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Sample records for current drug dependence

  1. Current Trends of Drug Resistance Patterns of Acinetobacter baumannii Infection in Blood Transfusion-dependent Thalassemia Patients.

    Science.gov (United States)

    Almani, Suhail Ahmed; Naseer, Ali; Maheshwari, Sanjay Kumar; Maroof, Pir; Naseer, Raza; Khoharo, Haji Khan

    2017-01-01

    The present study aimed to evaluate the current trends of drug resistance patterns of Acinetobacter baumannii infection in blood transfusion-dependent thalassemia patients. This study was a cross sectional study, conducted at the Liaquat University of Medical and Health Sciences, Jamshoro/Hyderabad, Sindh, Pakistan from October 2014 to January 2016. Of 921 blood samples, A. baumannii strains were isolated from 100 blood samples. Blood samples were processed for the isolation, identification, and drugs sensitivity as per the Clinical and Laboratory Standards Institute. A. baumannii strains were identified by microbiological methods and Gram's staining. API 20 E kit (Biomeriuex, USA) was also used for identification. Data were analyzed on Statisti × 8.1 (USA). Mean ± standard deviation age was 11.5 ± 2.8 years. Nearly 70% were male and 30% were female ( P = 0.0001). Of 921 blood transfusion-dependent thalassemia patients, 100 (10.8%) patients showed growth of A. baumannii . Drug resistance was observed against the ceftazidime, cefixime, cefepime, imipenem, meropenem, amikacin, minocycline, tigecycline, and tazocin except for the colistin. The present study reports drug-resistant A. baumannii in blood transfusion-dependent thalassemia patients. National multicenter studies are recommended to estimate the size of the problem.

  2. Drug Establishments Current Registration Site

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Drug Establishments Current Registration Site (DECRS) is a database of current information submitted by drug firms to register establishments (facilities) which...

  3. Current obesity drug treatment

    Directory of Open Access Journals (Sweden)

    Marcio C. Mancini

    2006-03-01

    Full Text Available Pharmacological treatment of obesity is an area of sudden changes,development of new drugs and treatment propositions. This articlepresents information on physiological agents that are currentlybeing used as well as drugs that were widely used but are nomore available.

  4. Antiretroviral therapy: current drugs.

    Science.gov (United States)

    Pau, Alice K; George, Jomy M

    2014-09-01

    The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date. Published by Elsevier Inc.

  5. Biosimilar drugs: Current status.

    Science.gov (United States)

    Kumar, Rajiv; Singh, Jagjit

    2014-07-01

    Biologic products are being developed over the past three decades. The expiry of patent protection for many biological medicines has led to the development of biosimilars in UK or follow on biologics in USA. This article reviews the literature on biosimilar drugs that covers the therapeutic status and regulatory guidelines. Appraisal of published articles from peer reviewed journals for English language publications, search from PubMed, and guidelines from European Medicines Agency, US Food Drug Administration (FDA) and India were used to identify data for review. Literature suggest that biosimilars are similar biological products, i.e., comparable but not identical to the reference product, are not generic version of innovator product and do not ensure therapeutic equivalence. Biosimilars present more challenges than conventional generics and marketing approval is also more complicated. To improve access, US Congress passed the Biologics Price Competition and Innovation act 2009 and US FDA allowed "abbreviated pathway" for their approval. U.S law has defined new standards and terms and EMA scientific guidelines have also set detailed approval standards. India being one of the most preferred manufacturing destinations of biosimilars, there is a need for stringent safety and regulatory guidelines. The New India Guidelines "Draft Guidelines on Similar Biologics were announced in June 2012, by Department of Biotechnology at Boston bio and available online.

  6. National Council on Alcoholism and Drug Dependence

    Science.gov (United States)

    ... Month NCADD National Council on Alcoholism and Drug Dependence Addiction is a Disease - Treatment is Available - Recovery ... years, The National Council on Alcoholism and Drug Dependence, Inc. (NCADD) has been a valuable resource for ...

  7. Current manufacturing processes of drug-eluting sutures.

    Science.gov (United States)

    Champeau, Mathilde; Thomassin, Jean-Michel; Tassaing, Thierry; Jérôme, Christine

    2017-11-01

    Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Two general approaches can be followed: (i) the ones that add the API into the material during the manufacturing process of the suture and (ii) the ones that load the API to an already manufactured suture. Areas covered: This review provides an overview of the current manufacturing processes for drug-eluting suture production and discusses their benefits and drawbacks depending on the type of drugs. The mechanical properties and the drug delivery profile of drug-eluting sutures are highlighted since these implants must fulfill both criteria. Expert opinion: For limited drug contents, melt extrusion and electrospinning are the emerging processes since the drug is added during the suture manufacture process. Advantageously, the drug release profile can be tuned by controlling the processing parameters specific to each process and the composition of the drug-containing polymer. If high drug content is targeted, the coating or grafting of a drug layer on a pre-manufactured suture allows for preservation of the tensile strength requirements of the suture.

  8. Role of endocannabinoids in regulating drug dependence

    Directory of Open Access Journals (Sweden)

    Daniela Parolaro

    2007-01-01

    Full Text Available Daniela Parolaro, Daniela Vigano’, Natalia Realini, Tiziana RubinoNeuroscience Center, DBSF, University of Insubria, Busto Arsizio, ItalyAbstract: This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.Keywords: Endocannabinoids, drug dependence, opioids, nicotine, alcohol, psychostimulants

  9. The Comparison of Maladaptive Schema and Lifestyles in Drug Dependence and Non-Drug Dependence People

    Directory of Open Access Journals (Sweden)

    Vahideh Purmohammad

    2013-04-01

    Full Text Available Objective: The aim of this study was to compare early maladaptive schemas and life styles in drug dependences and normal population to recognize their role in drug dependence. Due to their importance in interpretation of special situations, cognitive schemas and life styles have a significant role in cognitive theories. Methods: The method of this research were post-facto and sectional styles. The population were included of 100 drug dependence adults and 100 non-drug dependence who were selected by at-reach methods. Young early maladaptive schema-short form and Basic Adlerian scales for interpersonal success-adult form questionnaires were used. Findings: the results showed that there were significant differences between early maladaptive schemas and life styles in groups under research. Conclusion: the study showed that drug dependence people suffer from high levels of early maladaptive schemas and their life styles are maladaptive. As a result, in prediction of dependence to drug and in treating it too much attention must be given to cognitive factors.

  10. Is dependence on one drug associated with dependence on other drugs? The cases of alcohol, caffeine and nicotine.

    Science.gov (United States)

    Hughes, J R; Oliveto, A H; MacLaughlin, M

    2000-01-01

    Several studies have correlated the use of one drug with that of another drug; however, whether dependence on one drug is associated with dependence on another drug, independent of any use/use association, is unclear. We asked 196 randomly-selected subjects the DSM-IV criteria for dependence as applied to alcohol, caffeine, and nicotine. Among ever users, the severity of alcohol vs nicotine dependence and alcohol vs caffeine dependence was related, but this relationship was weak (r = .22 & .31). Nicotine and caffeine dependence were not correlated. These results fail to confirm theories of commonality that hypothesize dependence on one drug predisposes to dependence on another drug.

  11. Inhibition of cardiac inward rectifier currents by cationic amphiphilic drugs.

    Science.gov (United States)

    van der Heyden, M A G; Stary-Weinzinger, A; Sanchez-Chapula, J A

    2013-09-01

    Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.

  12. Drug Use, Dependence, and Addiction at a British Columbia University: Good News and Bad News.

    Science.gov (United States)

    Alexander, Bruce K.

    1985-01-01

    Two studies of perceived and actual drug use at Simon Fraser University found students estimating greater drug use among friends than for themselves, but 31 percent reported dependence and 5 percent reported current addiction, especially to caffeine and nicotine. An approach to drug abuse focusing on familiar substances is recommended. (MSE)

  13. Emerging drugs of abuse: current perspectives on synthetic cannabinoids

    Directory of Open Access Journals (Sweden)

    Debruyne D

    2015-10-01

    Full Text Available Danièle Debruyne,1,2 Reynald Le Boisselier1 1Centre for Evaluation and Information on Pharmacodependence - Addictovigilance (CEIP-A, 2Toxicology and Pharmacology Laboratory, Department of Pharmacology, University Hospital Centre Côte de Nacre, Caen, France Abstract: New psychoactive drugs that have appeared over the last decade are typically dominated by cathinones and synthetic cannabinoids (SCs. SCs have been emerging as recreational drugs because they mimic the euphoria effect of cannabis while still being legal. Sprayed on natural herb mixtures, SCs have been primarily sold as “herbal smoking blends” or “herbal incense” under brand names like “Spice” or “K2”. Currently, SCs pure compounds are available from websites for the combination with herbal materials or for the use in e-cigarettes. For the past 5 years, an ever increasing number of compounds, representative of different chemical classes, have been promoted and now represent a large assortment of new popular drugs of abuse, which are difficult to properly identify. Their legal status varies by country with many government institutions currently pushing for their control. The in vitro binding to CB1/CB2 receptors is usually well-known and considerable differences have been found in the CB1 versus CB2 selectivity and potency within the different SCs, with several structure-activity relations being evident. Desired effects by CB1 agonist users are relaxation/recreative, however, cardiovascular, gastrointestinal, or psychiatric/neurological side effects are commonly reported. At present there is no specific antidote existing if an overdose of designer drugs was to occur, and no curative treatment has been approved by health authorities. Management of acute toxic effects is mainly symptomatic and extrapolated from experience with cannabis. Keywords: synthetic cannabinoids, chemistry, analysis, pharmacology, toxicology, dependence, medical care

  14. Stop Negative Thinking Effects for Drug Dependence

    OpenAIRE

    Windiarti, Sri Endang; Indriati, Indriati; Surachmi, Fajar

    2013-01-01

    The purpose of this study was to determine the effect of therapy stop thinking negatively against drug addiction in Rehabilitation Orphanage Rumah Damai Gunung Pati Semarang. This research is quasy experiment with pretest - posttes without the control group design. Thirty respondents were taken to the reseach sujects. Stop thinking negative therapy before and after thebehavior of drug addiction there are differences (t = 0.00), so it can be stated that the therapy stop thinking negatively inf...

  15. Current trends in microsponge drug delivery system.

    Science.gov (United States)

    Gangadharappa, H V; Gupta, N Vishal; Prasad M, Sarat Chandra; Shivakumar, H G

    2013-08-01

    Microsponge is a microscopic sphere capable of absorbing skin secretions, therefore reducing the oiliness of the skin. Microsponge having particle size of 10-25 microns in diameter, have wide range of entrapment of various ingredients in a single microsponges system and release them at desired rates. Conventional topical preparations have various disadvantages due to irritancy, odour, greasiness and patient compliance. In many topical dosage forms fail to reach the systemic circulation in sufficient amounts in few cases. These problems overcome by the usage of formulation as microsponge in the areas of research. Drug release in microsponge is done by the external stimuli like pH, temperature and rubbing. It has several advantageous over the other topical preparations in being non-allergenic, non-toxic, non-irritant and non- mutagenic. These microsponges are used in the sun screens, creams, ointments, over-the-counter skin care preparations, recently nanosponge were reported in literature used in delivery of drug by the use of cyclodextrins to enhance the solubility of poorly water soluble drugs, which are meant for topical application.

  16. Comparative Survey of Mental Disorders and Personality Characteristics in Persons With Drug Dependent and Non Drug Dependent in Hamadan, Iran

    Directory of Open Access Journals (Sweden)

    A. Ghaleiha

    2008-07-01

    Full Text Available Introduction & Objective: The influence of genetic, biological, psychological, social and cultural factors on drug dependency and high rate comorbidity of this phenomenon with psychiatric disorders for example anxiety, depression and characteristics and personality disorders is emphasized. The aim of this study was the comparative investigation of mental disorders and personality traits in persons with drug dependent and non drug dependent in Hamadan city in 2001-2003 .Materials & Methods: Present research was a descriptive comparison and subjects were 100 drug dependent persons and 100 non drug dependent individuals .Case group was chosen through available sampling among persons who call on psychiatrist and control group was chosen through randomly simple sampling from general population. Measurement and diagnostic tools includes questionnaire for examining demographic characteristics, designed by researchers and MMPI, SCL90-R tests and DSM IV criteria diagnostic and also T test that was used for analyzing data.Results: Between two groups in clinical and validity scales of MMPI test expect for hypochondriasis and hysteria and scales of SCL 90-R test expect somatization and interpersonal sensitivity differences were statistically significant (P<0.05.Conclusion: We can conclude that persons with drug dependent display more signs of psychopathology and mental disorders in comparison with non drug dependent people and Major depressive disorder and personality disorder were frequent among drug dependent groups. Depression and personal disorders were frequent in non drug dependent persons too. Our results support the results of previous studies.

  17. Influence of depression and early adverse experiences on illicit drug dependence: a case-control study.

    Science.gov (United States)

    Ferigolo, Maristela; Stein, Airton T; Fuchs, Flavio D; Barros, Helena M T

    2009-06-01

    The purpose of this study was to investigate the association between depression and illicit drug dependence among a Latin-American population. illicit drug dependent patients (n = 137) and controls (n = 274) were interviewed using the Diagnostic Interview for Genetic Studies, in order to detect lifetime and current depressive disorder and illicit (cocaine, cannabis or inhalants) substance dependence. A regression analysis was used to estimate the odds ratio for drug dependence according to the diagnosis of depression. The lifetime diagnosis of depression (p = 0.001; OR = 4.9; 95% CI, 1.9-12.7) predicts illegal drugs dependence. Sociodemographic variables such as male gender (p drug dependence. Additional influent factors detected were having parents (p = 0.006; OR = 18.9; 95% CI, 2.3-158) or friends (p illicit drugs dependents. although a causal relationship between dependence on illicit drugs and depression cannot be determined, comparison of the sequence of events point to the occurrence of depression later in life than dependence. It remains to be determined whether depression is a comorbidity of dependence, sharing etiological factors, or a consequence of drug abuse and/or abstinence.

