pinto, Ana; Goldberg, Joseph F.; Yildiz, Ayşegül; Altshuler, Lori L.; Calabrese, Joseph R.; Mitchell, Philip B.; Thase, Michael E.; Koukopoulos, Athanasios; Colom, Francesc; Frye, Mark A.; Malhi, Gin S.; Fountoulakis, Konstantinos N.; Vázquez, Gustavo; Perlis, Roy H.; Ketter, Terence A.; Cassidy, Frederick; Akiskal, Hagop; Azorin, Jean-Michel; Valentí, Marc; Mazzei, Diego Hidalgo; Lafer, Beny; Kato, Tadafumi; Mazzarini, Lorenzo; Martínez-Aran, Anabel; Parker, Gordon; Souery, Daniel; Özerdem, Ayşegül; McElroy, Susan L.; Girardi, Paolo; Bauer, Michael; Yatham, Lakshmi N.; Zarate, Carlos A.; Nierenberg, Andrew A.; Birmaher, Boris; Kanba, Shigenobu; El-Mallakh, Rif S.; Serretti, Alessandro; Rihmer, Zoltan; Young, Allan H.; Kotzalidis, Georgios D.; MacQueen, Glenda M.; Bowden, Charles L.; Ghaemi, S. Nassir; Lopez-Jaramillo, Carlos; Rybakowski, Janusz; Ha, Kyooseob; Perugi, Giulio; Kasper, Siegfried; Amsterdam, Jay D.; Hirschfeld, Robert M.; Kapczinski, Flávio; Vieta, Eduard

2014-01-01

Objective The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. Method An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. Results There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. Conclusions Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications. PMID:24030475
Salient Features and Outline of the Joint Japanese Guidelines for Safe Handling of Cancer Chemotherapy Drugs

PubMed Central

Kanda, Kiyoko; Hirai, Kazue; Iino, Keiko; Nomura, Hisanaga; Yasui, Hisateru; Kano, Taro; Ichikawa, Chisato; Hiura, Sumiko; Morita, Tomoko; Mitsuma, Ayako; Komatsu, Hiroko

2017-01-01

The purpose of this paper is to introduce the outline and describe the salient features of the “Joint Guidelines for Safe Handling of Cancer Chemotherapy Drugs” (hereinafter, “Guideline”), which were published in July 2015. The purpose of this Guideline is to provide guidance to protect against occupational exposure to hazardous drugs (HDs) to all medical personnel involved in cancer chemotherapy, including physicians, pharmacists, and nurses and home health-care providers. The Guideline was developed according to the Medical Information Network Distribution Service guidance for developing clinical practice guidelines, with reference to five authoritative guidelines used worldwide. PubMed, Cumulative Index to Nursing and Allied Health Literature, Ichushi-Web, and Cochrane Central Register of Controlled Trials were used for a systematic search of the literature. Eight clinical questions (CQs) were eventually established, and the strength of recommendation for each CQ is presented based on 867 references. The salient features of the Guideline are that it was jointly developed by three societies (Japanese Society of Cancer Nursing, Japanese Society of Medical Oncology, and Japanese Society of Pharmaceutical Oncology), contains descriptions including the definition of HDs and the concept of hierarchy of controls, and addresses exposure control measures during handling of chemotherapy drugs. Our future task is to collect additional evidence for the recommended exposure control measures and to assess whether publication of the Guideline has led to adherence of measures to prevent occupational exposure. PMID:28966958
Effects of propranolol on conversational reciprocity in autism spectrum disorder: a pilot, double-blind, single-dose psychopharmacological challenge study.

PubMed

Zamzow, Rachel M; Ferguson, Bradley J; Stichter, Janine P; Porges, Eric C; Ragsdale, Alexandra S; Lewis, Morgan L; Beversdorf, David Q

2016-04-01

Pharmacological intervention for autism spectrum disorder (ASD) is an important addition to treatment, yet currently available agents target co-morbid psychiatric concerns, such as aggression and irritability. Propranolol, a beta-adrenergic antagonist with anxiolytic effects, has been shown to improve verbal fluency and working memory in adults and adolescents with ASD in single-dose challenges. The present pilot study explores the acute effects of propranolol on a measure of conversational reciprocity in this population. We also examined whether autonomic activity and anxiety moderate or mediate response to the drug, given relationships between these variables and ASD, as well as the drug's effects. In a within-subject crossover design, 20 individuals with ASD received a single dose of propranolol or placebo during two sessions in a double-blinded, counterbalanced manner. After drug administration, participants performed a conversational reciprocity task by engaging in a short conversation with the researcher. Measurements of autonomic activity and anxiety were obtained before and after drug administration. Propranolol significantly improved performance on the conversational reciprocity task total [d = 0.40] and nonverbal communication domain scores when compared to the placebo condition. However, neither autonomic activity nor anxiety was significantly associated with drug response. Acute propranolol administration improved conversational reciprocity in ASD. Further exploration of these preliminary findings, as well as other potential treatment response predictors, with serial doses is warranted.
Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory.

PubMed

Ladwig, Paula M; Barnidge, David R; Willrich, Maria A V

2017-05-01

Therapeutic monoclonal antibodies (MAbs) are an important class of drugs used to treat diseases ranging from autoimmune disorders to B cell lymphomas to other rare conditions thought to be untreatable in the past. Many advances have been made in the characterization of immunoglobulins as a result of pharmaceutical companies investing in technologies that allow them to better understand MAbs during the development phase. Mass spectrometry is one of the new advancements utilized extensively by pharma to analyze MAbs and is now beginning to be applied in the clinical laboratory setting. The rise in the use of therapeutic MAbs has opened up new challenges for the development of assays for monitoring this class of drugs. MAbs are larger and more complex than typical small-molecule therapeutic drugs routinely analyzed by mass spectrometry. In addition, they must be quantified in samples that contain endogenous immunoglobulins with nearly identical structures. In contrast to an enzyme-linked immunosorbent assay (ELISA) for quantifying MAbs, mass spectrometry-based assays do not rely on MAb-specific reagents such as recombinant antigens and/or anti-idiotypic antibodies, and time for development is usually shorter. Furthermore, using molecular mass as a measurement tool provides increased specificity since it is a first-order principle unique to each MAb. This enables rapid quantification of MAbs and multiplexing. This review describes how mass spectrometry can become an important tool for clinical chemists and especially immunologists, who are starting to develop assays for MAbs in the clinical laboratory and are considering mass spectrometry as a versatile platform for the task. Copyright © 2017 Ladwig et al.
Development and clinical application of an evidence-based pharmaceutical care service algorithm in acute coronary syndrome.

PubMed

Kang, J E; Yu, J M; Choi, J H; Chung, I-M; Pyun, W B; Kim, S A; Lee, E K; Han, N Y; Yoon, J-H; Oh, J M; Rhie, S J

2018-06-01

Drug therapies are critical for preventing secondary complications in acute coronary syndrome (ACS). The purpose of this study was to develop and apply a pharmaceutical care service (PCS) algorithm for ACS and confirm that it is applicable through a prospective clinical trial. The ACS-PCS algorithm was developed according to extant evidence-based treatment and pharmaceutical care guidelines. Quality assurance was conducted through two methods: literature comparison and expert panel evaluation. The literature comparison was used to compare the content of the algorithm with the referenced guidelines. Expert evaluations were conducted by nine experts for 75 questionnaire items. A trial was conducted to confirm its effectiveness. Seventy-nine patients were assigned to either the pharmacist-included multidisciplinary team care (MTC) group or the usual care (UC) group. The endpoints of the trial were the prescription rate of two important drugs, readmission, emergency room (ER) visit and mortality. The main frame of the algorithm was structured with three tasks: medication reconciliation, medication optimization and transition of care. The contents and context of the algorithm were compliant with class I recommendations and the main service items from the evidence-based guidelines. Opinions from the expert panel were mostly positive. There were significant differences in beta-blocker prescription rates in the overall period (P = .013) and ER visits (four cases, 9.76%, P = .016) in the MTC group compared to the UC group, respectively. We developed a PCS algorithm for ACS based on the contents of evidence-based drug therapy and the core concept of pharmacist services. © 2018 John Wiley & Sons Ltd.
Hormone Replacement Therapy: MedlinePlus Health Topic

MedlinePlus

... Cancer Institute) Also in Spanish Menopause: Medicines to Help You (Food and Drug Administration) ... Hormone Therapy for the Primary Prevention of Chronic Conditions (U.S. Preventive Services Task Force) - ...
Exploration of Phytochemicals Found in Terminalia sp. and their Antiretroviral Activities

PubMed Central

Dwevedi, Alka; Dwivedi, Raman; Sharma, Yogesh K

2016-01-01

The human immunodeficiency virus (HIV) infects cells of the immune system and destroys their function. Approximately, 2 million people die every year from HIV as reported by the World Health Organization. HIV/AIDS is difficult to treat as the virus continuously develops resistance to drugs being developed. Approach is now turning toward natural products for the development of anti-HIV drugs. Although HIV/AIDS is not a new disease, but research based on plant-derived products is still under clinical trials. Experimentally, it has been proven that plants have the potential for HIV treatment. The process involves identification of the active ingredients responsible for the reported anti-HIV activities, testing of the extract, and development of appropriate bioassays. Further development would require optimization of the formulation and manufacturing in compliance with preclinical safety and efficacy testing. The most challenging task for the natural product scientists is to separate these highly complex extracts containing several compounds into its individual components that are biologically active. Recently developed direct binding assay with mass spectrometry (MS) technology (viz., real-time time-of-flight-MS) is helpful in this respect but needs extensive optimization. At present, we have compiled all the information for the various phytochemicals present in Terminalia catappa having anti-HIV properties. These include tannins, gallotannins, ellagitannins, cyanidin, and flavonoids. Further, we have also discussed their pharmacological as well as pharmacokinetics studies. PMID:28082788
Using multicriteria decision analysis during drug development to predict reimbursement decisions.

PubMed

Williams, Paul; Mauskopf, Josephine; Lebiecki, Jake; Kilburg, Anne

2014-01-01

Pharmaceutical companies design clinical development programs to generate the data that they believe will support reimbursement for the experimental compound. The objective of the study was to present a process for using multicriteria decision analysis (MCDA) by a pharmaceutical company to estimate the probability of a positive recommendation for reimbursement for a new drug given drug and environmental attributes. The MCDA process included 1) selection of decisions makers who were representative of those making reimbursement decisions in a specific country; 2) two pre-workshop questionnaires to identify the most important attributes and their relative importance for a positive recommendation for a new drug; 3) a 1-day workshop during which participants undertook three tasks: i) they agreed on a final list of decision attributes and their importance weights, ii) they developed level descriptions for these attributes and mapped each attribute level to a value function, and iii) they developed profiles for hypothetical products 'just likely to be reimbursed'; and 4) use of the data from the workshop to develop a prediction algorithm based on a logistic regression analysis. The MCDA process is illustrated using case studies for three countries, the United Kingdom, Germany, and Spain. The extent to which the prediction algorithms for each country captured the decision processes for the workshop participants in our case studies was tested using a post-meeting questionnaire that asked the participants to make recommendations for a set of hypothetical products. The data collected in the case study workshops resulted in a prediction algorithm: 1) for the United Kingdom, the probability of a positive recommendation for different ranges of cost-effectiveness ratios; 2) for Spain, the probability of a positive recommendation at the national and regional levels; and 3) for Germany, the probability of a determination of clinical benefit. The results from the post-meeting questionnaire revealed a high predictive value for the algorithm developed using MCDA. Prediction algorithms developed using MCDA could be used by pharmaceutical companies when designing their clinical development programs to estimate the likelihood of a favourable reimbursement recommendation for different product profiles and for different positions in the treatment pathway.
Using multicriteria decision analysis during drug development to predict reimbursement decisions

