WorldWideScience

Sample records for drug response context

  1. Considering the context: social factors in responses to drugs in humans.

    Science.gov (United States)

    de Wit, Harriet; Sayette, Michael

    2018-04-01

    Drugs are typically used in social settings. Here, we consider two factors that may contribute to this observation: (i) the presence of other people may enhance the positive mood effects of a drug, and conversely, (ii) drugs may enhance the value of social stimuli. We review evidence from controlled laboratory studies with human volunteers, which investigated either of these interactions between social factors and responses to drugs. We examine the bidirectional effects of social stimuli and single doses of alcohol, stimulants, opioids, and cannabis. All four classes of drugs interact with social contexts, but the nature of these interactions varies across drugs, and depends on whether the context is positive or negative. Alcohol and stimulant drugs enhance the attractiveness of social stimuli and the desire to socialize, and social contexts, in turn, enhance these drugs' effects. In contrast, opioids and cannabis have subtler effects on social interactions and their effects are less influenced by the presence of others. Overall, there is stronger evidence that drugs enhance positive social contexts than that they dampen the negativity of unpleasant social settings. Controlled research is needed to understand the interactions between drugs of abuse and social contexts, to model and understand the determinants of drug use outside the laboratory.

  2. Diversity of contexts in drug use among street adolescents.

    Science.gov (United States)

    Goncalves de Moura, Yone; van der Meer Sanchez, Zila; Noto, Ana Regina

    2010-09-01

    In this study we aimed to investigate through ethnographic methods the different contexts of drug use by street adolescents in Sao Paulo, Brazil. Participant observations and semistructured interviews were performed at 11 major points of adolescent concentration in the streets of the city and in 10 care institutions. The sample was composed of 17 adolescents between 12 and 17 years of age. Data showed diverse patterns of drug use distributed by geographic situation and street circumstances. Observations were grouped into three main contexts: (a) immersion: greater intensity of drug use associated with greater involvement in the street culture; (b) surface: less drug use associated with family closeness; and (c) alternative-migratory: greater involvement with drug trafficking and prostitution associated with less family closeness and street culture. The drug use patterns varied in accordance with the diversity of street situations. Therefore, the peculiarities of each context should be taken into consideration in the development of social/ health policies.

  3. What is good governance in the context of drug policy?

    Science.gov (United States)

    Singleton, Nicola; Rubin, Jennifer

    2014-09-01

    The concept of governance is applied in a wide range of contexts, but this paper focuses on governance in relation to public administration, i.e. states and how they take action, and specifically governance of particular policy areas. In the current context of financial austerity and an era of globalisation, policy-makers face pressures and challenges from a growing range of interests and local, national and supranational actors. Drug policy is an example of a particularly contentious and polarised area in which governance-related challenges abound. In response to these challenges, interest has grown in developing agreed policy governance standards and processes and articulating policy-making guidelines, including the use of available evidence to inform policy-making. Attempts have been made to identify 'policy fundamentals' - factors or aspects of policy-making apparently associated with successful policy development and implementation (Hallsworth & Rutter, 2011; Laughrin, 2011) and, in the drug policy field, Hughes et al. (2010) reflecting on the co-ordination of Australian drug policy highlighted some of what they considered principles of good governance. But how useful is the concept of 'good governance'; how well can it be defined, and to what purpose? As part of a wider project considering the governance of drug policy, RAND Europe and the UK Drug Policy Commission undertook a targeted review of other research and sought expert views, from within and beyond drug policy, on principles, processes, structures and stakeholders associated with good drug policy governance. From this emerged some perceived characteristics of good governance that were then used by the UK Drug Policy Commission to assess the extent to which drug policy making in the UK fits with these perceived good governance characteristics, and to suggest possible improvements. Particular consideration was given to the range of interests at stake, the overarching aims of drug policy and the

  4. The experience of initiating injection drug use and its social context: a qualitative systematic review and thematic synthesis.

    Science.gov (United States)

    Guise, Andy; Horyniak, Danielle; Melo, Jason; McNeil, Ryan; Werb, Dan

    2017-12-01

    Understanding the experience of initiating injection drug use and its social contexts is crucial to inform efforts to prevent transitions into this mode of drug consumption and support harm reduction. We reviewed and synthesized existing qualitative scientific literature systematically to identify the socio-structural contexts for, and experiences of, the initiation of injection drug use. We searched six databases (Medline, Embase, PsychINFO, CINAHL, IBSS and SSCI) systematically, along with a manual search, including key journals and subject experts. Peer-reviewed studies were included if they qualitatively explored experiences of or socio-structural contexts for injection drug use initiation. A thematic synthesis approach was used to identify descriptive and analytical themes throughout studies. From 1731 initial results, 41 studies reporting data from 1996 participants were included. We developed eight descriptive themes and two analytical (higher-order) themes. The first analytical theme focused on injecting initiation resulting from a social process enabled and constrained by socio-structural factors: social networks and individual interactions, socialization into drug-using identities and choices enabled and constrained by social context all combine to produce processes of injection initiation. The second analytical theme addressed pathways that explore varying meanings attached to injection initiation and how they link to social context: seeking pleasure, responses to increasing tolerance to drugs, securing belonging and identity and coping with pain and trauma. Qualitative research shows that injection drug use initiation has varying and distinct meanings for individuals involved and is a dynamic process shaped by social and structural factors. Interventions should therefore respond to the socio-structural influences on injecting drug use initiation by seeking to modify the contexts for initiation, rather than solely prioritizing the reduction of individual

  5. Behavioural profile of drug users attending public drug-treatment centres in Sicily: the role of social context

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    Francesco Vitale

    2007-12-01

    Full Text Available

    Objective: Investigations of injecting drug users (IDUs have suggested that the social context may influence high-risk behaviours in this population. The aim of this study was to describe knowledge, attitudes and behaviours of IDUs attending public drug-treatment centres in our area.

    Study design and methods: A cross-sectional survey was conducted between July 2002 and February 2004, enrolling 607 drug users attending four public drug-treatment centres in the Palermo area. Two of them were located inside the urban area, whereas the other two were in rural districts near the city. All participants answered an anonymous questionnaire concerning social and demographic characteristic and potential high-risk behaviours.

    Results: IDUs living in urban context have a higher educational level, higher number of sexual partners, as well as a lower prevalence of exchanging sex for drugs. Conversely, IDUs living in suburban/rural context are less likely to share syringes and more likely to have used light drugs in the past. Suburban/rural IDUs drink more alcohol but smoke less cigarettes/day, although both groups are strong smokers.

    Conclusions: The results suggest that public drug-treatment centres should take in consideration the adoption of specific programs targeting specific groups, in line with the profile and needs of the subjects in each context in order to promote approaches leading to risk reduction.

  6. Women living in a drug (and violence context: the maternal role

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    Sueli Aparecida Frari Galera

    Full Text Available Although the drug problem is more present among men, women are an increasing group and a vulnerable subgroup, since many of them are involved in motherhood. In this paper, the partial results of an ethnographic study on maternal role-related perceptions, beliefs and attitudes are presented, as well as the context in which women with small children and are undergoing or underwent treatment for alcohol or drug addiction live. Mothers undergoing treatment participated in interviews about their maternal role and how it developed in a family context marked by violence, affective experiences and drug use.

  7. Interaction between the Basolateral Amygdala and Dorsal Hippocampus Is Critical for Cocaine Memory Reconsolidation and Subsequent Drug Context-Induced Cocaine-Seeking Behaviorin Rats

    Science.gov (United States)

    Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

    2011-01-01

    Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory…

  8. Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine.

    Science.gov (United States)

    Adhikary, Sweta; Caprioli, Daniele; Venniro, Marco; Kallenberger, Paige; Shaham, Yavin; Bossert, Jennifer M

    2017-07-01

    In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats' response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6 hours/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25 and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  9. Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice: Midbrain in drug choice

    Energy Technology Data Exchange (ETDEWEB)

    Moeller, Scott J.; Tomasi, Dardo; Woicik, Patricia A.; Maloney, Thomas; Alia-Klein, Nelly; Honorio, Jean; Telang, Frank; Wang, Gene-Jack; Wang, Ruiliang; Sinha, Rajita; Carise, Deni; Astone-Twerell, Janetta; Bolger, Joy; Volkow, Nora D.; Goldstein, Rita Z.

    2012-03-28

    Drug addiction is characterized by dysregulated dopamine neurotransmission. Although dopamine functioning appears to partially recover with abstinence, the specific regions that recover and potential impact on drug seeking remain to be determined. Here we used functional magnetic resonance imaging (fMRI) to study an ecologically valid sample of 15 treatment-seeking cocaine addicted individuals at baseline and 6-month follow-up. At both study sessions, we collected fMRI scans during performance of a drug Stroop task, clinical self-report measures of addiction severity and behavioral measures of cocaine seeking (simulated cocaine choice); actual drug use in between the two study sessions was also monitored. At 6-month follow-up (compared with baseline), we predicted functional enhancement of dopaminergically innervated brain regions, relevant to the behavioral responsiveness toward salient stimuli. Consistent with predictions, whole-brain analyses revealed responses in the midbrain (encompassing the ventral tegmental area/substantia nigra complex) and thalamus (encompassing the mediodorsal nucleus) that were higher (and more positively correlated) at follow-up than baseline. Increased midbrain activity from baseline to follow-up correlated with reduced simulated cocaine choice, indicating that heightened midbrain activations in this context may be marking lower approach motivation for cocaine. Normalization of midbrain function at follow-up was also suggested by exploratory comparisons with active cocaine users and healthy controls (who were assessed only at baseline). Enhanced self-control at follow-up was suggested by a trend for the commonly hypoactive dorsal anterior cingulate cortex to increase response during a drug-related context. Together, these results suggest that fMRI could be useful in sensitively tracking follow-up outcomes in drug addiction.

  10. Extinction produces context inhibition and multiple-context extinction reduces response recovery in human predictive learning.

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    Glautier, Steven; Elgueta, Tito; Nelson, James Byron

    2013-12-01

    Two experiments with human participants were used to investigate recovery of an extinguished learned response after a context change using ABC designs. In an ABC design, the context changes over the three successive stages of acquisition (context A), extinction (context B), and test (context C). In both experiments, we found reduced recovery in groups that had extinction in multiple contexts, and that the extinction contexts acquired inhibitory strength. These results confirm those of previous investigations, that multiple-context extinction can produce less response recovery than single-context extinction, and they also provide new evidence for the involvement of contextual inhibitory processes in extinction in humans. The foregoing results are broadly in line with a protection-from-extinction account of response recovery. Yet, despite the fact that we detected contextual inhibition, predictions based on protection-from-extinction were not fully reliable for the single- and multiple-context group differences that we observed in (1) rates of extinction and (2) the strength of context inhibition. Thus, although evidence was obtained for a protection-from-extinction account of response recovery, this account can not explain all of the data.

  11. Identifying mechanistic similarities in drug responses

    KAUST Repository

    Zhao, C.

    2012-05-15

    Motivation: In early drug development, it would be beneficial to be able to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit the desired response. One approach would be to quantitate the degree of similarity between the responses that cells show when exposed to drugs, so that consistencies in the regulation of cellular response processes that produce success or failure can be more readily identified.Results: We track drug response using fluorescent proteins as transcription activity reporters. Our basic assumption is that drugs inducing very similar alteration in transcriptional regulation will produce similar temporal trajectories on many of the reporter proteins and hence be identified as having similarities in their mechanisms of action (MOA). The main body of this work is devoted to characterizing similarity in temporal trajectories/signals. To do so, we must first identify the key points that determine mechanistic similarity between two drug responses. Directly comparing points on the two signals is unrealistic, as it cannot handle delays and speed variations on the time axis. Hence, to capture the similarities between reporter responses, we develop an alignment algorithm that is robust to noise, time delays and is able to find all the contiguous parts of signals centered about a core alignment (reflecting a core mechanism in drug response). Applying the proposed algorithm to a range of real drug experiments shows that the result agrees well with the prior drug MOA knowledge. © The Author 2012. Published by Oxford University Press. All rights reserved.

  12. Context Sensitive Modeling of Cancer Drug Sensitivity.

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    Bo-Juen Chen

    Full Text Available Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression, an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should-and should not-be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features.

  13. Variability in response to albuminuria-lowering drugs

    DEFF Research Database (Denmark)

    Petrykiv, Sergei I; de Zeeuw, Dick; Persson, Frederik

    2017-01-01

    AIMS: Albuminuria-lowering drugs have shown different effect size in different individuals. Since urine albumin levels are known to vary considerably from day-to-day, we questioned whether the between-individual variability in albuminuria response after therapy initiation reflects a random...... variability or a true response variation to treatment. In addition, we questioned whether the response variability is drug dependent. METHODS: To determine whether the response to treatment is random or a true drug response, we correlated in six clinical trials the change in albuminuria during placebo...... or active treatment (on-treatment) with the change in albuminuria during wash-out (off-treatment). If these responses correlate during active treatment, it suggests that at least part of the response variability can be attributed to drug response variability. We tested this for enalapril, losartan...

  14. A cocaine context renews drug seeking preferentially in a subset of individuals.

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    Saunders, Benjamin T; O'Donnell, Elizabeth G; Aurbach, Elyse L; Robinson, Terry E

    2014-11-01

    Addiction is characterized by a high propensity for relapse, in part because cues associated with drugs can acquire Pavlovian incentive motivational properties, and acting as incentive stimuli, such cues can instigate and invigorate drug-seeking behavior. There is, however, considerable individual variation in the propensity to attribute incentive salience to reward cues. Discrete and localizable reward cues act as much more effective incentive stimuli in some rats ('sign-trackers', STs), than others ('goal-trackers', GTs). We asked whether similar individual variation exists for contextual cues associated with cocaine. Cocaine context conditioned motivation was quantified in two ways: (1) the ability of a cocaine context to evoke conditioned hyperactivity and (2) the ability of a context in which cocaine was previously self-administered to renew cocaine-seeking behavior. Finally, we assessed the effects of intra-accumbens core flupenthixol, a nonselective dopamine receptor antagonist, on context renewal. In contrast to studies using discrete cues, a cocaine context spurred greater conditioned hyperactivity, and more robustly renewed extinguished cocaine seeking in GTs than STs. In addition, cocaine context renewal was blocked by antagonism of dopamine receptors in the accumbens core. Thus, contextual cues associated with cocaine preferentially acquire motivational control over behavior in different individuals than do discrete cues, and in these individuals the ability of a cocaine context to create conditioned motivation for cocaine requires dopamine in the core of the nucleus accumbens. We speculate that different individuals may be preferentially sensitive to different 'triggers' of relapse.

  15. Identifying mechanistic similarities in drug responses

    KAUST Repository

    Zhao, C.; Hua, J.; Bittner, M. L.; Ivanov, I.; Dougherty, a. E. R.

    2012-01-01

    Motivation: In early drug development, it would be beneficial to be able to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit the desired response. One approach

  16. Ion-Responsive Drug Delivery Systems.

    Science.gov (United States)

    Yoshida, Takayuki; Shakushiro, Kohsuke; Sako, Kazuhiro

    2018-02-08

    Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Persian Back Channel Responses in Formal versus Informal Contexts

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    Shahla Sharifi

    2012-01-01

    Full Text Available Utterances like /xob/ (okay, /doroste/ (right, /hmm/, /ee/, /?re/ (yeah, occur frequently in Persian conversations, but have thus far escaped from the systematic studies. Good listeners generally produce these short utterances, called "back channel responses", in appropriate times to show their participation in the conversation, but the rules governing back channeling vary from one context to another. The usage of back channel responses is different in various contexts, due to politeness or formality. This paper studies the types and functions of the back channel responses in both formal and informal settings and provides a comparison of the usage of these responses in these two kinds of contexts. The results show /bale/ (yes and /doroste/ (right are used with formal or polite verbal form, while /xob/ (okay is used with the informal style of speech and less polite verbal form. With respect to the function of back channels, signaling the understanding is the main function of back channels in informal contexts. Also, back channels signaling agreement are more frequent in formal contexts, where emotional function is less likely.

  18. Radioimmunoassay of drugs in body fluids in a forensic context

    International Nuclear Information System (INIS)

    Smith, R.N.

    1988-01-01

    The first article of the volume describes the theory and practice of RIA with particular reference to the analysis of drugs in body fluids in a forensic context. RIA theory is outlined from basic principles but the inherent assumptions are often inapplicable in practice and so the empirical design of an assay is considered in detail. Particular emphasis is given to the development of assays for drugs screening that detect classes of structurally related compounds rather than individual drugs. The preparation of radiolabelled drugs, the synthesis of immunogens for raising anitisera, the production of polyclonal and monoclonal antisera, and methods for separating free and antibody-bound antigens are reviewed. Quality assurance, trouble-shooting and the possible hazards of forensic RIA are discussed, and published RIA methods for drug analysis are tabulated. Many non-isotopic immunoassays have been developed in recent years but are omitted from this account because to date they are less applicable than RIA to samples such as haemolysed blood that are frequently encountered in forensic toxicology. Future progress in forensic drug RIA is likely to be concerned with applying the technique to more compounds, improving the methods for preparing immunogens and radiolabelled drugs, and investigating the use of monoclonal anti-drug antibodies. (orig./MG)

  19. Nonlinear dynamics of the patient’s response to drug effect during general anesthesia

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    Ionescu, Clara; Tenreiro Machado, Jose; De Keyser, Robin; Decruyenaere, Johan; Struys, Michel M. R. F.

    2015-03-01

    In today's healthcare paradigm, optimal sedation during anesthesia plays an important role both in patient welfare and in the socio-economic context. For the closed-loop control of general anesthesia, two drugs have proven to have stable, rapid onset times: propofol and remifentanil. These drugs are related to their effect in the bispectral index, a measure of EEG signal. In this paper wavelet time-frequency analysis is used to extract useful information from the clinical signals, since they are time-varying and mark important changes in patient's response to drug dose. Model based predictive control algorithms are employed to regulate the depth of sedation by manipulating these two drugs. The results of identification from real data and the simulation of the closed loop control performance suggest that the proposed approach can bring an improvement of 9% in overall robustness and may be suitable for clinical practice.

  20. Contested identities: Identity constructions in a youth recreational drug culture

    DEFF Research Database (Denmark)

    Ravn, Signe

    2012-01-01

    as responsible drug users. The article studies this recreational drug culture and its internal distinctions, conceptions and norms as they are expressed discursively. The analysis identifies six dimensions of the identity as a responsible, recreational drug user: drug practice, general drug knowledge, context...

  1. Application of xCELLigence RTCA Biosensor Technology for Revealing the Profile and Window of Drug Responsiveness in Real Time

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    Dan Kho

    2015-04-01

    Full Text Available The xCELLigence technology is a real-time cellular biosensor, which measures the net adhesion of cells to high-density gold electrode arrays printed on custom-designed E-plates. The strength of cellular adhesion is influenced by a myriad of factors that include cell type, cell viability, growth, migration, spreading and proliferation. We therefore hypothesised that xCELLigence biosensor technology would provide a valuable platform for the measurement of drug responses in a multitude of different experimental, clinical or pharmacological contexts. In this manuscript, we demonstrate how xCELLigence technology has been invaluable in the identification of (1 not only if cells respond to a particular drug, but (2 the window of drug responsiveness. The latter aspect is often left to educated guess work in classical end-point assays, whereas biosensor technology reveals the temporal profile of the response in real time, which enables both acute responses and longer term responses to be profiled within the same assay. In our experience, the xCELLigence biosensor technology is suitable for highly targeted drug assessment and also low to medium throughput drug screening, which produces high content temporal data in real time.

  2. Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner.

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    Taubenfeld, Stephen M; Muravieva, Elizaveta V; Garcia-Osta, Ana; Alberini, Cristina M

    2010-07-06

    Addicts repeatedly relapse to drug seeking even after years of abstinence, and this behavior is frequently induced by the recall of memories of the rewarding effects of the drug. Established memories, including those induced by drugs of abuse, can become transiently fragile if reactivated, and during this labile phase, known as reconsolidation, can be persistently disrupted. Here we show that, in rats, a morphine-induced place preference (mCPP) memory is linked to context-dependent withdrawal as disrupting the reconsolidation of the memory leads to a significant reduction of withdrawal evoked in the same context. Moreover, the hippocampus plays a critical role in linking the place preference memory with the context-conditioned withdrawal, as disrupting hippocampal protein synthesis and cAMP-dependent-protein kinase A after the reactivation of mCPP significantly weakens the withdrawal. Hence, targeting memories induced by drugs may represent an important strategy for attenuating context-conditioned withdrawal and therefore subsequent relapse in opiate addicts.

  3. Sex differences in emotional contexts modulation on response inhibition.

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    Ramos-Loyo, Julieta; Angulo-Chavira, Armando; Llamas-Alonso, Luis A; González-Garrido, Andrés A

    2016-10-01

    The aim of the present study was to explore sex differences in the effects that emotional contexts exert on the temporal course of response inhibition using event-related potentials (ERP). Participants performed a Go-NoGo response inhibition task under 3 context conditions: with 1) neutral background stimuli, and 2) pleasant, and 3) unpleasant emotional contexts. No sex differences were found in relation to accuracy. Women showed higher N2NoGo amplitudes than men in both emotional contexts; whereas during inhibition men tended to show higher P3NoGo amplitudes than women in the unpleasant context. Both groups experienced a relevant effect of the presence of the unpleasant context during inhibition processing, as shown by the enhancement of the N2NoGo amplitudes in frontal regions compared to results from the neutral and pleasant conditions. In addition, women showed differences between the pleasant and unpleasant contexts, with the latter inducing higher amplitude values. Only in men did inhibition accuracy correlate with higher N2NoGo and lower P3NoGo amplitudes in the emotional context conditions. These findings suggest that when an inhibition task is performed in an emotionally-neutral background context no sex differences are observed in either accuracy or ERP components. However, when the emotional context was introduced -especially the unpleasant one- some gender differences did become evident. The higher N2NoGo amplitude at the presence of the unpleasant context may reflect an effect on attention and conflict monitoring. In addition, results suggest that during earlier processing stages, women invested more resources to process inhibition than men. Furthermore, men who invested more neural resources during earlier stages showed better response inhibition than those who did it during later processing stages, more closely-related to cognitive and motor inhibition processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Context-dependent representation of response-outcome in monkey prefrontal neurons.

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    Tsujimoto, Satoshi; Sawaguchi, Toshiyuki

    2005-07-01

    For behaviour to be purposeful, it is important to monitor the preceding behavioural context, particularly for factors regarding stimulus, response and outcome. The dorsolateral prefrontal cortex (DLPFC) appears to play a major role in such a context-dependent, flexible behavioural control system, and this area is likely to have a neuronal mechanism for such retrospective coding, which associates response-outcome with the information and/or neural systems that guided the response. To address this hypothesis, we recorded neuronal activity from the DLPFC of monkeys performing memory- and sensory-guided saccade tasks, each of which had two conditions with reward contingencies. We found that post-response activity of a subset of DLPFC neurons was modulated by three factors relating to earlier events: the direction of the immediately preceding response, its outcome (reward or non-reward) and the information type (memory or sensory) that guided the response. Such neuronal coding should play a role in associating response-outcome with information and/or neural systems used to guide behaviour - that is, 'retrospective monitoring' of behavioural context and/or neural systems used for guiding behaviour - thereby contributing to context-dependent, flexible control of behaviours.

  5. Motivations for Prescription Drug Misuse among Young Adults: Considering Social and Developmental Contexts.

    Science.gov (United States)

    LeClair, Amy; Kelly, Brian C; Pawson, Mark; Wells, Brooke E; Parsons, Jeffrey T

    As part of a larger study on prescription drug misuse among young adults active in urban nightlife scenes, we examined participants' motivations for misuse. Prescription painkillers, stimulants and sedatives were the primary substances of interest. Participants were recruited from nightlife venues in New York using time-space sampling. Subjects completed a mixed-methods assessment at project research offices. The data presented here are from a subsample of 70 qualitative interviews conducted during the baseline assessment. We identified experimentation and a "work hard, play hard" ethos as key motivations for misusing prescription drugs and argue that these motivations are specific, though not necessarily unique, to the participants' social location as young adults. These findings highlight the role of life stage and social context in the misuse of prescription drugs. Future studies of prescription drug misuse should pay attention to the larger social contexts in which users are embedded and, therefore, make decisions about how and why to misuse. Moving beyond the very broad concepts of "recreation" and "self-medication" presently established in the research, policies targeting young adults may want to tailor intervention efforts based on motivations.

  6. Lessons for responsible innovation in the business context

    NARCIS (Netherlands)

    Lubberink, Rob; Blok, Vincent; Ophem, van Johan; Omta, Onno

    2017-01-01

    This paper aims to contribute to the ongoing conceptual debate on responsible innovation, and provides innovation practices and processes that can help to implement responsible innovation in the business context. Based on a systematic literature review of 72 empirical scholarly articles, it was

  7. Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats.

    Science.gov (United States)

    Lasseter, Heather C; Xie, Xiaohu; Arguello, Amy A; Wells, Audrey M; Hodges, Matthew A; Fuchs, Rita A

    2014-02-01

    Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

  8. Social representations of consumption of drugs in a university context, Medellin, Colombia, 2000

    Directory of Open Access Journals (Sweden)

    Silvia Henao H

    2012-04-01

    Full Text Available Objective: To identify and characterize the social representationsof drug use in a university context. Methodology: aframework was built by collecting the contributions of symbolicinteractionism, interpretive ethnography, and textualanalysis. Data collection was performed through 27 semistructuredinterviews and 7 focus groups. Likewise, the ReadingParadigm, proposed by a cultural hermeneutics of anthropologicalnature, was used as an analysis technique. Resultsand discussion: we observed social representations such asdrug use as a socializing element facilitating social relationsand as an element that gives meaning to life by putting thesubject in a context where he or she is accepted. Conclusion:certain socially constructed forms of knowledge appear in thesignifiers of drugs. They generate, through the functions of socialrepresentations, satisfiers that make it possible, throughcommunication, to construct languages that shape the identitywithin the group and favor adaptation to the social environmentof the university.

  9. The importance of drug checking outside the context of nightlife in Slovenia.

    Science.gov (United States)

    Sande, Matej; Šabić, Simona

    2018-01-12

    The main purpose of the research was to evaluate the implementation of the drug checking service in Slovenia and to obtain the opinion of users included in harm reduction programmes for high-risk drug users and of drug users in nightlife settings on drug checking, the reasons for drug checking, and their attitude towards adulterants in the drugs that they use. The two final unrepresentative research samples included 102 respondents from harm reduction programmes and 554 respondents from the online sample. The questionnaire was designed based on analysis of the interviews conducted with professionals from the programmes, who took part in the drug checking project, and based on previous research on drug use in nightlife. The main findings related to users' opinions on the drug checking service are that users from both samples perceive drug checking as a contribution to risk reduction and that they find providing information for them about the harmful adulterants and substances that they use very important. In addition, users from both samples considered accessibility of the drug checking service as very important and would be in favour of brief counselling at the collection of the drug sample. One of the salient differences between samples was that nightlife drug users found it more important to recognise substances in the drugs that they use. Drug users from two different samples attach a relatively high importance to the drug checking service, and they consider it to be a contribution to risk reduction. As well as drug users in nightlife settings, high-risk drug users also perceive the drug checking service to be important, which is relevant in the phase of planning drug checking services outside the context of nightlife and for the act of incorporating these services into contemporary harm reduction policy.

  10. 21 CFR 1301.91 - Employee responsibility to report drug diversion.

    Science.gov (United States)

    2010-04-01

    ... REGISTRATION OF MANUFACTURERS, DISTRIBUTORS, AND DISPENSERS OF CONTROLLED SUBSTANCES Employee Screening-Non-Practitioners § 1301.91 Employee responsibility to report drug diversion. Reports of drug diversion by fellow... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Employee responsibility to report drug diversion...

  11. Student-peer mentoring on a drug information response.

    Science.gov (United States)

    Rodis, Jennifer Lin; Backo, Jennifer; Schmidt, Brittany M; Pruchnicki, Maria C

    2014-03-12

    To implement a student peer-mentoring program with a drug information response assignment in an introductory pharmacy practice course. Second-year student pharmacists (P2 mentors) enrolled in an independent study course were randomly assigned first-year student pharmacists (P1 mentees) to mentor on a drug information assignment. The P2 mentors provided feedback to P1 mentees' assignment drafts. The P1 mentees had the opportunity to revise the draft prior to turning in the completed assignment to course faculty members for grading. Both P1 mentees and P2 mentors agreed the mentorship improved their ability to prepare a drug information response (76% and 100%, respectively). A majority of the student pharmacists would choose to be involved in the program again. The student peer-mentoring program was successful in improving student pharmacists' perceptions of ability to compose a drug information response.

  12. Perception in a social context: attention for response-functional means

    NARCIS (Netherlands)

    Faber, T.W.; Jonas, K.J.

    2013-01-01

    Research on automatic behavior has shown how social category priming can activate unique responses toward such categories. Recently, the importance of the context in which social category members are perceived has been demonstrated for the response selection process. While response selection has

  13. Identifying Demand Responses to Illegal Drug Supply Interdictions.

    Science.gov (United States)

    Cunningham, Scott; Finlay, Keith

    2016-10-01

    Successful supply-side interdictions into illegal drug markets are predicated on the responsiveness of drug prices to enforcement and the price elasticity of demand for addictive drugs. We present causal estimates that targeted interventions aimed at methamphetamine input markets ('precursor control') can temporarily increase retail street prices, but methamphetamine consumption is weakly responsive to higher drug prices. After the supply interventions, purity-adjusted prices increased then quickly returned to pre-treatment levels within 6-12 months, demonstrating the short-term effects of precursor control. The price elasticity of methamphetamine demand is -0.13 to -0.21 for self-admitted drug treatment admissions and between -0.24 and -0.28 for hospital inpatient admissions. We find some evidence of a positive cross-price effect for cocaine, but we do not find robust evidence that increases in methamphetamine prices increased heroin, alcohol, or marijuana drug use. This study can inform policy discussions regarding other synthesized drugs, including illicit use of pharmaceuticals. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Municipal Responses to ‘Illegality’: Urban Sanctuary across National Contexts

    Directory of Open Access Journals (Sweden)

    Harald Bauder

    2018-03-01

    Full Text Available Cities often seek to mitigate the highly precarious situation of Illegalized (or undocumented migrants. In this context, “sanctuary cites” are an innovative urban response to exclusionary national policies. In this article, we expand the geographical scope of sanctuary policies and practices beyond Canada, the USA, and the UK, where the policies and practices are well-known. In particular, we explore corresponding urban initiatives in Chile, Germany, and Spain. We find that varying kinds of urban-sanctuary policies and practices permit illegalized migrants to cope with their situations in particular national contexts. However, different labels, such as “city of refuge,” “commune of reception,” or “solidarity city” are used to describe such initiatives. While national, historical, and geopolitical contexts distinctly shape local efforts to accommodate illegalized migrants, recognizing similarities across national contexts is important to develop globally-coordinated and internationally-inspired responses at the urban scale.

  15. The social context of controlled drug use amongst young people in a slum area in Makassar, Indonesia.

    Science.gov (United States)

    Nasir, Sudirman; Rosenthal, Doreen; Moore, Timothy

    2011-11-01

    There are few studies exploring the social context of controlled drug use amongst young people in Indonesia. This qualitative study examines the experience of young people in a slum area (lorong) in Makassar, eastern Indonesia, who use drugs but are not drug dependent and who employ various forms of self regulation to control their use. Semi-structured interviews were conducted with eight controlled drug users. The study found that whilst controlled drug users lived in a drug risk environment, they were not deeply embedded in the street culture, risk-taking practises and drug scene within their locality. Their employment, albeit in the informal economy and in low-paid jobs, facilitated their perspective that the status of rewa (a local construct of masculinity) and gaul (being sociable and up-to-date) could and should be accomplished through conventional means such as jobs and halal (legitimate) income. Their employment generated both direct benefit (legitimate income) and indirect benefit, including meaningful activities, structured time, positive identity and wider social networks (bridging social capital). This enabled them to have a stake in mainstream society and provided an incentive to control drug use. All factors which are protective against escalation into problematic drug use. The study showed the importance of sociological concepts of direct and indirect benefits of employment and of social capital in understanding the social context of controlled drug use amongst young people in the lorong. Additionally, drug policy should be more cognizant of the social vulnerability in the lorong and of the need to increase access to employment amongst young people in order to potentially decrease the likelihood of problematic drug use. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. The Effects of Housing Status, Stability and the Social Contexts of Housing on Drug and Sexual Risk Behaviors.

    Science.gov (United States)

    Dickson-Gomez, Julia; McAuliffe, Timothy; Quinn, Katherine

    2017-07-01

    Research on the relationship between housing instability and HIV risk has often focused on two different conceptions of stability. In one conceptualization, housing stability is defined according to physical location with homeless or unstably housed individuals defined as those who reside in places not meant for human habitation or in emergency shelters. The other conceptualization has defined housing stability as individuals' degree of transience, often operationalized as the number of moves or evictions a person has had within a specified amount of time. Less studied has been the social context of living situation, e.g. living with other drug users, conflict over living expenses, or having to have sex in order to stay. This paper uses data from 392 low-income residents in Hartford, CT to explore how people in different housing situations-including those who are housed and homeless-experience housing stability, feelings of security in their homes, and the social context of their housing. We then explore how these varied measures of housing context affect drug use frequency and sexual risk. Results show that participants who are homeless feel more overall housing instability in terms of number of moves and negative reasons for moving. Those who were doubled up with family or friends were more likely to experience conflict over household expenses and more likely to live with drug users. Among homeless and housed, hard drug use was associated with experiencing violence in the place where they lived, perceiving greater housing stability, having moved for a positive reason, doubling up, and longer periods of homelessness, while number of moves and longer prison sentence predicted sexual risk. Among the housed, living with other drug users was associated with more hard drug use, while contributing money toward household expenses was associated with less hard drug use. Two significant interactions were associated with sexual risk among the housed. Those with longer

  17. Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction.

    Science.gov (United States)

    Neisewander, J L; Peartree, N A; Pentkowski, N S

    2012-11-01

    Social factors are important determinants of drug dependence and relapse. We reviewed pre-clinical literature examining the role of social experiences from early life through the development of drug dependence and relapse, emphasizing two aspects of these experiences: (1) whether the social interaction is appetitive or aversive and (2) whether the social interaction occurs within or outside of the drug-taking context. The models reviewed include neonatal care, isolation, social defeat, chronic subordination, and prosocial interactions. We review results from these models in regard to effects on self-administration and conditioned place preference established with alcohol, psychostimulants, and opiates. We suggest that in general, when the interactions occur outside of the drug-taking context, prosocial interactions are protective against drug abuse-related behaviors, whereas social stressors facilitate these behaviors. By contrast, positive or negative social interactions occurring within the drug-taking context may interact with other risk factors to enhance or inhibit these behaviors. Despite differences in the nature and complexity of human social behavior compared to other species, the evolving animal literature provides useful models for understanding social influences on drug abuse-related behavior that will allow for research on the behavioral and biological mechanisms involved. The models have contributed to understanding social influences on initiation and maintenance of drug use, but more research is needed to understand social influences on drug relapse.

  18. Nonlinear dynamics of the patient's response to drug effect during general anesthesia

    NARCIS (Netherlands)

    Ionescu, Clara; Machado, Jose Tenreiro; De Keyser, Robin; Decruyenaere, Johan; Struys, Michel M. R. F.

    In today's healthcare paradigm, optimal sedation during anesthesia plays an important role both in patient welfare and in the socio-economic context. For the closed-loop control of general anesthesia, two drugs have proven to have stable, rapid onset times: propofol and remifentanil. These drugs are

  19. DISIS: prediction of drug response through an iterative sure independence screening.

    Directory of Open Access Journals (Sweden)

    Yun Fang

    Full Text Available Prediction of drug response based on genomic alterations is an important task in the research of personalized medicine. Current elastic net model utilized a sure independence screening to select relevant genomic features with drug response, but it may neglect the combination effect of some marginally weak features. In this work, we applied an iterative sure independence screening scheme to select drug response relevant features from the Cancer Cell Line Encyclopedia (CCLE dataset. For each drug in CCLE, we selected up to 40 features including gene expressions, mutation and copy number alterations of cancer-related genes, and some of them are significantly strong features but showing weak marginal correlation with drug response vector. Lasso regression based on the selected features showed that our prediction accuracies are higher than those by elastic net regression for most drugs.

  20. Gendered contexts: Psychopathy and drug use in relation to sex work and exchange.

    Science.gov (United States)

    Edwards, Bethany G; Verona, Edelyn

    2016-05-01

    Few scholars have examined psychopathology correlates of sex work. It has been suggested that sex work may reflect manifestations of impulsive-antisocial psychopathic traits (e.g., reckless disregard, delinquency) in women more than men. The current work examined relative contributions of drug dependence and distinct psychopathic features in relation to traditional forms of sex work (i.e., prostitution) in women, along with gender differences in psychopathy relationships with casual forms of sex exchange (i.e., trading sex for necessities). Study 1 included 171 community-dwelling women offenders, and Study 2 included 319 participants (42.3% women) with histories of drug use and/or violence. Participants completed the Psychopathy Checklist: Screening Version, prostitution was measured as self-report and/or public record data across studies, and sex exchange in Study 2 was assessed using a questionnaire based on prior research on sexual risk-taking. Findings across both studies demonstrated that although psychopathic traits, particularly impulsive-antisocial features, were associated with prostitution in women above the use of drugs, drug dependence did not moderate the relationship between psychopathic traits and prostitution in women. Analyses of Study 2 data revealed that impulsive-antisocial traits were associated with sex exchange at low, but not high, levels of interpersonal-affective traits across participants. As well, interpersonal-affective traits were significantly positively related to sex exchange in men and not significantly (and negatively) related in women. In sum, impulsive-antisocial traits related to prostitution among women, suggesting that women may manifest these traits within intimate contexts. Moreover, findings indicated gender differences in the manifestation of interpersonal-affective traits within sexual exchange contexts. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  1. Gendered contexts: psychopathy and drug use in relation to sex work and exchange

    Science.gov (United States)

    Edwards, Bethany G.; Verona, Edelyn

    2016-01-01

    Few scholars have examined psychopathology correlates of sex work. It has been suggested that sex work may reflect manifestations of impulsive-antisocial psychopathic traits (e.g., reckless disregard, delinquency) in women more than men. The current work examined relative contributions of drug dependence and distinct psychopathic features in relation to traditional forms of sex work (i.e., prostitution) in women, along with gender differences in psychopathy relationships with casual forms of sex exchange (i.e., trading sex for necessities). Study 1 included 171 community-dwelling women offenders, and Study 2 included 319 participants (42.3% women) with histories of drug use and/or violence. Participants completed the Psychopathy Checklist: Screening Version, prostitution was measured as self-report and/or public record data across studies, and sex exchange in Study 2 was assessed using a questionnaire based on prior research on sexual risk-taking. Findings across both studies demonstrated that while psychopathic traits, particularly impulsive-antisocial features, were associated with prostitution in women above the use of drugs, drug dependence did not moderate the relationship between psychopathic traits and prostitution in women. Analyses of Study 2 data revealed that impulsive-antisocial traits were associated with sex exchange at low, but not high, levels of interpersonal-affective traits across participants. As well, interpersonal-affective traits were significantly positively related to sex exchange in men and not significantly (and negatively) related in women. In sum, impulsive-antisocial traits related to prostitution among women, suggesting that women may manifest these traits within intimate contexts. Moreover, findings indicated gender differences in the manifestation of interpersonal-affective traits within sexual exchange contexts. PMID:27030996

  2. A Procedure to Observe Context-induced Renewal of Pavlovian-conditioned Alcohol-seeking Behavior in Rats

    OpenAIRE

    Maddux, Jean-Marie; Lacroix, Franca; Chaudhri, Nadia

    2014-01-01

    Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian disc...

  3. Drug Brand Response and Its Impact on Compliance and Efficacy in Depression Patients.

    Science.gov (United States)

    Li, Mingming; Cai, Jian; Zhang, Ping; Fei, Chunhua; Xu, Feng

    2016-01-01

    Introduction: Patient's response to drug brand is a comprehensive physiological and psychological effect which might impact the compliance and efficacy of drugs. Whether the therapeutic outcome altered on patients with brand response after they experience drug switch is not clear. Methods: 459 outpatients with mild-to-moderate depression were divided into the imported (joint venture) drug group and the domestic drug group according to their current drug application. Two groups of patients were assessed by drug brand preference questionnaire and medication compliance questionnaire. Patients with brand preference in imported (joint venture) drugs group received rational use of limited medical resource and pharmacoeconomics education, and then switched with domestic drug for 8 weeks. Safety and efficacy were evaluated both before and after the drug switch. Results: Overall, there were 27% of patients in imported drug group and 35% of patients in domestic drug group have brand response, respectively. About 2/3 patients in both groups showed low or no brand response. The compliance was similar in both groups with no significant difference (6.04 ± 2.08 vs. 4.74 ± 2.13, respectively, P > 0.05). The efficacy of imported drug group was significantly better than of the domestic drug group. Correlation analysis showed that in imported (joint venture) drugs group, medication compliance was closely related with brand response, but negatively correlated with age and duration. In domestic drugs group, medication compliance was independent of brand response, but closely related with education, age, and duration. After drug switch with domestic drug on patients with brand response, patients continued to maintain good antidepressant effect, and no severe adverse reaction occurred. Conclusion: The results suggested that domestic drugs switch might be feasible for patients using imported drugs with brand response, while providing patients with rational use of drug education and

  4. Abuse of Prescription Drugs in the Context of Novel Psychoactive Substances (NPS): A Systematic Review.

    Science.gov (United States)

    Schifano, Fabrizio; Chiappini, Stefania; Corkery, John M; Guirguis, Amira

    2018-04-22

    Recently, a range of prescription and over-the-counter drugs have been reportedly used as Novel Psychoactive Substances (NPS), due to their potential for abuse resulting from their high dosage/idiosyncratic methods of self-administration. This paper provides a systematic review of the topic, focusing on a range of medications which have emerged as being used recreationally, either on their own or in combination with NPS. Among gabapentinoids, pregabalin may present with higher addictive liability levels than gabapentin, with pregabalin being mostly identified in the context of opioid, polydrug intake. For antidepressants, their dopaminergic, stimulant-like, bupropion activities may explain their recreational value and diversion from the therapeutic intended use. In some vulnerable clients, a high dosage of venlafaxine (‘baby ecstasy’) is ingested for recreational purposes, whilst the occurrence of a clinically-relevant withdrawal syndrome may be a significant issue for all venlafaxine-treated patients. Considering second generation antipsychotics, olanzapine appears to be ingested at very large dosages as an ‘ideal trip terminator’, whilst the immediate-release quetiapine formulation may possess proper abuse liability levels. Within the image- and performance- enhancing drugs (IPEDs) group, the beta-2 agonist clenbuterol (‘size zero pill’) is reported to be self-administered for aggressive slimming purposes. Finally, high/very high dosage ingestion of the antidiarrhoeal loperamide has shown recent increasing levels of popularity due to its central recreational, anti-withdrawal, opiatergic effects. The emerging abuse of prescription drugs within the context of a rapidly modifying drug scenario represents a challenge for psychiatry, public health and drug-control policies.

  5. State and Community Responses to Drug-related Violence in Mexico

    International Development Research Centre (IDRC) Digital Library (Canada)

    Violent conflict related to drug trafficking in Mexico has had a profound impact on the ... mostly due to illegal drug trafficking and the government's response to it, ... security forces and drug traffickers or in executions related to the drug trade.

  6. State and Community Responses to Drug-related Violence in Mexico

    International Development Research Centre (IDRC) Digital Library (Canada)

    Extrants. Études. State and community responses to drug-related violence in Mexico. Rapports. Respuestas estatales y comunitarias a la violencia asociada al narcotráfico en México : informe técnico. Rapports. State and community responses to drug-related violence in Mexico ...

  7. Headteachers' Readings of and Responses to Disadvantaged Contexts: Evidence from English Primary Schools

    Science.gov (United States)

    Lupton, Ruth; Thrupp, Martin

    2013-01-01

    Existing research demonstrates the impact of context on school organisation and management, curriculum and pedagogy and on student peer relations. New developments in English education policy will devolve more responsibility for dealing with these issues to headteachers. Headteachers' readings of their contexts and the responses that they make are…

  8. Report on psychoactive drug use among adolescents using ayahuasca within a religious context.

    Science.gov (United States)

    Doering-Silveira, Evelyn; Grob, Charles S; de Rios, Marlene Dobkin; Lopez, Enrique; Alonso, Luisa K; Tacla, Cristiane; Da Silveira, Dartiu Xavier

    2005-06-01

    Ritual use of ayahuasca within the context of the Brazilian ayahuasca churches often starts during late childhood or early adolescence. Premature access to psychoactive drugs may represent a risk factor for drug misuse. Conversely, religious affiliation seems to play a protective role in terms of substance abuse. The objective of this study was to describe patterns of drug use in a sample of adolescents using ayahuasca within a religious setting. Forty-one adolescents from a Brazilian ayahuasca sect were compared with 43 adolescents who never drank ayahuasca. No significant differences were identified in terms of lifetime substance consumption. Throughout the previous year period, ayahuasca adolescents used less alcohol (46.31%) than the comparison group (74.4%). Recent use of alcohol was also more frequent among the latter group (65.1%) than among ayahuasca drinkers (32.5%). Although not statistically significant, slight differences in terms of patterns of drug use were definitely observed among groups. Despite their early exposure to a hallucinogenic substance, adolescents using ayahuasca in a controlled setting were mostly comparable to controls except for a considerably smaller proportion of alcohol users. Religious affiliation may have played a central role as a possible protective factor for alcohol use. Thus, ayahuasca seems to be a relatively safe substance as far as drug misuse is concerned.

  9. Effects of extinction in multiple contexts on renewal of instrumental responses.

    Science.gov (United States)

    Bernal-Gamboa, Rodolfo; Nieto, Javier; Uengoer, Metin

    2017-09-01

    In two experiments with rats, we investigated the effects of using multiple contexts during extinction on renewal of lever-pressing behavior. During the first phase of both experiments, rats were reinforced to press a lever for food in Context A. Then, responses underwent extinction. For half of the animals, extinction sessions were conducted in a single context, whereas the other half received extinction in three different contexts. In Experiment 1, we observed that extinction in multiple contexts eliminated ABC renewal, but had no detectable impact on ABA renewal. Experiment 2 revealed that conducting extended extinction training in multiple contexts attenuated ABA renewal. Theoretical and clinical implications of the present findings are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Adult Literacy and Drug Addiction: What's the Connection?

    Science.gov (United States)

    Neri, Charles

    1990-01-01

    A core concept in dealing with drug addiction is the relationship between fear and drug use. In order to deal with fear, one response is a job skills class as a positive, ego-building experience in which literacy skills are emphasized in the context of self-discovery. (SK)

  11. Pharmacogenetic approaches to the prediction of drug response

    International Nuclear Information System (INIS)

    Vesell, E.S.

    1986-01-01

    The following review of pharmacogenetic progress and methodology is offered to stimulate and suggest analogous studies on drugs of abuse. It is readily acknowledged that formidable methodological problems are posed by adapting to drugs of abuse these pharmacogenetic approaches based on the administration of single safe doses of various prescription drugs to normal subjects under carefully controlled environmental conditions. Results of similarly designed studies on drugs of abuse in addicts might be uninterpretable because of confounding by numerous environmental perturbations, including the smoking of cigarettes and/or marijuana, nutritional variations, and intake of other drugs such as ethanol. Ethical considerations render objectionable the administration to unaddicted subjects of drugs at dosage levels usually ingested by drug abusers. Other approaches would have to be taken in such normal subjects. Possibilities include administration of tracer doses of /sup 14/C- or /sup 13/C- labeled drugs or growth of normal cells in culture to investigate their pharmacokinetic and/or pharmacodynamic responses to various drugs of abuse

  12. Drug–drug conditioning between citalopram and haloperidol or olanzapine in a conditioned avoidance response model: implications for polypharmacy in schizophrenia

    Science.gov (United States)

    Sparkman, Nathan L.; Li, Ming

    2016-01-01

    Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug–drug interactions. However, the pharmacological and behavioral mechanisms underlying drug–drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug–drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the

  13. Development of response inhibition in the context of relevant versus irrelevant emotions

    Directory of Open Access Journals (Sweden)

    Margot A Schel

    2013-07-01

    Full Text Available The present study examined the influence of relevant and irrelevant emotions on response inhibition from childhood to early adulthood. Ninety-four participants between 6 and 25 years of age performed two go/nogo tasks with emotional faces (neutral, happy, and fearful as stimuli. In one go/nogo task emotion formed a relevant dimension of the task and in the other go/nogo task emotion was irrelevant and participants had to respond to the color of the faces instead. A special feature of the latter task, in which emotion was irrelevant, was the inclusion of free choice trials, in which participants could freely decide between acting and inhibiting. Results showed a linear increase in response inhibition performance with increasing age both in relevant and irrelevant affective contexts. Relevant emotions had a pronounced influence on performance across age, whereas irrelevant emotions did not. Overall, participants made more false alarms on trials with fearful faces than happy faces, and happy faces were associated with better performance on go trials (higher percentage correct and faster RTs than fearful faces. The latter effect was stronger for young children in terms of accuracy. Finally, during the free choice trials participants did not base their decisions on affective context, confirming that irrelevant emotions do not have a strong impact on inhibition. Together, these findings suggest that across development relevant affective context has a larger influence on response inhibition than irrelevant affective context. When emotions are relevant, a context of positive emotions is associated with better performance compared to a context with negative emotions, especially in young children.

  14. Drug Brand Response and Its Impact on Compliance and Efficacy in Depression Patients

    OpenAIRE

    Li, Mingming; Cai, Jian; Zhang, Ping; Fei, Chunhua; Xu, Feng

    2017-01-01

    Introduction: Patient's response to drug brand is a comprehensive physiological and psychological effect which might impact the compliance and efficacy of drugs. Whether the therapeutic outcome altered on patients with brand response after they experience drug switch is not clear. Methods: 459 outpatients with mild-to-moderate depression were divided into the imported (joint venture) drug group and the domestic drug group according to their current drug application. Two groups of patients ...

  15. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery.

    Science.gov (United States)

    Cheng, Ru; Meng, Fenghua; Deng, Chao; Klok, Harm-Anton; Zhong, Zhiyuan

    2013-05-01

    In the past decades, polymeric nanoparticles have emerged as a most promising and viable technology platform for targeted and controlled drug delivery. As vehicles, ideal nanoparticles are obliged to possess high drug loading levels, deliver drug to the specific pathological site and/or target cells without drug leakage on the way, while rapidly unload drug at the site of action. To this end, various "intelligent" polymeric nanoparticles that release drugs in response to an internal or external stimulus such as pH, redox, temperature, magnetic and light have been actively pursued. These stimuli-responsive nanoparticles have demonstrated, though to varying degrees, improved in vitro and/or in vivo drug release profiles. In an effort to further improve drug release performances, novel dual and multi-stimuli responsive polymeric nanoparticles that respond to a combination of two or more signals such as pH/temperature, pH/redox, pH/magnetic field, temperature/reduction, double pH, pH and diols, temperature/magnetic field, temperature/enzyme, temperature/pH/redox, temperature/pH/magnetic, pH/redox/magnetic, temperature/redox/guest molecules, and temperature/pH/guest molecules have recently been developed. Notably, these combined responses take place either simultaneously at the pathological site or in a sequential manner from nanoparticle preparation, nanoparticle transporting pathways, to cellular compartments. These dual and multi-stimuli responsive polymeric nanoparticles have shown unprecedented control over drug delivery and release leading to superior in vitro and/or in vivo anti-cancer efficacy. With programmed site-specific drug delivery feature, dual and multi-stimuli responsive nanoparticulate drug formulations have tremendous potential for targeted cancer therapy. In this review paper, we highlight the recent exciting developments in dual and multi-stimuli responsive polymeric nanoparticles for precision drug delivery applications, with a particular focus

  16. Teachers' Responses to Bullying Incidents: Effects of Teacher Characteristics and Contexts

    Science.gov (United States)

    Yoon, Jina; Sulkowski, Michael L.; Bauman, Sheri A.

    2016-01-01

    School is a critical context of bullying. This study investigated teacher responses to bullying incidents and the effects of individual and contextual variables on these responses. Participating teachers (N = 236) viewed streaming video vignettes depicting physical, verbal, and relational bullying and reported how they would respond to bullies and…

  17. Context-dependent efficacy of a counter-conditioning strategy with atypical neuroleptic drugs in mice previously sensitized to cocaine.

    Science.gov (United States)

    Oliveira-Lima, A J; Marinho, Eav; Santos-Baldaia, R; Hollais, A W; Baldaia, M A; Talhati, F; Ribeiro, L T; Wuo-Silva, R; Berro, L F; Frussa-Filho, R

    2017-02-06

    We have previously demonstrated that treatment with ziprasidone and aripiprazole selectively inhibit the development of behavioral sensitization to cocaine in mice. We now investigate their effects on a counter-conditioning strategy in mice and the importance of the treatment environment for this phenomenon. Evaluate the context-specificity of ziprasidone and aripiprazole on conditioned locomotion to cocaine and cocaine-induced hyperlocomotion and behavioral sensitization in a counter-conditioning strategy in mice. Animals were sensitized with saline or cocaine injections in the open-field apparatus in a 15-day intermittent treatment and subsequently treated with vehicle, 5mg/kg ziprasidone or 0.1mg/kg aripiprazole paired to the open-field or the home-cage for 4 alternate days. Mice were then challenged with saline and cocaine in the open-field apparatus on subsequent days. While treatment with ziprasidone decreased spontaneous locomotion and conditioned locomotion alike, treatment with aripiprazole specifically attenuated the expression of conditioned hyperlocomotion to cocaine. Ziprasidone and aripiprazole had no effects on cocaine-induced conditioned hyperlocomotion observed during saline challenge after drug withdrawal. Treatment with either ziprasidone or aripiprazole when previously given in the cocaine-paired environment attenuated the subsequent expression of behavioral sensitization to cocaine. Animals treated with aripiprazole in the open-field, but not in the home-cage, showed a blunted response to cocaine when receiving a cocaine challenge for the first time. Both neuroleptic drugs showed a context-dependent effectiveness in attenuating long-term expression of cocaine-induced behavioral sensitization when administered in the cocaine-associated environment, with aripiprazole also showing effectiveness in blocking the expression of acute cocaine effects. Copyright © 2016. Published by Elsevier Inc.

  18. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  19. The context of illicit drug overdose deaths in British Columbia, 2006

    Directory of Open Access Journals (Sweden)

    Waheed Bilal

    2009-05-01

    Full Text Available Abstract Background Illicit drug overdose deaths (IDD relate to individual drug dose and context of use, including use with other drugs and alcohol. IDD peaked in British Columbia (BC in 1998 with 417 deaths, and continues to be a public health problem. The objective of this study was to examine IDD in 2006 in BC by place of residence, injury and death, decedents' age and sex and substances identified. Methods IDD data was obtained through the BC Coroners Office and entered into SPSS (version 14. Fisher's exact and Pearson's χ2 were used for categorical data; Mann-Whitney U-test for continuous variables. Rates were calculated using 2006 population estimates. Results We identified 223 IDD in BC; 54 (24% occurred in Vancouver. Vancouver decedents (compared to those occurring outside Vancouver were older (mean age 43.9 vs. 39.2 years; p Cocaine was identified in 80.3%, opiates 59.6%, methadone 13.9%, methamphetamine/amphetamine 6.3%, and alcohol in 22.9% of deaths. Poly-substance use was common, 2 substances were identified in 43.8% and 3 or more in 34.5% of deaths. Opiates were more frequently identified in Vancouver compared to outside Vancouver (74.1% vs. 55.0% p = 0.015. Conclusion Collaboration with the Coroner's office allowed us to analyze IDD in detail including place of death; cocaine, opiates and poly-substance use were commonly identified. Poly-substance use should be explored further to inform public health interventions.

  20. HIV Genetic Diversity and Drug Resistance

    Science.gov (United States)

    Santos, André F.; Soares, Marcelo A.

    2010-01-01

    Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. PMID:21994646

  1. In Vitro Drug Sensitivity Tests to Predict Molecular Target Drug Responses in Surgically Resected Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Ryohei Miyazaki

    Full Text Available Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs and anaplastic lymphoma kinase (ALK inhibitors have dramatically changed the strategy of medical treatment of lung cancer. Patients should be screened for the presence of the EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4-ALK fusion gene prior to chemotherapy to predict their clinical response. The succinate dehydrogenase inhibition (SDI test and collagen gel droplet embedded culture drug sensitivity test (CD-DST are established in vitro drug sensitivity tests, which may predict the sensitivity of patients to cytotoxic anticancer drugs. We applied in vitro drug sensitivity tests for cyclopedic prediction of clinical responses to different molecular targeting drugs.The growth inhibitory effects of erlotinib and crizotinib were confirmed for lung cancer cell lines using SDI and CD-DST. The sensitivity of 35 cases of surgically resected lung cancer to erlotinib was examined using SDI or CD-DST, and compared with EGFR mutation status.HCC827 (Exon19: E746-A750 del and H3122 (EML4-ALK cells were inhibited by lower concentrations of erlotinib and crizotinib, respectively than A549, H460, and H1975 (L858R+T790M cells were. The viability of the surgically resected lung cancer was 60.0 ± 9.8 and 86.8 ± 13.9% in EGFR-mutants vs. wild types in the SDI (p = 0.0003. The cell viability was 33.5 ± 21.2 and 79.0 ± 18.6% in EGFR mutants vs. wild-type cases (p = 0.026 in CD-DST.In vitro drug sensitivity evaluated by either SDI or CD-DST correlated with EGFR gene status. Therefore, SDI and CD-DST may be useful predictors of potential clinical responses to the molecular anticancer drugs, cyclopedically.

  2. Toxicological Analysis of Some Drugs of Abuse in Biological Samples

    OpenAIRE

    Anne Marie Ciobanu; Daniela Baconi; Cristian Bălălău; Carolina Negrei; Miriana Stan; Maria Bârcă

    2015-01-01

    Consumption of drugs of abuse is a scourge of modern world. Abuse, drug addiction and their consequences are one of the major current problems of European society because of the significant repercussions in individual, family, social and economic level. In this context, toxicological analysis of the drugs of abuse in biological samples is a useful tool for: diagnosis of drug addiction, checking an auto-response, mandatory screening in some treatment programs, identification of a substance ...

  3. An interfacially plasticized electro-responsive hydrogel for transdermal electro-activated and modulated (TEAM) drug delivery

    NARCIS (Netherlands)

    Indermun, S.; Choonara, Y.E.; Kumar, Pradeep; Toit, Du L.C.; Modi, G.; Luttge, R.; Pillay, V.

    2014-01-01

    This paper highlights the use of hydrogels in controlled drug delivery, and their application in stimuli responsive, especially electro-responsive, drug release. electro-conductive hydrogels (ECHs) displaying electro-responsive drug release were synthesized from semi-interpenetrating networks

  4. Corporate Social Responsibility in the Context of Labor Relations in SMEs

    OpenAIRE

    Villegas González, Yalenis del Valle

    2017-01-01

    The present research article was developed with the purpose of describing Corporate Social Responsibility in the context of Labor Relations and its context to generate attitudinal changes and transformations in Small and Medium Enterprises (SMEs) that have an impact on the transformation of business processes, for production and productivity, contributing to social welfare and the environment, having an impact on the quality of individual life. This research is justified as an emerging vision...

  5. On the demand for prescription drugs: heterogeneity in price responses.

    Science.gov (United States)

    Skipper, Niels

    2013-07-01

    This paper estimates the price elasticity of demand for prescription drugs using an exogenous shift in consumer co-payment caused by a reform in the Danish subsidy scheme for the general public. Using purchasing records for the entire Danish population, I show that the average price response for the most commonly used drug yields demand elasticities in the range of -0.36 to -0.5. The reform is shown to affect women, the elderly, and immigrants the most. Furthermore, this paper shows significant heterogeneity in the price response over different types of antibiotics, suggesting that the price elasticity of demand varies considerably even across relatively similar drugs. Copyright © 2012 John Wiley & Sons, Ltd.

  6. Social contexts modulate neural responses in the processing of others' pain: An event-related potential study.

    Science.gov (United States)

    Cui, Fang; Zhu, Xiangru; Luo, Yuejia

    2017-08-01

    Two hypotheses have been proposed regarding the response that is triggered by observing others' pain: the "empathizing hypothesis" and the "threat value of pain hypothesis." The former suggests that observing others' pain triggers an empathic response. The latter suggests that it activates the threat-detection system. In the present study, participants were instructed to observe pictures that showed an anonymous hand or foot in a painful or non-painful situation in a threatening or friendly social context. Event-related potentials were recorded when the participants passively observed these pictures in different contexts. We observed an interaction between context and picture in the early automatic N1 component, in which the painful pictures elicited a larger amplitude than the non-painful pictures only in the threatening context and not in the friendly context. We also observed an interaction between context and picture in the late P3 component, in which the painful pictures elicited a larger amplitude than the non-painful pictures only in the friendly context and not in the threatening context. These results indicate that specific social contexts can modulate the neural responses to observing others' pain. The "empathic hypothesis" and "threat value of pain hypothesis" are not mutually exclusive and do not contradict each other but rather work in different temporal stages.

  7. Iron oxide nanoparticles for magnetically-guided and magnetically-responsive drug delivery.

    Science.gov (United States)

    Estelrich, Joan; Escribano, Elvira; Queralt, Josep; Busquets, Maria Antònia

    2015-04-10

    In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.

  8. Response inhibition moderates the association between drug use and risky sexual behavior.

    Science.gov (United States)

    Nydegger, Liesl A; Ames, Susan L; Stacy, Alan W; Grenard, Jerry L

    2014-09-01

    HIV infection is problematic among all drug users, not only injection drug users. Drug users are at risk for contracting HIV by engaging in risky sexual behaviors. The present study sought to determine whether inhibitory processes moderate the relationship between problematic drug use and HIV-risk behaviors (unprotected sex and multiple sex partners). One hundred ninety-six drug offenders enrolled in drug education programs were administered a battery of computer-based assessments. Measures included a cued go/no-go assessment of inhibitory processes, the Drug Abuse Screening Test (DAST) assessment of problematic drug use, and self-report assessment of condom use and multiple sex partners. Findings revealed that response inhibition assessed by the proportion of false alarms on the cued go/no-go moderated the relationship between problematic drug use and an important measure of HIV risk (condom nonuse) among drug offenders. However, response inhibition did not moderate the relationship between problematic drug use and another measure of HIV risk: multiple sex partners. Among this sample of drug offenders, we have found a relationship between problematic drug use and condom nonuse, which is exacerbated by poor control of inhibition. These findings have implications for the development of HIV intervention components among high-risk populations.