  18. Risk factors in prevention of drug dependences

    NARCIS (Netherlands)

    Orosova, Ol'ga; Gajdosova, Beata; Madarasova-Geckova, Andrea; Van Dijk, Jitse P.

    2007-01-01

    The study presents the state-of-art of knowledge of risk factors of drug use as a form of risk behaviour in adolescents in individual, interpersonal, and environmental domain (family, school, society). The attention is paid to general deviation syndrome and to the construct of general tendency to

  19. Drug Education: An Emphasis on Chemical Dependency.

    Science.gov (United States)

    Violette, Ronald W.

    Efforts in the area of drug education have been less than successful over the years. The time has come to step back and reevaluate and reassess what it is we are trying to accomplish. Emphases in the past have certainly been well intentioned, but a new direction needs to be charted for the future. Health Educators and other professionals have…

  20. Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.

    Science.gov (United States)

    Dolman, M Emmy M; Poon, Evon; Ebus, Marli E; den Hartog, Ilona J M; van Noesel, Carel J M; Jamin, Yann; Hallsworth, Albert; Robinson, Simon P; Petrie, Kevin; Sparidans, Rolf W; Kok, Robbert J; Versteeg, Rogier; Caron, Huib N; Chesler, Louis; Molenaar, Jan J

    2015-11-15

    MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug. This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. ©2015 American Association for Cancer Research.

  1. Current situation and future usage of anticancer drug databases.

    Science.gov (United States)

    Wang, Hongzhi; Yin, Yuanyuan; Wang, Peiqi; Xiong, Chenyu; Huang, Lingyu; Li, Sijia; Li, Xinyi; Fu, Leilei

    2016-07-01

    Cancer is a deadly disease with increasing incidence and mortality rates and affects the life quality of millions of people per year. The past 15 years have witnessed the rapid development of targeted therapy for cancer treatment, with numerous anticancer drugs, drug targets and related gene mutations been identified. The demand for better anticancer drugs and the advances in database technologies have propelled the development of databases related to anticancer drugs. These databases provide systematic collections of integrative information either directly on anticancer drugs or on a specific type of anticancer drugs with their own emphases on different aspects, such as drug-target interactions, the relationship between mutations in drug targets and drug resistance/sensitivity, drug-drug interactions, natural products with anticancer activity, anticancer peptides, synthetic lethality pairs and histone deacetylase inhibitors. We focus on a holistic view of the current situation and future usage of databases related to anticancer drugs and further discuss their strengths and weaknesses, in the hope of facilitating the discovery of new anticancer drugs with better clinical outcomes.

  2. Behavioral Pharmacology of Human Drug Dependence

    Science.gov (United States)

    1981-07-01

    1978. pp. 1-37. Pickens, I., Thompson, T., and Muchow, D.C. Cannabis and phenoy- olidine self-adinistration by animals. In: Goldberg, L., and...phenyl- ethylamines: cocaine, caffeine , and nicotine. Cocaine maintained high levels of self-infusion performance through a broader range of doses than...any of the 16 other drugs tested (0.032-3.2 mg/kg). Figure 2 shows that mean levels of self-infusion of both nicotine and caffeine were within the

  3. Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.

    Science.gov (United States)

    Yasinzai, Masoom; Khan, Momin; Nadhman, Akhtar; Shahnaz, Gul

    2013-10-01

    Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered.

  4. Nicotine dependence, use of illegal drugs and psychiatric morbidity.

    Science.gov (United States)

    Martínez-Ortega, José María; Jurado, Dolores; Martínez-González, Miguel Angel; Gurpegui, Manuel

    2006-09-01

    The purpose of this study was to examine the association of smoking and nicotine dependence with psychiatric morbidity, controlling for the potential confounding effect of smoking on the relationship between the use of other substances and psychiatric morbidity. A sample of 290 adults were interviewed at a primary health centre (patients, 58%; patients' relatives, 34%; staff, 8%) to inquire about their tobacco, caffeine, alcohol, and illegal drug consumption. Psychiatric morbidity, defined by a score >6 on the General Health Questionnaire (GHQ-28), showed a strong direct association with nicotine dependence. The use of illegal drugs, but not of alcohol, was also strongly associated with psychiatric morbidity, after controlling for smoking. Both smoking and high nicotine dependence were also associated with use of caffeine, alcohol, cannabis and cocaine. High nicotine dependence may be considered as an expression of individual psychopathologic vulnerability. Tobacco may have a central facilitating role in the use of caffeine, alcohol, and illegal drug.

  5. [The costs of new drugs compared to current standard treatment].

    Science.gov (United States)

    Ujeyl, Mariam; Schlegel, Claudia; Gundert-Remy, Ursula

    2013-01-01

    Until AMNOG came into effect Germany had free pricing of new drugs. Our exemplary work investigates the costs of new drugs that were licensed in the two years prior to AMNOG, and compares them to the costs of standard treatment that has been used in pivotal trials. Also, the important components of pharmaceutical prices will be illustrated. We retrospectively analysed the European Public Assessment Reports of proprietary medicinal products that the European Medicinal Agency initially approved in 2009 and 2010 and that were tested against an active control in at least one pivotal trial. If the standard treatment was a generic, the average pharmacy retail price of new drugs was 7.4 times (median 7.1) higher than that of standard treatment. If the standard treatment was an originator drug the average price was 1.4 times (median 1.2) higher than that of the new drug. There was no clear correlation of an increase in costs for new drugs and their "grade of innovation" as rated according to the criteria of Fricke. Our study shows that prices of new drugs must be linked to the evidence of comparative benefit; since German drug pricing is complex, cost saving effects obtained thereby will depend on a range of other rules and decisions. Copyright © 2013. Published by Elsevier GmbH.

  6. Oral transmucosal drug delivery--current status and future prospects.

    Science.gov (United States)

    Sattar, Mohammed; Sayed, Ossama M; Lane, Majella E

    2014-08-25

    Oral transmucosal drug delivery (OTDD) dosage forms have been available since the 1980s. In contrast to the number of actives currently delivered locally to the oral cavity, the number delivered as buccal or sublingual formulations remains relatively low. This is surprising in view of the advantages associated with OTDD, compared with conventional oral drug delivery. This review examines a number of aspects related to OTDD including the anatomy of the oral cavity, models currently used to study OTDD, as well as commercially available formulations and emerging technologies. The limitations of current methodologies to study OTDD are considered as well as recent publications and new approaches which have advanced our understanding of this route of drug delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. The relevance of the psychological evaluation in drug dependence

    OpenAIRE

    Popescu, G; Negrei, C; B?l?l?u, D; Ciobanu, AM; Baconi, D

    2014-01-01

    Psychological interventions are considered a central part of the individual psychotherapy in the rehabilitation counseling of psychiatrically symptomatic drug-dependent patients during methadone maintenance treatment in community programs. The need for psychological counseling should be evaluated for each individual patient. Medication is an important part of the treatment and individual psychotherapy focuses on the reduction or total cessation of drug use. The Recipient is G.M. 31, sentenced...

  8. Cocaine Allergy in Drug-Dependent Patients and Allergic People.

    Science.gov (United States)

    Armentia, Alicia; Martín-Armentia, Blanca; Martín-Armentia, Sara; Ruiz-Muñoz, Pedro; Quesada, Jorge Martínez; Postigo, Idoia; Conde, Rosa; González-Sagrado, Manuel; Pineda, Fernando; Castillo, Miriam; Palacios, Ricardo; Tejedor, Jesús

    Adverse reactions to local anesthetics (LAs), especially esters, are not uncommon, but true allergy is rarely diagnosed. To our knowledge, currently there is no reliable method of determining IgE-mediated hypersensitivity to LAs and cocaine. To assess the clinical value of allergy tests (prick, IgE, challenges, and arrays) in people suffering hypersensitivity reactions (asthma and anaphylaxis) during local anesthesia with cocaine derivatives and drug abusers with allergic symptoms after cocaine inhalation. We selected cocaine-dependent patients and allergic patients who suffered severe reactions during local anesthesia from a database of 23,873 patients. The diagnostic yield (sensitivity, specificity, and predictive value) of allergy tests using cocaine and coca leaf extracts in determining cocaine allergy was assessed, taking a positive challenge as the criterion standard. After prick tests, specific IgE, and challenge with cocaine extract, 41 of 211 patients (19.4%) were diagnosed as sensitized to cocaine. Prick tests and IgE to coca leaves (coca tea) had a good sensitivity (95.1% and 92.7%, respectively) and specificity (92.3 and 98.8%, respectively) for the diagnosis of cocaine allergy and LA-derived allergy. Cocaine may be an important allergen. Drug abusers and patients sensitized to local anesthesia and tobacco are at risk. Both prick tests and specific IgE against coca leaf extract detected sensitization to cocaine. The highest levels were related to severe clinical profiles. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Voltage Dependence of a Neuromodulator-Activated Ionic Current123

    Science.gov (United States)

    2016-01-01

    Abstract The neuromodulatory inward current (IMI) generated by crab Cancer borealis stomatogastric ganglion neurons is an inward current whose voltage dependence has been shown to be crucial in the activation of oscillatory activity of the pyloric network of this system. It has been previously shown that IMI loses its voltage dependence in conditions of low extracellular calcium, but that this effect appears to be regulated by intracellular calmodulin. Voltage dependence is only rarely regulated by intracellular signaling mechanisms. Here we address the hypothesis that the voltage dependence of IMI is mediated by intracellular signaling pathways activated by extracellular calcium. We demonstrate that calmodulin inhibitors and a ryanodine antagonist can reduce IMI voltage dependence in normal Ca2+, but that, in conditions of low Ca2+, calmodulin activators do not restore IMI voltage dependence. Further, we show evidence that CaMKII alters IMI voltage dependence. These results suggest that calmodulin is necessary but not sufficient for IMI voltage dependence. We therefore hypothesize that the Ca2+/calmodulin requirement for IMI voltage dependence is due to an active sensing of extracellular calcium by a GPCR family calcium-sensing receptor (CaSR) and that the reduction in IMI voltage dependence by a calmodulin inhibitor is due to CaSR endocytosis. Supporting this, preincubation with an endocytosis inhibitor prevented W7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride)-induced loss of IMI voltage dependence, and a CaSR antagonist reduced IMI voltage dependence. Additionally, myosin light chain kinase, which is known to act downstream of the CaSR, seems to play a role in regulating IMI voltage dependence. Finally, a Gβγ-subunit inhibitor also affects IMI voltage dependence, in support of the hypothesis that this process is regulated by a G-protein-coupled CaSR. PMID:27257619

  10. [Development of antituberculous drugs: current status and future prospects].

    Science.gov (United States)

    Tomioka, Haruaki; Namba, Kenji

    2006-12-01

    Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are

  11. Seasonal dependence of large-scale Birkeland currents

    International Nuclear Information System (INIS)

    Fujii, R.; Iijima, T.; Potemra, T.A.; Sugiura, M.

    1981-01-01

    The seasonal dependence of large-scale Birkeland currents has been determined from the analysis of vector magnetic field data acquired by the TRIAD satellite in the northern hemisphere. Statistical characteristics of single sheet (i.e., net currents) and double sheet Birkeland currents were determined from 555 TRIAD passes during the summer, and 408 passes during the winter (more complicated multiple-sheet current systems were not included in this study). The average K/sub p/ value for the summer events is 1.9 and for the winter events is 2.0. The principal results include the following: (1) The single sheet Birkeland currents are statistically observed more often than the double sheet currents in the dayside of the auroral zone during any season. The single sheet currents are also observed more often in the summer than in the winter (as much as 2 to 3 times as often depending upon the MLT sector). (2) The intensities of the single and double sheet Birkeland currents on the dayside, from approximately 1000 MLT to 1800 MLT, are larger during the summer (in comparison to winter) by a factor of about 2. (3) The intensities of the double sheet Birkeland currents in the nightside (the dominant system in this local time) do not show a significant difference from summer to winter. (4) The single and double sheet currents in the dayside (between 0600 and 1800 MLT) appear at higher latitudes (by about 1 0 to 3 0 ) during the summer in comparison to the winter. These characterisctis suggest that the Birkeland current intensities are controlled by the ionosphere conductivity in the polar region. The greater occurrence of single sheet Birkeland currents during the summertime supports the suggestion that these currents close via the polar cap when the conductivity there is sufficiently high to permit it

  12. Low noise constant current source for bias dependent noise measurements

    International Nuclear Information System (INIS)

    Talukdar, D.; Bose, Suvendu; Bardhan, K. K.; Chakraborty, R. K.

    2011-01-01

    A low noise constant current source used for measuring the 1/f noise in disordered systems in ohmic as well as nonohmic regime is described. The source can supply low noise constant current starting from as low as 1 μA to a few tens of milliampere with a high voltage compliance limit of around 20 V. The constant current source has several stages, which can work in a standalone manner or together to supply the desired value of load current. The noise contributed by the current source is very low in the entire current range. The fabrication of a low noise voltage preamplifier modified for bias dependent noise measurements and based on the existing design available in the MAT04 data sheet is also described.