PubMed Central

Williams, Paul; Mauskopf, Josephine; Lebiecki, Jake; Kilburg, Anne

2014-01-01

Background Pharmaceutical companies design clinical development programs to generate the data that they believe will support reimbursement for the experimental compound. Objective The objective of the study was to present a process for using multicriteria decision analysis (MCDA) by a pharmaceutical company to estimate the probability of a positive recommendation for reimbursement for a new drug given drug and environmental attributes. Methods The MCDA process included 1) selection of decisions makers who were representative of those making reimbursement decisions in a specific country; 2) two pre-workshop questionnaires to identify the most important attributes and their relative importance for a positive recommendation for a new drug; 3) a 1-day workshop during which participants undertook three tasks: i) they agreed on a final list of decision attributes and their importance weights, ii) they developed level descriptions for these attributes and mapped each attribute level to a value function, and iii) they developed profiles for hypothetical products ‘just likely to be reimbursed’; and 4) use of the data from the workshop to develop a prediction algorithm based on a logistic regression analysis. The MCDA process is illustrated using case studies for three countries, the United Kingdom, Germany, and Spain. The extent to which the prediction algorithms for each country captured the decision processes for the workshop participants in our case studies was tested using a post-meeting questionnaire that asked the participants to make recommendations for a set of hypothetical products. Results The data collected in the case study workshops resulted in a prediction algorithm: 1) for the United Kingdom, the probability of a positive recommendation for different ranges of cost-effectiveness ratios; 2) for Spain, the probability of a positive recommendation at the national and regional levels; and 3) for Germany, the probability of a determination of clinical benefit. The results from the post-meeting questionnaire revealed a high predictive value for the algorithm developed using MCDA. Conclusions Prediction algorithms developed using MCDA could be used by pharmaceutical companies when designing their clinical development programs to estimate the likelihood of a favourable reimbursement recommendation for different product profiles and for different positions in the treatment pathway.
A Drug Discovery Partnership for Personalized Breast Cancer Therapy

DTIC Science & Technology

2015-09-01

antagonists) and then virtually screen the USDA Phytochemical, Chinese Herbal Medicine , and the FDA Marketed Drug Databases for new estrogens. Task 1...and antagonists that are in the registered pharmaceuticals and herbal medicine databases. The 29 analogs obtained have been characterized for...Marleesa Bastian, Technician at Xavier University (Sridhar lab and is now pursuing graduation at Meharry Medical College school of Medicine , Tennessee
Drugs on Campus at the Bimillennium: The Final Report of the Presidential Task Force on Substance Use Issues on Pennsylvania College and University Campuses.

ERIC Educational Resources Information Center

Colorado State Univ., Ft. Collins. Dept. of Technical Journalism.

This report addresses three aspects of the "drug problem" on Pennsylvania's college campuses: (1) education and prevention; (2) diagnosis and treatment; and (3) law enforcement. It describes a wide variety of campus responses to this challenge reflecting the enormous variety of institutions of higher education in the Commonwealth. The…
[Speed drugs].

PubMed

Piekoszewski, Wojciech; Florek, Ewa

2009-01-01

Until recently "speed drugs" have not awake higher social emotions. Usually they associate with Red Bull, allowed driving long time, and workaholic from modern enterprise to regenerate before next task. Currently on the base of new regulation on the list of controlled substances benzylpyperazine, its related compounds and 17 plants products were added. The article discussed the sources and biological action of these psychoactive substances, which are illegal in Poland.
Strongyloidiasis Current Status with Emphasis in Diagnosis and Drug Research

PubMed Central

Minori, Karen

2017-01-01

Strongyloidiasis is a parasitic neglected disease caused by the nematode Strongyloides stercoralis affecting 30 to 100 million people worldwide. Complications, strongly associated with alcoholism, organ transplants, and HTLV-1 virus, often arise due to late diagnosis, frequently leading to patient death. Lack of preemptive diagnosis is not the only difficulty when dealing with this parasite, since there are no gold standard diagnostic techniques, and the ones used have problems associated with sensitivity, resulting in false negatives. Treatment is also an issue as ivermectin and benzimidazoles administration leads to inconsistent cure rates and several side effects. Researching new anti-Strongyloides drugs is a difficult task since S. stercoralis does not develop until the adult stages in Mus musculus (with the exception of SCID mice), the main experimental host model. Fortunately, alternative parasite models can be used, namely, Strongyloides ratti and S. venezuelensis. However, even with these models, there are other complications in finding new drugs, which are associated with specific in vitro assay protocol steps, such as larvae decontamination. In this review, we highlight the challenges associated with new drug search, the compounds tested, and a list of published in vitro assay methodologies. We also point out advances being made in strongyloidiasis diagnosis so far. PMID:28210503
Chemical-induced disease relation extraction with various linguistic features.

PubMed

Gu, Jinghang; Qian, Longhua; Zhou, Guodong

2016-01-01

Understanding the relations between chemicals and diseases is crucial in various biomedical tasks such as new drug discoveries and new therapy developments. While manually mining these relations from the biomedical literature is costly and time-consuming, such a procedure is often difficult to keep up-to-date. To address these issues, the BioCreative-V community proposed a challenging task of automatic extraction of chemical-induced disease (CID) relations in order to benefit biocuration. This article describes our work on the CID relation extraction task on the BioCreative-V tasks. We built a machine learning based system that utilized simple yet effective linguistic features to extract relations with maximum entropy models. In addition to leveraging various features, the hypernym relations between entity concepts derived from the Medical Subject Headings (MeSH)-controlled vocabulary were also employed during both training and testing stages to obtain more accurate classification models and better extraction performance, respectively. We demoted relation extraction between entities in documents to relation extraction between entity mentions. In our system, pairs of chemical and disease mentions at both intra- and inter-sentence levels were first constructed as relation instances for training and testing, then two classification models at both levels were trained from the training examples and applied to the testing examples. Finally, we merged the classification results from mention level to document level to acquire final relations between chemicals and diseases. Our system achieved promisingF-scores of 60.4% on the development dataset and 58.3% on the test dataset using gold-standard entity annotations, respectively. Database URL:https://github.com/JHnlp/BC5CIDTask. © The Author(s) 2016. Published by Oxford University Press.
PREDOSE: A Semantic Web Platform for Drug Abuse Epidemiology using Social Media

PubMed Central

Cameron, Delroy; Smith, Gary A.; Daniulaityte, Raminta; Sheth, Amit P.; Dave, Drashti; Chen, Lu; Anand, Gaurish; Carlson, Robert; Watkins, Kera Z.; Falck, Russel

2013-01-01

Objectives The role of social media in biomedical knowledge mining, including clinical, medical and healthcare informatics, prescription drug abuse epidemiology and drug pharmacology, has become increasingly significant in recent years. Social media offers opportunities for people to share opinions and experiences freely in online communities, which may contribute information beyond the knowledge of domain professionals. This paper describes the development of a novel Semantic Web platform called PREDOSE (PREscription Drug abuse Online Surveillance and Epidemiology), which is designed to facilitate the epidemiologic study of prescription (and related) drug abuse practices using social media. PREDOSE uses web forum posts and domain knowledge, modeled in a manually created Drug Abuse Ontology (DAO) (pronounced dow), to facilitate the extraction of semantic information from User Generated Content (UGC). A combination of lexical, pattern-based and semantics-based techniques is used together with the domain knowledge to extract fine-grained semantic information from UGC. In a previous study, PREDOSE was used to obtain the datasets from which new knowledge in drug abuse research was derived. Here, we report on various platform enhancements, including an updated DAO, new components for relationship and triple extraction, and tools for content analysis, trend detection and emerging patterns exploration, which enhance the capabilities of the PREDOSE platform. Given these enhancements, PREDOSE is now more equipped to impact drug abuse research by alleviating traditional labor-intensive content analysis tasks. Methods Using custom web crawlers that scrape UGC from publicly available web forums, PREDOSE first automates the collection of web-based social media content for subsequent semantic annotation. The annotation scheme is modeled in the DAO, and includes domain specific knowledge such as prescription (and related) drugs, methods of preparation, side effects, routes of administration, etc. The DAO is also used to help recognize three types of data, namely: 1) entities, 2) relationships and 3) triples. PREDOSE then uses a combination of lexical and semantic-based techniques to extract entities and relationships from the scraped content, and a top-down approach for triple extraction that uses patterns expressed in the DAO. In addition, PREDOSE uses publicly available lexicons to identify initial sentiment expressions in text, and then a probabilistic optimization algorithm (from related research) to extract the final sentiment expressions. Together, these techniques enable the capture of fine-grained semantic information from UGC, and querying, search, trend analysis and overall content analysis of social media related to prescription drug abuse. Moreover, extracted data are also made available to domain experts for the creation of training and test sets for use in evaluation and refinements in information extraction techniques. Results A recent evaluation of the information extraction techniques applied in the PREDOSE platform indicates 85% precision and 72% recall in entity identification, on a manually created gold standard dataset. In another study, PREDOSE achieved 36% precision in relationship identification and 33% precision in triple extraction, through manual evaluation by domain experts. Given the complexity of the relationship and triple extraction tasks and the abstruse nature of social media texts, we interpret these as favorable initial results. Extracted semantic information is currently in use in an online discovery support system, by prescription drug abuse researchers at the Center for Interventions, Treatment and Addictions Research (CITAR) at Wright State University. Conclusion A comprehensive platform for entity, relationship, triple and sentiment extraction from such abstruse texts has never been developed for drug abuse research. PREDOSE has already demonstrated the importance of mining social media by providing data from which new findings in drug abuse research were uncovered. Given the recent platform enhancements, including the refined DAO, components for relationship and triple extraction, and tools for content, trend and emerging pattern analysis, it is expected that PREDOSE will play a significant role in advancing drug abuse epidemiology in future. PMID:23892295
PREDOSE: a semantic web platform for drug abuse epidemiology using social media.

PubMed

Cameron, Delroy; Smith, Gary A; Daniulaityte, Raminta; Sheth, Amit P; Dave, Drashti; Chen, Lu; Anand, Gaurish; Carlson, Robert; Watkins, Kera Z; Falck, Russel

2013-12-01

The role of social media in biomedical knowledge mining, including clinical, medical and healthcare informatics, prescription drug abuse epidemiology and drug pharmacology, has become increasingly significant in recent years. Social media offers opportunities for people to share opinions and experiences freely in online communities, which may contribute information beyond the knowledge of domain professionals. This paper describes the development of a novel semantic web platform called PREDOSE (PREscription Drug abuse Online Surveillance and Epidemiology), which is designed to facilitate the epidemiologic study of prescription (and related) drug abuse practices using social media. PREDOSE uses web forum posts and domain knowledge, modeled in a manually created Drug Abuse Ontology (DAO--pronounced dow), to facilitate the extraction of semantic information from User Generated Content (UGC), through combination of lexical, pattern-based and semantics-based techniques. In a previous study, PREDOSE was used to obtain the datasets from which new knowledge in drug abuse research was derived. Here, we report on various platform enhancements, including an updated DAO, new components for relationship and triple extraction, and tools for content analysis, trend detection and emerging patterns exploration, which enhance the capabilities of the PREDOSE platform. Given these enhancements, PREDOSE is now more equipped to impact drug abuse research by alleviating traditional labor-intensive content analysis tasks. Using custom web crawlers that scrape UGC from publicly available web forums, PREDOSE first automates the collection of web-based social media content for subsequent semantic annotation. The annotation scheme is modeled in the DAO, and includes domain specific knowledge such as prescription (and related) drugs, methods of preparation, side effects, and routes of administration. The DAO is also used to help recognize three types of data, namely: (1) entities, (2) relationships and (3) triples. PREDOSE then uses a combination of lexical and semantic-based techniques to extract entities and relationships from the scraped content, and a top-down approach for triple extraction that uses patterns expressed in the DAO. In addition, PREDOSE uses publicly available lexicons to identify initial sentiment expressions in text, and then a probabilistic optimization algorithm (from related research) to extract the final sentiment expressions. Together, these techniques enable the capture of fine-grained semantic information, which facilitate search, trend analysis and overall content analysis using social media on prescription drug abuse. Moreover, extracted data are also made available to domain experts for the creation of training and test sets for use in evaluation and refinements in information extraction techniques. A recent evaluation of the information extraction techniques applied in the PREDOSE platform indicates 85% precision and 72% recall in entity identification, on a manually created gold standard dataset. In another study, PREDOSE achieved 36% precision in relationship identification and 33% precision in triple extraction, through manual evaluation by domain experts. Given the complexity of the relationship and triple extraction tasks and the abstruse nature of social media texts, we interpret these as favorable initial results. Extracted semantic information is currently in use in an online discovery support system, by prescription drug abuse researchers at the Center for Interventions, Treatment and Addictions Research (CITAR) at Wright State University. A comprehensive platform for entity, relationship, triple and sentiment extraction from such abstruse texts has never been developed for drug abuse research. PREDOSE has already demonstrated the importance of mining social media by providing data from which new findings in drug abuse research were uncovered. Given the recent platform enhancements, including the refined DAO, components for relationship and triple extraction, and tools for content, trend and emerging pattern analysis, it is expected that PREDOSE will play a significant role in advancing drug abuse epidemiology in future. Copyright © 2013 Elsevier Inc. All rights reserved.
[The impact of the EU Regulation 536/2014 on the tasks and functioning of ethics committees in Germany].