  9. Potential and problems in ultrasound-responsive drug delivery systems

    Directory of Open Access Journals (Sweden)

    Zhao YZ

    2013-04-01

    Full Text Available Ying-Zheng Zhao,1,3 Li-Na Du,2 Cui-Tao Lu,1 Yi-Guang Jin,2 Shu-Ping Ge3 1Wenzhou Medical College, Wenzhou City, Zhejiang Province, 2Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China; 3St Christopher’s Hospital for Children/Drexel University College of Medicine, Philadelphia, PA, USA Abstract: Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington’s disease, thrombolysis, and disruption of the blood–brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future. Keywords: ultrasound, targeted therapy, clinical application

  10. Analysing task design and students' responses to context-based problems through different analytical frameworks

    Science.gov (United States)

    Broman, Karolina; Bernholt, Sascha; Parchmann, Ilka

    2015-05-01

    Background:Context-based learning approaches are used to enhance students' interest in, and knowledge about, science. According to different empirical studies, students' interest is improved by applying these more non-conventional approaches, while effects on learning outcomes are less coherent. Hence, further insights are needed into the structure of context-based problems in comparison to traditional problems, and into students' problem-solving strategies. Therefore, a suitable framework is necessary, both for the analysis of tasks and strategies. Purpose:The aim of this paper is to explore traditional and context-based tasks as well as students' responses to exemplary tasks to identify a suitable framework for future design and analyses of context-based problems. The paper discusses different established frameworks and applies the Higher-Order Cognitive Skills/Lower-Order Cognitive Skills (HOCS/LOCS) taxonomy and the Model of Hierarchical Complexity in Chemistry (MHC-C) to analyse traditional tasks and students' responses. Sample:Upper secondary students (n=236) at the Natural Science Programme, i.e. possible future scientists, are investigated to explore learning outcomes when they solve chemistry tasks, both more conventional as well as context-based chemistry problems. Design and methods:A typical chemistry examination test has been analysed, first the test items in themselves (n=36), and thereafter 236 students' responses to one representative context-based problem. Content analysis using HOCS/LOCS and MHC-C frameworks has been applied to analyse both quantitative and qualitative data, allowing us to describe different problem-solving strategies. Results:The empirical results show that both frameworks are suitable to identify students' strategies, mainly focusing on recall of memorized facts when solving chemistry test items. Almost all test items were also assessing lower order thinking. The combination of frameworks with the chemistry syllabus has been

  11. Improving measurement of injection drug risk behavior using item response theory.

    Science.gov (United States)

    Janulis, Patrick

    2014-03-01

    Recent research highlights the multiple steps to preparing and injecting drugs and the resultant viral threats faced by drug users. This research suggests that more sensitive measurement of injection drug HIV risk behavior is required. In addition, growing evidence suggests there are gender differences in injection risk behavior. However, the potential for differential item functioning between genders has not been explored. To explore item response theory as an improved measurement modeling technique that provides empirically justified scaling of injection risk behavior and to examine for potential gender-based differential item functioning. Data is used from three studies in the National Institute on Drug Abuse's Criminal Justice Drug Abuse Treatment Studies. A two-parameter item response theory model was used to scale injection risk behavior and logistic regression was used to examine for differential item functioning. Item fit statistics suggest that item response theory can be used to scale injection risk behavior and these models can provide more sensitive estimates of risk behavior. Additionally, gender-based differential item functioning is present in the current data. Improved measurement of injection risk behavior using item response theory should be encouraged as these models provide increased congruence between construct measurement and the complexity of injection-related HIV risk. Suggestions are made to further improve injection risk behavior measurement. Furthermore, results suggest direct comparisons of composite scores between males and females may be misleading and future work should account for differential item functioning before comparing levels of injection risk behavior.

  12. Iron Oxide Nanoparticles for Magnetically-Guided and Magnetically-Responsive Drug Delivery

    Directory of Open Access Journals (Sweden)

    Joan Estelrich

    2015-04-01

    Full Text Available In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.

  13. The Neural Responses to Social Cooperation in Gain and Loss Context.

    Directory of Open Access Journals (Sweden)

    Peng Sun

    Full Text Available Cooperation is pervasive and constitutes the core behavioral principle of human social life. Previous studies have revealed that mutual cooperation was reliably correlated with two reward-related brain regions, the ventral striatum and the orbitofrontal cortex. Using functional magnetic resonance imaging (fMRI, this study sought to investigate how the loss and gain contexts modulated the neural responses to mutual cooperation. Twenty-five female participants were scanned when they played a series of one-shot prisoner's dilemma games in the loss and gain contexts. Specifically, participants and partners independently chose to either cooperate with each other or not, and each was awarded or deprived of (in the gain context or the loss context, respectively a sum of money which depended upon the interaction of their choices. Behavioral results indicated that participants cooperated in nearly half of the experiment trials and reported higher level of positive emotions for mutual cooperation in both contexts, but they cooperated more in the gain than in the loss context. At the neural level, stronger activities in the orbitofrontal cortex were observed for mutual cooperation compared with the other three outcomes in both contexts, while stronger activation in ventral striatum associated with mutual cooperation was observed in the gain context only. Together, our data indicated that, even in the one-shot interaction under loss context, participants still exhibited preference for cooperation and the rewarding experience from a mutually cooperative social interaction activated the ventral striatum and the orbitofrontal cortex, but the loss context weakened the association between the ventral striatum activation and mutual cooperation.

  14. d-Cycloserine reduces context specificity of sexual extinction learning.

    Science.gov (United States)

    Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

    2015-11-01

    d-Cycloserine (DCS) enhances extinction processes in animals. Although classical conditioning is hypothesized to play a pivotal role in the aetiology of appetitive motivation problems, no research has been conducted on the effect of DCS on the reduction of context specificity of extinction in human appetitive learning, while facilitation hereof is relevant in the context of treatment of problematic reward-seeking behaviors. Female participants were presented with two conditioned stimuli (CSs) that either predicted (CS+) or did not predict (CS-) a potential sexual reward (unconditioned stimulus (US); genital vibrostimulation). Conditioning took place in context A and extinction in context B. Subjects received DCS (125mg) or placebo directly after the experiment on day 1 in a randomized, double-blind, between-subject fashion (Placebo n=31; DCS n=31). Subsequent testing for CS-evoked conditioned responses (CRs) in both the conditioning (A) and the extinction context (B) took place 24h later on day 2. Drug effects on consolidation were then assessed by comparing the recall of sexual extinction memories between the DCS and the placebo groups. Post learning administration of DCS facilitates sexual extinction memory consolidation and affects extinction's fundamental context specificity, evidenced by reduced conditioned genital and subjective sexual responses, relative to placebo, for presentations of the reward predicting cue 24h later outside the extinction context. DCS makes appetitive extinction memories context-independent and prevents the return of conditioned response. NMDA receptor glycine site agonists may be potential pharmacotherapies for the prevention of relapse of appetitive motivation disorders with a learned component. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. A survey of antiepileptic drug responses identifies drugs with potential efficacy for seizure control in Wolf-Hirschhorn syndrome.

    Science.gov (United States)

    Ho, Karen S; Markham, Leah M; Twede, Hope; Lortz, Amanda; Olson, Lenora M; Sheng, Xiaoming; Weng, Cindy; Wassman, E Robert; Newcomb, Tara; Wassman, E Robert; Carey, John C; Battaglia, Agatino

    2018-04-01

    Seizures are present in over 90% of infants and children with Wolf-Hirschhorn syndrome (WHS). When present, they significantly affect quality of life. The goal of this study was to use caregiver reports to describe the comparative efficacies of commonly used antiepileptic medications in a large population of individuals with WHS. A web-based, confidential caregiver survey was developed to capture seizure semiology and a chronologic record of seizure treatments as well as responses to each treatment. Adverse events for each drug were also cataloged. We received 141 complete survey responses (47% response rate) describing the seizures of individuals ranging in age from 4months to 61years (90 females: 51 males). Using the Early Childhood Epilepsy Severity Scale (E-Chess), WHS-associated seizures are demonstrably severe regardless of deletion size. The best-performing antiepileptic drugs (AEDs) for controlling seizures in this cohort were broad spectrum drugs clobazam, levetiracetam, and lamotrigine; whereas, the three commonly used carboxamide class drugs: carbamazepine, phenytoin, and oxcarbazepine, were reported to have little effect on, or even exacerbate, seizures. The carboxamide class drugs, along with phenobarbital and topiramate, were also associated with the highest rate of intolerance due to cooccurrence of adverse events. Levetiracetam, clobazam, and clonazepam demonstrated higher tolerability and comparatively less severe adverse events (Wilcoxon rank sum comparison between performance of levetiracetam and carboxamide class drugs gives a psyndromes which may have complex seizure etiologies. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Social innovation in the context of corporate social responsibility

    Directory of Open Access Journals (Sweden)

    María de Fátima León

    2012-10-01

    Full Text Available Faced with a reality characterized by unsolved social and environmental problems, it is common to observe the behavior of firms in terms of its contribution in the resolution or treatment of these problems. Many of these initiatives are examples of social innovations offering new products, processes and relationships in terms of benefiting the most disadvantaged groups in areas such as safety, health, education, environment, among others. In this sense, this documentary research examines the role of social innovation in the context of corporate social responsibility, through a review of theoretical topic of innovation, social innovation and corporate social responsibility. Also, through the filter of what can be considered social innovation, raises some examples of Venezuelan companies with socially responsible approaches moving toward maturity in a socially ethical enterprise.

  17. Relationship Between Time Consumption and Quality of Responses to Drug-related Queries

    DEFF Research Database (Denmark)

    Amundstuen Reppe, Linda; Lydersen, Stian; Schjøtt, Jan

    2016-01-01

    in score, –0.05 per hour of work; 95% CI, –0.08 to –0.01; P = 0.005). No such associations were found for the internal experts’ assessment. Implications To our knowledge, this is the first study of the association between time consumption and quality of responses to drug-related queries in DICs......Purpose The aims of this study were to assess the quality of responses produced by drug information centers (DICs) in Scandinavia, and to study the association between time consumption processing queries and the quality of the responses. Methods We posed six identical drug-related queries to seven...... DICs in Scandinavia, and the time consumption required for processing them was estimated. Clinical pharmacologists (internal experts) and general practitioners (external experts) reviewed responses individually. We used mixed model linear regression analyses to study the associations between time...

  18. Drug diffusion and biological responses of arteries using a drug-eluting stent with nonuniform coating

    Directory of Open Access Journals (Sweden)

    Saito N

    2016-03-01

    Full Text Available Noboru Saito, Yuhei Mori, Sayaka Uchiyama Terumo Corporation R&D Center, Inokuchi, Nakai-machi, Ashigarakami-gun, Kanagawa, Japan Abstract: The purpose of this study was to determine the effect of a nonuniform coating, abluminal-gradient coating (AGC, which leaves the abluminal surface of the curves and links parts of the stent free from the drug coating, on the diffusion direction of the drug and the biological responses of the artery to drug-eluting stent (DES by comparing the AGC-sirolimus stent and the conventional full-surface coating (CFC sirolimus stent. The study aimed to verify whether the AGC approach was appropriate for the development of a safer DES, minimizing the risks of stent thrombosis due to delayed endothelialization by the drug and distal embolization due to cracking of the coating layer on the hinge parts of the DES on stent expansion. In the in vitro local drug diffusion study, we used rhodamine B as a model drug, and rhodamine B released from the AGC stent diffused predominantly into the abluminal side of the alginate artery model. Conversely, rhodamine B released from the CFC stent quickly spread to the luminal side of the artery model, where endothelial cell regeneration is required. In the biological responses study, the luminal surface of the iliac artery implanted with the AGC-sirolimus stent in a rabbit iliac artery for 2 weeks was completely covered with endothelial-like cells. On the other hand, the luminal surface of the iliac artery implanted with the CFC-sirolimus stent for 2 weeks only showed partial coverage with endothelial-like cells. While thrombosis was observed in two of the three CFC-sirolimus stents, it was observed in only one of the three AGC-sirolimus stents. Taken together, these findings indicate that the designed nonuniform coating (AGC is an appropriate approach to ensure a safer DES. However, the number of studies is limited and a larger study should be conducted to reach a statistically

  19. Stimuli-Responsive Liposomes for Controlled Drug Delivery

    KAUST Repository

    Li, Wengang

    2014-09-01

    Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery applications. Herein, a novel method was devised for modification of liposomes with small molecules, polymers or nanoparticles to afford stimuli responsive systems that release on demand and stay relatively stable in the absence of the trigger.. This dissertation discusses thermosensitive, pH sensitive, light sensitive and magnetically triggered liposomes that have been prepared for controlled drug delivery application. RAFT polymerization was utilized for the preparation of thermosensitive liposomes (Cholesterol-PNIPAm) and acid-labile liposomes (DOPE-PAA). With low Mw Cholesterol-PNIPAm, the thermosensitive liposomes proved to be effective for controlled release and decreased the cytotoxicity of PNIPAm by eliciting the polymer doses. By crosslinking the DOPE-PAA on liposome surface with acid-labile diamine linkers, DOPE-PAA liposomes were verified to be sensitive at low pH. The effects of polymer structures (linear or hyperbranched) have also been studied for the stability and release properties of liposomes. Finally, a dual-responsive Au@SPIO embedded liposome hybrid (ALHs) was prepared with light-induced “on-and-off” function by photo-thermal process (visible light) and instant release properties triggered by alternating magnetic field, respectively. The ALH system would be further applied into the cellular imaging field as MRI contrast agent.

  20. Random Forest Segregation of Drug Responses May define Regions of Biological Significance

    Directory of Open Access Journals (Sweden)

    Qasim eBukhari

    2016-03-01

    Full Text Available The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF method to detect differences in the pharmacological MRI (phMRI response in rats to treatment with an analgesic drug (buprenorphine as compared to control (saline. Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD and high dose (HD, and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow an unsupervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies.

  1. The art of anger: reward context turns avoidance responses to anger-related objects into approach.

    Science.gov (United States)

    Aarts, Henk; Ruys, Kirsten I; Veling, Harm; Renes, Robert A; de Groot, Jasper H B; van Nunen, Anna M; Geertjes, Sarit

    2010-10-01

    Anger has a special status among the emotions in that it can elicit avoidance as well as approach motivation. This study tested the ignored role of reward context in potentiating approach rather than avoidance responses toward objects associated with anger. In Experiment 1, angry and neutral facial expressions were parafoveally paired with common objects, and responses to the objects were assessed by subjective reports of motivation to obtain them. In Experiment 2, objects were again paired with angry or neutral faces outside of participants' awareness, and responses toward the objects were indexed by physical effort expended in attempting to win them. Results showed that approach motivation toward anger-related objects can be observed when responding is framed in terms of rewards that one can obtain, whereas avoidance motivation occurs in the absence of such a reward context. These findings point to the importance of a reward context in modulating people's responses to anger.

  2. Predicting multi-level drug response with gene expression profile in multiple myeloma using hierarchical ordinal regression.

    Science.gov (United States)

    Zhang, Xinyan; Li, Bingzong; Han, Huiying; Song, Sha; Xu, Hongxia; Hong, Yating; Yi, Nengjun; Zhuang, Wenzhuo

    2018-05-10

    Multiple myeloma (MM), like other cancers, is caused by the accumulation of genetic abnormalities. Heterogeneity exists in the patients' response to treatments, for example, bortezomib. This urges efforts to identify biomarkers from numerous molecular features and build predictive models for identifying patients that can benefit from a certain treatment scheme. However, previous studies treated the multi-level ordinal drug response as a binary response where only responsive and non-responsive groups are considered. It is desirable to directly analyze the multi-level drug response, rather than combining the response to two groups. In this study, we present a novel method to identify significantly associated biomarkers and then develop ordinal genomic classifier using the hierarchical ordinal logistic model. The proposed hierarchical ordinal logistic model employs the heavy-tailed Cauchy prior on the coefficients and is fitted by an efficient quasi-Newton algorithm. We apply our hierarchical ordinal regression approach to analyze two publicly available datasets for MM with five-level drug response and numerous gene expression measures. Our results show that our method is able to identify genes associated with the multi-level drug response and to generate powerful predictive models for predicting the multi-level response. The proposed method allows us to jointly fit numerous correlated predictors and thus build efficient models for predicting the multi-level drug response. The predictive model for the multi-level drug response can be more informative than the previous approaches. Thus, the proposed approach provides a powerful tool for predicting multi-level drug response and has important impact on cancer studies.

  3. Photocuring of stimulus responsive membranes for controlled-release of drugs having different molecular weights

    International Nuclear Information System (INIS)

    Ng, Loo-Teck; Nakayama, Hiroshi; Kaetsu, Isao; Uchida, Kumao

    2005-01-01

    Intelligent drug delivery membranes were prepared by photocuring poly(acrylic acid) coatings onto poly(2-hydroxyethyl methacrylate) membranes each with model drugs of different molecular weights being incorporated. pH-responsive release behaviours of the model drugs which included sodium salicylate, nicotinamide, nicotinic acid, methylene blue, brilliant green and crystal violet were investigated. Only the membrane with methylene blue incorporated showed a clear pH-responsive release and other drug-incorporated membranes showed no intelligent behaviour. These phenomena were explained in terms of the difference in diffusivity of drugs through polymer matrices of the membranes attributable to the difference in the molecular weights of drugs

  4. Photocuring of stimulus responsive membranes for controlled-release of drugs having different molecular weights

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Loo-Teck [School of Science, Food and Horticulture, University of Western Sydney, Locked bag 1797, Penrith South DC, NSW 1797 (Australia)]. E-mail: l.ng@uws.edu.au; Nakayama, Hiroshi [Department of Nuclear Engineering, Faculty of Science and technology, Kinki University, Kowakae, 3-4-1, Higashi-Osaka 577-8502 (Japan); Kaetsu, Isao [Department of Nuclear Engineering, Faculty of Science and technology, Kinki University, Kowakae, 3-4-1, Higashi-Osaka 577-8502 (Japan)]. E-mail: kaetsu@ned.kindai.ac.jp; Uchida, Kumao [Department of Nuclear Engineering, Faculty of Science and technology, Kinki University, Kowakae, 3-4-1, Higashi-Osaka 577-8502 (Japan)

    2005-06-01

    Intelligent drug delivery membranes were prepared by photocuring poly(acrylic acid) coatings onto poly(2-hydroxyethyl methacrylate) membranes each with model drugs of different molecular weights being incorporated. pH-responsive release behaviours of the model drugs which included sodium salicylate, nicotinamide, nicotinic acid, methylene blue, brilliant green and crystal violet were investigated. Only the membrane with methylene blue incorporated showed a clear pH-responsive release and other drug-incorporated membranes showed no intelligent behaviour. These phenomena were explained in terms of the difference in diffusivity of drugs through polymer matrices of the membranes attributable to the difference in the molecular weights of drugs.

  5. Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses.

    Science.gov (United States)

    Morris, Aaron H; Mahal, Rajwant S; Udell, Jillian; Wu, Michelle; Kyriakides, Themis R

    2017-10-01

    Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Hydrophilic magnetic nanoclusters with thermo-responsive properties and their drug controlled release

    International Nuclear Information System (INIS)

    Meerod, Siraprapa; Rutnakornpituk, Boonjira; Wichai, Uthai; Rutnakornpituk, Metha

    2015-01-01

    Synthesis and drug controlled release properties of thermo-responsive magnetic nanoclusters grafted with poly(N-isopropylacrylamide) (poly(NIPAAm)) and poly(NIPAAm-co-poly(ethylene glycol) methyl ether methacrylate) (PEGMA) copolymers were described. These magnetic nanoclusters were synthesized via an in situ radical polymerization in the presence of acrylamide-grafted magnetic nanoparticles (MNPs). Poly(NIPAAm) provided thermo-responsive properties, while PEGMA played a role in good water dispersibility to the nanoclusters. The ratios of PEGMA to NIPAAm in the (co)polymerization in the presence of the MNPs were fine-tuned such that the nanoclusters with good water dispersibility, good magnetic sensitivity and thermo responsiveness were obtained. The size of the nanoclusters was in the range of 50–100 nm in diameter with about 100–200 particles/cluster. The nanoclusters were well dispersible in water at room temperature and can be suddenly agglomerated when temperature was increased beyond the lower critical solution temperature (LCST) (32 °C). The release behavior of an indomethacin model drug from the nanoclusters was also investigated. These novel magnetic nanoclusters with good dispersibility in water and reversible thermo-responsive properties might be good candidates for the targeting drug controlled release applications. - Highlights: • Nanoclusters with good water dispersibility and magnetic response were prepared. • They were grafted with thermo-responsive poly(NIPAAm) and/or poly(PEGMA). • Poly(NIPAAm) provided thermo-responsive properties to the nanoclusters. • Poly(PEGMA) provided good water dispersibilityto the nanoclusters. • Accelerated and controllable releases of a drug from the nanoclusters were shown

  7. Context-sensitive fluid administration: what, when and how much?

    African Journals Online (AJOL)

    As with all drugs, fluid therapy must be regarded as context sensitive. If a drug is given ... context of plasma volume replacement, the context is again different, and a ... Open Access article distributed under the terms of the. Creative Commons ...

  8. Plenary III–04: Responses to Drug Costs: Year Three of the Medicare Part D Program

    OpenAIRE

    Fung, Vicki; Reed, Mary; Hsu, John

    2010-01-01

    Background/Aims: Many Medicare Part D beneficiaries face substantial prescription drug cost-sharing. In the first year of the program, many beneficiaries reported substantial drug use changes in response to the coverage gap. In response, an increasing number of plans offer generic drug coverage during the gap. We compared responses to Part D costs among beneficiaries with generic-only gap coverage and full gap coverage in 2008, the third year of the Part D program.

  9. Women's responses to intimate partner violence in Rwanda: Rethinking agency in constrained social contexts.

    Science.gov (United States)

    Mannell, Jenevieve; Jackson, Sharon; Umutoni, Aline

    2016-01-01

    This paper explores instances of agency in women's responses to intimate partner violence (IPV) in Rwanda. The literature on women's responses to IPV conceptualises agency primarily as an individual's capacity to take action by reporting violence or leaving a relationship, obscuring other ways women may respond to violence in contexts where reporting or leaving are unlikely. We aim to replace this narrow conceptualisation of agency with a social constructivist focus on the meanings women attribute to possible IPV responses. We draw on data from a study of IPV in Rwanda, which includes semi-structured interviews with women experiencing violence and four focus group discussions with women community members (n = 39). Our findings highlight sociocultural, economic, political-legal and historical constraints that shape women's actions in this context. In relation to these constraints, women describe four possible responses to IPV: reporting the violence; seeking emotional support; 'fighting back' against violence; or remaining silent. While reporting and leaving violent relationships are identified, women also discuss the social constraints that make these actions extremely difficult. In designing effective strategies, we conclude that public health strategies need to consider women's understandings of their own actions, particularly in social contexts where certain actions may be constrained.

  10. Lack of renewal effect in extinction of naturally acquired conditioned eyeblink responses, but possible dependency on physical context.

    Science.gov (United States)

    Claassen, J; Mazilescu, L; Thieme, A; Bracha, V; Timmann, D

    2016-01-01

    Context dependency of extinction is well known and has extensively been studied in fear conditioning, but has rarely been assessed in eyeblink conditioning. One way to demonstrate context dependency of extinction is the renewal effect. ABA paradigms are most commonly used to show the renewal effect of extinguished learned fear: if acquisition takes place in context A, and extinction takes place in context B (extinction phase), learned responses will recover in subsequent extinction trials presented in context A (renewal phase). The renewal effect of the visual threat eyeblink response (VTER), a conditioned eyeblink response, which is naturally acquired in early infancy, was examined in a total of 48 young and healthy participants with two experiments using an ABA paradigm. Twenty paired trials were performed in context A (baseline trials), followed by 50 extinction trials in context B (extinction phase) and 50 extinction trials in context A (renewal phase). In 24 participants, contexts A and B were two different rooms, and in the other 24 participants, two different background colors (orange and blue) and noises were used. To rule out spontaneous recovery, an AAA design was used for comparison. There were significant effects of extinction in both experiments. No significant renewal effects were observed. In experiment 2, however, extinction was significantly less using orange background during extinction compared to the blue background. The present findings suggest that extinction of conditioned eyeblinks depends on the physical context. Findings add to the animal literature that context can play a role in the acquisition of classically conditioned eyeblink responses. Future studies, however, need to be performed to confirm the present findings. Lack of renewal effect may be explained by the highly overlearned character of the VTER.

  11. Meningococcal disease and future drug targets

    DEFF Research Database (Denmark)

    Gammelgaard, L K; Colding, H; Hartzen, S H

    2011-01-01

    recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets...... for novel neuroprotective adjuvants, which are needed in order to improve the clinical management of meningoencephalitis and patient prognosis....

  12. pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms.

    Science.gov (United States)

    Liu, Lin; Yao, WenDong; Rao, YueFeng; Lu, XiaoYang; Gao, JianQing

    2017-11-01

    Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.

  13. Neuroimaging Impaired Response Inhibition and Salience Attribution in Human Drug Addiction: A Systematic Review.

    Science.gov (United States)

    Zilverstand, Anna; Huang, Anna S; Alia-Klein, Nelly; Goldstein, Rita Z

    2018-06-06

    The impaired response inhibition and salience attribution (iRISA) model proposes that impaired response inhibition and salience attribution underlie drug seeking and taking. To update this model, we systematically reviewed 105 task-related neuroimaging studies (n > 15/group) published since 2010. Results demonstrate specific impairments within six large-scale brain networks (reward, habit, salience, executive, memory, and self-directed networks) during drug cue exposure, decision making, inhibitory control, and social-emotional processing. Addicted individuals demonstrated increased recruitment of these networks during drug-related processing but a blunted response during non-drug-related processing, with the same networks also being implicated during resting state. Associations with real-life drug use, relapse, therapeutic interventions, and the relevance to initiation of drug use during adolescence support the clinical relevance of the results. Whereas the salience and executive networks showed impairments throughout the addiction cycle, the reward network was dysregulated at later stages of abuse. Effects were similar in alcohol, cannabis, and stimulant addiction. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Ethics for pandemics beyond influenza: Ebola, drug-resistant tuberculosis, and anticipating future ethical challenges in pandemic preparedness and response.

    Science.gov (United States)

    Smith, Maxwell J; Silva, Diego S

    2015-01-01

    The unprecedented outbreak of Ebola virus disease (EVD) in West Africa has raised several novel ethical issues for global outbreak preparedness. It has also illustrated that familiar ethical issues in infectious disease management endure despite considerable efforts to understand and mitigate such issues in the wake of past outbreaks. To improve future global outbreak preparedness and response, we must examine these shortcomings and reflect upon the current state of ethical preparedness. To this end, we focus our efforts in this article on the examination of one substantial area: ethical guidance in pandemic plans. We argue that, due in part to their focus on considerations arising specifically in relation to pandemics of influenza origin, pandemic plans and their existing ethical guidance are ill-equipped to anticipate and facilitate the navigation of unique ethical challenges that may arise in other infectious disease pandemics. We proceed by outlining three reasons why this is so, and situate our analysis in the context of the EVD outbreak and the threat posed by drug-resistant tuberculosis: (1) different infectious diseases have distinct characteristics that challenge anticipated or existing modes of pandemic prevention, preparedness, response, and recovery, (2) clear, transparent, context-specific ethical reasoning and justification within current influenza pandemic plans are lacking, and (3) current plans neglect the context of how other significant pandemics may manifest. We conclude the article with several options for reflecting upon and ultimately addressing ethical issues that may emerge with different infectious disease pandemics.

  15. Apoptosis-related molecular differences for response to tyrosin kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

    Directory of Open Access Journals (Sweden)

    Jixia Li

    2013-01-01

    Full Text Available Context: The epidermal growth factor receptor (EGFR family is reportedly overexpressed in bladder cancer, and tyrosine kinaseinhibitors (TKIs have been suggested as treatment. Gefitinib is a selective inhibitor of the EGFR and lapatinib is a dual inhibitor of both the EGFR and HER2 (human EGFR type 2 receptor. Both compounds compete with the binding of adenosine triphosphate (ATP to the tyrosine kinase domain of the respective receptors to inhibit receptor autophosphorylation causing suppression of signal transduction. Unfortunately, resistance to these inhibitors is a major clinical problem. Aims: To compare the apoptosis signaling pathway(s induced by gefitinib and lapatinib, in UM-UC-5 (drug-sensitive and UM-UC-14 (drug-resistant bladder cancer cells and to identify molecular differences that might be useful predictors of their efficacy. Materials and Methods: Cell proliferation, cell cycle and apoptosis assay were used to detect the effect of TKIs on UM-UC-5 and UM-UC-14 cells. Molecular differences for response to TKIs were examined by protein array. Results: TKIs strongly inhibited cell proliferation and induced cell cycle G1 arrest and apoptosis in UM-UC-5 cells. Most notable apoptosis molecular differences included decreased claspin, trail, and survivin by TKIs in the sensitive cells. In contrast, TKIs had no effect on resistant cells. Conclusions: Claspin, trail, and survivin might be used to determine the sensitivity of bladder cancers to TKIs.

  16. Thermo-responsive polymer-functionalized mesoporous carbon for controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Shenmin, E-mail: smzhu@sjtu.edu.cn [State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China); Chen Chenxin [State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China); Chen Zhixin [Faculty of Engineering, University of Wollongong, Wollongong, NSW 2522 (Australia); Liu Xinye; Li Yao; Shi Yang; Zhang Di [State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China)

    2011-03-15

    Research highlights: {yields} A responsive drug delivery system based on poly(N-isopropyl acrylamide) (PNIPAM) functionalized ordered mesoporous carbon (CMK-3) is developed. {yields} A combination of surface modification of CMK-3 and in situ internal polymerization of PNIPAM was used. {yields} The system exhibited a pronounced transition at around 20-25 deg. C. - Abstract: A novel responsive drug delivery system based on poly(N-isopropyl acrylamide) (PNIPAM) functionalized ordered mesoporous carbon (CMK-3) is developed. The polymer-functionalized CMK-3 was obtained by a combination of simple surface modification of CMK-3 and in situ internal polymerization of PNIPAM. The formation of the PNIPAM inside the CMK-3 was confirmed by thermal gravimetric analysis, Fourier transform-infrared spectroscopy, scanning and transmission electron microscopy and N{sub 2} adsorption/desorption measurements. Controlled drug release tests through the porous network of the PNIPAM functionalized CMK-3 were carried out by measuring the uptake and release of ibuprofen in vitro. The release profiles exhibited a pronounced transition at around 20-25 deg. C. This thermo-sensitive release property of this delivery system was further confirmed by temperature-variable hydrogen nuclear magnetic resonance analysis. The internal PNIPAM layers acted as a storage gate as well as a release switch in response to the stimuli of environment.

  17. Pavlovian conditioning of multiple opioid-like responses in mice

    OpenAIRE

    Bryant, Camron D.; Roberts, Kristofer W.; Culbertson, Christopher S.; Le, Alan; Evans, Christopher J.; Fanselow, Michael S.

    2009-01-01

    Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2 mg/kg, i.p.) in a novel context and subsequently g...

  18. Proteomic profiling of the antifungal drug response of Aspergillus fumigatus to voriconazole.

    Science.gov (United States)

    Amarsaikhan, Nansalmaa; Albrecht-Eckardt, Daniela; Sasse, Christoph; Braus, Gerhard H; Ogel, Zumrut B; Kniemeyer, Olaf

    2017-10-01

    Antifungal resistance is an emerging problem and one of the reasons for treatment failure of invasive aspergillosis (IA). Voriconazole has become a standard therapeutic for the treatment of this often fatal infection. We studied the differentially expressed proteins as a response of Aspergillus fumigatus to voriconazole by employing the two-dimensional difference gel electrophoresis (DIGE) technique. Due to addition of drug, a total of 135 differentially synthesized proteins were identified by MALDI-TOF/TOF-mass spectrometry. In particular, the level of proteins involved in the general stress response and cell detoxification increased prominently. In contrast, cell metabolism and energy proteins were down-regulated, which suggests the cellular effort to maintain balance in energy utilization while trying to combat the cellular stress exerted by the drug. We detected several so-far uncharacterized proteins which may play a role in stress response and drug metabolism and which could be future targets for antifungal treatment. A mutant strain, which is deleted in the cross-pathway control gene cpcA, was treated with voriconazole to investigate the contribution of the general control of amino acid biosynthesis to drug resistance. We compared the mutant strain's protein expression profile with the wild-type strain. The absence of CpcA led to an increased resistance to voriconazole and a reduced activation of some general stress response proteins, while the transcript level of the triazole target gene erg11A (cyp51A) remained unchanged. In contrast, the sensitivity of strain ΔcpcA to terbinafine and amphotericin B was slightly increased. These findings imply a role of CpcA in the cellular stress response to azole drugs at the post transcriptional level. Copyright © 2017 Elsevier GmbH. All rights reserved.

  19. Capturing community context of human response to forest disturbance by insects: a multi-method assessment

    Science.gov (United States)

    Hua Qin; Courtney G. Flint

    2010-01-01

    The socioeconomic and environmental features of local places (community context) influence the relationship between humans and their physical environment. In times of environmental disturbance, this community context is expected to influence human perceptual and behavioral responses. Residents from nine Colorado communities experiencing a large outbreak of mountain...

  20. Value Creation in the Context of Sustainable Corporate Social Responsibility

    Science.gov (United States)

    Šmida, Ľubomír; Sakál, Peter

    2014-12-01

    Under the influence of the new rules of the economy and the society, companies are achieving a notional line of a necessary change in the approach to creating new value, wealth. Implementation of changes in the system of wealth creation requires a review of existing assumptions of unlimited growth of the global economy and wealth creation in the environment accepting economic interests, society and the environment as a holistic unit. The main purpose of this paper is the clarification of a new requirements for business, presentation of the questionnaire survey Sustainable Corporate Social Responsibility and inform on value creation in the context of Sustainable Corporate Social Responsibility.

  1. Value Creation in the Context of Sustainable Corporate Social Responsibility

    Directory of Open Access Journals (Sweden)

    Šmida Ľubomír

    2014-12-01

    Full Text Available Under the influence of the new rules of the economy and the society, companies are achieving a notional line of a necessary change in the approach to creating new value, wealth. Implementation of changes in the system of wealth creation requires a review of existing assumptions of unlimited growth of the global economy and wealth creation in the environment accepting economic interests, society and the environment as a holistic unit. The main purpose of this paper is the clarification of a new requirements for business, presentation of the questionnaire survey Sustainable Corporate Social Responsibility and inform on value creation in the context of Sustainable Corporate Social Responsibility.

  2. Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Valerio Costa

    2016-06-01

    Full Text Available Type 2 diabetes (T2D is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9 or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG. However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene—currently annotated as intronic—fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP, currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing.

  3. Pavlovian conditioning of multiple opioid-like responses in mice.

    Science.gov (United States)

    Bryant, Camron D; Roberts, Kristofer W; Culbertson, Christopher S; Le, Alan; Evans, Christopher J; Fanselow, Michael S

    2009-07-01

    Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to "demonstrator" mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in "observer" mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice.

  4. Magnetocaloric effect in magnetothermally-responsive nanocarriers for hyperthermia-triggered drug release

    International Nuclear Information System (INIS)

    Li Jianbo; Qu Yang; Ren Jie; Yuan Weizhong; Shi Donglu

    2012-01-01

    The magnetocaloric effects and lower critical solution temperature (LCST) were investigated in a magnetothermally-responsive nanocarrier for magnetothermal drug release under alternating magnetic field (AMF). The Mn 0.2 Zn 0.8 Fe 2 O 4 nanoparticles with low T c were dispersed in a polymeric matrix consisting of N-Isopropyl acrylamide (NIPAAm) and N-hydroxymethyl acrylamide (HMAAm). The magnetocaloric effects and LCST of the nanocarriers were characterized by using high-resolution electron transmission microscopy, thermogravimetric analyses, and vibrating sample magnetometer. The maximum self-heating temperature of 42.9 °C was achieved by optimizing the Mn 0.2 Zn 0.8 Fe 2 O 4 concentration in the polymer matrix. By adjusting the NIPAAm to HMAAm ratio, the LCST was controlled at an ideal level of 40.1 °C for efficient thermosensitive drug delivery. Magnetothermally responsive drug release of Doxorubicin, an anticancer drug, was significantly enhanced by application of an external AMF on the nanocarriers. The cytotoxicity experimental results in vitro show good biocompatibility and efficient therapeutic effects in cancer treatment. (paper)

  5. Drug response prediction in high-risk multiple myeloma

    DEFF Research Database (Denmark)

    Vangsted, A J; Helm-Petersen, S; Cowland, J B

    2018-01-01

    from high-risk patients by GEP70 at diagnosis from Total Therapy 2 and 3A to predict the response by the DRP score of drugs used in the treatment of myeloma patients. The DRP score stratified patients further. High-risk myeloma with a predicted sensitivity to melphalan by the DRP score had a prolonged...

  6. Defining and redefining harm reduction in the Lao context

    Directory of Open Access Journals (Sweden)

    Sychareun Vanphanom

    2012-07-01

    Full Text Available Abstract 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.

  7. Typical Responses in Giving Evaluation: An Analysis of High and Low Context Culture Communication

    Directory of Open Access Journals (Sweden)

    Ferany Arifin

    2013-05-01

    Full Text Available This paper aims at discussing high and low context in responses given by the students to evaluate their friend’s impromptu speech performance. The study focuses on the characteristics of high and low context represented specifically on (1 direct-indirect (2 simple-complex response, and (3 relationship orientation. The study is based on the analysis of ten responses given by ten students with different sexes. Classroom observation followed by transcription analysis is used. The data were collected naturally at undergraduate campus. The result shows that using indirect and complex responses can maintain harmonious relationship with others. The basic asumption is that the students tend to communicate in high level context. Penelitian ini bertujuan untuk membahas konteks tinggi dan rendah dalam mengevaluasi performansi pidato tanpa persiapan temannya. Penelitian ini memusatkan perhatian pada ciri konteks tinggi dan rendah yang direpresentasikan oleh (1 tanggapan langsung-tak langsung (2 sederhana-kompleks, dan (3 orientasi hubungan. Penelitian ini didasarkan pada sepuluh tanggapan yang diberikan oleh sepuluh mahasiswa pria dan wanita. Pengamatan kelas yang diikuti dengan analisis transkripsi digunakan untuk pengumpulan data. Data dikumpulkan di kampus diploma. Analisis menunjukkan bahwa siswa cenderung menggunakan tanggapan kompleks dan tak langsung agar dapat menjaga keharmonisan hubungan dengan temannya. Oleh karena itu asumsi dasarnya adalah bahwa siswa cenderung berkomunikasi dalam konteks level tinggi.

  8. Encapsulation of Liposomes within pH Responsive Microspheres for Oral Colonic Drug Delivery

    Directory of Open Access Journals (Sweden)

    M. J. Barea

    2012-01-01

    Full Text Available A novel liposome-in-microsphere (LIM formulation has been created comprising drug-loaded liposomes within pH responsive Eudragit S100 microspheres. The liposomes contained the model drug 5-ASA and were coated with chitosan in order to protect them during encapsulation within the microspheres and to improve site-specific release characteristics. In vitro drug release studies showed that LIMs prevented drug release within simulated stomach and small intestine conditions with subsequent drug release occurring in large intestine conditions. The formulation therefore has potential for oral colonic drug delivery.

  9. A novel thermal and pH responsive drug delivery system based on ZnO@PNIPAM hybrid nanoparticles

    International Nuclear Information System (INIS)

    Tan, Licheng; Liu, Jian; Zhou, Weihua; Wei, Junchao; Peng, Zhiping

    2014-01-01

    A smart ZnO@PNIPAM hybrid was prepared by grafting thermal responsive poly(N-isopropylacrylamide) (PNIPAM) on zinc oxide (ZnO) nanoparticles via surface-initiated atom transfer radical polymerization (ATRP). The thermal gravimetric analysis (TGA) shows that the grafting amount of PNIPAM was about 38%, and the SEM images show that the PNIPAM chains can prevent the aggregation of ZnO nanoparticles. The responsive properties of ZnO@PNIPAM were measured by photoluminescence spectra, and the results demonstrate that the PNIPAM chains grafted on ZnO surfaces can realize reversible thermal responsive and photoluminescence properties. An anticancer drug, doxorubicin (Dox), was used as a model drug and loaded into the hybrid nanoparticles, and an in vitro drug release test implied that ZnO@PNIPAM could work as a thermal responsive drug delivery system. Furthermore, pH sensitive drug releases were carried out in acetate buffer at pH 5.0 and pH 6.0 and in water at pH 7.0, and the results showed evident pH dependency, showing its pH responsive properties. - Graphical abstract: In this manuscript, thermal responsive poly(N-isopropylacrylamide) (PNIPAM) was grafted on the surface of ZnO nanoparticles. The obtained ZnO@PNIPAM hybrid showed reversible thermal responsive photoluminescent properties, and can also work as a thermal and pH responsive drug delivery system. - Highlights: • The ZnO@PNIPAM hybrid was prepared via ATRP. • The ZnO@PNIPAM hybrid showed thermal responsive properties. • The ZnO@PNIPAM hybrid can work as a thermal and pH responsive drug delivery system

  10. Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma.

    Science.gov (United States)

    Eberl, Markus; Mangelberger, Doris; Swanson, Jacob B; Verhaegen, Monique E; Harms, Paul W; Frohm, Marcus L; Dlugosz, Andrzej A; Wong, Sunny Y

    2018-02-12

    Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh + /Notch + suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh +++ /Notch - basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three-dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. From the Stimulus-Response to the Person-Context Model

    Directory of Open Access Journals (Sweden)

    Arturo Barraza Macías

    2007-07-01

    Full Text Available In this manuscript, an alternative reading of the field of study of the stress is made that leads to raise the existence of two models: the Stimulus-Response and the Person-Context Models about Stress. Each one of them is presented with base in four indicators: historical antecedents, postulates, development and characteristics. In the end a critical valuation is made that the author leads to recognize in the Person-Surroundings Research Program of Stress, and in its tendency to the modeling, the route of development of the field of study of stress.

  12. Psychopathic traits modulate brain responses to drug cues in incarcerated offenders

    Directory of Open Access Journals (Sweden)

    Lora M Cope

    2014-02-01

    Full Text Available Recent neuroscientific evidence indicates that psychopathy is associated with abnormal function and structure in limbic and paralimbic areas. Psychopathy and substance use disorders are highly comorbid, but clinical experience suggests that psychopaths abuse drugs for different reasons than non-psychopaths, and that psychopaths do not typically experience withdrawal and craving upon becoming incarcerated. These neurobiological abnormalities may be related to psychopaths’ different motivations for – and symptoms of – drug use. This study examined the modulatory effect of psychopathic traits on the neurobiological craving response to pictorial drug stimuli. Drug-related pictures and neutral pictures were presented and rated by participants while hemodynamic activity was monitored using functional magnetic resonance imaging. These data were collected at two correctional facilities in New Mexico using the Mind Research Network mobile magnetic resonance imaging system. The sample comprised 137 incarcerated adult males and females (93 females with histories of substance dependence. The outcome of interest was the relation between psychopathy scores (using the Hare Psychopathy Checklist-Revised and hemodynamic activity associated with viewing drug-related pictures versus neutral pictures. There was a negative association between psychopathy scores and hemodynamic activity for viewing drug-related cues in the anterior cingulate, posterior cingulate, hippocampus, amygdala, caudate, globus pallidus, and parts of the prefrontal cortex. Psychopathic traits modulate the neurobiological craving response and suggest that individual differences are important for understanding and treating substance abuse.

  13. Evaluating Drug Cost per Response with SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Lopez, Janice M S; Macomson, Brian; Ektare, Varun; Patel, Dipen; Botteman, Marc

    2015-09-01

    The sodium-glucose cotransporter 2 (SGLT2) inhibitors, which include canagliflozin, dapagliflozin, and empagliflozin, represent a new class of antihyperglycemic agents. Few studies have assessed their cost per response, with "cost per response" being the total cost of a select drug, divided by the resulting change in glycated hemoglobin (HbA1c) levels. To examine the drug cost of SGLT2 inhibitors per a reduction in placebo-adjusted 1% HbA1c in patients with type 2 diabetes mellitus who received treatment during 26 weeks with canagliflozin, dapagliflozin, or empagliflozin. The drug cost per response for each of the 3 agents individually was assessed based on data from a subset of clinical trials discussed in the prescribing information for each drug that were all placebo-controlled studies evaluating each drug as monotherapy, dual therapy (combined with metformin), and triple therapy (combined with metformin and a sulfonylurea) in patients with uncontrolled, type 2 diabetes mellitus. The US 2015 wholesale acquisition cost for each drug was used to calculate each drug's treatment costs over 26 weeks. The average cost per response for each drug was defined as the prescription drug cost of each SGLT2 inhibitor, divided by the average, placebo-adjusted HbA1c reduction at 26 weeks. The drug cost per unit dose was the same for canagliflozin (100 mg or 300 mg), dapagliflozin (5 mg or 10 mg), and empagliflozin (10 mg or 25 mg), at $11.43. The drug cost per placebo-adjusted 1% HbA1c reduction varied by agent and by dose, as a result of the differences in the treatment responses for each of the 3 drugs. The costs per response for canagliflozin 100 mg as monotherapy, dual therapy, and triple therapy regimens ranged from $2286 to $3355, and for canagliflozin 300 mg, from $1793 to $2702. The costs per response for dapagliflozin 5 mg as monotherapy and dual therapy (triple therapy was not available at the time of the study) ranged from $4161 to $5201; the cost for dapagliflozin

  14. Pavlovian drug-sickness pairings result in the conditioning of an antisickness response.

    Science.gov (United States)

    Lett, B T

    1983-10-01

    After a drug conditioned stimulus (CS) has been injected prior to lithium chloride as the unconditioned stimulus (US) on five occasions, the drug CS becomes able to evoke a conditioned antisickness response (CAR). This CAR is implied by the finding that the CS drug mitigates the conditioned saccharin aversion produced by lithium when it is administered in the interval between saccharin consumption and lithium injection. The following drugs were tested and are listed in approximate order of their effectiveness in producing a conditioned antisickness effect: pentobarbital, ethanol, morphine, amphetamine, and chlordiazepoxide.

  15. Application of drug selective electrode in the drug release study of pH-responsive microgels.

    Science.gov (United States)

    Tan, Jeremy P K; Tam, Kam C

    2007-03-12

    The colloidal phenomenon of soft particles is becoming an important field of research due to the growing interest in using polymeric system in drug delivery. Previous studies have focused on techniques that require intermediate process step such as dialysis or centrifugation, which introduces additional errors in obtaining the diffusion kinetic data. In this study, a drug selective electrode was used to directly measure the concentration of procaine hydrochloride (PrHy) released from methacrylic acid-ethyl acrylate (MAA-EA) microgel, thereby eliminating the intermediate process step. PrHy selective membrane constructed using a modified poly (vinyl chloride) (PVC) membrane and poly (ethylene-co-vinyl acetate-co-carbon monoxide) as plasticizer exhibited excellent reproducibility and stability. The response was reproducible at pH of between 3 to 8.5 and the selectivity coefficients against various organic and inorganic cations were evaluated. Drug release was conducted using the drug electrode under different pHs and the release rate increased with pH. The release behavior of the system under different pH exhibited obvious gradient release characteristics.

  16. A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications.

    Science.gov (United States)

    Pillay, Viness; Tsai, Tong-Sheng; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Modi, Girish; Naidoo, Dinesh; Tomar, Lomas K; Tyagi, Charu; Ndesendo, Valence M K

    2014-06-01

    Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an "on-off" drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The "on-off" drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. Copyright © 2013 Wiley Periodicals, Inc.

  17. A procedure to observe context-induced renewal of pavlovian-conditioned alcohol-seeking behavior in rats.

    Science.gov (United States)

    Maddux, Jean-Marie; Lacroix, Franca; Chaudhri, Nadia

    2014-09-19

    Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context-induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues.

  18. Teaching about Refugees: Developing Culturally Responsive Educators in Contexts of Politicised Transnationalism

    Science.gov (United States)

    Gagné, Antoinette; Schmidt, Clea; Markus, Paula

    2017-01-01

    This article addresses issues of teaching about refugees in initial teacher education and professional development for practicing teachers. We respond to the who, what, where, when, why and how of teaching about refugees and developing culturally responsive pedagogy in contexts of politicised transnationalism, where the wider politics around…

  19. Variation in the suppression or enhancement of responses related to drug habits as a function of stimulus classes and competing response categories.

    Science.gov (United States)

    Haertzen, C A; Ross, F E

    1980-08-01

    Male prisoners who were opiate addicts (N = 47) were given three Process Association Tests of Addiction containing stimuli which evoked responses characteristic of three levels of drug habits: beginning and ending stage of addiction, intermediate stage of addiction, and an advanced level of addiction. Each test required subjects to associate 278 word stimuli with one of five options which were randomly selected from among 20 options covering the stages of addiction, steps in drug taking, and drug effects. The purpose of the study was to determine whether responses to particular options suppressed or enhanced responses to other options. A strong interaction was found between the classes of stimuli and the response options which produced suppression or enhancement. This interaction made it possible to develop a suppression scale to measure the effect of each class of stimulus. Popular responses most frequently suppressed responses of other options. Thus, when the stimuli were clean, responses of "to be clean" and "to live a normal life," which are sensitive indicators of the beginning or ending stages of addiction , suppressed responses of other stages. The response of "to be high," a prime indicator of an intermediate habit, suppressed responses of other options when the stimuli were drug names. Responses of "to be hooked" and "to fix," which are specific indicators of a strong habit, and "to be high," which is a nonspecific indicator of a strong habit, suppressed responses of many other options. In the development of new association tests the analysis of suppression could provide a basis for selectively varying option groupings in order to increase or decrease the frequently of certain responses.

  20. Rapid assessment response (RAR study: drug use and health risk - Pretoria, South Africa

    Directory of Open Access Journals (Sweden)

    Trautmann Franz

    2011-06-01

    Full Text Available Abstract Background Within a ten year period South Africa has developed a substantial illicit drug market. Data on HIV risk among drug using populations clearly indicate high levels of HIV risk behaviour due to the sharing of injecting equipment and/or drug-related unprotected sex. While there is international evidence on and experience with adequate responses, limited responses addressing drug use and drug-use-related HIV and other health risks are witnessed in South Africa. This study aimed to explore the emerging problem of drug-related HIV transmission and to stimulate the development of adequate health services for the drug users, by linking international expertise and local research. Methods A Rapid Assessment and Response (RAR methodology was adopted for the study. For individual and focus group interviews a semi-structured questionnaire was utilised that addressed key issues. Interviews were conducted with a total of 84 key informant (KI participants, 63 drug user KI participants (49 males, 14 females and 21 KI service providers (8 male, 13 female. Results and Discussion Adverse living conditions and poor education levels were cited as making access to treatment harder, especially for those living in disadvantaged areas. Heroin was found to be the substance most available and used in a problematic way within the Pretoria area. Participants were not fully aware of the concrete health risks involved in drug use, and the vague ideas held appear not to allow for concrete measures to protect themselves. Knowledge with regards to substance related HIV/AIDS transmission is not yet widespread, with some information sources disseminating incorrect or unspecific information. Conclusions The implementation of pragmatic harm-reduction and other evidence-based public health care policies that are designed to reduce the harmful consequences associated with substance use and HIV/AIDS should be considered. HIV testing and treatment services also need to

  1. Lipid solubility of sedative-hypnotic drugs influences hypothermic and hypnotic responses of long-sleep and short-sleep mice.

    Science.gov (United States)

    De Fiebre, N C; Marley, R J; Wehner, J M; Collins, A C

    1992-10-01

    The anesthetic potency of many agents, including alcohols, barbiturates and other sedative-hypnotic drugs, is influenced by lipid solubility. Previous studies from our laboratory, however, have demonstrated that genetic factors influence this relationship. We have reported that mouse lines selectively bred for differences in duration of ethanol-induced anesthesia, the long-sleep (LS) and short-sleep (SS) mice, differ in sleep-time response to water-soluble, but not lipid-soluble, sedative-hypnotic drugs. The studies described here sought to determine whether this same relationship exists for the hypothermic response produced by 17 sedative-hypnotic drugs in the LS and SS mice. Dose-response and time course relationships for hypothermic actions were determined and were compared with the dose-related anesthetic effects of the drugs. Hypothermic potencies increased along with lipid solubility for both the LS and SS mouse lines, but the rate of change differed for the two mouse lines. LS mice were more responsive to ethanol and other water-soluble drugs whereas the SS were more responsive to lipid-soluble drugs; significant correlations were obtained between lipid solubility (log P-octanol-water partition coefficient) and relative LS-SS responsiveness to both the hypothermic and hypnotic actions of the 17 test drugs. Thus, both hypnotic and hypothermic actions of sedative-hypnotic drugs are correlated with lipid solubility. Possible explanation for these correlations include greater LS central nervous system sensitivity to water-soluble drugs and LS-SS differences in distribution of lipid-soluble drugs.

  2. Are drug companies living up to their human rights responsibilities? The Merck perspective.

    Directory of Open Access Journals (Sweden)

    Geralyn S Ritter

    2010-09-01

    Full Text Available BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

  3. Are drug companies living up to their human rights responsibilities? Moving toward assessment.

    Science.gov (United States)

    Gruskin, Sofia; Raad, Zyde

    2010-09-28

    The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

  4. Are drug companies living up to their human rights responsibilities? The Merck perspective.

    Science.gov (United States)

    Ritter, Geralyn S

    2010-09-28

    The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

  5. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations

    Science.gov (United States)

    Jmel, Haifa; Romdhane, Lilia; Ben Halima, Yosra; Hechmi, Meriem; Naouali, Chokri; Dallali, Hamza; Hamdi, Yosr; Shan, Jingxuan; Abid, Abdelmajid; Jamoussi, Henda; Trabelsi, Sameh; Chouchane, Lotfi; Luiselli, Donata; Abdelhak, Sonia

    2018-01-01

    Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with

  6. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations.

    Science.gov (United States)

    Jmel, Haifa; Romdhane, Lilia; Ben Halima, Yosra; Hechmi, Meriem; Naouali, Chokri; Dallali, Hamza; Hamdi, Yosr; Shan, Jingxuan; Abid, Abdelmajid; Jamoussi, Henda; Trabelsi, Sameh; Chouchane, Lotfi; Luiselli, Donata; Abdelhak, Sonia; Kefi, Rym

    2018-01-01

    Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with

  7. Smart surface coating of drug nanoparticles with cross-linkable polyethylene glycol for bio-responsive and highly efficient drug delivery

    Science.gov (United States)

    Wei, Weijia; Zhang, Xiujuan; Chen, Xianfeng; Zhou, Mengjiao; Xu, Ruirui; Zhang, Xiaohong

    2016-04-01

    Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future.Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability

  8. Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications.

    Science.gov (United States)

    Zangabad, Parham Sahandi; Mirkiani, Soroush; Shahsavari, Shayan; Masoudi, Behrad; Masroor, Maryam; Hamed, Hamid; Jafari, Zahra; Taghipour, Yasamin Davatgaran; Hashemi, Hura; Karimi, Mahdi; Hamblin, Michael R

    2018-02-01

    Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus-responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications.

  9. "The first shot": the context of first injection of illicit drugs, ongoing injecting practices, and hepatitis C infection in Rio de Janeiro, Brazil.

    Science.gov (United States)

    Oliveira, Maria de Lourdes Aguiar; Hacker, Mariana A; Oliveira, Sabrina Alberti Nóbrega de; Telles, Paulo Roberto; O, Kycia Maria Rodrigues do; Yoshida, Clara Fumiko Tachibana; Bastos, Francisco I

    2006-04-01

    The context of first drug injection and its association with ongoing injecting practices and HCV (hepatitis C virus) infection were investigated. Injection drug users (IDUs) (N = 606) were recruited in "drug scenes" (public places, bars) in Rio de Janeiro, Brazil, interviewed, and tested for HCV. Sharing of needles/syringes was more prevalent at the first injection (51.3%) than at the baseline interview (36.8%). Those who shared syringes/needles at first injection were more likely to be currently engaged in direct/indirect sharing practices. Among young injectors (drug injection were identified as independent predictors of HCV infection. To effectively curb HCV transmission among IDUs and minimize harms associated with risk behaviors, preventive strategies should target individuals initiating drug injection beginning with their very first injection and discourage the transition from non-injecting use to the self-injection of illicit drugs.

  10. Corporate Social Responsibility in the context of International Financial Institutions

    OpenAIRE

    Gajdosova, Katarina

    2015-01-01

    The term Corporate Social Responsibility (CSR) is becoming more and more often spelled out in various contexts of the academic and corporate life. The concept of CSR is rather broad and the term CSR could be defined in various ways, as there has been no unified definition established so far. Yet the word ‘corporate’ in the term could indicate that CSR is exclusive matter of private companies. However, as demonstrated in this paper, the non-corporate institutions, in particular the Internation...

  11. Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook

    Directory of Open Access Journals (Sweden)

    Song Y

    2016-12-01

    Full Text Available Yuanhui Song, Yihong Li, Qien Xu, Zhe Liu Wenzhou Institute of Biomaterials and Engineering (WIBE, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Abstract: With the development of nanotechnology, the application of nanomaterials in the field of drug delivery has attracted much attention in the past decades. Mesoporous silica nanoparticles as promising drug nanocarriers have become a new area of interest in recent years due to their unique properties and capabilities to efficiently entrap cargo molecules. This review describes the latest advances on the application of mesoporous silica nanoparticles in drug delivery. In particular, we focus on the stimuli-responsive controlled release systems that are able to respond to intracellular environmental changes, such as pH, ATP, GSH, enzyme, glucose, and H2O2. Moreover, drug delivery induced by exogenous stimuli including temperature, light, magnetic field, ultrasound, and electricity is also summarized. These advanced technologies demonstrate current challenges, and provide a bright future for precision diagnosis and treatment. Keywords: mesoporous silica nanoparticle, drug delivery system, controlled release, stimuli-responsive, chemotherapy

  12. Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators

    Science.gov (United States)

    McMahon-Pratt, Diane; Saravia, Nancy Gore

    2015-01-01

    Background Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. Methodology To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. Principal Findings Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine

  13. Cortisol awakening response in drug-naïve panic disorder

    Directory of Open Access Journals (Sweden)

    Jakuszkowiak-Wojten K

    2016-06-01

    Full Text Available Katarzyna Jakuszkowiak-Wojten, Jerzy Landowski, Mariusz S Wiglusz, Wiesław Jerzy Cubała Department of Psychiatry, Medical University of Gdansk, Gdansk, Poland Background: It is unclear whether hypothalamic–pituitary–adrenal axis is involved in the pathophysiology of panic disorder (PD. The findings remain inconsistent. Cortisol awakening response (CAR is a noninvasive biomarker of stress system activity. We designed the study to assess CAR in drug-naïve PD patients.   Materials and methods: We assessed CAR in 14 psychotropic drug-naïve outpatients with PD and 14 healthy controls. The severity of PD was assessed with Panic and Agoraphobia Scale. The severity of anxiety and depression was screened with Hospital Anxiety and Depression Scale.   Results: No significant difference in CAR between PD patients and control group was found. No correlations were observed between CAR and anxiety severity measures in PD patients and controls.   Limitations: The number of participating subjects was relatively small, and the study results apply to nonsuicidal drug-naïve PD patients without agoraphobia and with short-illness duration. There was a lack of control on subjects’ compliance with the sampling instructions.  Conclusion: The study provides no support for elevated CAR levels in drug-naïve PD patients without agoraphobia. Keywords: panic disorder, PD, CAR, cortisol awakening response, HPA axis, hypothalamic–pituitary–adrenal axis

  14. Thizzin'-Ecstasy use contexts and emergent social meanings.

    Science.gov (United States)

    Lee, Juliet P; Battle, Robynn S; Soller, Brian; Brandes, Naomi

    2011-01-01

    The drug "Ecstasy" has been most commonly associated with raves, or electronic music dance events, and attributed with sexual disinhibition. In an ethnographic investigation of drug use among second-generation Southeast Asian youth in Northern California (2003), respondents described little use of or interest in using Ecstasy; yet in a second study, Ecstasy was the fourth most commonly-used substance. This paper investigates the social contexts for this change in use patterns. Respondents were second-generation Southeast Asian youths and young adults between the ages of 15 and 26 who were currently or recently drug-involved. We compared qualitative data from the two studies and found emerging patterns of meaning and context related to the observed change in use patterns. Ecstasy use among co-resident African American youth within the context of the local "hyphy" hip-hop music subculture had influenced Southeast Asian youths' uptake of the drug, known as "thizz." Respondents referred to the effects of the drug as "thizzin'," described as energizing, disinhibiting, numbing, and emotion enhancing. Reported consequences of "thizzin'" included violence and aggression as well as fun, while sexual disinhibition was rarely mentioned. The meanings assigned to drugs, including the effects ascribed to them, may be relative to the social contexts within which users are exposed to and consume drugs. The findings indicate the susceptibility of youths to local trends in drug use, particularly associated with popular cultural movements and music. Second-generation youths may be particularly susceptible relative to the conditions of their immigration and processes of identity formation unique to them.

  15. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    International Nuclear Information System (INIS)

    Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il

    2012-01-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: ► High performance of transdermal drug delivery system with an easy control of voltage. ► Improved thermal response of hydrogel by graphite oxide incorporation. ► Efficient micro heater fabricated by a joule heating method.

  16. Context and strain-dependent behavioral response to stress

    Directory of Open Access Journals (Sweden)

    Baum Amber E

    2008-06-01

    Full Text Available Abstract Background This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized. Methods We studied male Fisher 344 (F344 and Wistar Kyoto (WKY rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM and the open field (OFT, both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests. Results Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs. Conclusion Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.