  13. The Study of early maladaptive Schemas in Men Dependent on Drugs and those Not Dependent

    Directory of Open Access Journals (Sweden)

    MR Firoozi

    2015-11-01

    Full Text Available Introduction and Objectives of the Study Dependence on drugs is a prevalent problem throughout the world, in general and in Iran, in particular. Such a phenomenon is associated with numerous negative consequences. Given the changes in the consumption patterns in different countries, especially in Iran, and the abuse of drugs, identifying the factors which may pave the way for drug abuse is absolutely essential, which can be taken into account in setting the objectives of therapy programs. Cognizant of this, the present study has sought to study early maladaptive schemas in men dependent on drugs and those that are not. Materials and Method: The research design adopted in the present study was causal-comparative. The populaiton of interest was all the men dependent on drugs in the city of Yasouj, who had presented to recovery centers affiliated to welfare organization and Yasouj University of Medical Sciences in the year 2014 and were undergoing treatment. Using multi-stage cluster sampling, initially out of 23 centers for recovery programs, four centers were randomly chosen. Following that, out of each center, 20 and in total, 80 clients were chosen as the sample through convenience sampling. In addition, 80 men not dependent on drugs were chosen through matching with the sample dependent on drugs in terms of age, gender and locality. For the purpsoe of measuing early maladaptive schemas, we made use of the short version of Young’s early maladaptive Schemas Questionnaire. In order to determine the prevalent schemas in men dependent on drugs and those not dependent and the difference between the two groups, use was made of independent-sample t-test and effect size (d. Findings: The findings suggest that mean values of those dependent on drugs in all the schemas in quesiton were significantly higher than those of men not dependent. Although the difference in effect size of all schemas fell in the domain of the large effect, the largest

  14. Beam position dependence of a wall-current monitor

    International Nuclear Information System (INIS)

    Tamiya, K.; Asami, A.; Suwada, T.; Urano, T.; Kobayashi, H.

    1995-01-01

    It was pointed out recently that there exists an appreciable beam position dependence in the wall-current monitor widely used in electron accelerators. Detailed study of this dependence is performed on a test bench varying the pulse width and the frequency of the input signal simulating the beam. The results of experiments show that when the pulse width becomes shorter more appreciable becomes the dependence, and it approaches to that of calculated from the method of images. A unified analysis is under way. (author)

  15. The current status of community drug testing via the analysis of drugs and drug metabolites in sewage

    Directory of Open Access Journals (Sweden)

    Malcolm J. Reid

    2011-12-01

    Full Text Available Over the past few years the analysis of drug residues in sewage has been promoted as a means of estimating the level of drug use in communities. Measured drug residue concentrations in the sewage are used to determine the load (total mass of the drug being used by the entire community. Knowledge of the size or population of the community then allows for the calculation of drug-use relative to population (typically drug-mass/day/1000 inhabitants which facilitates comparisons between differing communities or populations. Studies have been performed in many European countries, including Norway, as well as in the US and Australia. The approach has successfully estimated the use of cocaine, amphetamine, methamphetamine, MDMA, cannabis, nicotine and alcohol. The analysis of biomarkers of drug use in sewage has great potential to support and complement existing techniques for estimating levels of drug use, and as such has been identified as a promising development by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA; www.emcdda.europa.eu/wastewater-analysis. The approach is not without its challenges, and ongoing collaboration across Europe aims at agreeing upon best-practice and harmonising the methods being used. In Norway development is being performed through the NFR RUSMIDDEL funded DrugMon (www.niva.no/drugmon project that has led to the development of many new techniques, significantly improved our understanding of the uncertainties associated with the approach and allowed the coordination of Europe wide collaboration which has included all important intercalibration exercises. Application of the technique can provide evidence-based and real-time estimates of collective drug use with the resulting data used to improve the much needed estimates of drug use and dependency.

  16. Can tobacco dependence provide insights into other drug addictions?

    Directory of Open Access Journals (Sweden)

    Joseph R. DiFranza

    2016-10-01

    Full Text Available Abstract Within the field of addiction research, individuals tend to operate within silos of knowledge focused on specific drug classes. The discovery that tobacco dependence develops in a progression of stages and that the latency to the onset of withdrawal symptoms after the last use of tobacco changes over time have provided insights into how tobacco dependence develops that might be applied to the study of other drugs. As physical dependence on tobacco develops, it progresses through previously unrecognized clinical stages of wanting, craving and needing. The latency to withdrawal is a measure of the asymptomatic phase of withdrawal, extending from the last use of tobacco to the emergence of withdrawal symptoms. Symptomatic withdrawal is characterized by a wanting phase, a craving phase, and a needing phase. The intensity of the desire to smoke that is triggered by withdrawal correlates with brain activity in addiction circuits. With repeated tobacco use, the latency to withdrawal shrinks from as long as several weeks to as short as several minutes. The shortening of the asymptomatic phase of withdrawal drives an escalation of smoking, first in terms of the number of smoking days/month until daily smoking commences, then in terms of cigarettes smoked/day. The discoveries of the stages of physical dependence and the latency to withdrawal raises the question, does physical dependence develop in stages with other drugs? Is the latency to withdrawal for other substances measured in weeks at the onset of dependence? Does it shorten over time? The research methods that uncovered how tobacco dependence emerges might be fruitfully applied to the investigation of other addictions.

  17. Role of the limbic system in dependence on drugs.

    Science.gov (United States)

    Rodríguez de Fonseca, F; Navarro, M

    1998-08-01

    The limbic system is a group of structurally and functionally related areas of the brain that provides the anatomical substrate for emotions and motivated behaviour, including the circuitry for the stress response and reward-related events. This system is strongly implicated in drug abuse from the pleasure and/or positive side associated with acute exposure to the dysphoria and craving associated with withdrawal. The contribution of the main cortical and subcortical elements of the limbic system to drug dependence is briefly reviewed in the present work with a focus on the role of the extended amygdala and its connections as well as on the peripheral feedback signals mediated by adrenal glucocorticoids. The elucidation of the neuroadaptive responses of the limbic system to chronic drug exposure will undoubtedly help to design rational strategies for the treatment of addiction.

  18. Measurement of Drug Craving in Persian Speaking Subjects; a Review on Current Experiences and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Masoomeh Maarefvand

    2012-09-01

    Full Text Available Background: Drug craving is considered as one of the main cores of drug dependency and addiction. Multidimensionality of drug craving, its cultural-bounded features and its intra individual rapidly changing nature makes it difficult to be measured. Nowadays, regarding different psychometric approaches, there are various instruments available for measurement of different aspects of drug craving but mainly for Latin-based languages in North America and European countries. High prevalence and special conditions, and unique subcultures in substance abuse and addiction in many countries, like Iran, make the design of culturally validated instruments for drug craving assessment priority. Materials and Methods: Comprehensive review on drug craving measurement instruments for Persian speaking subjects have been performed by searching in databases (ELSEVIER, Science Direct and Scientific Information Database (SID and investigating of related documents on regional experiences. Results: In this article seven main categories of drug craving instruments have been reviewed focusing on validated versions in Persian language including: self-reports, reinforcement “proxies”, drug self administration, psycho physiological responding, neurobiological responding, cognitive processing and expressive methods. Conclusion: Reviewing on weak and strength points of each instrument group and national and regional experiences shows that designing and validating a new series of ecologically-validated instruments for multidimensional measurement of drug craving in different addiction subcultures should be prioritized to cover current methodological gaps in substance abuse studies in Iran.

  19. Treatment of drug dependence with Brazilian herbal medicines

    Directory of Open Access Journals (Sweden)

    Elisaldo A. Carlini

    Full Text Available The topic "Herbal Medicines in the Treatment of Addictions" in a country must be preceded by answers to four questions: 1. Does the country in question possess a biodiversity rich enough to allow the discovery of useful medicines? 2. Do local people have tradition and culture to look for and use resources from Nature to alleviate and cure diseases, including drug dependence? 3. Is drug dependence (or addiction present in the country in question? 4. Do people of that country recognize and diagnose such problem as a serious one? Alcohol is, by far, the most serious health problem when drug abuse is considered, reaching all of Brazilian society, including the Indians. On the contrary, other drugs may be considered as minor problems and they are not the main focus of this manuscript. The people living in Brazilian hinterland don’t have access to public health systems. Consequently, these people seek assistance from "curandeiros" and "raizeiros"; the Indians are assisted by the shaman. These "folk doctors" do not know the academic medicine and therapeutics, and resort to the local plants to treat different ailments of their patients. Furthermore, alcohol abuse and dependence are not recognized by them, according to the rules and criteria of academic medicine. We have conducted a survey in many Brazilian books, Thesis concerning phytotherapy, and several databank. The results of such searches were very disappointing. No published papers from Brazilian authors concerning the use of plants for the treatment of addictions were found in the databases and there were only three very short notes in the masterly book written by Shultes and Raffauf (1990. From the Brazilian books on folk medicine employing medicinal plants, ten mentions were disclosed: most of them dealing with treatment of alcohol problems and two to counteract "Ayahuasca" dependence.

  20. Structured outpatient treatment of alcohol vs. drug dependencies.

    Science.gov (United States)

    Washton, A M

    1990-01-01

    This chapter describes the rationale, indications, design, and use of a structured outpatient treatment approach as an effective alternative to residential treatment for alcohol and drug dependencies. An increasing demand for outpatient treatment services is being created by a combination of clinical and economic factors, including the influx of employed drug abusers who do not need or desire residential care and mounting financial pressures to contain health care costs. To be effective as a primary treatment modality, outpatient programs must be highly structured and intensive and able to deal with the full spectrum of alcohol and drug addictions. Perpetuating the historical separation between alcoholism and drug abuse treatment programs is unnecessary and counterproductive, although certain modifications in treatment approaches are needed to accommodate the distinctive characteristics of particular classes of drugs and the people who use them. The "outpatient rehab," a treatment model that approximates the intensity of inpatient treatment on an outpatient basis, may help to maximize the clinical efficacy and cost-effectiveness of outpatient treatment as a viable alternative to residential care. Initial treatment results with this model are encouraging.

  1. Effectiveness of multiple sclerosis treatment with current immunomodulatory drugs.

    Science.gov (United States)

    Milo, Ron

    2015-04-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of a putative autoimmune origin characterized by neurologic dysfunction disseminated in space and time due to demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of the disease resulted in the introduction of numerous effective immunomodulatoty drugs having diverse mechanisms of action, modes of administration and risk-benefit profiles. This results in more complex albeit more promising treatment selection and choices. The epidemiology, clinical features, pathogenesis and diagnosis of the disease are discussed. The mode of action and main characteristics of current immunomodulatory drugs for MS and their place in the therapeutic algorithm of the disease based on evidence from clinical trials are described. Speculation on new paradigms, treatment goals and outcome measures aimed at improving the landscape of MS treatment is presented. Multiple disease, drug and patient-related factors should be taken into consideration when selecting the appropriate drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS.

  2. Current knowledge of microRNA-mediated regulation of drug metabolism in humans.

    Science.gov (United States)

    Nakano, Masataka; Nakajima, Miki

    2018-05-01

    Understanding the factors causing inter- and intra-individual differences in drug metabolism potencies is required for the practice of personalized or precision medicine, as well as for the promotion of efficient drug development. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, epigenetic regulation, such as DNA methylation and histone acetylation, and post-translational modification. In addition to such regulation mechanisms, recent studies revealed that microRNAs (miRNAs), endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs, significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. Areas covered: This review summarizes the current knowledge regarding miRNAs-dependent regulation of drug-metabolizing enzymes and transcriptional factors and its physiological and clinical significance. We also describe recent advances in miRNA-dependent regulation research, showing that the presence of pseudogenes, single-nucleotide polymorphisms, and RNA editing affects miRNA targeting. Expert opinion: It is unwavering fact that miRNAs are critical factors causing inter- and intra-individual differences in the expression of drug-metabolizing enzymes. Consideration of miRNA-dependent regulation would be a helpful tool for optimizing personalized and precision medicine.

  3. Current advances in transdermal delivery of drugs for Alzheimer's disease

    Science.gov (United States)

    Nguyen, Thuy Trang; Giau, Vo Van; Vo, Tuong Kha

    2017-01-01

    Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the disadvantages of current pharmaceutical dosage options for this chronic disorder. They could have different strengths, such as offering a stable diffusion of active substance, avoiding the first pass metabolism, and reducing system adverse reactions. This article reviews the technical principles, novel techniques of transdermal delivery drug, and prospects for future development for the management of cognitive and behavioral dysfunctions in AD patients. PMID:28706327

  4. Current advances in transdermal delivery of drugs for Alzheimer's disease.

    Science.gov (United States)

    Nguyen, Thuy Trang; Giau, Vo Van; Vo, Tuong Kha

    2017-01-01

    Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the disadvantages of current pharmaceutical dosage options for this chronic disorder. They could have different strengths, such as offering a stable diffusion of active substance, avoiding the first pass metabolism, and reducing system adverse reactions. This article reviews the technical principles, novel techniques of transdermal delivery drug, and prospects for future development for the management of cognitive and behavioral dysfunctions in AD patients.

  5. Storm-time ring current: model-dependent results

    Directory of Open Access Journals (Sweden)

    N. Yu. Ganushkina

    2012-01-01

    Full Text Available The main point of the paper is to investigate how much the modeled ring current depends on the representations of magnetic and electric fields and boundary conditions used in simulations. Two storm events, one moderate (SymH minimum of −120 nT on 6–7 November 1997 and one intense (SymH minimum of −230 nT on 21–22 October 1999, are modeled. A rather simple ring current model is employed, namely, the Inner Magnetosphere Particle Transport and Acceleration model (IMPTAM, in order to make the results most evident. Four different magnetic field and two electric field representations and four boundary conditions are used. We find that different combinations of the magnetic and electric field configurations and boundary conditions result in very different modeled ring current, and, therefore, the physical conclusions based on simulation results can differ significantly. A time-dependent boundary outside of 6.6 RE gives a possibility to take into account the particles in the transition region (between dipole and stretched field lines forming partial ring current and near-Earth tail current in that region. Calculating the model SymH* by Biot-Savart's law instead of the widely used Dessler-Parker-Sckopke (DPS relation gives larger and more realistic values, since the currents are calculated in the regions with nondipolar magnetic field. Therefore, the boundary location and the method of SymH* calculation are of key importance for ring current data-model comparisons to be correctly interpreted.