PubMed

Hasford, Joerg

2017-08-01

The EU Clinical Trial Regulation 536/2014 (CTR) and its implementation in Germany led to substantial changes of the established, well-accepted and effective system of reviewing clinical trial applications by ethics committees (ECs), which impair their independence. For the first time, the German federal legislator specified in detail the composition, functioning, tasks and responsibilities of ECs. ECs have to be registered with the federal drug authority BfArM and if an EC does not perform properly the registration can be withdrawn. In addition, the drug authorities may override the negative opinion expressed by an EC. The ECs will also lose their financial autonomy as the fees will be fixed by the federal government. The tasks and responsibilities of the ECs remain almost entirely unchanged, however. The ECs remain involved in the assessment of both parts of the application dossier. Part I is assessed together with the drug authorities, the drug authorities having the lead. The assessment of part II remains the sole responsibility of the EC. As the deadlines for the assessment became rather short, in particular for multinational trials, and the communication with the sponsor will be in writing only, the established procedures of ECs have to be modified. Up to now it was common to verbally discuss problematic issues with the sponsor. The CTR is focused on written communication with the sponsor via the EU portal. ECs, their office staff and chairpersons will need considerable professionalism and respective training. The future workflow requires substantial IT support. The ECs and the Association of Medical Ethics Committees in Germany will do their utmost to protect efficiently the research subjects and to promote Germany as a major destination for clinical research.
Electrophysiological evidence of atypical processing underlying mental set shifting in ecstasy polydrug and polydrug users.

PubMed

Roberts, Carl A; Fairclough, Stephen H; McGlone, Francis P; Fisk, John E; Montgomery, Catharine

2013-12-01

Executive functioning deficits are reported in ecstasy users. However research into mental set switching has been equivocal, with behavioral studies suggesting the function is preserved. The current study sought to address the issue of switching deficits in ecstasy users by combining behavioral performance with electrophysiological correlates (electroencephalography; EEG). Twenty ecstasy polydrug users, 20 nonecstasy polydrug users, and 20 drug naive controls were recruited. Participants completed questionnaires about their drug use, sleep quality, fluid intelligence, and current mood state. Each participant completed a mental set switching task (the number-letter task) while EEG measures were recorded. Analysis of variance (ANOVA) revealed no between-group differences on performance of the task; however a regression suggested that ecstasy use was a significant predictor for performance, after controlling for cannabis use. Mixed ANOVA revealed a significant effect of group on the P3, with significant differences between both drug groups and naives. There was also an interaction between electrode and group on the P2 component, with ecstasy users differing from both other groups. On the P3 component the results suggest a reduction in positivity at parieto-occipital electrodes for drug users compared to controls. Furthermore a significant increase in negativity in ecstasy users compared to control groups could be observed in several occipito-parietal electrodes at an N2 component as well as observable atypicalities in early processing (P2) displayed by ecstasy users and polydrug controls. The present study provides evidence of atypical processing of attentional shifting in ecstasy and polydrug users. Deficits in this executive function could reflect cognitive inflexibility and paucity of rapid behavioral adjustment, which may be problematic in real world situations.

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

PubMed

Gallagher, Denis T; Hadjiefthyvoulou, Florentia; Fisk, John E; Montgomery, Catharine; Robinson, Sarita J; Judge, Jeannie

2014-01-01

Neuroimaging evidence suggests that ecstasy-related reductions in SERT densities relate more closely to the number of tablets typically consumed per session rather than estimated total lifetime use. To better understand the basis of drug related deficits in prospective memory (p.m.) we explored the association between p.m. and average long-term typical dose and long-term frequency of use. Study 1: Sixty-five ecstasy/polydrug users and 85 nonecstasy users completed an event-based, a short-term and a long-term time-based p.m. task. Study 2: Study 1 data were merged with outcomes on the same p.m. measures from a previous study creating a combined sample of 103 ecstasy/polydrug users, 38 cannabis-only users, and 65 nonusers of illicit drugs. Study 1: Ecstasy/polydrug users had significant impairments on all p.m. outcomes compared with nonecstasy users. Study 2: Ecstasy/polydrug users were impaired in event-based p.m. compared with both other groups and in long-term time-based p.m. compared with nonillicit drug users. Both drug using groups did worse on the short-term time-based p.m. task compared with nonusers. Higher long-term average typical dose of ecstasy was associated with poorer performance on the event and short-term time-based p.m. tasks and accounted for unique variance in the two p.m. measures over and above the variance associated with cannabis and cocaine use. The typical ecstasy dose consumed in a single session is an important predictor of p.m. impairments with higher doses reflecting increasing tolerance giving rise to greater p.m. impairment.
Impaired Decision-Making, Higher Impulsivity, and Drug Severity in Substance Dependence and Pathological Gambling.

PubMed

Krmpotich, Theodore; Mikulich-Gilbertson, Susan; Sakai, Joseph; Thompson, Laetitia; Banich, Marie T; Tanabe, Jody

2015-01-01

Substance use disorder is characterized by impaired decision making, impulsivity, and risk taking. Pathological gambling shares many of these characteristics, and having both diagnoses may be associated with greater problems than either diagnosis alone. We investigated whether among substance-dependent individuals, comorbid pathological gambling would be associated with worse decision making, greater impulsivity, risk taking, and drug severity. Ninety-six substance-dependent individuals were recruited from a residential treatment program and divided into 1 of the 2 groups depending on whether they met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for pathological gambling (SDPG, n = 26) or not (SD, n = 70). Ninety-two controls were recruited from the community. Participants completed a decision-making task (modified Iowa Gambling Task), measures of impulsivity (Barratt Impulsivity Scale and Delay Discounting), and risk taking (Balloon Analog Risk Task). Decision making was analyzed using a computational model. We tested for group differences using analysis of covariance or Kruskal-Wallis and appropriate post-hoc tests. The groups differed in decision-making parameters (P < 0.001) and self-reported impulsivity (P < 0.001). All post-hoc comparisons were significant on these measures, and indicated stepwise changes in controls, followed by SD, followed by SDPG, with SDPG performing worse on decision making and being more impulsive. Compared with SD, SDPG had greater drug severity (P < 0.001). No group differences were observed in delay discounting or risk taking. Compared with individuals with substance dependence without pathological gambling, those with both disorders demonstrated worse decision making and significantly more drug-related symptoms. When evaluating patients with substance dependence, clinicians should consider diagnostic assessments for gambling, as the co-occurrence of both disorders may impact clinical characteristics.
Effect profile of paracetamol, Δ9-THC and promethazine using an evoked pain test battery in healthy subjects.

PubMed

van Amerongen, G; Siebenga, P; de Kam, M L; Hay, J L; Groeneveld, G J

2018-04-10

A battery of evoked pain tasks (PainCart) was developed to investigate the pharmacodynamic properties of novel analgesics in early-phase clinical research. As part of its clinical validation, compounds with different pharmacological mechanisms of actions are investigated. The aim was to investigate the analgesic effects of classic and nonclassic analgesics compared to a sedating negative control in a randomized placebo-controlled crossover study in 24 healthy volunteers using the PainCart. The PainCart consisted of pain tasks eliciting electrical, pressure, heat, cold and inflammatory pain. Subjective scales for cognitive functioning and psychotomimetic effects were included. Subjects were administered each of the following oral treatments: paracetamol (1000 mg), Δ9-THC (10 mg), promethazine (50 mg) or matching placebo. Pharmacodynamic measurements were performed at baseline and repeated up to 10 h postdose. Paracetamol did not show a significant reduction in pain sensation or subjective cognitive functioning compared to placebo. Promethazine induced a statistically significant reduction in PTT for cold pressor and pressure stimulation. Furthermore, reduced subjective alertness was observed. Δ9-THC showed a statistically significant decrease in PTT for electrical and pressure stimulation. Δ9-THC also demonstrated subjective effects, including changes in alertness and calmness, as well as feeling high and psychotomimetic effects. This study found a decreased pain tolerance due to Δ9-THC and promethazine, or lack thereof, using an evoked pain task battery. Pain thresholds following paracetamol administration remained unchanged, which may be due to insufficient statistical power. We showed that pain thresholds determined using this pain test battery are not driven by sedation. The multimodal battery of evoked pain tasks utilized in this study may play an important role in early-phase clinical drug development. This battery of pain tasks is not sensitive to the effects of sedation alone, and thus suitable to investigate the analgesic potential of novel analgesic compounds. © 2018 European Pain Federation - EFIC®.
Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results.

PubMed

Cody, John T

2002-05-01

Medical Review Officer interpretation of laboratory results is an important component of drug testing programs. The clinical evaluation of laboratory results to assess the possibility of appropriate medical use of a drug is a task with many different facets, depending on the drug class considered. This intercession prevents the reporting of positive results unless it is apparent that drugs were used illicitly. In addition to the commonly encountered prescribed drugs that yield positive drug testing results, other sources of positive results must be considered. This review describes a series of compounds referred to as "precursor" drugs that are metabolized by the body to amphetamine and/or methamphetamine. These compounds lead to positive results for amphetamines even though neither amphetamine nor methamphetamine were used, a possibility that must be considered in the review of laboratory results. Description of the drugs, their clinical indications, and results seen following administration are provided. This information allows for the informed evaluation of results with regard to the potential involvement of these drugs.
Recommendations on evidence needed to support measurement equivalence between electronic and paper-based patient-reported outcome (PRO) measures: ISPOR ePRO Good Research Practices Task Force report.

PubMed

Coons, Stephen Joel; Gwaltney, Chad J; Hays, Ron D; Lundy, J Jason; Sloan, Jeff A; Revicki, Dennis A; Lenderking, William R; Cella, David; Basch, Ethan

2009-06-01

Patient-reported outcomes (PROs) are the consequences of disease and/or its treatment as reported by the patient. The importance of PRO measures in clinical trials for new drugs, biological agents, and devices was underscored by the release of the US Food and Drug Administration's draft guidance for industry titled "Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims." The intent of the guidance was to describe how the FDA will evaluate the appropriateness and adequacy of PRO measures used as effectiveness end points in clinical trials. In response to the expressed need of ISPOR members for further clarification of several aspects of the draft guidance, ISPOR's Health Science Policy Council created three task forces, one of which was charged with addressing the implications of the draft guidance for the collection of PRO data using electronic data capture modes of administration (ePRO). The objective of this report is to present recommendations from ISPOR's ePRO Good Research Practices Task Force regarding the evidence necessary to support the comparability, or measurement equivalence, of ePROs to the paper-based PRO measures from which they were adapted. The task force was composed of the leadership team of ISPOR's ePRO Working Group and members of another group (i.e., ePRO Consensus Development Working Group) that had already begun to develop recommendations regarding ePRO good research practices. The resulting task force membership reflected a broad array of backgrounds, perspectives, and expertise that enriched the development of this report. The prior work became the starting point for the Task Force report. A subset of the task force members became the writing team that prepared subsequent iterations of the report that were distributed to the full task force for review and feedback. In addition, review beyond the task force was sought and obtained. Along with a presentation and discussion period at an ISPOR meeting, a draft version of the full report was distributed to roughly 220 members of a reviewer group. The reviewer group comprised individuals who had responded to an emailed invitation to the full membership of ISPOR. This Task Force report reflects the extensive internal and external input received during the 16-month good research practices development process. RESULTS/RECOMMENDATIONS: An ePRO questionnaire that has been adapted from a paper-based questionnaire ought to produce data that are equivalent or superior (e.g., higher reliability) to the data produced from the original paper version. Measurement equivalence is a function of the comparability of the psychometric properties of the data obtained via the original and adapted administration mode. This comparability is driven by the amount of modification to the content and format of the original paper PRO questionnaire required during the migration process. The magnitude of a particular modification is defined with reference to its potential effect on the content, meaning, or interpretation of the measure's items and/or scales. Based on the magnitude of the modification, evidence for measurement equivalence can be generated through combinations of the following: cognitive debriefing/testing, usability testing, equivalence testing, or, if substantial modifications have been made, full psychometric testing. As long as only minor modifications were made to the measure during the migration process, a substantial body of existing evidence suggests that the psychometric properties of the original measure will still hold for the ePRO version. Hence, an evaluation limited to cognitive debriefing and usability testing only may be sufficient. However, where more substantive changes in the migration process has occurred, confirming that the adaptation to the ePRO format did not introduce significant response bias and that the two modes of administration produce essentially equivalent results is necessary. Recommendations regarding the study designs and statistical approaches for assessing measurement equivalence are provided. The electronic administration of PRO measures offers many advantages over paper administration. We provide a general framework for decisions regarding the level of evidence needed to support modifications that are made to PRO measures when they are migrated from paper to ePRO devices. The key issues include: 1) the determination of the extent of modification required to administer the PRO on the ePRO device and 2) the selection and implementation of an effective strategy for testing the measurement equivalence of the two modes of administration. We hope that these good research practice recommendations provide a path forward for researchers interested in migrating PRO measures to electronic data collection platforms.
Examining Object Location and Object Recognition Memory in Mice

PubMed Central

Vogel-Ciernia, Annie; Wood, Marcelo A.