  17. The thalamus in drug addiction: from rodents to humans.

    Science.gov (United States)

    Huang, Anna S; Mitchell, Jameson A; Haber, Suzanne N; Alia-Klein, Nelly; Goldstein, Rita Z

    2018-03-19

    Impairments in response inhibition and salience attribution (iRISA) have been proposed to underlie the clinical symptoms of drug addiction as mediated by cortico-striatal-thalamo-cortical networks. The bulk of evidence supporting the iRISA model comes from neuroimaging research that has focused on cortical and striatal influences with less emphasis on the role of the thalamus. Here, we highlight the importance of the thalamus in drug addiction, focusing on animal literature findings on thalamic nuclei in the context of drug-seeking, structural and functional changes of the thalamus as measured by imaging studies in human drug addiction, particularly during drug cue and non-drug reward processing, and response inhibition tasks. Findings from the animal literature suggest that the paraventricular nucleus of the thalamus, the lateral habenula and the mediodorsal nucleus may be involved in the reinstatement, extinction and expression of drug-seeking behaviours. In support of the iRISA model, the human addiction imaging literature demonstrates enhanced thalamus activation when reacting to drug cues and reduced thalamus activation during response inhibition. This pattern of response was further associated with the severity of, and relapse in, drug addiction. Future animal studies could widen their field of focus by investigating the specific role(s) of different thalamic nuclei in different phases of the addiction cycle. Similarly, future human imaging studies should aim to specifically delineate the structure and function of different thalamic nuclei, for example, through the application of advanced imaging protocols at higher magnetic fields (7 Tesla).This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'. © 2018 The Author(s).

  18. Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment

    Directory of Open Access Journals (Sweden)

    Chendi Ding

    2016-12-01

    Full Text Available Benefiting from the development of nanotechnology, drug delivery systems (DDSs with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs, quantum dots (QDs and carbon nanotubes (CNTs. The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules and extrinsic (temperature, light irradiation, magnetic field and ultrasound ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

  19. Analysis of Drug Policy in the Republic of Slovenia and in the EU Context: A Platform for Prevention in Schools

    Science.gov (United States)

    Kvaternik, Ines; Rihter, Liljana

    2012-01-01

    Aims: This article presents an overview of the strategies and measures used in the context of school-based prevention in Slovenia, both on a declaratory and on a practical level. Methods: A review of the Resolution on the National Programme on Drugs in the Republic of Slovenia [ReNPPD (2004). Resolucija o nacionalnem programu na podrocju drog…

  20. Comparing speech and nonspeech context effects across timescales in coarticulatory contexts.

    Science.gov (United States)

    Viswanathan, Navin; Kelty-Stephen, Damian G

    2018-02-01

    Context effects are ubiquitous in speech perception and reflect the ability of human listeners to successfully perceive highly variable speech signals. In the study of how listeners compensate for coarticulatory variability, past studies have used similar effects speech and tone analogues of speech as strong support for speech-neutral, general auditory mechanisms for compensation for coarticulation. In this manuscript, we revisit compensation for coarticulation by replacing standard button-press responses with mouse-tracking responses and examining both standard geometric measures of uncertainty as well as newer information-theoretic measures that separate fast from slow mouse movements. We found that when our analyses were restricted to end-state responses, tones and speech contexts appeared to produce similar effects. However, a more detailed time-course analysis revealed systematic differences between speech and tone contexts such that listeners' responses to speech contexts, but not to tone contexts, changed across the experimental session. Analyses of the time course of effects within trials using mouse tracking indicated that speech contexts elicited fewer x-position flips but more area under the curve (AUC) and maximum deviation (MD), and they did so in the slower portions of mouse-tracking movements. Our results indicate critical differences between the time course of speech and nonspeech context effects and that general auditory explanations, motivated by their apparent similarity, be reexamined.

  1. Tacrolimus drug level and response to treatment in idiopathic childhood steroid resistant nephrotic syndrome

    International Nuclear Information System (INIS)

    Shah, S.S.; Hafeez, F.; Akhtar, N.

    2015-01-01

    The management of Steroid Resistant Nephrotic Syndrome (SRNS) is an uphill task for paediatric nephrologists as immunosuppressive agents are the mainstay of treatment in these patients. Tacrolimus is used along with steroids. This study is conducted to see the relationship between the tacrolimus dose, drug level and response in the management of SRNS. Methods: This quasi experimental study was conducted at The Childrens Hospital Lahore over a period of one year. Patients with SRNS of either sex and 1-10 years of age were included and those with secondary nephrotic syndrome were excluded. Tacrolimus was given at a dose of 0.05-0.1 mg/kg/day in 2 divided doses along with steroids. The follow-up was done for six months with proteinuria monitoring and tacrolimus drug levels done two weeks after initiation of treatment. Results: Out of 42 patients, 27 (64.3%) were males and 15 (35.7%) were females. The most common histological diagnosis observed was mesangio-proliferative glomerulonephritis in 30 (71.4%) patients. The tacrolimus trough level range was 0.5-15.20 ng/ml with a mean value of 4.68 ng/ml±2.85. Forty-one (97.6%) children showed complete response to treatment while one patient showed partial response. Conclusion: This study suggests that tacrolimus is an effective drug for treatment of SRNS in paediatric patients and there is no linear relationship between the drug dose, response and drug level. (author)

  2. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines.

    Directory of Open Access Journals (Sweden)

    Edwin Choy

    2008-11-01

    Full Text Available Lymphoblastoid cell lines (LCLs, originally collected as renewable sources of DNA, are now being used as a model system to study genotype-phenotype relationships in human cells, including searches for QTLs influencing levels of individual mRNAs and responses to drugs and radiation. In the course of attempting to map genes for drug response using 269 LCLs from the International HapMap Project, we evaluated the extent to which biological noise and non-genetic confounders contribute to trait variability in LCLs. While drug responses could be technically well measured on a given day, we observed significant day-to-day variability and substantial correlation to non-genetic confounders, such as baseline growth rates and metabolic state in culture. After correcting for these confounders, we were unable to detect any QTLs with genome-wide significance for drug response. A much higher proportion of variance in mRNA levels may be attributed to non-genetic factors (intra-individual variance--i.e., biological noise, levels of the EBV virus used to transform the cells, ATP levels than to detectable eQTLs. Finally, in an attempt to improve power, we focused analysis on those genes that had both detectable eQTLs and correlation to drug response; we were unable to detect evidence that eQTL SNPs are convincingly associated with drug response in the model. While LCLs are a promising model for pharmacogenetic experiments, biological noise and in vitro artifacts may reduce power and have the potential to create spurious association due to confounding.

  3. Disease-responsive drug delivery: the next generation of smart delivery devices.

    Science.gov (United States)

    Wanakule, Prinda; Roy, Krishnendu

    2012-01-01

    With the advent of highly potent and cytotoxic drugs, it is increasingly critical that they be targeted and released only in cells of diseased tissues, while sparing physiologically normal neighbors. Simple ligand-based targeting of drug carriers, although promising, cannot always provide the required specificity to achieve this since often normal cells also express significant levels of the targeted receptors. Therefore, stimuli-responsive delivery systems are being explored to allow drug release from nano- and microcarriers and implantable devices, primarily in the presence of physiological or disease-specific pathophysiological signals. Designing smart biomaterials that respond to temperature or pH changes, protein and ligand binding, disease-specific degradation, e.g. enzymatic cleavage, has become an integral part of this approach. These strategies are used in combination with nano- and microparticle systems to improve delivery efficiency through several routes of administration, and with injectable or implantable systems for long term controlled release. This review focuses on recent developments in stimuli-responsive systems, their physicochemical properties, release profiles, efficacy, safety and biocompatibility, as well as future perspectives.

  4. Synthesis and characterization of novel dual-responsive nanogels and their application as drug delivery systems

    Science.gov (United States)

    Peng, Jinrong; Qi, Tingting; Liao, Jinfeng; Fan, Min; Luo, Feng; Li, He; Qian, Zhiyong

    2012-03-01

    In this study, a temperature/pH dual-response nanogel based on NIPAm, MAA, and PEGMA was synthesized via emulsion polymerization and characterized by 1H-NMR, FT-IR, TEM and DLS. By introducing a novel initiator, through which PEG-AIBN-PEG was synthesized, it was revealed that the PEG segments from PEG-AIBN-PEG with a dosage of initiator had a significant influence over the macro-state and stability of the nanogels. In order to optimize the feeding prescription for better application as a drug delivery system, the effect of the co-monomer contents on the response to stimuli (temperature and pH value) and cytotoxicity of the nanogels has been studied in detail. The results demonstrated that the responsiveness, reversibility and volume phase transition critical value of the nanogels could be controlled by adjusting the feeding ratio of the co-monomers in the synthesis process. MTT assay results revealed that nanogels with appropriate compositions showed good biocompatibility and relatively low toxicity. Most importantly, by studying the drug loading behavior, it was found that the dimensions of the drug molecules had a considerable influence on the drug loading efficiency and loading capacity of the nanogels, and that the mechanism by which drug molecule sizes influence the drug loading behavior of nanogels needs further investigation. The results indicated that such PNMP nanogels might have potential applications in drug delivery and other medical applications, but that the drug loading mechanism must be further developed.

  5. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Jumi [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Lee, Dae Hoon [Environment Research Division, Korea Institute of Machinery and Materials, 171 Jang-dong, Yusong-gu, Daejeon 305-343 (Korea, Republic of); Im, Ji Sun [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Kim, Hyung-Il, E-mail: hikim@cnu.ac.kr [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of)

    2012-08-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: Black-Right-Pointing-Pointer High performance of transdermal drug delivery system with an easy control of voltage. Black-Right-Pointing-Pointer Improved thermal response of hydrogel by graphite oxide incorporation. Black-Right-Pointing-Pointer Efficient micro heater fabricated by a joule heating method.

  6. Contribution of positron emission tomography for the study of response variability to opioid drugs

    International Nuclear Information System (INIS)

    Auvity, Sylvain

    2017-01-01

    There is a high variability between patients in the initial analgesic response to opioid drugs. The chronic use of opioids leads to tolerance and may induce dependence or addiction. Current Positron Emission Tomography (PET) imaging methods, focusing on the impact of opioids on neuronal and synaptic functions, have failed to elucidate the parameters that control this variability of therapeutic response. A wealth of preclinical studies has addressed the possibility for neuro-immune or neuro-pharmacokinetic parameters to control the response to opioid drugs. Dedicated tools are thus required to investigate their impact on the pharmacology of opioid drugs in vivo and test their implication for variability in therapeutic response. The aim of this PhD project was to develop or to evaluate original methods to study the neuro-immune and neuro-pharmacokinetic components of the variability of response to opioid drugs. Opioid drugs were shown to interact with the innate immune System in the central nervous System (CNS) and to modulate the activity of glial cells. Glial cell activity is often hypothesized to modulate the analgesic efficacy of opioids and account for the development of tolerance and dependence. PET imaging using TSPO (Translocator protein 18 kDa) radioligands such as "1"8F-DPA-714 is the most advanced approach to non-invasively study glial cell activation. In nonhuman primates, we showed that acute morphine exposure increased the brain distribution of "1"8F-DPA-714, suggesting glial cell activation. The extent of the increase was linked to the baseline brain distribution of "1"8F-DPA-714, suggesting the presence of priming parameters in controlling the neuro-immune response to morphine exposure. In healthy rats, we showed that morphine-induced tolerance and withdrawal did not detectably increase the brain distribution of "1"8F-DPA-714 as well as the expression of other bio-markers of glial/micro-glial activation. Dedicated methods were then proposed to

  7. Electromagnetically powered electrolytic pump and thermo-responsive valve for drug delivery

    KAUST Repository

    Yi, Ying; Zaher, Amir; Yassine, Omar; Buttner, Ulrich; Kosel, Jü rgen; Foulds, Ian G.

    2015-01-01

    A novel drug delivery device is presented, implementing an electrolytic pump and a thermo-responsive valve. The device is remotely operated by an AC electromagnetic field (40.5∼58.5 mT, 450 kHz) that provides the power for the pump and the valve. It is suitable for long-term therapy applications, which use a solid drug in reservoir (SDR) approach and avoids unwanted drug diffusion. When the electromagnetic field is on, the electrolytic pump drives the drug towards the valve. The valve is made of a magnetic composite consisting of a smart hydrogel: Poly (N-Isopropylacrylamide) (PNIPAm) and iron powder. The heat generated in the iron powder via magnetic losses causes the PNIPAm to shrink, allowing the drug to flow past it. When the electromagnetic field is off, the PNIPAm swells, sealing the outlet. In the meantime, the bubbles generated by electrolysis recombine into water, causing a pressure reduction in the pumping chamber. This draws fresh fluid from outside the pump into the drug reservoir before the valve is fully sealed. The recombination can be accelerated by a platinum (Pt) coated catalytic reformer, allowing more fluid to flow back to the drug reservoir and dissolve the drug. By repeatedly turning on and off the magnetic field, the drug solution can be delivered cyclically. © 2015 IEEE.

  8. Electromagnetically powered electrolytic pump and thermo-responsive valve for drug delivery

    KAUST Repository

    Yi, Ying

    2015-04-01

    A novel drug delivery device is presented, implementing an electrolytic pump and a thermo-responsive valve. The device is remotely operated by an AC electromagnetic field (40.5∼58.5 mT, 450 kHz) that provides the power for the pump and the valve. It is suitable for long-term therapy applications, which use a solid drug in reservoir (SDR) approach and avoids unwanted drug diffusion. When the electromagnetic field is on, the electrolytic pump drives the drug towards the valve. The valve is made of a magnetic composite consisting of a smart hydrogel: Poly (N-Isopropylacrylamide) (PNIPAm) and iron powder. The heat generated in the iron powder via magnetic losses causes the PNIPAm to shrink, allowing the drug to flow past it. When the electromagnetic field is off, the PNIPAm swells, sealing the outlet. In the meantime, the bubbles generated by electrolysis recombine into water, causing a pressure reduction in the pumping chamber. This draws fresh fluid from outside the pump into the drug reservoir before the valve is fully sealed. The recombination can be accelerated by a platinum (Pt) coated catalytic reformer, allowing more fluid to flow back to the drug reservoir and dissolve the drug. By repeatedly turning on and off the magnetic field, the drug solution can be delivered cyclically. © 2015 IEEE.

  9. Sex differences in neural responses to stress and alcohol context cues.

    Science.gov (United States)

    Seo, Dongju; Jia, Zhiru; Lacadie, Cheryl M; Tsou, Kristen A; Bergquist, Keri; Sinha, Rajita

    2011-11-01

    Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. This study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue, and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (P left anterior insula, striatum, and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the left dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala, and hippocampus than women, whereas women showed greater alcohol-cue-related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion-modulation regions, including the medial OFC, ventromedial PFC, left superior-mPFC, and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal, and ventral) in men, supporting its involvement in alcohol "urge" in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders. Copyright © 2010 Wiley-Liss, Inc.

  10. 'At-risk' individuals' responses to direct to consumer advertising of prescription drugs: a nationally representative cross-sectional study.

    Science.gov (United States)

    Khalil Zadeh, Neda; Robertson, Kirsten; Green, James A

    2017-12-06

    The factors determining individuals' self-reported behavioural responses to direct to consumer advertising of prescription drugs were explored with an emphasis on 'at-risk' individuals' responses. Nationally representative cross-sectional survey. Community living adults in New Zealand. 2057 adults (51% women). Self-reported behavioural responses to drug advertising (asking a physician for a prescription, asking a physician for more information about an illness, searching the internet for more information regarding an illness and asking a pharmacist for more information about a drug). Multivariate logistic regressions determined whether participants' self-reported behavioural responses to drug advertising were predicted by attitudes towards advertising and drug advertising, judgements about safety and effectiveness of advertised drugs, self-reported health status, materialism, online search behaviour as well as demographic variables. Identifying as Indian and to a less extent Chinese, Māori and 'other' ethnicities were the strongest predictors of one or more self-reported responses (ORs 1.76-5.00, Ps advertising (ORs 1.34-1.61, all Psadvertising and may make uninformed decisions accordingly. The outcomes raise significant concerns relating to the ethicality of drug advertising and suggest a need for stricter guidelines to ensure that drug advertisements provided by pharmaceutical companies are ethical. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  11. Role of cues and contexts on drug-seeking behaviour

    Science.gov (United States)

    Perry, Christina J; Zbukvic, Isabel; Kim, Jee Hyun; Lawrence, Andrew J

    2014-01-01

    Environmental stimuli are powerful mediators of craving and relapse in substance-abuse disorders. This review examined how animal models have been used to investigate the cognitive mechanisms through which cues are able to affect drug-seeking behaviour. We address how animal models can describe the way drug-associated cues come to facilitate the development and persistence of drug taking, as well as how these cues are critical to the tendency to relapse that characterizes substance-abuse disorders. Drug-associated cues acquire properties of conditioned reinforcement, incentive motivation and discriminative control, which allow them to influence drug-seeking behaviour. Using these models, researchers have been able to investigate the pharmacology subserving the behavioural impact of environmental stimuli, some of which we highlight. Subsequently, we examine whether the impact of drug-associated stimuli can be attenuated via a process of extinction, and how this question is addressed in the laboratory. We discuss how preclinical research has been translated into behavioural therapies targeting substance abuse, as well as highlight potential developments to therapies that might produce more enduring changes in behaviour. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20 PMID:24749941

  12. A Model of Consumer Response to Over-the-Counter Drug Advertising: Antecedents and Influencing Factors.

    Science.gov (United States)

    Huh, Jisu; Delorme, Denise E; Reid, Leonard N

    2016-01-01

    Given the importance of over-the-counter (OTC) drugs in the health care marketplace and lack of systematic research on OTC drug advertising (OTCA) effects, this study tested a theory-based, product category-specific OTCA effects model. Structural equation modeling analysis of data for 1 OTC drug category, analgesics, supported the proposed model, explaining the OTCA effect process from key consumer antecedents to ad involvement, from ad involvement to ad attention, from ad attention to cognitive responses, then to affective/evaluative responses, leading to the final behavioral outcome. Several noteworthy patterns also emerged: (a) Product involvement was directly linked to ad attention, rather than exerting an indirect influence through ad involvement; (b) ad attention was significantly related to both cognitive and affective/evaluative responses to different degrees, with stronger links to cognitive responses; and (c) ad-prompted actions were influenced by both ad trust and ad attitude.

  13. A Semi-Supervised Approach for Refining Transcriptional Signatures of Drug Response and Repositioning Predictions.

    Directory of Open Access Journals (Sweden)

    Francesco Iorio

    Full Text Available We present a novel strategy to identify drug-repositioning opportunities. The starting point of our method is the generation of a signature summarising the consensual transcriptional response of multiple human cell lines to a compound of interest (namely the seed compound. This signature can be derived from data in existing databases, such as the connectivity-map, and it is used at first instance to query a network interlinking all the connectivity-map compounds, based on the similarity of their transcriptional responses. This provides a drug neighbourhood, composed of compounds predicted to share some effects with the seed one. The original signature is then refined by systematically reducing its overlap with the transcriptional responses induced by drugs in this neighbourhood that are known to share a secondary effect with the seed compound. Finally, the drug network is queried again with the resulting refined signatures and the whole process is carried on for a number of iterations. Drugs in the final refined neighbourhood are then predicted to exert the principal mode of action of the seed compound. We illustrate our approach using paclitaxel (a microtubule stabilising agent as seed compound. Our method predicts that glipizide and splitomicin perturb microtubule function in human cells: a result that could not be obtained through standard signature matching methods. In agreement, we find that glipizide and splitomicin reduce interphase microtubule growth rates and transiently increase the percentage of mitotic cells-consistent with our prediction. Finally, we validated the refined signatures of paclitaxel response by mining a large drug screening dataset, showing that human cancer cell lines whose basal transcriptional profile is anti-correlated to them are significantly more sensitive to paclitaxel and docetaxel.

  14. Intracellular drug delivery nanocarriers of glutathione-responsive degradable block copolymers having pendant disulfide linkages.

    Science.gov (United States)

    Khorsand, Behnoush; Lapointe, Gabriel; Brett, Christopher; Oh, Jung Kwon

    2013-06-10

    Self-assembled micelles of amphiphilic block copolymers (ABPs) with stimuli-responsive degradation (SRD) properties have a great promise as nanotherapeutics exhibiting enhanced release of encapsulated therapeutics into targeted cells. Here, thiol-responsive degradable micelles based on a new ABP consisting of a pendant disulfide-labeled methacrylate polymer block (PHMssEt) and a hydrophilic poly(ethylene oxide) (PEO) block were investigated as effective intracellular nanocarriers of anticancer drugs. In response to glutathione (GSH) as a cellular trigger, the cleavage of pendant disulfide linkages in hydrophobic PHMssEt blocks of micellar cores caused the destabilization of self-assembled micelles due to change in hydrophobic/hydrophilic balance. Such GSH-triggered micellar destabilization changed their size distribution with an appearance of large aggregates and led to enhanced release of encapsulated anticancer drugs. Cell culture results from flow cytometry and confocal laser scanning microscopy for cellular uptake as well as cell viability measurements for high anticancer efficacy suggest that new GSH-responsive degradable PEO-b-PHMssEt micelles offer versatility in multifunctional drug delivery applications.

  15. Stress- and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse.

    Science.gov (United States)

    Frank, Matthew G; Watkins, Linda R; Maier, Steven F

    2011-06-01

    Stress and stress-induced glucocorticoids (GCs) sensitize drug abuse behavior as well as the neuroinflammatory response to a subsequent pro-inflammatory challenge. Stress also predisposes or sensitizes individuals to develop substance abuse. There is an emerging evidence that glia and glia-derived neuroinflammatory mediators play key roles in the development of drug abuse. Drugs of abuse such as opioids, psychostimulants, and alcohol induce neuroinflammatory mediators such as pro-inflammatory cytokines (e.g. interleukin (IL)-1β), which modulate drug reward, dependence, and tolerance as well as analgesic properties. Drugs of abuse may directly activate microglial and astroglial cells via ligation of Toll-like receptors (TLRs), which mediate the innate immune response to pathogens as well as xenobiotic agents (e.g. drugs of abuse). The present review focuses on understanding the immunologic mechanism(s) whereby stress primes or sensitizes the neuroinflammatory response to drugs of abuse and explores whether stress- and GC-induced sensitization of neuroimmune processes predisposes individuals to drug abuse liability and the role of neuroinflammatory mediators in the development of drug addiction. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Applications for approval to market a new drug; complete response letter; amendments to unapproved applications. Final rule.

    Science.gov (United States)

    2008-07-10

    The Food and Drug Administration (FDA) is amending its regulations on new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for approval to market new drugs and generic drugs (drugs for which approval is sought in an ANDA). The final rule discontinues FDA's use of approvable letters and not approvable letters when taking action on marketing applications. Instead, we will send applicants a complete response letter to indicate that the review cycle for an application is complete and that the application is not ready for approval. We are also revising the regulations on extending the review cycle due to the submission of an amendment to an unapproved application and starting a new review cycle after the resubmission of an application following receipt of a complete response letter. In addition, we are adding to the regulations on biologics license applications (BLAs) provisions on the issuance of complete response letters to BLA applicants. We are taking these actions to implement the user fee performance goals referenced in the Prescription Drug User Fee Amendments of 2002 (PDUFA III) that address procedures and establish target timeframes for reviewing human drug applications.

  17. Gene expression analysis of two extensively drug-resistant tuberculosis isolates show that two-component response systems enhance drug resistance.

    Science.gov (United States)

    Yu, Guohua; Cui, Zhenling; Sun, Xian; Peng, Jinfu; Jiang, Jun; Wu, Wei; Huang, Wenhua; Chu, Kaili; Zhang, Lu; Ge, Baoxue; Li, Yao

    2015-05-01

    Global analysis of expression profiles using DNA microarrays was performed between a reference strain H37Rv and two clinical extensively drug-resistant isolates in response to three anti-tuberculosis drug exposures (isoniazid, capreomycin, and rifampicin). A deep analysis was then conducted using a combination of genome sequences of the resistant isolates, resistance information, and related public microarray data. Certain known resistance-associated gene sets were significantly overrepresented in upregulated genes in the resistant isolates relative to that observed in H37Rv, which suggested a link between resistance and expression levels of particular genes. In addition, isoniazid and capreomycin response genes, but not rifampicin, either obtained from published works or our data, were highly consistent with the differentially expressed genes of resistant isolates compared to those of H37Rv, indicating a strong association between drug resistance of the isolates and genes differentially regulated by isoniazid and capreomycin exposures. Based on these results, 92 genes of the studied isolates were identified as candidate resistance genes, 10 of which are known resistance-related genes. Regulatory network analysis of candidate resistance genes using published networks and literature mining showed that three two-component regulatory systems and regulator CRP play significant roles in the resistance of the isolates by mediating the production of essential envelope components. Finally, drug sensitivity testing indicated strong correlations between expression levels of these regulatory genes and sensitivity to multiple anti-tuberculosis drugs in Mycobacterium tuberculosis. These findings may provide novel insights into the mechanism underlying the emergence and development of drug resistance in resistant tuberculosis isolates and useful clues for further studies on this issue. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. 21 CFR 1405.400 - What are my responsibilities as a(n) Office of National Drug Control Policy awarding official?

    Science.gov (United States)

    2010-04-01

    ...) Responsibilities of Office of National Drug Control Policy Awarding Officials § 1405.400 What are my... 21 Food and Drugs 9 2010-04-01 2010-04-01 false What are my responsibilities as a(n) Office of National Drug Control Policy awarding official? 1405.400 Section 1405.400 Food and Drugs OFFICE OF NATIONAL...

  19. Stress psychobiology in the context of addiction medicine: from drugs of abuse to behavioral addictions.

    Science.gov (United States)

    Lemieux, Andrine; al'Absi, Mustafa

    2016-01-01

    In this chapter, we briefly review the basic biology of psychological stress and the stress response. We propose that psychological stress and the neurobiology of the stress response play in substance use initiation, maintenance, and relapse. The proposed mechanisms for this include, on the one hand, the complex interactions between biological mediators of the stress response and the dopaminergic reward system and, on the other hand, mediators of the stress response and other systems crucial in moderating key addiction-related behaviors such as endogenous opioids, the sympathetic-adrenal-medullary system, and endocannabinoids. Exciting new avenues of study including genomics, sex as a moderator of the stress response, and behavioral addictions (gambling, hypersexuality, dysfunctional internet use, and food as an addictive substance) are also briefly presented within the context of stress as a moderator of the addictive process. © 2016 Elsevier B.V. All rights reserved.

  20. Responsiveness to physicians' requests for information concerning drug interactions: a comparison of brand and generic companies.

    Science.gov (United States)

    Thomas, M; Lexchin, J

    1990-01-01

    Research-based pharmaceutical companies maintain that there are important differences between themselves and their generic competitors. Prominent among them is an alleged greater ability to provide accurate and rapid responses to requests from physicians for information about drug products. This study evaluates pharmaceutical company behavior with regard to these issues. Two drug-drug interactions were identified, along with all of the companies in Canada marketing any of the four drugs involved. Each company received a letter describing symptoms suggestive of an interaction in a patient taking its particular product and the relevant second drug. The companies were asked if they were aware of any evidence of an interaction involving the two drugs. They were also asked to provide references regarding the interaction. Responses were received from all companies contacted except one. There were no significant differences (in the hypothesized direction) between the generic and brand companies with regard to either the accuracy or promptness of the response, or the usefulness of the references cited. On the contrary, generic firms were markedly quicker to respond than were brand manufacturers. The latter were slightly more likely to acknowledge evidence of an adverse drug interaction, and to provide useful references to relevant published research.

  1. Factors influencing consumers' attitudinal and behavioral responses to direct-to-consumer and over-the-counter drug advertising.

    Science.gov (United States)

    Lee, Mina; Whitehill King, Karen; Reid, Leonard N

    2015-04-01

    Using a model developed from the research literature, the authors compared consumers' attitudinal and behavioral responses to direct-to-consumer prescription drug advertising (DCTA) and over-the-counter nonprescription drug advertising (OTCA) of drugs. Adults 18 years of age and older who had taken any prescription drugs in the past 6 months completed online survey questionnaires. Variables measured included demographics (age, gender, race, education, and income), health-related characteristics (health status, prescription and over-the-counter drug use, health consciousness, and involvement with prescription or over-the-counter drugs), perceived amount of attention and exposure to DTCA and OTCA, attitudinal outcomes (skepticism toward DTCA/OTCA and attitude toward DTCA/OTCA), and behavioral outcomes triggered by DTCA and OTCA. The findings indicate that exposure to drug advertising is one of the most significant predictors of attitudinal and behavioral outcomes. Some audience factors such as health status, involvement with drugs, health consciousness, drug use, income, and age also were differentially associated with consumer responses to drug advertising.

  2. Regulatory aspects of oncology drug safety evaluation: Past practice, current issues, and the challenge of new drugs

    International Nuclear Information System (INIS)

    Rosenfeldt, Hans; Kropp, Timothy; Benson, Kimberly; Ricci, M. Stacey; McGuinn, W. David; Verbois, S. Leigh

    2010-01-01

    The drug development of new anti-cancer agents is streamlined in response to the urgency of bringing effective drugs to market for patients with limited life expectancy. FDA's regulation of oncology drugs has evolved from the practices set forth in Arnold Lehman's seminal work published in the 1950s through the current drafting of a new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) safety guidance for anti-cancer drug nonclinical evaluations. The ICH combines the efforts of the regulatory authorities of Europe, Japan, and the United States and the pharmaceutical industry from these three regions to streamline the scientific and technical aspects of drug development. The recent development of new oncology drug classes with novel mechanisms of action has improved survival rates for some cancers but also brings new challenges for safety evaluation. Here we present the legacy of Lehman and colleagues in the context of past and present oncology drug development practices and focus on some of the current issues at the center of an evolving harmonization process that will generate a new safety guidance for oncology drugs, ICH S9. The purpose of this new guidance will be to facilitate oncology drug development on a global scale by standardizing regional safety requirements.

  3. Tunable thermo-responsive hydrogels: synthesis, structural analysis and drug release studies.

    Science.gov (United States)

    Cirillo, Giuseppe; Spataro, Tania; Curcio, Manuela; Spizzirri, U Gianfranco; Nicoletta, Fiore Pasquale; Picci, Nevio; Iemma, Francesca

    2015-03-01

    Thermo-responsive hydrogel films, synthesized by UV-initiated radical polymerization, are proposed as delivery devices for non-steroidal anti-inflammatory drugs (Diclofenac sodium and Naproxen). N-isopropylacrylamide and N,N'-ethylenebisacrylamide were chosen as thermo-sensitive monomer and crosslinker, respectively. Infrared spectroscopy was used to assess the incorporation of monomers into the network, and the network density of hydrogel films was found to strictly depend on both feed composition and film thickness. Calorimetric analyses showed negative thermo-responsive behaviour with shrinking/swelling transition values in the range 32.8-36.1°C. Equilibrium swelling studies around the LCST allowed the correlation between the structural changes and the temperature variations. The mesh size, indeed, rapidly changed from a collapsed to a swollen state, with beneficial effects in applications such as size-selective permeation or controlled drug delivery, while the crosslinking degree, the film thickness, and the loading method deeply influenced the drug release profiles at 25 and 40°C. The analysis of both 3D-network structure, release kinetics and diffusional constraints at different temperatures was evaluated by mathematical modelling. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy.

    Science.gov (United States)

    Joubert, Nicolas; Denevault-Sabourin, Caroline; Bryden, Francesca; Viaud-Massuard, Marie-Claude

    2017-12-15

    The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris ® and Kadcyla ® made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's "magic bullet". However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms. In this context, alternative non-internalizing ADCs and prodrugs have been developed to circumvent these limitations, in which the drug can be selectively released by an extracellular stimulus in the tumor microenvironment. Each strategy and method of activation will be discussed as potential alternatives to internalizing ADCs for cancer therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. ‘At-risk’ individuals’ responses to direct to consumer advertising of prescription drugs: a nationally representative cross-sectional study

    Science.gov (United States)

    2017-01-01

    Objectives The factors determining individuals’ self-reported behavioural responses to direct to consumer advertising of prescription drugs were explored with an emphasis on ‘at-risk’ individuals’ responses. Design Nationally representative cross-sectional survey. Setting Community living adults in New Zealand. Participants 2057 adults (51% women). Primary outcome measures Self-reported behavioural responses to drug advertising (asking a physician for a prescription, asking a physician for more information about an illness, searching the internet for more information regarding an illness and asking a pharmacist for more information about a drug). Methods Multivariate logistic regressions determined whether participants’ self-reported behavioural responses to drug advertising were predicted by attitudes towards advertising and drug advertising, judgements about safety and effectiveness of advertised drugs, self-reported health status, materialism, online search behaviour as well as demographic variables. Results Identifying as Indian and to a less extent Chinese, Māori and ‘other’ ethnicities were the strongest predictors of one or more self-reported responses (ORs 1.76–5.00, Psmaterialism (ORs 1.02–1.03, Ps<0.01) also predicted one or more self-reported responses. Conclusions Taken together, the findings suggest individuals, especially those who are ‘at-risk’ (ie, with poorer self-reported health status, older, less educated, lower income and ethnic minorities), may be more vulnerable to drug advertising and may make uninformed decisions accordingly. The outcomes raise significant concerns relating to the ethicality of drug advertising and suggest a need for stricter guidelines to ensure that drug advertisements provided by pharmaceutical companies are ethical. PMID:29217723

  6. UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery.

    Science.gov (United States)

    Wang, Lei; Li, Baoqiang; Xu, Feng; Xu, Zheheng; Wei, Daqing; Feng, Yujie; Wang, Yaming; Jia, Dechang; Zhou, Yu

    2017-10-15

    Innovative drug delivery technologies based on smart hydrogels for localized on-demand drug delivery had aroused great interest. To acquire smart UV-crosslinkable chitosan hydrogel for NIR-triggered localized on-demanded drug release, a novel UV-crosslinkable and thermo-responsive chitosan was first designed and synthesized by grafting with poly N-isopropylacrylamide, acetylation of methacryloyl groups and embedding with photothermal carbon. The UV-crosslinkable unit (methacryloyl groups) endowed chitosan with gelation via UV irradiation. The thermo-responsive unit (poly N-isopropylacrylamide) endowed chitosan hydrogel with temperature-triggered volume shrinkage and reversible swelling/de-swelling behavior. The chitosan hybrid hydrogel embedded with photothermal carbon exhibited distinct NIR-triggered volume shrinkage (∼42% shrinkage) in response to temperature elevation as induced by NIR laser irradiation. As a demonstration, doxorubicin release rate was accelerated and approximately 40 times higher than that from non-irradiated hydrogels. The UV-crosslinkable and thermal-responsive hybrid hydrogel served as in situ forming hydrogel-based drug depot is developed for NIR-triggered localized on-demand release. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Aging, Genetic Variations, and Ethnopharmacology: Building Cultural Competence Through Awareness of Drug Responses in Ethnic Minority Elders.

    Science.gov (United States)

    Woods, Diana Lynn; Mentes, Janet C; Cadogan, Mary; Phillips, Linda R

    2017-01-01

    Unique drug responses that may result in adverse events are among the ethnocultural differences described by the Agency for Healthcare Research and Quality. These differences, often attributed to a lack of adherence on the part of the older adult, may be linked to genetic variations that influence drug responses in different ethnic groups. The paucity of research coupled with a lack of knowledge among health care providers compound the problem, contributing to further disparities, especially in this era of personalized medicine and pharmacogenomics. This article examines how age-related changes and genetic differences influence variations in drug responses among older adults in unique ethnocultural groups. The article starts with an overview of age-related changes and ethnopharmacology, moves to describing genetic differences that affect drug responses, with a focus on medications commonly prescribed for older adults, and ends with application of these issues to culturally congruent health care. © The Author(s) 2015.

  8. Pharmacogenomics and Global Precision Medicine in the Context of Adverse Drug Reactions: Top 10 Opportunities and Challenges for the Next Decade.

    Science.gov (United States)

    Alessandrini, Marco; Chaudhry, Mamoonah; Dodgen, Tyren M; Pepper, Michael S

    2016-10-01

    In a move indicative of the enthusiastic support of precision medicine, the U.S. President Barack Obama announced the Precision Medicine Initiative in January 2015. The global precision medicine ecosystem is, thus, receiving generous support from the United States ($215 million), and numerous other governments have followed suit. In the context of precision medicine, drug treatment and prediction of its outcomes have been important for nearly six decades in the field of pharmacogenomics. The field offers an elegant solution for minimizing the effects and occurrence of adverse drug reactions (ADRs). The Clinical Pharmacogenetics Implementation Consortium (CPIC) plays an important role in this context, and it aims at specifically guiding the translation of clinically relevant and evidence-based pharmacogenomics research. In this forward-looking analysis, we make particular reference to several of the CPIC guidelines and their role in guiding the treatment of highly relevant diseases, namely cardiovascular disease, major depressive disorder, cancer, and human immunodeficiency virus, with a view to predicting and managing ADRs. In addition, we provide a list of the top 10 crosscutting opportunities and challenges facing the fields of precision medicine and pharmacogenomics, which have broad applicability independent of the drug class involved. Many of these opportunities and challenges pertain to infrastructure, study design, policy, and science culture in the early 21st century. Ultimately, rational pharmacogenomics study design and the acquisition of comprehensive phenotypic data that proportionately match the genomics data should be an imperative as we move forward toward global precision medicine.

  9. Effectiveness of HIV prevention social marketing with injecting drug users.

    Science.gov (United States)

    Gibson, David R; Zhang, Guili; Cassady, Diana; Pappas, Les; Mitchell, Joyce; Kegeles, Susan M

    2010-10-01

    Social marketing involves applying marketing principles to promote social goods. In the context of health behavior, it has been used successfully to reduce alcohol-related car crashes, smoking among youths, and malaria transmission, among other goals. Features of social marketing, such as audience segmentation and repeated exposure to prevention messages, distinguish it from traditional health promotion programs. A recent review found 8 of 10 rigorously evaluated social marketing interventions responsible for changes in HIV-related behavior or behavioral intentions. We studied 479 injection drug users to evaluate a community-based social marketing campaign to reduce injection risk behavior among drug users in Sacramento, California. Injecting drugs is associated with HIV infection in more than 130 countries worldwide.

  10. In Situ Probing Intracellular Drug Release from Redox-Responsive Micelles by United FRET and AIE.

    Science.gov (United States)

    Wang, Xuelin; Li, Juanjuan; Yan, Qi; Chen, Yanrui; Fan, Aiping; Wang, Zheng; Zhao, Yanjun

    2018-03-01

    Redox-responsive micelles are versatile nanoplatforms for on-demand drug delivery, but the in situ evaluation of drug release is challenging. Fluorescence resonance energy transfer (FRET) technique shows potential for addressing this, while the aggregation-caused quenching effect limits the assay sensitivity. The aim of the current work is to combine aggregation-induced emission (AIE) probe with FRET to realize drug release assessment from micelles. Tetraphenylethene (TPE) is selected as AIE dye and curcumin (Cur) is chosen as the model drug as well as FRET receptor. The drug is covalently linked to a block copolymer via the disulfide bond linker and TPE is also chemically linked to the polymer via an amide bond; the obtained amphiphilic polymer conjugate self-assembles into micelles with a hydrodynamic size of ≈125 nm. Upon the supplement of glutathione or tris(2-carboxyethyl)phosphine) trigger (10 × 10 -3 m), the drug release induces the fluorescence increase of both TPE and Cur. Accompanied with the FRET decay, absorption enhancement and particle size increase are observed. The same phenomenon is observed in MCF-7 cells. The FRET-AIE approach can be a useful addition to the spectrum of available methods for monitoring drug release from stimuli-responsive nanomedicine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Photo-cured pH-responsive polyampholyte-coated membranes for controlled release of drugs with different molecular weights and charges

    International Nuclear Information System (INIS)

    Ng, Loo-Teck; Ng, Kheng-Seong

    2008-01-01

    Intelligent drug delivery membranes were synthesised by photocuring poly(acrylic acid) (PAA) or polyampholytes comprised of copolymers of acrylic acid (AA)/2-(diethylamino)ethyl methacrylate (DEAEMA) with varying monomeric compositions onto poly(2-hydroxyethyl methacrylate) (PHEMA) membranes, each with model drugs of different molecular weights and charges being incorporated. pH-responsive release behaviours of the model drugs which included methylene blue (cationic), metanil yellow (anionic) and caffeine (neutral) were studied. Only membranes with methylene blue and caffeine incorporated displayed clear pH-responsive releases though all coatings. This study demonstrates that drug diffusion through pH-responsive membranes depends to a large extent on the attractive interaction between the drug and the appropriate functional group/s in the coating

  12. pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

    International Nuclear Information System (INIS)

    Yang, Ke-Ni; Zhang, Chun-Qiu; Wang, Wei; Wang, Paul C.; Zhou, Jian-Ping; Liang, Xing-Jie

    2014-01-01

    In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles (MSNs) with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanoparticles, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail

  13. Sustained, Controlled and Stimuli-Responsive Drug Release Systems Based on Nanoporous Anodic Alumina with Layer-by-Layer Polyelectrolyte

    Science.gov (United States)

    Porta-i-Batalla, Maria; Eckstein, Chris; Xifré-Pérez, Elisabet; Formentín, Pilar; Ferré-Borrull, J.; Marsal, Lluis F.

    2016-08-01

    Controlled drug delivery systems are an encouraging solution to some drug disadvantages such as reduced solubility, deprived biodistribution, tissue damage, fast breakdown of the drug, cytotoxicity, or side effects. Self-ordered nanoporous anodic alumina is an auspicious material for drug delivery due to its biocompatibility, stability, and controllable pore geometry. Its use in drug delivery applications has been explored in several fields, including therapeutic devices for bone and dental tissue engineering, coronary stent implants, and carriers for transplanted cells. In this work, we have created and analyzed a stimuli-responsive drug delivery system based on layer-by-layer pH-responsive polyelectrolyte and nanoporous anodic alumina. The results demonstrate that it is possible to control the drug release using a polyelectrolyte multilayer coating that will act as a gate.

  14. Grafting of graphene oxide with stimuli-responsive polymers by using ATRP for drug release

    International Nuclear Information System (INIS)

    Zhu Shenmin; Li Jingbo; Chen Yuhang; Chen Zhixin; Chen Chenxin; Li Yao; Cui Zhaowen; Zhang Di

    2012-01-01

    A thermo-responsive drug delivery system was reported based on grafting of stimuli-responsive poly(N-isopropylacrylamide) (PNIPA) on the surface of graphene oxide (GO) via atom transfer radical polymerization. The successful synthesis of PNIPA attached on GO (GO–PNIPA) was confirmed by X-ray photoelectron spectrum, X-ray diffraction, atomic force microscope, field-emission scanning electron microscopy, and transmission electron microscopy measurements. Control of drug release through the composite GO–PNIPA was performed by measuring the uptake and release of ibuprofen (IBU). It was found the delivery system demonstrated a much high IBU storage of 280 wt%, attributing to the formation of the hydrogen bonding between the polymers on the GO surface and IBU as well as the large number of internal cavities of the PNIPA chains. In vitro test of IBU release exhibited a narrow pronounced transition at around 22 °C, indicating an attractive thermo-sensitive release property of this delivery system. The strategy may pave the way for the use of GO in numerous applications, from drug delivery to thermally responsive micro- and nano-devices.

  15. Grafting of graphene oxide with stimuli-responsive polymers by using ATRP for drug release

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Shenmin, E-mail: smzhu@sjtu.edu.cn; Li Jingbo; Chen Yuhang [Shanghai Jiao Tong University, State Key Laboratory of Metal Matrix Composites, School of Electronic, Information and Electrical Engineering (China); Chen Zhixin [University of Wollongong, Faculty of Engineering (Australia); Chen Chenxin; Li Yao; Cui Zhaowen; Zhang Di, E-mail: zhangdi@sjtu.edu.cn [Shanghai Jiao Tong University, State Key Laboratory of Metal Matrix Composites, School of Electronic, Information and Electrical Engineering (China)

    2012-09-15

    A thermo-responsive drug delivery system was reported based on grafting of stimuli-responsive poly(N-isopropylacrylamide) (PNIPA) on the surface of graphene oxide (GO) via atom transfer radical polymerization. The successful synthesis of PNIPA attached on GO (GO-PNIPA) was confirmed by X-ray photoelectron spectrum, X-ray diffraction, atomic force microscope, field-emission scanning electron microscopy, and transmission electron microscopy measurements. Control of drug release through the composite GO-PNIPA was performed by measuring the uptake and release of ibuprofen (IBU). It was found the delivery system demonstrated a much high IBU storage of 280 wt%, attributing to the formation of the hydrogen bonding between the polymers on the GO surface and IBU as well as the large number of internal cavities of the PNIPA chains. In vitro test of IBU release exhibited a narrow pronounced transition at around 22 Degree-Sign C, indicating an attractive thermo-sensitive release property of this delivery system. The strategy may pave the way for the use of GO in numerous applications, from drug delivery to thermally responsive micro- and nano-devices.

  16. Chitosan-Gated Magnetic-Responsive Nanocarrier for Dual-Modal Optical Imaging, Switchable Drug Release, and Synergistic Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hui [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA; Mu, Qingxin [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA; Revia, Richard [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA; Wang, Kui [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA; Zhou, Xuezhe [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA; Pauzauskie, Peter J. [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA; Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland WA 99354 USA; Zhou, Shuiqin [Department of Chemistry, The College of Staten Island, City University of New York, Staten Island NY 10314 USA; Zhang, Miqin [Department of Materials Science and Engineering, University of Washington, Seattle WA 98195 USA

    2017-01-25

    In this study, we present a multifunctional yet structurally simple nanocarrier that has a high drug loading capacity, releases drug in response to onset of an AC magnetic field, and can serve as a long-term imaging contrast agent and effectively kills cancer cells by synergistic action. This nanocarrier (HMMC-NC) has a spherical shell structure with a center cavity of 80 nm in diameter. The shell is comprised of two layers: an inner layer of magnetite that exhibits superparamagnetism and an outer layer of mesoporous carbon embedded with carbon dots that exhibit photoluminescence property. Thus in addition to being a drug carrier, HMMC-NC is also a contrast agent for bioimaging. The switchable drug release is enabled by the chitosan molecules attached on the nanocarrier as the switching material which turns on or off the drug release in response to the application or withdrawal of an AC magnetic field.

  17. Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Jiao, Jian; Li, Xian; Zhang, Sha; Liu, Jie; Di, Donghua [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016 (China); Zhang, Ying [School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, PR China. (China); Zhao, Qinfu, E-mail: zqf021110505@163.com [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016 (China); Wang, Siling, E-mail: silingwang@syphu.edu.cn [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016 (China)

    2016-10-01

    In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10 mM GSH or in pH 5.0 release medium. Moreover, the release of DOX was further improved in pH 5.0 PBS with 10 mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy. - Highlights: • Hollow mesoporous silica nanoparticles (HMSN) were used as a drug carrier. • Chitosan (CS) and PEG were grafted on the surface of HMSN via disulfide bonds. • The DOX loaded DOX/HMSN-SS-CS@PEG had a high drug loading efficiency up to 32.8%. • DOX/HMSN-SS-CS@PEG showed redox/pH dual-responsive drug release property in vitro. • The grafted PEG could increase the biocompatibility and stability of HMSN.

  18. Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release

    International Nuclear Information System (INIS)

    Jiao, Jian; Li, Xian; Zhang, Sha; Liu, Jie; Di, Donghua; Zhang, Ying; Zhao, Qinfu; Wang, Siling

    2016-01-01

    In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10 mM GSH or in pH 5.0 release medium. Moreover, the release of DOX was further improved in pH 5.0 PBS with 10 mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy. - Highlights: • Hollow mesoporous silica nanoparticles (HMSN) were used as a drug carrier. • Chitosan (CS) and PEG were grafted on the surface of HMSN via disulfide bonds. • The DOX loaded DOX/HMSN-SS-CS@PEG had a high drug loading efficiency up to 32.8%. • DOX/HMSN-SS-CS@PEG showed redox/pH dual-responsive drug release property in vitro. • The grafted PEG could increase the biocompatibility and stability of HMSN.

  19. Republic of Georgia estimates for prevalence of drug use: Randomized response techniques suggest under-estimation.

    Science.gov (United States)

    Kirtadze, Irma; Otiashvili, David; Tabatadze, Mzia; Vardanashvili, Irina; Sturua, Lela; Zabransky, Tomas; Anthony, James C

    2018-06-01

    Validity of responses in surveys is an important research concern, especially in emerging market economies where surveys in the general population are a novelty, and the level of social control is traditionally higher. The Randomized Response Technique (RRT) can be used as a check on response validity when the study aim is to estimate population prevalence of drug experiences and other socially sensitive and/or illegal behaviors. To apply RRT and to study potential under-reporting of drug use in a nation-scale, population-based general population survey of alcohol and other drug use. For this first-ever household survey on addictive substances for the Country of Georgia, we used the multi-stage probability sampling of 18-to-64-year-old household residents of 111 urban and 49 rural areas. During the interviewer-administered assessments, RRT involved pairing of sensitive and non-sensitive questions about drug experiences. Based upon the standard household self-report survey estimate, an estimated 17.3% [95% confidence interval, CI: 15.5%, 19.1%] of Georgian household residents have tried cannabis. The corresponding RRT estimate was 29.9% [95% CI: 24.9%, 34.9%]. The RRT estimates for other drugs such as heroin also were larger than the standard self-report estimates. We remain unsure about what is the "true" value for prevalence of using illegal psychotropic drugs in the Republic of Georgia study population. Our RRT results suggest that standard non-RRT approaches might produce 'under-estimates' or at best, highly conservative, lower-end estimates. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. HIV and injecting drug use in Indonesia: epidemiology and national response.

    Science.gov (United States)

    Afriandi, Irvan; Aditama, Tjandra Yoga; Mustikawati, Dyah; Oktavia, Martiani; Alisjahbana, Bachti; Riono, Pandu

    2009-07-01

    Indonesia is facing one of the most rapidly growing HIV-epidemics in Asia. Risk behaviour associated with injecting drug use, such as sharing contaminated needles, is the main risk factor for HIV infection. Among the general population the prevalence of HIV-infection is still low (0.2%), but up to 50% or more of the estimated 145.000 - 170.000 injecting drug users are already HIV-positive. Overrepresentation of injecting drug users and continued risk behavior inside Indonesian prisons contribute to spread of HIV. Through sexual contacts, HIV is transmitted from current or previous injecting drug users to their non-injecting sexual partners; 10-20% of this group may already be infected. The national response targeted to limit spread of HIV through injecting drug use has included needle and syringe program (NSP), methadone maintenance treatment (MMT), voluntary counseling and testing (VCT), and outreach program as priority programs. However coverage and utilization of the harm reduction services is still limited, but effective integration with HIV testing and treatment is expanding. By 2008, there were 110 service points for NSP and 24 operational MMT clinics. Nevertheless, utilization of these services has been less satisfactory and their effectiveness has been questioned. Besides effective prevention, HIV- testing and earlier treatment of HIV-seropositve individuals, including those with a history of injecting drug use, will help control the growing HIV-epidemic in Indonesia.

  1. Toxicological Analysis of Some Drugs of Abuse in Biological Samples

    Directory of Open Access Journals (Sweden)

    Anne Marie Ciobanu

    2015-10-01

    Full Text Available Consumption of drugs of abuse is a scourge of modern world. Abuse, drug addiction and their consequences are one of the major current problems of European society because of the significant repercussions in individual, family, social and economic level. In this context, toxicological analysis of the drugs of abuse in biological samples is a useful tool for: diagnosis of drug addiction, checking an auto-response, mandatory screening in some treatment programs, identification of a substance in the case of an overdose, determining compliance of the treatment. The present paper aims to address the needs of healthcare professionals involved in drugs addiction treatment through systematic presentation of information regarding their toxicological analysis. Basically, it is a tool that help you to select the suitable biological sample and the right collecting time, as well as the proper analysis technique, depending on the purpose of analysis, pharmacokinetic characteristics of the drugs of abuse, available equipment and staff expertise.

  2. Quality assessment of structure and language elements of written responses given by seven Scandinavian drug information centres

    DEFF Research Database (Denmark)

    Reppe, Linda Amundstuen; Spigset, Olav; Kampmann, Jens Peter

    2017-01-01

    PURPOSE: The aim of this study was to identify structure and language elements affecting the quality of responses from Scandinavian drug information centres (DICs). METHODS: Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The centres were blinded for wh...... on drug-related queries with respect to language and text structure. Giving specific advice and precise conclusions and avoiding too compressed language and non-standard abbreviations may aid to reach this goal....... of responses was generally judged as satisfactory to good. Presenting specific advice and conclusions were considered to improve the quality of the responses. However, small nuances in language formulations could affect the individual judgments of the experts, e.g. on whether or not advice was given. Some...... and explaining pharmacological terms to ensure that enquirers understand the response as intended. In addition, more use of active voice and less compressed text structure would be desirable. CONCLUSIONS: This evaluation of responses to DIC queries may give some indications on how to improve written responses...

  3. Nanoparticle-stabilized liposomes for pH-responsive gastric drug delivery.

    Science.gov (United States)

    Thamphiwatana, Soracha; Fu, Victoria; Zhu, Jingying; Lu, Diannan; Gao, Weiwei; Zhang, Liangfang

    2013-10-01

    We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However, when the stabilized liposomes are present in an environment with neutral pH, the gold stabilizers detach from the liposomes, resulting in free liposomes that can actively fuse with bacterial membranes. Using Helicobacter pylori as a model bacterium and doxycycline as a model antibiotic, we demonstrate such pH-responsive fusion activity and drug release profile of the nanoparticle-stabilized liposomes. Particularly, at neutral pH the gold nanoparticles detach, and thus the doxycycline-loaded liposomes rapidly fuse with bacteria and cause superior bactericidal efficacy as compared to the free doxycycline counterpart. Our results suggest that the reported liposome system holds a substantial potential for gastric drug delivery; it remains inactive (stable) in the stomach lumen but actively interacts with bacteria once it reaches the mucus layer of the stomach where the bacteria may reside.

  4. "The first shot": the context of first injection of illicit drugs, ongoing injecting practices, and hepatitis C infection in Rio de Janeiro, Brazil

    Directory of Open Access Journals (Sweden)

    Maria de Lourdes Aguiar Oliveira

    Full Text Available The context of first drug injection and its association with ongoing injecting practices and HCV (hepatitis C virus infection were investigated. Injection drug users (IDUs (N = 606 were recruited in "drug scenes" (public places, bars in Rio de Janeiro, Brazil, interviewed, and tested for HCV. Sharing of needles/syringes was more prevalent at the first injection (51.3% than at the baseline interview (36.8%. Those who shared syringes/needles at first injection were more likely to be currently engaged in direct/indirect sharing practices. Among young injectors (< 30 years, those reporting sharing of needles/ syringes at the first injection were about four times more likely to have been infected by HCV. Hepatitis C virus prevalence among active IDUs (n = 272 was 11%. Prison history and longer duration of drug injection were identified as independent predictors of HCV infection. To effectively curb HCV transmission among IDUs and minimize harms associated with risk behaviors, preventive strategies should target individuals initiating drug injection beginning with their very first injection and discourage the transition from non-injecting use to the self-injection of illicit drugs.

  5. SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

    Science.gov (United States)

    Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing

    2017-08-01

    Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . jing.tang@helsinki.fi. © The Author(s) 2017. Published by Oxford University Press.

  6. Radiation response of drug-resistant variants of a human breast cancer cell line

    International Nuclear Information System (INIS)

    Lehnert, S.; Greene, D.; Batist, G.

    1989-01-01

    The radiation response of drug-resistant variants of the human tumor breast cancer cell line MCF-7 has been investigated. Two sublines, one resistant to adriamycin (ADRR) and the other to melphalan (MLNR), have been selected by exposure to stepwise increasing concentrations of the respective drugs. ADRR cells are 200-fold resistant to adriamycin and cross-resistant to a number of other drugs and are characterized by the presence of elevated levels of selenium-dependent glutathione peroxidase and glutathione-S-transferase. MLNR cells are fourfold resistant to melphalan and cross-resistant to some other drugs. The only mechanism of drug resistance established for MLNR cells to date is an enhancement of DNA excision repair processes. While the spectrum of drug resistance and the underlying mechanisms differ for the two sublines, their response to radiation is qualitatively similar. Radiation survival curves for ADRR and MLNR cells differ from that for wild-type cells in a complex manner with, for the linear-quadratic model, a decrease in the size of alpha and an increase in the size of beta. There is a concomitant decrease in the size of the alpha/beta ratio which is greater for ADRR cells than for MLNR cells. Analysis of results using the multitarget model gave values of D0 of 1.48, 1.43, and 1.67 Gy for MCF-7 cells are not a consequence of cell kinetic differences between these sublines. Results of split-dose experiments indicated that for both drug-resistant sublines the extent of sublethal damage repair reflected the width of the shoulder on the single-dose survival curve. For MCF-7 cells in the stationary phase of growth, the drug-resistant sublines did not show cross-resistance to radiation; however, delayed subculture following irradiation of stationary-phase cultures increased survival to a greater extent for ADRR and MLNR cells than for wild-type cells

  7. Social-structural contexts of needle and syringe sharing behaviours of HIV-positive injecting drug users in Manipur, India: a mixed methods investigation

    Directory of Open Access Journals (Sweden)

    Shunmugam Murali

    2011-05-01

    Full Text Available Abstract Background Few investigations have assessed risk behaviours and social-structural contexts of risk among injecting drug users (IDUs in Northeast India, where injecting drug use is the major route of HIV transmission. Investigations of risk environments are needed to inform development of effective risk reduction interventions. Methods This mixed methods study of HIV-positive IDUs in Manipur included a structured survey (n = 75, two focus groups (n = 17, seven in-depth interviews, and two key informant interviews. Results One-third of survey participants reported having shared a needle/syringe in the past 30 days; among these, all the men and about one-third of the women did so with persons of unknown HIV serostatus. A variety of social-structural contextual factors influenced individual risk behaviours: barriers to carrying sterile needles/syringes due to fear of harassment by police and "anti-drug" organizations; lack of sterile needles/syringes in drug dealers' locales; limited access to pharmacy-sold needles/syringes; inadequate coverage by needle and syringe programmes (NSPs; non-availability of sterile needles/syringes in prisons; and withdrawal symptoms superseding concern for health. Some HIV-positive IDUs who shared needles/syringes reported adopting risk reduction strategies: being the 'last receiver' of needles/syringes and not a 'giver;' sharing only with other IDUs they knew to be HIV-positive; and, when a 'giver,' asking other IDUs to wash used needles/syringes with bleach before using. Conclusions Effective HIV prevention and care programmes for IDUs in Northeast India may hinge on several enabling contexts: supportive government policy on harm reduction programmes, including in prisons; an end to harassment by the police, army, and anti-drug groups, with education of these entities regarding harm reduction, creation of partnerships with the public health sector, and accountability to government policies that protect IDUs

  8. From Addiction to Infection: Managing Drug Abuse in the Context of ...

    African Journals Online (AJOL)

    People who use drugs are at higher risk of HIV: directly through the sharing of injecting equipment, indirectly through associated risk behavior, and physiologically through the substances' impact on the immune system. Drug users, especially people who inject drugs (PWID) are a bridge to the general population.

  9. From Addiction to Infection: Managing Drug Abuse in the Context of ...

    African Journals Online (AJOL)

    AJRH Managing Editor

    Pretoria, South Africa. *For Correspondence: E-mail: taiwo.akindipe@gmail.com; Phone: +234 803 388 1391 ... 18[3]: 47-54). Keywords: Drug users, Drug addiction, Substance use, HIV infection, Africa. Résumé ... potentially weak social support systems, ..... electronic media need to highlight the relationship between drug ...

  10. Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis

    DEFF Research Database (Denmark)

    Glintborg, Bente; Gudbjornsson, Bjorn; Krogh, Niels Steen

    2014-01-01

    Icelandic patients at baseline [median 3.1 (interquartile range 3.0-3.8) vs 2.3 (2.1-2.9) mg/kg, P drug survival than...... Icelandic patients (1183 vs 483 days). In univariate analyses stratified by country, time until dose escalation, response rates, drug survival and 1-year's disease activity were independent of starting dose. Drug survival was shorter among patients not receiving concomitant MTX. CONCLUSION: In clinical...... practice, > 70% of Icelandic and Danish PsA patients treated with infliximab received sustained doses below the 5 mg/kg every 8 weeks recommended in international guidelines. Lower starting doses did not affect drug survival or response....

  11. Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

    Science.gov (United States)

    Goldstein, Rita Z.; Volkow, Nora D.

    2005-01-01

    Objective Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. Method An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. Results The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to track, update, and modulate the salience of a reinforcer as a function of context and expectation and the ability to control and inhibit prepotent responses. Conclusions These results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervaluing of alternative reinforcers, and deficits in inhibitory control for drug responses. These changes in addiction, which the authors call I-RISA (impaired response inhibition and salience attribution), expand the traditional concepts of drug dependence that emphasize limbic-regulated responses to pleasure and reward. PMID:12359667

  12. Thermo-responsive magnetic liposomes for hyperthermia-triggered local drug delivery.

    Science.gov (United States)

    Dai, Min; Wu, Cong; Fang, Hong-Ming; Li, Li; Yan, Jia-Bao; Zeng, Dan-Lin; Zou, Tao

    2017-06-01

    We prepared and characterised thermo-responsive magnetic liposomes, which were designed to combine features of magnetic targeting and thermo-responsive control release for hyperthermia-triggered local drug delivery. The particle size and zeta-potential of the thermo-responsive magnetic ammonium bicarbonate (MagABC) liposomes were about 210 nm and -14 mV, respectively. The MagABC liposomes showed encapsulation efficiencies of about 15% and 82% for magnetic nanoparticles (mean crystallite size 12 nm) and doxorubicin (DOX), respectively. The morphology of the MagABC liposomes was visualised using transmission electron microscope (TEM). The MagABC liposomes showed desired thermo-responsive release. The MagABC liposomes, when physically targeted to tumour cells in culture by a permanent magnetic field yielded a substantial increase in intracellular accumulation of DOX as compared to non-magnetic ammonium bicarbonate (ABC) liposomes. This resulted in a parallel increase in cytotoxicity for DOX loaded MagABC liposomes over DOX loaded ABC liposomes in tumour cells.

  13. EPR response characterization of drugs excipients for applying in accident dosimetry

    International Nuclear Information System (INIS)

    Marczewski, Barbara S.; Rodrigues Junior, Orlando; Galante, Ocimar L.; Costa, Zelia M. da; Campos, Leticia L.