  6. The relevance of the psychological evaluation in drug dependence.

    Science.gov (United States)

    Popescu, G; Negrei, C; Bălălău, D; Ciobanu, A M; Baconi, D

    2014-01-01

    Psychological interventions are considered a central part of the individual psychotherapy in the rehabilitation counseling of psychiatrically symptomatic drug-dependent patients during methadone maintenance treatment in community programs. The need for psychological counseling should be evaluated for each individual patient. Medication is an important part of the treatment and individual psychotherapy focuses on the reduction or total cessation of drug use. The Recipient is G.M. 31, sentenced to a seven-year term of imprisonment for trafficking and use of and high-risk drugs, diagnosed on admission with opioid and methadone dependence, withdrawal syndrome. Following the observation and psychological evaluation, psychiatric and clinical examination, initiation of methadone substitution treatment was recommended, according to the following regimen: twelve 2.5 mg tablets for the first 2 days, followed by increase with about 5 mg per week until the complete remission of withdrawal symptoms, stabilization of the dose but not exceeding 200 mg methadone hydrochloride per day. Specialist monitoring, specialized counseling and individual and group psychotherapy were provided.

  7. A gauge invariant theory for time dependent heat current

    International Nuclear Information System (INIS)

    Chen, Jian; ShangGuan, Minhui; Wang, Jian

    2015-01-01

    In this work, we develop a general gauge-invariant theory for AC heat current through multi-probe systems. Using the non-equilibrium Green’s function, a general expression for time-dependent electrothermal admittance is obtained where we include the internal potential due to the Coulomb interaction explicitly. We show that the gauge-invariant condition is satisfied for heat current if the self-consistent Coulomb interaction is considered. It is known that the Onsager relation holds for dynamic charge conductance. We show in this work that the Onsager relation for electrothermal admittance is violated, except for a special case of a quantum dot system with a single energy level. We apply our theory to a nano capacitor where the Coulomb interaction plays an essential role. We find that, to the first order in frequency, the heat current is related to the electrochemical capacitance as well as the phase accumulated in the scattering event. (paper)

  8. Current status of accreditation for drug testing in hair.

    Science.gov (United States)

    Cooper, Gail; Moeller, Manfred; Kronstrand, Robert

    2008-03-21

    At the annual meeting of the Society of Hair Testing in Vadstena, Sweden in 2006, a committee was appointed to address the issue of guidelines for hair testing and to assess the current status of accreditation amongst laboratories offering drug testing in hair. A short questionnaire was circulated amongst the membership and interested parties. Fifty-two responses were received from hair testing laboratories providing details on the amount and type of hair tests they offered and the status of accreditation within their facilities. Although the vast majority of laboratories follow current guidelines (83%), only nine laboratories were accredited to ISO/IEC 17025 for hair testing. A significant number of laboratories reporting that they were in the process of developing quality systems with a view to accrediting their methods within 2-3 years. This study provides an insight into the status of accreditation in hair testing laboratories and supports the need for guidelines to encourage best practice.

  9. Drugs in development for toxoplasmosis: advances, challenges, and current status.

    Science.gov (United States)

    Alday, P Holland; Doggett, Joseph Stone

    2017-01-01

    Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

  10. TID-dependent current measurements of IBL readout chips

    Energy Technology Data Exchange (ETDEWEB)

    Dette, Karola [TU Dortmund, Experimentelle Physik IV (Germany); CERN (Switzerland); Collaboration: ATLAS Pixel-Collaboration

    2016-07-01

    The ATLAS detector consists of several subsystems with a hybrid pixel detector as the innermost component of the tracking system. The pixel detector has been composed of three layers of silicon sensor assemblies during the first data taking run of the LHC and has been upgraded with a new 4th layer, the so-called Insertable B-Layer (IBL), in summer 2014. Each silicon sensor of the IBL is connected to a Front End readout chip (FE-I4) via bump bonds. During the first year of data taking an increase of the LV current produced by the readout chips was observed. This increase could be traced back to radiation damage inside the silicon. The dependence of the current on the Total Ionizing Dose (TID) and temperature has been tested with X-ray irradiations and will be presented in this talk.

  11. Alcohol and drug misuse, abuse, and dependence in women veterans.

    Science.gov (United States)

    Hoggatt, Katherine J; Jamison, Andrea L; Lehavot, Keren; Cucciare, Michael A; Timko, Christine; Simpson, Tracy L

    2015-01-01

    We conducted a systematic literature review on substance misuse, abuse, and dependence in women veterans, including National Guard/reserve members. We identified 837 articles published between 1980 and 2013. Of 56 included studies, 32 reported rates of alcohol misuse, binge drinking, or other unhealthy alcohol use not meeting diagnostic criteria for abuse or dependence, and 33 reported rates of drug misuse or diagnosed alcohol or drug use disorders. Rates ranged from 4% to 37% for alcohol misuse and from 7% to 25% for binge drinking; among Veterans Health Administration (VA) health-care system outpatients, rates ranged from 3% to 16% for substance use disorder. Studies comparing women veterans and civilians reported no clear differences in binge or heavy drinking. Substance misuse rates were generally lower among women veterans than men veterans. Substance misuse was associated with higher rates of trauma, psychiatric and medical conditions, and increased mortality and suicide rates. Most studies included only VA patients, and many used only VA medical record data; therefore, the reported substance misuse rates likely do not reflect true prevalence. Rates also varied by assessment method, source of data, and the subgroups studied. Further efforts to develop epidemiologically valid prevalence estimates are needed to capture the true health burden of substance misuse in women veterans, particularly those not using VA care. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  12. Medication development of ibogaine as a pharmacotherapy for drug dependence.

    Science.gov (United States)

    Mash, D C; Kovera, C A; Buck, B E; Norenberg, M D; Shapshak, P; Hearn, W L; Sanchez-Ramos, J

    1998-05-30

    The potential for deriving new psychotherapeutic medications from natural sources has led to renewal interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.

  13. Reimbursed Price of Orphan Drugs: Current Strategies and Potential Improvements.

    Science.gov (United States)

    Mincarone, Pierpaolo; Leo, Carlo Giacomo; Sabina, Saverio; Sarriá-Santamera, Antonio; Taruscio, Domenica; Serrano-Aguilar, Pedro Guillermo; Kanavos, Panos

    2017-01-01

    The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost-benefit ratio of early dialogs needs to be demonstrated and the "regulatory capture" effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases. © 2017 S. Karger AG, Basel.

  14. Orphan drugs in development for urea cycle disorders: current perspectives

    Directory of Open Access Journals (Sweden)

    Häberle J

    2014-09-01

    Full Text Available Johannes Häberle,1 Shawn E McCandless2 1Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; 2Center for Human Genetics, University Hospitals Case Medical Center, and Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA Abstract: The urea cycle disorders are caused by deficiency of one of the six hepatic enzymes or two transporters involved in detoxification of ammonia. The resulting hyperammonemia causes severe brain injury unless aggressive steps are taken to reduce the accumulation of ammonia, which is thought to be the most toxic metabolite. This review describes the current state of chronic management of urea cycle disorders, focusing on new and emerging therapies. Management strategies include the mainstay of treatment, namely dietary protein restriction and supplementation with l-arginine or l-citrulline. Several currently approved medications utilize and enhance alternative pathways of waste nitrogen excretion (sodium benzoate, sodium phenylacetate, sodium phenylbutyrate in several formulations, and glycerol phenylbutyrate, working through conjugation of the drug to either glycine (in the case of benzoate or glutamine, the products of which are excreted in the urine. Carglumic acid activates the first committed step of conversion of ammonia to urea, carbamoylphosphate synthetase, and thus effectively treats defective synthesis of the endogenous activator, N-acetylglutamate, whether due to genetic defects or biochemical inhibition of the N-acetylglutamate synthase enzyme. Approaches to neuroprotection during episodes of hyperammonemia are discussed, including the use of controlled hypothermia (brain cooling, as well as proposed, but as yet untested, pharmacologic therapies. Finally, cell-based therapies, including liver transplantation, infusion of fresh or cryopreserved hepatocytes, use of stem cells, and new approaches to gene

  15. 21 CFR 212.2 - What is current good manufacturing practice for PET drugs?

    Science.gov (United States)

    2010-04-01

    ..., holding, or distribution of PET drugs intended for human use. Current good manufacturing practice is... 21 Food and Drugs 4 2010-04-01 2010-04-01 false What is current good manufacturing practice for... HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  16. Ethical Implications in Vaccine Pharmacotherapy for Treatment and Prevention of Drug of Abuse Dependence.

    Science.gov (United States)

    Carfora, Anna; Cassandro, Paola; Feola, Alessandro; La Sala, Francesco; Petrella, Raffaella; Borriello, Renata

    2018-03-01

    Different immunotherapeutic approaches are in the pipeline for the treatment of drug dependence. "Drug vaccines" aim to induce the immune system to produce antibodies that bind to drugs and prevent them from inducing rewarding effects in the brain. Drugs of abuse currently being tested using these new approaches are opioids, nicotine, cocaine, and methamphetamine. In human clinical trials, "cocaine and nicotine vaccines" have been shown to induce sufficient antibody levels while producing few side effects. Studies in humans, determining how these vaccines interact in combination with their target drug, are underway. However, although vaccines can become a reasonable treatment option for drugs of abuse, there are several disadvantages that must be considered. These include i) great individual variability in the formation of antibodies, ii) the lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice, and iii) the lack of an effect on the drug desire that may predispose an addict to relapse. In addition, a comprehensive overview of several crucial ethical issues has not yet been widely discussed in order to have not only a biological approach to immunotherapy of addiction. Overall, immunotherapy offers a range of possible treatment options: the pharmacological treatment of addiction, the treatment of overdoses, the prevention of toxicity to the brain or the heart, and the protection of the fetus during pregnancy. So far, the results obtained from a small-scale experiment using vaccines against cocaine and nicotine suggest that a number of important technical challenges still need to be overcome before such vaccines can be approved for clinical use.

  17. Emerging drugs of abuse: current perspectives on substituted cathinones

    Directory of Open Access Journals (Sweden)

    Paillet-Loilier M

    2014-05-01

    Full Text Available Magalie Paillet-Loilier,1 Alexandre Cesbron,1 Reynald Le Boisselier,2 Joanna Bourgine,1 Danièle Debruyne1,2 1Toxicology and Pharmacology Laboratory, 2Centre d'Evaluation et d'Information sur la Pharmacodépendance – Addictovigilance (CEIP-A, Department of Pharmacology, University Hospital Centre, Caen, France Abstract: Substituted cathinones are synthetic analogs of cathinone that can be considered as derivatives of phenethylamines with a beta-keto group on the side chain. They appeared in the recreational drug market in the mid-2000s and now represent a large class of new popular drugs of abuse. Initially considered as legal highs, their legal status is variable by country and is rapidly changing, with government institutions encouraging their control. Some cathinones (such as diethylpropion or pyrovalerone have been used in a medical setting and bupropion is actually indicated for smoking cessation. Substituted cathinones are widely available from internet websites, retail shops, and street dealers. They can be sold under chemical, evocative or generic names, making their identification difficult. Fortunately, analytical methods have been developed in recent years to solve this problem. Available as powders, substituted cathinones are self-administered by snorting, oral injestion, or intravenous injection. They act as central nervous system stimulants by causing the release of catecholamines (dopamine, noradrenaline, and serotonin and blocking their reuptake in the central and peripheral nervous system. They may also decrease dopamine and serotonin transporter function as nonselective substrates or potent blockers and may inhibit monoamine oxidase effects. Nevertheless, considerable differences have been found in the potencies of the different substituted cathinones in vitro. Desired effects reported by users include increased energy, empathy, and improved libido. Cardiovascular (tachycardia, hypertension and psychiatric

  18. Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who inject drugs.