2014-01-01

Unit Introduction The ability to store and recall our life experiences defines a person's identity. Consequently, the loss of long-term memory is a particularly devastating part of a variety of cognitive disorders, diseases and injuries. There is a great need to develop therapeutics to treat memory disorders, and thus a variety of animal models and memory paradigms have been developed. Mouse models have been widely used both to study basic disease mechanisms and to evaluate potential drug targets for therapeutic development. The relative ease of genetic manipulation of Mus musculus has led to a wide variety of genetically altered mice that model cognitive disorders ranging from Alzheimer's disease to autism. Rodents, including mice, are particularly adept at encoding and remembering spatial relationships, and these long-term spatial memories are dependent on the medial temporal lobe of the brain. These brain regions are also some of the first and most heavily impacted in disorders of human memory including Alzheimer's disease. Consequently, some of the simplest and most commonly used tests of long-term memory in mice are those that examine memory for objects and spatial relationships. However, many of these tasks, such as Morris water maze and contextual fear conditioning, are dependent upon the encoding and retrieval of emotionally aversive and inherently stressful training events. While these types of memories are important, they do not reflect the typical day-to-day experiences or memories most commonly affected in human disease. In addition, stress hormone release alone can modulate memory and thus obscure or artificially enhance these types of tasks. To avoid these sorts of confounds, we and many others have utilized tasks testing animals’ memory for object location and novel object recognition. These tasks involve exploiting rodents’ innate preference for novelty, and are inherently not stressful. In this protocol we detail how memory for object location and object identity can be used to evaluate a wide variety of mouse models and treatments. PMID:25297693
Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline

PubMed Central

Berglund, Lars; Brunzell, John D.; Goldberg, Anne C.; Goldberg, Ira J.; Sacks, Frank; Murad, Mohammad Hassan; Stalenhoef, Anton F. H.

2012-01-01

Objective: The aim was to develop clinical practice guidelines on hypertriglyceridemia. Participants: The Task Force included a chair selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), five additional experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence, e-mail discussion, conference calls, and one in-person meeting. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: The Task Force recommends that the diagnosis of hypertriglyceridemia be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of > 1000 mg/dl) be considered a risk for pancreatitis. The Task Force also recommends that patients with hypertriglyceridemia be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease. The Task Force recommends that the treatment goal in patients with moderate hypertriglyceridemia be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate should be used as a first-line agent. PMID:22962670
Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall.

PubMed

Hampson, Robert E; Song, Dong; Robinson, Brian S; Fetterhoff, Dustin; Dakos, Alexander S; Roeder, Brent M; She, Xiwei; Wicks, Robert T; Witcher, Mark R; Couture, Daniel E; Laxton, Adrian W; Munger-Clary, Heidi; Popli, Gautam; Sollman, Myriam J; Whitlow, Christopher T; Marmarelis, Vasilis Z; Berger, Theodore W; Deadwyler, Sam A

2018-06-01

We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patient's own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.
Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall

NASA Astrophysics Data System (ADS)

Hampson, Robert E.; Song, Dong; Robinson, Brian S.; Fetterhoff, Dustin; Dakos, Alexander S.; Roeder, Brent M.; She, Xiwei; Wicks, Robert T.; Witcher, Mark R.; Couture, Daniel E.; Laxton, Adrian W.; Munger-Clary, Heidi; Popli, Gautam; Sollman, Myriam J.; Whitlow, Christopher T.; Marmarelis, Vasilis Z.; Berger, Theodore W.; Deadwyler, Sam A.

2018-06-01

Objective. We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patient’s own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. Approach. We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results. MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. Significance. These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.
Daily morphine administration increases impulsivity in rats responding under a 5‐choice serial reaction time task

PubMed Central

Maguire, DR; Henson, C

2016-01-01

Background and Purpose Repeated administration of a μ opioid receptor agonist can enhance some forms of impulsivity, such as delay discounting. However, it is unclear whether repeated administration alters motor impulsivity. Experimental Approach We examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a five‐choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity. Key Results Administered acutely, morphine (0.1–10 mg·kg−1, i.p.) increased omissions and modestly, although not significantly, premature responding without affecting response accuracy; amphetamine (0.1–1.78 mg·kg−1, i.p.) increased premature responding without changing omissions or response accuracy. After 3 weeks of 10 mg·kg−1·day−1 morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately fourfold, compared with baseline. Effects of amphetamine were not significantly affected by daily morphine administration. Conclusions and Implications These data suggest that repeated administration of morphine increased effects of morphine on motor impulsivity, although tolerance developed to other effects, such as omissions. To the extent that impulsivity is a risk factor for drug abuse, repeated administration of μ opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse. PMID:26776751
The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

PubMed

Marek, Gerard J; Day, Mark; Hudzik, Thomas J

2016-03-01

Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Canadian Headache Society guideline for migraine prophylaxis.

PubMed

Pringsheim, Tamara; Davenport, W Jeptha; Mackie, Gordon; Worthington, Irene; Aubé, Michel; Christie, Suzanne N; Gladstone, Jonathan; Becker, Werner J

2012-03-01

The primary objective of this guideline is to assist the practitioner in choosing an appropriate prophylactic medication for an individual with migraine, based on current evidence in the medical literature and expert consensus. This guideline is focused on patients with episodic migraine (headache on ≤ 14 days a month). Through a comprehensive search strategy, randomized, double blind, controlled trials of drug treatments for migraine prophylaxis and relevant Cochrane reviews were identified. Studies were graded according to criteria developed by the US Preventive Services Task Force. Recommendations were graded according to the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. In addition, a general literature review and expert consensus were used for aspects of prophylactic therapy for which randomized controlled trials are not available. Prophylactic drug choice should be based on evidence for efficacy, side-effect profile, migraine clinical features, and co-existing disorders. Based on our review, 11 prophylactic drugs received a strong recommendation for use (topiramate, propranolol, nadolol, metoprolol, amitriptyline, gabapentin, candesartan, butterbur, riboflavin, coenzyme Q10, and magnesium citrate) and 6 received a weak recommendation (divalproex sodium, flunarizine, pizotifen, venlafaxine, verapamil, and lisinopril). Quality of evidence for different medications varied from high to low. Prophylactic treatment strategies were developed to assist the practitioner in selecting a prophylactic drug for specific clinical situations. These strategies included: first time strategies for patients who have not had prophylaxis before (a beta-blocker and a tricyclic strategy), low side effect strategies (including both drug and herbal/vitamin/mineral strategies), a strategy for patients with high body mass index, strategies for patients with co-existent hypertension or with co-existent depression and /or anxiety, and additional monotherapy drug strategies for patients who have failed previous prophylactic trials. Further strategies included a refractory migraine strategy and strategies for prophylaxis during pregnancy and lactation. There is good evidence from randomized controlled trials for use of a number of different prophylactic medications in patients with migraine. Medication choice for an individual patient requires careful consideration of patient clinical features.
Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

PubMed Central

Cox, Adrienne D.; Der, Channing J.; Philips, Mark R.

2015-01-01

RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. PMID:25878363
Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS.

PubMed

Nair, Madhavan; Jayant, Rahul Dev; Kaushik, Ajeet; Sagar, Vidya

2016-08-01

In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central nervous system (CNS) remains a formidable task. The incapability of ARV to go across the blood-brain barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific size therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano-enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS. Copyright © 2016 Elsevier B.V. All rights reserved.
Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making.

PubMed

Amemori, Ken-ichi; Graybiel, Ann M

2012-05-01

The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost-benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi-electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making.
Design of study without drugs--a Surinamese school-based drug-prevention program for adolescents.

PubMed

Ishaak, Fariel; de Vries, Nanne Karel; van der Wolf, Kees

2015-10-12

The aim of this study was to design the content and accompanying materials for a school-based program--Study without Drugs--for adolescents in junior secondary schools in Suriname based on the starting points and tasks of the fourth step of the Intervention Mapping protocol (which consists of six steps). A program based on this protocol should include a combination of theory, empirical evidence, and qualitative and quantitative research. Two surveys were conducted when designing the program. In Survey I, teachers and students were asked to complete a questionnaire to determine which school year they thought would be most appropriate for implementing a drug-prevention program for adolescents (we completed a similar survey as part of previous research). An attempt was made to identify suitable culturally sensitive elements to include in the program. In Survey II, the same teachers were asked to complete a questionnaire to determine the programs' scope, sequence, structure, and topics as well as the general didactic principles to serve as a basis for program design. After outlining the program plan, lessons, and materials, we conducted a formative pretest evaluation among teachers, students, and parents. That evaluation included measures related to the program's attractiveness, comprehensibility, and usefulness. The resulting lessons were presented to the teachers for assessment. The drug-prevention program we developed comprises 10 activities and lasts 2-2.5 months in an actual school setting. The activities take place during Dutch, biology, physical education, art, religion, and social studies lessons. We based the structure of the lessons in the program on McGuire's Persuasion Communication Model, which takes into account important didactic principles. Evaluations of the program materials and lesson plans by students, teachers, and parents were mostly positive. We believe that using the fourth step of the Intervention Mapping protocol to develop a drug-prevention intervention for adolescents has a produced promising, feasible program.
European perspectives on pediatric formulations.

PubMed

Breitkreutz, Jörg

2008-11-01

The 2007 European Union (EU) regulation on medicinal products for pediatric use may change the present unsatisfying situation in the EU by stimulating research and development of medicines for use in children through rewards and incentives. This commentary reflects on the new EU regulations and guidelines, with special attention paid to the impact on pediatric formulation science. The focus of this article is on the EU perspective for pediatric formulations and highlights the differences compared with the pediatric drug formulation situation in the United States. Materials for this article were gathered during a literature search of MEDLINE and Chemical Abstracts (1970-October 2008) using the following terms: paediatric/pediatric drug formulations, age-appropriate dosage forms, child-appropriate medicines, and paediatric/pediatric regulation. Since the EU legislation on medicines for children came into force in 2007, a great emphasis has been placed on creating new organizations, scientific networks, and programs dealing with pediatric medicines and child-appropriate drug formulations. Although the US legislation was an appropriate model, the EU introduced some novel measures to improve the current situation, such as the Paediatric Investigation Plan and the Paediatric Use Marketing Authorisation. For globally operating pharmaceutical companies, the peculiarities of the European market have a strong impact on their product development strategies. Because the European approach demands early investigations into drug formulations for children, various issues must be resolved, including the following: choosing formulations for each age group, determining which excipients may be used in the formulation and which delivery device is appropriate, and predicting the taste sensation of an oral formulation. Numerous initiatives and networks are evolving in Europe. An important future task will be the coordination of these activities and the linking to other groups working on pediatric formulations outside the EU. Similar to the research in pediatric drug formulations that was stimulated by the US legislation and incentives of the last decade, the 2007 EU legislation promises improvements in the availability of child-appropriate drugs in Europe.
Development and implementation of clinical algorithms in occupational health practice.