    2002-01-01

    Some drugs are widely used by the population and can be employed to dose retrospective. The carbohydrates (saccharides), commonly used as excipients in the pharmaceutical industry, produce a quantity of free radicals after gamma irradiation, making them useful for dosimetry in emergency or accident situations that imply in dose evaluation from the materials found nearly or in contact with victims. In general, EPR signal from pulverized pills of some drugs are very complex due to the variety of components in the formulation. Because of this fact, some pharmaceutical excipients identified in the pill composition were also analysed by EPR spectrometry. On the counter drugs were studied: Cebion glucose, AAS, Aspirina, Conmel, Lacto-Purga and sugar substitutive ZeroCal. The excipients were: lactose, amide, anhydrous glucose and magnesium stearate. In some samples the number of radicals produced increased with the dose, showing a linear response for a dose range of interest and an adequate sensibility for dosimetry in accident cases

  14. Prediction of resistance development against drug combinations by collateral responses to component drugs

    DEFF Research Database (Denmark)

    Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika

    2014-01-01

    the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during...... adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance......Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability...

  15. An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

    Science.gov (United States)

    Najer, Adrian; Wu, Dalin; Nussbaumer, Martin G.; Schwertz, Geoffrey; Schwab, Anatol; Witschel, Matthias C.; Schäfer, Anja; Diederich, François; Rottmann, Matthias; Palivan, Cornelia G.; Beck, Hans-Peter; Meier, Wolfgang

    2016-08-01

    Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL-1. Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (+/-)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.Medical applications of anticancer and antimalarial drugs often suffer from low aqueous

  16. Parental responsibility beliefs: associations with parental anxiety and behaviours in the context of childhood anxiety disorders.

    Science.gov (United States)

    Apetroaia, Adela; Hill, Claire; Creswell, Cathy

    2015-12-01

    High levels of parental anxiety are associated with poor treatment outcomes for children with anxiety disorders. Associated parental cognitions and behaviours have been implicated as impediments to successful treatment. We examined the association between parental responsibility beliefs, maternal anxiety and parenting behaviours in the context of childhood anxiety disorders. Anxious and non-anxious mothers of 7-12 year old children with a current anxiety disorder reported their parental responsibility beliefs using a questionnaire measure. Parental behaviours towards their child during a stressor task were measured. Parents with a current anxiety disorder reported a greater sense of responsibility for their child's actions and wellbeing than parents who scored within the normal range for anxiety. Furthermore, higher parental responsibility was associated with more intrusive and less warm behaviours in parent-child interactions and there was an indirect effect between maternal anxiety and maternal intrusive behaviours via parental responsibility beliefs. The sample was limited to a treatment-seeking, relatively high socio-economic population and only mothers were included so replication with more diverse groups is needed. The use of a range of stressor tasks may have allowed for a more comprehensive assessment of parental behaviours. The findings suggest that parental anxiety disorder is associated with an elevated sense of parental responsibility and may promote parental behaviours likely to inhibit optimum child treatment outcomes. Parental responsibility beliefs may therefore be important to target in child anxiety treatments in the context of parental anxiety disorders. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Responsive Boronic Acid-Decorated (Copolymers: From Glucose Sensors to Autonomous Drug Delivery

    Directory of Open Access Journals (Sweden)

    Gertjan Vancoillie

    2016-10-01

    Full Text Available Boronic acid-containing (copolymers have fascinated researchers for decades, garnering attention for their unique responsiveness toward 1,2- and 1,3-diols, including saccharides and nucleotides. The applications of materials that exert this property are manifold including sensing, but also self-regulated drug delivery systems through responsive membranes or micelles. In this review, some of the main applications of boronic acid containing (copolymers are discussed focusing on the role of the boronic acid group in the response mechanism. We hope that this summary, which highlights the importance and potential of boronic acid-decorated polymeric materials, will inspire further research within this interesting field of responsive polymers and polymeric materials.

  18. Intracellular antioxidants dissolve man-made antioxidant nanoparticles: using redox vulnerability of nanoceria to develop a responsive drug delivery system.

    Science.gov (United States)

    Muhammad, Faheem; Wang, Aifei; Qi, Wenxiu; Zhang, Shixing; Zhu, Guangshan

    2014-01-01

    Regeneratable antioxidant property of nanoceria has widely been explored to minimize the deleterious influences of reactive oxygen species. Limited information is, however, available regarding the biological interactions and subsequent fate of nanoceria in body fluids. This study demonstrates a surprising dissolution of stable and ultrasmall (4 nm) cerium oxide nanoparticles (CeO2 NPs) in response to biologically prevalent antioxidant molecules (glutathione, vitamin C). Such a redox sensitive behavior of CeO2 NPs is subsequently exploited to design a redox responsive drug delivery system for transporting anticancer drug (camptothecin). Upon exposing the CeO2 capped and drug loaded nanoconstruct to vitamin c or glutathione, dissolution-accompanied aggregation of CeO2 nanolids unleashes the drug molecules from porous silica to achieve a significant anticancer activity. Besides stimuli responsive drug delivery, immobilization of nanoceria onto the surface of mesoporous silica also facilitates us to gain a basic insight into the biotransformation of CeO2 in physiological mediums.

  19. Medical jurisprudence in the local context.

    Science.gov (United States)

    Rajah, K S

    1987-04-01

    Medical jurisprudence in the local context would require the examination of a wide area. This paper focuses on liability producing conduct arising from the providing of medical services, other than liability for criminal negligent conduct. It examines the circumstances in which the physician-patient relationship emerges, in medical jurisprudence as against practice by medical practitioners. Tort law is the dominant legal theory, and reference is made to some intentional and miscellaneous torts. Implied contracts creating the relationship are touched upon, besides the reference to vicarious liability. Insanity and diminished responsibility in the criminal law, particularly the issue of whether the status quo is satisfactory and reliance on medical reports for purposes of treatment under drug laws are examined. Where abortion is performed, the question whether the husband has any right to prevent his wife from having a lawful abortion is discussed in the local context. Some thoughts on the medical (therapy, education and research) Act 1972 are expressed in relation to the living body, the corpse and the parts of the human body. The patient's right to determination and information in the light of the above legislation is also discussed.

  20. Suicidal behaviours in male and female users of illicit drugs recruited in drug treatment facilities

    Directory of Open Access Journals (Sweden)

    Elisabet Arribas-Ibar

    2017-07-01

    Conclusions: Prevalence of suicidal ideation/plans was high among illicit drug users recruited from healthcare facilities. Besides psychological variables, participation in illegal market activities and crime ought to be considered in drug users’ suicidal prevention. Suicide risk needs to be evaluated in drug treatment facilities and psychological status and context contemplated.

  1. Microfluidic synthesis of microfibers for magnetic-responsive controlled drug release and cell culture.

    Directory of Open Access Journals (Sweden)

    Yung-Sheng Lin

    Full Text Available This study demonstrated the fabrication of alginate microfibers using a modular microfluidic system for magnetic-responsive controlled drug release and cell culture. A novel two-dimensional fluid-focusing technique with multi-inlets and junctions was used to spatiotemporally control the continuous laminar flow of alginate solutions. The diameter of the manufactured microfibers, which ranged from 211 µm to 364 µm, could be well controlled by changing the flow rate of the continuous phase. While the model drug, diclofenac, was encapsulated into microfibers, the drug release profile exhibited the characteristic of a proper and steady release. Furthermore, the diclofenac release kinetics from the magnetic iron oxide-loaded microfibers could be controlled externally, allowing for a rapid drug release by applying a magnetic force. In addition, the successful culture of glioblastoma multiforme cells in the microfibers demonstrated a good structural integrity and environment to grow cells that could be applied in drug screening for targeting cancer cells. The proposed microfluidic system has the advantages of ease of fabrication, simplicity, and a fast and low-cost process that is capable of generating functional microfibers with the potential for biomedical applications, such as drug controlled release and cell culture.

  2. Illicit drug use in seven Latin American countries: critical perspectives of families and familiars.

    Science.gov (United States)

    Silva, Jaqueline da; Ventura, Carla Aparecida Arena; Vargens, Octavio Muniz da Costa; Loyola, Cristina Maria Douat; Albarracín, Daniel Gonzalo Eslava; Diaz, Jorge; Funes, Gladys Magdalena Rodríguez; Hernández, Mabell Granados; Torres, Ruth Magdalena Gallegos; Rodriguez, Ruth Jakeline Oviedo

    2009-01-01

    This cross-sectional multi-centre study explored how family members and friends of illicit drug users perceived protective and risk factors, treatment facilities and policies and laws regarding illicit drug use. Family members and friends of illicit drug users were recruited in 10 urban health care outpatient units in 7 Latin American countries (Brazil, Colombia, Costa Rica, Ecuador, Guatemala, Honduras and Mexico) to complete a questionnaire. The majority of the respondents chose psycho-social factors over genetic or biological explanations as causes of drug problems. Respondents felt that families and governments were responsible for preventing drug problems. Church/religious institutions were most often mentioned in the context of accessible treatment. When asked about access to treatment facilities, the majority said that there were not enough. Shame about drug use, cost, and limited treatment options were most often cited as barriers to treatment.

  3. DrugSig: A resource for computational drug repositioning utilizing gene expression signatures.

    Directory of Open Access Journals (Sweden)

    Hongyu Wu

    Full Text Available Computational drug repositioning has been proved as an effective approach to develop new drug uses. However, currently existing strategies strongly rely on drug response gene signatures which scattered in separated or individual experimental data, and resulted in low efficient outputs. So, a fully drug response gene signatures database will be very helpful to these methods. We collected drug response microarray data and annotated related drug and targets information from public databases and scientific literature. By selecting top 500 up-regulated and down-regulated genes as drug signatures, we manually established the DrugSig database. Currently DrugSig contains more than 1300 drugs, 7000 microarray and 800 targets. Moreover, we developed the signature based and target based functions to aid drug repositioning. The constructed database can serve as a resource to quicken computational drug repositioning. Database URL: http://biotechlab.fudan.edu.cn/database/drugsig/.

  4. Adverse Drug Reaction Reporting Pattern in Turkey: Analysis of the National Database in the Context of the First Pharmacovigilance Legislation.

    Science.gov (United States)

    Ozcan, Gulnihal; Aykac, Emel; Kasap, Yelda; Nemutlu, Nergiz T; Sen, Ebru; Aydinkarahaliloglu, N Demet

    2016-03-01

    In Turkey, pharmacovigilance began in 1985. A fully structured adverse drug reaction (ADR)-reporting system was established with the publication of the first pharmacovigilance regulation in 2005. Subsequent regulation published in 2014 brought further improvements to the system. In this study, we aimed to analyse the ADR-reporting pattern in the context of the first pharmacovigilance legislation in Turkey. We analysed ADR reports submitted to the Turkish Pharmacovigilance Center (TUFAM) from 2005 to 2014 with respect to reporting rate (RR), patient characteristics, type of the ADRs, suspected drugs, source of the report and the profession of the reporter. The annual RR increased gradually over the study period. RRs for females were greater than those for males. RRs were highly correlated with age. Most commonly reported ADRs were skin and subcutaneous tissue disorders. Most commonly suspected drugs were antineoplastic and immunomodulating agents. There was no remarkable change in reporting pattern of ADRs, patient characteristics or classes of suspected drugs over the years. The most common source of reports was spontaneous reporting. Contribution of the reports from studies increased gradually. Most of the reports were reported by physicians. RRs by pharmacists increased substantially over the years. This study showed that the annual RR increased gradually over the 9-year study period. This increase was neither due to an increased reporting of a specific group of ADRs or drugs, nor to an increased reporting in a specific group of patients. There was a general increase in RR in parallel to pharmacovigilance activities.

  5. A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations.

    Science.gov (United States)

    Litichevskiy, Lev; Peckner, Ryan; Abelin, Jennifer G; Asiedu, Jacob K; Creech, Amanda L; Davis, John F; Davison, Desiree; Dunning, Caitlin M; Egertson, Jarrett D; Egri, Shawn; Gould, Joshua; Ko, Tak; Johnson, Sarah A; Lahr, David L; Lam, Daniel; Liu, Zihan; Lyons, Nicholas J; Lu, Xiaodong; MacLean, Brendan X; Mungenast, Alison E; Officer, Adam; Natoli, Ted E; Papanastasiou, Malvina; Patel, Jinal; Sharma, Vagisha; Toder, Courtney; Tubelli, Andrew A; Young, Jennie Z; Carr, Steven A; Golub, Todd R; Subramanian, Aravind; MacCoss, Michael J; Tsai, Li-Huei; Jaffe, Jacob D

    2018-04-25

    Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the "connectivity" framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Open source machine-learning algorithms for the prediction of optimal cancer drug therapies.

    Science.gov (United States)

    Huang, Cai; Mezencev, Roman; McDonald, John F; Vannberg, Fredrik

    2017-01-01

    Precision medicine is a rapidly growing area of modern medical science and open source machine-learning codes promise to be a critical component for the successful development of standardized and automated analysis of patient data. One important goal of precision cancer medicine is the accurate prediction of optimal drug therapies from the genomic profiles of individual patient tumors. We introduce here an open source software platform that employs a highly versatile support vector machine (SVM) algorithm combined with a standard recursive feature elimination (RFE) approach to predict personalized drug responses from gene expression profiles. Drug specific models were built using gene expression and drug response data from the National Cancer Institute panel of 60 human cancer cell lines (NCI-60). The models are highly accurate in predicting the drug responsiveness of a variety of cancer cell lines including those comprising the recent NCI-DREAM Challenge. We demonstrate that predictive accuracy is optimized when the learning dataset utilizes all probe-set expression values from a diversity of cancer cell types without pre-filtering for genes generally considered to be "drivers" of cancer onset/progression. Application of our models to publically available ovarian cancer (OC) patient gene expression datasets generated predictions consistent with observed responses previously reported in the literature. By making our algorithm "open source", we hope to facilitate its testing in a variety of cancer types and contexts leading to community-driven improvements and refinements in subsequent applications.

  7. Open source machine-learning algorithms for the prediction of optimal cancer drug therapies.

    Directory of Open Access Journals (Sweden)

    Cai Huang

    Full Text Available Precision medicine is a rapidly growing area of modern medical science and open source machine-learning codes promise to be a critical component for the successful development of standardized and automated analysis of patient data. One important goal of precision cancer medicine is the accurate prediction of optimal drug therapies from the genomic profiles of individual patient tumors. We introduce here an open source software platform that employs a highly versatile support vector machine (SVM algorithm combined with a standard recursive feature elimination (RFE approach to predict personalized drug responses from gene expression profiles. Drug specific models were built using gene expression and drug response data from the National Cancer Institute panel of 60 human cancer cell lines (NCI-60. The models are highly accurate in predicting the drug responsiveness of a variety of cancer cell lines including those comprising the recent NCI-DREAM Challenge. We demonstrate that predictive accuracy is optimized when the learning dataset utilizes all probe-set expression values from a diversity of cancer cell types without pre-filtering for genes generally considered to be "drivers" of cancer onset/progression. Application of our models to publically available ovarian cancer (OC patient gene expression datasets generated predictions consistent with observed responses previously reported in the literature. By making our algorithm "open source", we hope to facilitate its testing in a variety of cancer types and contexts leading to community-driven improvements and refinements in subsequent applications.

  8. Magnetically responsive microparticles for targeted drug and radionuclide delivery

    International Nuclear Information System (INIS)

    Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

    2004-01-01

    We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 (micro)m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 (micro)m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 (micro)m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

  9. Responsive Boronic Acid-Decorated (Co)polymers: From Glucose Sensors to Autonomous Drug Delivery.

    Science.gov (United States)

    Vancoillie, Gertjan; Hoogenboom, Richard

    2016-10-19

    Boronic acid-containing (co)polymers have fascinated researchers for decades, garnering attention for their unique responsiveness toward 1,2- and 1,3-diols, including saccharides and nucleotides. The applications of materials that exert this property are manifold including sensing, but also self-regulated drug delivery systems through responsive membranes or micelles. In this review, some of the main applications of boronic acid containing (co)polymers are discussed focusing on the role of the boronic acid group in the response mechanism. We hope that this summary, which highlights the importance and potential of boronic acid-decorated polymeric materials, will inspire further research within this interesting field of responsive polymers and polymeric materials.

  10. Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery.

    Science.gov (United States)

    Liu, Dongfei; Zhang, Hongbo; Herranz-Blanco, Bárbara; Mäkilä, Ermei; Lehto, Vesa-Pekka; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

    2014-05-28

    We report an advanced drug delivery platform for combination chemotherapy by concurrently incorporating two different drugs into microcompoistes with ratiometric control over the loading degree. Atorvastatin and celecoxib were selected as model drugs due to their different physicochemical properties and synergetic effect on colorectal cancer prevention and inhibition. To be effective in colorectal cancer prevention and inhibition, the produced microcomposite contained hypromellose acetate succinate, which is insoluble in acidic conditions but highly dissolving at neutral or alkaline pH conditions. Taking advantage of the large pore volume of porous silicon (PSi), atorvastatin was firstly loaded into the PSi matrix, and then encapsulated into the pH-responsive polymer microparticles containing celecoxib by microfluidics in order to obtain multi-drug loaded polymer/PSi microcomposites. The prepared microcomposites showed monodisperse size distribution, multistage pH-response, precise ratiometric controlled loading degree towards the simultaneously loaded drug molecules, and tailored release kinetics of the loaded cargos. This attractive microcomposite platform protects the payloads from being released at low pH-values, and enhances their release at higher pH-values, which can be further used for colon cancer prevention and treatment. Overall, the pH-responsive polymer/PSi-based microcomposite can be used as a universal platform for the delivery of different drug molecules for combination therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review.

    Science.gov (United States)

    Kanamala, Manju; Wilson, William R; Yang, Mimi; Palmer, Brian D; Wu, Zimei

    2016-04-01

    As the mainstay in the treatment of various cancers, chemotherapy plays a vital role, but still faces many challenges, such as poor tumour selectivity and multidrug resistance (MDR). Targeted drug delivery using nanotechnology has provided a new strategy for addressing the limitations of the conventional chemotherapy. In the last decade, the volume of research published in this area has increased tremendously, especially with functional nano drug delivery systems (nanocarriers). Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for improving therapeutic outcomes. Among the various stimuli, pH triggered delivery is regarded as the most general strategy, targeting the acidic extracellular microenvironment and intracellular organelles of solid tumours. In this review, we discuss recent advances in the development of pH-sensitive nanocarriers for tumour-targeted drug delivery. The review focuses on the chemical design of pH-sensitive biomaterials, which are used to fabricate nanocarriers for extracellular and/or intracellular tumour site-specific drug release. The pH-responsive biomaterials bring forth conformational changes in these nanocarriers through various mechanisms such as protonation, charge reversal or cleavage of a chemical bond, facilitating tumour specific cell uptake or drug release. A greater understanding of these mechanisms will help to design more efficient drug delivery systems to address the challenges encountered in conventional chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Temperature-responsive nanogel multilayers of poly(N-vinylcaprolactam) for topical drug delivery.

    Science.gov (United States)

    Zavgorodnya, Oleksandra; Carmona-Moran, Carlos A; Kozlovskaya, Veronika; Liu, Fei; Wick, Timothy M; Kharlampieva, Eugenia

    2017-11-15

    We report nanothin temperature-responsive hydrogel films of poly(N-vinylcaprolactam) nanoparticles (νPVCL) with remarkably high loading capacity for topical drug delivery. Highly swollen (νPVCL) n multilayer hydrogels, where n denotes the number of nanoparticle layers, are produced by layer-by-layer hydrogen-bonded assembly of core-shell PVCL-co-acrylic acid nanoparticles with linear PVPON followed by cross-linking of the acrylic acid shell with either ethylene diamine (EDA) or adipic acid dihydrazide (AAD). We demonstrate that a (νPVCL) 5 film undergoes dramatic and reversible swelling up to 9 times its dry thickness at pH = 7.5, indicating 89v/v % of water inside the network. These hydrogels exhibit highly reversible ∼3-fold thickness changes with temperature variations from 25 to 50°C at pH = 5, the average pH of human skin. We also show that a (νPVCL) 30 hydrogel loaded with ∼120µgcm -2 sodium diclofenac, a non-steroidal anti-inflammatory drug used for osteoarthritis pain management, provides sustained permeation of this drug through an artificial skin membrane for up to 24h at 32°C (the average human skin surface temperature). The cumulative amount of diclofenac transported at 32°C from the (νPVCL) 30 hydrogel after 24h is 12 times higher than that from the (νPVCL) 30 hydrogel at 22°C. Finally, we demonstrate that the (νPVCL) hydrogels can be used for multiple drug delivery by inclusion of Nile red, fluorescein and DAPI dyes within the νPVCL nanoparticles prior to hydrogel assembly. Using confocal microscopy we observed the presence of separate dye-loaded νPVCL compartments within the hydrogel matrix with all three dyes confined to the nanogel particles without intermixing between the dyes. Our study provides opportunity for development of temperature-responsive multilayer hydrogel coatings made via the assembly of core-shell nanogel particles which can be used for skin-sensitive materials for topical drug delivery. Copyright © 2017

  13. Comparison of self-administration behavior and responsiveness to drug-paired cues in rats running an alley for intravenous heroin and cocaine.

    Science.gov (United States)

    Su, Zu-In; Wenzel, Jennifer; Baird, Rebeccah; Ettenberg, Aaron

    2011-04-01

    Evidence suggests that responsiveness to a drug-paired cue is predicted by the reinforcing magnitude of the drug during prior self-administration. It remains unclear, however, if this principle holds true when comparisons are made across drug reinforcers. The current study was therefore devised to test the hypothesis that differences in the animals' responsiveness to a cocaine- or heroin-paired cue presented during extinction would reflect differences in the patterns of prior cocaine and heroin runway self-administration. Rats ran a straight alley for single intravenous injections of either heroin (0.1 mg/kg/inj) or cocaine (1.0 mg/kg/inj) each paired with a distinct olfactory cue. Animals experienced 15 trials with each drug reinforcer in a counterbalanced manner. Start latencies, run times, and retreat behaviors (a form of approach-avoidance conflict) provided behavioral indices of the subjects' motivation to seek the reinforcer on each trial. Responsiveness to each drug-paired cue was assessed after 7, 14, or 21 days of non-reinforced extinction trials. Other animals underwent conditioned place preference (CPP) testing to ensure that the two drug reinforcers were capable of producing drug-cue associations. While both drugs produced comparable CPPs, heroin served as a stronger incentive stimulus in the runway as evidenced by faster start and run times and fewer retreats. In contrast, cocaine- but not heroin-paired cues produced increases in drug-seeking behavior during subsequent extinction trials. The subjects' responsiveness to drug-paired cues during extinction was not predicted by differences in the motivation to seek heroin versus cocaine during prior drug self-administration.

  14. Glutamatergic Targets for Enhancing Extinction Learning in Drug Addiction

    OpenAIRE

    Cleva, R.M; Gass, J.T; Widholm, J.J; Olive, M.F

    2010-01-01

    The persistence of the motivational salience of drug-related environmental cues and contexts is one of the most problematic obstacles to successful treatment of drug addiction. Behavioral approaches to extinguishing the salience of drug-associated cues, such as cue exposure therapy, have generally produced disappointing results which have been attributed to, among other things, the context specificity of extinction and inadequate consolidation of extinction learning. Extinction of any behavio...

  15. Responsibility as a dimension of HIV prevention normative beliefs: measurement in three drug-using samples.

    Science.gov (United States)

    Ross, M W; Timpson, S C; Williams, M L; Amos, C; McCurdy, S; Bowen, A M; Kilonzo, G P

    2007-03-01

    The concept of responsibility was derived originally from principles of morality, as part of a network of rights, duties and obligations. HIV risk-related studies have suggested that a sense of responsibility for condom use to protect a partner is a potentially important predictor of condom use in drug-using populations. We created a four-item scale measuring Self responsibility to use condoms and Partner's responsibility to use condoms. Data were collected from three drug-using samples: crack smokers, HIV seropositive crack smokers in an intervention study in Houston, Texas, and Tanzanian heroin users in Dar es Salaam. Data indicated that the four responsibility items had high alpha coefficients in each sample, and that there were moderate to high intercorrelations between equivalent self and partner responsibility items. There were significant differences in scale scores between the crack smokers and the HIV positive crack smokers and the Tanzanian samples, but no significant differences between the HIV positive and Tanzanian samples. Comparing within the first crack-smoker sample those who were HIV positive and negative showed significant differences in the direction of higher beliefs in responsibility to use condoms in the HIV positive group. These data suggest that responsibility is measurable, holds similar psychometric properties across three samples differing in culture and HIV serostatus, and that condom use responsibility is conceptualized as a measure of general responsibility rather than as a reciprocal self/partner responsibility.

  16. "A'ole" Drugs! Cultural Practices and Drug Resistance of Rural Hawai'ian Youths

    Science.gov (United States)

    Po'A-Kekuawela, Ka'Ohinani; Okamoto, Scott K.; Nebre, La Risa H.; Helm, Susana; Chin, Coralee I. H.

    2009-01-01

    This qualitative study examined how Native Hawai'ian youths from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from five different middle schools participated in gender-specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawai'ian…

  17. Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

    Science.gov (United States)

    Ding, Kuan-Fu; Petricoin, Emanuel F; Finlay, Darren; Yin, Hongwei; Hendricks, William P D; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar; LoRusso, Patricia M; Vuori, Kristiina; Trent, Jeffrey M; Schork, Nicholas J

    2018-01-12

    Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC 50 ). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC 50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC 50 -based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.

  18. Violent Victimization in the Prison Context: An Examination of the Gendered Contexts of Prison.

    Science.gov (United States)

    Teasdale, Brent; Daigle, Leah E; Hawk, Shila R; Daquin, Jane C

    2016-07-01

    Currently there are few published, multilevel studies of physical assault victimization of prisoners. This study builds on the extant research by utilizing a nationally representative sample of correctional facilities (n = 326) and inmates (n = 17,640) to examine the impacts of a large set of theoretically and empirically derived individual- and contextual-level variables on prison victimization, including how the gendered context of prison impacts victimization. Results support the lifestyles/routine activities approach. Inmates who were charged with a violent offense, were previously victimized, were smaller in size, were not married, were without a work assignment, misbehaved, did not participate in programs, used alcohol or drugs, and those who had a depression or personality disorder were more likely to be victimized. In addition, the data suggest that 8% of the variance in victimization is due to the prison context. Prisons with high proportions of violent offenders, males, inmates from multiracial backgrounds, and inmates with major infractions had increased odds of victimization. Moreover, the sex-composition of the prison has significant main and interactive effects predicting victimization. Specifically, we find that the effects of being convicted of a drug crime, drug use, military service, major infractions, and diagnosed personality disorders are all gendered in their impacts on victimization. © The Author(s) 2015.

  19. Effect of clinical response to active drugs and placebo on antipsychotics and mood stabilizers relative efficacy for bipolar depression and mania: A meta-regression analysis.

    Science.gov (United States)

    Bartoli, Francesco; Clerici, Massimo; Di Brita, Carmen; Riboldi, Ilaria; Crocamo, Cristina; Carrà, Giuseppe

    2018-04-01

    Randomised placebo-controlled trials investigating treatments for bipolar disorder have been hampered by wide variations of active drugs and placebo clinical response rates. It is important to estimate whether the active drug or placebo response has a greater influence in determining the relative efficacy of drugs for psychosis (antipsychotics) and relapse prevention (mood stabilisers) for bipolar depression and mania. We identified 53 randomised, placebo-controlled trials assessing antipsychotic or mood stabiliser monotherapy ('active drugs') for bipolar depression or mania. We carried out random-effects meta-regressions, estimating the influence of active drugs and placebo response rates on treatment relative efficacy. Meta-regressions showed that treatment relative efficacy for bipolar mania was influenced by the magnitude of clinical response to active drugs ( p=0.002), but not to placebo ( p=0.60). On the other hand, treatment relative efficacy for bipolar depression was influenced by response to placebo ( p=0.047), but not to active drugs ( p=0.98). Despite several limitations, our unexpected findings showed that antipsychotics / mood stabilisers relative efficacy for bipolar depression seems unrelated to active drugs response rates, depending only on clinical response to placebo. Future research should explore strategies to reduce placebo-related issues in randomised, placebo-controlled trials for bipolar depression.

  20. Controlled breast cancer microarrays for the deconvolution of cellular multilayering and density effects upon drug responses.

    Directory of Open Access Journals (Sweden)

    Maria Håkanson

    Full Text Available Increasing evidence shows that the cancer microenvironment affects both tumorigenesis and the response of cancer to drug treatment. Therefore in vitro models that selectively reflect characteristics of the in vivo environment are greatly needed. Current methods allow us to screen the effect of extrinsic parameters such as matrix composition and to model the complex and three-dimensional (3D cancer environment. However, 3D models that reflect characteristics of the in vivo environment are typically too complex and do not allow the separation of discrete extrinsic parameters.In this study we used a poly(ethylene glycol (PEG hydrogel-based microwell array to model breast cancer cell behavior in multilayer cell clusters that allows a rigorous control of the environment. The innovative array fabrication enables different matrix proteins to be integrated into the bottom surface of microwells. Thereby, extrinsic parameters including dimensionality, type of matrix coating and the extent of cell-cell adhesion could be independently studied. Our results suggest that cell to matrix interactions and increased cell-cell adhesion, at high cell density, induce independent effects on the response to Taxol in multilayer breast cancer cell clusters. In addition, comparing the levels of apoptosis and proliferation revealed that drug resistance mediated by cell-cell adhesion can be related to altered cell cycle regulation. Conversely, the matrix-dependent response to Taxol did not correlate with proliferation changes suggesting that cell death inhibition may be responsible for this effect.The application of the PEG hydrogel platform provided novel insight into the independent role of extrinsic parameters controlling drug response. The presented platform may not only become a useful tool for basic research related to the role of the cancer microenvironment but could also serve as a complementary platform for in vitro drug development.

  1. Injections, cocktails and diviners: therapeutic flexibility in the context of malaria elimination and drug resistance in Northeast Cambodia.

    Directory of Open Access Journals (Sweden)

    Charlotte Gryseels

    Full Text Available BACKGROUND: Adherence to effective malaria medication is extremely important in the context of Cambodia's elimination targets and drug resistance containment. Although the public sector health facilities are accessible to the local ethnic minorities of Ratanakiri province (Northeast Cambodia, their illness itineraries often lead them to private pharmacies selling "cocktails" and artemether injections, or to local diviners prescribing animal sacrifices to appease the spirits. METHODS: The research design consisted of a mixed methods study, combining qualitative (in-depth interviews and participant observation and quantitative methods (household and cross-sectional survey. RESULTS: Three broad options for malaria treatment were identified: i the public sector; ii the private sector; iii traditional treatment based on divination and ceremonial sacrifice. Treatment choice was influenced by the availability of treatment and provider, perceived side effects and efficacy of treatments, perceived etiology of symptoms, and patient-health provider encounters. Moreover, treatment paths proved to be highly flexible, changing mostly in relation to the perceived efficacy of a chosen treatment. CONCLUSIONS: Despite good availability of anti-malarial treatment in the public health sector, attendance remained low due to both structural and human behavioral factors. The common use and under-dosage of anti-malaria monotherapy in the private sector (single-dose injections, single-day drug cocktails represents a threat not only for individual case management, but also for the regional plan of drug resistance containment and malaria elimination.

  2. Drug policy in Nicaragua, between need-oriented activities and aggression.

    Science.gov (United States)

    Laporte, J R; Tognoni, G

    1985-01-01

    In this case study from Nicaragua, an account is given of how the Essential Drugs Program developed in a context which relectss exceptional political, economic and military pressures. The overall picture could provide a useful guide to the issues behind such an apparently simple concept as the essential drugs list. The criteria for including drugs in the National Formulary were those of the WHO report on essential drugs: proven efficacy, acceptable risks associated with their use, favorable cost, and need. A proposal of the basic list of drugs, classified in therapeutic groups and according to their priority and level of use, was prepared by a central Committee for the National Drug Formulary. An annotated Formulary was prepared to ensure consistency with rigorous scientific standards and to meet the needs of daily practice. The annotated therapeutic formulary has been distributed to all physicians, other health workers responsible for peripheral health centers, pharmacists, and medical students. It has been adopted as the main reference textbook for teaching clinical pharmacology and therapeutics to medical students. A training program in clinical pharmacology has been started at the University Autonoma de Barcelona. It pays particular attention to drug evaluation, drug epidemiology methods, and retrieval and preparation of drug information for health workers.

  3. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The first time ...

  4. Functionalized silica nanoparticles as a carrier for Betamethasone Sodium Phosphate: Drug release study and statistical optimization of drug loading by response surface method.

    Science.gov (United States)

    Ghasemnejad, M; Ahmadi, E; Mohamadnia, Z; Doustgani, A; Hashemikia, S

    2015-11-01

    Mesoporous silica nanoparticles with a hexagonal structure (SBA-15) were synthesized and modified with (3-aminopropyl) triethoxysilane (APTES), and their performance as a carrier for drug delivery system was studied. Chemical structure and morphology of the synthesized and modified SBA-15 were characterized by SEM, BET, TEM, FT-IR and CHN technique. Betamethasone Sodium Phosphate (BSP) as a water soluble drug was loaded on the mesoporous silica particle for the first time. The response surface method was employed to obtain the optimum conditions for the drug/silica nanoparticle preparation, by using Design-Expert software. The effect of time, pH of preparative media, and drug/silica ratio on the drug loading efficiency was investigated by the software. The maximum loading (33.69%) was achieved under optimized condition (pH: 1.8, time: 3.54 (h) and drug/silica ratio: 1.7). The in vitro release behavior of drug loaded particles under various pH values was evaluated. Finally, the release kinetic of the drug was investigated using the Higuchi and Korsmeyer-Peppas models. Cell culture and cytotoxicity assays revealed the synthesized product doesn't have any cytotoxicity against human bladder cell line 5637. Accordingly, the produced drug-loaded nanostructures can be applied via different routes, such as implantation and topical or oral administration. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Exercise physiological responses to drug treatments in chronic thromboembolic pulmonary hypertension

    Science.gov (United States)

    Charalampopoulos, Athanasios; Gibbs, J. Simon R.; Davies, Rachel J.; Gin-Sing, Wendy; Murphy, Kevin; Sheares, Karen K.; Pepke-Zaba, Joanna; Jenkins, David P.

    2016-01-01

    We tested the hypothesis that patients with chronic thromboembolic pulmonary hypertension (CTEPH) that was deemed to be inoperable were more likely to respond to drugs for treating pulmonary arterial hypertension (PAH) by using cardiopulmonary exercise (CPX) testing than those with CTEPH that was deemed to be operable. We analyzed CPX testing data of all patients with CTEPH who were treated with PAH drugs and had undergone CPX testing before and after treatment at a single pulmonary hypertension center between February 2009 and March 2013. Suitability for pulmonary endarterectomy (PEA) was decided by experts in PEA who were associated with a treatment center. The group with inoperable CTEPH included 16 patients, the operable group included 26 patients. There were no differences in demographics and baseline hemodynamic data between the groups. Unlike patients in the operable group, after drug treatment patients with inoperable CTEPH had a significantly higher peak V̇o2 (P < 0.001), work load (P = 0.002), and oxygen pulse (P < 0.001). In terms of gas exchange, there was an overall net trend toward improved V̇e/V̇co2 in the group with inoperable CTEPH, with an increased PaCO2 (P = 0.01), suggesting reduced hyperventilation. No changes were observed in patients with operable CTEPH. In conclusion, treatment with PAH drug therapy reveals important pathophysiological differences between inoperable and operable CTEPH, with significant pulmonary vascular and cardiac responses in inoperable disease. Drug effects on exercise function observed in inoperable CTEPH cannot be translated to all forms of CTEPH. PMID:27418685

  6. Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence

    Science.gov (United States)

    Murphy, Anna; Nestor, Liam J; McGonigle, John; Paterson, Louise; Boyapati, Venkataramana; Ersche, Karen D; Flechais, Remy; Kuchibatla, Shankar; Metastasio, Antonio; Orban, Csaba; Passetti, Filippo; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor; Robbins, Trevor W; Lingford-Hughes, Anne; Nutt, David J; Deakin, John FW; Elliott, Rebecca

    2017-01-01

    Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction. PMID:28042871

  7. From Addiction to Infection: Managing Drug Abuse in the Context of ...

    African Journals Online (AJOL)

    AJRH Managing Editor

    Keywords: Drug users, Drug addiction, Substance use, HIV infection, Africa. Résumé ... Recent efforts in the prevention of HIV ... have sex with men (MSM) and people who inject ..... generic health and social care services: a qualitative study of ...

  8. Learning from diverse contexts: equity and inclusion in the responses to AIDS.

    Science.gov (United States)

    Loewenson, R

    2007-01-01

    This paper situates the findings of the diverse studies reported in this journal supplement in a global context that both fuels the epidemic through inequality and poverty and also provides new opportunities for global commitments, solidarity and resources. The studies in this issue signal that, while information and awareness about HIV and AIDS is now high, there is still poor access to services for people to know their own risk and a deeper need to address the asymmetries of power and access to resources that influence the control people have over their sexual relationships and lives. The studies in this supplement describe, in very different contexts, responses to the impact of AIDS that are grounded within the actions of individuals, households and extended families, against a background of existing disadvantage in assets, endowment and access to state and private sector resources. Community networks reduce social isolation and provide solidarity to households struggling to respond to AIDS. The extra work involved is often done by women, particularly where the weakening of the state has left communities disadvantaged. The paper argues that connections across communities to support survival need vertical links to national and global resources, services and markets to support, sustain and transform lives. The studies demonstrate the positive effect of this through primary healthcare systems, non-government organisation support and the social movements of people living with HIV and AIDS. If the first wave of the global response to AIDS built awareness and an emergency response to prevention, treatment and care, there is now need for a 'second wave' that provides strong measures to connect communities to social, national and global resources. Elements of this 'second wave' include people's--especially women and young people's--access to services to know their individual risk, measures that enhance their autonomy and the need for a massive increase in investment in

  9. Exploring strategies for PrEP adherence and dosing preferences in the context of sexualized recreational drug use among MSM: a qualitative study.

    Science.gov (United States)

    Closson, Elizabeth F; Mitty, Jennifer A; Malone, Jowanna; Mayer, Kenneth H; Mimiaga, Matthew J

    2018-02-01

    The use of recreational drugs while having sex is associated with increased HIV incidence among men who have sex with men (MSM). Taking a daily antiretroviral pill, or pre-exposure prophylaxis (PrEP) is a biomedical intervention to prevent HIV. However, the efficacy of PrEP is closely tied with high levels of adherence. While PrEP has the potential to reduce HIV acquisition, the use of recreational drugs may impede adherence. We explored perceptions of PrEP utilization and regimen preferences among 40 HIV-negative, MSM who reported concurrent recreational drug use and condomless anal sex with a man. Semi-structured qualitative interviews were conducted and the data were analyzed using a qualitative descriptive approach. Participants perceived that it would be challenging to take PrEP while high on crystal meth, crack, powder cocaine, ecstasy and/or GHB. However, men identified strategies for using PrEP when they were not high on these drugs, including taking the pill when they started their day and integrating PrEP into an established routine, such as when taking other medications or preparing for sex. PrEP regimen preferences seemed to be shaped by the frequency in which participants used drugs and their ability to plan for sex. Taking PrEP everyday was appealing for those who regularly engaged in sexualized recreational drug use. Accounts depict these sexual interactions as frequent but unpredictable. A daily regimen would allow them to be prepared for sex without having to plan. An event-driven regimen was acceptable to men who occasionally used recreational drugs in the context of sex. For this group, sex usually occurred was generally prearranged. Patterns of sex and recreational drug use figured largely into participants' framings of how they would use PrEP. These behaviors will likely play a role in the uptake of and adherence to PrEP among this population.

  10. Poly(ethyl glyoxylate)-Poly(ethylene oxide) Nanoparticles: Stimuli-Responsive Drug Release via End-to-End Polyglyoxylate Depolymerization.

    Science.gov (United States)

    Fan, Bo; Gillies, Elizabeth R

    2017-08-07

    The ability to disrupt polymer assemblies in response to specific stimuli provides the potential to release drugs selectively at certain sites or conditions in vivo. However, most stimuli-responsive delivery systems require many stimuli-initiated events to release drugs. "Self-immolative polymers" offer the potential to provide amplified responses to stimuli as they undergo complete end-to-end depolymerization following the cleavage of a single end-cap. Herein, linker end-caps were developed to conjugate self-immolative poly(ethyl glyoxylate) (PEtG) with poly(ethylene oxide) (PEO) to form amphiphilic block copolymers. These copolymers were self-assembled to form nanoparticles in aqueous solution. Cleavage of the linker end-caps were triggered by a thiol reducing agent, UV light, H 2 O 2 , and combinations of these stimuli, resulting in nanoparticle disintegration. Low stimuli concentrations were effective in rapidly disrupting the nanoparticles. Nile red, doxorubin, and curcumin were encapsulated into the nanoparticles and were selectively released upon application of the appropriate stimulus. The ability to tune the stimuli-responsiveness simply by changing the linker end-cap makes this new platform highly attractive for applications in drug delivery.

  11. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  12. Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems.

    Science.gov (United States)

    Kumar, Santosh; Rao, P S S; Earla, Ravindra; Kumar, Anil

    2015-03-01

    Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse.

  13. Intensive care unit drug costs in the context of total hospital drug expenditures with suggestions for targeted cost containment efforts.

    Science.gov (United States)

    Altawalbeh, Shoroq M; Saul, Melissa I; Seybert, Amy L; Thorpe, Joshua M; Kane-Gill, Sandra L

    2018-04-01

    To assess costs of intensive care unit (ICU) related pharmacotherapy relative to hospital drug expenditures, and to identify potential targets for cost-effectiveness investigations. We offer the unique advantage of comparing ICU drug costs with previously published data a decade earlier to describe changes over time. Financial transactions for all ICU patients during fiscal years (FY) 2009-2012 were retrieved from the hospital's data repository. ICU drug costs were evaluated for each FY. ICU departments' charges were also retrieved and calculated as percentages of total ICU charges. Albumin, prismasate (dialysate), voriconazole, factor VII and alteplase denoted the highest percentages of ICU drug costs. ICU drug costs contributed to an average of 31% (SD 1.0%) of the hospital's total drug costs. ICU drug costs per patient day increased by 5.8% yearly versus 7.8% yearly for non-ICU drugs. This rate was higher for ICU drugs costs at 12% a decade previous. Pharmacy charges contributed to 17.7% of the total ICU charges. Growth rates of costs per year have declined but still drug expenditures in the ICU are consistently a significant driver in this resource intensive environment with a high impact on hospital drug expenditures. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Exposure–response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development

    Science.gov (United States)

    Han, Seunghoon; Jeon, Sangil; Hong, Taegon; Lee, Jongtae; Bae, Soo Hyeon; Park, Wan-su; Park, Gab-jin; Youn, Sunil; Jang, Doo Yeon; Kim, Kyung-Soo; Yim, Dong-Seok

    2015-01-01

    No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure–response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120). Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure–response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects’ sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg) and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure–response model, which included the placebo effect, is the first example of a quantitative model that can be used to predict the efficacy of weight-control drugs. Similar approaches can help decision-making during clinical development of novel weight-loss drugs. PMID:26392753

  15. Exposure-response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development.

    Science.gov (United States)

    Han, Seunghoon; Jeon, Sangil; Hong, Taegon; Lee, Jongtae; Bae, Soo Hyeon; Park, Wan-su; Park, Gab-jin; Youn, Sunil; Jang, Doo Yeon; Kim, Kyung-Soo; Yim, Dong-Seok

    2015-01-01

    No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure-response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120). Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure-response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects' sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg) and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure-response model, which included the placebo effect, is the first example of a quantitative model that can be used to predict the efficacy of weight-control drugs. Similar approaches can help decision-making during clinical development of novel weight-loss drugs.

  16. Effects of Antipsychotic Drugs Haloperidol and Clozapine on Visual Responses of Retinal Ganglion Cells in a Rat Model of Retinitis Pigmentosa.

    Science.gov (United States)

    Jensen, Ralph J

    2016-12-01

    In the P23H rat model of retinitis pigmentosa, the dopamine D2 receptor antagonists sulpiride and eticlopride appear to improve visual responses of retinal ganglion cells (RGCs) by increasing light sensitivity of RGCs and transforming abnormal, long-latency ON-center RGCs into OFF-center cells. Antipsychotic drugs are believed to mediate their therapeutic benefits by blocking D2 receptors. This investigation was conducted to test whether haloperidol (a typical antipsychotic drug) and clozapine (an atypical antipsychotic drug) could similarly alter the light responses of RGCs in the P23H rat retina. Extracellular recordings were made from RGCs in isolated P23H rat retinas. Responses of RGCs to flashes of light were evaluated before and during bath application of a drug. Both haloperidol and clozapine increased light sensitivity of RGCs on average by ∼0.3 log unit. For those ON-center RGCs that exhibit an abnormally long-latency response to the onset of a small spot of light, both haloperidol and clozapine brought out a short-latency OFF response and markedly reduced the long-latency ON response. The selective serotonin 5-HT2A antagonist MDL 100907 had similar effects on RGCs. The effects of haloperidol on light responses of RGCs can be explained by its D2 receptor antagonism. The effects of clozapine on light responses of RGCs on the other hand may largely be due to its 5-HT2A receptor antagonism. Overall, the results suggest that antipsychotic drugs may be useful in improving vision in patients with retinitis pigmentosa.

  17. The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs.

    Directory of Open Access Journals (Sweden)

    José A G Agúndez

    Full Text Available UNLABELLED: Non-steroidal anti-inflammatory drugs (NSAIDs are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191, which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3-2.1; Pc  = 0.0003 with a gene-dose effect (P = 0.0001. The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively. CONCLUSIONS AND IMPLICATIONS: The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.

  18. Effects of a Context Shift and Multiple Context Extinction on Reactivity to Alcohol Cues

    Science.gov (United States)

    MacKillop, James; Lisman, Stephen A.

    2008-01-01

    Cue exposure treatment (CET) attempts to reduce the influence of conditioned substance cues on addictive behavior via prolonged cue exposure with response prevention (i.e., extinction), but has received only modest empirical support in clinical trials. This may be because extinction learning appears to be context dependent and a change in context may result in a return of conditioned responding (i.e., renewal), although this has received only limited empirical examination. The current study used a four-session laboratory analogue of CET to examine whether a change in context following three sessions of alcohol cue exposure with response prevention would result in renewal of conditioned responding. In addition, this study examined whether conducting extinction in multiple contexts would attenuate renewal of conditioned responding. In a one-way between-subjects design, 73 heavy drinkers (71% male) were randomized to three conditions: 1) single context extinction (extinction to alcohol cues in the same context for three sessions followed by a context shift at the fourth session); 2) multiple context extinction (extinction to alcohol cues in different contexts each day for all four sessions); and 3) pseudo-extinction control condition (exposure to neutral cues in the same context for three sessions followed by exposure to alcohol cues at the fourth session). The results revealed the predicted cue reactivity and extinction effects, but the hypotheses that a context shift would generate renewed cue reactivity and that multiple contexts would enhance extinction were not supported. Methodological aspects of the study and the need for parametric data on the context dependency of extinction to alcohol cues are discussed. PMID:18729687

  19. Reporting the characteristics of the policy context for population-level alcohol interventions: a proposed 'Transparent Reporting of Alcohol Intervention ContExts' (TRAICE) checklist.

    Science.gov (United States)

    Holmes, John; Meier, Petra S; Booth, Andrew; Brennan, Alan

    2014-11-01

    Effectiveness of alcohol policy interventions varies across times and places. The circumstances under which effective polices can be successfully transferred between contexts are typically unexplored with little attention given to developing reporting requirements that would facilitate systematic investigation. Using purposive sampling and expert elicitation methods, we identified context-related factors impacting on the effectiveness of population-level alcohol policies. We then drew on previous characterisations of alcohol policy contexts and methodological-reporting checklists to design a new checklist for reporting contextual information in evaluation studies. Six context factor domains were identified: (i) baseline alcohol consumption, norms and harm rates; (ii) baseline affordability and availability; (iii) social, microeconomic and demographic contexts; (iv) macroeconomic context; (v) market context; and (vi) wider policy, political and media context. The checklist specifies information, typically available in national or international reports, to be reported in each domain. The checklist can facilitate evidence synthesis by providing: (i) a mechanism for systematic and more consistent reporting of contextual data for meta-regression and realist evaluations; (ii) information for policy-makers on differences between their context and contexts of evaluations; and (iii) an evidence base for adjusting prospective policy simulation models to account for policy context. Our proposed checklist provides a tool for gaining better understanding of the influence of policy context on intervention effectiveness. Further work is required to rationalise and aggregate checklists across interventions types to make such checklists practical for use by journals and to improve reporting of important qualitative contextual data. © 2014 The Authors. Drug and Alcohol Review published by Wiley Publishing Asia Pty Ltd on behalf of Australasian Professional Society on Alcohol and

  20. Combining physical and virtual contexts through augmented reality: design and evaluation of a prototype using a drug box as a marker for antibiotic training

    Science.gov (United States)

    Tomson, Tanja; Zary, Nabil

    2014-01-01

    Introduction. Antimicrobial resistance is a global health issue. Studies have shown that improved antibiotic prescription education among healthcare professionals reduces mistakes during the antibiotic prescription process. The aim of this study was to investigate novel educational approaches that through the use of Augmented Reality technology could make use of the real physical context and thereby enrich the educational process of antibiotics prescription. The objective is to investigate which type of information related to antibiotics could be used in an augmented reality application for antibiotics education. Methods. This study followed the Design-Based Research Methodology composed of the following main steps: problem analysis, investigation of information that should be visualized for the training session, and finally the involvement of the end users the development and evaluation processes of the prototype. Results. Two of the most important aspects in the antibiotic prescription process, to represent in an augmented reality application, are the antibiotic guidelines and the side effects. Moreover, this study showed how this information could be visualized from a mobile device using an Augmented Reality scanner and antibiotic drug boxes as markers. Discussion. In this study we investigated the usage of objects from a real physical context such as drug boxes and how they could be used as educational resources. The logical next steps are to examine how this approach of combining physical and virtual contexts through Augmented Reality applications could contribute to the improvement of competencies among healthcare professionals and its impact on the decrease of antibiotics resistance. PMID:25548733

  1. Combining physical and virtual contexts through augmented reality: design and evaluation of a prototype using a drug box as a marker for antibiotic training

    Directory of Open Access Journals (Sweden)

    Sokratis Nifakos

    2014-12-01

    Full Text Available Introduction. Antimicrobial resistance is a global health issue. Studies have shown that improved antibiotic prescription education among healthcare professionals reduces mistakes during the antibiotic prescription process. The aim of this study was to investigate novel educational approaches that through the use of Augmented Reality technology could make use of the real physical context and thereby enrich the educational process of antibiotics prescription. The objective is to investigate which type of information related to antibiotics could be used in an augmented reality application for antibiotics education.Methods. This study followed the Design-Based Research Methodology composed of the following main steps: problem analysis, investigation of information that should be visualized for the training session, and finally the involvement of the end users the development and evaluation processes of the prototype.Results. Two of the most important aspects in the antibiotic prescription process, to represent in an augmented reality application, are the antibiotic guidelines and the side effects. Moreover, this study showed how this information could be visualized from a mobile device using an Augmented Reality scanner and antibiotic drug boxes as markers.Discussion. In this study we investigated the usage of objects from a real physical context such as drug boxes and how they could be used as educational resources. The logical next steps are to examine how this approach of combining physical and virtual contexts through Augmented Reality applications could contribute to the improvement of competencies among healthcare professionals and its impact on the decrease of antibiotics resistance.

  2. Combining physical and virtual contexts through augmented reality: design and evaluation of a prototype using a drug box as a marker for antibiotic training.

    Science.gov (United States)

    Nifakos, Sokratis; Tomson, Tanja; Zary, Nabil

    2014-01-01

    Introduction. Antimicrobial resistance is a global health issue. Studies have shown that improved antibiotic prescription education among healthcare professionals reduces mistakes during the antibiotic prescription process. The aim of this study was to investigate novel educational approaches that through the use of Augmented Reality technology could make use of the real physical context and thereby enrich the educational process of antibiotics prescription. The objective is to investigate which type of information related to antibiotics could be used in an augmented reality application for antibiotics education. Methods. This study followed the Design-Based Research Methodology composed of the following main steps: problem analysis, investigation of information that should be visualized for the training session, and finally the involvement of the end users the development and evaluation processes of the prototype. Results. Two of the most important aspects in the antibiotic prescription process, to represent in an augmented reality application, are the antibiotic guidelines and the side effects. Moreover, this study showed how this information could be visualized from a mobile device using an Augmented Reality scanner and antibiotic drug boxes as markers. Discussion. In this study we investigated the usage of objects from a real physical context such as drug boxes and how they could be used as educational resources. The logical next steps are to examine how this approach of combining physical and virtual contexts through Augmented Reality applications could contribute to the improvement of competencies among healthcare professionals and its impact on the decrease of antibiotics resistance.

  3. pH-responsive polymer–drug conjugates as multifunctional micelles for cancer-drug delivery

    International Nuclear Information System (INIS)

    Kang, Yang; Ha, Wei; Ma, Yuan; Ding, Li-Sheng; Li, Bang-Jing; Liu, Ying-Qian; Fan, Min-Min; Zhang, Sheng

    2014-01-01

    We developed a novel linear pH-sensitive conjugate methoxy poly(ethylene glycol)-4β-aminopodophyllotoxin (mPEG-NPOD-I) by a covalently linked 4β-aminopodophyllotoxin (NPOD) and PEG via imine bond, which was amphiphilic and self-assembled to micelles in an aqueous solution. The mPEG-NPOD-I micelles simultaneously served as an anticancer drug conjugate and as drug carriers. As a drug conjugate, mPEG-NPOD-I showed a significantly faster NPOD release at a mildly acidic pH of 5.0 and 4.0 than a physiological pH of 7.4. Notably, it was confirmed that this drug conjugate could efficiently deliver NPOD to the nuclei of the tumor cells and led to much more cytotoxic effects to A549, Hela, and HepG2 cancer cells than the parent NPOD. The half maximal inhibitory concentration (IC 50 ) of mPEG-NPOD-I was about one order magnitude lower than that of the NPOD. In vivo, mPEG-NPOD-I reduced the size of the tumors significantly, and the biodistribution studies indicated that this drug conjugate could selectively accumulate in tumor tissues. As drug carriers, the mPEG-NPOD-I micelles encapsulated hydrophobic PTX with drug-loading efficiencies of 57% and drug-loading content of 16%. The loaded PTX also showed pH-triggered fast release behavior, and good additive cytotoxicity effect was observed for the PEG-NPOD-I/PTX. We are convinced that these multifunctional drug conjugate micelles have tremendous potential for targeted cancer therapy. (paper)

  4. An Analysis of the Global Code of Ethics for Tourism in the Context of Corporate Social Responsibility

    OpenAIRE

    Buzar Stipe

    2015-01-01

    The author analyzes the Global Code of Ethics for Tourism in the context of corporate social responsibility and the need for discussing this topic in ethical codes within the business and tourism sector. The text first offers an overview of the fundamental ethical concepts in business ethics and corporate social responsibility and briefly conceptualizes the relationship between these two fields. At the end, the author analyzes the content of the Global Code of Ethics for Tourism with emphasis...

  5. An Analysis of the Global Code of Ethics for Tourism in the Context of Corporate Social Responsibility

    Directory of Open Access Journals (Sweden)

    Buzar Stipe

    2015-12-01

    Full Text Available The author analyzes the Global Code of Ethics for Tourism in the context of corporate social responsibility and the need for discussing this topic in ethical codes within the business and tourism sector. The text first offers an overview of the fundamental ethical concepts in business ethics and corporate social responsibility and briefly conceptualizes the relationship between these two fields. At the end, the author analyzes the content of the Global Code of Ethics for Tourism with emphasis on the elements pertaining to corporate social responsibility, after which he offers a critical opinion about the contribution of the aforemntioned code.

  6. Drug delivery interfaces in the 21st century: from science fiction ideas to viable technologies.

    Science.gov (United States)

    Chertok, Beata; Webber, Matthew J; Succi, Marc D; Langer, Robert

    2013-10-07

    Early science fiction envisioned the future of drug delivery as targeted micrometer-scale submarines and "cyborg" body parts. Here we describe the progression of the field toward technologies that are now beginning to capture aspects of this early vision. Specifically, we focus on the two most prominent types of systems in drug delivery: the intravascular micro/nano drug carriers for delivery to the site of pathology and drug-loaded implantable devices that facilitate release with the predefined kinetics or in response to a specific cue. We discuss the unmet clinical needs that inspire these designs, the physiological factors that pose difficult challenges for their realization, and viable technologies that promise robust solutions. We also offer a perspective on where drug delivery may be in the next 50 years based on expected advances in material engineering and in the context of future diagnostics.

  7. Revisiting the left-wing response to sociobiology: the case of Finland in a European context.

    Science.gov (United States)

    Lepistö, Antti

    2015-01-01

    This article revisits the left-wing response to sociobiology in the 1970s and 1980s by examining the sociobiology debate in Finland in a larger European context. It argues that the Finnish academic left's response to sociobiology represents a "third way" alongside the purely negative, often Marxist denial of biology's relevance, which characterized the left's response to sociobiology in many European countries such as Hungary and Sweden, and alongside the disregard that sociobiology confronted in most parts of Eastern Europe, as well as in Germany. In the context of the last great political conflict of the Cold War in Europe, the controversy over the American "Euromissiles" (Pershing II and Tomahawk) in 1979-1983, the Finnish academic left challenged the allegedly fatalistic sociobiological aggression and war theories with an alternative biological language, turning the increasing enthusiasm over evolutionary ideas into a pacifist cause. Using leftist and pacifist forums to inform citizens and politicians of such biologically evolved human characteristics as mutual care and sociability, the Finnish critics of sociobiology wished to boost the public spirit, and to rationalize the pacifist ideal of the European-wide popular movement against nuclear weapons and militarism. As a result, the academic leftists in Finland revived the early twentieth-century tradition of "peace biology." A proper understanding of this development calls for an analysis that acknowledges Finland's special geopolitical and cultural position in the Cold War world between East and West.

  8. Glutamatergic transmission in drug reward: implications for drug addiction.

    Science.gov (United States)

    D'Souza, Manoranjan S

    2015-01-01

    Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding) effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

  9. Using social cognitive theory to explain consumers' behavioral intentions in response to direct-to-consumer prescription drug advertising.

    Science.gov (United States)

    Young, Henry N; Lipowski, Earlene E; Cline, Rebecca J W

    2005-06-01

    Previous research describing consumers' communication behaviors in response to direct-to-consumer advertising (DTCA) suggests a social cognitive rationale to explain DTCA-related communication behavior. Guided by social cognitive theory, the objective of this study was to explore outcome expectancy and self-efficacy beliefs as predictors of individuals' intentions to communicate with their physicians about an advertised drug. One hundred and seven female college students completed a questionnaire, read an advertisement for an oral contraceptive drug, and completed a second questionnaire. The questionnaires assessed participants' self-efficacy and outcome expectancy beliefs, intended communication behavior, and demographic information. Pearson product-moment correlation analyses showed that outcome expectancy (r=0.75, Pbehavior (B=1.56, Padvertised drug [t(106)=14.75, Pconsumers' plans for interacting with physicians in response to DTCA. Health care providers can use these results to guide communication with patients regarding DTCA and meet patients' drug-related informational expectations.

  10. Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

    Science.gov (United States)

    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.

  11. The application of skin metabolomics in the context of transdermal drug delivery.

    Science.gov (United States)

    Li, Jinling; Xu, Weitong; Liang, Yibiao; Wang, Hui

    2017-04-01

    Metabolomics is a powerful emerging tool for the identification of biomarkers and the exploration of metabolic pathways in a high-throughput manner. As an administration site for percutaneous absorption, the skin has a variety of metabolic enzymes, except other than hepar. However, technologies to fully detect dermal metabolites remain lacking. Skin metabolomics studies have mainly focused on the regulation of dermal metabolites by drugs or on the metabolism of drugs themselves. Skin metabolomics techniques include collection and preparation of skin samples, data collection, data processing and analysis. Furthermore, studying dermal metabolic effects via metabolomics can provide novel explanations for the pathogenesis of some dermatoses and unique insights for designing targeted prodrugs, promoting drug absorption and controlling drug concentration. This paper reviews current progress in the field of skin metabolomics, with a specific focus on dermal drug delivery systems and dermatosis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  12. When the Research Design Matters in EFL Context: A Case of Different Responses to Open-response and Closed-response Questions on Motivational Orientation

    Directory of Open Access Journals (Sweden)

    Ma‘ssoumeh Bemani Naeini

    2012-11-01

    Full Text Available This study aimed at investigating and exploring the degree of motivational orientation (i.e. instrumental and integrative motivation among sixty Iranian TEFL students. A survey research design was used to collect both quantitative and qualitative data, using a Likert-scale questionnaire containing six open-response items. Inferential analysis of quantitative data identified the subjects of the study with integrative orientation. However, descriptive analysis of open responses in terms of coded recurrent themes indicated contradictory results. In sum, the findings suggest a gap between Iranian TEFL students’ “desirable motivation” and “desired motivation”. The researcher attributes the contradictory results not only to the social context, but also to the type of questionnaire and the psychological status of respondents. Also, the findings provide support for other components of motivation other than just instrumentality and integrativeness, mainly “personal” aspects as proposed by Benson’s model of motivation.

  13. Self-reported responsiveness to direct-to-consumer drug advertising and medication use: results of a national survey

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    Somes Grant W

    2011-09-01

    Full Text Available Abstract Background Direct-to-consumer (DTC marketing of pharmaceuticals is controversial, yet effective. Little is known relating patterns of medication use to patient responsiveness to DTC. Methods We conducted a secondary analysis of data collected in national telephone survey on knowledge of and attitudes toward DTC advertisements. The survey of 1081 U.S. adults (response rate = 65% was conducted by the Food and Drug Administration (FDA. Responsiveness to DTC was defined as an affirmative response to the item: "Has an advertisement for a prescription drug ever caused you to ask a doctor about a medical condition or illness of your own that you had not talked to a doctor about before?" Patients reported number of prescription and over-the-counter (OTC medicines taken as well as demographic and personal health information. Results Of 771 respondents who met study criteria, 195 (25% were responsive to DTC. Only 7% respondents taking no prescription were responsive, whereas 45% of respondents taking 5 or more prescription medications were responsive. This trend remained significant (p trend .0009 even when controlling for age, gender, race, educational attainment, income, self-reported health status, and whether respondents "liked" DTC advertising. There was no relationship between the number of OTC medications taken and the propensity to discuss health-related problems in response to DTC advertisements (p = .4. Conclusion There is a strong cross-sectional relationship between the number of prescription, but not OTC, drugs used and responsiveness to DTC advertising. Although this relationship could be explained by physician compliance with patient requests for medications, it is also plausible that DTC advertisements have a particular appeal to patients prone to taking multiple medications. Outpatients motivated to discuss medical conditions based on their exposure to DTC advertising may require a careful medication history to evaluate for

  14. Self-reported responsiveness to direct-to-consumer drug advertising and medication use: results of a national survey.