    Science.gov (United States)

    Smirnov, Andrew; Kemp, Robert; Ward, James; Henderson, Suzanna; Williams, Sidney; Dev, Abhilash; Najman, Jake M

    2016-09-01

    Despite over-representation of Indigenous Australians in sentinel studies of injecting drug use, little is known about relevant patterns of drug use and dependence. This study compares drug dependence and possible contributing factors in Indigenous and non-Indigenous Australians who inject drugs. Respondent-driven sampling was used in major cities and 'peer recruitment' in regional towns of Queensland to obtain a community sample of Indigenous (n = 282) and non-Indigenous (n = 267) injectors. Data are cross sectional. Multinomial models were developed for each group to examine types of dependence on injected drugs (no dependence, methamphetamine-dependent only, opioid-dependent only, dependent on methamphetamine and opioids). Around one-fifth of Indigenous and non-Indigenous injectors were dependent on both methamphetamine and opioids in the previous 12 months. Psychological distress was associated with dual dependence on these drugs for Indigenous [adjusted relative risk (ARR) 4.86, 95% confidence interval (CI) 2.08-11.34] and non-Indigenous (ARR 4.14, 95% CI 1.59-10.78) participants. Unemployment (ARR 8.98, 95% CI 2.25-35.82) and repeated (> once) incarceration as an adult (ARR 3.78, 95% CI 1.43-9.97) were associated with dual dependence for Indigenous participants only. Indigenous participants had high rates of alcohol dependence, except for those dependent on opioids only. The drug dependence patterns of Indigenous and non-Indigenous people who inject drugs were similar, including the proportions dependent on both methamphetamine and opioids. However, for Indigenous injectors, there was a stronger association between drug dependence and contextual factors such as unemployment and incarceration. Expansion of treatment options and community-level programs may be required. [Smirnov A, Kemp R, Ward J, Henderson S, Williams S, Dev A, Najman J M. Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who

  19. Cognitive dysfunction and anxious-impulsive personality traits are endophenotypes for drug dependence.

    Science.gov (United States)

    Ersche, Karen D; Turton, Abigail J; Chamberlain, Samuel R; Müller, Ulrich; Bullmore, Edward T; Robbins, Trevor W

    2012-09-01

    Not everyone who takes drugs becomes addicted, but the likelihood of developing drug addiction is greater in people with a family history of drug or alcohol dependence. Relatively little is known about how genetic risk mediates the development of drug dependence. By comparing the phenotypic profile of individuals with and without a family history of addiction, the authors sought to clarify the extent to which cognitive dysfunction and personality traits are shared by family members--and therefore likely to have predated drug dependence--and which aspects are specific to drug-dependent individuals. The authors assessed cognitive function and personality traits associated with drug dependence in stimulant-dependent individuals (N=50), their biological siblings without a history of drug dependence (N=50), and unrelated healthy volunteers (N=50). Cognitive function was significantly impaired in the stimulant-dependent individuals across a range of domains. Deficits in executive function and response control were identified in both the stimulant-dependent individuals and in their non-drug-dependent siblings. Drug-dependent individuals and their siblings also exhibited elevated anxious-impulsive personality traits relative to healthy comparison volunteers. Deficits in executive function and response regulation as well as anxious-impulsive personality traits may represent endophenotypes associated with the risk of developing cocaine or amphetamine dependence. The identification of addiction endophenotypes may be useful in facilitating the rational development of therapeutic and preventive strategies.

  20. Current status of the New Antiepileptic drugs in chronic pain.

    Directory of Open Access Journals (Sweden)

    Harpreet Singh Sidhu

    2016-08-01

    Full Text Available Antiepileptic drugs (AEDs are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various Non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer’s Lyrica become the market leading brand by 2018. In this review we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder

  1. Vaginal drug delivery systems: A Review of Current Status | Dobaria ...

    African Journals Online (AJOL)

    Among the various routes of drug delivery, the vaginal route offers many advantages due to its large permeation area, rich vascularization, avoidance of first pass metabolism and relatively low enzymatic activity. Several studies have shown that the vaginal cavity is an effective route for drug administration intended mainly ...

  2. Social policy and drug dependence: an historical case study.

    Science.gov (United States)

    Smart, C

    1985-11-01

    A detailed examination is presented of the background to the reports and policy developments concerning drug dependence which emerged in Britain during the 1960s. Analysis of documents and interviews with policy makers, officials and doctors involved in the events of the period, reveal that explanatory models in terms of 'moral panic' or 'power struggle' tend to oversimplify the complex processes involved. The role in policy formation of the media, government departments and groups within the medical profession is considered. The patterns of conflict and convergence are seen to overlap simple lines of 'interest'--we find conflict within the medical profession, convergence between the Home Office (legal) and elements of the medical professions (medical). The resulting legal and institutional framework involved only loose guidelines from the centre about treatment, and the shape of policy was determined by individual doctors in the new hospital treatment centres. The apparent re-run of the 1960s being staged in the 1980s will require detailed research in the future in order to avoid superficial comparisons.

  3. Onset of fast "ideal" tearing in thin current sheets: Dependence on the equilibrium current profile

    Science.gov (United States)

    Pucci, F.; Velli, M.; Tenerani, A.; Del Sarto, D.

    2018-03-01

    In this paper, we study the scaling relations for the triggering of the fast, or "ideal," tearing instability starting from equilibrium configurations relevant to astrophysical as well as laboratory plasmas that differ from the simple Harris current sheet configuration. We present the linear tearing instability analysis for equilibrium magnetic fields which (a) go to zero at the boundary of the domain and (b) contain a double current sheet system (the latter previously studied as a Cartesian proxy for the m = 1 kink mode in cylindrical plasmas). More generally, we discuss the critical aspect ratio scalings at which the growth rates become independent of the Lundquist number S, in terms of the dependence of the Δ' parameter on the wavenumber k of unstable modes. The scaling Δ'(k) with k at small k is found to categorize different equilibria broadly: the critical aspect ratios may be even smaller than L/a ˜ Sα with α = 1/3 originally found for the Harris current sheet, but there exists a general lower bound α ≥ 1/4.

  4. Access to orphan drugs in Europe: current and future issues.

    Science.gov (United States)

    Michel, Morgane; Toumi, Mondher

    2012-02-01

    Orphan drugs target small populations of patients. In order to make the field more attractive to pharmaceutical companies and encourage R&D in rare diseases, incentives were put forward by the EU, which are discussed in this article. Because they often are the only available option to treat a disease, some orphan drugs are considered to have high value and as such benefit from high prices on national markets. This has made orphan drugs an attractive market for pharmaceutical companies, with approximately 40 approved orphan drugs generating over $200 million each in yearly sales. The resulting burden this puts on national health insurances may lead to a change in regulation and will certainly lead to new national pricing and reimbursement strategies. They will need to be coherent, fair, effective and sustainable so as to be predictable for companies. Reflection on the subject needs to be initiated.

  5. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS: CURRENT ASPECTS OF THEIR USE

    Directory of Open Access Journals (Sweden)

    N. A. Shostak

    2014-07-01

    Full Text Available The paper shows the basic mechanisms of action of nonsteroidal antinflammatory drugs (NSAID and their classification. It considers riskfactors for NSAID gastropathy and the possibilities of its treatment, prevention in the context of modern medicine.

  6. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS: CURRENT ASPECTS OF THEIR USE

    Directory of Open Access Journals (Sweden)

    N. A. Shostak

    2013-01-01

    Full Text Available The paper shows the basic mechanisms of action of nonsteroidal antinflammatory drugs (NSAID and their classification. It considers riskfactors for NSAID gastropathy and the possibilities of its treatment, prevention in the context of modern medicine.

  7. Modifiable risk factors of ecstasy use: risk perception, current dependence, perceived control, and depression

    Science.gov (United States)

    Leung, Kit Sang; Ben Abdallah, Arbi; Cottler, Linda B.

    2009-01-01

    Risk perception, perceived behavioral control of obtaining ecstasy (PBC-obtaining), current ecstasy dependence, and recent depression have been associated with past ecstasy use, however, their utility in predicting ecstasy use has not been demonstrated. This study aimed to determine whether these four modifiable risk factors could predict ecstasy use after controlling for socio-demographic covariates and recent polydrug use. Data from 601 ecstasy users in the National Institute on Drug Abuse funded TriCity Study of Club Drug Use, Abuse and Dependence were analyzed using multivariate logistic regression. Participants were interviewed twice within a 2-week period using standardized instruments. Thirteen percent (n=80) of the participants reported using ecstasy between the two interviews. Low risk perception, high PBC-obtaining (an estimated ecstasy procurement time ecstasy dependence were statistically associated with ecstasy use between the two interviews. Recent depression was not a significant predictor. Despite not being a target predictor, recent polydrug use was also statistically associated with ecstasy use. The present findings may inform the development of interventions targeting ecstasy users. PMID:19880258

  8. Chemical dependency and drug testing in the workplace.

    OpenAIRE

    Osterloh, J D; Becker, C E

    1990-01-01

    Urine testing for drug use in the workplace is now widespread, with the prevalence of positive drug tests in the work force being 0% to 15%. The prevalence of marijuana use is highest, and this can be reliably tested. Though it is prudent to rid the workplace of drug use, there is little scientific study on the relationship of drug use and workplace outcomes, such as productivity and safety. Probable-cause testing and preemployment testing are the most common applications. Random testing has ...

  9. Direct-to-consumer marketing of prescription drugs: a current perspective for neurologists and psychiatrists.

    Science.gov (United States)

    Hollon, Matthew F

    2004-01-01

    In the US and New Zealand, the past decade has seen tremendous growth in the marketing of prescription drugs directly to patients. The pharmaceutical industry has applied pressure in other countries to relax regulations governing such marketing although this has not yet been successful. While we still have much to learn about the potential impact on the public's health of direct-to-consumer (DTC) marketing, some data are available. This article summarises the current literature on the benefits and risks of DTC marketing. This marketing strategy has grown substantially in the US, but only select drugs are advertised. Whether there is net benefit or harm to the public's health as a result of DTC marketing depends critically on which drugs are advertised and the quality of the information provided in promotional material. Critical reviews of this promotional material suggest the information is of poor quality. Notably, 18% of the 50 drugs advertised most intensively in the US were medications used to treat psychiatric and neurological disorders. The impairments in decisional capacity often seen in psychiatric and neurological illness leave patients vunerable to the controlling influence of DTC marketing and, thus, undermine the patient autonomy that is said to be promoted by this marketing strategy. If there is any benefit from DTC marketing it is for significantly undertreated conditions. International restrictions on DTC marketing should remain in place until further evidence of net benefit or harm emerges from the DTC marketing experiment that is taking place in the US and New Zealand.

  10. Molecular weight-dependent degradation and drug release of surface-eroding poly(ethylene carbonate).

    Science.gov (United States)

    Bohr, Adam; Wang, Yingya; Harmankaya, Necati; Water, Jorrit J; Baldursdottír, Stefania; Almdal, Kristoffer; Beck-Broichsitter, Moritz

    2017-06-01

    Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough physicochemical characterization of diverse PEC (molecular weights: 85, 110, 133, 174 and 196kDa), the degradation and drug release behavior of rifampicin- and bovine serum albumin-loaded PEC films was investigated in vitro (in the presence and absence of cholesterol esterase), in cell culture (RAW264.7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half-lives correlated well with the observed in vitro half-times of drug delivery (R 2 =0.96). Here, the PEC of the highest molecular weight resulted in the fastest degradation/drug release. When incubated with macrophages or implanted in animals, the degradation rate of PEC films superimposed the results of in vitro incubations with cholesterol esterase. Interestingly, SEM analysis indicated a distinct surface erosion process for enzyme-, macrophage- and in vivo-treated polymer films in a molecular weight-dependent manner. Overall, the molecular weight of surface-eroding PEC was identified as an essential parameter to control the spatial and temporal on-demand degradation and drug release from the employed delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. A survey of current trends in computational drug repositioning.

    Science.gov (United States)

    Li, Jiao; Zheng, Si; Chen, Bin; Butte, Atul J; Swamidass, S Joshua; Lu, Zhiyong

    2016-01-01

    Computational drug repositioning or repurposing is a promising and efficient tool for discovering new uses from existing drugs and holds the great potential for precision medicine in the age of big data. The explosive growth of large-scale genomic and phenotypic data, as well as data of small molecular compounds with granted regulatory approval, is enabling new developments for computational repositioning. To achieve the shortest path toward new drug indications, advanced data processing and analysis strategies are critical for making sense of these heterogeneous molecular measurements. In this review, we show recent advancements in the critical areas of computational drug repositioning from multiple aspects. First, we summarize available data sources and the corresponding computational repositioning strategies. Second, we characterize the commonly used computational techniques. Third, we discuss validation strategies for repositioning studies, including both computational and experimental methods. Finally, we highlight potential opportunities and use-cases, including a few target areas such as cancers. We conclude with a brief discussion of the remaining challenges in computational drug repositioning. Published by Oxford University Press 2015. This work is written by US Government employees and is in the public domain in the US.

  12. Diameter dependent failure current density of gold nanowires

    International Nuclear Information System (INIS)

    Karim, S; Maaz, K; Ali, G; Ensinger, W

    2009-01-01

    Failure current density of single gold nanowires is investigated in this paper. Single wires with diameters ranging from 80 to 720 nm and length 30 μm were electrochemically deposited in ion track-etched single-pore polycarbonate membranes. The maximum current density was investigated while keeping the wires embedded in the polymer matrix and ramping up the current until failure occurred. The current density is found to increase with diminishing diameter and the wires with a diameter of 80 nm withstand 1.2 x 10 12 A m -2 before undergoing failure. Possible reasons for these results are discussed in this paper.

  13. Current trend of drug sensitivity in bovine mastitis

    Directory of Open Access Journals (Sweden)

    Rajeev Ranjan

    2010-02-01

    Full Text Available The study was conducted on 190 milk samples of bovine mastitis and 138 samples were confirmed positives for microorganisms. All the 138 samples were subjected to drug sensitivity test. The most effective antibiotic was enrofloxacin (91.67% followed by ciprofloxacin (90.15%, amikacin (87.12%, ceftriaxone (84.10%, chloramphenicol (80.31%, cefotaxime (79.55% and gentamicin (77.27%. Microorganisms were mostly resistant to drugs like streptomycin, penicillinG, ampicillin, cloxacillin, amoxycillin and neomycin in increasing order of resistance. Hence, it is suggested that the line of treatment should be based on antibiogram study of various isolates from bovine mastitis. Further, the selection of drugs after culture and sensitivity test should be based on their ability to cross blood tissue barrier or mammary parenchyma, lipophilicity and ability to work in alkaline pH. [Vet. World 2010; 3(1.000: 17-20

  14. Role of Urine Drug Testing in the Current Opioid Epidemic.

    Science.gov (United States)

    Mahajan, Gagan

    2017-12-01

    While the evidence for urine drug testing for patients on chronic opioid therapy is weak, the guidelines created by numerous medical societies and state and federal regulatory agencies recommend that it be included as one of the tools used to monitor patients for compliance with chronic opioid therapy. To get the most comprehensive results, clinicians should order both an immunoassay screen and confirmatory urine drug test. The immunoassay screen, which can be performed as an in-office point-of-care test or as a laboratory-based test, is a cheap and convenient study to order. Limitations of an immunoassay screen, however, include having a high threshold of detectability and only providing qualitative information about a select number of drug classes. Because of these restrictions, clinicians should understand that immunoassay screens have high false-positive and false-negative rates. Despite these limitations, though, the results can assist the clinician with making preliminary treatment decisions. In comparison, a confirmatory urine drug test, which can only be performed as a laboratory-based test, has a lower threshold of detectability and provides both qualitative and quantitative information. A urine drug test's greater degree of specificity allows for a relatively low false-negative and false-positive rate in contrast to an immunoassay screen. Like any other diagnostic test, an immunoassay screen and a confirmatory urine drug test both possess limitations. Clinicians must keep this in mind when interpreting an unexpected test result and consult with their laboratory when in doubt about the meaning of the test result to avoid making erroneous decisions that negatively impact both the patient and clinician.