PubMed

Ghafur, Imran; Lalloo, Drushca; Macdonald, Ewan B; Menon, Manju

2013-12-01

Occupational health (OH) practice is framed by legal, ethical, and regulatory requirements. Integrating this information into daily practice can be a difficult task. We devised evidence-based framework standards of good practice that would aid clinical management, and assessed their impact. The clinical algorithm was the method deemed most appropriate to our needs. Using "the first OH consultation" as an example, the development, implementation, and evaluation of an algorithm is described. The first OH consultation algorithm was developed. Evaluation demonstrated an overall improvement in recording of information, specifically consent, recreational drug history, function, and review arrangements. Clinical algorithms can be a method for assimilating and succinctly presenting the various facets of OH practice, for use by all OH clinicians as a practical guide and as a way of improving quality in clinical record-keeping.
Effect of Combined Treatment with AT1 Receptor Antagonists and Tiagabine on Seizures, Memory and Motor Coordination in Mice.

PubMed

Łukawski, Krzysztof; Janowska, Agnieszka; Czuczwar, Stanisław J

2015-01-01

Losartan and telmisartan, angiotensin AT1 receptor antagonists, are widely used antihypertensive drugs in patients. It is also known that arterial hypertension is often present in people with epilepsy, therefore, drug interactions between AT1 receptor antagonists and antiepileptic drugs can occur in clinical practice. The aim of the current study was to assess the effect of losartan and telmisartan on the anticonvulsant activity of tiagabine, a second-generation antiepileptic drug, in mice. Additionally, the effect of the combined treatment with AT1 receptor antagonists and TGB on long-term memory and motor coordination has been assessed in animals. The study was performed on male Swiss mice. Convulsions were examined in the maximal electroshock seizure threshold test. Long-term memory was measured in the passive-avoidance task and motor coordination was evaluated in the chimney test. AT1 receptor antagonists and TGB were administered intraperitoneally. Losartan (50 mg/kg) or telmisartan (30 mg/kg) did not influence the anticonvulsant activity of TGB applied at doses of 2, 4 and 6 mg/kg. However, both AT1 receptor antagonists in combinations with TGB (6 mg/kg) impaired motor coordination in the chimney test. The concomitant treatment of the drugs did not decrease retention in the passive avoidance task. It is suggested that losartan and telmisartan should not affect the anticonvulsant action of TGB in people with epilepsy. Because the combined treatment with AT1 receptor antagonists and TGB led to neurotoxic effects in animals, caution is advised during concomitant use of these drugs in patients.
Using an in Silico Approach to Teach 3D Pharmacodynamics of the Drug-Target Interaction Process Focusing on Selective COX2 Inhibition by Celecoxib

ERIC Educational Resources Information Center

Tavares, Maurício T.; Primi, Marina C.; Silva, Nuno A. T. F.; Carvalho, Camila F.; Cunha, Micael R.; Parise-Filho, Roberto

2017-01-01

Teaching the molecular aspects of drug-target interactions and selectivity is not always an easy task. In this context, the use of alternative and engaging approaches could help pharmacy and chemistry students better understand this important topic of medicinal chemistry. Herein a 4 h practical exercise that uses freely available software as a…

A System Approach to Navy Medical Education and Training. Appendix 2. Task Inventory Booklet (Form N21-Physicians).

DTIC Science & Technology

1974-08-31

STOREC PROPERLY 37 ICHECK INSTRUMENTS ANn SUPPLIES FOR STERILIZATION INDICATORS 38 IDETERMINE ADEQUACY OF STERILIZATION PROCEDURES 39 IINSPECT SUPPLIES...NARCOTICS/CONTROLLED DRUGS/ALCOHCL TO WARO/CLINIC/OTHER IDEPARTMENTS 5 ISEARCH FOR UNACCOUNTABLE WARD/CLINIC NARCOTICSICONTPOLLED DRUGS 6 ICHECK ...SOURCES OF BACTERIAL CONTAMINATICN 30 IREVIEW -ND EVALUATE ASEPTIC TECHNIQUES 31 IINSPECT SPACES FOR INSECT INFESTATION 32 ICHECK EQUIPMENT FCR
A Constraint Generation Approach to Learning Stable Linear Dynamical Systems

DTIC Science & Technology

2008-01-01

task of learning dynamic textures from image sequences as well as to modeling biosurveillance drug-sales data. The constraint generation approach...previous methods in our experiments. One application of LDSs in computer vision is learning dynamic textures from video data [8]. An advantage of...over-the-counter (OTC) drug sales for biosurveillance , and sunspot numbers from the UCR archive [9]. Comparison to the best alternative methods [7, 10
Memory modulation across neural systems: intra-amygdala glucose reverses deficits caused by intraseptal morphine on a spatial task but not on an aversive task.

PubMed

McNay, E C; Gold, P E

1998-05-15

Based largely on dissociations of the effects of different lesions on learning and memory, memories for different attributes appear to be organized in independent neural systems. Results obtained with direct injections of drugs into one brain region at a time support a similar conclusion. The present experiments investigated the effects of simultaneous pharmacological manipulation of two neural systems, the amygdala and the septohippocampal system, to examine possible interactions of memory modulation across systems. Morphine injected into the medial septum impaired memory both for avoidance training and during spontaneous alternation. When glucose was concomitantly administered to the amygdala, glucose reversed the morphine-induced deficits in memory during alternation but not for avoidance training. These results suggest that the amygdala is involved in modulation of spatial memory processes and that direct injections of memory-modulating drugs into the amygdala do not always modulate memory for aversive events. These findings are contrary to predictions from the findings of lesion studies and of studies using direct injections of drugs into single brain areas. Thus, the independence of neural systems responsible for processing different classes of memory is less clear than implied by studies using lesions or injections of drugs into single brain areas.
Executive control deficits in substance-dependent individuals: a comparison of alcohol, cocaine, and methamphetamine and of men and women.

PubMed

van der Plas, Ellen A A; Crone, Eveline A; van den Wildenberg, Wery P M; Tranel, Daniel; Bechara, Antoine

2009-08-01

Substance dependence is associated with executive function deficits, but the nature of these executive defects and the effect that different drugs and sex have on these defects have not been fully clarified. Therefore, we compared the performance of alcohol- (n = 33; 18 women), cocaine- (n = 27; 14 women), and methamphetamine-dependent individuals (n = 38; 25 women) with sex-matched healthy comparisons (n = 36; 17 women) on complex decision making as measured with the Iowa Gambling Task, working memory, cognitive flexibility, and response inhibition. Cocaine- and methamphetamine-dependent individuals were impaired on complex decision making, working memory, and cognitive flexibility, but not on response inhibition. The deficits in working memory and cognitive flexibility were milder than the decision-making deficits and did not change as a function of memory load or task switching. Interestingly, decision making was significantly more impaired in women addicted to cocaine or methamphetamine than in men addicted to these drugs. Together, these findings suggest that drug of choice and sex have different effects on executive functioning, which, if replicated, may help tailor intervention.
Effects of signal salience and noise on performance and stress in an abbreviated vigil

NASA Astrophysics Data System (ADS)

Helton, William Stokely

Vigilance or sustained attention tasks traditionally require observers to detect predetermined signals that occur unpredictably over periods of 30 min to several hours (Warm, 1984). These tasks are taxing and have been useful in revealing the effects of stress agents, such as infectious disease and drugs, on human performance (Alluisi, 1969; Damos & Parker, 1994; Warm, 1993). However, their long duration has been an inconvenience. Recently, Temple and his associates (Temple et al., 2000) developed an abbreviated 12-min vigilance task that duplicates many of the findings with longer duration vigils. The present study was designed to explore further the similarity of the abbreviated task to long-duration vigils by investigating the effects of signal salience and jet-aircraft engine noise on performance, operator stress, and coping strategies. Forty-eight observers (24 males and 24 females) were assigned at random to each of four conditions resulting from the factorial combination of signal salience (high and low contrast signals) and background noise (quiet and jet-aircraft noise). As is the case with long-duration vigils (Warm, 1993), signal detection in the abbreviated task was poorer for low salience than for high salience signals. In addition, stress scores, as indexed by the Dundee Stress State Questionnaire (Matthews, Joiner, Gilliland, Campbell, & Falconer, 1999), were elevated in the low as compared to the high salience condition. Unlike longer vigils, however, (Becker, Warm, Dember, & Hancock, 1996), signal detection in the abbreviated task was superior in the presence of aircraft noise than in quiet. Noise also attenuated the stress of the vigil, a result that is counter to previous findings regarding the effects of noise in a variety of other scenarios (Clark, 1984). Examination of observers' coping responses, as assessed by the Coping Inventory for Task Situations (Matthews & Campbell, 1998), indicated that problem-focused coping was the overwhelming coping strategy adopted by observers in the study and that the level of this coping strategy increased in noise. The beneficial effects of jet-aircraft noise for the abbreviated task differentiates it from longer vigilance tasks and suggests that noise may have short-term positive value in vigilance.
Behavioral toxicology of cognition: extrapolation from experimental animal models to humans: behavioral toxicology symposium overview.

PubMed

Paule, Merle G; Green, Leonard; Myerson, Joel; Alvarado, Maria; Bachevalier, Jocelyne; Schneider, Jay S; Schantz, Susan L

2012-03-01

A variety of behavioral instruments are available for assessing important aspects of cognition in both animals and humans and, in many cases, the same instruments can be used in both. While nonhuman primates are phylogenetically closest to humans, rodents, pigeons and other animals also offer behaviors worthy of note. Delay Discounting procedures are as useful as any in studies of impulsivity and may have utility in shedding light on processes associated with drug abuse. Specific memory tests such as Visual Paired Comparisons tasks (similar to the Fagan test of infant intelligence) can be modified to allow for assessment of different aspects of memory such as spatial memory. Use of these and other specific memory tasks can be used to directly monitor aspects of cognitive development in infant animals, particularly in nonhuman primates such as monkeys, and children and to draw inferences with respect to possible neuroanatomical substrates sub-serving their functions. Tasks for assessing working memory such as Variable Delayed Response (VDR), modified VDR and Spatial Working Memory tasks are now known to be affected in Parkinson's disease (PD). These and other cognitive function tasks are being used in a monkey model of PD to assess the ability of anti-Parkinson's disease therapies to ameliorate these cognitive deficits without diminishing their therapeutic effects on motor dysfunction. Similarly, in a rat model of the cognitive deficits associated with perinatal exposure to polychlorinated biphenyls (PCBs), clear parallels with children can be seen in at least two areas of executive function: cognitive flexibility and response inhibition. In the rat model, discrimination reversal tasks were utilized to assess cognitive flexibility, a function often assessed in humans using the Wisconsin Card Sorting Task. Response inhibition was assessed using performance in a Differential Reinforcement of Low Response Rates (DRL) task. As the data continue to accumulate, it becomes more clear that our attempts to adapt animal-appropriate tasks for the study of important aspects of human cognition have proven to be very fruitful. Published by Elsevier Inc.
Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.

PubMed

Koek, Wouter; Gerak, Lisa R; France, Charles P

2015-08-01

In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9)-tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks.
Boosting drug named entity recognition using an aggregate classifier.

PubMed

Korkontzelos, Ioannis; Piliouras, Dimitrios; Dowsey, Andrew W; Ananiadou, Sophia

2015-10-01

Drug named entity recognition (NER) is a critical step for complex biomedical NLP tasks such as the extraction of pharmacogenomic, pharmacodynamic and pharmacokinetic parameters. Large quantities of high quality training data are almost always a prerequisite for employing supervised machine-learning techniques to achieve high classification performance. However, the human labour needed to produce and maintain such resources is a significant limitation. In this study, we improve the performance of drug NER without relying exclusively on manual annotations. We perform drug NER using either a small gold-standard corpus (120 abstracts) or no corpus at all. In our approach, we develop a voting system to combine a number of heterogeneous models, based on dictionary knowledge, gold-standard corpora and silver annotations, to enhance performance. To improve recall, we employed genetic programming to evolve 11 regular-expression patterns that capture common drug suffixes and used them as an extra means for recognition. Our approach uses a dictionary of drug names, i.e. DrugBank, a small manually annotated corpus, i.e. the pharmacokinetic corpus, and a part of the UKPMC database, as raw biomedical text. Gold-standard and silver annotated data are used to train maximum entropy and multinomial logistic regression classifiers. Aggregating drug NER methods, based on gold-standard annotations, dictionary knowledge and patterns, improved the performance on models trained on gold-standard annotations, only, achieving a maximum F-score of 95%. In addition, combining models trained on silver annotations, dictionary knowledge and patterns are shown to achieve comparable performance to models trained exclusively on gold-standard data. The main reason appears to be the morphological similarities shared among drug names. We conclude that gold-standard data are not a hard requirement for drug NER. Combining heterogeneous models build on dictionary knowledge can achieve similar or comparable classification performance with that of the best performing model trained on gold-standard annotations. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery.