    Science.gov (United States)

    Dieringer, Nicholas J; Kukkamma, Lisa; Somes, Grant W; Shorr, Ronald I

    2011-09-23

    ABSTRACT: BACKGROUND: Direct-to-consumer (DTC) marketing of pharmaceuticals is controversial, yet effective. Little is known relating patterns of medication use to patient responsiveness to DTC. METHODS: We conducted a secondary analysis of data collected in national telephone survey on knowledge of and attitudes toward DTC advertisements. The survey of 1081 U.S. adults (response rate = 65%) was conducted by the Food and Drug Administration (FDA). Responsiveness to DTC was defined as an affirmative response to the item: "Has an advertisement for a prescription drug ever caused you to ask a doctor about a medical condition or illness of your own that you had not talked to a doctor about before?" Patients reported number of prescription and over-the-counter (OTC) medicines taken as well as demographic and personal health information. RESULTS: Of 771 respondents who met study criteria, 195 (25%) were responsive to DTC. Only 7% respondents taking no prescription were responsive, whereas 45% of respondents taking 5 or more prescription medications were responsive. This trend remained significant (p trend .0009) even when controlling for age, gender, race, educational attainment, income, self-reported health status, and whether respondents "liked" DTC advertising. There was no relationship between the number of OTC medications taken and the propensity to discuss health-related problems in response to DTC advertisements (p = .4). CONCLUSION: There is a strong cross-sectional relationship between the number of prescription, but not OTC, drugs used and responsiveness to DTC advertising. Although this relationship could be explained by physician compliance with patient requests for medications, it is also plausible that DTC advertisements have a particular appeal to patients prone to taking multiple medications. Outpatients motivated to discuss medical conditions based on their exposure to DTC advertising may require a careful medication history to evaluate for therapeutic

  15. The discourses about the drugs and the experiential languages of the consumers in the city of Rio de Janeiro: notes on continuity and discontinuity in drugs use

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    Frederico Policarpo de Mendonça Filho

    2010-07-01

    Full Text Available It is very common to talk about drug use with the reference to Psychology or Law to tackle the issues surrounding the consumption and trade of drugs. For that reason, categories such as “addict”; ”user”; and “dealer”; are often used in a naturalized way, without any reference both to the context in which they were drawn as to the context of action that account. Thus, they appear as if they were absolute analytical categories.In this paper I present data from some relational contexts of drug users who had access, in an attempt to present the experiential language deployed by them to participate in the drug market. From this description, I´ll show situations where some consumers put questions about their personal consumption, creating the possibility of reconfiguration their participation on the drug market influencing the continuation or not of drug use.

  16. Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment

    DEFF Research Database (Denmark)

    Phillips, Andrew N; Cambiano, Valentina; Miners, Alec

    2014-01-01

    BACKGROUND: With continued roll-out of antiretroviral therapy (ART) in resource-limited settings, evidence is emerging of increasing levels of transmitted drug-resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial...

  17. Systemic or Intra-Amygdala Infusion of the Benzodiazepine, Midazolam, Impairs Learning, but Facilitates Re-Learning to Inhibit Fear Responses in Extinction

    Science.gov (United States)

    Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

    2010-01-01

    A series of experiments used rats to study the effect of a systemic or intra-amygdala infusion of the benzodiazepine, midazolam, on learning and re-learning to inhibit context conditioned fear (freezing) responses. Rats were subjected to two context-conditioning episodes followed by extinction under drug or vehicle, or to two cycles of context…

  18. Oxytocin differentially modulates pavlovian cue and context fear acquisition.

    Science.gov (United States)

    Cavalli, Juliana; Ruttorf, Michaela; Pahi, Mario Rosero; Zidda, Francesca; Flor, Herta; Nees, Frauke

    2017-06-01

    Fear acquisition and extinction have been demonstrated as core mechanisms for the development and maintenance of mental disorders, with different contributions of processing cues vs contexts. The hypothalamic peptide oxytocin (OXT) may have a prominent role in this context, as it has been shown to affect fear learning. However, investigations have focused on cue conditioning, and fear extinction. Its differential role for cue and context fear acquisition is still not known. In a randomized, double-blind, placebo (PLC)-controlled design, we administered an intranasal dose of OXT or PLC before the acquisition of cue and context fear conditioning in healthy individuals (n = 52), and assessed brain responses, skin conductance responses and self-reports (valence/arousal/contingency). OXT compared with PLC significantly induced decreased responses in the nucleus accumbens during early cue and context acquisition, and decreased responses of the anterior cingulate cortex and insula during early as well as increased hippocampal response during late context, but not cue acquisition. The OXT group additionally showed significantly higher arousal in late cue and context acquisition. OXT modulates various aspects of cue and context conditioning, which is relevant from a mechanism-based perspective and might have implications for the treatment of fear and anxiety. © The Author (2017). Published by Oxford University Press.

  19. Stimuli-Responsive Soft Untethered Grippers for Drug Delivery and Robotic Surgery

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    Arijit Ghosh

    2017-07-01

    Full Text Available Untethered microtools that can be precisely navigated into deep in vivo locations are important for clinical procedures pertinent to minimally invasive surgery and targeted drug delivery. In this mini-review, untethered soft grippers are discussed, with an emphasis on a class of autonomous stimuli-responsive gripping soft tools that can be used to excise tissues and release drugs in a controlled manner. The grippers are composed of polymers and hydrogels and are thus compliant to soft tissues. They can be navigated using magnetic fields and controlled by robotic path-planning strategies to carry out tasks like pick-and-place of microspheres and biological materials either with user assistance, or in a fully autonomous manner. It is envisioned that the use of these untethered soft grippers will translate from laboratory experiments to clinical scenarios and the challenges that need to be overcome to make this transition are discussed.

  20. Stimuli-Responsive Liposomes for Controlled Drug Delivery

    KAUST Repository

    Li, Wengang

    2014-01-01

    Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery

  1. NIR responsive liposomal system for rapid release of drugs in cancer therapy

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    Chen MM

    2017-06-01

    Full Text Available Ming-Mao Chen,1 Yuan-Yuan Liu,1 Guang-Hao Su,2 Fei-Fei Song,1 Yan Liu,3 Qi-Qing Zhang1,4 1Institute of Biomedical and Pharmaceutical Technology, Fuzhou University, Fuzhou, 2Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, 3State Key Lab of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 4Key Laboratory of Biomedical Material of Tianjin, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, People’s Republic of China Abstract: To design a rapid release liposomal system for cancer therapy, a NIR responsive bubble-generating thermosensitive liposome (BTSL system combined with photothermal agent (Cypate, doxorubicin (DOX, and NH4HCO3 was developed. Cypate/DOX-BTSL exhibited a good aqueous stability, photostability, and photothermal effect. In vitro release suggested that the amounts of DOX released from BTSL were obviously higher than that of (NH42SO4 liposomes at 42°C. After NIR irradiation, the hyperthermic temperature induced by Cypate led to the decomposition of NH4HCO3 and the generation of a large number of CO2 bubbles, triggering a rapid release of drugs. Confocal laser scanning microscope and acridine orange staining indicated that Cypate/DOX-BTSL upon irradiation could facilitate to disrupt the lysosomal membranes and realize endolysosomal escape into cytosol, improving the intracellular uptake of DOX clearly. MTT and trypan blue staining implied that the cell damage of Cypate/DOX-BTSL with NIR irradiation was more severe than that in the groups without irradiation. In vivo results indicated that Cypate/DOX-BTSL with irradiation could dramatically increase the accumulation of DOX in tumor, inhibit tumor growth, and reduce systemic side effects of DOX. These data demonstrated that Cypate/DOX-BTSL has the potential to be used as a NIR responsive liposomal system for a rapid

  2. Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase-responsive nanoparticles.

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    Rutian Li

    Full Text Available AIMS: The matrix metalloproteinase (MMP 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG-PCL by inserting a gelatinase cleavable peptide (PVGLIG between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery. MATERIALS AND METHODS: mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM and atomic force microscopy (AFM. The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted. RESULTS: The Gel-NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs. CONCLUSION: The results in

  3. Male injection drug users try new drugs following U.S. deportation to Tijuana, Mexico.

    Science.gov (United States)

    Robertson, Angela M; Rangel, M Gudelia; Lozada, Remedios; Vera, Alicia; Ojeda, Victoria D

    2012-01-01

    Among male injection drug users (IDUs) in Tijuana, Mexico, U.S. deportation is associated with HIV transmission. Changing drug use behaviors following deportation, including the use of new drugs, may increase HIV risk but are understudied. We identify correlates of trying new drugs following male IDUs' most recent U.S. deportation to Mexico. In 2010, we recruited 328 deported male IDUs in Tijuana, Mexico. Questionnaires collected retrospective data on drug use and other HIV risk behaviors throughout migratory events. Logistic regression identified correlates of trying new drugs/combinations following their most recent deportations. Informed consent was obtained from all participants. Nearly one in six men (n=52, 16%) tried new drugs following their most recent deportation, including heroin (n=31), methamphetamine (n=5), and heroin/methamphetamine combined (n=17). Trying new drugs following deportation was independently associated with U.S. incarceration (adjusted odds ratio [AOR]=3.96; 95% confidence interval [C.I.] 1.78, 8.84), increasing numbers of U.S. deportations (AOR=1.11 per deportation; C.I. 1.03, 1.20), feeling sad following deportation (AOR 2.69; C.I. 1.41, 5.14), and perceiving that one's current lifestyle increases HIV/AIDS risk (AOR 3.91; C.I. 2.05, 7.44). Trying new drugs following U.S. deportation may be related to the unique contexts and stressors experienced by drug-abusing migrants as they attempt to reestablish their lives in Mexico. Findings imply an unmet need for health and social programs to alleviate pre- and post-deportation stressors faced by undocumented and return migrants in the U.S.-Mexico context. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  4. Drug Stroop: Mechanisms of response to computerized cognitive behavioral therapy for cocaine dependence in a randomized clinical trial.

    Science.gov (United States)

    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.

  5. Skin Permeation Enhancers and their Effects on Narcotic Transdermal Drug Delivery Systems through Response Surface Experimental Design

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    A. Moghimi

    2014-02-01

    Full Text Available Drug delivery through skin is often obstructed by low permeability of skin towards most drugs; however, such problem would be solved by application of skin penetration enhancers in the formulations. In the present study, a drug in adhesive patch with buprenorphine as active ingredient was prepared. Drug-in-adhesive transdermal drug delivery systems with different chemical penetration enhancers were designed. For this purpose a response-surface experimental design was used. Response surface methodology based on a three-level, three-variable Box–Behnken design was used to evaluate the interactive effects of dependent variables such as: the rate of skin permeation and adhesion properties including peel strength and tack value. The parameters such as drug release and adhesion were used as independent variables. Levulinic acid, lauryl alcohol and Tween 80 were used as penetration enhancers. In order to prepare samples, buprenorphine with constant concentration was incorporated into acrylic pressure sensitive adhesive with carboxylic functionality and this mixture was added to chemical penetration enhancer with different concentrations. The results show that the cumulative amount of drug release in presence of Tween 80 is 462.9 ± 0.006 μg so it is higher than cumulative amount of drug release in presence of levulinic acid (357.9 ± 0.005 μg and lauryl alcohol (269.5 ± 0.001 μg. Results of adhesion properties such as peel strength and tack reveal that using levulinic acid and lauryl alcohol will increase peel strength while Tween 80 will decrease it. Besides, the results show that all these permeation enhancers have increased tack values.

  6. Label-free detection of cellular drug responses by high-throughput bright-field imaging and machine learning.

    Science.gov (United States)

    Kobayashi, Hirofumi; Lei, Cheng; Wu, Yi; Mao, Ailin; Jiang, Yiyue; Guo, Baoshan; Ozeki, Yasuyuki; Goda, Keisuke

    2017-09-29

    In the last decade, high-content screening based on multivariate single-cell imaging has been proven effective in drug discovery to evaluate drug-induced phenotypic variations. Unfortunately, this method inherently requires fluorescent labeling which has several drawbacks. Here we present a label-free method for evaluating cellular drug responses only by high-throughput bright-field imaging with the aid of machine learning algorithms. Specifically, we performed high-throughput bright-field imaging of numerous drug-treated and -untreated cells (N = ~240,000) by optofluidic time-stretch microscopy with high throughput up to 10,000 cells/s and applied machine learning to the cell images to identify their morphological variations which are too subtle for human eyes to detect. Consequently, we achieved a high accuracy of 92% in distinguishing drug-treated and -untreated cells without the need for labeling. Furthermore, we also demonstrated that dose-dependent, drug-induced morphological change from different experiments can be inferred from the classification accuracy of a single classification model. Our work lays the groundwork for label-free drug screening in pharmaceutical science and industry.

  7. A mRNA-Responsive G-Quadruplex-Based Drug Release System

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    Hidenobu Yaku

    2015-04-01

    Full Text Available G-quadruplex-based drug delivery carriers (GDDCs were designed to capture and release a telomerase inhibitor in response to a target mRNA. Hybridization between a loop on the GDDC structure and the mRNA should cause the G-quadruplex structure of the GDDC to unfold and release the bound inhibitor, anionic copper(II phthalocyanine (CuAPC. As a proof of concept, GDDCs were designed with a 10-30-mer loop, which can hybridize with a target sequence in epidermal growth factor receptor (EGFR mRNA. Structural analysis using circular dichroism (CD spectroscopy showed that the GDDCs form a (3 + 1 type G-quadruplex structure in 100 mM KCl and 10 mM MgCl2 in the absence of the target RNA. Visible absorbance titration experiments showed that the GDDCs bind to CuAPC with Ka values of 1.5 × 105 to 5.9 × 105 M−1 (Kd values of 6.7 to 1.7 μM at 25 °C, depending on the loop length. Fluorescence titration further showed that the G-quadruplex structure unfolds upon binding to the target RNA with Ka values above 1.0 × 108 M−1 (Kd values below 0.01 μM at 25 °C. These results suggest the carrier can sense and bind to the target RNA, which should result in release of the bound drug. Finally, visible absorbance titration experiments demonstrated that the GDDC release CuAPC in response to the target RNA.

  8. Exposure–response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development

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    Han S

    2015-09-01

    Full Text Available Seunghoon Han,1,2 Sangil Jeon,1,2 Taegon Hong,1,2 Jongtae Lee,1,2 Soo Hyeon Bae,1,2 Wan-su Park,1,2 Gab-jin Park,1,2 Sunil Youn,1,2 Doo Yeon Jang,1,2 Kyung-Soo Kim,3 Dong-Seok Yim1,2 1Department of Pharmacology, College of Medicine, The Catholic University of Korea, 2Pharmacometrics Institute for Practical Education and Training, 3Department of Family Medicine, Seoul St Mary’s Hospital, Seochogu, Seoul, Republic of KoreaAbstract: No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure–response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120. Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost <2 kg after 4 weeks’ treatment were escalated to 12.55 mg. The duration of treatment was 24 weeks. Drug concentration and body weight were measured predose and at 4 weeks, 8 weeks, and 24 weeks after treatment initiation. Exposure and response to sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure–response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects’ sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure–response model, which

  9. Drug-induced and genetic alterations in stress-responsive systems: Implications for specific addictive diseases.

    Science.gov (United States)

    Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

    2010-02-16

    From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor, and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants, and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin, and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review. Copyright 2009 Elsevier B.V. All rights reserved.

  10. Are predictions of cancer response to targeted drugs, based on effects in unrelated tissues, the 'Black Swan' events?

    Science.gov (United States)

    Kurbel, Beatrica; Golem, Ante Zvonimir; Kurbel, Sven

    2015-01-01

    Adverse effects of targeted drugs on normal tissues can predict the cancer response. Rash correlates with efficacy of erlotinib, cetuximab and gefitinib and onset of arterial hypertension with response to bevacizumab, sunitinib, axitinib and sorafenib, possible examples of 'Black Swan' events, unexpected scientific observations, as described by Karl Popper in 1935. The proposition is that our patients have individual intrinsic variants of cell growth control, important for tumor response and adverse effects on tumor-unrelated tissue. This means that the lack of predictive side effects in healthy tissue is linked with poor results of tumor therapy when tumor resistance is caused by mechanisms that protect all cells of that patient from the targeted drug effects.

  11. Preparation and Investigation of Poly (N-isopropylacrylamide-acrylamide Membranes in Temperature Responsive Drug Delivery

    Directory of Open Access Journals (Sweden)

    Elham Khodaverdi

    2010-06-01

    Full Text Available Objective(sPhysiological changes in the body may be utilized as potential triggers for controlled drug delivery. Based on these mechanisms, stimulus–responsive drug delivery has been developed.Materials and MethodsIn this study, a kind of poly (N-isopropylacrylamide-acrylamide membrane was prepared by radical copolymerization. Changes in swelling ratios and diameters of the membrane were investigated in terms of temperature. On-off regulation of drug permeation through the membrane was then studied at temperatures below and above the phase transition temperature of the membrane. Two drugs, vitamin B12 and acetaminophen were chosen as models of high and low molecular weights here, respectively. ResultsIt was indicated that at temperatures below the phase transition temperature of the membrane, copolymer was in a swollen state. Above the phase transition temperature, water was partially expelled from the functional groups of the copolymer. Permeation of high molecular weight drug models such as vitamin B12 was shown to be much more distinct at temperatures below the phase transition temperature when the copolymer was in a swollen state. At higher temperatures when the copolymer was shrunken, drug permeation through the membrane was substantially decreased. However for acetaminophen, such a big change in drug permeation around the phase transition temperature of the membrane was not observed. ConclusionAccording to the pore mechanism of drug transport through hydrogels, permeability of solutes decreased with increasing molecular size. As a result, the relative permeability, around the phase transition temperature of the copolymer, was higher for solutes of high molecular weight.

  12. Enviromental Education as a Response to Chaos Socio-Environmental in the Context of Risk Society

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    Dayla Barbosa Pinto

    2016-12-01

    Full Text Available With the imbalance in the relation man-nature settled a social-environmental crisis, whose own humanity began to suffer the consequences of its consumerist onslaughts. Within this context, Environmental Education is a valuable tool, capable of freeing man from the living circle of consumerism and putting him on the axis of his own existence again. Thus, this study seeks to demonstrate that the equilibrium in the relationship between man and nature and the management of the socio-environmental crisis must start from the (re education of humanity regarding modernity and its effects, adopting for this the methodology of qualitative bibliographical research, Analysis of doctrine and scientific articles. Thus, the exploratory method of the proposed theme was used, pointing to environmental education as a response mechanism to the disorder imposed in the context of the risk society.

  13. Glutamatergic transmission in drug reward: Implications for drug addiction

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    Manoranjan S Dsouza

    2015-11-01

    Full Text Available Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc and the ventral tegmental area (VTA, which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

  14. The future of drugs: recreational drug use and sexual health among gay and other men who have sex with men.

    Science.gov (United States)

    Race, Kane; Lea, Toby; Murphy, Dean; Pienaar, Kiran

    2017-02-01

    There are complex historical connections between sexual minoritisation and desires to chemically alter bodily experience. For gay men, drug and alcohol use can be a creative or experimental response to social marginalisation - and not necessarily a problematic one in every instance. Numerous studies have found that infection with HIV and other sexually transmissible infections (STIs) is more likely among gay and men who have sex with men (MSM) who use recreational drugs than those who do not, but the causal nature of these relations is uncertain. Sexualised drug use is associated with a range of other problems, including dependence, mental health issues, accident and overdose. A growing body of work in the Alcohol and Other Drugs (AOD) field demonstrates the action of drugs and their purported effects to be a product of their relations with various other actors, contexts and practices. Given these contingencies, it is impossible to predict the future of drugs or their effect on the sexual health of gay and MSM with any degree of certainty. This article outlines some of the conditions most likely to mediate such futures in the medium term. Public funding for lesbian, gay, bisexual, transgender and queer drug issues should not remain restricted to questions of HIV prevention and sexual health. It should be expanded to equip sexual health and AOD service providers with the cultural and sexual literacy to mitigate stigma and allow them to respond constructively to drug problems among sexual and gender minorities as a matter of priority.

  15. Peptide Drug Release Behavior from Biodegradable Temperature-Responsive Injectable Hydrogels Exhibiting Irreversible Gelation

    Directory of Open Access Journals (Sweden)

    Kazuyuki Takata

    2017-10-01

    Full Text Available We investigated the release behavior of glucagon-like peptide-1 (GLP-1 from a biodegradable injectable polymer (IP hydrogel. This hydrogel shows temperature-responsive irreversible gelation due to the covalent bond formation through a thiol-ene reaction. In vitro sustained release of GLP-1 from an irreversible IP formulation (F(P1/D+PA40 was observed compared with a reversible (physical gelation IP formulation (F(P1. Moreover, pharmaceutically active levels of GLP-1 were maintained in blood after subcutaneous injection of the irreversible IP formulation into rats. This system should be useful for the minimally invasive sustained drug release of peptide drugs and other water-soluble bioactive reagents.

  16. Average Revisited in Context

    Science.gov (United States)

    Watson, Jane; Chick, Helen

    2012-01-01

    This paper analyses the responses of 247 middle school students to items requiring the concept of average in three different contexts: a city's weather reported in maximum daily temperature, the number of children in a family, and the price of houses. The mixed but overall disappointing performance on the six items in the three contexts indicates…

  17. Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response.

    Science.gov (United States)

    Zervantonakis, Ioannis K; Iavarone, Claudia; Chen, Hsing-Yu; Selfors, Laura M; Palakurthi, Sangeetha; Liu, Joyce F; Drapkin, Ronny; Matulonis, Ursula; Leverson, Joel D; Sampath, Deepak; Mills, Gordon B; Brugge, Joan S

    2017-08-28

    The lack of effective chemotherapies for high-grade serous ovarian cancers (HGS-OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro-apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-X L ) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.

  18. The Andrews’ Principles of Risk, Need, and Responsivity as Applied in Drug Abuse Treatment Programs: Meta-Analysis of Crime and Drug Use Outcomes

    Science.gov (United States)

    Prendergast, Michael L.; Pearson, Frank S.; Podus, Deborah; Hamilton, Zachary K.; Greenwell, Lisa

    2013-01-01

    Objectives The purpose of the present meta-analysis was to answer the question: Can the Andrews principles of risk, needs, and responsivity, originally developed for programs that treat offenders, be extended to programs that treat drug abusers? Methods Drawing from a dataset that included 243 independent comparisons, we conducted random-effects meta-regression and ANOVA-analog meta-analyses to test the Andrews principles by averaging crime and drug use outcomes over a diverse set of programs for drug abuse problems. Results For crime outcomes, in the meta-regressions the point estimates for each of the principles were substantial, consistent with previous studies of the Andrews principles. There was also a substantial point estimate for programs exhibiting a greater number of the principles. However, almost all of the 95% confidence intervals included the zero point. For drug use outcomes, in the meta-regressions the point estimates for each of the principles was approximately zero; however, the point estimate for programs exhibiting a greater number of the principles was somewhat positive. All of the estimates for the drug use principles had confidence intervals that included the zero point. Conclusions This study supports previous findings from primary research studies targeting the Andrews principles that those principles are effective in reducing crime outcomes, here in meta-analytic research focused on drug treatment programs. By contrast, programs that follow the principles appear to have very little effect on drug use outcomes. Primary research studies that experimentally test the Andrews principles in drug treatment programs are recommended. PMID:24058325

  19. A remotely operated drug delivery system with an electrolytic pump and a thermo-responsive valve

    KAUST Repository

    Yi, Ying

    2015-07-22

    Implantable drug delivery devices are becoming attractive due to their abilities of targeted and controlled dose release. Currently, two important issues are functional lifetime and non-controlled drug diffusion. In this work, we present a drug delivery device combining an electrolytic pump and a thermo-responsive valve, which are both remotely controlled by an electromagnetic field (40.5 mT and 450 kHz). Our proposed device exhibits a novel operation mechanism for long-term therapeutic treatments using a solid drug in reservoir approach. Our device also prevents undesired drug liquid diffusions. When the electromagnetic field is on, the electrolysis-induced bubble drives the drug liquid towards the Poly (N-Isopropylacrylamide) (PNIPAM) valve that consists of PNIPAM and iron micro-particles. The heat generated by the iron micro-particles causes the PNIPAM to shrink, resulting in an open valve. When the electromagnetic field is turned off, the PNIPAM starts to swell. In the meantime, the bubbles are catalytically recombined into water, reducing the pressure inside the pumping chamber, which leads to the refilling of the fresh liquid from outside the device. A catalytic reformer is included, allowing more liquid refilling during the limited valve\\'s closing time. The amount of body liquid that refills the drug reservoir can further dissolve the solid drug, forming a reproducible drug solution for the next dose. By repeatedly turning on and off the electromagnetic field, the drug dose can be cyclically released, and the exit port of the device is effectively controlled.

  20. A remotely operated drug delivery system with an electrolytic pump and a thermo-responsive valve

    KAUST Repository

    Yi, Ying; Zaher, Amir; Yassine, Omar; Kosel, Jü rgen; Foulds, Ian G.

    2015-01-01

    Implantable drug delivery devices are becoming attractive due to their abilities of targeted and controlled dose release. Currently, two important issues are functional lifetime and non-controlled drug diffusion. In this work, we present a drug delivery device combining an electrolytic pump and a thermo-responsive valve, which are both remotely controlled by an electromagnetic field (40.5 mT and 450 kHz). Our proposed device exhibits a novel operation mechanism for long-term therapeutic treatments using a solid drug in reservoir approach. Our device also prevents undesired drug liquid diffusions. When the electromagnetic field is on, the electrolysis-induced bubble drives the drug liquid towards the Poly (N-Isopropylacrylamide) (PNIPAM) valve that consists of PNIPAM and iron micro-particles. The heat generated by the iron micro-particles causes the PNIPAM to shrink, resulting in an open valve. When the electromagnetic field is turned off, the PNIPAM starts to swell. In the meantime, the bubbles are catalytically recombined into water, reducing the pressure inside the pumping chamber, which leads to the refilling of the fresh liquid from outside the device. A catalytic reformer is included, allowing more liquid refilling during the limited valve's closing time. The amount of body liquid that refills the drug reservoir can further dissolve the solid drug, forming a reproducible drug solution for the next dose. By repeatedly turning on and off the electromagnetic field, the drug dose can be cyclically released, and the exit port of the device is effectively controlled.

  1. Prediction of clinical response to drugs in ovarian cancer using the chemotherapy resistance test (CTR-test).

    Science.gov (United States)

    Kischkel, Frank Christian; Meyer, Carina; Eich, Julia; Nassir, Mani; Mentze, Monika; Braicu, Ioana; Kopp-Schneider, Annette; Sehouli, Jalid

    2017-10-27

    In order to validate if the test result of the Chemotherapy Resistance Test (CTR-Test) is able to predict the resistances or sensitivities of tumors in ovarian cancer patients to drugs, the CTR-Test result and the corresponding clinical response of individual patients were correlated retrospectively. Results were compared to previous recorded correlations. The CTR-Test was performed on tumor samples from 52 ovarian cancer patients for specific chemotherapeutic drugs. Patients were treated with monotherapies or drug combinations. Resistances were classified as extreme (ER), medium (MR) or slight (SR) resistance in the CTR-Test. Combination treatment resistances were transformed by a scoring system into these classifications. Accurate sensitivity prediction was accomplished in 79% of the cases and accurate prediction of resistance in 100% of the cases in the total data set. The data set of single agent treatment and drug combination treatment were analyzed individually. Single agent treatment lead to an accurate sensitivity in 44% of the cases and the drug combination to 95% accuracy. The detection of resistances was in both cases to 100% correct. ROC curve analysis indicates that the CTR-Test result correlates with the clinical response, at least for the combination chemotherapy. Those values are similar or better than the values from a publication from 1990. Chemotherapy resistance testing in vitro via the CTR-Test is able to accurately detect resistances in ovarian cancer patients. These numbers confirm and even exceed results published in 1990. Better sensitivity detection might be caused by a higher percentage of drug combinations tested in 2012 compared to 1990. Our study confirms the functionality of the CTR-Test to plan an efficient chemotherapeutic treatment for ovarian cancer patients.

  2. 21 CFR 314.420 - Drug master files.

    Science.gov (United States)

    2010-04-01

    ... the context of an application under part 312 or this part. A drug master file may contain information... incorporate by reference all or part of the contents of any drug master file in support of the submission if... information in a drug master file (except the list required under paragraph (d) of this section) is required...

  3. Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

    Science.gov (United States)

    Seely, Kathryn A; Prather, Paul L; James, Laura P; Moran, Jeffery H

    2011-02-01

    The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.

  4. Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

    Science.gov (United States)

    Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

    2017-02-01

    Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Algorithmic Mapping and Characterization of the Drug-Induced Phenotypic-Response Space of Parasites Causing Schistosomiasis.

    Science.gov (United States)

    Singh, Rahul; Beasley, Rachel; Long, Thavy; Caffrey, Conor R

    2018-01-01

    Neglected tropical diseases, especially those caused by helminths, constitute some of the most common infections of the world's poorest people. Amongst these, schistosomiasis (bilharzia or 'snail fever'), caused by blood flukes of the genus Schistosoma, ranks second only to malaria in terms of human impact: two hundred million people are infected and close to 800 million are at risk of infection. Drug screening against helminths poses unique challenges: the parasite cannot be cloned and is difficult to target using gene knockouts or RNAi. Consequently, both lead identification and validation involve phenotypic screening, where parasites are exposed to compounds whose effects are determined through the analysis of the ensuing phenotypic responses. The efficacy of leads thus identified derives from one or more or even unknown molecular mechanisms of action. The two most immediate and significant challenges that confront the state-of-the-art in this area are: the development of automated and quantitative phenotypic screening techniques and the mapping and quantitative characterization of the totality of phenotypic responses of the parasite. In this paper, we investigate and propose solutions for the latter problem in terms of the following: (1) mathematical formulation and algorithms that allow rigorous representation of the phenotypic response space of the parasite, (2) application of graph-theoretic and network analysis techniques for quantitative modeling and characterization of the phenotypic space, and (3) application of the aforementioned methodology to analyze the phenotypic space of S. mansoni - one of the etiological agents of schistosomiasis, induced by compounds that target its polo-like kinase 1 (PLK 1) gene - a recently validated drug target. In our approach, first, bio-image analysis algorithms are used to quantify the phenotypic responses of different drugs. Next, these responses are linearly mapped into a low- dimensional space using Principle

  6. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines.

    Science.gov (United States)

    Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M; Pritzker, Laura B; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

    2016-02-24

    Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced "RNA disruption" is, the extent to which it is associated with drug response or what the underlying mechanisms are. Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor. All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3'-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption. Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues and is

  7. Modulating the innate immune response to influenza A virus: potential therapeutic use of anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Irene eRamos

    2015-07-01

    Full Text Available Infection by influenza A viruses (IAV is frequently characterized by robust inflammation that is usually more pronounced in the case of avian influenza. It is becoming clearer that the morbidity and pathogenesis caused by IAV is a consequence of this inflammatory response, with several components of the innate immune system acting as the main players. It has been postulated that using a therapeutic approach to limit the innate immune response in combination with antiviral drugs has the potential to diminish symptoms and tissue damage caused by IAV infection. Indeed, some anti-inflammatory agents have been shown to be effective in animal models at reducing IAV pathology as a proof of principle. The main challenge in developing such therapies is to selectively modulate signaling pathways that contribute to lung injury while maintaining the ability of the host cells to mount an antiviral response to control virus replication. However, the dissection of those pathways is very complex given the numerous components regulated by the same factors (i.e. NF kappa B transcription factors and the large number of players involved in this regulation, some of which may be undescribed or unknown. This article provides a comprehensive review of the current knowledge regarding the innate immune responses associated with tissue damage by IAV infection, the understanding of which is essential for the development of effective immunomodulatory drugs. Furthermore, we summarize the recent advances on the development and evaluation of such drugs as well as the lessons learned from those studies.

  8. Smart Polymers in Nasal Drug Delivery.

    Science.gov (United States)

    Chonkar, Ankita; Nayak, Usha; Udupa, N

    2015-01-01

    Nasal drug delivery has now been recognized as a promising route for drug delivery due to its capability of transporting a drug to systemic circulation and central nervous system. Though nasal mucosa offers improved bioavailability and quick onset of action of the drug, main disadvantage associated with nasal drug delivery is mucocilliary clearance due to which drug particles get cleared from the nose before complete absorption through nasal mucosa. Therefore, mucoadhesive polymeric approach can be successfully used to enhance the retention of the drug on nasal mucosal surface. Here, some of the aspects of the stimuli responsive polymers have been discussed which possess liquid state at the room temperature and in response to nasal temperature, pH and ions present in mucous, can undergo in situ gelation in nasal cavity. In this review, several temperature responsive, pH responsive and ion responsive polymers used in nasal delivery, their gelling mechanisms have been discussed. Smart polymers not only able to enhance the retention of the drug in nasal cavity but also provide controlled release, ease of administration, enhanced permeation of the drug and protection of the drug from mucosal enzymes. Thus smart polymeric approach can be effectively used for nasal delivery of peptide drugs, central nervous system dugs and hormones.

  9. A fundamental role for context in instrumental learning and extinction.

    Science.gov (United States)

    Bouton, Mark E; Todd, Travis P

    2014-05-01

    The purpose of this article is to review recent research that has investigated the effects of context change on instrumental (operant) learning. The first part of the article discusses instrumental extinction, in which the strength of a reinforced instrumental behavior declines when reinforcers are withdrawn. The results suggest that extinction of either simple or discriminated operant behavior is relatively specific to the context in which it is learned: As in prior studies of Pavlovian extinction, ABA, ABC, and AAB renewal effects can all be observed. Further analysis supports the idea that the organism learns to refrain from making a specific response in a specific context, or in more formal terms, an inhibitory context-response association. The second part of the article then discusses research suggesting that the context also controls instrumental behavior before it is extinguished. Several experiments demonstrate that a context switch after either simple or discriminated operant training causes a decrement in the strength of the response. Over a range of conditions, the animal appears to learn a direct association between the context and the response. Under some conditions, it can also learn a hierarchical representation of context and the response-reinforcer relation. Extinction is still more context-specific than conditioning, as indicated by ABC and AAB renewal. Overall, the results establish that the context can play a significant role in both the acquisition and extinction of operant behavior. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Self-face recognition in social context.

    Science.gov (United States)

    Sugiura, Motoaki; Sassa, Yuko; Jeong, Hyeonjeong; Wakusawa, Keisuke; Horie, Kaoru; Sato, Shigeru; Kawashima, Ryuta

    2012-06-01

    The concept of "social self" is often described as a representation of the self-reflected in the eyes or minds of others. Although the appearance of one's own face has substantial social significance for humans, neuroimaging studies have failed to link self-face recognition and the likely neural substrate of the social self, the medial prefrontal cortex (MPFC). We assumed that the social self is recruited during self-face recognition under a rich social context where multiple other faces are available for comparison of social values. Using functional magnetic resonance imaging (fMRI), we examined the modulation of neural responses to the faces of the self and of a close friend in a social context. We identified an enhanced response in the ventral MPFC and right occipitoparietal sulcus in the social context specifically for the self-face. Neural response in the right lateral parietal and inferior temporal cortices, previously claimed as self-face-specific, was unaffected for the self-face but unexpectedly enhanced for the friend's face in the social context. Self-face-specific activation in the pars triangularis of the inferior frontal gyrus, and self-face-specific reduction of activation in the left middle temporal gyrus and the right supramarginal gyrus, replicating a previous finding, were not subject to such modulation. Our results thus demonstrated the recruitment of a social self during self-face recognition in the social context. At least three brain networks for self-face-specific activation may be dissociated by different patterns of response-modulation in the social context, suggesting multiple dynamic self-other representations in the human brain. Copyright © 2011 Wiley-Liss, Inc.

  11. Distribution of the Most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia

    Directory of Open Access Journals (Sweden)

    Nestorovska Kapedanovska A.

    2014-12-01

    Full Text Available Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response.

  12. Microfluidic assembly of a nano-in-micro dual drug delivery platform composed of halloysite nanotubes and a pH-responsive polymer for colon cancer therapy.

    Science.gov (United States)

    Li, Wei; Liu, Dongfei; Zhang, Hongbo; Correia, Alexandra; Mäkilä, Ermei; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

    2017-01-15

    Harsh conditions of the gastrointestinal tract hinder the oral delivery of many drugs. Developing oral drug delivery systems based on commercially available materials is becoming more challenging due to the demand for simultaneously delivering physicochemically different drugs for treating complex diseases. A novel architecture, namely nanotube-in-microsphere, was developed as a drug delivery platform by encapsulating halloysite nanotubes (HNTs) in a pH-responsive hydroxypropyl methylcellulose acetate succinate polymer using microfluidics. HNTs were selected as orally acceptable clay mineral and their lumen was enlarged by selective acid etching. Model drugs (atorvastatin and celecoxib) with different physicochemical properties and synergistic effect on colon cancer prevention and inhibition were simultaneously incorporated into the microspheres at a precise ratio, with atorvastatin and celecoxib being loaded in the HNTs and polymer matrix, respectively. The microspheres showed spherical shape, narrow particle size distribution and pH-responsive dissolution behavior. This nanotube/pH-responsive polymer composite protected the loaded drugs from premature release at pH⩽6.5, but allowed their fast release and enhanced the drug permeability, and the inhibition of colon cancer cell proliferation at pH 7.4. Overall, the nano-in-micro drug delivery composite fabricated by microfluidics is a promising and flexible platform for the delivery of multiple drugs for combination therapy. Halloysite nanotubes (HNTs) are attracting increasing attention for drug delivery applications. However, conventional HNTs-based oral drug delivery systems are lack of the capability to precisely control the drug release at a desired site in the gastrointestinal tract. In this study, a nanotube-in-microsphere drug delivery platform is developed by encapsulating HNTs in a pH-responsive polymer using microfluidics. Drugs with different physicochemical properties and synergistic effect on colon

  13. Extinction of drug- and withdrawal-paired cues in animal models: relevance to the treatment of addiction.

    Science.gov (United States)

    Myers, Karyn M; Carlezon, William A

    2010-11-01

    Conditioned drug craving and withdrawal elicited by cues paired with drug use or acute withdrawal are among the many factors contributing to compulsive drug taking. Understanding how to stop these cues from having these effects is a major goal of addiction research. Extinction is a form of learning in which associations between cues and the events they predict are weakened by exposure to the cues in the absence of those events. Evidence from animal models suggests that conditioned responses to drug cues can be extinguished, although the degree to which this occurs in humans is controversial. Investigations into the neurobiological substrates of extinction of conditioned drug craving and withdrawal may facilitate the successful use of drug cue extinction within clinical contexts. While this work is still in the early stages, there are indications that extinction of drug- and withdrawal-paired cues shares neural mechanisms with extinction of conditioned fear. Using the fear extinction literature as a template, it is possible to organize the observations on drug cue extinction into a cohesive framework. Copyright © 2010 Elsevier Ltd. All rights reserved.

  14. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided platinum-based 2-drug chemotherapy for unresectable nonsmall-cell lung cancer.

    Science.gov (United States)

    Moon, Yong Wha; Choi, Sung Ho; Kim, Yong Tai; Sohn, Joo Hyuk; Chang, Joon; Kim, Se Kyu; Park, Moo Suk; Chung, Kyung Young; Lee, Hyoun Ju; Kim, Joo-Hang

    2007-05-01

    The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC). The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC. Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P=.036), longer progression-free survival (P=.060), and longer overall survival (P=.025). Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups. Copyright (c) 2007 American Cancer Society

  15. Targeted Drug Delivery and Treatment of Endoparasites with Biocompatible Particles of pH-Responsive Structure.

    Science.gov (United States)

    Mathews, Patrick D; Fernandes Patta, Ana C M; Gonçalves, Joao V; Gama, Gabriella Dos Santos; Garcia, Irene Teresinha Santos; Mertins, Omar

    2018-02-12

    Biomaterials conceived for vectorization of bioactives are currently considered for biomedical, biological, and environmental applications. We have produced a pH-sensitive biomaterial composed of natural source alginate and chitosan polysaccharides for application as a drug delivery system via oral administration. The composite particle preparation was in situ monitored by means of isothermal titration calorimetry. The strong interaction established between the macromolecules during particle assembly led to 0.60 alginate/chitosan effective binding sites with an intense exothermic effect and negative enthalpy variation on the order of a thousand kcal/mol. In the presence of model drugs mebendazole and ivermectin, with relatively small and large structures, respectively, mebendazole reduced the amount of chitosan monomers available to interact with alginate by 27%, which was not observed for ivermectin. Nevertheless, a state of intense negative Gibbs energy and large entropic decrease was achieved, providing evidence that formation of particles is thermodynamically driven and favored. Small-angle X-ray scattering provided further evidence of similar surface aspects independent of the presence of drug. The physical responses of the particles to pH variation comprise partial hydration, swelling, and the predominance of positive surface charge in strong acid medium, whereas ionization followed by deprotonation leads to compaction and charge reversal rather than new swelling in mild and slightly acidic mediums, respectively. In vivo performance was evaluated in the treatment of endoparasites in Corydoras fish. Systematically with a daily base oral administration, particles significantly reduced the infections over 15 days of treatment. The experiments provide evidence that utilizing particles granted and boosted the action of the antiparasitic drugs, leading to substantial reduction or elimination of infection. Hence, the pH-responsive particles represent a biomaterial

  16. An ethnographic exploration of drug markets in Kisumu, Kenya.

    Science.gov (United States)

    Syvertsen, Jennifer L; Ohaga, Spala; Agot, Kawango; Dimova, Margarita; Guise, Andy; Rhodes, Tim; Wagner, Karla D

    2016-04-01

    Illegal drug markets are shaped by multiple forces, including local actors and broader economic, political, social, and criminal justice systems that intertwine to impact health and social wellbeing. Ethnographic analyses that interrogate multiple dimensions of drug markets may offer both applied and theoretical insights into drug use, particularly in developing nations where new markets and local patterns of use traditionally have not been well understood. This paper explores the emergent drug market in Kisumu, western Kenya, where our research team recently documented evidence of injection drug use. Our exploratory study of injection drug use was conducted in Kisumu from 2013 to 2014. We draw on 151 surveys, 29 in-depth interviews, and 8 months of ethnographic fieldwork to describe the drug market from the perspective of injectors, focusing on their perceptions of the market and reports of drug use therein. Injectors described a dynamic market in which the availability of drugs and proliferation of injection drug use have taken on growing importance in Kisumu. In addition to reports of white and brown forms of heroin and concerns about drug adulteration in the market, we unexpectedly documented widespread perceptions of cocaine availability and injection in Kisumu. Examining price data and socio-pharmacological experiences of cocaine injection left us with unconfirmed evidence of its existence, but opened further possibilities about how the chaos of new drug markets and diffusion of injection-related beliefs and practices may lend insight into the sociopolitical context of western Kenya. We suggest a need for expanded drug surveillance, education and programming responsive to local conditions, and further ethnographic inquiry into the social meanings of emergent drug markets in Kenya and across sub-Saharan Africa. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Craving Responses to Methamphetamine and Sexual Visual Cues in Individuals With Methamphetamine Use Disorder After Long-Term Drug Rehabilitation

    Directory of Open Access Journals (Sweden)

    Shucai Huang

    2018-04-01

    Full Text Available Studies utilizing functional magnetic resonance imaging (fMRI cue-reactivity paradigms have demonstrated that short-term abstinent or current methamphetamine (MA users have increased brain activity in the ventral striatum, caudate nucleus and medial frontal cortex, when exposed to MA-related visual cues. However, patterns of brain activity following cue-reactivity in subjects with long-term MA abstinence, especially long-term compulsory drug rehabilitation, have not been well studied. To enrich knowledge in this field, functional brain imaging was conducted during a cue-reactivity paradigm task in 28 individuals with MA use disorder following long-term compulsory drug rehabilitation, and 27 healthy control subjects. The results showed that, when compared with controls, individuals with MA use disorder displayed elevated activity in the bilateral medial prefrontal cortex (mPFC and right lateral posterior cingulate cortex in response to MA-related images. Additionally, the anterior cingulate region of mPFC activation during the MA-related cue-reactivity paradigm was positively correlated with craving alterations and previous frequency of drug use. No significant differences in brain activity in response to pornographic images were found between the two groups. Compared to MA cues, individuals with MA use disorder had increased activation in the occipital lobe when exposed to pornographic cues. In conclusion, the present study indicates that, even after long-term drug rehabilitation, individuals with MA use disorder have unique brain activity when exposed to MA-related cues. Additionally, our results illustrate that the libido brain response might be restored, and that sexual demand might be more robust than drug demand, in individuals with MA use disorder following long-term drug rehabilitation.

  18. Craving Responses to Methamphetamine and Sexual Visual Cues in Individuals With Methamphetamine Use Disorder After Long-Term Drug Rehabilitation.

    Science.gov (United States)

    Huang, Shucai; Zhang, Zhixue; Dai, Yuanyuan; Zhang, Changcun; Yang, Cheng; Fan, Lidan; Liu, Jun; Hao, Wei; Chen, Hongxian

    2018-01-01

    Studies utilizing functional magnetic resonance imaging (fMRI) cue-reactivity paradigms have demonstrated that short-term abstinent or current methamphetamine (MA) users have increased brain activity in the ventral striatum, caudate nucleus and medial frontal cortex, when exposed to MA-related visual cues. However, patterns of brain activity following cue-reactivity in subjects with long-term MA abstinence, especially long-term compulsory drug rehabilitation, have not been well studied. To enrich knowledge in this field, functional brain imaging was conducted during a cue-reactivity paradigm task in 28 individuals with MA use disorder following long-term compulsory drug rehabilitation, and 27 healthy control subjects. The results showed that, when compared with controls, individuals with MA use disorder displayed elevated activity in the bilateral medial prefrontal cortex (mPFC) and right lateral posterior cingulate cortex in response to MA-related images. Additionally, the anterior cingulate region of mPFC activation during the MA-related cue-reactivity paradigm was positively correlated with craving alterations and previous frequency of drug use. No significant differences in brain activity in response to pornographic images were found between the two groups. Compared to MA cues, individuals with MA use disorder had increased activation in the occipital lobe when exposed to pornographic cues. In conclusion, the present study indicates that, even after long-term drug rehabilitation, individuals with MA use disorder have unique brain activity when exposed to MA-related cues. Additionally, our results illustrate that the libido brain response might be restored, and that sexual demand might be more robust than drug demand, in individuals with MA use disorder following long-term drug rehabilitation.

  19. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  20. Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes.

    Science.gov (United States)

    Jeong, Hyunyoung

    2010-06-01

    Medication use during pregnancy is prevalent, but pharmacokinetic information of most drugs used during pregnancy is lacking in spite of known effects of pregnancy on drug disposition. Accurate pharmacokinetic information is essential for optimal drug therapy in mother and fetus. Thus, understanding how pregnancy influences drug disposition is important for better prediction of pharmacokinetic changes of drugs in pregnant women. Pregnancy is known to affect hepatic drug metabolism, but the underlying mechanisms remain unknown. Physiological changes accompanying pregnancy are probably responsible for the reported alteration in drug metabolism during pregnancy. These include elevated concentrations of various hormones such as estrogen, progesterone, placental growth hormones and prolactin. This review covers how these hormones influence expression of drug-metabolizing enzymes (DMEs), thus potentially responsible for altered drug metabolism during pregnancy. The reader will gain a greater understanding of the altered drug metabolism in pregnant women and the regulatory effects of pregnancy hormones on expression of DMEs. In-depth studies in hormonal regulatory mechanisms as well as confirmatory studies in pregnant women are warranted for systematic understanding and prediction of the changes in hepatic drug metabolism during pregnancy.

  1. Double stimuli-responsive polymer systems: How to use crosstalk between pH- and thermosensitivity for drug depots

    Czech Academy of Sciences Publication Activity Database

    Bogomolova, Anna; Kaberov, Leonid; Sedláček, Ondřej; Filippov, Sergey K.; Štěpánek, Petr; Král, V.; Wang, X. Y.; Liu, S. L.; Ye, X. D.; Hrubý, Martin

    2016-01-01

    Roč. 84, November (2016), s. 54-64 ISSN 0014-3057 R&D Projects: GA MŠk(CZ) LH14292; GA ČR(CZ) GC15-10527J Institutional support: RVO:61389013 Keywords : drug depot formulation * double responsive system * pH-responsive polymer Subject RIV: CC - Organic Chemistry Impact factor: 3.531, year: 2016

  2. The Potential of Stimuli-Responsive Nanogels in Drug and Active Molecule Delivery for Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Marta Vicario-de-la-Torre

    2017-05-01

    Full Text Available Nanogels (NGs are currently under extensive investigation due to their unique properties, such as small particle size, high encapsulation efficiency and protection of active agents from degradation, which make them ideal candidates as drug delivery systems (DDS. Stimuli-responsive NGs are cross-linked nanoparticles (NPs, composed of polymers, natural, synthetic, or a combination thereof that can swell by absorption (uptake of large amounts of solvent, but not dissolve due to the constituent structure of the polymeric network. NGs can undergo change from a polymeric solution (swell form to a hard particle (collapsed form in response to (i physical stimuli such as temperature, ionic strength, magnetic or electric fields; (ii chemical stimuli such as pH, ions, specific molecules or (iii biochemical stimuli such as enzymatic substrates or affinity ligands. The interest in NGs comes from their multi-stimuli nature involving reversible phase transitions in response to changes in the external media in a faster way than macroscopic gels or hydrogels due to their nanometric size. NGs have a porous structure able to encapsulate small molecules such as drugs and genes, then releasing them by changing their volume when external stimuli are applied.

  3. Common biology of craving across legal and illegal drugs - a quantitative meta-analysis of cue-reactivity brain response.

    Science.gov (United States)

    Kühn, Simone; Gallinat, Jürgen

    2011-04-01

    The present quantitative meta-analysis set out to test whether cue-reactivity responses in humans differ across drugs of abuse and whether these responses constitute the biological basis of drug craving as a core psychopathology of addiction. By means of activation likelihood estimation, we investigated the concurrence of brain regions activated by cue-induced craving paradigms across studies on nicotine, alcohol and cocaine addicts. Furthermore, we analysed the concurrence of brain regions positively correlated with self-reported craving in nicotine and alcohol studies. We found direct overlap between nicotine, alcohol and cocaine cue reactivity in the ventral striatum. In addition, regions of close proximity were observed in the anterior cingulate cortex (ACC; nicotine and cocaine) and amygdala (alcohol, nicotine and cocaine). Brain regions of concurrence in drug cue-reactivity paradigms that overlapped with brain regions of concurrence in self-reported craving correlations were found in the ACC, ventral striatum and right pallidum (for alcohol). This first quantitative meta-analysis on drug cue reactivity identifies brain regions underlying nicotine, alcohol and cocaine dependency, i.e. the ventral striatum. The ACC, right pallidum and ventral striatum were related to drug cue reactivity as well as self-reported craving, suggesting that this set of brain regions constitutes the core circuit of drug craving in nicotine and alcohol addiction. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  4. Increasing the effectiveness of messages promoting responsible undergraduate drinking: tailoring to personality and matching to context.

    Science.gov (United States)

    York, Valerie K; Brannon, Laura A; Miller, Megan M

    2012-01-01

    This study addressed the serious problem of college student binge drinking by identifying factors that improve the effectiveness of messages encouraging responsible drinking presented through a website simulation. We tested schema matching (i.e., whether the message matches the person's self-schema type or not) and two types of context matching (i.e., whether the message matches the topic or values of the message context) to determine their relative influence on the effectiveness of the message. We expected that messages matched to any of these factors would be more effective than messages not matched. Schema matching reduced intentions to drink while staying in/home, but topic matching reduced intentions to drink when going out, suggesting that different factors are important for messages targeting drinking behavior in different locations. Significant interactions between topic matching and value matching on message evaluation variables indicated that the message should not match the message context too closely. That is, there appears to be a matching threshold: Increasing the number of factors the message matches does not increase message effectiveness, possibly because it makes the message too redundant with the surrounding content.

  5. "It's Like Spiderman … with Great Power Comes Great Responsibility": School Autonomy, School Context and the Audit Culture

    Science.gov (United States)

    Keddie, Amanda

    2014-01-01

    This paper explores issues of school autonomy within the context of the performative demands of the audit culture. The focus is on a case study of Clementine Academy, a large and highly diverse English secondary school. Specific situated, professional, material and external factors at the school were significant in shaping Clementine's response to…

  6. RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy.

    Science.gov (United States)

    Pritzker, Kenneth; Pritzker, Laura; Generali, Daniele; Bottini, Alberto; Cappelletti, Maria Rosa; Guo, Baoqing; Parissenti, Amadeo; Trudeau, Maureen

    2015-05-01

    As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an

  7. Mussel-Inspired Protein Nanoparticles Containing Iron(III)-DOPA Complexes for pH-Responsive Drug Delivery.

    Science.gov (United States)

    Kim, Bum Jin; Cheong, Hogyun; Hwang, Byeong Hee; Cha, Hyung Joon

    2015-06-15

    A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH-responsive drug release exploits the pH-dependent changes in the coordination stoichiometry of iron(III)-3,4-dihydroxyphenylalanine (DOPA) complexes, which play a major cross-linking role in mussel byssal threads. Doxorubicin-loaded polymeric NPs that are based on Fe(III)-DOPA complexation were thus synthesized with a DOPA-modified recombinant mussel adhesive protein through a co-electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe(III)-DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe(III)-DOPA complexation can be successfully utilized as a new design principle for pH-responsive NPs for diverse controlled drug-delivery applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Intracellular trafficking of a pH-responsive drug metal complex.

    Science.gov (United States)

    Kheirolomoom, Azadeh; Ingham, Elizabeth S; Commisso, Joel; Abushaban, Neveen; Ferrara, Katherine W

    2016-12-10

    We previously developed a pH-responsive copper-doxorubicin (CuDox) cargo in lysolipid-based temperature-sensitive liposomes (LTSLs). The CuDox complex is released from the particle by elevated temperature; however, full release of doxorubicin from CuDox requires a reduced pH, such as that expected in lysosomes. The primary goal of this study is to evaluate the cellular uptake and intracellular trafficking of the drug-metal complex in comparison with intact liposomes and free drug. We found that the CuDox complex was efficiently internalized by mammary carcinoma cells after release from LTSLs. Intracellular doxorubicin and copper were 6-fold and 5-fold greater, respectively, after a 0.5h incubation with the released CuDox complex, as compared to incubation with intact liposomes containing the complex. Total cellular doxorubicin fluorescence was similar following CuDox and free doxorubicin incubation. Imaging and mass spectrometry assays indicated that the CuDox complex was initially internalized intact but breaks down over time within cells, with intracellular copper decreasing more rapidly than intracellular doxorubicin. Doxorubicin fluorescence was reduced when complexed with copper, and nuclear fluorescence was reduced when cells were incubated with the CuDox complex as compared with free doxorubicin. Therapeutic efficacy, which typically results from intercalation of doxorubicin with DNA, was equivalent for the CuDox complex and free doxorubicin and was superior to that of liposomal doxorubicin formulations. Taken together, the results suggest that quenched CuDox reaches the nucleus and remains efficacious. In order to design protocols for the use of these temperature-sensitive particles in cancer treatment, the timing of hyperthermia relative to drug administration must be examined. When cells were heated to 42°C prior to the addition of free doxorubicin, nuclear drug accumulation increased by 1.8-fold in cancer cells after 5h, and cytotoxicity increased 1

  9. The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases

    Directory of Open Access Journals (Sweden)

    Antje Egners

    2016-01-01

    Full Text Available Lack of oxygen (hypoxia is a hallmark of a multitude of acute and chronic diseases and can be either beneficial or detrimental for organ restitution and recovery. In the context of inflammation, hypoxia is particularly important and can significantly influence the course of inflammatory diseases. Macrophages and neutrophils, the chief cellular components of innate immunity, display distinct properties when exposed to hypoxic conditions. Virtually every aspect of macrophage and neutrophil function is affected by hypoxia, amongst others, morphology, migration, chemotaxis, adherence to endothelial cells, bacterial killing, differentiation/polarization, and protumorigenic activity. Prominent arenas of macrophage and neutrophil function, for example, acute/chronic inflammation and the microenvironment of solid tumors, are characterized by low oxygen levels, demonstrating the paramount importance of the hypoxic response for proper function of these cells. Members of the hypoxia-inducible transcription factor (HIF family emerged as pivotal molecular regulators of macrophages and neutrophils. In this review, we will summarize the molecular responses of macrophages and neutrophils to hypoxia in the context of cancer and other chronic inflammatory diseases and discuss the potential avenues for therapeutic intervention that arise from this knowledge.

  10. Evaluation of Radiation Response and Gold Nanoparticle Enhancement in Drug-Resistant Pancreatic Cancer Cells

    Science.gov (United States)

    Abourabia, Assya

    Pancreatic cancer is a major cause of cancer-related death worldwide after lung cancer and colorectal cancer Pancreatic treatment modalities consist of surgery, chemotherapy, and radiation therapy or combination of these therapies. These modalities are good to some extents but they do have some limitations. For example, during the chemotherapy, tumor cells can develop some escape mechanisms and become chemoresistant to protect themselves against the chemo drugs and pass on theses escape mechanisms to their offspring, despite the treatment given. Cancer Cells can become chemoresistant by many mechanisms, for example, decreased drug influx mechanisms, decreased of drug transport molecules, decreased drug activation, altered drug metabolism that diminishes the capacity of cytotoxic drugs, and enhanced repair of DNA damage. Given that some of these chemoresistance mechanisms may impact sensitivity to radiation. Therefore, there is a strong need for a new alternative treatment option to amplify the therapeutic efficacy of radiotherapy and eventually increase the overall efficacy of cancer treatment. Nano-radiation therapy is an emerging and promising modality aims to enhance the therapeutic efficacy of radiotherapy through the use of radiosensitizing nanoparticles. The primary goal of using GNP-enhanced radiation is that GNPs are potent radiosensitizer agents that sensitize the tumor cells to radiation, and these agents promote generation of the free radicals produced by Photo- and Auger- electrons emission at the molecular level which can enhance the effectiveness of radiation-induced cancer cell death. The main aim of this research is to analyze and compare the response to radiation of pancreatic cancer cells, PANC-1, and PANC-1 cells that are resistant to oxaliplatin, PANC-1/OR, and investigate the radiation dose enhancement effect attributable to GNP when irradiating the cells with low-energy (220 kVp) beam at various doses. Based on evidence from the existing

  11. Parents who use drugs

    DEFF Research Database (Denmark)

    Rhodes, Tim; Bernays, Sarah; Houmøller, Kathrin

    2010-01-01

    Parents who use drugs parent in a context of heightened concern regarding the damaging effects of parental drug use on child welfare and family life. Yet there is little research exploring how parents who use drugs account for such damage and its limitation. We draw here upon analyses of audio......-recorded depth qualitative interviews, conducted in south-east England between 2008 and 2009, with 29 parents who use drugs. Our approach to thematic analysis treated accounts as co-produced and socially situated. An over-arching theme of accounts was 'damage limitation'. Most damage limitation work centred...... on efforts to create a sense of normalcy of family life, involving keeping drug use secret from children, and investing heavily in strategies to maintain ambiguity regarding children's awareness. Our analysis highlights that damage limitation strategies double-up in accounts as resources of child protection...

  12. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines

    International Nuclear Information System (INIS)

    Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M.; Pritzker, Laura B.; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

    2016-01-01

    Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced “RNA disruption” is, the extent to which it is associated with drug response or what the underlying mechanisms are. Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor. All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3’-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption. Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues

  13. Implicit emotion regulation in the context of viewing artworks: ERP evidence in response to pleasant and unpleasant pictures.

    Science.gov (United States)

    Van Dongen, Noah N N; Van Strien, Jan W; Dijkstra, Katinka

    2016-08-01

    Presenting affective pictures as a work of art could change perceivers' judgment and strength in emotional reactions. Aesthetic theory states that perceivers of art emotionally distance themselves, allowing them to appreciate works of art depicting gruesome events. To examine whether implicit emotion regulation is induced by an art context, we assessed whether presenting pleasant and unpleasant IAPS pictures as either "works of art comprising paintings, digital renderings, and photographs of staged scenes" or "photographs depicting real events" modulated perceivers' Late Positive Potentials (LPP) and likability ratings. In line with previous research and aesthetic theory, participants evaluated the IAPS pictures as more likable when they were presented as works of art than when they were presented as photographs. Moreover, participants' late LPP amplitudes (600-900ms post picture onset) in response to the pictures were attenuated in the art context condition. These results provide evidence for an implicit emotion regulation induced by the art context. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Generation of pH responsive fluorescent nano capsules through simple steps for the oral delivery of low pH susceptible drugs

    Science.gov (United States)

    Radhakumary, Changerath; Sreenivasan, Kunnatheeri

    2016-11-01

    pH responsive nano capsules are promising as it can encapsulate low pH susceptible drugs like insulin and guard them from the hostile environments in the intestinal tract. The strong acidity of the gastro-intestinal tract and the presence of proteolytic enzymes are the tumbling blocks for the design of drug delivery vehicles through oral route for drugs like insulin. Nano capsules are normally built over templates which are subsequently removed by further steps. Such processes are complex and often lead into deformed and collapsed capsules. In this study, we choose calcium carbonate (CaCO3) nano particles to serve as template. Over CaCO3 nanoparticles, silica layers were built followed by polymethacrylic acid chains to acquire pH responsiveness. During the polymerization process of the methacrylic acid, the calcium carbonate core particles were dissolved leading to the formation of nano hollow capsules having a size that ranges from 225 to 246 nm and thickness from 19 to 58 nm. The methodology is simple and devoid of additional steps. The nano shells exhibited 80% release of the loaded model drug, insulin at pH 7.4 while at pH 2.0 the capsules nearly stopped the release of the drug. Polymethacrylic acid shows pH responsive swelling behavior that it swells at intestinal pH (7.0-7.5) and shrinks at gastric pH (˜2.0) thus enabling the safe unloading of the drug from the nano capsules.