  15. Positive Selection on Loci Associated with Drug and Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Brooke Sadler

    Full Text Available Much of the evolution of human behavior remains a mystery, including how certain disadvantageous behaviors are so prevalent. Nicotine addiction is one such phenotype. Several loci have been implicated in nicotine related phenotypes including the nicotinic receptor gene clusters (CHRNs on chromosomes 8 and 15. Here we use 1000 Genomes sequence data from 3 populations (Africans, Asians and Europeans to examine whether natural selection has occurred at these loci. We used Tajima's D and the integrated haplotype score (iHS to test for evidence of natural selection. Our results provide evidence for strong selection in the nicotinic receptor gene cluster on chromosome 8, previously found to be significantly associated with both nicotine and cocaine dependence, as well as evidence selection acting on the region containing the CHRNA5 nicotinic receptor gene on chromosome 15, that is genome wide significant for risk for nicotine dependence. To examine the possibility that this selection is related to memory and learning, we utilized genetic data from the Collaborative Studies on the Genetics of Alcoholism (COGA to test variants within these regions with three tests of memory and learning, the Wechsler Adult Intelligence Scale (WAIS Block Design, WAIS Digit Symbol and WAIS Information tests. Of the 17 SNPs genotyped in COGA in this region, we find one significantly associated with WAIS digit symbol test results. This test captures aspects of reaction time and memory, suggesting that a phenotype relating to memory and learning may have been the driving force behind selection at these loci. This study could begin to explain why these seemingly deleterious SNPs are present at their current frequencies.

  16. Context-Dependent Modulation of GABAAR-Mediated Tonic Currents

    DEFF Research Database (Denmark)

    Patel, Bijal; Bright, Damian P; Mortensen, Martin

    2016-01-01

    UNLABELLED: Tonic GABA currents mediated by high-affinity extrasynaptic GABAA receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABAA receptor signaling that results in modified tonic GABA currents is associated with a number o...

  17. Chemical dependency and drug testing in the workplace.

    Science.gov (United States)

    Osterloh, J D; Becker, C E

    1990-05-01

    Urine testing for drug use in the workplace is now widespread, with the prevalence of positive drug tests in the work force being 0% to 15%. The prevalence of marijuana use is highest, and this can be reliably tested. Though it is prudent to rid the workplace of drug use, there is little scientific study on the relationship of drug use and workplace outcomes, such as productivity and safety. Probable-cause testing and preemployment testing are the most common applications. Random testing has been less accepted owing to its higher costs, unresolved legal issues, and predictably poor test reliability. Legal issues have focused on the right to policy, discrimination, and the lack of due process. The legal cornerstone of a good program is a policy that is planned and agreed on by both labor and management, which serves both as a contract and as a procedure in which expectations and consequences are known. The National Institute on Drug Abuse is certifying laboratories doing employee drug testing. Testing methods when done correctly are less prone to error than in the past, but screening tests can be defeated by adulterants. Although the incidence of false-positive results is low, such tests are less reliable when the prevalence of drug abuse is also low.

  18. [Harm reduction interventions in drug users: current situation and recommendations].

    Science.gov (United States)

    Bosque-Prous, Marina; Brugal, María Teresa

    2016-11-01

    Harm reduction encompasses interventions, programmes and policies that seek to reduce the negative consequences of the consumption of both legal and illegal drugs on the individual and public health. Harm reduction looks to mitigate the harm suffered by drug users through drug use monitoring and prevention, and promotes initiatives that respect and protect the human rights of this population. The harm reduction policies that have proven effective and efficient are: opioid substitution maintenance therapy (methadone); needle and syringe exchange programmes; supervised drug consumption rooms; and overdose prevention through peer-based naloxone distribution. In order to be effective, these policies must have comprehensive coverage and be implemented in areas where the target population is prevalent. Resident-based opposition to the implementation of these policies is known as the NIMBY (Not In My Back Yard) phenomenon, which is characterised by being against the implementation of new measures in a particular place, but does not question their usefulness. Given that any NIMBY phenomenon is a complex social, cultural and political phenomenon, it is important to conduct a thorough analysis of the situation prior to implementing any of these measures. Harm reduction policies must be extended to other substances such as alcohol and tobacco, as well as to other conditions beyond infectious/contagious diseases and overdose. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. Current and future drug targets in weight management

    NARCIS (Netherlands)

    Witkamp, R.F.

    2011-01-01

    Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being

  20. 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.

  1. Maximum time-dependent space-charge limited diode currents

    Energy Technology Data Exchange (ETDEWEB)

    Griswold, M. E. [Tri Alpha Energy, Inc., Rancho Santa Margarita, California 92688 (United States); Fisch, N. J. [Princeton Plasma Physics Laboratory, Princeton University, Princeton, New Jersey 08543 (United States)

    2016-01-15

    Recent papers claim that a one dimensional (1D) diode with a time-varying voltage drop can transmit current densities that exceed the Child-Langmuir (CL) limit on average, apparently contradicting a previous conjecture that there is a hard limit on the average current density across any 1D diode, as t → ∞, that is equal to the CL limit. However, these claims rest on a different definition of the CL limit, namely, a comparison between the time-averaged diode current and the adiabatic average of the expression for the stationary CL limit. If the current were considered as a function of the maximum applied voltage, rather than the average applied voltage, then the original conjecture would not have been refuted.

  2. Measurement of Nuclear Dependence in Inclusive Charged Current Neutrino Scattering

    Energy Technology Data Exchange (ETDEWEB)

    Tice, Brian George [Rutgers Univ., New Brunswick, NJ (United States)

    2014-01-01

    Neutrino experiments use heavy nuclei (C, Fe, Pb) to achieve necessary statistics. However, the use of heavy nuclei exposes these experiments to the nuclear dependence of neutrino-nucleus cross sections, which are poorly known and difficult to model. This dissertation presents an analysis of the nuclear dependence of inclusive chargedcurrent neutrino scattering using events in carbon, iron, lead, and scintillator targets of the MINERvA detector. MINERvA (Main INjector ExpeRiment for -A) is a few-GeV neutrinonucleus scattering experiment at Fermilab.

  3. Fluorescence lifetime assays: current advances and applications in drug discovery.

    Science.gov (United States)

    Pritz, Stephan; Doering, Klaus; Woelcke, Julian; Hassiepen, Ulrich

    2011-06-01

    Fluorescence lifetime assays complement the portfolio of established assay formats available in drug discovery, particularly with the recent advances in microplate readers and the commercial availability of novel fluorescent labels. Fluorescence lifetime assists in lowering complexity of compound screening assays, affording a modular, toolbox-like approach to assay development and yielding robust homogeneous assays. To date, materials and procedures have been reported for biochemical assays on proteases, as well as on protein kinases and phosphatases. This article gives an overview of two assay families, distinguished by the origin of the fluorescence signal modulation. The pharmaceutical industry demands techniques with a robust, integrated compound profiling process and short turnaround times. Fluorescence lifetime assays have already helped the drug discovery field, in this sense, by enhancing productivity during the hit-to-lead and lead optimization phases. Future work will focus on covering other biochemical molecular modifications by investigating the detailed photo-physical mechanisms underlying the fluorescence signal.

  4. Current French system of post-marketing drug surveillance.

    Science.gov (United States)

    Albengres, E; Gauthier, F; Tillement, J P

    1990-07-01

    The French system of drug surveillance is characterized by several original features: thirty regional centres are selected to cover all of France to collect, analyze and enter the adverse drug events in the national data bank. The system is based on a bank of well documented files submitted to a decision of imputation; the report of severe events by prescribers is mandatory; cases are collected either by spontaneous reporting (routine) or by direct request (intensive validation study); the system is being involved in studies of epidemiological type as carried out by the national system of health or a few societies of medicine as well as by the centres themselves in cooperative works on defined populations.

  5. Current advances in transdermal delivery of drugs for alzheimer's disease

    OpenAIRE

    Thuy Trang Nguyen; Vo Van Giau; Tuong Kha Vo

    2017-01-01

    Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the...

  6. 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.

  7. Drugs currently under investigation for the treatment of invasive candidiasis.

    Science.gov (United States)

    McCarthy, Matthew W; Walsh, Thomas J

    2017-07-01

    The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed. Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials. Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis.

  8. Strongyloidiasis Current Status with Emphasis in Diagnosis and Drug Research

    Directory of Open Access Journals (Sweden)

    Tiago Mendes

    2017-01-01

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

  9. Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A.

    Science.gov (United States)

    Yadav, Jaydeep; Korzekwa, Ken; Nagar, Swati

    2018-05-07

    Time-dependent inactivation (TDI) of cytochrome P450s (CYPs) is a leading cause of clinical drug-drug interactions (DDIs). Current methods tend to overpredict DDIs. In this study, a numerical approach was used to model complex CYP3A TDI in human-liver microsomes. The inhibitors evaluated included troleandomycin (TAO), erythromycin (ERY), verapamil (VER), and diltiazem (DTZ) along with the primary metabolites N-demethyl erythromycin (NDE), norverapamil (NV), and N-desmethyl diltiazem (NDD). The complexities incorporated into the models included multiple-binding kinetics, quasi-irreversible inactivation, sequential metabolism, inhibitor depletion, and membrane partitioning. The resulting inactivation parameters were incorporated into static in vitro-in vivo correlation (IVIVC) models to predict clinical DDIs. For 77 clinically observed DDIs, with a hepatic-CYP3A-synthesis-rate constant of 0.000 146 min -1 , the average fold difference between the observed and predicted DDIs was 3.17 for the standard replot method and 1.45 for the numerical method. Similar results were obtained using a synthesis-rate constant of 0.000 32 min -1 . These results suggest that numerical methods can successfully model complex in vitro TDI kinetics and that the resulting DDI predictions are more accurate than those obtained with the standard replot approach.

  10. Liposomal Drug Product Development and Quality: Current US Experience and Perspective.

    Science.gov (United States)

    Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M

    2017-05-01

    Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.

  11. Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs

    DEFF Research Database (Denmark)

    Tischbirek, Carsten H.; Wenzel, Eva M.; Zheng, Fang

    2012-01-01

    Tischbirek et al. find that weak-base antipsychotic drugs are accumulated in synaptic vesicles and are secreted upon exocytosis, leading to increased extracellular drug concentrations following neuronal activity. The secretion of the drugs in turn inhibits synaptic transmission in a use-dependent...

  12. Persistence of drug use during imprisonment: relationship of drug type, recency of use and severity of dependence to use of heroin, cocaine and amphetamine in prison.

    Science.gov (United States)

    Strang, John; Gossop, Michael; Heuston, Joan; Green, John; Whiteley, Christopher; Maden, Anthony

    2006-08-01

    To investigate the persistence of use of heroin, cocaine and amphetamine drugs during imprisonment, and to identify factors associated with increased levels of persistence. The use of heroin, cocaine and amphetamine by current prison inmates has been examined and, in particular, the relationship between drug use within prison and the type of drug used prior to imprisonment, recency of use and severity of dependence. A randomly selected sample of 1009 adult male prisoners in 13 prisons in England and Wales during 1994/95; structured confidential interviews conducted by independent research staff. Enquiry about prior use of heroin, cocaine or amphetamine focused on three time-periods (ever, last year and last month pre-prison) and the use of these drugs during the first month of imprisonment. A total of 557 (55%) of the 1009 prisoners had used previously one of the three drugs selected for study: 58% had used heroin, 69% cocaine and 75% amphetamine. More than half (59%; 327/557) had used these drugs in the month before the current imprisonment. Drug use in prisons was most likely to occur among those who had used in the month prior to imprisonment. The persistence of heroin use in prison occurred more frequently (70%) than use of cocaine (20%) or amphetamine (15%). Of those using heroin pre-imprisonment, 67% considered they were dependent, compared to 15% and 22%, respectively, for cocaine and amphetamine users. Changes in the drug-taking behaviour of drug users after imprisonment vary according to the type of drug being taken. Prisoners were much more likely to continue to use heroin than either cocaine or amphetamines while in prison. Heroin was most likely to be used by those who had been using heroin during the immediate pre-imprisonment period, and particularly by the two-thirds of heroin users who considered themselves dependent. In view of the high prevalence of prior use of these drugs by individuals currently imprisoned, continuing attention is required to

  13. Impedance of thin film cathodes: thickness and current collector dependence

    NARCIS (Netherlands)

    Boukamp, Bernard A.; Hildenbrand, N.; Bouwmeester, Henricus J.M.; Blank, David H.A.