PubMed

Plichta, Michael M; Schwarz, Adam J; Grimm, Oliver; Morgen, Katrin; Mier, Daniela; Haddad, Leila; Gerdes, Antje B M; Sauer, Carina; Tost, Heike; Esslinger, Christine; Colman, Peter; Wilson, Frederick; Kirsch, Peter; Meyer-Lindenberg, Andreas

2012-04-15

Even more than in cognitive research applications, moving fMRI to the clinic and the drug development process requires the generation of stable and reliable signal changes. The performance characteristics of the fMRI paradigm constrain experimental power and may require different study designs (e.g., crossover vs. parallel groups), yet fMRI reliability characteristics can be strongly dependent on the nature of the fMRI task. The present study investigated both within-subject and group-level reliability of a combined three-task fMRI battery targeting three systems of wide applicability in clinical and cognitive neuroscience: an emotional (face matching), a motivational (monetary reward anticipation) and a cognitive (n-back working memory) task. A group of 25 young, healthy volunteers were scanned twice on a 3T MRI scanner with a mean test-retest interval of 14.6 days. FMRI reliability was quantified using the intraclass correlation coefficient (ICC) applied at three different levels ranging from a global to a localized and fine spatial scale: (1) reliability of group-level activation maps over the whole brain and within targeted regions of interest (ROIs); (2) within-subject reliability of ROI-mean amplitudes and (3) within-subject reliability of individual voxels in the target ROIs. Results showed robust evoked activation of all three tasks in their respective target regions (emotional task=amygdala; motivational task=ventral striatum; cognitive task=right dorsolateral prefrontal cortex and parietal cortices) with high effect sizes (ES) of ROI-mean summary values (ES=1.11-1.44 for the faces task, 0.96-1.43 for the reward task, 0.83-2.58 for the n-back task). Reliability of group level activation was excellent for all three tasks with ICCs of 0.89-0.98 at the whole brain level and 0.66-0.97 within target ROIs. Within-subject reliability of ROI-mean amplitudes across sessions was fair to good for the reward task (ICCs=0.56-0.62) and, dependent on the particular ROI, also fair-to-good for the n-back task (ICCs=0.44-0.57) but lower for the faces task (ICC=-0.02-0.16). In conclusion, all three tasks are well suited to between-subject designs, including imaging genetics. When specific recommendations are followed, the n-back and reward task are also suited for within-subject designs, including pharmaco-fMRI. The present study provides task-specific fMRI reliability performance measures that will inform the optimal use, powering and design of fMRI studies using comparable tasks. Copyright Â© 2012 Elsevier Inc. All rights reserved.
Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users.

PubMed

Childs, Emma; de Wit, Harriet

2006-05-01

Caffeine produces mild psychostimulant effects that are thought to underlie its widespread use. However, the direct effects of caffeine are difficult to evaluate in regular users of caffeine because of tolerance and withdrawal. Indeed, some researchers hypothesize that the psychostimulant effects of caffeine are due largely to the reversal of withdrawal and question whether there are direct effects of caffeine consumption upon mood, alertness, or mental performance in nondependent individuals. This study investigated the physiological, subjective, and behavioral effects of 0, 50, 150, and 450 mg caffeine in 102 light, nondependent caffeine users. Using a within-subjects design, subjects participated in four experimental sessions, in which they received each of the four drug conditions in random order under double blind conditions. Participants completed subjective effects questionnaires and vital signs were measured before and at repeated time points after drug administration. Forty minutes after the capsules were ingested, subjects completed behavioral tasks that included tests of sustained attention, short-term memory, psychomotor performance, and behavioral inhibition. Caffeine significantly increased blood pressure, and produced feelings of arousal, positive mood, and high. Caffeine increased the number of hits and decreased reaction times in a vigilance task, but impaired performance on a memory task. We confirm that acute doses of caffeine, at levels typically found in a cup of coffee, produce stimulant-like subjective effects and enhance performance in light, nondependent caffeine users. These findings support the idea that the drug has psychoactive effects even in the absence of withdrawal.
Ensuring that consumers receive appropriate information from drug ads: what is the FDA's role?

PubMed

Waxman, Henry A

2004-01-01

The promise of direct-to-consumer (DTC) prescription drug advertisements lies in their potential to educate consumers about medical conditions and the possibility of treatment. But this promise can only be fulfilled if consumers are given clear and accurate information. The responsibility for ensuring that this occurs falls on the Food and Drug Administration (FDA). Recent congressional investigations have indicated that the agency is failing at this task, as FDA enforcement actions against false and misleading ads have declined precipitously in recent years. Other FDA efforts, such as its recently released guidelines on prescription drugs, do not appear to be helpful, potentially confusing consumers more than helping them.
[How I treat: from specialized pharmacology to drug therapy: a plea for an optimal educational program for rational therapeutics, from decision making to drug prescription].

PubMed

Scheen, A J

2000-09-01

Clinical pharmacology and therapeutics are two complementary disciplines which should lead the medical student, through an optimized training, to a rational prescription of drugs, ultimate and important step of the medical approach. Such a learning should occur progressively throughout the medical education, focusing, first, on the therapeutic reasoning ("why?") and, second, on the practical application leading to the prescription ("how?"). The medical student should learn the difficult task of integrating disease, drug and patient, in order to optimize the benefit/risk ratio, while being informed about new concepts such as "Evidence-Based Medicine" and pharmacoeconomics.
Rapid inverse planning for pressure-driven drug infusions in the brain.

PubMed

Rosenbluth, Kathryn H; Martin, Alastair J; Mittermeyer, Stephan; Eschermann, Jan; Dickinson, Peter J; Bankiewicz, Krystof S

2013-01-01

Infusing drugs directly into the brain is advantageous to oral or intravenous delivery for large molecules or drugs requiring high local concentrations with low off-target exposure. However, surgeons manually planning the cannula position for drug delivery in the brain face a challenging three-dimensional visualization task. This study presents an intuitive inverse-planning technique to identify the optimal placement that maximizes coverage of the target structure while minimizing the potential for leakage outside the target. The technique was retrospectively validated using intraoperative magnetic resonance imaging of infusions into the striatum of non-human primates and into a tumor in a canine model and applied prospectively to upcoming human clinical trials.
Medication competency of nurses according to theoretical and drug calculation online exams: A descriptive correlational study.

PubMed

Sneck, Sami; Saarnio, Reetta; Isola, Arja; Boigu, Risto

2016-01-01

Medication administration is an important task of registered nurses. According to previous studies, nurses lack theoretical knowledge and drug calculation skills and knowledge-based mistakes do occur in clinical practice. Finnish health care organizations started to develop a systematic verification processes for medication competence at the end of the last decade. No studies have yet been made of nurses' theoretical knowledge and drug calculation skills according to these online exams. The aim of this study was to describe the medication competence of Finnish nurses according to theoretical and drug calculation exams. A descriptive correlation design was adopted. Participants and settings All nurses who participated in the online exam in three Finnish hospitals between 1.1.2009 and 31.05.2014 were selected to the study (n=2479). Quantitative methods like Pearson's chi-squared tests, analysis of variance (ANOVA) with post hoc Tukey tests and Pearson's correlation coefficient were used to test the existence of relationships between dependent and independent variables. The majority of nurses mastered the theoretical knowledge needed in medication administration, but 5% of the nurses struggled with passing the drug calculation exam. Theoretical knowledge and drug calculation skills were better in acute care units than in the other units and younger nurses achieved better results in both exams than their older colleagues. The differences found in this study were statistically significant, but not high. Nevertheless, even the tiniest deficiency in theoretical knowledge and drug calculation skills should be focused on. It is important to identify the nurses who struggle in the exams and to plan targeted educational interventions for supporting them. The next step is to study if verification of medication competence has an effect on patient safety. Copyright © 2015 Elsevier Ltd. All rights reserved.
Communications System Architecture Development for Air Traffic Management and Aviation Weather Information Dissemination

NASA Technical Reports Server (NTRS)

Gallagher, Seana; Olson, Matt; Blythe, Doug; Heletz, Jacob; Hamilton, Griff; Kolb, Bill; Homans, Al; Zemrowski, Ken; Decker, Steve; Tegge, Cindy

2000-01-01

This document is the NASA AATT Task Order 24 Final Report. NASA Research Task Order 24 calls for the development of eleven distinct task reports. Each task was a necessary exercise in the development of comprehensive communications systems architecture (CSA) for air traffic management and aviation weather information dissemination for 2015, the definition of the interim architecture for 2007, and the transition plan to achieve the desired End State. The eleven tasks are summarized along with the associated Task Order reference. The output of each task was an individual task report. The task reports that make up the main body of this document include Task 5, Task 6, Task 7, Task 8, Task 10, and Task 11. The other tasks provide the supporting detail used in the development of the architecture. These reports are included in the appendices. The detailed user needs, functional communications requirements and engineering requirements associated with Tasks 1, 2, and 3 have been put into a relational database and are provided electronically.
Neural mechanisms of working memory in ecstasy (MDMA) users who continue or discontinue ecstasy and amphetamine use: evidence from an 18-month longitudinal functional magnetic resonance imaging study.

PubMed

Daumann, Jörg; Fischermann, Thomas; Heekeren, Karsten; Thron, Armin; Gouzoulis-Mayfrank, Euphrosyne

2004-09-01

Working memory processing in ecstasy (3,4-methylenedioxymethamphetamine) users is associated with neural alterations as measured by functional magnetic resonance imaging. Here, we examined whether cortical activation patterns change after prolonged periods of continued use or abstinence from ecstasy and amphetamine. We used an n-back task and functional magnetic resonance imaging in 17 ecstasy users at baseline (t(1)) and after 18 months (t(2)). Based on the reported drug use at t(2) we separated subjects with continued ecstasy and amphetamine use from subjects reporting abstinence during the follow-up period (n = 9 and n = 8, respectively). At baseline both groups had similar task performance and similar cortical activation patterns. Task performance remained unchanged in both groups. Furthermore, there were no detectable functional magnetic resonance imaging signal changes from t(1) to t(2) in the follow-up abstinent group. However, the continuing users showed a dose-dependent increased parietal activation for the 2-back task after the follow-up period. Our data suggest that ecstasy use, particularly in high doses, is associated with greater parietal activation during working memory performance. An altered activation pattern might appear before changes in cognitive performance become apparent and, hence, may reflect an early stage of neuronal injury from the neurotoxic drug ecstasy.
Acute effects of the designer drugs benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) using functional magnetic resonance imaging (fMRI) and the Stroop task--a pilot study.

PubMed

Curley, Louise E; Kydd, Rob R; Robertson, Michelle C; Pillai, Avinesh; McNair, Nicolas; Lee, HeeSeung; Kirk, Ian J; Russell, Bruce R

2015-08-01

A novel group of designer drugs containing benzylpiperazine (BZP) and/or trifluoromethylphenylpiperazine (TFMPP) have been available worldwide for more than a decade; however, their effects on human brain function have not been extensively described. In a double-blind, placebo-controlled crossover study, the acute effects of BZP and TFMPP (alone and in combination) on the neural networks involved in executive function were investigated using an event-related Stroop functional magnetic resonance imaging (fMRI) paradigm. Thirteen healthy participants aged 18-40 years undertook the Stroop task 90 min after taking an oral dose of either BZP (200 mg), TFMPP (either 50 or 60 mg), BZP + TFMPP (100 + 30 mg) or placebo. A change in activity in neural regions reflects an increase in local demand for oxygen, due to an increase in neuronal activity. Relative to placebo, an increase in neural activation was observed in the dorsal striatum following BZP, and in the thalamus following TFMPP, when performing the Stroop task. These data suggest that additional compensatory resources were recruited to maintain performance during the Stroop task. When BZP and TFMPP were administered together, both the dorsal striatum and thalamus were activated. However, the combination of BZP/TFMPP attenuated activation in the caudate, possibly due to TFMPP's indirect effects on dopamine release via 5HT2C receptors.
Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study.

PubMed

Bolstad, Ingeborg; Andreassen, Ole A; Groote, Inge; Server, Andres; Sjaastad, Ivar; Kapur, Shitij; Jensen, Jimmy

2015-12-01

The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
Selective attention to smoking cues in former smokers.