  15. Are drug companies living up to their human rights responsibilities? The perspective of the former United Nations Special Rapporteur (2002-2008.

    Directory of Open Access Journals (Sweden)

    Paul Hunt

    2010-09-01

    Full Text Available BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

  16. Are drug companies living up to their human rights responsibilities? The perspective of the former United Nations Special Rapporteur (2002-2008).

    Science.gov (United States)

    Hunt, Paul; Khosla, Rajat

    2010-09-28

    The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

  17. Towards Hypoxia-responsive Drug-eluting Embolization Beads.

    Science.gov (United States)

    Ashrafi, Koorosh; Heaysman, Clare L; Phillips, Gary J; Lloyd, Andrew W; Lewis, Andrew L

    2017-05-30

    Drug release from chemoembolization microspheres stimulated by the presence of a chemically reducing environment may provide benefits for targeting drug resistant and metastatic hypoxic tumours. A water-soluble disulfide-based bifunctional cross-linker bis(acryloyl)-(l)-cystine (BALC) was synthesised, characterised and incorporated into a modified poly(vinyl) alcohol (PVA) hydrogel beads at varying concentrations using reverse suspension polymerisation. The beads were characterised to confirm the amount of cross-linker within each formulation and its effects on the bead properties. Elemental and UV/visible spectroscopic analysis confirmed the incorporation of BALC within the beads and sizing studies showed that in the presence of a reducing agent, all bead formulations increased in mean diameter. The BALC beads could be loaded with doxorubicin hydrochloride and amounts in excess of 300mg of drug per mL of hydrated beads could be achieved but required conversion of the carboxylic acid groups of the BALC to their sodium carboxylate salt forms. Elution of doxorubicin from the beads demonstrated a controlled release via ionic exchange. Some formulations exhibited an increase in size and release of drug in the presence of a reducing agent, and therefore demonstrated the ability to respond to an in vitro reducing environment. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  18. Retrieval practice after multiple context changes, but not long retention intervals, reduces the impact of a final context change on instrumental behavior.

    Science.gov (United States)

    Trask, Sydney; Bouton, Mark E

    2018-06-01

    Recent evidence from this laboratory suggests that a context switch after operant learning consistently results in a decrement in responding. One way to reduce this decrement is to train the response in multiple contexts. One interpretation of this result, rooted in stimulus sampling theory, is that conditioning of a greater number of common stimulus elements arising from more contexts causes better generalization to new contexts. An alternative explanation is that each change of context causes more effortful retrieval, and practice involving effortful retrieval results in learning that is better able to transfer to new situations. The current experiments were designed to differentiate between these two explanations for the first time in an animal learning and memory task. Experiment 1 demonstrated that the detrimental impact of a context change on an instrumental nose-poking response can be reduced by training the response in multiple contexts. Experiment 2 then found that a training procedure which inserted extended retention intervals between successive training sessions did not reduce the detrimental impact of a final context change. This occurred even though the inserted retention intervals had a detrimental impact on responding (and, thus, presumably retrieval) similar to the effect that context switches had in Experiment 1. Together, the results suggest that effortful retrieval practice may not be sufficient to reduce the negative impact of a context change on instrumental behavior. A common elements explanation which supposes that physical and temporal contextual cues do not overlap may account for the findings more readily.

  19. Neural Correlates of Drug-Related Attentional Bias in Heroin Dependence

    Directory of Open Access Journals (Sweden)

    Qinglin Zhao

    2018-01-01

    Full Text Available The attention of drug-dependent persons tends to be captured by stimuli associated with drug consumption. This involuntary cognitive process is considered as attentional bias (AB. AB has been hypothesized to have causal effects on drug abuse and drug relapse, but its underlying neural mechanisms are still unclear. This study investigated the neural basis of AB in abstinent heroin addicts (AHAs, combining event-related potential (ERP analysis and source localization techniques. Electroencephalography data were collected in 21 abstinent heroin addicts and 24 age- and gender-matched healthy controls (HCs during a dot-probe task. In the task, a pair of drug-related image and neutral image was presented randomly in left and right side of the cross fixation, followed by a dot probe replacing one of the images. Behaviorally, AHAs had shorter reaction times (RTs for the congruent condition compared to the incongruent condition, whereas this was not the case in the HCs. This finding demonstrated the presence of AB towards drug cues in AHAs. Furthermore, the image-evoked ERPs in AHAs had significant shorter P1 latency compared to HCs, as well as larger N1, N2, and P2 amplitude, suggesting that drug-related stimuli might capture attention early and overall require more attentional resources in AHAs. The target-related P3 had significantly shorter latency and lower amplitude in the congruent than incongruent condition in AHAs compared to HCs. Moreover, source localization of ERP components revealed increased activity for AHAs as compared to HCs in the dorsal posterior cingulate cortex (dPCC, superior parietal lobule and inferior frontal gyrus (IFG for image-elicited responses, and decreased activity in the occipital and the medial parietal lobes for target-elicited responses. Overall, the results of our study confirmed that AHAs may exhibit AB in drug-related contexts, and suggested that the bias might be related to an abnormal neural activity, both in

  20. The emerging role of non-coding RNAs in drug addiction

    Directory of Open Access Journals (Sweden)

    Gregory Charles Sartor

    2012-06-01

    Full Text Available Prolonged drug use causes long-lasting neuroadaptations in reward-related brain areas that contribute to addiction. Despite significant amount of research dedicated to understanding the underlying mechanisms of addiction, the molecular underpinnings remain unclear. At the same time, much of the pervasive transcription that encompasses the human genome occurs in the nervous system and contributes to its heterogeneity and complexity. Recent evidence suggests that non-coding RNAs (ncRNAs play an important and dynamic role in transcriptional regulation, epigenetic signaling, stress response, and plasticity in the nervous system. Dysregulation of ncRNAs are thought to contribute to many, and perhaps all, neurological disorders, including addiction. Here, we review recent insights in the functional relevance of ncRNAs, including both microRNAs (miRNAs and long non-coding RNAs (lncRNAs, and then illustrate specific examples of ncRNA regulation in the context of drug addiction. We conclude that ncRNAs are importantly involved in the persistent neuroadaptations associated with addiction-related behaviors, and that therapies that target specific ncRNAs may represent new avenues for the treatment of drug addiction.

  1. Nano-anisotropic surface coating based on drug immobilized pendant polymer to suppress macrophage adhesion response.

    Science.gov (United States)

    Kaladhar, K; Renz, H; Sharma, C P

    2015-04-01

    Exploring drug molecules for material design, to harness concepts of nano-anisotropy and ligand-receptor interactions, are rather elusive. The aim of this study is to demonstrate the bottom-up design of a single-step and bio-interactive polymeric surface coating, based on drug based pendant polymer. This can be applied on to polystyrene (PS) substrates, to suppress macrophage adhesion and spreading. The drug molecule is used in this coating for two purposes. The first one is drug as a "pendant" group, to produce nano-anisotropic properties that can enable adhesion of the coatings to the substrate. The second purpose is to use the drug as a "ligand", to produce ligand-receptor interaction, between the bound ligand and receptors of albumin, to develop a self-albumin coat over the surface, by the preferential binding of albumin in biological environment, to reduce macrophage adhesion. Our in silico studies show that, diclofenac (DIC) is an ideal drug based "ligand" for albumin. This can also act as a "pendant" group with planar aryl groups. The combination of these two factors can help to harness, both nano-anisotropic properties and biological functions to the polymeric coating. Further, the drug, diclofenac (DIC) is immobilized to the polyvinyl alcohol (PVA), to develop the pendant polymer (PVA-DIC). The interaction of bound DIC with the albumin is a ligand-receptor based interaction, as per the studies by circular dichroism, differential scanning calorimetry, and SDS-PAGE. The non-polar π-π* interactions are regulating; the interactions between PVA bound DIC-DIC interactions, leading to "nano-anisotropic condensation" to form distinct "nano-anisotropic segments" inside the polymeric coating. This is evident from, the thermo-responsiveness and uniform size of nanoparticles, as well as regular roughness in the surface coating, with similar properties as that of nanoparticles. In addition, the hydrophobic DIC-polystyrene (PS) interactions, between the PVA

  2. Continuous carryover of temporal context dissociates response bias from perceptual influence for duration.

    Directory of Open Access Journals (Sweden)

    Martin Wiener

    Full Text Available Recent experimental evidence suggests that the perception of temporal intervals is influenced by the temporal context in which they are presented. A longstanding example is the time-order-error, wherein the perception of two intervals relative to one another is influenced by the order in which they are presented. Here, we test whether the perception of temporal intervals in an absolute judgment task is influenced by the preceding temporal context. Human subjects participated in a temporal bisection task with no anchor durations (partition method. Intervals were demarcated by a Gaussian blob (visual condition or burst of white noise (auditory condition that persisted for one of seven logarithmically spaced sub-second intervals. Crucially, the order in which stimuli were presented was first-order counterbalanced, allowing us to measure the carryover effect of every successive combination of intervals. The results demonstrated a number of distinct findings. First, the perception of each interval was biased by the prior response, such that each interval was judged similarly to the preceding trial. Second, the perception of each interval was also influenced by the prior interval, such that perceived duration shifted away from the preceding interval. Additionally, the effect of decision bias was larger for visual intervals, whereas auditory intervals engendered greater perceptual carryover. We quantified these effects by designing a biologically-inspired computational model that measures noisy representations of time against an adaptive memory prior while simultaneously accounting for uncertainty, consistent with a Bayesian heuristic. We found that our model could account for all of the effects observed in human data. Additionally, our model could only accommodate both carryover effects when uncertainty and memory were calculated separately, suggesting separate neural representations for each. These findings demonstrate that time is susceptible to

  3. Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery

    Science.gov (United States)

    Wang, Sheng; Wang, Hanjie; Liu, Zhongyun; Wang, Liangliang; Wang, Xiaomin; Su, Lin; Chang, Jin

    2014-06-01

    To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (~50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a

  4. Surface Modified Multifunctional and Stimuli Responsive Nanoparticles for Drug Targeting: Current Status and Uses

    Directory of Open Access Journals (Sweden)

    Panoraia I. Siafaka

    2016-08-01

    Full Text Available Nanocarriers, due to their unique features, are of increased interest among researchers working with pharmaceutical formulations. Polymeric nanoparticles and nanocapsules, involving non-toxic biodegradable polymers, liposomes, solid lipid nanoparticles, and inorganic–organic nanomaterials, are among the most used carriers for drugs for a broad spectrum of targeted diseases. In fact, oral, injectable, transdermal-dermal and ocular formulations mainly consist of the aforementioned nanomaterials demonstrating promising characteristics such as long circulation, specific targeting, high drug loading capacity, enhanced intracellular penetration, and so on. Over the last decade, huge advances in the development of novel, safer and less toxic nanocarriers with amended properties have been made. In addition, multifunctional nanocarriers combining chemical substances, vitamins and peptides via coupling chemistry, inorganic particles coated by biocompatible materials seem to play a key role considering that functionalization can enhance characteristics such as biocompatibility, targetability, environmental friendliness, and intracellular penetration while also have limited side effects. This review aims to summarize the “state of the art” of drug delivery carriers in nanosize, paying attention to their surface functionalization with ligands and other small or polymeric compounds so as to upgrade active and passive targeting, different release patterns as well as cell targeting and stimuli responsibility. Lastly, future aspects and potential uses of nanoparticulated drug systems are outlined.

  5. Individual differences and vulnerability to drug addiction: a focus on the endocannabinoid system.

    Science.gov (United States)

    Sagheddu, Claudia; Melis, Miriam

    2015-01-01

    Vulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed.

  6. Alizarin Complexone Functionalized Mesoporous Silica Nanoparticles: A Smart System Integrating Glucose-Responsive Double-Drugs Release and Real-Time Monitoring Capabilities.

    Science.gov (United States)

    Zou, Zhen; He, Dinggeng; Cai, Linli; He, Xiaoxiao; Wang, Kemin; Yang, Xue; Li, Liling; Li, Siqi; Su, Xiaoya

    2016-04-06

    The outstanding progress of nanoparticles-based delivery systems capable of releasing hypoglycemic drugs in response to glucose has dramatically changed the outlook of diabetes management. However, the developed glucose-responsive systems have not offered real-time monitoring capabilities for accurate quantifying hypoglycemic drugs released. In this study, we present a multifunctional delivery system that integrates both delivery and monitoring issues using glucose-triggered competitive binding scheme on alizarin complexone (ALC) functionalized mesoporous silica nanoparticles (MSN). In this system, ALC is modified on the surface of MSN as the signal reporter. Gluconated insulin (G-Ins) is then introduced onto MSN-ALC via benzene-1,4-diboronic acid (BA) mediated esterification reaction, where G-Ins not only blocks drugs inside the mesopores but also works as a hypoglycemic drug. In the absence of glucose, the sandwich-type boronate ester structure formed by BA binding to the diols of ALC and G-Ins remains intact, resulting in an fluorescence emission peak at 570 nm and blockage of pores. Following a competitive binding, the presence of glucose cause the dissociation of boronate ester between ALC and BA, which lead to the pores opening and disappearance of fluorescence. As proof of concept, rosiglitazone maleate (RSM), an insulin-sensitizing agent, was doped into the MSN to form a multifunctional MSN (RSM@MSN-ALC-BA-Ins), integrating with double-drugs loading, glucose-responsive performance, and real-time monitoring capability. It has been demonstrated that the glucose-responsive release behaviors of insulin and RSM in buffer or in human serum can be quantified in real-time through evaluating the changes of fluorescence signal. We believe that this developed multifunctional system can shed light on the invention of a new generation of smart nanoformulations for optical diagnosis, individualized treatment, and noninvasive monitoring of diabetes management.

  7. Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia

    DEFF Research Database (Denmark)

    Abdissa, Alemseged; Yilma, Daniel; Fonager, Jannik

    2014-01-01

    BACKGROUND: The ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub-Saharan Af...... mutations among failing patients justify increased vigilance by improving the availability and systematic use of VL testing to monitor ART response, and underlines the need for rapid, inexpensive tests to identify the most common drug resistance mutations....

  8. Bleaching response of coral species in the context of assemblage response

    Science.gov (United States)

    Swain, Timothy D.; DuBois, Emily; Goldberg, Scott J.; Backman, Vadim; Marcelino, Luisa A.

    2017-06-01

    Caribbean coral reefs are declining due to a mosaic of local and global stresses, including climate change-induced thermal stress. Species and assemblage responses differ due to factors that are not easily identifiable or quantifiable. We calculated a novel species-specific metric of coral bleaching response, taxon- α and - β, which relates the response of a species to that of its assemblages for 16 species over 18 assemblages. By contextualizing species responses within the response of their assemblages, the effects of environmental factors are removed and intrinsic differences among taxa are revealed. Most corals experience either a saturation response, overly sensitive to weak stress ( α > 0) but under-responsive compared to assemblage bleaching ( β bleaching ( β > 1). This metric may help reveal key factors of bleaching susceptibility and identify species as targets for conservation.

  9. Neuropharmacological Consequences of Variant Drugs

    Directory of Open Access Journals (Sweden)

    Mahnoor Amjad Butt

    2017-11-01

    Full Text Available Neuropharmacological effects deals with the influence of drugs on nervous system which harvest the changes in mood, behavioral action of an individual. The drugs are characterized by the chemical substances that communicate with the neurons which have different impacts on nervous system. It may either conducts the abusive or pleasure response which depends on the neural chemicals activity and concerns with the licit and illicit drugs. The elucidation of drugs via LC/MS shows its exertion on the brain components. The computational model helps in the identification of signaling pathways that trigger or inhibit the neurotransmitters. The licit drugs have indisputable responses on CNS. It imparts neuroprotection by either stimulating or inhibiting the receptor, by down regulation yield antinociceptors. However, the illicit drugs have negative acknowledgment on the body as in nicotine the fewer amounts provides benefits but in higher amount mimics the activity of brain receptors and replaces it. Many other drugs induce neurodegenerative disorders. Due to advances in field of neuropharmacology innumerable drugs are available for feasible treatment. The main objective of this review is neuropharmacological consequences in correlation to licit and illicit drugs that what type of responses generated by using these drugs, the neurodegenerative disorders, and their restoration via current treatment.

  10. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  11. Electrophysiological indices of response inhibition in a Go/NoGo task predict self-control in a social context.

    Directory of Open Access Journals (Sweden)

    Kyle Nash

    Full Text Available Recent research demonstrates that response inhibition-a core executive function-may subserve self-regulation and self-control. However, it is unclear whether response inhibition also predicts self-control in the multifaceted, high-level phenomena of social decision-making. Here we examined whether electrophysiological indices of response inhibition would predict self-control in a social context. Electroencephalography was recorded as participants completed a widely used Go/NoGo task (the cued Continuous Performance Test. Participants then interacted with a partner in an economic exchange game that requires self-control. Results demonstrated that greater NoGo-Anteriorization and larger NoGo-P300 peak amplitudes-two established electrophysiological indices of response inhibition-both predicted more self-control in this social game. These findings support continued integration of executive function and self-regulation and help extend prior research into social decision-making processes.

  12. Monitoring early tumor response to drug therapy with diffuse optical tomography

    Science.gov (United States)

    Flexman, Molly L.; Vlachos, Fotios; Kim, Hyun Keol; Sirsi, Shashank R.; Huang, Jianzhong; Hernandez, Sonia L.; Johung, Tessa B.; Gander, Jeffrey W.; Reichstein, Ari R.; Lampl, Brooke S.; Wang, Antai; Borden, Mark A.; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2012-01-01

    Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy--thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture physiologic changes in tumors through visualization of oxygenated, deoxygenated, and total hemoglobin concentrations, using non-ionizing radiation with near-infrared light. We employed a small animal model to ascertain if tumor response to bevacizumab (BV), an anti-angiogenic agent that targets vascular endothelial growth factor (VEGF), could be detected at early time points using DOT. We detected a significant decrease in total hemoglobin levels as soon as one day after BV treatment in responder xenograft tumors (SK-NEP-1), but not in SK-NEP-1 control tumors or in non-responder control or BV-treated NGP tumors. These results are confirmed by magnetic resonance imaging T2 relaxometry and lectin perfusion studies. Noninvasive DOT imaging may allow for earlier and more effective control of anti-angiogenic therapy.

  13. Study on Chitosan-Polyvinyl Alcohol Inter polymeric ph-Responsive Hydrogels for Controlled Drug Delivery

    International Nuclear Information System (INIS)

    Abdel-Bary, E.M.; El-Sherbiny, I.M.; Abdelaal, M.Y.; Abdel-Razik, E.A.

    2005-01-01

    Two series of ph-responsive biodegradable interpenetrating polymeric (IPN) hydrogels composed of chitosan and poly(vinyl alcohol) (PVA) were prepared for controlled drug release investigations. The first series was chemically crosslinked with different concentrations of glutaraldehyde as a crosslinked and the second series was crosslinked by gamma-radiation. Degree of crosslinking has been controlled by the concentration of crosslinked as well as by gamma irradiation dose. The equilibrium swelling -reflecting the degree of crosslinks - were carried out for the gels at 37 degree C in buffer solutions of ph 2.1 and 7.4 (simulated gastric and intestinal fluids respectively). 5-fluorouracil (5- FU) was entrapped, as a model therapeutic agent, in the hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels at 37 degree C. The in-vitro release profiles of the drug were established at 37 degree C in ph 2.1 and 7.4. FT-IR was employed to investigate the structural changes of the gels with different degrees of crosslinking

  14. Recipes for obstetric spinal hypotension: The clinical context counts

    African Journals Online (AJOL)

    strategies need to be adapted to match available clinical skill, drug .... management strategies that target a specific clinical context, and ..... Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dosedependent effects of.

  15. [Vaccines for the treatment of drug addiction].

    Science.gov (United States)

    Zorzoli, Ermanno; Marino, Maria Giulia; Bagnato, Barbara; Franco, Elisabetta

    2016-01-01

    The treatment of drug addiction is a very wide-ranging sector within modern medicine. The use of immunotherapy in this context represents an innovative approach. The purpose of this paper is to illustrate, through a literature review, the main avenues of research and the results obtained with immunotherapy in the treatment of drug addiction.

  16. Polymer-Block-Polypeptides and Polymer-Conjugated Hybrid Materials as Stimuli-Responsive Nanocarriers for Biomedical Applications.

    Science.gov (United States)

    John, Johnson V; Johnson, Renjith P; Heo, Min Seon; Moon, Byeong Kyu; Byeon, Seong Jin; Kim, Il

    2015-01-01

    Stimuli-responsive nanocarriers are a class of soft materials that includes natural polymers, synthetic polymers, and polypeptides. Recently, modern synthesis tools such as atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, nitroxide-mediated radical polymerization, ring-opening polymerization of α-amino acid N-carboxyanhydrides, and various "click" chemistry strategies were simultaneously employed for the design and synthesis of nanosized drug delivery vehicles. Importantly, the research focused on the improvement of the nanocarrier targetability and the site-specific, triggered release of therapeutics with high drug loading efficiency and minimal drug leakage during the delivery to specific targets. In this context, nanocarriers responsive to common stimuli such as pH, temperature, redox potential, light, etc. have been widely used for the controlled delivery of therapeutics to pathological sites. Currently, different synthesis and self-assembly strategies improved the drug loading efficacy and targeted delivery of therapeutic agents to the desired site. In particular, polypeptide-containing hybrid materials have been developed for the controlled delivery of therapeutic agents. Therefore, stimuli-sensitive synthetic polypeptide-based materials have been extensively investigated in recent years. This review focuses on recent advances in the development of polymer-block-polypeptides and polymer-conjugated hybrid materials that have been designed and evaluated for various stimuli-responsive drug and gene delivery applications.

  17. Time-lagged response of carabid species richness and composition to past management practices and landscape context of semi-natural field margins.

    Science.gov (United States)

    Alignier, Audrey; Aviron, Stéphanie

    2017-12-15

    Field margins are key features for the maintenance of biodiversity and associated ecosystem services in agricultural landscapes. Little is known about the effects of management practices of old semi-natural field margins, and their historical dimension regarding past management practices and landscape context is rarely considered. In this paper, the relative influence of recent and past management practices and landscape context (during the last five years) were assessed on the local biodiversity (species richness and composition) of carabid assemblages of field margins in agricultural landscapes of northwestern France. The results showed that recent patterns of carabid species richness and composition were best explained by management practices and landscape context measured four or five years ago. It suggests the existence of a time lag in the response of carabid assemblages to past environmental conditions of field margins. The relative contribution of past management practices and past landscape context varied depending on the spatial scale at which landscape context was taken into account. Carabid species richness was higher in grazed or sprayed field margins probably due to increased heterogeneity in habitat conditions. Field margins surrounded by grasslands and crops harbored species associated with open habitats whilst forest species dominated field margins surrounded by woodland. Landscape effect was higher at fine spatial scale, within 50 m around field margins. The present study highlights the importance of considering time-lagged responses of biodiversity when managing environment. It also suggests that old semi-natural field margins should not be considered as undisturbed habitats but more as management units being part of farming activities in agricultural landscapes, as for arable fields. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Curcumin exerts its antitumor effects in a context dependent fashion.

    Science.gov (United States)

    Kreutz, Dominique; Sinthuvanich, Chomdao; Bileck, Andrea; Janker, Lukas; Muqaku, Besnik; Slany, Astrid; Gerner, Christopher

    2018-06-30

    Proteome profiling profoundly contributes to the understanding of cell response mechanisms to drug actions. Such knowledge may become a key to improve personalized medicine. In the present study, the effects of the natural remedy curcumin on breast cancer model systems were investigated. MCF-7, ZR-75-1 and TGF-β1 pretreated fibroblasts, mimicking cancer-associated fibroblasts (CAFs), were treated independently as well as in tumor cell/CAF co-cultures. Remarkably, co-culturing with CAF-like cells (CLCs) induced different proteome alterations in MCF-7 and ZR-75-1 cells, respectively. Curcumin significantly induced HMOX1 in single cell type models and co-cultures. However, other curcumin effects differed. In the MCF-7/CLC co-culture, curcumin significantly down-regulated RC3H1, a repressor of inflammatory signaling. In the ZR-75-1/CLC co-culture, curcumin significantly down-regulated PEG10, an anti-apoptotic protein, and induced RRAGA, a pro-apoptotic protein involved in TNF-alpha signaling. Furthermore, curcumin induced AKR1C2, an important enzyme for progesterone metabolism. None of these specific curcumin effects were observed in single cell type cultures. All high-resolution mass spectrometry data are available via ProteomeXchange with the identifier PXD008719. The present data demonstrate that curcumin induces proteome alterations, potentially accounting for its known antitumor effects, in a strongly context-dependent fashion. Better means to understand and potentially predict individual variations of drug effects are urgently required. The present proteome profiling study of curcumin effects demonstrates the massive impact of the cell microenvironment on cell responses to drug action. Co-culture models apparently provide more biologically relevant information regarding curcumin effects than single cell type cultures. Copyright © 2018. Published by Elsevier B.V.

  19. Therapeutic Response for Functional Abdominal Pain in Children with Occult Constipation: Laxatives versus Prokinetic Drugs.

    Science.gov (United States)

    Ha, Eun Kyo; Jang, Homin; Jeong, Su Jin

    2017-01-01

    The relationship between functional abdominal pain (FAP) and occult constipation (OC) in children who did not meet the Rome III criteria for constipation has rarely been reported. This study aimed to estimate the prevalence of OC in patients with FAP and to compare the effectiveness of prokinetic drugs and laxatives for FAP and OC. Pediatric outpatients (n = 212; aged 4-15 years) who satisfied the Rome III criteria for childhood FAP were divided into 2 groups based on Leech scores: group 1 pain severity was assessed after 2 weeks, 1 month, and 3 months. A total 52.4% (111/212) of patients had OC in this study. More patients who received laxatives had reduced pain scores compared with those who received prokinetic drugs. Those treated with laxatives in group 2 had a better response than those treated with prokinetic drugs throughout the study period (P < 0.001, P < 0.001, and P = 0.002 after 2 weeks, 1 month, and 3 months, respectively). OC was frequently encountered in children with FAP. Laxatives can be more effective than prokinetic drugs for relieving symptoms of FAP in children with a Leech score ≥ 8 and suspected OC.

  20. Multitriggered Tumor-Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation.

    Science.gov (United States)

    Zhang, Ning; Zhao, Fenfang; Zou, Qianli; Li, Yongxin; Ma, Guanghui; Yan, Xuehai

    2016-11-01

    Tumor-responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein-based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross-linking and surface polyethylene glycol coupling, can be used as versatile tumor-responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6-encapsulated nanospheres (Ce6-Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6-Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6-Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6-Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6-Ns and the biocompatibility of Ce6-Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Fluorescent, thermo-responsive biotin-P(NIPAAm-co-NDAPM)- b-PCL micelles for cell-tracking and drug delivery

    International Nuclear Information System (INIS)

    Li Yongyong; Zhang Xianzheng; Cheng Han; Zhu Jingling; Li Unnam; Cheng Sixue; Zhuo Renxi

    2007-01-01

    An amphiphilic, biotinylated poly(N-isopropylacrylamide-co-N-(3-dimethylamino propyl)methacrylamide)-block- poly(ε-caprolactone) (biotin-P(NIPAAm-co-NDAPM)- b-PCL) block copolymer was synthesized. The cytotoxicity study showed that the copolymer exhibited no apparent cytotoxicity. In aqueous solution, biotin-P(NIPAAm-co-NDAPM)- b-PCL copolymer was able to self-assemble into micelles of around 60 nm in diameter with a critical micellar concentration (CMC) of 36 mg l -1 . Biotin-P(NIPAAm- co-NDAPM)-b-PCL micelles were thermo-responsive and the cloud point temperature was at 36.5 deg. C. The fluorescent group, fluorescein isothiocyanate (FITC) was further introduced to label the biotin-P(NIPAAm-co-NDAPM)- b-PCL copolymer. A cell internalization experiment was conducted and it was found that the fluorescent micelles could be internalized into the cells. The drug release behavior of drug-loading micelles was also examined and the drug-loaded biotin-P(NIPAAm-co-NDAPM)- b-PCL micelles showed slow drug release at 27 deg. C and fast drug release at 37 deg. C

  2. Three-dimensional quick response code based on inkjet printing of upconversion fluorescent nanoparticles for drug anti-counterfeiting

    Science.gov (United States)

    You, Minli; Lin, Min; Wang, Shurui; Wang, Xuemin; Zhang, Ge; Hong, Yuan; Dong, Yuqing; Jin, Guorui; Xu, Feng

    2016-05-01

    Medicine counterfeiting is a serious issue worldwide, involving potentially devastating health repercussions. Advanced anti-counterfeit technology for drugs has therefore aroused intensive interest. However, existing anti-counterfeit technologies are associated with drawbacks such as the high cost, complex fabrication process, sophisticated operation and incapability in authenticating drug ingredients. In this contribution, we developed a smart phone recognition based upconversion fluorescent three-dimensional (3D) quick response (QR) code for tracking and anti-counterfeiting of drugs. We firstly formulated three colored inks incorporating upconversion nanoparticles with RGB (i.e., red, green and blue) emission colors. Using a modified inkjet printer, we printed a series of colors by precisely regulating the overlap of these three inks. Meanwhile, we developed a multilayer printing and splitting technology, which significantly increases the information storage capacity per unit area. As an example, we directly printed the upconversion fluorescent 3D QR code on the surface of drug capsules. The 3D QR code consisted of three different color layers with each layer encoded by information of different aspects of the drug. A smart phone APP was designed to decode the multicolor 3D QR code, providing the authenticity and related information of drugs. The developed technology possesses merits in terms of low cost, ease of operation, high throughput and high information capacity, thus holds great potential for drug anti-counterfeiting.Medicine counterfeiting is a serious issue worldwide, involving potentially devastating health repercussions. Advanced anti-counterfeit technology for drugs has therefore aroused intensive interest. However, existing anti-counterfeit technologies are associated with drawbacks such as the high cost, complex fabrication process, sophisticated operation and incapability in authenticating drug ingredients. In this contribution, we developed a

  3. Spirituality in the Treatment of Drug Addictions

    OpenAIRE

    ZAHRADNÍKOVÁ, Kateřina

    2015-01-01

    The thesis deals with the spirituality of a drug addiction therapy. The first chapter classifies drugs and characterizes drug addictions and their therapies. To clear up the context and point of view, the second chapter explains the meaning of spirituality in relation to its development. First, it intorduces the ancient spirituality, based on heatheninsmas, a meaning of Sanctity in relation to our ethnic origin. Further on, it pictures the Christian spirituality with its practical aspects. Ne...

  4. Research on drug abuse and addiction treatment in prisons

    OpenAIRE

    Kljajević Srđan

    2017-01-01

    The causes of drug abuse and criminal behavior are closely linked. Not surprisingly, there is a high percentage of prisoners who during sentence execution abuse or are dependent on drugs. Antisocial personality disorder can be considered a common predictor of committing criminal offenses and drug abuse. A review of studies has revealed a high prevalence of inmates who use drugs while serving a sentence. Also, prison environment represents only a new context of the continuum of drug abuse by i...

  5. Genotyping three SNPs affecting warfarin drug response by isothermal real-time HDA assays.

    Science.gov (United States)

    Li, Ying; Jortani, Saeed A; Ramey-Hartung, Bronwyn; Hudson, Elizabeth; Lemieux, Bertrand; Kong, Huimin

    2011-01-14

    The response to the anticoagulant drug warfarin is greatly affected by genetic polymorphisms in the VKORC1 and CYP2C9 genes. Genotyping these polymorphisms has been shown to be important in reducing the time of the trial and error process for finding the maintenance dose of warfarin thus reducing the risk of adverse effects of the drug. We developed a real-time isothermal DNA amplification system for genotyping three single nucleotide polymorphisms (SNPs) that influence warfarin response. For each SNP, real-time isothermal Helicase Dependent Amplification (HDA) reactions were performed to amplify a DNA fragment containing the SNP. Amplicons were detected by fluorescently labeled allele specific probes during real-time HDA amplification. Fifty clinical samples were analyzed by the HDA-based method, generating a total of 150 results. Of these, 148 were consistent between the HDA-based assays and a reference method. The two samples with unresolved HDA-based test results were repeated and found to be consistent with the reference method. The HDA-based assays demonstrated a clinically acceptable performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and 1075A>C) for the CYP2C9 enzyme (CYP2C9*2 and CYP2C9*3), all of which are relevant in warfarin pharmacogenentics. Copyright © 2010 Elsevier B.V. All rights reserved.

  6. Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery.

    Science.gov (United States)

    Zhao, Qinfu; Geng, Hongjian; Wang, Ying; Gao, Yikun; Huang, Jiahao; Wang, Yan; Zhang, Jinghai; Wang, Siling

    2014-11-26

    A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.

  7. Estimating the response times of human operators working in the main control room of nuclear power plants based on the context of a seismic event – A case study

    International Nuclear Information System (INIS)

    Park, Jinkyun; Kim, Yochan; Kim, Jung Han; Jung, Wondea; Jang, Seung Cheol

    2015-01-01

    Highlights: • Response times under seismic events are necessary for human reliability analysis. • Conceptual framework to estimate response times under a seismic event is suggested. • Four kinds of representative contexts in seismic events are considered. • Rules for estimating response times on the representative contexts are extracted. - Abstract: After the Fukushima accident, a couple of novel issues have raised in terms of the safety assessment of nuclear power plants (NPPs). This means that the performance of human operators should be properly evaluated under an extreme event. However, it is unrealistic to collect a sufficient amount of human performance data from a real event, such as a great earthquake. As one of the promising solutions, a conceptual framework is suggested in this paper, which is helpful for estimating the response time data of human operators working in the main control room of NPPs under a seismic event. To this end, the four kinds of representative contexts that could be anticipated from seismic events are identified. Then the response times of human operators who are faced with similar contexts are reviewed from existing literatures and databases. As a result, a couple of rules that allow us to extrapolate the response times of human operators under seismic events are extracted. Although underlying rationales being used for determining these rules are still arguable, it is expected that response times under seismic events could be properly understood along with accumulating those of human operators against non-seismic conditions

  8. Prediction of individual patient response to chemotherapy by the fluorometric microculture cytotoxicity assay (FMCA) using drug specific cut-off limits and a Bayesian model.

    Science.gov (United States)

    Larsson, R; Nygren, P

    1993-01-01

    The semiautomated fluorometric microculture cytotoxicity assay (FMCA) based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein in microtiter plates, has been used for determination of cytotoxic drug resistance of tumor cells from patients with hematological and solid tumors. In the present study we describe a calibration procedure based on statistically derived cut-off limits and assay-predicted response probabilities using Bayes' theorem. Test results at a specified drug concentration were divided into three categories: low, intermediate or extreme drug resistance (LDR, IDR and EDR, respectively) using the median and median +1 standard deviation as the cut-off limits. When correlated with clinical outcome, LDR samples showed a higher response rate than expected, IDR a lower and EDR samples no response at all. The sensitivity and specificity of the test, using the median as cut-off limit, were 0.92 and 0.69 respectively. By fitting these test characteristics to a statistical model based on Bayes' theorem it is possible to calculate response probabilities for each individual patient taking into consideration not only the test characteristics and the particular assay result, but also the clinical and patient specific characteristics influencing the pre-test probability of response. EDR predicts clinical drug resistance with high specificity and is also observed in tumor types with high response rate.

  9. One-pot synthesis of redox-responsive polymers-coated mesoporous silica nanoparticles and their controlled drug release.

    Science.gov (United States)

    Sun, Jiao-Tong; Piao, Ji-Gang; Wang, Long-Hai; Javed, Mohsin; Hong, Chun-Yan; Pan, Cai-Yuan

    2013-09-01

    A versatile one-pot strategy for the preparation of reversibly cross-linked polymer-coated mesoporous silica nanoparticles (MSNs) via surface reversible addition-fragmentation chain transfer (RAFT) polymerization is presented for the first time in this paper. The less reactive monomer oligo(ethylene glycol) acrylate (OEGA) and the more reactive cross-linker N,N'-cystaminebismethacrylamide (CBMA) are chosen to be copolymerized on the external surfaces of RAFT agent-functionalized MSNs to form the cross-linked polymer shells. Owing to the reversible cleavage and restoration of disulfide bonds via reduction/oxidation reactions, the polymer shells can control the on/off switching of the nanopores and regulate the drug loading and release. The redox-responsive release of doxorubicin (DOX) from this drug carrier is realized. The protein adsorption, in vitro cytotoxicity assays, and endocytosis studies demonstrate that this biocompatible vehicle is a potential candidate for delivering drugs. It is expected that this versatile grafting strategy may help fabricate satisfying MSN-based drug delivery systems for clinical application. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Influence of polymer network parameters of tragacanth gum-based pH responsive hydrogels on drug delivery.

    Science.gov (United States)

    Singh, Baljit; Sharma, Vikrant

    2014-01-30

    The present article deals with design of tragacanth gum-based pH responsive hydrogel drug delivery systems. The characterization of hydrogels has been carried out by SEMs, EDAX, FTIR, (13)C NMR, XRD, TGA/DTA/DTG and swelling studies. The correlation between reaction conditions and structural parameters of polymer networks such as polymer volume fraction in the swollen state (ϕ), Flory-Huggins interaction parameter (χ), molecular weight of the polymer chain between two neighboring cross links (M¯c), crosslink density (ρ) and mesh size (ξ) has been determined. The different kinetic models such as zero order, first order, Higuchi square root law, Korsmeyer-Peppas model and Hixson-Crowell cube root model were applied and it has been observed that release profile of amoxicillin best followed the first order model for the release of drug from the polymer matrix. The swelling of the hydrogels and release of drug from the drug loaded hydrogels occurred through non-Fickian diffusion mechanism in pH 7.4 solution. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Light-responsive micelles of spiropyran initiated hyperbranched polyglycerol for smart drug delivery.

    Science.gov (United States)

    Son, Suhyun; Shin, Eeseul; Kim, Byeong-Su

    2014-02-10

    Light-responsive polymeric micelles have emerged as site-specific and time-controlled systems for advanced drug delivery. Spiropyran (SP), a well-known photochromic molecule, was used to initiate the ring-opening multibranching polymerization of glycidol to afford a series of hyperbranched polyglycerols (SP-hb-PG). The micelle assembly and disassembly were induced by an external light source owing to the reversible photoisomerization of hydrophobic SP to hydrophilic merocyanine (MC). Transmission electron microscopy, atomic force microscopy, UV/vis spectroscopy, and dynamic light scattering demonstrated the successful assembly and disassembly of SP-hb-PG micelles. In addition, the critical micelle concentration (CMC) was determined through the fluorescence analysis of pyrene to confirm the amphiphilicity of respective SP-hb-PGn (n = 15, 29, and 36) micelles, with CMC values ranging from 13 to 20 mg/L, which is correlated to the length of the polar polyglycerol backbone. Moreover, the superior biocompatibility of the prepared SP-hb-PG was evaluated using WI-38 cells and HeLa cells, suggesting the prospective applicability of the micelles in smart drug delivery systems.

  12. Cross-linked chitosan-dextran sulphate vehicle system for controlled release of ciprofloxaxin drug: An ophthalmic application

    Directory of Open Access Journals (Sweden)

    Chetan Chavan

    2017-01-01

    Full Text Available The major challenge associated with conventional eye-drop is the rapid drug loss due to precorneal defence barrier. In this context, controlled-release system of ciprofloxacin-conjugated chitosan (CS-Dextran sulphate (DS nanoparticles (NPs have been synthesized, to increase the bioavailability. The formulated drug delivery vehicle was evaluated for its therapeutic value in the simulated tear fluidat pH 7.4. Ophthalmic microbes were tested with this formulation, to confirm the drug efficacy; which showed conducive therapeutic values of both MIC and MBC. Ocular irritancy test was performed using HET-CAM test, which showed that the CS-DS system did not yield any vascular response, offering it to be a non-irritant to the ocular surface. The release studies showed monotonous controlled-release for duration of 21 h. A fine cross-linking between CS and DS has been demonstrated to form CS-DS NPs and their interaction with drug has been evaluated using conventional characterization tools.

  13. Differentiation of drug and non-drug Cannabis using a single nucleotide polymorphism (SNP) assay.

    Science.gov (United States)

    Rotherham, D; Harbison, S A

    2011-04-15

    Cannabis sativa is both an illegal drug and a legitimate crop. The differentiation of illegal drug Cannabis from non-drug forms of Cannabis is relevant in the context of the growth of fibre and seed oil varieties of Cannabis for commercial purposes. This differentiation is currently determined based on the levels of tetrahydrocannabinol (THC) in adult plants. DNA based methods have the potential to assay Cannabis material unsuitable for analysis using conventional means including seeds, pollen and severely degraded material. The purpose of this research was to develop a single nucleotide polymorphism (SNP) assay for the differentiation of "drug" and "non-drug"Cannabis plants. An assay was developed based on four polymorphisms within a 399 bp fragment of the tetrahydrocannabinolic acid (THCA) synthase gene, utilising the snapshot multiplex kit. This SNP assay was tested on 94 Cannabis plants, which included 10 blind samples, and was able to differentiate between "drug" and "non-drug"Cannabis in all cases, while also differentiating between Cannabis and other species. Non-drug plants were found to be homozygous at the four sites assayed while drug Cannabis plants were either homozygous or heterozygous. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  14. Teacher drug use: a response to occupational stress.

    Science.gov (United States)

    Watts, W D; Short, A P

    1990-01-01

    Work-related stress is predicted to be correlated with wanting to leave the teaching profession and drug use. A stratified random sample of 500 Texas teachers was surveyed (56.5% responded), regarding working conditions, collegial and supervisory relationships, job satisfaction, rigidity of attitudes and drug use. Two-thirds of teachers may want to quit the profession, while 36.4 percent are likely to quit. Teachers report higher rates than a national sample of lifetime alcohol, amphetamine, and tranquilizer use and higher rates of alcohol use in the last year and last month. Selected measures of stress are correlated with drug use, particularly amphetamine use, over the lifetime, last year, and last month.

  15. A Unique Fungal Two-Component System Regulates Stress Responses, Drug Sensitivity, Sexual Development, and Virulence of Cryptococcus neoformans

    Science.gov (United States)

    Bahn, Yong-Sun; Kojima, Kaihei; Cox, Gary M.

    2006-01-01

    The stress-activated mitogen-activated protein kinase (MAPK) pathway is widely used by eukaryotic organisms as a central conduit via which cellular responses to the environment effect growth and differentiation. The basidiomycetous human fungal pathogen Cryptococcus neoformans uniquely uses the stress-activated Pbs2-Hog1 MAPK system to govern a plethora of cellular events, including stress responses, drug sensitivity, sexual reproduction, and virulence. Here, we characterized a fungal “two-component” system that controls these fundamental cellular functions via the Pbs2-Hog1 MAPK cascade. A typical response regulator, Ssk1, modulated all Hog1-dependent phenotypes by controlling Hog1 phosphorylation, indicating that Ssk1 is the major upstream signaling component of the Pbs2-Hog1 pathway. A second response regulator, Skn7, governs sensitivity to Na+ ions and the antifungal agent fludioxonil, negatively controls melanin production, and functions independently of Hog1 regulation. To control these response regulators, C. neoformans uses multiple sensor kinases, including two-component–like (Tco) 1 and Tco2. Tco1 and Tco2 play shared and distinct roles in stress responses and drug sensitivity through the Hog1 MAPK system. Furthermore, each sensor kinase mediates unique cellular functions for virulence and morphological differentiation. Our findings highlight unique adaptations of this global two-component MAPK signaling cascade in a ubiquitous human fungal pathogen. PMID:16672377

  16. Formulation and optimization of a novel oral fast dissolving film containing drug nanoparticles by Box-Behnken design-response surface methodology.

    Science.gov (United States)

    Shen, Chengying; Shen, Baode; Xu, He; Bai, Jinxia; Dai, Ling; Lv, Qingyuan; Han, Jin; Yuan, Hailong

    2014-05-01

    The purpose of this study was to design and optimize a novel drug nanoparticles-loaded oral fast dissolving film (NP-OFDF) using Box-Behnken design-response surface methodology. Drug nanosuspensions produced from high pressure homogenization were transformed into oral fast dissolving film containing drug nanoparticles by casting methods. Herpetrione (HPE), a novel and potent antiviral agent with poor water solubility that was extracted from Herpetospermum caudigerum, was studied as the model drug. The formulations of oral fast dissolving film containing HPE nanoparticles (HPE-NP-OFDF) were optimized by employing Box-Behnken design-response surface methodology and then systematically characterized. The optimized HPE-NP-OFDF was disintegrated in water within 20 s with reconstituted nanosuspensions particle size of 299.31 nm. Scanning electron microscopy (SEM) images showed that well-dispersed HPE nanoparticles with slight adhesion to each other were exposed on the surface of film or embedded in film. The X-ray diffractogram (XRD) analysis suggested that HPE in the HPE-NP-OFDF was in the amorphous state. In-vitro release study, approximate 77.23% of HPE was released from the HPE-NP-OFDF within 5 min, which was more than eight times compared with that of HPE raw materials (9.57%). The optimized HPE-NP-OFDF exhibits much faster drug release rates compared to HPE raw material, which indicated that this novel NP-OFDF may provide a potential opportunity for oral delivery of drugs with poor water solubility.

  17. Pharmacogenomics of GPCR Drug Targets

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian; Chavali, Sreenivas; Masuho, Ikuo

    2018-01-01

    Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs...... and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug......- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants...

  18. Drug-specific characteristics of thrombocytopenia caused by non-cytotoxic drugs

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Andersen, M; Hansen, P B

    1999-01-01

    OBJECTIVE: To analyse drug-specific clinical characteristics and to investigate the possible influence of epidemiological and other factors on thrombocytopenia induced by selected non-cytotoxic drugs. METHODS: A retrospective analysis of drug-induced thrombocytopenia reported to the Danish...... determined by the drug itself and also by its usage pattern. No specific patient-related factor responsible for the heterogeneity of the clinical appearance of the adverse reaction was identified. Factors related to the physician, such as monitoring recommendations or level of attention towards the adverse...

  19. Responses to GM food content in context with food integrity issues: results from Australian population surveys.

    Science.gov (United States)

    Mohr, Philip; Golley, Sinéad

    2016-01-25

    This study examined community responses to use of genetically modified (GM) content in food in the context of responses to familiar food additives by testing an empirically and theoretically derived model of the predictors of responses to both GM content and food integrity issues generally. A nationwide sample of 849 adults, selected at random from the Australian Electoral Roll, responded to a postal Food and Health Survey. Structural equation modelling analyses confirmed that ratings of general concern about food integrity (related to the presence of preservatives and other additives) strongly predicted negativity towards GM content. Concern about food integrity was, in turn, predicted by environmental concern and health engagement. In addition, both concern about food integrity generally and responses to GM content specifically were weakly predicted by attitudes to benefits of science and an intuitive (i.e., emotionally-based) reasoning style. Data from a follow-up survey conducted under the same conditions (N=1184) revealed that ratings of concern were significantly lower for use of genetic engineering in food than for four other common food integrity issues examined. Whereas the question of community responses to GM is often treated as a special issue, these findings support the conclusion that responses to the concept of GM content in food in Australia are substantially a specific instance of a general sensitivity towards the integrity of the food supply. They indicate that the origins of responses to GM content may be largely indistinguishable from those of general responses to preservatives and other common food additives. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Baseline Antihypertensive Drug Count and Patient Response to Hypertension Medication Management.

    Science.gov (United States)

    Crowley, Matthew J; Olsen, Maren K; Woolson, Sandra L; King, Heather A; Oddone, Eugene Z; Bosworth, Hayden B

    2016-04-01

    Telemedicine-based medication management improves hypertension control, but has been evaluated primarily in patients with low antihypertensive drug counts. Its impact on patients taking three or more antihypertensive agents is not well-established. To address this evidence gap, the authors conducted an exploratory analysis of an 18-month, 591-patient trial of telemedicine-based hypertension medication management. Using general linear models, the effect of medication management on blood pressure for patients taking two or fewer antihypertensive agents at study baseline vs those taking three or more was compared. While patients taking two or fewer antihypertensive agents had a significant reduction in systolic blood pressure with medication management, those taking three or more had no such response. The between-subgroup effect difference was statistically significant at 6 months (-6.4 mm Hg [95% confidence interval, -12.2 to -0.6]) and near significant at 18 months (-6.0 mm Hg [95% confidence interval, -12.2 to 0.2]). These findings suggest that baseline antihypertensive drug count may impact how patients respond to hypertension medication management and emphasize the need to study management strategies specifically in patients taking three or more antihypertensive medications. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  1. Effect of drug law enforcement on drug market violence: a systematic review.

    Science.gov (United States)

    Werb, Dan; Rowell, Greg; Guyatt, Gordon; Kerr, Thomas; Montaner, Julio; Wood, Evan

    2011-03-01

    Violence is amongst the primary concerns of communities around the world and research has demonstrated links between violence and the illicit drug trade, particularly in urban settings. Given the growing emphasis on evidence-based policy-making, and the ongoing severe drug market violence in Mexico and other settings, we conducted a systematic review to examine the impacts of drug law enforcement on drug market violence. We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Specifically, we undertook a search of English language electronic databases (Academic Search Complete, PubMed, PsycINFO, EMBASE, Web of Science, Sociological Abstracts, Social Service Abstracts, PAIS International and Lexis-Nexis), the Internet (Google, Google Scholar), and article reference lists, from database inception to January 24, 2011. Overall, 15 studies were identified that evaluated the impact of drug law enforcement on drug market violence, including 11 (73%) longitudinal analyses using linear regression, 2 (13%) mathematical drug market models, and 2 (13%) qualitative studies. Fourteen (93%) studies reported an adverse impact of drug law enforcement on levels of violence. Ten of the 11 (91%) studies employing longitudinal qualitative analyses found a significant association between drug law enforcement and drug market violence. Our findings suggest that increasing drug law enforcement is unlikely to reduce drug market violence. Instead, the existing evidence base suggests that gun violence and high homicide rates may be an inevitable consequence of drug prohibition and that disrupting drug markets can paradoxically increase violence. In this context, and since drug prohibition has not meaningfully reduced drug supply, alternative regulatory models will be required if drug supply and drug market violence are to be meaningfully reduced. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. A Randomized Trial of Contingency Management Delivered in the Context of Group Counseling

    Science.gov (United States)

    Petry, Nancy M.; Weinstock, Jeremiah; Alessi, Sheila M.

    2011-01-01

    Objective: Contingency management (CM) is efficacious in reducing drug use. Typically, reinforcers are provided on an individual basis to patients for submitting drug-negative samples. However, most treatment is provided in a group context, and poor attendance is a substantial concern. This study evaluated whether adding CM to group-based…

  3. Reinforcement principles for addiction medicine; from recreational drug use to psychiatric disorder.

    Science.gov (United States)

    Edwards, Scott

    2016-01-01

    The transition from recreational drug use to addiction can be conceptualized as a pathological timeline whereby the psychological mechanisms responsible for disordered drug use evolve from positive reinforcement to favor elements of negative reinforcement. Abused substances (ranging from alcohol to psychostimulants) are initially ingested at regular occasions according to their positive reinforcing properties. Importantly, repeated exposure to rewarding substances sets off a chain of secondary reinforcing events, whereby cues and contexts associated with drug use may themselves become reinforcing and thereby contribute to the continued use and possible abuse of the substance(s) of choice. Indeed, the powerful reinforcing efficacy of certain drugs may eclipse that of competing social rewards (such as career and family) and lead to an aberrant narrowing of behavioral repertoire. In certain vulnerable individuals, escalation of drug use over time is thought to drive specific molecular neuroadaptations that foster the development of addiction. Research has identified neurobiological elements of altered reinforcement following excessive drug use that comprise within-circuit and between-circuit neuroadaptations, both of which contribute to addiction. Central to this process is the eventual potentiation of negative reinforcement mechanisms that may represent the final definitive criterion locking vulnerable individuals into a persistent state of addiction. Targeting the neural substrates of reinforcement likely represents our best chances for therapeutic intervention for this devastating disease. © 2016 Elsevier B.V. All rights reserved.

  4. Context counts! Social anxiety modulates the processing of fearful faces in the context of chemosensory anxiety signals

    Directory of Open Access Journals (Sweden)

    Dirk eAdolph

    2013-06-01

    Full Text Available During emotion perception, context is an important source of information. Whether contextual cues from modalities other than vision or audition influence the perception of social emotional information has not been investigated.Thus, the present study aimed at testing emotion perception and regulation in response to fearful facial expressions presented in the context of chemosensory stimuli derived from sweat of anxious individuals. In groups of high (HSA and low socially anxious (LSA participants we recorded the startle reflex (Experiment I, and analysed event-related potentials (ERPs; Experiment II while they viewed anxious facial expressions in the context of chemosensory anxiety signals and chemosensory control stimuli. Results revealed that N1/P1 and N170 amplitudes were larger while Late Positive Potential (LPP activity was smaller for facial expressions presented in the context of the anxiety and the chemosensory control stimulus as compared to facial expressions without a chemosensory context. Furthermore, HSA participants were highly sensitive to the contextual anxiety signals. They showed enhanced motivated attention allocation (LPP, Study II, as well as larger startle responses towards faces in the context of chemosensory anxiety signals than did LSA participants (Study I. Chemosensory context had no effect on emotion regulation, and both LSA and HSA participants showed effective emotion regulation (Study I and II. In conclusion, both anxiety and chemosensory sport context stimuli enhanced early attention allocation and structural encoding, but diminished motivated attention allocation to the facial expressions. The current results show that visual and chemosensory information is integrated on virtually all levels of stimulus processing and that socially anxious individuals might be especially sensitive to chemosensory contextual social information.

  5. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

    Directory of Open Access Journals (Sweden)

    Adam A Friedman

    Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

  6. Sex Differences in Cardiovascular Drug Response

    NARCIS (Netherlands)

    E.M. Rodenburg (Eline)

    2012-01-01

    textabstractIn the early sixties, a prominent professor in Clinical Pharmacology at the University College in London, D.R. Laurence, stated: “There are no clinically important sex differences in drug action, except, of course, to sex steroid hormones, but the subject is poorly documented. Women

  7. Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine.

    Science.gov (United States)

    Xia, Yan; Portugal, George S; Fakira, Amanda K; Melyan, Zara; Neve, Rachael; Lee, H Thomas; Russo, Scott J; Liu, Jie; Morón, Jose A

    2011-11-09

    Glutamatergic systems, including AMPA receptors (AMPARs), are involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are not fully understood. In the present study, we investigated the effects of repeated morphine administration on AMPAR expression, synaptic plasticity, and context-dependent behavioral sensitization to morphine. We found that morphine treatment produced changes of synaptic AMPAR expression in the hippocampus, a brain area that is critically involved in learning and memory. These changes could be observed 1 week after the treatment, but only when mice developed context-dependent behavioral sensitization to morphine in which morphine treatment was associated with drug administration environment. Context-dependent behavioral sensitization to morphine was also associated with increased basal synaptic transmission and disrupted hippocampal long-term potentiation (LTP), whereas these effects were less robust when morphine administration was not paired with the drug administration environment. Interestingly, some effects may be related to the prior history of morphine exposure in the drug-associated environment, since alterations of AMPAR expression, basal synaptic transmission, and LTP were observed in mice that received a saline challenge 1 week after discontinuation of morphine treatment. Furthermore, we demonstrated that phosphorylation of GluA1 AMPAR subunit plays a critical role in the acquisition and expression of context-dependent behavioral sensitization, as this behavior is blocked by a viral vector that disrupts GluA1 phosphorylation. These data provide evidence that glutamatergic signaling in the hippocampus plays an important role in context-dependent sensitization to morphine and supports further investigation of glutamate-based strategies for treating opiate addiction.

  8. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

    International Nuclear Information System (INIS)

    Cosgrove, Benjamin D.; King, Bracken M.; Hasan, Maya A.; Alexopoulos, Leonidas G.; Farazi, Paraskevi A.; Hendriks, Bart S.; Griffith, Linda G.; Sorger, Peter K.; Tidor, Bruce; Xu, Jinghai J.

    2009-01-01

    Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.

  9. Drugs, money, and power: the Canadian drug shortage.

    Science.gov (United States)

    Kaposy, Chris

    2014-03-01

    This article describes the shortage of generic injectable medications in Canada that affected hospitals in 2012. It traces the events leading up to the drug shortage, the causes of the shortage, and the responses by health administrators, pharmacists, and ethicists. The article argues that generic drug shortages are an ethical problem because health care organizations and governments have an obligation to avoid exposing patients to resource scarcity. The article also discusses some options governments could pursue in order to secure the drug supply and thereby fulfill their ethical obligations.

  10. Drug-induced apnea.

    Science.gov (United States)

    Boutroy, M J

    1994-01-01

    Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

  11. The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

    Science.gov (United States)

    El Rawas, Rana; Saria, Alois

    2016-03-01

    Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug's effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or "agonistic" versus the hostile or "antagonistic" social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence.

  12. Common drug-drug interactions in antifungal treatments for superficial fungal infections.

    Science.gov (United States)

    Gupta, Aditya K; Versteeg, Sarah G; Shear, Neil H

    2018-04-01

    Antifungal agents can be co-administered alongside several other medications for a variety of reasons such as the presence of comorbidities. Pharmacodynamic interactions such as synergistic and antagonistic interactions could be the result of co-administered medications. Pharmacokinetic interactions could also transpire through the inhibition of metabolizing enzymes and drug transport systems, altering the absorption, metabolism and excretion of co-administered medications. Both pharmacodynamic and pharmacokinetic interactions can result in hospitalization due to serious adverse effects associated with antifungal agents, lower therapeutic doses required to achieve desired antifungal activity, and prevent antifungal resistance. Areas covered: The objective of this review is to summarize pharmacodynamic and pharmacokinetic interactions associated with common antifungal agents used to treat superficial fungal infections. Pharmacodynamic and pharmacokinetic interactions that impact the therapeutic effects of antifungal agents and drugs that are influenced by the presence of antifungal agents was the context to which these antifungal agents were addressed. Expert opinion: The potential for drug-drug interactions is minimal for topical antifungals as opposed to oral antifungals as they have minimal exposure to other co-administered medications. Developing non-lipophilic antifungals that have unique metabolizing pathways and are topical applied are suggested properties that could help limit drug-drug interactions associated with future treatments.

  13. Stories of change in drug treatment

    DEFF Research Database (Denmark)

    Andersen, Ditte

    2015-01-01

    ’ (story content) and ‘the hows’ (storying process) the article presents four findings: (1) stories of change function locally as an institutional requirement; (2) professional drug treatment providers edit young people's storytelling through different techniques; (3) the narrative environment of the drug...... treatment. Building on the sociology of storytelling and ethnographic fieldwork conducted at two drug treatment institutions for young people in Denmark, this article argues that studying stories in the context of their telling brings forth novel insights. Through a narrative analysis of both ‘the whats...... treatment institution shapes how particular stories make sense of the past, present and future; and (4) storytelling in drug treatment is an interactive achievement. A fine-grained analysis illuminates in particular how some stories on gender and drug use are silenced, while others are encouraged...

  14. Context-dependent responses to neighbours and strangers in wild European rabbits (Oryctolagus cuniculus).

    Science.gov (United States)

    Monclús, Raquel; Saavedra, Irene; de Miguel, Javier

    2014-07-01

    Territorial animals defend their territories against intruders. The level of aggression directed to intruders depends on the familiarity and/or the relative threat they pose, and it could be modified by the context of the interaction. We explored in a wild social mammal, the European rabbit (Oryctolagus cuniculus), whether residents responded more aggressively to strangers or to neighbours (dear enemy or nasty neighbour effects, respectively). We simulated the intrusion of neighbours or strangers in different parts of the territory of wild European rabbits in a suburban area in central Spain. For that, we placed faecal pellets of neighbouring or stranger rabbits in the territory of 5 rabbit colonies. Resident rabbits counter-marked preferably the odour stations with stranger odour, compared to the ones with neighbour odour, and they did not make a difference between neighbour and a non-odour control stimuli. The results suggest that rabbits show a dear enemy effect. However, repeated intrusions escalated the responses of rabbits towards neighbours. The location within the territory or the sex of the stranger did not affect the level of response. We conclude that in rabbits the relative threat posed by the intruder triggers the intensity of the interaction. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Sex as a biological variable: Drug use and abuse.

    Science.gov (United States)

    Riley, Anthony L; Hempel, Briana J; Clasen, Matthew M

    2018-04-01

    The study of sex as a biological variable is a necessary emphasis across a wide array of endpoints, including basic neuroscience, medicine, mental health, physiology and behavior. The present review summarizes work from clinical and preclinical populations on sex differences in drug use and abuse, ranging from initiation to escalation/dysregulation and from drug cessation/abstinence to relapse. These differences are analyzed in the context of the addiction cycle conceptualization of Koob and his colleagues and address patterns of drug use (binge/intoxication), motivation underlying its use (withdrawal/negative affect) and likelihood and causes of craving and relapse of drug taking (preoccupation/anticipation). Following this overview, an assessment of the basis for the reported sex differences is discussed in the context of the affective (rewarding and aversive) properties of drugs of abuse and how such properties and their balance vary with sex and contribute to drug intake. Finally, the interaction of sex with several experiential (drug history) and subject (age) factors and how these interactions affect reward and aversion are discussed to highlight the importance of understanding such interactions in predicting drug use and abuse. We note that sex as a biological variable remains one of critical evaluation and that such investigations of sex differences in drug use and abuse continue and be expanded to assess all facets of their mediation, including these affective properties, how their balance may be impacted by the multiple conditions under which drugs are taken and how this overall balance affects drug use and addiction vulnerability. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Food and Drug Administration Drug Approval Process: A History and Overview.

    Science.gov (United States)

    Williams, Christopher Ty

    2016-03-01

    In this article, the processing of investigational and new drug applications is described and the standard and expedited review processes are examined. The efforts of the US Food and Drug Administration to ensure greater agency transparency and fiscal responsibility and intensify oversight during the drug development and approval process are reviewed. Often attributed to a decrease in the number of uninsured adults, both the increase in prescription drug sales and the high costs associated with bringing a new drug to market highlight the necessity for a streamlined and cost-effective process to deliver these drugs safely and effectively. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Non-medical use of prescription drugs among illicit drug users: A case study on an online drug forum.