    2015-01-01

    The influence of the layer thickness of mixed ionic–electronic conducting (MIEC) cathodes and the type of noble metal current collector on the apparent surface exchange resistance is studied with impedance spectroscopy. The impedance data is analyzed with the ‘General Finite Length Diffusion’

  14. Current approaches for the discovery of drugs that deter substance and drug abuse.

    Science.gov (United States)

    Yasgar, Adam; Simeonov, Anton

    2014-11-01

    Much has been presented and debated on the topic of drug abuse and its multidimensional nature, including the role of society and its customs and laws, economical factors, and the magnitude and nature of the burden. Given the complex nature of the receptors and pathways implicated in regulation of the cognitive and behavioral processes associated with addiction, a large number of molecular targets have been interrogated during recent years to discover starting points for development of small-molecule interventions. This review describes recent developments in the field of early drug discovery for drug abuse interventions with an emphasis on the advances published during the 2012 - 2014 period. Technologically, the processes/platforms utilized in drug abuse drug discovery are nearly identical to those used in the other disease areas. A key complicating factor in drug abuse research is the enormous biological complexity surrounding the brain processes involved and the associated difficulty in finding 'good' targets and achieving exquisite selectivity of treatment agents. While tremendous progress has been made during recent years to use the power of high-throughput technologies to discover proof-of-principle molecules for many new targets, next-generation models will be especially important in this field. Examples include: seeking advantageous drug-drug combinations, the use of automated whole-animal behavioral screening systems, advancing our understanding of the role of epigenetics in drug addiction and the employment of organoid-level 3D test platforms (also referred to as tissue-chip or organs-on-chip).

  15. Cardiovascular effects of current and future anti-obesity drugs

    DEFF Research Database (Denmark)

    Comerma Steffensen, Simon Gabriel; Grann, Martin; Andersen, Charlotte U

    2014-01-01

    cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular...... side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol...

  16. Dependence of the current renormalisation constants on the quark mass

    CERN Document Server

    Crisafulli, M.; Martinelli, G.; Vladikas, A.; Crisafulli, M; Lubicz, V; Martinelli, G; Vladikas, A

    1995-01-01

    We study the behaviour of the vector and axial current renormalisation constants Z_V and Z_A as a function of the quark mass, m_q. We show that sizeable O(am_q) and O(g_0^2 a m_q) systematic effects are present in the Wilson and Clover cases respectively. We find that the prescription of Kronfeld, Lepage and Mackenzie for correcting these artefacts is not always successful.

  17. Drug ratio-dependent antagonism: a new category of multidrug resistance and strategies for its circumvention.

    Science.gov (United States)

    Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D

    2010-01-01

    A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.

  18. Current knowledge on biodegradable microspheres in drug delivery.

    Science.gov (United States)

    Prajapati, Vipul D; Jani, Girish K; Kapadia, Jinita R

    2015-08-01

    Biodegradable microspheres have gained popularity for delivering a wide variety of molecules via various routes. These types of products have been prepared using various natural and synthetic biodegradable polymers through suitable techniques for desired delivery of various challenging molecules. Selection of biodegradable polymers and technique play a key role in desired drug delivery. This review describes an overview of the fundamental knowledge and status of biodegradable microspheres in effective delivery of various molecules via desired routes with consideration of outlines of various compendial and non-compendial biodegradable polymers, formulation techniques and release mechanism of microspheres, patents and commercial biodegradable microspheres. There are various advantages of using biodegradable polymers including promise of development with different types of molecules. Biocompatibility, low dosage and reduced side effects are some reasons why usage biodegradable microspheres have gained in popularity. Selection of biodegradable polymers and formulation techniques to create microspheres is the biggest challenge in research. In the near future, biodegradable microspheres will become the eco-friendly product for drug delivery of various genes, hormones, proteins and peptides at specific site of body for desired periods of time.

  19. A theory of drug tolerance and dependence II: the mathematical model.

    Science.gov (United States)

    Peper, Abraham

    2004-08-21

    The preceding paper presented a model of drug tolerance and dependence. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The present paper discusses the mathematical model in terms of its design. The model is a nonlinear, learning feedback system, fully satisfying control theoretical principles. It accepts any form of the stimulus-the drug intake-and describes how the physiological processes involved affect the distribution of the drug through the body and the stability of the regulation loop. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes.

  20. Associations Between Family History of Substance Use, Childhood Trauma, and Age of First Drug Use in Persons With Methamphetamine Dependence.

    Science.gov (United States)

    Svingen, Leah; Dykstra, Rita E; Simpson, Jamie L; Jaffe, Anna E; Bevins, Rick A; Carlo, Gustavo; DiLillo, David; Grant, Kathleen M

    2016-01-01

    The current study examined the association among family history of substance use problems, childhood maltreatment, and age of first drug use in a sample of men and women seeking treatment for methamphetamine dependence. Various forms of childhood maltreatment were considered as mediators of the association between family history of substance use problems and age of first drug use. Participants (N = 99, 40% women, mean age 33) who were under treatment for methamphetamine dependence completed a baseline interview that obtained demographic information, past substance use by participants, history of drug/alcohol problems in their family of origin, and age at first use of any drug (excluding alcohol and tobacco). The Early Trauma Inventory Self-Report-Short Form was used to assess child maltreatment experiences before the age of 18. Family history of substance use problems and childhood physical (but not emotional or sexual) trauma significantly predicted age of first drug use. Further, childhood physical trauma mediated the association between family history of substance use problems and age of first drug use. These findings suggest that the experience of childhood physical abuse may be an important mechanism through which family history of substance use is associated with an earlier age of first drug use.

  1. The clinical implication of drug dependency in children and adults with inflammatory bowel disease: a review

    DEFF Research Database (Denmark)

    Duricova, Dana; Pedersen, Natalia; Lenicek, Martin

    2011-01-01

    Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug...... corticosteroid dependency. Infliximab dependency was described in 42-66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients...... was suggested to postpone if not avoid the need of surgery. Lastly, mesalazine dependency was identified in 23% of adults with Crohn's disease. These patients were characterized by mild disease course and lower surgical risk compared to non-responders to mesalazine (32 vs. 61%). Identification of drug...

  2. Current status and burning issues in immunotoxicity testing of drugs

    International Nuclear Information System (INIS)

    Laan, Jan Willem van der; Loveren, Henk van

    2005-01-01

    Besides pathology endpoints, additional immune function endpoints have been included in the Note for Guidance on Repeated Dose Toxicity by the European Union (July 2001), which concern the analysis of antibody responses to a T-cell-dependent antigen. Guidance papers of other regulatory authorities are published as well. The main issue is the need for functional immunotoxicity testing to detect unintended immunosuppression. The International Conference on Harmonization (ICH) has surveyed studies from the files of the pharmaceutical industry to find the proportion of compounds that can be detected by additional immunotoxicity testing. Preliminary analysis shows that 10-15% of the compounds in the survey only react positively to the additional tests. More data are requested from the pharmaceutical industry. The Expert Working Group of the ICH has decided to choose a cause-for-concern approach to immmunotoxicity rather than a routine-screening approach. The causes for concern are to be defined during ICH negotiations

  3. PERCEPTION AND PERFORMANCE OF THE INTERDISCIPLINARY TEAM IN SERVING DRUG DEPENDENTS IN SPECIALIZED NETWORK OF MENTAL HEALTH SINOP, MATO GROSSO

    Directory of Open Access Journals (Sweden)

    P. V. C. Santos

    2017-08-01

    Full Text Available Chemical dependency is currently one of the most important public health problems in our country. The study deals with a quantitative and qualitative research, whose goal is to evaluate the perception and performance of the interdisciplinary team in serving drug dependents in specialized network of mental health Sinop, Mato Grosso. Applied a semi-structured questionnaire with objective and subjective questions with 11 professionals in health care at the Psychosocial Care Center (CAPS and Medical Specialties Center (EMC. The results reveal the importance of the preparation of these professionals to work in service to dependents and interdisciplinarity proved to be the best option to achieve a dignified and humane care

  4. The current status of orphan drug development in Europe and the US

    OpenAIRE

    Hall, Anthony K; Carlson, Marilyn R

    2014-01-01

    Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, e...

  5. Purification of drugs from biological fluids by counter-current chromatography.

    Science.gov (United States)

    Hochlowski, Jill E; Pan, Jeffrey Y; Searle, Philip A; Buck, Wayne R; Spanton, Stephen G

    2009-08-21

    Experiments were performed to demonstrate the potential of counter-current chromatography (CCC) for the isolation of drugs and their metabolites from biological matrices relevant to the metabolism studies of pharmaceutical research. Examples of typical drugs are spiked into biological media ex vivo to provide test samples for analysis. A mass spectrometer hyphenated to a CCC allows for the detection of small molecule drugs within the matrix through selected ion monitoring, and fraction collection can provide material for further structural elucidation by NMR.

  6. COMPUTER DYNAMICS SIMULATION OF DRUG DEPENDENCE THROUGH ARTIFICIAL NEURONAL NETWORK: PEDAGOGICAL AND CLINICAL IMPLICATIONS

    Directory of Open Access Journals (Sweden)

    G. SANTOS

    2008-05-01

    Full Text Available To develop and to evaluate the efficiency of a software able to simulate a virtual patient at different stages of addition was the main goal and challenge of this work. We developed the software in Borland™ Delphi  5®  programming language. Techniques of artificial intelligence, neuronal networks and expert systems, were responsible for modeling the neurobiological structures and mechanisms of the interaction with the drugs used. Dynamical simulation and  hypermedia were designed to increase the software’s interactivity which was able to show graphical information from virtual instrumentation and from realistic functional magnetic resonance imaging display. Early, the program was designed to be used by undergraduate students to improve their neurophysiologic learn, based not only in an interaction of membrane receptors with drugs, but in such a large behavioral simulation. The experimental manipulation of the software was accomplished by: i creating a virtual patient from a normal mood to a behavioral addiction, increasing gradatively: alcohol, opiate or cocaine doses. ii designing an approach to treat the patient, to get total or partial remission of behavioral disorder by combining psychopharmacology and psychotherapy. Integration of dynamic simulation with hypermedia and artificial intelligence has been able to point out behavioral details as tolerance, sensitization and level of addiction to drugs of abuse and so on, turned into a potentially useful tool in the development of teaching activities on several ways, such as education as well clinical skills, in which it could assist patients, families and health care to improve and test their knowledge and skills about different faces supported by drugs dependency. Those features are currently under investigation.

  7. Similarity and Difference in Drug Addiction Process Between Heroin- and Methamphetamine-Dependent Users.

    Science.gov (United States)

    Wang, Ziyun; Li, Wei-Xiu; Zhi-Min, Liu

    2017-03-21

    This study aimed to compare the drug addiction process between Chinese heroin- and methamphetamine (MA)-dependent users via a modified 4-stage addiction model (experimentation, occasional use, regular use, and compulsive use). A descriptive study was conducted among 683 eligible participants. In the statistical analysis, we selected 340 heroin- and 295 MA-dependent users without illicit drug use prior to onset of heroin or MA use. The addiction process of heroin-dependent users was shorter than that of MA-dependent users, with shorter transitions from the onset of drug-use to the first drug craving (19.5 vs. 50.0 days), regular use (30.0 vs. 60.0 days), and compulsive use (50.0 vs. 85.0 days). However, no significant differences in the addiction process were observed in frequency of drug administration, except that heroin users reported more administrations of the drug (20.0 vs. 15.0) before progressing to the stage of compulsive drug use. A larger proportion of regular heroin users progressed to use illicit drugs recklessly than did MA users. Most heroin and MA users reported psychological dependence as their primary motivation for compulsive drug use, but more heroin users selected uncomfortable symptoms upon ceasing drug use as further reason to continue. Our results suggest that typical heroin and MA users may experience a similar four-stage addiction process, but MA users might undergo a longer addiction process (in days). More research is necessary to further explore factors influencing the drug addiction process.

  8. Non-monotonic field dependence of critical current in composite superconductors

    International Nuclear Information System (INIS)

    Andrianov, V.V.; Baev, V.P.; Ivanov, S.S.

    1982-01-01

    The nonmonotonic field dependence of critical current Im(B/sub a/ in composite superconductors is investigated experimentally for current and field varying simultaneously with final rates I and B/sub a/

  9. Electromagnetic pulse-driven spin-dependent currents in semiconductor quantum rings.

    Science.gov (United States)

    Zhu, Zhen-Gang; Berakdar, Jamal

    2009-04-08

    We investigate the non-equilibrium charge and spin-dependent currents in a quantum ring with a Rashba spin-orbit interaction (SOI) driven by two asymmetric picosecond electromagnetic pulses. The equilibrium persistent charge and persistent spin-dependent currents are investigated as well. It is shown that the dynamical charge and the dynamical spin-dependent currents vary smoothly with a static external magnetic flux and the SOI provides a SU(2) effective flux that changes the phases of the dynamic charge and the dynamic spin-dependent currents. The period of the oscillation of the total charge current with the delay time between the pulses is larger in a quantum ring with a larger radius. The parameters of the pulse fields control to a certain extent the total charge and the total spin-dependent currents. The calculations are applicable to nanometre rings fabricated in heterojunctions of III-V and II-VI semiconductors containing several hundreds of electrons.

  10. THE RESOCIALIZATION OF DRUG-DEPENDENT PEOPLE IN REHABILITATION CENTERS: SOCIAL AND PEDAGOGICAL ASPECTS

    Directory of Open Access Journals (Sweden)

    Юлія Чернецька

    2015-12-01

    Full Text Available The article deals with the resocialization of drug-dependent people in rehabilitation centers.  In the of resocialization the restoration of social relationships (social rehabilitation and social adaptation, and the accumulation of new socially positive experience are ensured. Resocialization is possible through the study and assimilation of cultural values, norms, attitudes, patterns of behavior, and the implementation of social activity of drug-dependent people in various activities. The article explains the meaning of “resocialization” through the categories of “social environment” and “social education”. It is roved that the resocialization of drug-dependent personality is carried out directly under the influence of social conditions (environmental factors. This process is the product of direct relations between the subjects of environment (agents and is determined by the influence material culture (means which depend on the result of resocialization is dependent.