PubMed

Rehme, Anne K; Bey, Katharina; Frommann, Ingo; Mogg, Karin; Bradley, Brendan P; Bludau, Julia; Block, Verena; Sträter, Birgitta; Schütz, Christian G; Wagner, Michael

2018-02-01

Repeated drug use modifies the emotional and cognitive processing of drug-associated cues. These changes are supposed to persist even after prolonged abstinence. Several studies demonstrated that smoking cues selectively attract the attention of smokers, but empirical evidence for such an attentional bias among successful quitters is inconclusive. Here, we investigated whether attentional biases persist after smoking cessation. Thirty-eight former smokers, 34 current smokers, and 29 non-smokers participated in a single experimental session. We used three measures of attentional bias for smoking stimuli: A visual probe task with short (500ms) and long (2000ms) picture stimulus durations, and a modified Stroop task with smoking-related and neutral words. Former smokers and current smokers, as compared to non-smokers, showed an attentional bias in visual orienting to smoking pictures in the 500ms condition of the visual probe task. The Stroop interference index of smoking words was negatively related to nicotine dependence in current smokers. Former smokers and mildly dependent smokers, as compared to non-smokers, showed increased interference by smoking words in the Stroop task. Neither current nor former smokers showed an attentional bias in maintained attention (2000ms visual probe task). In conclusion, even after prolonged abstinence smoking cues retain incentive salience in former smokers, who differed from non-smokers on two attentional bias indices. Attentional biases in former smokers operate mainly in early involuntary rather than in controlled processing, and may represent a vulnerability factor for relapse. Therefore, smoking cessation programs should strengthen self-control abilities to prevent relapses. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.
Prediction of Drug-Target Interaction Networks from the Integration of Protein Sequences and Drug Chemical Structures.

PubMed

Meng, Fan-Rong; You, Zhu-Hong; Chen, Xing; Zhou, Yong; An, Ji-Yong

2017-07-05

Knowledge of drug-target interaction (DTI) plays an important role in discovering new drug candidates. Unfortunately, there are unavoidable shortcomings; including the time-consuming and expensive nature of the experimental method to predict DTI. Therefore, it motivates us to develop an effective computational method to predict DTI based on protein sequence. In the paper, we proposed a novel computational approach based on protein sequence, namely PDTPS (Predicting Drug Targets with Protein Sequence) to predict DTI. The PDTPS method combines Bi-gram probabilities (BIGP), Position Specific Scoring Matrix (PSSM), and Principal Component Analysis (PCA) with Relevance Vector Machine (RVM). In order to evaluate the prediction capacity of the PDTPS, the experiment was carried out on enzyme, ion channel, GPCR, and nuclear receptor datasets by using five-fold cross-validation tests. The proposed PDTPS method achieved average accuracy of 97.73%, 93.12%, 86.78%, and 87.78% on enzyme, ion channel, GPCR and nuclear receptor datasets, respectively. The experimental results showed that our method has good prediction performance. Furthermore, in order to further evaluate the prediction performance of the proposed PDTPS method, we compared it with the state-of-the-art support vector machine (SVM) classifier on enzyme and ion channel datasets, and other exiting methods on four datasets. The promising comparison results further demonstrate that the efficiency and robust of the proposed PDTPS method. This makes it a useful tool and suitable for predicting DTI, as well as other bioinformatics tasks.

One-step sonochemical synthesis of 1D β-stannous tungstate nanorods: An efficient and excellent electrocatalyst for the selective electrochemical detection of antipsychotic drug chlorpromazine.

PubMed

Kokulnathan, Thangavelu; Kumar, Jeyaraj Vinoth; Chen, Shen-Ming; Karthik, Raj; Elangovan, Arumugam; Muthuraj, Velluchamy

2018-06-01

In the modern world, the contamination of ecosystem by human and veterinary pharmaceutical drugs through the metabolic excretion, improper disposal/industrial waste has been subjected to a hot issue. Therefore, exploitation of exclusive structured material and reliable technique is a necessary task to the precise detection of drugs. With this regards, we made an effort for the fabrication of novel one-dimensional (1D) stannous tungstate nanorods (β-SnW NRs) via simple sonochemical approach and used as an electrochemical sensor for the detection of antipsychotic drug chlorpromazine (CPZ) for the first time. The crystallographic structure, surface topology, elemental compositions and their distributions and ionic states were enquired by different spectroscopic techniques such as XRD, FTIR, SEM, EDS, elemental mapping and XPS analysis. The developed β-SnW NRs/GCE sensor exhibits a rapid and sensitive electrochemical response towards CPZ sensing with wide linear response range (0.01-457 µM), high sensitivity (2.487 µA µM -1  cm -2 ), low detection limit (0.003 µM) and excellent selectivity. Besides, the as-proposed electrochemical sensor was successfully applied to real sample analysis in commercial CPZ drug and biological fluids and the acquired recovery results are quite satisfactory. The proposed sonochemical method for the preparation of β-SnW NRs is low cost, very simple, fast and efficient for sensor applications. Copyright © 2018 Elsevier B.V. All rights reserved.
Interactions between ACE inhibitors and classical antiepileptic drugs in the mouse maximal electroshock seizures.

PubMed

Łukawski, Krzysztof; Jakubus, Tomasz; Janowska, Agnieszka; Czuczwar, Stanisław J

2011-11-01

This study evaluated the effect of two angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, commonly used antihypertensive drugs, on the protective efficacy of the classical antiepileptics - carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB). For this purpose, we used the maximal electroshock seizure (MES) test in mice. Additionally, adverse effects of combined treatment with ACE inhibitors and antiepileptic drugs in the passive avoidance task and chimney test were assessed. All drugs were administered intraperitoneally. Neither enalapril (10, 20 and 30 mg/kg) nor cilazapril (5, 10 and 20mg/kg) affected the threshold for electroconvulsions. Enalapril (30 mg/kg) but not cilazapril (20mg/kg), enhanced the protective action of VPA, decreasing its ED(50) value from 249.5 to 164.9 mg/kg (p<0.01). Free plasma (non-protein-bound) and total brain concentrations of VPA were not significantly influenced by enalapril. Therefore, the observed interaction could be pharmacodynamic in nature. The combinations of ACE inhibitors with other antiepileptics (CBZ, PHT, and PB) were ineffective in that their ED(50) values against MES were not significantly changed. Enalapril and cilazapril remained ineffective as regards memory retention in the passive avoidance task or motor performance in the chimney test. The current study suggests that there are no negative interactions between the studied ACE inhibitors and classical antiepileptic drugs. Enalapril was even documented to enhance the anticonvulsant activity of VPA. Copyright © 2011 Elsevier Inc. All rights reserved.
TU-EF-210-01: HIFU, Drug Delivery, and Immunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrara, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less
Amphetamine primes motivation to gamble and gambling-related semantic networks in problem gamblers.

PubMed

Zack, Martin; Poulos, Constantine X

2004-01-01

Previous research suggests that gambling can induce effects that closely resemble a psychostimulant drug effect. Modest doses of addictive drugs can prime motivation for drugs with similar properties. Together, these findings imply that a dose of a psychostimulant drug could prime motivation to gamble in problem gamblers. This study assessed priming effects of oral D-amphetamine (AMPH) (30 mg) in a within-subject, counter-balanced, placebo-controlled design in problem gamblers (n=10), comorbid gamblerdrinkers (n=6), problem drinkers (n=8), and healthy controls (n=12). Modified visual analog scales assessed addictive motivation and subjective effects. A modified rapid reading task assessed pharmacological activation of words from motivationally relevant and irrelevant semantic domains (Gambling, Alcohol, Positive Affect, Negative Affect, Neutral). AMPH increased self-reported motivation for gambling in problem gamblers. Severity of problem gambling predicted positive subjective effects of AMPH and motivation to gamble under the drug. There was little evidence that AMPH directly primed motivation for alcohol in problem drinkers. On the reading task, AMPH produced undifferentiated improvement in reading speed to all word classes in Nongamblers. By contrast, in the two problem gambler groups, AMPH improved reading speed to Gambling words while profoundly slowing reading speed to motivationally irrelevant Neutral words. The latter finding was interpreted as directly congruent with models, which contend that priming of addictive motivation involves a linked suppression of motivationally irrelevant stimuli. This study provides experimental evidence that psychostimulant-like neurochemical activation is an important component of gambling addiction.
Short-term and long-term effects of diazepam on the memory for discrimination and generalization of scopolamine.

PubMed

Casasola-Castro, C; Weissmann-Sánchez, L; Calixto-González, E; Aguayo-Del Castillo, A; Velázquez-Martínez, D N

2017-10-01

Benzodiazepines are among the most widely prescribed and misused psychopharmaceutical drugs. Although they are well-tolerated, they are also capable of producing amnestic effects similar to those observed after pharmacological or organic cholinergic dysfunction. To date, the effect of benzodiazepine diazepam on the memory for discrimination of anticholinergic drugs has not been reported. The aim of the present study was to analyze the immediate and long-term effects of diazepam on a drug discrimination task with scopolamine. Male Wistar rats were trained to discriminate between scopolamine and saline administration using a two-lever discrimination task. Once discrimination was acquired, the subjects were divided into three independent groups, (1) control, (2) diazepam, and (3) diazepam chronic administration (10 days). Subsequently, generalization curves for scopolamine were obtained. Additionally, the diazepam and control groups were revaluated after 90 days without having been given any other treatment. The results showed that diazepam produced a significant reduction in the generalization gradient for scopolamine, indicating an impairment of discrimination. The negative effect of diazepam persisted even 90 days after drug had been administered. Meanwhile, the previous administration of diazepam for 10 days totally abated the generalization curve and the general performance of the subjects. The results suggest that diazepam affects memory for the stimulus discrimination of anticholinergic drugs and does so persistently, which could be an important consideration during the treatment of amnesic patients with benzodiazepines.
Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States. Vol. 47, No. RR-2

DTIC Science & Technology

1998-01-30

Science Center at Brooklyn Brooklyn, NY Angus Nicoll, M.D. PHLS Communicable Disease Surveillance Centre London, England MaryJoO’Sullivan, M.D...preliminary evaluation of genotypic resistance in pregnant women in PACTG 076, ZDV-resistant virus was present at delivery in only one of seven women who...developed genotypic resistance to ZDV during the study period did not transmit HIV-1 to her infant. In PACTG 076, similar rates of congenital abnormalities
Selection and utilization of assessment instruments in substance abuse treatment trials: the National Drug Abuse Treatment Clinical Trials Network experience.

PubMed

Rosa, Carmen; Ghitza, Udi; Tai, Betty

2012-07-17

Based on recommendations from a US Institute of Medicine report, the National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999, to accelerate the translation of science-based addiction treatment research into community-based practice, and to improve the quality of addiction treatment, using science as the vehicle. One of the CTN's primary tasks is to serve as a platform to forge bi-directional communications and collaborations between providers and scientists, to enhance the relevance of research, which generates empirical results that impact practice. Among many obstacles in moving research into real-world settings, this commentary mainly describes challenges and iterative experiences in regard to how the CTN develops its research protocols, with focus on how the CTN study teams select and utilize assessment instruments, which can reasonably balance the interests of both research scientists and practicing providers when applied in CTN trials. This commentary also discusses the process by which the CTN further selects a core set of common assessment instruments that may be applied across all trials, to allow easier cross-study analyses of comparable data.
Molecular Pathology: A Requirement for Precision Medicine in Cancer.

PubMed

Dietel, Manfred

2016-01-01

The increasing importance of targeting drugs and check-point inhibitors in the treatment of several tumor entities (breast, colon, lung, malignant melanoma, lymphoma, etc.) and the necessity of a companion diagnostic (HER2, (pan)RAS, EGFR, ALK, BRAF, ROS1, MET, PD-L1, etc.) is leading to new challenges for surgical pathology. Since almost all the biomarkers to be specifically detected are tissue based, a precise and reliable diagnostic is absolutely crucial. To meet this challenge surgical pathology has adapted a number of molecular methods (semi-quantitative immunohistochemistry, fluorescence in situ hybridization, PCR and its multiple variants, (pyro/Sanger) sequencing, next generation sequencing (amplicon, whole exome, whole genome), DNA arrays, methylation analyses, etc.) to be applicable for formalin-fixed paraffin-embedded tissue. Reading a patient's tissue as 'deeply' as possible and obtaining information on the morphological, genetic, proteomic and epigenetic background are the tasks of pathologists and molecular biologists and provide the clinicians with information relevant for precision medicine. Intensified cooperation between clinicians and pathologists will provide the basis of improved clinical drug selection and guide development of new cancer gene therapies and molecularly targeted drugs by research units and the pharmaceutical industry. © 2016 S. Karger GmbH, Freiburg.
Prenatal exposure to psychostimulants increases impulsivity, compulsivity, and motivation for rewards in adult mice.