    Science.gov (United States)

    Rönkä, Sanna; Katainen, Anu

    2017-01-01

    The non-medical use of prescription drugs is a growing phenomenon associated with increasing health-related harms. However, little is known about the drivers of this process among illicit drug users. Our aim is to show how the qualities of pharmaceutical drugs, pharmaceutical related knowledge, online communities sharing this knowledge and medical professionals mediate and transform the consumption behaviour related to pharmaceutical drugs. The data consist of discussion threads from an online drug use forum. Using actor network theory (ANT), we analysed translations that mediate the online user community's relationship with pharmaceutical drugs. Differences in experienced drug effects are explained both as a process of 'learning' and as differences in brain chemistry at the receptor level. Both science- and experience-based information are shared on best practices to optimise use, avoid adverse health effects and maximise the experience of intoxication. The expanded context of doctors' practices places stress on the medical framework for drug use. Our analysis shows how the non-medical use of psychoactive pharmaceuticals relates to joint, medicalised ideas of bodies as sites of medical experimentation, as well as to the collective process of constructing 'pharmaceutical competences' in user networks. Understandings of intoxication have increasingly been permeated with the pharmacological and scientific logic of knowledge. The forum works as a platform for harm reduction inspired exchange of knowledge. However, the user community's knowledge sharing practices can generate a shared perception of a sufficient or even superior drug use experience and knowledge. This may lead to overdoses and other risky behaviour, and thereby contribute to increased harms related to non-medical use of prescription drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Producing the 'problem of drugs': A cross national-comparison of 'recovery' discourse in two Australian and British reports.

    Science.gov (United States)

    Lancaster, Kari; Duke, Karen; Ritter, Alison

    2015-07-01

    The notion of 'recovery' as an overarching approach to drug policy remains controversial. This cross-national analysis considers how the problem of drugs was constructed and represented in two key reports on the place of 'recovery' in drug policy, critically examining how the problem of drugs (and the people who use them) are constituted in recovery discourse, and how these problematisations are shaped and disseminated. Bacchi's poststructuralist approach is applied to two documents (one in Britain and one in Australia) to analyse how the 'problem of drugs' and the people who use them are constituted: as problematic users, constraining alternative understandings of the shifting nature of drug use; as responsibilised individuals (in Britain) and as patients (in Australia); as worthy of citizenship in the context of treatment and recovery, silencing the assumption of unworthiness and the loss of rights for those who continue to use drugs in 'problematic' ways. The position of the organisations which produced the reports is considered, with the authority of both organisations resting on their status as independent, apolitical bodies providing 'evidence-based' advice. There is a need to carefully weigh up the desirable and undesirable political effects of these constructions. The meaning of 'recovery' and how it could be realised in policy and practice is still being negotiated. By comparatively analysing how the problem of drugs was produced in 'recovery' discourse in two jurisdictions, at two specific points in the policy debate, we are reminded that ways of thinking about 'problems' reflect specific contexts, and how we are invoked to think about policy responses will be dependent upon these conditions. As 'recovery' continues to evolve, opening up spaces to discuss its contested meanings and effects will be an ongoing endeavour. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Genotype distribution and treatment response among incarcerated drug-dependent patients with chronic hepatitis C infection.

    Directory of Open Access Journals (Sweden)

    Chun-Han Cheng

    Full Text Available The prevalence of hepatitis C virus (HCV infection is disproportionately high among prisoners, especially among those who are drug-dependent. However, current screening and treatment recommendations are inconsistent for this population, and appropriate care is not reliably provided. To address these problems, the present study aimed to identify unique characteristics and clinical manifestations of incarcerated patients with HCV infection. We included incarcerated patients who received treatment with pegylated-interferon combined with ribavirin at Mackay Memorial Hospital in Taitung and were serving sentences at either the Taiyuan Skill Training Institute or the Yanwan Training Institute. HCV genotypes 1 (41.4%, 3 (25.9%, and 6 (24.1% were the most prevalent in the incarcerated patients. During the study period, we analyzed treatment response among 58 incarcerated patients and compared obtained results with treatment response among 52 patients who were living in the community. Higher sustained virological response rate was observed among patients with incarceration and HCV genotype other than 1. The odds ratios (corresponding 95% confidence intervals for incarceration and genotype 1 were 2.75 (1.06-7.11 and 0.37 (0.14-0.99, respectively. Better treatment compliance among incarcerated patients might partially explain these results. The results of this study suggest that treatment of prisoners with HCV infection is feasible and effective. More appropriate and timely methods are needed to prevent HCV transmission among injection drug users inside prisons.

  20. Multifunctional pH-Responsive Folate Receptor Mediated Polymer Nanoparticles for Drug Delivery.

    Science.gov (United States)

    Cai, Xiaoqing; Yang, Xiaoye; Wang, Fang; Zhang, Chen; Sun, Deqing; Zhai, Guangxi

    2016-07-01

    Multifunctional pH-responsive folate receptor mediated targeted polymer nanoparticles (TPNps) were developed for docetaxel (DTX) delivery based on poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)poly (β-amino ester) (P123-PAE) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)-folate (P123-FA) copolymers. The DTX was loaded into the TPNps with a decent drug loading content of 15.02 ± 0.14 wt%. In vitro drug release results showed that the DTX was released from the TPNps at a pH-dependent manner. Tetrazolium dye (MTT) assay revealed that the bland polymer nanoparticles displayed almost nontoxicity at 200 μg/mL concentration. However, the DTX-loaded TPNps showed high anti-tumor activity at low IC50 (0.72 μg/mL) for MCF-7 cells following 48 h incubation. Cellular uptake experiments revealed that the TPNps had higher degree of cellular uptake than nontargeted polymer nanoparticles, indicating that the nanoparticles were internalized into the cells via FA receptor-mediated endocytosis. Moreover, the cellular uptake pathways for the FA grafted polymer were involved in energy-dependent, clathrin-mediated and caveolae-mediated endocytosis. The cell killing effect and cellular uptake of the DTX-TPNps by the MCF-7 cells were all enhanced by about two folds at pH 5.5 when compared with pH 7.4. The TPNps also significantly prolonged the in vivo retention time for the DTX. These results suggest that the biocompatible pH responsive folate-modified polymer nanoparticles present a promising safe nanosystem for intracellular targeted delivery of DTX.

  1. The Limits of Dialogue among Teachers from Different National Contexts

    Science.gov (United States)

    Shim, Jenna Min

    2015-01-01

    In this study, the author investigates the dynamics of dialogue among teachers in different national contexts based on their responses to different cultural practices. Employing Pierre Bourdieu's sociological theory of practice and his concept of habitus, the author shows that, as the teachers' responses are not entirely context-specific, they are…

  2. Incorporating Stakeholder Engagement, Financial Implications and Values in Corporate Social Responsibility: A Proposed Model from an African Context

    OpenAIRE

    Hamidu, Aminu Ahmadu; Haron, Md. Harashid; Amran, Azlan

    2017-01-01

    Corporate Social Responsibility in Africa is mainly characterised by the features of socio-economic environment like; poverty, underdevelopment, poor infrastructures, weak governmental functionaries. This makes all the drivers or motivating reasons to be an avenue for addressing issues relating to socio-economic development of communities. The motivating factors for CSR from an African context present a set of reasons to engage in CSR with a view to fulfil obligations to society. Stakeholder ...

  3. Beyond antidoping and harm minimisation: a stakeholder-corporate social responsibility approach to drug control for sport.

    Science.gov (United States)

    Mazanov, Jason

    2016-04-01

    Debate about the ethics of drug control in sport has largely focused on arguing the relative merits of the existing antidoping policy or the adoption of a health-based harm minimisation approach. A number of ethical challenges arising from antidoping have been identified, and a number of, as yet, unanswered questions remain for the maturing ethics of applying harm minimisation principles to drug control for sport. This paper introduces a 'third approach' to the debate, examining some implications of applying a stakeholder theory of corporate social responsibility (CSR) to the issue of doping in sport. The introduction of the stakeholder-CSR model creates an opportunity to challenge the two dominant schools by enabling a different perspective to contribute to the development of an ethically robust drug control for sport. 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/

  4. Impairment of context memory by β-amyloid peptide in terrestrial snail

    Directory of Open Access Journals (Sweden)

    2008-09-01

    Full Text Available We examined influence of the β-amyloid peptide (25-35 neurotoxic fragment (βAP on Helix lucorum food-aversion learning. Testing with aversively conditioned carrot showed that 2, 5, and 14 days after training the βAP-injected group responded in a significantly larger number of cases and with a significantly smaller latency than the sham-injected control group. The results demonstrate that the amyloid peptide partially impairs the learning process. In an attempt to specify what component of memory is impaired we compared responses in a context in which the snails were aversively trained, and in a neutral context. It was found that the sham-injected learned snails significantly less frequently took the aversively conditioned food in the context in which the snails were shocked, while the βAP-injected snails remembered the aversive context 2 days after associative training, but were not able to distinguish two contexts 5, and 14 days after training. In a separate series of experiments a specific context was associated with electric shock, and changes in general responsiveness were tested in two contexts several days later. It was found that the βAP-injected snails significantly increased withdrawal responses in all tested contexts, while the sham-injected control animals selectively increased responsiveness only in the context in which they were reinforced with electric shocks. These results demonstrate that the β-amyloid peptide (25-35 interferes with the learning process, and may play a significant role in behavioral plasticity and memory by selectively impairing only one

  5. Criminal offences in trans-border territories. Drug trade in the Province of Tamarugal, Chile

    Directory of Open Access Journals (Sweden)

    Alejandro Corder Tapia

    2013-01-01

    Full Text Available This research addresses the drug trade in Tamarugal Province for the years 2003 to 2010, through an analysis of crime statistics from the police (Chilean Carabineros and Police Investigations Unit, and penal system institutions (National Prison Service and the Office of the Prosecutor. The analysis of the drug trade situates the drug trafficking issue in the international context of globalization and in a border area emergency that does not necessarily correspond to the traditional definition of the nation state. The research proposes to situate this issue of criminal offence in the context of the international legal order, focusing on the specific characteristics of the Tarapacá region and its condition as a trans border territory. It also proposes to situate this issue in a regional context, as well as in terms of the efforts of the international order to control illegal trafficking of drugs.

  6. Personalized Medicine: Pharmacogenomics and Drug Development

    Directory of Open Access Journals (Sweden)

    Somayeh Mirsadeghi

    2017-03-01

    Full Text Available Personalized medicine aims is to supply the proper drug to the proper patient within the right dose. Pharmacogenomics (PGx is to recognize genetic variants that may influence drug efficacy and toxicity. All things considered, the fields cover a wide area, including basic drug discovery researches, the genetic origin of pharmacokinetics and pharmacodynamics, novel drug improvement, patient genetic assessment and clinical patient administration. At last, the objective of Pharmacogenomics is to anticipate a patient’s genetic response to a particular drug as a way of presenting the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and decrease the incidence of adverse side effect.

  7. Response of predatory mites to a herbivore-induced plant volatile: genetic variation for context-dependent behaviour.

    Science.gov (United States)

    Sznajder, Beata; Sabelis, Maurice W; Egas, Martijn

    2010-07-01

    Plants infested with herbivores release specific volatile compounds that are known to recruit natural enemies. The response of natural enemies to these volatiles may be either learned or genetically determined. We asked whether there is genetic variation in the response of the predatory mite Phytoseiulus persimilis to methyl salicylate (MeSa). MeSa is a volatile compound consistently produced by plants being attacked by the two-spotted spider mite, the prey of P. persimilis. We predicted that predators express genetically determined responses during long-distance migration where previously learned associations may have less value. Additionally, we asked whether these responses depend on odors from uninfested plants as a background to MeSa. To infer a genetic basis, we analyzed the variation in response to MeSa among iso-female lines of P. persimilis by using choice-tests that involved either (1) MeSa presented as a single compound or (2) MeSa with background-odor from uninfested lima bean plants. These tests were conducted for starved and satiated predators, i.e., two physiological states, one that approximates migration and another that mimics local patch exploration. We found variation among iso-female lines in the responses to MeSa, thus showing genetic variation for this behavior. The variation was more pronounced in the starved predators, thus indicating that P. persimilis relies on innate preferences when migrating. Background volatiles of uninfested plants changed the predators' responses to MeSa in a manner that depended on physiological state and iso-female line. Thus, it is possible to select for context-dependent behavioral responses of natural enemies to plant volatiles.

  8. Use of malaria RDTs in various health contexts across sub-Saharan Africa: a systematic review.

    Science.gov (United States)

    Boyce, Matthew R; O'Meara, Wendy P

    2017-05-18

    The World Health Organization recommends parasitological confirmation of malaria prior to treatment. Malaria rapid diagnostic tests (RDTs) represent one diagnostic method that is used in a variety of contexts to overcome limitations of other diagnostic techniques. Malaria RDTs increase the availability and feasibility of accurate diagnosis and may result in improved quality of care. Though RDTs are used in a variety of contexts, no studies have compared how well or effectively RDTs are used across these contexts. This review assesses the diagnostic use of RDTs in four different contexts: health facilities, the community, drug shops and schools. A comprehensive search of the Pubmed database was conducted to evaluate RDT execution, test accuracy, or adherence to test results in sub-Saharan Africa. Original RDT and Plasmodium falciparum focused studies conducted in formal health care facilities, drug shops, schools, or by CHWs between the year 2000 and December 2016 were included. Studies were excluded if they were conducted exclusively in a research laboratory setting, where staff from the study team conducted RDTs, or in settings outside of sub-Saharan Africa. The literature search identified 757 reports. A total of 52 studies were included in the analysis. Overall, RDTs were performed safely and effectively by community health workers provided they receive proper training. Analogous information was largely absent for formal health care workers. Tests were generally accurate across contexts, except for in drug shops where lower specificities were observed. Adherence to RDT results was higher among drug shop vendors and community health workers, while adherence was more variable among formal health care workers, most notably with negative test results. Malaria RDTs are generally used well, though compliance with test results is variable - especially in the formal health care sector. If low adherence rates are extrapolated, thousands of patients may be incorrectly

  9. Attenuated neural response to gamble outcomes in drug-naive patients with Parkinson’s disease

    DEFF Research Database (Denmark)

    van der Vegt, Joyce P M; Hulme, Oliver J; Zittel, Simone

    2013-01-01

    healthy age-matched control subjects underwent whole-brain functional magnetic resonance imaging while they performed a simple two-choice gambling task resulting in stochastic and parametrically variable monetary gains and losses. In patients with Parkinson's disease, the neural response to reward outcome......Parkinson's disease results from the degeneration of dopaminergic neurons in the substantia nigra, manifesting as a spectrum of motor, cognitive and affective deficits. Parkinson's disease also affects reward processing, but disease-related deficits in reinforcement learning are thought to emerge...... at a slower pace than motor symptoms as the degeneration progresses from dorsal to ventral striatum. Dysfunctions in reward processing are difficult to study in Parkinson's disease as most patients have been treated with dopaminergic drugs, which sensitize reward responses in the ventral striatum, commonly...

  10. Social context of HIV risk behaviours among male-to-female transgenders of colour.

    Science.gov (United States)

    Nemoto, T; Operario, D; Keatley, J; Villegas, D

    2004-08-01

    To explore the social context of drug use and sexual behaviours that put male-to-female (MTF) transgenders at risk for HIV, focus groups were conducted consisting of African American, Latina and Asian and Pacific Islander MTF transgenders (N = 48) who reside or work in San Francisco, California. Participants were likely to report having unprotected sex with primary partners to signify love and emotional connection, as well as to receive gender validation from their partners. In contrast, viewing sex work with customers as a business encouraged intentious to use condoms. Safer sex intentions with customers were frequently undermined by urgent financial needs, which stemmed from transphobia, employment discrimination and costly procedures associated with gender transition. Participants reported using drugs as a way to cope with or escape life stresses associated with relationships, sex work, transphobia and financial hardship. Interventions with at-risk MTF transgenders should address the interpersonal and social context of unsafe sex and drug use, particularly the unique roles of relationship issues with male partners, stigma, discrimination and community norms regarding sex work and drug use.

  11. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    International Nuclear Information System (INIS)

    Chintamani; Singhal, Vinay; Singh, JP; Lyall, Ashima; Saxena, Sunita; Bansal, Anju

    2004-01-01

    Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins) brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio). Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide) were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was assessed using chi-square test and coefficient

  12. Radiation and platinum drug interaction

    International Nuclear Information System (INIS)

    Nias, A.H.W.

    1985-01-01

    The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. Electron-affinic agents are employed with this aim, but the commoner platinum drugs are only weakly electron-affinic. They do have a quasi-alkylating action however, and this DNA targeting may account for the radiosensitizing effect which occurs with both pre- and post-radiation treatments. Because toxic drug dosage is usually required for this, the evidence of the biological responses to the drug and to the radiation, as well as to the combination, requires critical analysis before any claim of true enhancement, rather than simple additivity, can be accepted. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships. (author)

  13. Addressing the challenge of high-priced prescription drugs in the era of precision medicine : A systematic review of drug life cycles, therapeutic drug markets and regulatory frameworks

    NARCIS (Netherlands)

    Gronde, T.V. (Toon van der); C.A. Uyl-de Groot (Carin); Pieters, T. (Toine)

    2017-01-01

    markdownabstractCONTEXT: Recent public outcry has highlighted the rising cost of prescription drugs worldwide, which in several disease areas outpaces other health care expenditures and results in a suboptimal global availability of essential medicines. METHOD: A systematic review of Pubmed, the

  14. Narrative self-appropriation: embodiment, alienness, and personal responsibility in the context of borderline personality disorder.

    Science.gov (United States)

    Køster, Allan

    2017-12-01

    It is often emphasised that persons diagnosed with borderline personality disorder (BPD) show difficulties in understanding their own psychological states. In this article, I argue that from a phenomenological perspective, BPD can be understood as an existential modality in which the embodied self is profoundly saturated by an alienness regarding the person's own affects and responses. However, the balance of familiarity and alienness is not static, but can be cultivated through, e.g., psychotherapy. Following this line of thought, I present the idea that narrativising experiences can play an important role in processes of appropriating such embodied self-alienness. Importantly, the notion of narrative used is that of a scalar conception of narrativity as a variable quality of experience that comes in degrees. From this perspective, narrative appropriation is a process of gradually attributing the quality of narrativity to experiences, thereby familiarising the moods, affects, and responses that otherwise govern 'from behind'. Finally, I propose that the idea of a narrative appropriation of embodied self-alienness is also relevant to the much-debated question of personal responsibility in BPD, particularly as this question plays out in psychotherapeutic contexts where a narrative self-appropriation may facilitate an increase in sense of autonomy and reduce emotions of guilt and shame.

  15. Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

    Science.gov (United States)

    Strazielle, Nathalie; Ghersi-Egea, Jean-François

    2016-01-01

    The blood-brain interfaces restrict the cerebral bioavailability of pharmacological compounds. Various drug delivery strategies have been developed to improve drug penetration into the brain. Most strategies target the microvascular endothelium forming the blood-brain barrier proper. Targeting the blood-cerebrospinal fluid (CSF) barrier formed by the epithelium of the choroid plexuses in addition to the blood-brain barrier may offer added-value for the treatment of central nervous system diseases. For instance, targeting the CSF spaces, adjacent tissue, or the choroid plexuses themselves is of interest for the treatment of neuroinflammatory and infectious diseases, cerebral amyloid angiopathy, selected brain tumors, hydrocephalus or neurohumoral dysregulation. Selected CSF-borne materials seem to reach deep cerebral structures by mechanisms that need to be understood in the context of chronic CSF delivery. Drug delivery through both barriers can reduce CSF sink action towards parenchymal drugs. Finally, targeting the choroid plexus-CSF system can be especially relevant in the context of neonatal and pediatric diseases of the central nervous system. Transcytosis appears the most promising mechanism to target in order to improve drug delivery through brain barriers. The choroid plexus epithelium displays strong vesicular trafficking and secretory activities that deserve to be explored in the context of cerebral drug delivery. Folate transport and exosome release into the CSF, plasma protein transport, and various receptor-mediated endocytosis pathways may prove useful mechanisms to exploit for efficient drug delivery into the CSF. This calls for a clear evaluation of transcytosis mechanisms at the blood-CSF barrier, and a thorough evaluation of CSF drug delivery rates. PMID:27464721

  16. Functionalization of Strongly Interacting Magnetic Nanocubes with (Thermo)responsive Coating and their Application in Hyperthermia and Heat-Triggered Drug Delivery

    KAUST Repository

    Kakwere, Hamilton; Pernia Leal, Manuel; Materia, Maria-Elena; Curcio, Alberto; Guardia, Pablo; Niculaes, Dina; Marotta, Roberto; Falqui, Andrea; Pellegrino, Teresa

    2015-01-01

    Herein we prepare nanohybrids by incorporating iron oxide nanocubes (cubic-IONPs) within a thermo-responsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR) but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermo-responsive shell is composed of poly(N-isopropyl acrylamide-co-polyethylene glycolmethylether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 °C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 °C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes.

  17. Functionalization of Strongly Interacting Magnetic Nanocubes with (Thermo)responsive Coating and their Application in Hyperthermia and Heat-Triggered Drug Delivery

    KAUST Repository

    Kakwere, Hamilton

    2015-04-03

    Herein we prepare nanohybrids by incorporating iron oxide nanocubes (cubic-IONPs) within a thermo-responsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR) but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermo-responsive shell is composed of poly(N-isopropyl acrylamide-co-polyethylene glycolmethylether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 °C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 °C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes.

  18. Do national drug policies influence antiretroviral drug prices? Evidence from the Southern African Development community.

    Science.gov (United States)

    Liu, Yao; Galárraga, Omar

    2017-03-01

    The efficacy of low- and middle-income countries’ (LMIC) national drug policies in managing antiretroviral (ARV) pharmaceutical prices is not well understood. Though ARV drug prices have been declining in LMIC over the past decade, little research has been done on the role of their national drug policies. This study aims to (i) analyse global ARV prices from 2004 to 2013 and (ii) examine the relationship of national drug policies to ARV prices. Analysis of ARV drug prices utilized data from the Global Price Reporting Mechanism from the World Health Organization (WHO). Ten of the most common ARV drugs (first-line and second-line) were selected. National drug policies were also assessed for 12 countries in the South African Development Community (SADC), which self-reported their policies through WHO surveys. The best predictor of ARV drug price was generic status—the generic versions of 8 out of 10 ARV drugs were priced lower than branded versions. However, other factors such as transaction volume, HIV prevalence, national drug policies and PEPFAR/CHAI involvement were either not associated with ARV drug price or were not consistent predictors of price across different ARV drugs. In the context of emerging international trade agreements, which aim to strengthen patent protections internationally and potentially delay the sale of generic drugs in LMIC, this study shines a spotlight on the importance of generic drugs in controlling ARV prices. Further research is needed to understand the impact of national drug policies on ARV prices.

  19. Federal Strategy for Prevention of Drug Abuse and Drug Trafficking, 1982. Prepared for the President Pursuant to the Drug Abuse Office and Treatment Act of 1972.

    Science.gov (United States)

    Office of Policy Development, Washington, DC.

    This document describes the Federal response to drug abuse and drug trafficking. The actions of President Reagan, in Executive Order 12368, establishing an official advisor on drug abuse policy matters, and the priorities, issues, and objectives (international cooperation, drug law enforcement, education and prevention, detoxification and…

  20. Value relevance and corporate responsibility reporting in the South African context: An alternate view post King-III

    Directory of Open Access Journals (Sweden)

    Adrian Marcia

    2015-11-01

    Full Text Available This study tests for the value relevance of corporate responsibility reporting (CRR based on a sample of companies listed on the Johannesburg Stock Exchange (JSE. It also provides evidence of the statistical significance of the potential contribution of CRR to share price values in the South African context at a particular point. On the basis of a sample of 82 companies on the JSE, hierarchical regression analysis was used to test the contribution of levels of corporate social responsibility disclosures to company share prices, over and above the contribution of the size of a firm’s equity and net income. In contrast with other findings which predict a positive relationship between company share price and levels of corporate social responsibility disclosures, the latter are found to have no significant association with company share price over and above the associations of the size of a firm’s equity and net income. Bivariate associations, however, indicate a significant association between share price and levels of corporate social responsibility disclosures. On the basis of these findings, it is argued that disclosures increase for firms with larger endowments of equity, yet corporate social responsibility disclosures do not necessarily add value to company share price.

  1. A systematic study on drug-response associated genes using baseline gene expressions of the Cancer Cell Line Encyclopedia

    Science.gov (United States)

    Liu, Xiaoming; Yang, Jiasheng; Zhang, Yi; Fang, Yun; Wang, Fayou; Wang, Jun; Zheng, Xiaoqi; Yang, Jialiang

    2016-03-01

    We have studied drug-response associated (DRA) gene expressions by applying a systems biology framework to the Cancer Cell Line Encyclopedia data. More than 4,000 genes are inferred to be DRA for at least one drug, while the number of DRA genes for each drug varies dramatically from almost 0 to 1,226. Functional enrichment analysis shows that the DRA genes are significantly enriched in genes associated with cell cycle and plasma membrane. Moreover, there might be two patterns of DRA genes between genders. There are significantly shared DRA genes between male and female for most drugs, while very little DRA genes tend to be shared between the two genders for a few drugs targeting sex-specific cancers (e.g., PD-0332991 for breast cancer and ovarian cancer). Our analyses also show substantial difference for DRA genes between young and old samples, suggesting the necessity of considering the age effects for personalized medicine in cancers. Lastly, differential module and key driver analyses confirm cell cycle related modules as top differential ones for drug sensitivity. The analyses also reveal the role of TSPO, TP53, and many other immune or cell cycle related genes as important key drivers for DRA network modules. These key drivers provide new drug targets to improve the sensitivity of cancer therapy.

  2. Adulteration Practices of Psychoactive Illicit Drugs: An Updated Review.

    Science.gov (United States)

    Solimini, Renata; Rotolo, Maria C; Pellegrini, Manuela; Minutillo, Adele; Pacifici, Roberta; Busardò, Francesco P; Zaami, Simona

    2017-01-01

    Powdery drugs such as cocaine and heroin are frequently adulterated or diluted predominantly to obtain more doses and to increase the drug dealer's profits, but also to enhance, to modify or to oppose drug effects. The aim of this report is to provide an overview of the recent scientific literature on medicines as well as on new psychoactive substances, used as cutting agents (i.e. pharmacologically active adulterants) and on the related adverse health effects on consumers, possibly due to the synergistic effect of the adulterants laced with substances of abuse. A literature search up to January 2017 was performed on MEDLINE, Scopus and Web of Science and reports and documents of international agencies or institutions were also searched. Pharmacologically active substances such as: paracetamol, caffeine, dextromethorphan, clenbuterol for heroin; levamisole, phenacetine, lidocaine, hydroxyzine and diltiazem for cocaine; caffeine and phentermine for amphetamine, have been identified over the years. Furthermore, since cocaine and morphine (this latter as a precursor of heroin) are both extracted from natural products, some impurities and minor alkaloids can be present in the final preparation. In this context, it is worth considering that new psychoactive substances are also used as cutting agents. The wide availability of illicit psychotropic drugs is the most serious hazard threatening consumers. Indeed emergency departments are often responsible in evaluating damages caused not only by the base substance, but also by other eventual compounds added to mimic or antagonize drug effects or simply dilute the drug amount, with a possible harmful synergic toxic action. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Police bribery and access to methadone maintenance therapy within the context of drug policy reform in Tijuana, Mexico.

    Science.gov (United States)

    Werb, D; Wagner, K D; Beletsky, L; Gonzalez-Zuniga, Patricia; Rangel, Gudelia; Strathdee, S A

    2015-03-01

    In 2009, Mexico passed legislation to decriminalize drug possession and improve access to addiction treatment. We undertook research to assess the implementation of the reform among a cohort of people who inject drugs (PWID) in Tijuana. This study specifically sought to determine whether discretionary policing practices like extortion impact access to methadone maintenance therapy (MMT) in Tijuana, a city characterized by high levels of drug-related harms. Generalized estimating equation analyses were used to construct longitudinal confounding models to determine the association between paying a police bribe and MMT enrolment among PWID in Tijuana enrolled in a prospective cohort study. Outcome of interest was MMT enrolment in the past six months. Data on police interactions and MMT enrolment were also obtained. Between October, 2011 and September, 2013, 637 participants provided 1825 observations, with 143 (7.8%) reports of MMT enrolment during the study period. In a final confounding model, recently reporting being forced to pay a bribe to police was significantly associated with an increased likelihood of accessing MMT (adjusted odds ratio=1.69, 95% confidence interval: 1.02-2.81, p=0.043). However, in 56 (39.2%) cases, MMT enrolment ceased within six months. The majority of participant responses cited the fact that MMT was too expensive (69.1%). Levels of MMT access were low. PWID who experienced police extortion were more likely to access MMT at baseline, though this association decreased during the study period. Coupled with the costs of MMT, this may compromise MMT retention among PWID. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. [The issue of harm reduction in Polish legislation concerning drug addiction. A comparative study].

    Science.gov (United States)

    Sobeyko, Justyna

    2008-01-01

    The aim of work is the assessment of legal permissibility for health and social harm reduction programmes resulting from drug use in the context of the polish legislation on narcotic drug use and drug addiction. The thesis outlines harm reduction programmes implemented worldwide, role of penal code in counteracting both narcotic drug supply and demand, attitude of United Nations and European Union to the drug problem including harm reduction programmes, solutions adopted in the selected European Union member states. The main part of the thesis presents the evolution of polish legislation regarding drug use and analysis of legal permissibility for harm reduction programmes in this context. The conclusion inferred is the statement that implementation of the harm reduction programmes requires a certain minimal depenalisation of the drug use by a legislator and the fact that restrictive legal system impedes programme realization. Thus the thesis postulates depenalisation of small drug quantities for personal use.

  5. Age and the purchase of prescription drug insurance by older adults.

    Science.gov (United States)

    Szrek, Helena; Bundorf, M Kate

    2011-06-01

    The Medicare Part D Prescription Drug Program places an unprecedented degree of choice in the hands of older adults despite concerns over their ability to make effective decisions and desire to have extensive choice in this context. While previous research has compared older adults to younger adults along these dimensions, our study, in contrast, examines how likelihood to delay decision making and preferences for choice differ by age among older age cohorts. Our analysis is based on responses of older adults to a simulation of enrollment in Medicare Part D. We examine how age, numeracy, cognitive reflection, and the interaction between age and performance on these instruments are related to the decision to enroll in a Medicare prescription drug plan and preference for choice in this context. We find that numeracy and cognitive reflection are positively associated with enrollment likelihood and that they are more important determinants of enrollment than age. We also find that greater numeracy is associated with a lower willingness to pay for choice. Hence, our findings raise concern that older adults, and, in particular, those with poorer numerical processing skills, may need extra support in enrolling in the program: they are less likely to enroll than those with stronger numerical processing skills, even though they show greater willingness to pay for choice. (c) 2011 APA, all rights reserved.

  6. The Expected Net Present Value of Developing Weight Management Drugs in the Context of Drug Safety Litigation.

    Science.gov (United States)

    Chawla, Anita; Carls, Ginger; Deng, Edmund; Tuttle, Edward

    2015-07-01

    Following withdrawals, failures, and significant litigation settlements, drug product launches in the anti-obesity category slowed despite a large and growing unmet need. Litigation concerns, a more risk-averse regulatory policy, and the difficulty of developing a product with a compelling risk-benefit profile in this category may have limited innovators' expected return on investment and restricted investment in this therapeutic area. The objective of the study was to estimate perceived manufacturer risk associated with product safety litigation and increased development costs vs. revenue expectations on anticipated return on investment and to determine which scenarios might change a manufacturer's investment decision. Expected net present value of a weight-management drug entering pre-clinical trials was calculated for a range of scenarios representing evolving expectations of development costs, revenue, and litigation risk over the past 25 years. These three factors were based on published estimates, historical data, and analogs from other therapeutic areas. The main driver in expected net present value calculations is expected revenue, particularly if one assumes that litigation risk and demand are positively correlated. Changes in development costs associated with increased regulatory concern with potential safety issues for the past 25 years likely did not impact investment decisions. Regulatory policy and litigation risk both played a role in anti-obesity drug development; however, product revenue-reflecting efficacy at acceptable levels of safety-was by far the most important factor. To date, relatively modest sales associated with recent product introductions suggest that developing a product that is sufficiently efficacious with an acceptable level of safety continues to be the primary challenge in this market.

  7. Imaging drugs with and without clinical analgesic efficacy.

    Science.gov (United States)

    Upadhyay, Jaymin; Anderson, Julie; Schwarz, Adam J; Coimbra, Alexandre; Baumgartner, Richard; Pendse, G; George, Edward; Nutile, Lauren; Wallin, Diana; Bishop, James; Neni, Saujanya; Maier, Gary; Iyengar, Smriti; Evelhoch, Jeffery L; Bleakman, David; Hargreaves, Richard; Becerra, Lino; Borsook, David

    2011-12-01

    The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

  8. Drug development in neuropsychopharmacology.

    Science.gov (United States)

    Fritze, Jürgen

    2008-03-01

    Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

  9. Sex, drugs and moral goals: reproductive strategies and views about recreational drugs

    Science.gov (United States)

    Kurzban, Robert; Dukes, Amber; Weeden, Jason

    2010-01-01

    Humans, unlike most other species, show intense interest in the activities of conspecifics, even when the activities in question pose no obvious fitness threat or opportunity. Here, we investigate one content domain in which people show substantial interest, the use of drugs for non-medical purposes. Drawing from two subject populations—one undergraduate and one Internet-based—we look at the relationships among (i) abstract political commitments; (ii) attitudes about sexuality; and (iii) views surrounding recreational drugs. Whereas some theories suggest that drug views are best understood as the result of abstract political ideology, we suggest that these views can be better understood in the context of reproductive strategy. We show that, as predicted by a strategic construal, drug attitudes are best predicted by sexual items rather than abstract political commitments and, further, that the relationship between factors such as political ideology and drugs, while positive, are reduced to zero or nearly zero when items assessing sexuality are controlled for. We conclude that considering morality from the standpoint of strategic interests is a potentially useful way to understand why humans care about third party behaviour. PMID:20554547

  10. International Guidelines on Human Rights and Drug Control: A Tool for Securing Women's Rights in Drug Control Policy.

    Science.gov (United States)

    Schleifer, Rebecca; Pol, Luciana

    2017-06-01

    Discrimination and inequality shape women's experiences of drug use and in the drug trade and the impact of drug control efforts on them, with disproportionate burdens faced by poor and otherwise marginalized women. In recent years, UN member states and UN drug control and human rights entities have recognized this issue and made commitments to integrate a 'gender perspective' into drug control policies, with 'gender' limited to those conventionally deemed women. But the concept of gender in international law is broader, rooted in socially constructed and culturally determined norms and expectations around gender roles, sex, and sexuality. Also, drug control policies often fail to meaningfully address the specific needs and circumstances of women (inclusively defined), leaving them at risk of recurrent violations of their rights in the context of drugs. This article explores what it means to 'mainstream' this narrower version of gender into drug control efforts, using as examples various women's experiences as people who use drugs, in the drug trade, and in the criminal justice system. It points to international guidelines on human rights and drug control as an important tool to ensure attention to women's rights in drug control policy design and implementation.

  11. Drug-perturbation-based stratification of blood cancer

    Science.gov (United States)

    Dietrich, Sascha; Lu, Junyan; Wu, Bian; Hüllein, Jennifer; da Silva Liberio, Michelle; Walther, Tatjana; Wagner, Lena; Rabe, Sophie; Ghidelli-Disse, Sonja; Bantscheff, Marcus; Słabicki, Mikołaj; Mock, Andreas; Oakes, Christopher C.; Wang, Shihui; Oppermann, Sina; Lukas, Marina; Kim, Vladislav; Sill, Martin; Jauch, Anna; Sutton, Lesley Ann; Rosenquist, Richard; Liu, Xiyang; Jethwa, Alexander; Lee, Kwang Seok; Lewis, Joe; Putzker, Kerstin; Lutz, Christoph; Rossi, Davide; Oellerich, Thomas; Herling, Marco; Nguyen-Khac, Florence; Plass, Christoph; von Kalle, Christof; Ho, Anthony D.; Hensel, Manfred; Dürig, Jan; Ringshausen, Ingo; Huber, Wolfgang

    2017-01-01

    As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care. PMID:29227286

  12. What you find depends on where you look: responses to proximate habitat vary with landscape context

    Directory of Open Access Journals (Sweden)

    Mary Ann Cunningham

    2016-12-01

    Full Text Available There is persistent interest in understanding responses of passerine birds to habitat fragmentation, but research findings have been inconsistent and sometimes contradictory in conclusions about how birds respond to characteristics of sites they occupy, such as habitat patch size or edge density. We examined whether these inconsistencies could result from differences in the amount of habitat in the surrounding landscape, e.g., for woodland birds, the amount of tree cover in the surrounding landscape. We compared responses of 22 woodland bird species to proximate-scale tree cover in open landscapes versus wooded landscapes. Our main expectation was that woodland birds would tolerate less suitable sites (less tree cover at the site scale in open environments where they had little choice-where little tree cover was available in the surrounding area. We compared responses using logistic regression coefficients and loess plots in open and wooded landscapes in eastern North Dakota, USA. Responses to proximate-scale tree cover were stronger, not weaker, as expected, in open landscapes. In some cases the sign of the response changed from positive to negative in contrasting landscapes. We draw two conclusions: First, observed responses to proximate habitat measures such as habitat extent or edge density cannot be interpreted reliably unless landscape context is specified. Second, birds appear more selective, not less so, where habitat is sparse. Habitat loss and fragmentation at the landscape scale are likely to reduce the usefulness of local habitat conservation, and regional drivers in land-use change can have important effects for site-scale habitat use.

  13. Addressing the challenge of high-priced prescription drugs in the era of precision medicine : a systematic review of drug life cycles, therapeutic drug markets and regulatory frameworks.

    NARCIS (Netherlands)

    van der Gronde, T.; Uyl-de Groot, Carin A; Pieters, A.H.L.M.

    2017-01-01

    Context. Recent public outcry has highlighted the rising cost of prescription drugs worldwide, which in several disease areas outpaces other health care expenditures and results in a suboptimal global availability of essential medicines. Method. A systematic review of Pubmed, the Financial Times,

  14. Intra- and interspecies gene expression models for predicting drug response in canine osteosarcoma.

    Science.gov (United States)

    Fowles, Jared S; Brown, Kristen C; Hess, Ann M; Duval, Dawn L; Gustafson, Daniel L

    2016-02-19

    Genomics-based predictors of drug response have the potential to improve outcomes associated with cancer therapy. Osteosarcoma (OS), the most common primary bone cancer in dogs, is commonly treated with adjuvant doxorubicin or carboplatin following amputation of the affected limb. We evaluated the use of gene-expression based models built in an intra- or interspecies manner to predict chemosensitivity and treatment outcome in canine OS. Models were built and evaluated using microarray gene expression and drug sensitivity data from human and canine cancer cell lines, and canine OS tumor datasets. The "COXEN" method was utilized to filter gene signatures between human and dog datasets based on strong co-expression patterns. Models were built using linear discriminant analysis via the misclassification penalized posterior algorithm. The best doxorubicin model involved genes identified in human lines that were co-expressed and trained on canine OS tumor data, which accurately predicted clinical outcome in 73 % of dogs (p = 0.0262, binomial). The best carboplatin model utilized canine lines for gene identification and model training, with canine OS tumor data for co-expression. Dogs whose treatment matched our predictions had significantly better clinical outcomes than those that didn't (p = 0.0006, Log Rank), and this predictor significantly associated with longer disease free intervals in a Cox multivariate analysis (hazard ratio = 0.3102, p = 0.0124). Our data show that intra- and interspecies gene expression models can successfully predict response in canine OS, which may improve outcome in dogs and serve as pre-clinical validation for similar methods in human cancer research.

  15. Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Vik-Mo Audun O

    2006-10-01

    Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

  16. Provider and pharmacist responses to warfarin drug–drug interaction alerts: a study of healthcare downstream of CPOE alerts

    Science.gov (United States)

    Boro, Maureen S; Korman, Nancy E; Davoren, J Ben

    2011-01-01

    Objective To categorize the appropriateness of provider and pharmacist responses to warfarin critical drug–drug interaction (cDDI) alerts, assess responses and actions to the cDDI, and determine the occurrence of warfarin adverse drug events (ADE) after alerts. Design An 18-month, retrospective study of acute care admissions at a single Veterans Affairs medical center using computerized provider order entry (CPOE). Measurements Patients included had at least one warfarin cDDI alert. Chart reviews included baseline laboratory values and demographics, provider actions, patient outcomes, and associated factors, including other interacting medications and number of simultaneously processed alerts. Results 137 admissions were included (133 unique patients). Amiodarone, vitamin E in a multivitamin, sulfamethoxazole, and levothyroxine accounted for 75% of warfarin cDDI. Provider responses were clinically appropriate in 19.7% of admissions and pharmacist responses were appropriate in 9.5% of admissions. There were 50 ADE (36.6% of admissions) with warfarin; 80% were rated as having no or mild clinical effect. An increased number of non-critical alerts at the time of the reference cDDI alert was the only variable associated with an inappropriate provider response (p=0.01). Limitations This study was limited by being a retrospective review and the possibility of confounding variables, such as other interacting medications. Conclusion The large number of CPOE alerts may lead to inappropriate responses by providers and pharmacists. The high rate of ADE suggests a need for improved medication management systems for patients on warfarin. This study highlights the possibility of alert fatigue contributing to the high prevalence of inappropriate alert over-ride text responses. PMID:22037888

  17. When 'drugs' become 'drugs': issues of pharmaceutical abuse in France from the 1960s to the 1990s.

    Science.gov (United States)

    Marchant, Alexandre

    2014-01-01

    Since the 1970s, media frenzies about drug addiction have focused mainly on illicit drugs taken by rebellious or marginalised addicts, relegating iatrogenic drug abuse, and policies and problems linked to psychotropic pharmaceuticals available by prescription or over-the-counter to the shadows. In this article I go beyond the division between illicit drugs and medicines still configuring both public representations and historiography: using archival materials from the 1960s-1990s in France, I highlight some blind spots in drug history. Firstly I demonstrate the role of pharmaceutical abuse in the career of addicts, and then examine regulation policies, which are the dark side, however complementary, of drug policies and prohibition. Finally, I analyse the role of physicians and pharmacists in this control, and discuss the various professional debates relating to the legal supply of psychoactive drugs. In all these issues, the frame of the Cold War context will also be highlighted.

  18. Dual stimuli-responsive nano-vehicles for controlled drug delivery: mesoporous silica nanoparticles end-capped with natural chitosan.

    Science.gov (United States)

    Hakeem, Abdul; Duan, Ruixue; Zahid, Fouzia; Dong, Chao; Wang, Boya; Hong, Fan; Ou, Xiaowen; Jia, Yongmei; Lou, Xiaoding; Xia, Fan

    2014-11-11

    Herein, we report natural chitosan end-capped MCM-41 type MSNPs as novel, dual stimuli, responsive nano-vehicles for controlled anticancer drug delivery. The chitosan nanovalves tightly close the pores of the MSNPs to control premature cargo release under physiological conditions but respond to lysozyme and acidic media to release the trapped cargo.

  19. Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

    Science.gov (United States)

    Kutlu, Munir Gunes

    2016-01-01

    It has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms. In this review, we explored these hypotheses and the involvement of the hippocampus in the development and maintenance of addiction to widely abused drugs such as cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Studies suggest that initial exposure to stimulants (i.e., cocaine, nicotine, and amphetamine) and alcohol may enhance hippocampal function and, therefore, the formation of augmented drug-context associations that contribute to the development of addiction. In line with the self-medication hypothesis, withdrawal from stimulants, ethanol, and cannabis results in hippocampus-dependent learning and memory deficits, which suggest that an attempt to alleviate these deficits may contribute to relapse to drug use and maintenance of addiction. Interestingly, opiate withdrawal leads to enhancement of hippocampus-dependent learning and memory. Given that a conditioned aversion to drug context develops during opiate withdrawal, the cognitive enhancement in this case may result in the formation of an augmented association between withdrawal-induced aversion and withdrawal context. Therefore, individuals with opiate addiction may return to opiate use to avoid aversive symptoms triggered by the withdrawal context. Overall, the systematic examination of the role of the hippocampus in drug addiction may help to formulate a better understanding of addiction and underlying neural substrates. PMID:27634143

  20. Responsible vendors, intelligent consumers: Silk Road, the online revolution in drug trading.

    Science.gov (United States)

    Van Hout, Marie Claire; Bingham, Tim

    2014-03-01

    Silk Road is located on the Deep Web and provides an anonymous transacting infrastructure for the retail of drugs and pharmaceuticals. Members are attracted to the site due to protection of identity by screen pseudonyms, variety and quality of product listings, selection of vendors based on reviews, reduced personal risks, stealth of product delivery, development of personal connections with vendors in stealth modes and forum activity. The study aimed to explore vendor accounts of Silk Road as retail infrastructure. A single and holistic case study with embedded units approach (Yin, 2003) was chosen to explore the accounts of vendor subunits situated within the Silk Road marketplace. Vendors (n=10) completed an online interview via the direct message facility and via Tor mail. Vendors described themselves as 'intelligent and responsible' consumers of drugs. Decisions to commence vending operations on the site centred on simplicity in setting up vendor accounts, and opportunity to operate within a low risk, high traffic, high mark-up, secure and anonymous Deep Web infrastructure. The embedded online culture of harm reduction ethos appealed to them in terms of the responsible vending and use of personally tested high quality products. The professional approach to running their Silk Road businesses and dedication to providing a quality service was characterised by professional advertising of quality products, professional communication and visibility on forum pages, speedy dispatch of slightly overweight products, competitive pricing, good stealth techniques and efforts to avoid customer disputes. Vendors appeared content with a fairly constant buyer demand and described a relatively competitive market between small and big time market players. Concerns were evident with regard to Bitcoin instability. The greatest threat to Silk Road and other sites operating on the Deep Web is not law enforcement or market dynamics, it is technology itself. Copyright © 2013 Elsevier

  1. Regulating drug release from pH- and temperature-responsive electrospun CTS-g-PNIPAAm/poly(ethylene oxide) hydrogel nanofibers

    International Nuclear Information System (INIS)

    Yuan, Huihua; Li, Biyun; Liang, Kai; Lou, Xiangxin; Zhang, Yanzhong

    2014-01-01

    Temperature- and pH-responsive polymers have been widely investigated as smart drug release systems. However, dual-sensitive polymers in the form of nanofibers, which is advantageous in achieving rapid transfer of stimulus to the smart polymeric structures for regulating drug release behavior, have rarely been explored. In this study, chitosan-graft-poly(N-isopropylacrylamide) (CTS-g-PNIPAAm) copolymer was synthesized by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxy succinimide (NHS) as grafting agents to graft carboxyl-terminated PNIPAAm (PNIPAAm-COOH) chains onto the CTS biomacromolecules, and then CTS-g-PNIPAAm with or without bovine serum albumin (BSA) was fabricated into nanofibers through electrospinning using poly(ethylene oxide) (PEO, 10 wt%) as a fiber-forming facilitating additive. The BSA laden CTS-g-PNIPAAm/PEO hydrogel nanofibers were tested to determine their drug release profiles by varying pH and temperature. Finally, cytotoxicity of the CTS-g-PNIPAAm/PEO hydrogel nanofibers was evaluated by assaying the L929 cell proliferation using the MTT method. It was found that the synthesized CTS-g-PNIPAAm possessed a temperature-induced phase transition and lower critical solution temperature (LCST) at 32° C in aqueous solutions. The rate of BSA release could be well modulated by altering the environmental pH and temperature of the hydrogel nanofibers. The CTS-g-PNIPAAm/PEO hydrogel nanofibers supported L929 cell growth, indicative of appropriate cytocompatibility. Our current work could pave the way towards developing multi-stimuli responsive nanofibrous smart materials for potential applications in the fields of drug delivery and tissue engineering. (paper)

  2. pH- and ion-sensitive polymers for drug delivery

    Science.gov (United States)

    Yoshida, Takayuki; Lai, Tsz Chung; Kwon, Glen S; Sako, Kazuhiro

    2013-01-01

    Introduction Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. Areas covered Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. Expert opinion Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients. PMID:23930949

  3. pH- and ion-sensitive polymers for drug delivery.

    Science.gov (United States)

    Yoshida, Takayuki; Lai, Tsz Chung; Kwon, Glen S; Sako, Kazuhiro

    2013-11-01

    Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.

  4. A new method to assess Pavlovian conditioning of psychostimulant drug effects.

    Science.gov (United States)

    Damianopoulos, E N; Carey, R J

    1994-07-01

    Experimental studies of psychoactive drugs by pavlovian drug-conditioning methods, which originally began with investigations of drug-induced responses mediated by the autonomic nervous system, have now been expanded to include drug-induced response effects expressed as modulations of spontaneous motoric behaviors. In the latter application, however, equivalent behavioral response outcomes in post-treatment tests for conditioning can occur following a psychostimulant drug treatment either through drug interference effects on habituation processes, drug-induced stress effects and/or by pavlovian conditioning of the drug-induced motoric activation effect. Current methodologies for the study of pavlovian conditioned drug effects and/or drug sensitization cannot distinguish among these possibilities. This methodological inadequacy was addressed by a modification of the conventional paired-unpaired treatment protocol. In the new protocol, the animal is sequentially placed into two test compartments with the drug treatment administered in conjunction with placement into the second test compartment. This design permits a differentiation of a pavlovian conditioned drug responses from non-conditioned drug effects through continuous measurement of the non-drug behavioral baseline in both the drug and non-drug control treatment groups combined with multiple response measurements and post-treatment tests for conditioning at variable post-conditioning intervals. The present study details the use of the new modified pavlovian protocol with repeated cocaine (10 mg/kg) treatment. A cocaine conditioned response at 1, 7, and 21 days post-conditioning was identified and distinguished from habituation and stress effects.

  5. A Multiyear Assessment of Public Response to a Statewide Drug Take-Back and Disposal Campaign, 2010 to 2012.

    Science.gov (United States)

    Yanovitzky, Itzhak

    2017-08-01

    This study is the first to analyze public response to a drug take-back program, the American Medicine Chest Challenge, in a single state over a period of 3 years (2010-2012). The study utilized a three-wave repeated cross-sectional design and an annual phone survey conducted with a representative sample of adults ( N = 906 in 2010, N = 907 in 2011, and N = 906 in 2012), which assessed exposure to the campaign, drug disposal behaviors, possible mediators of campaign effects (risk appraisal, personal agency, normative influence, and interpersonal talk), and potential confounders. Logistic regression and causal mediation analysis were employed to estimate confounder-adjusted direct and mediated effects of the campaign. Results showed that the campaign reached a sizable portion (50% to 60%) of state adults and that campaign exposure was associated with increased likelihood of having conversations with others about this topic. About 55% of all adults in the state reported taking at least one of the actions recommended by the campaign, and campaign exposure was associated with increased likelihood of disposing of prescription drugs at a drug collection day event (adjusted odds ratio = 4) and of talking to a child about the risks associated with prescription drug abuse (adjusted odds ratio = 2). The causal mediation analysis demonstrated that the campaign influenced audiences by reinforcing their efficacy to safely dispose of prescription drugs, but also potentially by stimulating conversations among community members about this topic. Drug take-back campaigns can be an effective mechanism to decrease the availability of prescription drugs in communities.

  6. Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016.

    Directory of Open Access Journals (Sweden)

    Arif Khan

    Full Text Available Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension.For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms. Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures.Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018 and effect size (R2 = 0.013, p = 0.187 drug-placebo difference (R2 = 0.013, p = 0.182 and success rate (134/142, 94.4% have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, p<0.001. Treatment arms are likely overpowered with sample sizes increasing over time (R2 = 0.387, p<0.0001 and stable, large effect sizes (0.78 ±0.37. The exploratory analysis of sample size, trial duration, baseline blood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877, antihypertensive-placebo differences (p = 0.752, or p-values (p = 0.963 but was correlated with antihypertensive response

  7. Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016

    Science.gov (United States)

    Fahl Mar, Kaysee; Schilling, Joshua; Brown, Walter A.

    2018-01-01

    Background Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension. Method For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms). Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures. Results Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018) and effect size (R2 = 0.013, p = 0.187) drug-placebo difference (R2 = 0.013, p = 0.182) and success rate (134/142, 94.4%) have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, parms are likely overpowered with sample sizes increasing over time (R2 = 0.387, pblood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877), antihypertensive-placebo differences (p = 0.752), or p-values (p = 0.963) but was correlated with antihypertensive response (R2 = 0.347, p<0.0001). Conclusions As hypothesized, this study shows that placebo response is increasing in clinical

  8. Comparative Analysis and Predictors of 10-year Tumor Necrosis Factor Inhibitors Drug Survival in Patients with Spondyloarthritis: First-year Response Predicts Longterm Drug Persistence.

    Science.gov (United States)

    Flouri, Irini D; Markatseli, Theodora E; Boki, Kyriaki A; Papadopoulos, Ioannis; Skopouli, Fotini N; Voulgari, Paraskevi V; Settas, Loukas; Zisopoulos, Dimitrios; Iliopoulos, Alexios; Geborek, Pierre; Drosos, Alexandros A; Boumpas, Dimitrios T; Sidiropoulos, Prodromos

    2018-04-01

    To evaluate the 10-year drug survival of the first tumor necrosis factor inhibitor (TNFi) administered to patients with spondyloarthritis (SpA) overall and comparatively between SpA subsets, and to identify predictors of drug retention. Patients with SpA in the Hellenic Registry of Biologic Therapies, a prospective multicenter observational cohort, starting their first TNFi between 2004-2014 were analyzed. Kaplan-Meier curves and Cox regression models were used. Overall, 404 out of 1077 patients (37.5%) discontinued treatment (followup: 4288 patient-yrs). Ten-year drug survival was 49%. In the unadjusted analyses, higher TNFi survival was observed in patients with ankylosing spondylitis (AS) compared to undifferentiated SpA and psoriatic arthritis [PsA; significant beyond the first 2.5 (p = 0.003) years and 7 years (p < 0.001), respectively], and in patients treated for isolated axial versus peripheral arthritis (p = 0.001). In all multivariable analyses, male sex was a predictor for longer TNFi survival. Use of methotrexate (MTX) was a predictor in PsA and in patients with peripheral arthritis. Absence of peripheral arthritis and use of a monoclonal antibody (as opposed to non-antibody TNFi) independently predicted longer TNFi survival in axial disease because of lower rates of inefficacy. Achievement of major responses during the first year in either axial or peripheral arthritis was the strongest predictor of longer therapy retention (HR 0.33, 95% CI 0.26-0.41 for Ankylosing Spondylitis Disease Activity Score inactive disease, and HR 0.35, 95% CI 0.24-0.50 for 28-joint Disease Activity Score remission). The longterm retention of the first TNFi administered to patients with SpA is high, especially for males with axial disease. The strongest predictor of longterm TNFi survival is a major response within the first year of treatment.

  9. Impact of the Enhanced Permeability and Retention (EPR Effect and Cathepsins Levels on the Activity of Polymer-Drug Conjugates

    Directory of Open Access Journals (Sweden)

    Amit K. Rajora

    2014-08-01

    Full Text Available Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR effect and (ii the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B. Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates. An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer, although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

  10. Prefrontal neurons encode context-based response execution and inhibition in reward seeking and extinction

    Science.gov (United States)

    Moorman, David E.; Aston-Jones, Gary

    2015-01-01

    The prefrontal cortex (PFC) guides execution and inhibition of behavior based on contextual demands. In rodents, the dorsal/prelimbic (PL) medial PFC (mPFC) is frequently considered essential for execution of goal-directed behavior (“go”) whereas ventral/infralimbic (IL) mPFC is thought to control behavioral suppression (“stop”). This dichotomy is commonly seen for fear-related behaviors, and for some behaviors related to cocaine seeking. Overall, however, data for reward-directed behaviors are ambiguous, and few recordings of PL/IL activity have been performed to demonstrate single-neuron correlates. We recorded neuronal activity in PL and IL during discriminative stimulus driven sucrose seeking followed by multiple days of extinction of the reward-predicting stimulus. Contrary to a generalized PL-go/IL-stop hypothesis, we found cue-evoked activity in PL and IL during reward seeking and extinction. Upon analyzing this activity based on resultant behavior (lever press or withhold), we found that neurons in both areas encoded contextually appropriate behavioral initiation (during reward seeking) and withholding (during extinction), where context was dictated by response–outcome contingencies. Our results demonstrate that PL and IL signal contextual information for regulation of behavior, irrespective of whether that involves initiation or suppression of behavioral responses, rather than topographically encoding go vs. stop behaviors. The use of context to optimize behavior likely plays an important role in maximizing utility-promoting exertion of activity when behaviors are rewarded and conservation of energy when not. PMID:26170333

  11. From empowerment to response-ability: rethinking socio-spatial, environmental justice, and nature-culture binaries in the context of STEM education

    Science.gov (United States)

    Kayumova, Shakhnoza; McGuire, Chad J.; Cardello, Suzanne

    2018-04-01

    In this conceptual paper, we draw upon the insights of Feminist Science Studies, in particular Karen Barad's concept of agential realism, as a critical analytical tool to re-think nature and culture binaries in dominant science knowledge-making practices and explanatory accounts, and their possible implications for science education in the context of socio-spatial and environmental injustices. Barad's framework proposes a relational and more expansive approach to justice, which takes into account consequential effects of nature-culture practices on humans, non-humans, and more than human vitalities. In efforts to understand potentialities of Barad's theory of agential realism, we situate our argument in the "story" of local children who encounter a bottle of cyanide in a former manufacturing building. The story takes place in a post-industrial urban city located in the U.S., caught up in an inverse relationship between the technological and scientific advances observed "globally" and the deteriorating environmental and living conditions experienced "locally" as the result of erstwhile industrial activity. Based on agential realist readings of the story and taking into consideration children's developing subjectivities, we argue that equity-oriented scholarship in science education might not be able to achieve justice devoid of understanding of the relatedness to plurality of life forms. We invite our readers to consider (re)configuring socio-spatial and environmental issues as an ethical response-ability that is constituted through relationships of care, recognition, openness, and responsiveness to vitalities of humans and nonhumans equally, one which cannot be conceptualized from a priori and distant calculations, but rather continuous entangled relations.

  12. Tunable pH and redox-responsive drug release from curcumin conjugated γ-polyglutamic acid nanoparticles in cancer microenvironment.

    Science.gov (United States)

    Pillarisetti, Shameer; Maya, S; Sathianarayanan, S; Jayakumar, R

    2017-11-01

    Tunable pH and redox responsive polymer was prepared using γ-polyglutamic acid (γ-PGA) with linker 3-mercaptopropionic acid (3-MPA) (γ-PGA_SH) via oxidation to obtain redox responsive disulfide (γ-PGA_SS) backbone and adipic acid dihydrazide (ADH) (γ-PGA_SS_ADH) with hydrazide functional group for pH responsiveness. Further curcumin (Cur) was conjugated through hydrazone bond of the γ-PGA_SS_ADH via Schiff base reaction to obtain (γ-PGA_SS_ADH_Cur). The prepared systems were characterized by Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, Electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Qq-TOF-MS/MS) and Solid state nuclear magnetic resonance (SS NMR) techniques. γ-PGA_SS_ADH_Cur formed self-assembled core shell nanoparticles (NPs) in existence of stabilized aqueous medium. γ-PGA_SS_ADH_Cur NPs maintained its stability in physiological condition. NPs tunable Cur release and cytotoxicity were observed for γ-PGA_SS_ADH_Cur NPs in both acidic and redox conditions mimicking the cancer microenvironment. γ-PGA_SS_ADH_Cur NPs uptake study showed via endocytosis mechanism resulted in the lysosomal entrapment of these NPs within the cell. γ-PGA_SS_ADH_Cur NPs exhibited a dual stimuli responsive drug delivery and can be used as a smart and potential drug delivery system in cancer microenvironment. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers

    Directory of Open Access Journals (Sweden)

    Charles D. Morris

    2017-02-01

    Full Text Available Broadly neutralizing antibodies (bNAbs have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively. Trimeric scaffolds were also identified to stabilize the MPER-containing BG505 gp140.681 trimer in a native-like conformation. Following structural and antigenic evaluation, a subset of scaffold and trimer antigens was selected for immunization in BALB/c mice. Serum binding revealed distinct patterns of antibody responses to these two bNAb targets presented in different structural contexts. For example, the N332 nanoparticles elicited glycan epitope-specific antibody responses that could also recognize the native trimer, while a scaffolded BG505 gp140.681 trimer generated a stronger and more rapid antibody response to the trimer apex than its parent gp140.664 trimer. Furthermore, next-generation sequencing (NGS of mouse splenic B cells revealed expansion of antibody lineages with long heavy-chain complementarity-determining region 3 (HCDR3 loops upon activation by MPER scaffolds, in contrast to the steady repertoires primed by N332 nanoparticles and a soluble gp140.664 trimer. These findings will facilitate the future development of a coherent vaccination strategy that combines both epitope-focused and trimer-based approaches.

  14. Drug-domain interaction networks in myocardial infarction.

    Science.gov (United States)

    Wang, Haiying; Zheng, Huiru; Azuaje, Francisco; Zhao, Xing-Ming

    2013-09-01

    It has been well recognized that the pace of the development of new drugs and therapeutic interventions lags far behind biological knowledge discovery. Network-based approaches have emerged as a promising alternative to accelerate the discovery of new safe and effective drugs. Based on the integration of several biological resources including two recently published datasets i.e., Drug-target interactions in myocardial infarction (My-DTome) and drug-domain interaction network, this paper reports the association between drugs and protein domains in the context of myocardial infarction (MI). A MI drug-domain interaction network, My-DDome, was firstly constructed, followed by topological analysis and functional characterization of the network. The results show that My-DDome has a very clear modular structure, where drugs interacting with the same domain(s) within each module tend to have similar therapeutic effects. Moreover it has been found that drugs acting on blood and blood forming organs (ATC code B) and sensory organs (ATC code S) are significantly enriched in My-DDome (p drugs, their known targets, and seemingly unrelated proteins can be revealed.