PubMed

Lloyd, S A; Oltean, C; Pass, H; Phillips, B; Staton, K; Robertson, C L; Shanks, R A

2013-07-02

Given the widespread use and misuse of methamphetamine (METH) and methylphenidate (MPD), especially in relation to women of childbearing age, it is important to consider the long-lasting effects of these drugs on the brain of the developing fetus. Male and female C57Bl/6J mice were prenatally exposed to METH (5mg/kg), MPD (10mg/kg), or saline. Following a 3-month washout, behavioral analysis using the 5-Choice Serial Reaction Time Task (5CSRTT) was performed on adult mice. After reaching training criteria, performance on a pseudo-random intertrial interval test session revealed decrements in 5CSRTT behavior. Prenatally-treated METH and MPD mice demonstrated significant increases in impulsivity, compulsivity, and motivation for reward compared to their saline controls. There were sex by drug interactions indicating a possible sexually dimorphic response to these prenatal drug exposures. Of particular clinical interest, we find that mice prenatally exposed to METH or MPD express characteristics of both inhibitory control decrements and heightened motivation for rewards, which represent core symptoms of addiction and other impulse control disorders. Copyright © 2013 Elsevier Inc. All rights reserved.
Aerodynamics and deposition effects of inhaled submicron drug aerosol in airway diseases.

PubMed

Faiyazuddin, Md; Mujahid, Md; Hussain, Talib; Siddiqui, Hefazat H; Bhatnagar, Aseem; Khar, Roop K; Ahmad, Farhan J

2013-01-01

Particle engineering is the prime focus to improve pulmonary drug targeting with the splendor of nanomedicines. In recent years, submicron particles have emerged as prettyful candidate for improved fludisation and deposition. For effective deposition, the particle size must be in the range of 0.5-5 μm. Inhalers design for the purpose of efficient delivery of powders to lungs is again a crucial task for pulmonary scientists. A huge number of DPI devices exist in the market, a significant number are awaiting FDA approval, some are under development and a large number have been patented or applied for patent. Even with superior design, the delivery competence is still deprived, mostly due to fluidisation problems which cause poor aerosol generation and deposition. Because of the cohesive nature and poor flow characteristics, they are difficult to redisperse upon aerosolization with breath. These problems are illustrious in aerosol research, much of which is vastly pertinent to pulmonary therapeutics. A technical review is presented here of advances that have been utilized in production of submicron drug particles, their in vitro/in vivo evaluations, aerosol effects and pulmonary fate of inhaled submicron powders.
Place and direction learning in a spatial T-maze task by neonatal piglets

PubMed Central

Elmore, Monica R. P.; Dilger, Ryan N.; Johnson, Rodney W.

2013-01-01

Pigs are a valuable animal model for studying neurodevelopment in humans due to similarities in brain structure and growth. The development and validation of behavioral tests to assess learning and memory in neonatal piglets are needed. The present study evaluated the capability of 2-wk old piglets to acquire a novel place and direction learning spatial T-maze task. Validity of the task was assessed by the administration of scopolamine, an anti-cholinergic drug that acts on the hippocampus and other related structures, to impair spatial memory. During acquisition, piglets were trained to locate a milk reward in a constant place in space, as well as direction (east or west), in a plus-shaped maze using extra-maze visual cues. Following acquisition, reward location was reversed and piglets were re-tested to assess learning and working memory. The performance of control piglets in the maze improved over time (P < 0.0001), reaching performance criterion (80% correct) on day 5 of acquisition. Correct choices decreased in the reversal phase (P < 0.0001), but improved over time. In a separate study, piglets were injected daily with either phosphate buffered saline (PBS; control) or scopolamine prior to testing. Piglets administered scopolamine showed impaired performance in the maze compared to controls (P = 0.03), failing to reach performance criterion after 6 days of acquisition testing. Collectively, these data demonstrate that neonatal piglets can be tested in a spatial T-maze task to assess hippocampal-dependent learning and memory. PMID:22526690
Sex differences in chronic stress effects on cognition in rodents

PubMed Central

Luine, Victoria; Gomez, Juan; Beck, Kevin; Bowman, Rachel

2016-01-01

Chronic stress causes deleterious changes in physiological function in systems ranging from neural cells in culture to laboratory rodents, sub-human primates and humans. It is notable, however, that the vast majority of research in this area has been conducted in males. In this review, we provide information about chronic stress effects on cognition in female rodents and contrast it with responses in male rodents. In general, females show cognitive resilience to chronic stressors which impair male cognitive function using spatial tasks including the radial arm maze, radial arm water maze, Morris water maze, Y-maze and object placement. Moreover, stress often enhances female performance in some of these cognitive tasks. Memory in females is not affected by stress in non-spatial memory tasks like recognition memory and temporal order recognition memory while males show impaired memory following stress. We discuss possible bases for these sex-dependent differences including the use of different strategies by the sexes to solve cognitive tasks. Whether the sex differences result from changes in non-mnemonic factors is also considered. Sex-dependent differences in alcohol and drug influences on stress responses are also described. Finally, the role of neurally derived estradiol in driving sex differences and providing resilience to stress in females is shown. The importance of determining the nature and extent of sex differences in stress responses is that such differences may provide vital information for understanding why some stress related diseases have different incidence rates between the sexes and for developing novel therapeutic treatments. PMID:27566290
Initial development of the Systems Approach to Home Medication Management (SAHMM) model.

PubMed

Doucette, William R; Vinel, Shanrae'l; Pennathur, Priyadarshini

Adverse drug events and medication nonadherence are two problems associated with prescription medication use for chronic conditions. These issues often develop because patients have difficulty managing their medications at home. To guide patients and providers for achieving safe and effective medication use at home, the Systems Approach to Home Medication Management (SAHMM) model was derived from a systems engineering model for health care workplace safety. To explore how well concepts from the SAHMM model can represent home medication management by using patient descriptions of how they take prescription medications at home. Twelve patients were interviewed about home medication management using an interview guide based on the factors of the SAHMM model. Each interview was audio-taped and then transcribed verbatim. Interviews were coded to identify themes for home medication management using MAXQDA for Windows. SAHMM concepts extracted from the coded interview transcripts included work system components of person, tasks, tools & technology, internal environment, external environment, and household. Concepts also addressed work processes and work outcomes for home medication management. Using the SAHMM model for studying patients' home medication management is a promising approach to improving our understanding of the factors that influence patient adherence to medication and the development of adverse drug events. Copyright Â© 2016 Elsevier Inc. All rights reserved.
The process of collecting and evaluating evidences for the development of Guidelines for the management of rheumatoid arthritis, Japan College of Rheumatology 2014: Utilization of GRADE approach.

PubMed

Kojima, Masayo; Nakayama, Takeo; Kawahito, Yutaka; Kaneko, Yuko; Kishimoto, Mitsumasa; Hirata, Shintaro; Seto, Yohei; Endo, Hirahito; Ito, Hiromu; Kojima, Toshihisa; Nishida, Keiichiro; Matsushita, Isao; Tsutani, Kiichiro; Igarashi, Ataru; Kamatani, Naoyuki; Hasegawa, Mieko; Miyasaka, Nobuyuki; Yamanaka, Hisashi

2016-01-01

To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan. The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003-2012). A questionnaire survey and focus group interview were performed to capture the patients' values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients. Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined. Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.
Comparative Effects of Antihistamines on Aircrew Performance of Simple and Complex Tasks Under Sustained Operations

DTIC Science & Technology

1991-12-01

personnel by identifying the potential symptoms and side effects of each antihistamine and a lactose intolerance reaction. These "symptoms" were then...bachelors degree. All subjects were screened for current prescription medication use, history of antihistamine use, and known lactose sensitivity. Study...assigned drug condition (Seldane, Benadryl, or lactose placebo; see Table 1). Drug group assignment was double-blind. Neither the investigators nor the
Autophagy and TGF-Beta Antagonist Signaling in Breast Cancer Dormancy at Premetastatic Sites

DTIC Science & Technology

2015-06-01

blocking Coco and other players involved in reactivation of dormant legions. These inhibitors will be the drug leads for further medicinal chemistry and...blocking Coco and other players involved in reactivation of dormant legions. These inhibitors will be the drug leads for further medicinal chemistry and... protocol . Below we report our progress, starting with the SOW check list below followed by detailed description. Statement of Work (SOW): Task-1
The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

PubMed Central

Seymour, Lesley; Ivy, S. Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

2010-01-01

The optimal design of phase II studies continues to be the subject of vigorous debate, especially with regards to studies of newer molecularly targeted agents. The observations that many new therapeutics ‘fail’ in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials further emphasizes the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force(CTD-TF)of the NCI Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on Phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations regarding aspects of phase II trial design which are the subject of frequent debate such as endpoints(response vs. progression free survival), randomization(single arm designs vs. randomization), inclusion of biomarkers, biomarker based patient enrichment strategies, and statistical design(e.g. two stage designs vs. multiple-group adaptive designs). While these recommendations in general encourage the use of progression-free survival as the primary endpoint, the use of randomization, the inclusion of biomarkers and the incorporation of newer designs, we acknowledge that objective response as an endpoint, and single arm designs, remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on the characteristic specific to the situation. PMID:20215557
Pharmacy component of a hospital end-product cost-accounting system.

PubMed

Smith, J E; Sheaffer, S L; Meyer, G E; Giorgilli, F

1988-04-01

Determination of pharmacy department standard costs for providing drug products to patients at Thomas Jefferson University Hospital in Philadelphia is described. The hospital is implementing a cost-accounting system (CAS) that uses software developed at the New England Medical Center, Boston. The pharmacy identified nine categories of intermediate products on the basis of labor consumption. Standard labor times for each product category are based on measurement or estimation of time for each task in the preparation and distribution of a dose. Variable-labor standard time was determined by adjusting the cumulative time for the tasks to account for nonproductive time and nonroutine activities, and a variable-labor standard cost for each category was calculated. The standard cost per dose included the costs of labor and supplies (variable and fixed) and equipment; this standard cost plus the acquisition cost of a drug line item is the total intermediate product cost. Because the CAS is based on the hospital's patient charges, clinical pharmacy services are excluded. Intermediate products that substantially affect end-product costs (costs per patient case) will be identified for inclusion in CAS reports. The CAS will give a more accurate picture of resource consumption, enabling managers to focus their efforts to improve efficiency and productivity and reduce supply use; it could also improve the accuracy of the budgeting process. The CAS will support hospital administration decisions about marketing end products and department managers' decisions about controlling intermediate-product costs.
Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development.

PubMed

Wanigasekera, Vishvarani; Mezue, Melvin; Andersson, Jesper; Kong, Yazhuo; Tracey, Irene

2016-01-01

Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor. The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses. Only gabapentin suppressed the secondary mechanical hyperalgesia-evoked neural response in a region of the brainstem's descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6. Functional imaging with central sensitization can be used as a sensitive mechanism-based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.
Drug dosing in chronic kidney disease.

PubMed

Gabardi, Steven; Abramson, Stuart

2005-05-01

Patients with chronic kidney disease (CKD) are at high risk for adverse drug reactions and drug-drug interactions. Drug dosing in these patients often proves to be a difficult task. Renal dysfunction-induced changes in human pathophysiology regularly results may alter medication pharmacodynamics and handling. Several pharmacokinetic parameters are adversely affected by CKD, secondary to a reduced oral absorption and glomerular filtration; altered tubular secretion; and reabsorption and changes in intestinal, hepatic, and renal metabolism. In general, drug dosing can be accomplished by multiple methods; however, the most common recommendations are often to reduce the dose or expand the dosing interval, or use both methods simultaneously. Some medications need to be avoided all together in CKD either because of lack of efficacy or increased risk of toxicity. Nevertheless, specific recommendations are available for dosing of certain medications and are an important resource, because most are based on clinical or pharmacokinetic trials.

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