  15. Context: The strategic management Rosetta Stone

    Directory of Open Access Journals (Sweden)

    R. V. Weeks

    2007-12-01

    Full Text Available Purpose: The purpose of this paper is to analyse context as a means for interpreting and making sense of evolving strategic management theory and practice. Problem investigated: Traditional strategic management theory based on rational deductive methodologies assumes contextual predictability, yet contemporary conditions tend to contradict this assumption. In response, alternative theories and practices for dealing with complex contexts have emerged (Brews & Purohit, 2006; Grant, 2003; Kurt & Snowden, 2003and Stacey, 1995. Methodology: A literature study was undertaken to determine the nature of emergent strategic management theory and practice, in response to contextual complexity and how it differs from traditional practice (Mintzberg, 1994 and Weeks &Lessing, 1993. Findings: An important conclusion drawn from the study is that context acts as a determinant for making sense of the evolution of strategic management theory and practice. While traditional strategic management practice still assumes relevance in contexts of linear causality, it breaks down in complex contexts. Emergent strategic management theory, based on complex adaptive systems, is increasingly assuming relevance. Notably, many institutions are still attempting to make use of scenario planning in an attempt to deal with contextual complexity, a practice not supported by leading researchers(Stacey, 1995 and Kurt & Snowden, 2003. Value of the research: The insights gained from the study assume relevance, in view of the contextual complexity confronting modern-day institutions. The findings suggest that emergent strategy based on complex adaptive system theory needs to be considered as a means for dealing with increasing environmental turbulence. Conclusion: It is concluded that context serves as the Rosetta stone for making sense of strategic management theory and practice. In view of the research findings, as reflected in the literature, it would seem that the use of complex

  16. The role of exosomes and miRNAs in drug-resistance of cancer cells.

    Science.gov (United States)

    Bach, Duc-Hiep; Hong, Ji-Young; Park, Hyen Joo; Lee, Sang Kook

    2017-07-15

    Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40-150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell-to-cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer-secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome-wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV-mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment. © 2017 UICC.

  17. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    Directory of Open Access Journals (Sweden)

    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  18. Analysis of how the health systems context shapes responses to the control of human immunodeficiency virus: case-studies from the Russian Federation.

    Science.gov (United States)

    Atun, Rifat A.; McKee, Martin; Drobniewski, Francis; Coker, Richard

    2005-01-01

    OBJECTIVE: To develop a methodology and an instrument that allow the simultaneous rapid and systematic examination of the broad public health context, the health care systems, and the features of disease-specific programmes. METHODS: Drawing on methodologies used for rapid situational assessments of vertical programmes for tackling communicable disease, we analysed programmes for the control human of immunodeficiency virus (HIV) and their health systems context in three regions in the Russian Federation. The analysis was conducted in three phases: first, analysis of published literature, documents and routine data from the regions; second, interviews with key informants, and third, further data collection and analysis. Synthesis of findings through exploration of emergent themes, with iteration, resulted in the identification of the key systems issues that influenced programme delivery. FINDINGS: We observed a complex political economy within which efforts to control HIV sit, an intricate legal environment, and a high degree of decentralization of financing and operational responsibility. Although each region displays some commonalities arising from the Soviet traditions of public health control, there are considerable variations in the epidemiological trajectories, cultural responses, the political environment, financing, organization and service delivery, and the extent of multisectoral work in response to HIV epidemics. CONCLUSION: Within a centralized, post-Soviet health system, centrally directed measures to enhance HIV control may have varying degrees of impact at the regional level. Although the central tenets of effective vertical HIV programmes may be present, local imperatives substantially influence their interpretation, operationalization and effectiveness. Systematic analysis of the context within which vertical programmes are embedded is necessary to enhance understanding of how the relevant policies are prioritized and translated to action. PMID

  19. Invisible Legitimacy at Global Scale vs. Visible Legitimacy at Local Context

    DEFF Research Database (Denmark)

    Ramirez, Jacobo; Velez-Zapata, Claudia Patricia

    responses to consequences of armed conflict, for example in Europe –asylum seekers or in Africa and Latin America ex-combats of armed groups. In the current global context, we would like to explore and analyze the impact of armed conflict and crisis on BS’ emerging strategy to responses to such contexts...

  20. Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings

    NARCIS (Netherlands)

    Schellekens, R.C.A.; Stellaard, F.; Mitrovic, D.; Stuurman, F.E.; Kosterink, J.G.W.; Frijlink, H.W.

    2008-01-01

    Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of

  1. Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2016-10-01

    It has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms. In this review, we explored these hypotheses and the involvement of the hippocampus in the development and maintenance of addiction to widely abused drugs such as cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Studies suggest that initial exposure to stimulants (i.e., cocaine, nicotine, and amphetamine) and alcohol may enhance hippocampal function and, therefore, the formation of augmented drug-context associations that contribute to the development of addiction. In line with the self-medication hypothesis, withdrawal from stimulants, ethanol, and cannabis results in hippocampus-dependent learning and memory deficits, which suggest that an attempt to alleviate these deficits may contribute to relapse to drug use and maintenance of addiction. Interestingly, opiate withdrawal leads to enhancement of hippocampus-dependent learning and memory. Given that a conditioned aversion to drug context develops during opiate withdrawal, the cognitive enhancement in this case may result in the formation of an augmented association between withdrawal-induced aversion and withdrawal context. Therefore, individuals with opiate addiction may return to opiate use to avoid aversive symptoms triggered by the withdrawal context. Overall, the systematic examination of the role of the hippocampus in drug addiction may help to formulate a better understanding of addiction and underlying neural substrates. © 2016 Kutlu and Gould; Published by Cold Spring Harbor Laboratory Press.

  2. Reduction-responsive interlayer-crosslinked micelles prepared from star-shaped copolymer via click chemistry for drug controlled release

    Science.gov (United States)

    Dai, Yu; Wang, Hongquan; Zhang, Xiaojin

    2017-12-01

    To improve the stability of polymeric micelles, here we describe interlayer-crosslinked micelles prepared from star-shaped copolymer via click chemistry. The formation of interlayer-crosslinked micelles was investigated and confirmed by proton nuclear magnetic resonance, Fourier-transform infrared spectroscopy, and fluorescence spectroscopy. The morphology of un-crosslinked micelles and crosslinked micelles observed by transmission electron microscope is both uniform nano-sized spheres (approximately 20 nm). The crosslinking enhances the stability of polymeric micelles and improves the drug loading capacity of polymeric micelles. The interlayer-crosslinked micelles prepared from star-shaped copolymer and a crosslinker containing a disulfide bond are reduction-responsive and can release the drug quickly in the presence of the reducing agents such as glutathione (GSH).

  3. Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Giovanni Sotgiu

    2015-03-01

    Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

  4. Race, pharmacogenomics, and marketing: putting BiDil in context.

    Science.gov (United States)

    Kahn, Jonathan

    2006-01-01

    This article endeavors to place into context recent developments surrounding the United States Food and Drug Administration recent approval of BiDil (isosorbide dinitrate/hydralazine hydrochloride) (NitroMed, Inc., Lexington, MA) as the first ever race-specific drug--in this case to treat heart failure in African Americans. It focuses in particular on both commercial incentives and statistical manipulation of medical data as framing the drive to bring BiDil to market as a race-specific drug. In current discourse about pharmacogenomics, targeting a racial audience is perceived as necessary because at this point the technology and resources do not exist to scan efficiently every individual's genetic profile. The article argues that medical researchers may say they are using race as a surrogate to target biology in drug development, but corporations are using biology as a surrogate to target race in drug marketing. Pharmacogenomics may hold great promise, but on our way to that Promised Land, it is imperative to review such short cuts with a critical eye.

  5. Dissociable neural effects of stimulus valence and preceding context during the inhibition of responses to emotional faces.

    Science.gov (United States)

    Schulz, Kurt P; Clerkin, Suzanne M; Halperin, Jeffrey M; Newcorn, Jeffrey H; Tang, Cheuk Y; Fan, Jin

    2009-09-01

    Socially appropriate behavior requires the concurrent inhibition of actions that are inappropriate in the context. This self-regulatory function requires an interaction of inhibitory and emotional processes that recruits brain regions beyond those engaged by either processes alone. In this study, we isolated brain activity associated with response inhibition and emotional processing in 24 healthy adults using event-related functional magnetic resonance imaging (fMRI) and a go/no-go task that independently manipulated the context preceding no-go trials (ie, number of go trials) and the valence (ie, happy, sad, and neutral) of the face stimuli used as trial cues. Parallel quadratic trends were seen in correct inhibitions on no-go trials preceded by increasing numbers of go trials and associated activation for correct no-go trials in inferior frontal gyrus pars opercularis, pars triangularis, and pars orbitalis, temporoparietal junction, superior parietal lobule, and temporal sensory association cortices. Conversely, the comparison of happy versus neutral faces and sad versus neutral faces revealed valence-dependent activation in the amygdala, anterior insula cortex, and posterior midcingulate cortex. Further, an interaction between inhibition and emotion was seen in valence-dependent variations in the quadratic trend in no-go activation in the right inferior frontal gyrus and left posterior insula cortex. These results suggest that the inhibition of response to emotional cues involves the interaction of partly dissociable limbic and frontoparietal networks that encode emotional cues and use these cues to exert inhibitory control over the motor, attention, and sensory functions needed to perform the task, respectively. 2008 Wiley-Liss, Inc.

  6. Drug abuse: consequences in terms of family pathology and disintegration.

    Science.gov (United States)

    Visser, L

    1991-01-01

    This article examines some of the consequences of drug addiction in terms of family pathology and family disintegration. It briefly elucidates the role of the family in developing and maintaining drug addiction in family members. The concept of 'secondary' sufferers of the illness of drug addiction is examined. An actual case history will be presented in order to facilitate analysis of some of the forms of pathology and disintegration so often seen in the family of the drug addict. Within the family context, the question of who, if anyone, is the victim of drug addiction, is raised.

  7. Addiction: from context-induced hedonia to appetite, based on transition of micro-behaviors in morphine abstinent tree shrews

    Directory of Open Access Journals (Sweden)

    Ying eDuan

    2016-06-01

    Full Text Available AbstractDrug addiction is viewed as a maladaptive memory induced by contextual cues even in the abstinent state. However, the variations of hedonia and appetite induced by the context during the abstinence have been neglected. To distinguish the representative behaviors between hedonia and appetite, micro-behaviors in abstinent animal such as psycho-activity and drug seeking behaviors were observed in morphine conditioned place preference (CPP. To confirm the different effects of reward between drug and natural reward, a palatable food CPP paradigm was compared in current work. After a 10-day training in CPP with morphine or food, the preference was tested on day 1, 14, 28, and the changes of micro-behaviors were analyzed further. Our data showed that tree shrews treated with morphine performed more jumps on day 1 and more visits to saline paired side on day 28, which indicated a featured behavioral transition from psycho-activity to seeking behavior during drug abstinence. Meanwhile, food-conditioned animals only displayed obvious seeking behaviors in the three tests. The results suggest that the variations of micro-behaviors could imply such a transition from hedonic response to appetitive behaviors during morphine abstinence, which provided a potential behavioral basis for further neural mechanism studies.

  8. Control of drug releasing from biodegradable polymer drug delivery system by gamma-ray irradiation

    International Nuclear Information System (INIS)

    Yoshioka, Sumie; Aso, Yukio; Kojima, Shigeo

    1999-01-01

    In order to introduce the drug to the target organ, we developed a gel to control the drug releasing velocity by response to change of temperature by means of γ-ray irradiation to gelatin-GMA modified dextran mixture aqueous solution. A certain level of molecular weight of drug is necessary. The response to the temperature (change of drug releasing velocity) was affected by the concentration of gelatin and the modification rate of GMA. The Higuchi equation was applied to the releasing of β-galactosidase from gelatin-dextran gel and the releasing velocity was calculated. The releasing velocity decreased with increasing GMA modification rate at 37degC and 15degC. The releasing velocity of β-galactosidase decreased with increasing the concentration of gelatin at 15degC, but the velocity increased with increasing the concentration at 37degC. These results indicated that the good drug releasing conditions are obtained by controlling the GMA modification rate and the concentration of gelatin. (S.Y.)

  9. Student Drug Use.

    Science.gov (United States)

    Nowlis, Helen H.

    This paper discusses the nature and extent of student drug use, its meaning and significance, society's response to it, and some of the problems resulting from efforts to control it. Drugs are any substance which by its chemical nature affects the structure or function of the living organism. Abuse refers to any use of a non-medically approved…

  10. Young People, Drug Use and Family Conflict: Pathways into Homelessness

    Science.gov (United States)

    Mallett, Shelley; Rosenthal, Doreen; Keys, Deborah

    2005-01-01

    Young people who experience homelessness, in Australia and in other western contexts (US, Canada, England), are widely perceived to use and abuse alcohol and drugs. The available research indicates that homeless young people use all drug types, whether injected or otherwise, more frequently than their home-based peers. Debate exists in the…

  11. The Moderating Role of Age in Responses to Direct-to-Consumer Prescription Drug Advertising.

    Science.gov (United States)

    Ball, Jennifer G; Manika, Danae; Stout, Patricia A

    2016-01-01

    Age is an important factor that can influence processing of and response to health messages. Many studies examining evaluations of and responses to direct-to-consumer prescription drug advertising (DTCA) have incorporated age as a predictor variable, moderating variable, or sample criterion. However, findings have been inconsistent. This study attempts to add clarity to this body of research by assessing age differences in the antecedent factors of various DTCA outcomes. A multigroup structural equation modeling analysis revealed several significant differences in variable relationships between older (50+) and younger (behavioral intentions among older adults while showing a straightforward positive association with attention among younger adults. Further analysis indicated that health status accounted for some but not all of the age differences. It is suggested that younger adults are more open to seeking additional information following DTCA exposure, whereas older adults remain ambivalent.

  12. Family context and externalizing correlates of childhood animal cruelty in adjudicated delinquents.

    Science.gov (United States)

    Walters, Glenn D; Noon, Alexandria

    2015-05-01

    The purpose of this study was to determine whether childhood animal cruelty is primarily a feature of family context or of externalizing behavior. Twenty measures of family context and proactive (fearlessness) and reactive (disinhibition) externalizing behavior were correlated with the retrospective accounts of childhood animal cruelty provided by 1,354 adjudicated delinquents. A cross-sectional analysis revealed that all 20 family context, proactive externalizing, and reactive externalizing variables correlated significantly with animal cruelty. Prospective analyses showed that when the animal cruelty variable was included in a regression equation with the 10 family context variables (parental arguing and fighting, parental drug use, parental hostility, and parental knowledge and monitoring of offspring behavior) or in a regression equation with the five reactive externalizing variables (interpersonal hostility, secondary psychopathy, weak impulse control, weak suppression of aggression, and short time horizon), it continued to predict future violent and income (property + drug) offending. The animal cruelty variable no longer predicted offending, however, when included in a regression equation with the five proactive externalizing variables (early onset behavioral problems, primary psychopathy, moral disengagement, positive outcome expectancies for crime, and lack of consideration for others). These findings suggest that while animal cruelty correlates with a wide range of family context and externalizing variables, it may serve as a marker of violent and nonviolent offending by virtue of its position on the proactive subdimension of the externalizing spectrum. © The Author(s) 2014.

  13. Context effects in embodied lexical-semantic processing

    Directory of Open Access Journals (Sweden)

    Wessel O Van Dam

    2010-10-01

    Full Text Available The embodied view of language comprehension proposes that the meaning of words is grounded in perception and action rather than represented in abstract amodal symbols. Support for embodied theories of language processing comes from behavioural studies showing that understanding a sentence about an action can modulate congruent and incongruent physical responses, suggesting motor involvement during comprehension of sentences referring to bodily movement. Additionally, several neuroimaging studies have provided evidence that comprehending single words denoting manipulable objects elicits specific responses in the neural motor system. An interesting question that remains is whether action semantic knowledge is directly activated as motor simulations in the brain, or rather modulated by the semantic context in which action words are encountered. In the current paper we investigated the nature of conceptual representations using a go/no-go lexical decision task. Specifically, target words were either presented in a semantic context that emphasized dominant action features (features related to the functional use of an object or non-dominant action features. The response latencies in a lexical decision task reveal that participants were faster to respond to words denoting objects for which the functional use was congruent with the prepared movement. This facilitation effect, however, was only apparent when the semantic context emphasized corresponding motor properties. These findings suggest that motor involvement during comprehension of sentences is not automatic. Rather, the results suggest that conceptual processing is a context-dependent process that incorporates motor-related knowledge in a flexible manner.

  14. 3,4-Methylenedioxymethamphetamine (MDMA) alters acute gammaherpesvirus burden and limits Interleukin 27 responses in a mouse model of viral infection

    Science.gov (United States)

    Nelson, Daniel A.; Singh, Sam J.; Young, Amy B.; Tolbert, Melanie D.; Bost, Kenneth L.

    2011-01-01

    Aims To test whether 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) abuse might increase the susceptibility, or alter the immune response, to murine gammaherpesvirus 68 (HV-68) and/or bacterial lipopolysaccharide. Methods Groups of experimental and control mice were subjected to three day binges of MDMA, and the effect of this drug abuse on acute and latent HV-68 viral burden were assessed. In vitro and in vivo studies were also performed to assess the MDMA effect on IL-27 expression in virally infected or LPS-exposed macrophages and dendritic cells, and latently infected animals, exposed to this drug of abuse. Results Acute viral burden was significantly increased in MDMA-treated mice when compared to controls. However the latent viral burden, and physiological and behavioral responses were not altered in infected mice despite repeated bingeing with MDMA. MDMA could limit the IL-27 response of HV-68 infected or LPS-exposed macrophages and dendritic cells in vitro and in vivo, demonstrating the ability of this drug to alter normal cytokine responses in the context of a viral infection and/or a TLR4 agonist. Conclusion MDMA bingeing could alter the host’s immune response resulting in greater acute viral replication and reductions in the production of the cytokine, IL-27 during immune responses. PMID:21269783

  15. Drugs and development: the global impact of drug use and trafficking on social and economic development.

    Science.gov (United States)

    Singer, Merrill

    2008-12-01

    Locating development efforts within the context of globalism and global drug capitalism, this article examines the significant health and social impact both legal and illegal drugs have on international development efforts. The paper takes on an issue that is generally overlooked in the development debate and is not much addressed in the current international development standard, the Millennium Development Goals, and yet is one that places serious constraints on the ability of underdeveloped nations to achieve improvement. The relationship between psychotropic or "mind/mood altering" drugs and sustainable development is rooted in the contribution that the legal and illegal drug trade makes to a set of barriers to development, including: (1) interpersonal crime and community violence; (2) the corruption of public servants and the disintegration of social institutions; (3) the emergence of new or enhanced health problems; (4) the lowering of worker productivity; (5) the ensnarement of youth in drug distribution and away from productive education or employment; (6) the skewing of economies to drug production and money laundering. The paper emphasizes the need for new approaches for diminishing the burden placed by drugs on development.

  16. A Near-Infrared Photothermal Effect-Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin-Loaded Polymeric Micelles Mediated by Reversible Diels-Alder Reaction.

    Science.gov (United States)

    Li, Hui; Li, Junjie; Ke, Wendong; Ge, Zhishen

    2015-10-01

    Near-infrared light (NIR) possesses great advantages for light-responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR-responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)-loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)-block-poly(furfuryl methacrylate) (POEGMA-b-PFMA), are synthesized by sequential reversible addition-fragmentation chain-transfer (RAFT) polymerization, followed by modification with N-octyl maleimide through Diels-Alder (DA) reaction to produce POEGMA-b-POMFMA. The self-assembly of POEGMA-b-POMFMA by nano-precipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase-induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR-triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Drug-induced status epilepticus.

    Science.gov (United States)

    Cock, Hannah R

    2015-08-01

    Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case ascertainment and establishing causation substantially weaken epidemiological estimates. Some antiepileptic drugs, particularly those with sodium channel or GABA(γ-aminobutyric acid)-ergic properties, frequently exacerbate seizures and may lead to SE if used inadvertently in generalized epilepsies or less frequently in other epilepsies. Tiagabine seems to have a particular propensity for triggering nonconvulsive SE sometimes in patients with no prior history of seizures. In therapeutic practice, SE is most commonly seen in association with antibiotics (cephalosporins, quinolones, and some others) and immunotherapies/chemotherapies, the latter often in the context of a reversible encephalopathy syndrome. Status epilepticus following accidental or intentional overdoses, particularly of antidepressants or other psychotropic medications, has also featured prominently in the literature: whilst there are sometimes fatal consequences, this is more commonly because of cardiorespiratory or metabolic complications than as a result of seizure activity. A high index of suspicion is required in identifying those at risk and in recognizing potential clues from the presentation, but even with a careful analysis of patient and drug factors, establishing causation can be difficult. In addition to eliminating the potential trigger, management should be as for SE in any other circumstances, with the exception that phenobarbitone is recommended as a second-line treatment for suspected toxicity-related SE where the risk of cardiovascular complications is higher anyways and may be exacerbated by phenytoin. There are also specific recommendations/antidotes in some situations. The outcome of drug-induced status epilepticus is mostly good when promptly identified and treated, though less so in the context of overdoses. This article is

  18. Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites.

    Directory of Open Access Journals (Sweden)

    Andrea Harrer

    2010-10-01

    Full Text Available Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs like diclofenac (DF can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity.DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14% displayed drug/metabolite-specific IgG.We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded.

  19. Context and Crossmodal Interactions: An ERP Study

    Directory of Open Access Journals (Sweden)

    Beatriz R Sarmiento

    2011-10-01

    Full Text Available In a previous behavioural study, we reported that a particular context of stimulus congruency influenced audiovisual interactions. In particular, audiovisual interaction, measured in terms of congruency effect, was reduced when a high proportion of incongruent trials was presented. We argued that this modulation was due to changes in participants' control set as a function of the context of congruency, with greater control applied when most of the trials were incongruent. Since behavioural data do not allow to specify the level at which control was affecting audiovisual interaction, we conducted an event-related potentials (ERPs study to further investigate each context of audiovisual congruency. Participants performed an audiovisual congruency task, where the stimulus onset could be present on two different contexts mixed at random: a high proportion congruent context and a low proportion congruent context. The context manipulation was found to modulate brain ERPs related to perceptual and response selection processes, ie, the N2 and P3 components. The N2 amplitude was larger for the less common trials on both high and low congruent proportion contexts, while the P3 amplitude and latency were differentially modulated by incongruent trials on the two contexts.

  20. Psychoactive drug advertising: content analysis.

    Science.gov (United States)

    Mastroianni, Patrícia C; Vaz, Amanda Cristina R; Noto, Ana Regina; Galduróz, José Carlos F

    2008-10-01

    The goal of this study was to describe the human figures portrayed in psychoactive drug advertising in terms of gender, age, ethnic group, and social context. Content analysis for 86 new pieces of printed advertisements released in 2005 was carried out. Fisher exact test was used to analyze the association between categories. There was a preponderance of women (62.8%) who were four times more present in advertisements for antidepressants and anxyolitics than men. Most of the people shown were Caucasian (98.8%) young adults (72%). These people were pictured in leisure activities (46.5%), at home (29%), or in contact with nature (16.2%). The message conveyed was that the drugs treat routinely felt subjective symptoms of discomfort, inducing in an irrational appeal that may affect drug prescription.

  1. Price Sensitivity of Demand for Prescription Drugs

    DEFF Research Database (Denmark)

    Skipper, Lars; Simonsen, Marianne; Skipper, Niels

    This paper investigates price sensitivity of demand for prescription drugs using drug purchase records for at 20% random sample of the Danish population. We identify price responsiveness by exploiting exogenous variation in prices caused by kinked reimbursement schemes and implement a regression ...... education and income are, however, more responsive to the price. Also, essential drugs that prevent deterioration in health and prolong life have lower associated average price sensitivity....

  2. How do researchers categorize drugs, and how do drug users categorize them?

    Science.gov (United States)

    Lee, Juliet P; Antin, Tamar M J

    2012-01-01

    This paper considers drug classifications and terms widely used in US survey research, and compares these to classifications and terms used by drug users. We begin with a critical review of drug classification systems, including those oriented to public policy and health services as well as survey research. We then consider the results of a pile sort exercise we conducted with 76 respondents within a mixed method study of Southeast Asian American adolescent and young adult drug users in urban Northern California, USA. We included the pile sort to clarify how respondents handled specific terms which we understood to be related to Ecstasy and methamphetamines. Results of the pile sort were analyzed using graphic layout algorithms as well as content analysis of pile labels. Similar to the national surveys, our respondents consistently differentiated Ecstasy terms from methamphetamine terms. We found high agreement between some specific local terms ( thizz , crystal ) and popular drug terms, while other terms thought to be mainstream ( crank , speed ) were reported as unknown by many respondents. In labeling piles, respondents created taxonomies based on consumption method (in particular, pill ) as well as the social contexts of use. We conclude by proposing that divergences between drug terms utilized in survey research and those used by drug users may reflect two opposing tendencies: the tendency of survey researchers to utilize standardized language that constructs persons and experiences as relatively homogeneous, varying only within measurable degrees, and the tendency of drug users to utilize specialized language (argot) that reflects their understandings of their experiences as hybrid and diverse. The findings problematize the validity of drug terms and categories used in survey research.

  3. Research on drug abuse and addiction treatment in prisons

    Directory of Open Access Journals (Sweden)

    Kljajević Srđan

    2017-01-01

    Full Text Available The causes of drug abuse and criminal behavior are closely linked. Not surprisingly, there is a high percentage of prisoners who during sentence execution abuse or are dependent on drugs. Antisocial personality disorder can be considered a common predictor of committing criminal offenses and drug abuse. A review of studies has revealed a high prevalence of inmates who use drugs while serving a sentence. Also, prison environment represents only a new context of the continuum of drug abuse by inmates. There are different theoretical approaches in explaining this phenomenon. Treatment programs based on empirically validated principles that guarantee the effectiveness, may be one strategy for solving the problem of drug abuse in prisons, with multiple positive effects.

  4. Drug user organizations in the Nordic countries--local, national, and international dimensions.

    Science.gov (United States)

    Frank, Vibeke Asmussen; Anker, Jørgen; Tammi, Tuukka

    2012-04-01

    The article focuses on drug user organizations that represent and advocate for active "hard drug" users in the Nordic countries. It discusses the opportunities and challenges that these organizations face in their search for legitimacy and political influence. The comparative perspective points at similarities and differences in national contexts that both support and challenges the existence of drug user organizations, including drug policy, social welfare policy, trends in drug use, and organizational conditions. The article also discusses the importance of international network and transnational organizations that support drug user organizations.

  5. Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine.

    Science.gov (United States)

    Carey, R J

    1991-01-01

    Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.

  6. Response process and test–retest reliability of the Context Assessment for Community Health tool in Vietnam

    Directory of Open Access Journals (Sweden)

    Duong M. Duc

    2016-06-01

    Full Text Available Background: The recently developed Context Assessment for Community Health (COACH tool aims to measure aspects of the local healthcare context perceived to influence knowledge translation in low- and middle-income countries. The tool measures eight dimensions (organizational resources , community engagement, monitoring services for action, sources of knowledge, commitment to work, work culture, leadership, and informal payment through 49 items. Objective: The study aimed to explore the understanding and stability of the COACH tool among health providers in Vietnam. Designs: To investigate the response process, think-aloud interviews were undertaken with five community health workers, six nurses and midwives, and five physicians. Identified problems were classified according to Conrad and Blair's taxonomy and grouped according to an estimation of the magnitude of the problem's effect on the response data. Further, the stability of the tool was examined using a test–retest survey among 77 respondents. The reliability was analyzed for items (intraclass correlation coefficient (ICC and percent agreement and dimensions (ICC and Bland–Altman plots. Results: In general, the think-aloud interviews revealed that the COACH tool was perceived as clear, well organized, and easy to answer. Most items were understood as intended. However, seven prominent problems in the items were identified and the content of three dimensions was perceived to be of a sensitive nature. In the test–retest survey, two-thirds of the items and seven of eight dimensions were found to have an ICC agreement ranging from moderate to substantial (0.5–0.7, demonstrating that the instrument has an acceptable level of stability. Conclusions: This study provides evidence that the Vietnamese translation of the COACH tool is generally perceived to be clear and easy to understand and has acceptable stability. There is, however, a need to rephrase and add generic examples to clarify

  7. Response process and test-retest reliability of the Context Assessment for Community Health tool in Vietnam.

    Science.gov (United States)

    Duc, Duong M; Bergström, Anna; Eriksson, Leif; Selling, Katarina; Thi Thu Ha, Bui; Wallin, Lars

    2016-01-01

    The recently developed Context Assessment for Community Health (COACH) tool aims to measure aspects of the local healthcare context perceived to influence knowledge translation in low- and middle-income countries. The tool measures eight dimensions (organizational resources, community engagement, monitoring services for action, sources of knowledge, commitment to work, work culture, leadership, and informal payment) through 49 items. The study aimed to explore the understanding and stability of the COACH tool among health providers in Vietnam. To investigate the response process, think-aloud interviews were undertaken with five community health workers, six nurses and midwives, and five physicians. Identified problems were classified according to Conrad and Blair's taxonomy and grouped according to an estimation of the magnitude of the problem's effect on the response data. Further, the stability of the tool was examined using a test-retest survey among 77 respondents. The reliability was analyzed for items (intraclass correlation coefficient (ICC) and percent agreement) and dimensions (ICC and Bland-Altman plots). In general, the think-aloud interviews revealed that the COACH tool was perceived as clear, well organized, and easy to answer. Most items were understood as intended. However, seven prominent problems in the items were identified and the content of three dimensions was perceived to be of a sensitive nature. In the test-retest survey, two-thirds of the items and seven of eight dimensions were found to have an ICC agreement ranging from moderate to substantial (0.5-0.7), demonstrating that the instrument has an acceptable level of stability. This study provides evidence that the Vietnamese translation of the COACH tool is generally perceived to be clear and easy to understand and has acceptable stability. There is, however, a need to rephrase and add generic examples to clarify some items and to further review items with low ICC.

  8. Hybrid nanostructured drug carrier with tunable and controlled drug release

    International Nuclear Information System (INIS)

    Depan, D.; Misra, R.D.K.

    2012-01-01

    We describe here a transformative approach to synthesize a hybrid nanostructured drug carrier that exhibits the characteristics of controlled drug release. The synthesis of the nanohybrid architecture involved two steps. The first step involved direct crystallization of biocompatible copolymer along the long axis of the carbon nanotubes (CNTs), followed by the second step of attachment of drug molecule to the polymer via hydrogen bonding. The extraordinary inorganic–organic hybrid architecture exhibited high drug loading ability and is physically stable even under extreme conditions of acidic media and ultrasonic irradiation. The temperature and pH sensitive characteristics of the hybrid drug carrier and high drug loading ability merit its consideration as a promising carrier and utilization of the fundamental aspects used for synthesis of other promising drug carriers. The higher drug release response during the application of ultrasonic frequency is ascribed to a cavitation-type process in which the acoustic bubbles nucleate and collapse releasing the drug. Furthermore, the study underscores the potential of uniquely combining CNTs and biopolymers for drug delivery. - Graphical abstract: Block-copolymer crystallized on carbon nanotubes (CNTs). Nanohybrid drug carrier synthesized by attaching doxorubicin (DOX) to polymer crystallized CNTs. Crystallized polymer on CNTs provide mechanical stability. Triggered release of DOX. Highlights: ► The novel synthesis of a hybrid nanostructured drug carrier is described. ► The drug carrier exhibits high drug loading ability and is physically stable. ► The high drug release is ascribed to a cavitation-type process.

  9. [Generic drugs: good or bad? Physician's knowledge of generic drugs and prescribing habits].

    Science.gov (United States)

    García, A J; Martos, F; Leiva, F; Sánchez de la Cuesta, F

    2003-01-01

    In this article we analyze the responses of 1220 Spanish physicians who participated in a survery about generic drugs. A previously validated questionnaire was sent to physicians through the Spanish Medical Councils of the different provinces. Four items were analyzed: what doctors know about generic drugs (knowledge); physicians' prescribing habits concerning these drugs (attitude and professional competence); how prescription of generic drugs effects pharmaceutical costs amd, finally, what doctors believe a generic drug should be. The influence of physician-related variables (age, type of contract, specialty, workload, etc.) on prescribing of generic drugs was also analyzed. In view of the results, we believe that to rationalize expenditure through and appropriate policy on generic drugs Spanish health authorities should offer more and better training and information (clear and independent) about what generic drugs are.

  10. The Proposal Concept of Development and Implementation in Strategy of Sustainable Corporate Social Responsibility in the Context of the HCS Model 3E

    Science.gov (United States)

    Sakál, Peter; Hrdinová, Gabriela

    2016-06-01

    This article is the result of a conceptual design methodology for the development of a sustainable strategy of sustainable corporate social responsibility (SCSR) in the context of the HCS model 3E formed, as a co-author within the stated grants and dissertation. On the basis of the use of propositional logic, the SCSR procedure is proposed for incorporation into the corporate strategy of sustainable development and the integrated management system (IMS) of the industrial enterprise. The aim of this article is the proposal of the concept of development and implementation strategy of SCSR in the context of the HCS model 3E.

  11. Does the use of melatonin overcome drug resistance in cancer chemotherapy?

    Science.gov (United States)

    Asghari, Mohammad Hossein; Ghobadi, Emad; Moloudizargari, Milad; Fallah, Marjan; Abdollahi, Mohammad

    2018-03-01

    Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound. Reduced sensitivity and also resistance of cancer cells to antineoplastic agents are common events which might arise as a result of genomic instability of the malignant cells. Genetic mutations provide numerous mechanisms for these cells to resist cytotoxic therapies. Melatonin, due to its pleitropic effects, is able to correct these alterations in favour of sensitization to antineoplastic agents as evident by increased response to treatment via modulating the expression and phosphorylation status of drug targets, the reduced clearance of drugs by affecting their metabolism and transport within the body, decreased survival of malignant cells via altering DNA repair and telomerase activity, and enhanced responsiveness to cell death-associated mechanisms such as apoptosis and autophagy. These effects are presumably governed by melatonin's interventions in the main signal transduction pathways such as Akt and MAPK, independent of its antioxidant properties. Possessing such a signaling altering nature, melatonin can considerably affect the drug-resistance mechanisms employed by the malignant cells in breast, lung, hepatic, and colon cancers as well as different types of leukemia which are the subject of the current review. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Enantiomeric profiling of chiral illicit drugs in a pan-European study

    NARCIS (Netherlands)

    Castrignanò, E.; Yang, Z.; Bade, R.; Baz-Lomba, J.A.; Castiglioni, S.; Causanilles, A.; Covaci, A.; Gracia-Lor, E.; Hernández, F.; Kinyua, J.; McCall, A.-K.; van Nuijs, A.L.N.; Ort, C.; Plósz, B.G.; Ramin, P.; Rousis, N.I.; Ryu, Y.; Thomas, K.V.; de Voogt, P.; Zuccato, E.; Kasprzyk-Hordern, B.

    2018-01-01

    The aim of this paper is to present the first study on spatial and temporal variation in the enantiomeric profile of chiral drugs in eight European cities. Wastewater-based epidemiology (WBE) and enantioselective analysis were combined to evaluate trends in illicit drug use in the context of their

  13. [Rational and emotional appeals in prescription drug advertising: study of a weight loss drug].

    Science.gov (United States)

    Huertas, Melby Karina Zuniga; Campomar, Marcos Cortez

    2008-04-01

    The Direct-to-Consumer (DTC) advertising of medicines encourages people to ask doctors for certain medicines and treatments that require medical prescription. In order to enhance their persuasive power, advertising models recommend matching the appeals (rational and/or emotional) to the consumer's attitude (cognitive and/ or affective) towards the product. This recommendation leads to controversies in the context of DTC advertising. Emotional appeals, although frequently used, would always be inadequate in that kind of advertising. In absence of empiric evidence of the consumer's perspective, a descriptive research was undertaken with the objective of evaluating: i) the components of the attitude toward medicines; ii) attitude and behavioral intentions in response to DTC ads (one appealing to reason and the other appealing to emotion). A prescription weight loss drug was chosen for this purpose. The results revealed a predominantly cognitive attitude toward the product and an attitude and behavioral intention more favorable to the rational ad. Negative cognition about the product played an outstanding role canceling the persuasive power of emotional appeals.

  14. Parental Substance Abuse As an Early Traumatic Event. Preliminary Findings on Neuropsychological and Personality Functioning in Young Drug Addicts Exposed to Drugs Early.

    Science.gov (United States)

    Parolin, Micol; Simonelli, Alessandra; Mapelli, Daniela; Sacco, Marianna; Cristofalo, Patrizia

    2016-01-01

    Parental substance use is a major risk factor for child development, heightening the risk of drug problems in adolescence and young adulthood, and exposing offspring to several types of traumatic events. First, prenatal drug exposure can be considered a form of trauma itself, with subtle but long-lasting sequelae at the neuro-behavioral level. Second, parents' addiction often entails a childrearing environment characterized by poor parenting skills, disadvantaged contexts and adverse childhood experiences (ACEs), leading to dysfunctional outcomes. Young adults born from/raised by parents with drug problems and diagnosed with a Substance Used Disorder (SUD) themselves might display a particularly severe condition in terms of cognitive deficits and impaired personality function. This preliminary study aims to investigate the role of early exposure to drugs as a traumatic event, capable of affecting the psychological status of young drug addicts. In particular, it intends to examine the neuropsychological functioning and personality profile of young adults with severe SUDs who were exposed to drugs early in their family context. The research involved three groups, each consisting of 15 young adults (aged 18-24): a group of inpatients diagnosed with SUDs and exposed to drugs early, a comparison group of non-exposed inpatients and a group of non-exposed youth without SUDs. A neuropsychological battery (Esame Neuropsicologico Breve-2), an assessment procedure for personality disorders (Shedler-Westen Assessment Procedure-200) and the Symptom CheckList-90-Revised were administered. According to present preliminary results, young drug addicts exposed to drugs during their developmental age were characterized by elevated rates of neuropsychological impairments, especially at the expense of attentive and executive functions (EF); personality disorders were also common but did not differentiate them from non-exposed youth with SUDs. Alternative multi-focused prevention and

  15. Context in a wider context

    Directory of Open Access Journals (Sweden)

    John Traxler

    2011-07-01

    Full Text Available This paper attempts to review and reconsider the role of context in mobile learning and starts by outlining definitions of context-aware mobile learning as the technologies have become more mature, more robust and more widely available and as the notion of context has become progressively richer. The future role of context-aware mobile learning is considered within the context of the future of mobile learning as it moves from the challenges and opportunities of pedagogy and technology to the challenges and opportunities of policy, scale, sustainability, equity and engagement with augmented reality, «blended learning», «learner devices», «user-generated contexts» and the «internet of things». This is essentially a perspective on mobile learning, and other forms of technology-enhanced learning (TEL, where educators and their institutions set the agenda and manage change. There are, however, other perspectives on context. The increasing availability and use of smart-phones and other personal mobile devices with similar powerful functionality means that the experience of context for many people, in the form of personalized or location-based services, is an increasingly social and informal experience, rather than a specialist or educational experience. This is part of the transformative impact of mobility and connectedness on our societies brought about by these universal, ubiquitous and pervasive technologies. This paper contributes a revised understanding of context in the wider context (sic of the transformations taking place in our societies. These are subtle but pervasive transformations of jobs, work and the economy, of our sense of time, space and place, of knowing and learning, and of community and identity. This leads to a radical reconsideration of context as the notions of ‹self› and ‹other› are transformed.

  16. The neuroendocrine response to stress under the effect of drugs: Negative synergy between amphetamine and stressors.

    Science.gov (United States)

    Gómez-Román, Almudena; Ortega-Sánchez, Juan A; Rotllant, David; Gagliano, Humberto; Belda, Xavier; Delgado-Morales, Raúl; Marín-Blasco, Ignacio; Nadal, Roser; Armario, Antonio

    2016-01-01

    There have been numerous studies into the interaction between stress and addictive drugs, yet few have specifically addressed how the organism responds to stress when under the influence of psychostimulants. Thus, we studied the effects of different acute stressors (immobilization, interleukin-1β and forced swimming) in young adult male rats simultaneously exposed to amphetamine (AMPH, 4 mg/kg SC), evaluating classic biological markers. AMPH administration itself augmented the plasma hypothalamic-pituitary-adrenal (HPA) hormones, adrenocorticotropin (ACTH) and corticosterone, without affecting plasma glucose levels. By contrast, this drug dampened the peripheral HPA axis, as well as the response of glucose to the three stressors. We also found that AMPH administration completely blocked the forced swim-induced expression of the corticotropin-releasing hormone (hnCRH) and it partially reduced c-fos expression in the paraventricular nucleus of the hypothalamus (PVN). Indeed, this negative synergy in the forced swim test could even be observed with a lower dose of AMPH (1mg/kg, SC), a dose that is usually received in self-administration experiments. In conclusion, when rats that receive AMPH are subjected to stress, a negative synergy occurs that dampens the prototypic peripheral physiological response to stress and activation of the PVN. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Perspectives on Health among Adult Users of Illicit Stimulant Drugs in Rural Ohio

    Science.gov (United States)

    Siegal, Harvey A.; Draus, Paul J.; Carlson, Robert G.; Falck, Russel S.; Wang, Jichuan

    2006-01-01

    Context: Although the nonmedical use of stimulant drugs such as cocaine and methamphetamine is increasingly common in many rural areas of the United States, little is known about the health beliefs of people who use these drugs. Purpose: This research describes illicit stimulant drug users' views on health and health-related concepts that may…

  18. Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities.

    Directory of Open Access Journals (Sweden)

    Rui-Ru Ji

    2009-09-01

    Full Text Available The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901 across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.

  19. Pavlovian influences over food and drug intake.

    Science.gov (United States)

    Woods, S C; Ramsay, D S

    2000-06-01

    Consuming food and taking drugs share several important characteristics. In particular, each causes changes in important physiological parameters that are constantly being monitored and regulated by the brain. As examples, blood glucose increases after meals; and body temperature decreases after ethanol is taken. Such changes elicit neurally-mediated homeostatic responses that serve to reduce the magnitude and duration of the perturbation. It is argued that when an individual can accurately anticipate pending meals or drugs, it can make appropriate responses to minimize or totally neutralize the meal/drug-elicited perturbations. This phenomenon, which is the basis for meal and drug tolerance, relies upon Pavlovian conditioning. Literature is reviewed which documents the role of conditioning processes in the development of tolerance. The argument is made that conditioned responses enable individuals to derive necessary or desirable aspects of food and drugs while minimizing some of their negative effects. In a final section, drug tolerance is discussed as a natural consequence of evolution-derived, meal-related learning processes, with associated negative consequences.

  20. Cellular mechanisms in drug - radiation interaction

    International Nuclear Information System (INIS)

    Trott, K.R.

    1979-01-01

    Some cytotoxic drugs, especially those belonging to the group of antibiotics and antimetabolites, sensitize the cells having survived drug treatment to the subsequent irradiation by either increasing the slope of the radiation dose response curves or by decreasing extrapolation number. Bleomycin was found to interact with radiation in L-cells and FM3A cells, but not in HeLa-cells. The data with EMT-6 cells suggest that the interaction depends on drug dose: no interaction occurred after the exposure to bleomycin which killed only 20 - 40% of the cells; yet the exposure to bleomycin which killed 90% of the cells in addition sensitized the surviving cells by the DMF of 1.3. The sensitization found 24 hr after the exposure of HeLa cells to methotrexate was due to cell synchronization. Other cytostatic drugs were found to synchronize proliferating cells even better. Therefore, the fluctuation of radiosensitivity has been commonly observed after the termination of exposure to these drugs. Preirradiation may lead to the change in drug dose response curves. The recruitment of resting cells into cycle occurs hours or days later, in some irradiated normal and malignant tissues. Since many cytostatic drugs are far more active in proliferating cells than in resting cells, the recruitment after irradiation may lead to the sudden increase in drug sensitivity, days after the irradiation. No single, simple theory seems to exist to classify and predict the cellular response to combined modality treatment. (Yamashita, S.)

  1. Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells.

    Science.gov (United States)

    Levine, B L

    2015-03-01

    Performance enhancement of the immune system can now be generated through ex vivo gene modification of T cells in order to redirect native specificity to target tumor antigens. This approach combines the specificity of antibody therapy, the expanded response of cellular therapy and the memory activity of vaccine therapy. Recent clinical trials of chimeric antigen receptor (CAR) T cells directed toward CD19 as a stand-alone therapy have shown sustained complete responses in patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia. As these drug products are individually derived from a patient's own cells, a different manufacturing approach is required for this kind of personalized therapy compared with conventional drugs. Key steps in the CAR T-cell manufacturing process include the selection and activation of isolated T cells, transduction of T cells to express CARs, ex vivo expansion of modified T cells and cryopreservation in infusible media. In this review, the steps involved in isolating, genetically modifying and scaling-out the CAR T cells for use in a clinical setting are described in the context of in-process and release testing and regulatory standards.

  2. The role of polyamine catabolism in anti-tumour drug response.

    Science.gov (United States)

    Casero, R A; Wang, Y; Stewart, T M; Devereux, W; Hacker, A; Wang, Y; Smith, R; Woster, P M

    2003-04-01

    Interest in polyamine catabolism has increased since it has been directly associated with the cytotoxic response of multiple tumour types to exposure to specific anti-tumour polyamine analogues. Human polyamine catabolism was considered to be a two-step pathway regulated by the rate-limiting enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (APAO). Further, the super-induction of SSAT by several anti-tumour polyamine analogues has been implicated in the cytotoxic response of specific solid-tumour phenotypes to these agents. This high induction of SSAT has been correlated with cellular response to the anti-tumour polyamine analogues in several systems and considerable progress has been made in understanding the molecular mechanisms that regulate the analogue-induced expression of SSAT. A polyamine response element has been identified and the transacting transcription factors that bind and stimulate transcription of SSAT have been cloned and characterized. The link between SSAT activity and cellular toxicity is thought to be based on the production of H(2)O(2) by the activity of the constitutive APAO that uses the SSAT-produced acetylated polyamines. The high induction of SSAT and the subsequent activity of APAO are linked to the cytotoxic response of some tumour cell types to specific polyamine analogues. However, we have recently cloned a variably spliced human polyamine oxidase (PAOh1) that is inducible by specific polyamine analogues, efficiently uses unacetylated spermine as a substrate, and also produces toxic H(2)O(2) as a product. The results of studies with PAOh1 suggest that it is an additional enzyme in polyamine catabolism that has the potential to significantly contribute to polyamine homoeostasis and drug response. Most importantly, PAOh1 is induced by specific polyamine analogues in a tumour-phenotype-specific manner in cell lines representative of the major forms of solid tumours, including

  3. Context specificity of the ANS stress response during two regrouping experiments in goats

    Directory of Open Access Journals (Sweden)

    Antonia Patt

    2016-08-01

    concept that stress response patterns are context-specific.

  4. miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer.

    Science.gov (United States)

    Corcoran, Claire; Rani, Sweta; Breslin, Susan; Gogarty, Martina; Ghobrial, Irene M; Crown, John; O'Driscoll, Lorraine

    2014-03-24

    While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630's regulation of mRNA, proteins and their phosphorylated forms. We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630's regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells

  5. Fear Conditioning Effects on Sensitivity to Drug Reward

    Science.gov (United States)

    2010-06-01

    motivational responses and self-administration behaviors (Robbins et al., 2008). Pavlovian conditioning mechanisms link unconditioned drug responses...model. Induction of fear conditioning is followed by measurement of sensitivity to drug reward using a conditioned place preference (CPP) model to...morphine. Conditioned drug reward is a relevant model in addiction because environmental cues (e.g. a barroom) induce craving and persistent

  6. Positive Psychology in Context: Effects of Expressing Gratitude in Ongoing Relationships Depend on Perceptions of Enactor Responsiveness.

    Science.gov (United States)

    Algoe, Sara B; Zhaoyang, Ruixue

    2016-01-01

    Recent correlational evidence implicates gratitude in personal and relational growth, for both members of ongoing relationships. From these observations, it would be tempting to prescribe interpersonal gratitude exercises to improve relationships. In this experiment, couples were randomly assigned to express gratitude over a month, or to a relationally-active control condition. Results showed modest effects of condition on personal and relational well-being. However, those whose partners were perceived as being particularly responsive when expressing gratitude at the initial lab session showed greater well-being across a range of outcomes, whereas this was not so for people in the control condition. Notably, evidence raises concerns about the effectiveness of artificial injections of gratitude when the partner is perceived to be low in responsiveness. Given the importance of close relationships, this work highlights the need for more theory-driven basic research tested in context before assuming what appears to work naturally will also work artificially.

  7. Association of a single nucleotide polymorphic variation in the human chromosome 19q13.3 with drug responses in the NCI60 cell lines

    DEFF Research Database (Denmark)

    Nissen, K.K.; Vogel, Ulla Birgitte; Nexo, B.A.

    2009-01-01

    the correlations between the responses of the NCI60 cells to different anticancer drugs and their respective alleles of five DNA polymorphisms located in a cancer-related chromosomal area. One polymorphism, located in the 5' noncoding region of the gene ASE-1, alias CD3EAP, proved to be associated with drug...

  8. Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac ▿

    Science.gov (United States)

    van Leeuwen, Jolanda S.; Vermeulen, Nico P. E.; Vos, J. Chris

    2011-01-01

    Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as a model eukaryote with which to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during the initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. In particular, pleiotropic drug resistance (PDR) genes and genes under the control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. We tested if these processes or pathways were directly involved in diclofenac toxicity or resistance. Of the pleiotropic drug resistance gene products, the multidrug transporter Pdr5p was crucially important for diclofenac tolerance. Furthermore, deletion of components of the cell wall stress-responsive PKC pathway increased diclofenac toxicity, whereas incubation of cells with the cell wall stressor calcofluor white before the addition of diclofenac decreased its toxicity. Also, diclofenac induced flocculation, which might trigger the cell wall alterations. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as were zinc-responsive genes. Paradoxically, deletion of the zinc-responsive transcription factor Zap1p or addition of the zinc chelator 1,10-phenanthroline significantly increased diclofenac toxicity, establishing a regulatory role for zinc in diclofenac resistance. In conclusion, we have identified three new pathways involved in diclofenac tolerance in yeast, namely, Pdr5p as the main contributor to the PDR response, cell wall signaling via the PKC pathway, and zinc homeostasis, regulated by Zap1p. PMID:21724882

  9. Evaluating the impact of Mexico's drug policy reforms on people who inject drugs in Tijuana, B.C., Mexico, and San Diego, CA, United States: a binational mixed methods research agenda.

    Science.gov (United States)

    Robertson, Angela M; Garfein, Richard S; Wagner, Karla D; Mehta, Sanjay R; Magis-Rodriguez, Carlos; Cuevas-Mota, Jazmine; Moreno-Zuniga, Patricia Gonzalez; Strathdee, Steffanie A

    2014-02-12

    collection procedures have been implemented successfully, demonstrating the importance of binational collaboration in evaluating the impact of structural-level drug policy reforms on the behaviors, health, and wellbeing of PWID across an international border. Our prospective, mixed methods approach allows each study to be responsive to emerging phenomena within local contexts while regular collaboration promotes sharing insights across studies. The strengths and limitations of this approach may serve as a guide for other evaluations of harm reduction policies internationally.

  10. The Nuclear Age: Context for Family Interaction.

    Science.gov (United States)

    Ptacek, Carmen

    1988-01-01

    Suggests that concerns regarding the nuclear threat are prevalent among family members; parents and children feel powerless in response to the nuclear threat; response to the nuclear threat is a family issue; responding to the nuclear threat requires empowering families and changing the social context; and nuclear concerns need to be addressed in…

  11. HIV and AIDS among adolescents who use drugs: opportunities for drug policy reform within the sustainable development agenda.

    Science.gov (United States)

    Tinasti, Khalid

    2018-02-01

    The international community's commitment to halve by 2015 the HIV transmission among people who inject drugs has not only been largely missed, instead new HIV infections have increased by 30%. Moreover, drug injection remains one of the drivers of new HIV infections due to punitive responses and lack of harm reduction resourcing. In the midst of this situation, adolescents are a forgotten component of the global response to illegal drugs and their link with HIV infection. The Sustainable Development Goals (SDGs) present an opportunity to achieve the global objective of ending AIDS among adolescents who use drugs, by addressing the structural vulnerabilities they face be they economic, social, criminal, health-related or environmental. The implementation of the SDGs presents an opportunity to address the horizontal nature of drug policy and to efficiently address the drugs-adolescents-HIV risk nexus. Adolescent-focused drug policies are linked to goals 1, 3, 4, 10, 16 and 17. Goals 3 and 16 are the most relevant; the targets of the latter link to the criminalization of drug use and punitive policy environments and their impact on adolescents' health and HIV transmission risks. Moreover, it presents an opportunity to include adolescent needs that are missing in the three drug control conventions (1961, 1971 and 1988), and link them with the provisions of the Convention on the Rights of the Child (1989). Finally, the six principles to deliver on sustainable development are also an opportunity to divert adolescents who use drugs away from criminalization and punitive environments in which their vulnerability to HIV is greater. Addressing HIV among adolescents who use drugs is an extremely complex policy issue depending on different sets of binding and non-binding commitments, interventions and stakeholders. The complexity requires a horizontal response provided by the SDGs framework, starting with the collection of disaggregated data on this specific subgroup. Ending

  12. Blinded prospective evaluation of computer-based mechanistic schizophrenia disease model for predicting drug response.

    Directory of Open Access Journals (Sweden)

    Hugo Geerts

    Full Text Available The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2 antagonist and ocaperidone, a very high affinity dopamine D(2 antagonist, using only pharmacology and human positron emission tomography (PET imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS total score and the higher extra-pyramidal symptom (EPS liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

  13. Cross-border drug injection relationships among injection drug users in Tijuana, Mexico

    Science.gov (United States)

    Wagner, Karla D.; Pollini, Robin A.; Patterson, Thomas L.; Lozada, Remedios; Ojeda, Victoria D.; Brouwer, Kimberly C.; Vera, Alicia; Volkmann, Tyson A.; Strathdee, Steffanie A.

    2010-01-01

    Background International borders are unique social and environmental contexts characterized by high levels of mobility. Among drug users, mobility increases risk for human immunodeficiency virus (HIV) in part through its effects on the social environment. However, the social dynamics of drug users living in border regions are understudied. Methods 1056 injection drug users (IDUs) residing in Tijuana, Mexico were recruited using respondent-driven sampling (RDS) from 2006 to 2007, and underwent surveys and testing for HIV, syphilis, and tuberculosis (TB). Using logistic regression on baseline data, we identified correlates of having ever injected drugs with someone from the US. Results Almost half (48%) reported ever injecting drugs with someone from the US. In RDS-adjusted logistic regression, factors independently associated with having ever injected with someone from the US included: having greater than middle school education (Adjusted Odds Ratio [AOR] 2.91; 95% Confidence Interval [C.I.] 1.52, 5.91), speaking English (AOR 3.24, 95% C.I. 1.96, 5.36), age (AOR 1.10 per year; 95% C.I. 1.07, 1.14), age at initiation of injection drug use (AOR 0.90 per year; 95% C.I. 0.86, 0.94), homelessness (AOR 2.61; 95% C.I. 1.27, 5.39), and having ever been incarcerated (AOR 11.82; 95% C.I., 5.22, 26.77). No associations with HIV, syphilis, TB, drug use, or injection risk behavior were detected. Conclusion Findings suggest that IDU networks in Mexico and the US may transcend international borders, with implications for cross-border transmission of infectious disease. Binational programs and policies need to consider the structure and geographic distribution of drug using networks. PMID:20889270

  14. The context dependency of extinction negates the effectiveness of cognitive enhancement to reduce cocaine-primed reinstatement.

    Science.gov (United States)

    Hammond, Sherri; Wagner, John J

    2013-09-01

    With respect to the treatment of addiction, the objective of extinction training is to decrease drug-seeking behavior by repeatedly exposing the patient to cues in the absence of unconditioned reinforcement. Such exposure therapy typically takes place in a novel (clinical) environment. This is potentially problematic, as the effects of extinction training include a context dependent component and therefore diminished efficacy is expected upon the patient's return to former drug-seeking/taking environments. We have reported that treatment with the NMDAR coagonist d-serine is effective in facilitating the effects of extinction to reduce cocaine-primed reinstatement. The present study assesses d-serine's effectiveness in reducing drug-primed reinstatement under conditions in which extinction training occurs in a novel environment. After 22 days of cocaine self-administration (0.5 mg/kg) in context "A", animals underwent 5 extinction training sessions in context "B". Immediately after each extinction session in "B", animals received either saline or d-serine (60 mg/kg) treatment. Our results indicate that d-serine treatment following extinction in "B" had no effect on either IV or IP cocaine-primed reinstatement conducted in "A". These results stand in contrast to our previous findings where extinction occurred in "A", indicating that d-serine's effectiveness in facilitating extinction training to reduce drug-primed reinstatement is not transferable to a novel extinction environment. This inability of d-serine treatment to reduce the context specificity of extinction training may explain the inconsistent effects observed in clinical studies published to date in which adjunctive cognitive enhancement treatment has been combined with behavioral therapy without significant benefit. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Price Sensitivity of Demand for Prescription Drugs

    DEFF Research Database (Denmark)

    Simonsen, Marianne; Skipper, Lars; Skipper, Niels

    2016-01-01

    We investigate price sensitivity of demand for prescription drugs, using drug purchase records for the entire Danish population. We identify price responsiveness by exploiting variation in prices caused by kinked reimbursement schemes and implement a regression kink design. The results suggest some...... price responsiveness with corresponding price elasticities ranging from −0.2 to −0.7. Individuals with chronic disease and especially individuals above the age of 65 respond less to the price of drugs....

  16. Drug Intoxicated Irregular Fighters: Complications, Dangers, and Responses

    National Research Council Canada - National Science Library

    Kan, Paul R

    2008-01-01

    .... Drug consumption in contemporary wars has coincided with the use of child soldiers, has led to increased unpredictability among irregular fighters, provided the conditions for the breakdown of social...

  17. The Candida albicans Ddr48 protein is essential for filamentation, stress response, and confers partial antifungal drug resistance.

    Science.gov (United States)

    Dib, Leila; Hayek, Peter; Sadek, Helen; Beyrouthy, Berna; Khalaf, Roy A

    2008-06-01

    Candida albicans is a dimorphic pathogenic fungus that causes mucosal and systemic infections. C. albicans pathogenicity is attributed to its ability to exist in different morphologic states and to respond to stress by up regulating several key genes. DDR48 is a stress-associated gene involved in DNA repair and in response to antifungal drug exposure. One allele of DDR48 was knocked out by homologous recombination that inserted a marker cassette in its position. Furthermore, reintroducing DDR48 on a plasmid created a revertant strain. Strains were grown on filamentation inducing and noninducing media, subjected to an oxidative stress challenge, injected into mice to assess virulence, and assayed for antifungal susceptibility by the E-test method. DDR48 was found to be haploid insufficient and possibly essential, since only a heterozygote, but not a homozygous, null mutant was generated. The mutant was filamentation defective on all hyphal media tested including serum and corn meal agar. Discrepancies in drug resistance profiles also were present: compared with the parental strain, DDR48/ddr48 heterozygote strain was susceptible in a dose-dependent manner to itraconazole and fluconazole and susceptible to ketoconazole. The mutant also appeared to be hypersensitive to a potentially lethal hydrogen peroxide challenge. However, no reduction in virulence of the mutant was observed. The present findings provide evidence that DDR48 is essential for filamentation, stress response, and possibly viability of C. albicans, making it a prime target for antifungal drug design.

  18. Trust-Based and Context-Aware Authentication in a Software Architecture for Context and Proximity-Aware Services

    Science.gov (United States)

    Lenzini, Gabriele

    We describe an existing software architecture for context and proximity aware services that enables trust-based and context-aware authentication. A service is proximity aware when it automatically detects the presence of entities in its proximity. Authentication is context-aware when it uses contextual information to discern among different identities and to evaluate to which extent they are authentic. The software architecture that we describe here is functioning in our Institute: It manages a sensor network to detect the presence and location of users and their devices. A context manager is responsible to merge the different sources of contextual information, to solve potential contradictions, and to determine the level of authentication of the identity of the person approaching one of the services offered in the coffee-break corners of our Institute. In our solution for context-aware authentication, sensors are managed as if they were recommenders having subjective belief, disbelief, and uncertainty (i.e., trust) on the position and identity of users. A sensor’s subjective trust depends on what it has been sensing in the environment. We discuss the results of an array of simulations that we conducted to validate our concept of trust-based and context-aware authentication. We use Subjective Logic to manage trust.

  19. Parents who use drugs: accounting for damage and its limitation.

    Science.gov (United States)

    Rhodes, Tim; Bernays, Sarah; Houmoller, Kathrin

    2010-10-01

    Parents who use drugs parent in a context of heightened concern regarding the damaging effects of parental drug use on child welfare and family life. Yet there is little research exploring how parents who use drugs account for such damage and its limitation. We draw here upon analyses of audio-recorded depth qualitative interviews, conducted in south-east England between 2008 and 2009, with 29 parents who use drugs. Our approach to thematic analysis treated accounts as co-produced and socially situated. An over-arching theme of accounts was 'damage limitation'. Most damage limitation work centred on efforts to create a sense of normalcy of family life, involving keeping drug use secret from children, and investing heavily in strategies to maintain ambiguity regarding children's awareness. Our analysis highlights that damage limitation strategies double-up in accounts as resources of child protection as well as self protection. This illuminates tensions in the multiple functions that accounts of damage limitation can serve. We draw a distinction between accounts in which damage is qualified and those in which damage is accepted. Accounts of damage qualification highlight a theme of 'good enough' parenting. Accounts of damage acceptance highlight a theme of 'recovery'. We find that the interview accounts operate in response to a regulative norm of 'good parenting' in which one strives to deflect damaged identity through narratives of damage qualification and to seek understanding and acceptance through narratives of recovery. Noting the absence of space for parents who use drugs to openly reflect or talk about the challenges they face, we identify the need for social change interventions to create enabling environments for earlier help seeking and talking. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. [International cooperation in combatting illicit drugs in Mozambique].

    Science.gov (United States)

    Buvana, Flávia; Ventura, Carla Aparecida Arena

    2011-06-01

    Countries from Southern Africa have formed a Development Community (SADC) to stimulate common actions in several areas, among them illicit drugs combat. In this context, the goal of this qualitative study was to identify information and perception about the cooperation set up between Mozambique and other SADC members in combatting illicit drugs. Data were collected through semi-structured interviews with public employees developing actions directed at the implementation of the Protocol to Combat Drugs in SADC. After transcriptions, the interviews were analyzed by content analysis and resulted in the categories: "Mozambique as a drugs corridor", "Cooperation Initiatives on Drugs among African countries", "Cooperation Difficulties in Africa", "Problems in Protocol Implementation" and "Difficulties to implement a control policy". As a consequence, there is a need to review and update the policies and strategies in the drugs area, as they are not contextualized in the country's current reality.