  11. LANGUAGE PSYCHODYNAMIC ANALYSIS IN THE DRUG DEPENDENT PATIENT

    Directory of Open Access Journals (Sweden)

    José Alonso Andrade Salazar

    2011-07-01

    Full Text Available Addictions are currently the starting point of many behaviors that border on the maladaptive and have a dynamic articulation in the patient language, the same is expressed in his words, the dynamic relationship between the origins of their addiction and inherent conflict consumption added. Dynamic analysis seeks to generate a cathartic process, in order to achieve an unleash chain reaction, significant value-content, then, is in the gorge of the word, bringing together the split of speech grounds, a point from where the reorganization of the reality principle parts, in the addict and his psycho detoxification. This is a basic research with qualitative cut, approached by Psychoanalysis epistemology and methodology principles. The paradigms leading the research are psychological determinism and phenomenological.

  12. 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.

  13. Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity

    Science.gov (United States)

    Ellinwood, Nicholas; Dobrev, Dobromir; Morotti, Stefano; Grandi, Eleonora

    2017-09-01

    The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti

  14. A theory of drug tolerance and dependence I: a conceptual analysis.

    Science.gov (United States)

    Peper, Abraham

    2004-08-21

    A mathematical model of drug tolerance and its underlying theory is presented. The model extends a first approach, published previously. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behavior to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes. In addition, it establishes a relation between the drug dose at any moment, and the resulting drug effect and relates the magnitude of the reactions following withdrawal to the rate of tolerance and other parameters involved in the tolerance process. The present paper analyses the concept behind the model. The next paper discusses the mathematical model.

  15. 38 CFR 17.82 - Contracts for outpatient services for veterans with alcohol or drug dependence or abuse...

    Science.gov (United States)

    2010-07-01

    ... services for veterans with alcohol or drug dependence or abuse disabilities. 17.82 Section 17.82 Pensions... Agencies § 17.82 Contracts for outpatient services for veterans with alcohol or drug dependence or abuse... sponsored residents to adjust to and maintain freedom from dependence on or involvement with alcohol or drug...

  16. Chronic disease and recent addiction treatment utilization among alcohol and drug dependent adults

    Directory of Open Access Journals (Sweden)

    Samet Jeffrey

    2011-10-01

    Full Text Available Abstract Background Chronic medical diseases require regular and longitudinal care and self-management for effective treatment. When chronic diseases include substance use disorders, care and treatment of both the medical and addiction disorders may affect access to care and the ability to focus on both conditions. The objective of this paper is to evaluate the association between the presence of chronic medical disease and recent addiction treatment utilization among adults with substance dependence. Methods Cross-sectional secondary data analysis of self-reported baseline data from alcohol and/or drug-dependent adults enrolled in a randomized clinical trial of a disease management program for substance dependence in primary care. The main independent variable was chronic medical disease status, categorized using the Katz Comorbidity Score as none, single condition of lower severity, or higher severity (multiple conditions or single higher severity condition, based on comorbidity scores determined from self-report. Asthma was also examined in secondary analyses. The primary outcome was any self-reported addiction treatment utilization (excluding detoxification in the 3 months prior to study entry, including receipt of any addiction-focused counseling or addiction medication from any healthcare provider. Logistic regression models were adjusted for sociodemographics, type of substance dependence, recruitment site, current smoking, and recent anxiety severity. Results Of 563 subjects, 184 (33% reported any chronic disease (20% low severity; 13% higher severity and 111 (20% reported asthma; 157 (28% reported any addiction treatment utilization in the past 3 months. In multivariate regression analyses, no significant effect was detected for chronic disease on addiction treatment utilization (adjusted odds ratio [AOR] 0.88 lower severity vs. none, 95% confidence interval (CI: 0.60, 1.28; AOR 1.29 higher severity vs. none, 95% CI: 0.89, 1.88 nor for

  17. Detecting peptidic drugs, drug candidates and analogs in sports doping: current status and future directions.

    Science.gov (United States)

    Thevis, Mario; Thomas, Andreas; Schänzer, Wilhelm

    2014-12-01

    With the growing availability of mature systems and strategies in biotechnology and the continuously expanding knowledge of cellular processes and involved biomolecules, human sports drug testing has become a considerably complex field in the arena of analytical chemistry. Proving the exogenous origin of peptidic drugs and respective analogs at lowest concentration levels in biological specimens (commonly blood, serum and urine) of rather limited volume is required to pursue an action against cheating athletes. Therefore, approaches employing chromatographic-mass spectrometric, electrophoretic, immunological and combined test methods have been required and developed. These allow detecting the misuse of peptidic compounds of lower (such as growth hormone-releasing peptides, ARA-290, TB-500, AOD-9604, CJC-1295, desmopressin, luteinizing hormone-releasing hormones, synacthen, etc.), intermediate (e.g., insulins, IGF-1 and analogs, 'full-length' mechano growth factor, growth hormone, chorionic gonadotropin, erythropoietin, etc.) and higher (e.g., stamulumab) molecular mass with desired specificity and sensitivity. A gap between the technically possible detection and the day-to-day analytical practice, however, still needs to be closed.

  18. Hospitalizations for Endocarditis and Associated Health Care Costs Among Persons with Diagnosed Drug Dependence - North Carolina, 2010-2015.

    Science.gov (United States)

    Fleischauer, Aaron T; Ruhl, Laura; Rhea, Sarah; Barnes, Erin

    2017-06-09

    Opioid dependence and overdose have increased to epidemic levels in the United States. The 2014 National Survey on Drug Use and Health estimated that 4.3 million persons were nonmedical users of prescription pain relievers (1). These users are 40 times more likely than the general population to use heroin or other injection drugs (2). Furthermore, CDC estimated a near quadrupling of heroin-related overdose deaths during 2002-2014 (3). Although overdose contributes most to drug-associated mortality, infectious complications of intravenous drug use constitute a major cause of morbidity leading to hospitalization (4). In addition to infections from hepatitis C virus (HCV) and human immunodeficiency virus (HIV), injecting drug users are at increased risk for acquiring invasive bacterial infections, including endocarditis (5,6). Evidence that hospitalizations for endocarditis are increasing in association with the current opioid epidemic exists (7-9). To examine trends in hospitalizations for endocarditis among persons in North Carolina with drug dependence during 2010-2015, data from the North Carolina Hospital Discharge database were analyzed. The incidence of hospital discharge diagnoses for drug dependence combined with endocarditis increased more than twelvefold from 0.2 to 2.7 per 100,000 persons per year over this 6-year period. Correspondingly, hospital costs for these patients increased eighteenfold, from $1.1 million in 2010 to $22.2 million in 2015. To reduce the risk for morbidity and mortality related to opioid-associated endocarditis, public health programs and health care systems should consider collaborating to implement syringe service programs, harm reduction strategies, and opioid treatment programs.

  19. Definition of drug resistance of Mycobacterium tuberculosis to antituberculosis drugs in patients with multidrugresistant tuberculosis and TB with extremely drug resistant depending on the case of the disease

    Directory of Open Access Journals (Sweden)

    Kryzhanovsky D.G.

    2014-11-01

    Full Text Available There was studied the profile of drug resistance to the main (I line and reserve (II line antituberculosis drugs in patients with MDR and XDR tuberculosis, depending of the case of the disease. According to the randomized retrospective research 200 patients with MDR and XDR tuberculosis, who received treatment in the clinic of hospital Municipal institution «Dnipropetrovsk rigional clinical association «Phthisiology» Dnipropetrovsk regional Council» during the period 2010 – 2012 were involved. Data about patients contained the data on a case of the disease and the results of the test of drug sensitivity to MBT. XDR – TB was revealed in 7.5% of patients with MDR tuberculosis. In patients with MDR tuberculosis as compared with patients with XDR tuberculosis «new cases» were diagnosed in 19.5% against 18.5% (p <0.05. In patients with MDR tuberculosis and with XDR tuberculosis resistance to the antituberculosis drug more commonly developed to S - 88.5%, E - 55% and Z - 24%. The presence of MDR-TB and XDR-TB prevails in patients, who underwent previous courses of treatment with anti-TB drugs in case history as compared with patients with «new cases» of treatment. The development of resistance to anti-TB drugs depends on the availability of these drugs in the previous treatment regimens.

  20. Current Situation, Determinants, and Solutions to Drug Shortages in Shaanxi Province, China: A Qualitative Study.

    Science.gov (United States)

    Yang, Caijun; Wu, Lina; Cai, Wenfang; Zhu, Wenwen; Shen, Qian; Li, Zongjie; Fang, Yu

    2016-01-01

    Drug shortages were a complex global problem. The aim of this study was to analyze, characterize, and assess the drug shortages, and identify possible solutions in Shaanxi Province, western China. A qualitative methodological approach was conducted during May-June 2015 and December 2015-January 2016. Semi-structured interviews were performed to gather information from representatives of hospital pharmacists, wholesalers, pharmaceutical producers, and local health authorities. Thirty participants took part in the study. Eight traditional Chinese medicines and 87 types of biologicals and chemicals were reported to be in short supply. Most were essential medicines. Five main determinants of drug shortages were detected: too low prices, too low market demands, Good Manufacturing Practice (GMP) issues, materials issues, and approval issues for imported drugs. Five different solutions were proposed by the participants: 1) let the market decide the drug price; 2) establish an information platform; 3) establish a reserve system; 4) enhance the communication among the three parties in the supply chain; and 5) improve hospital inventory management. Western China was currently experiencing a serious drug shortage. Numerous reasons for the shortage were identified. Most drug shortages in China were currently because of "too low prices." To solve this problem, all of the stakeholders, especially the government, needed to participate in managing the drug shortages.

  1. Fed-state gastric media and drug analysis techniques: Current status and points to consider.

    Science.gov (United States)

    Baxevanis, Fotios; Kuiper, Jesse; Fotaki, Nikoletta

    2016-10-01

    Gastric fed state conditions can have a significant effect on drug dissolution and absorption. In vitro dissolution tests with simple aqueous media cannot usually predict drugs' in vivo response, as several factors such as the meal content, the gastric emptying and possible interactions between food and drug formulations can affect drug's pharmacokinetics. Good understanding of the effect of the in vivo fed gastric conditions on the drug is essential for the development of biorelevant dissolution media simulating the gastric environment after the administration of the standard high fat meal proposed by the FDA and the EMA in bioavailability/bioequivalence (BA/BE) studies. The analysis of drugs in fed state media can be quite challenging as most analytical protocols currently employed are time consuming and labour intensive. In this review, an overview of the in vivo gastric conditions and the biorelevant media used for their in vitro simulation are described. Furthermore an analysis of the physicochemical properties of the drugs and the formulations related to food effect is given. In terms of drug analysis, the protocols currently used for the fed state media sample treatment and analysis and the analytical challenges and needs emerging for more efficient and time saving techniques for a broad spectrum of compounds are being discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Molecular weight-dependent degradation and drug release of surface-eroding poly(ethylene carbonate)

    DEFF Research Database (Denmark)

    Bohr, Adam; Wang, Yingya; Harmankaya, Necati

    2017-01-01

    .7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half......Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough...... to control the spatial and temporal on-demand degradation and drug release from the employed delivery system....

  3. Overlooked and underestimated? Problematic alcohol use in clients recovering from drug dependence.

    Science.gov (United States)

    Staiger, Petra K; Richardson, Ben; Long, Caroline M; Carr, Victoria; Marlatt, G Alan

    2013-07-01

    Despite recognition of the harms related to alcohol misuse and its potential to interfere substantially with sustained recovery from drug dependency, research evaluating drug treatment outcomes has not addressed the issue comprehensively. It has been overlooked possibly because treatment research has been framed according to the primary drug of choice, rather than investigating the interactions between different combinations of drugs and/or alcohol use. This paper reports on a systematic review investigating whether concurrent alcohol use could impede recovery from illicit drug use in two potential ways: first, alcohol could become a substitute addiction and/or secondly, alcohol misuse post-treatment may place an individual at risk for relapse to their primary drug problem. A systematic search of four relevant databases was undertaken to identify peer-reviewed, quantitative drug treatment outcome studies that reported alcohol use pre-, post-treatment and follow-up. The search revealed 567 papers, of which 13 were assessed as fulfilling the key inclusion criteria.The review indicated inconsistent and therefore inconclusive support for the substitution hypothesis. However, the data revealed consistent support for the hypothesis that alcohol use increases relapse to drug use. (i) The potential negative impact of alcohol misuse on drug treatment outcomes remains under-researched and overlooked; (ii) alcohol consumption post-drug treatment may increase the likelihood that an individual will relapse to their primary drug; (ii) existing evidence regarding the substitution hypothesis is inconclusive, although there was an indication that a subgroup of participants will be vulnerable to alcohol becoming the primary addiction instead of drugs. We argue that future drug treatment outcome studies need to include detailed analysis of the influence of alcohol use pre- and post-drug treatment. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

  4. Magnetic field dependence of the critical current density in YBa2Cu3Ox ceramics

    International Nuclear Information System (INIS)

    Zhukov, A.A.; Moshchalkov, V.V.; Komarkov, D.A.; Shabatin, V.P.; Gordeev, S.N.; Shelomov, D.V.

    1989-01-01

    Three magnetic field ranges corresponding to different critical current density j c behavior have been found out. They correlate with grain magnetization changes. The inverse critical current density is shown to depend linearly on the sample cross-section due to the magnetic field induced by the flowing current

  5. Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery.

    Science.gov (United States)

    Muddineti, Omkara Swami; Ghosh, Balaram; Biswas, Swati

    2017-06-01

    Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years. Areas covered: Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters. Expert opinion: The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.

  6. Current good manufacturing practice and investigational new drugs intended for use in clinical trials. Final rule.

    Science.gov (United States)

    2008-07-15

    The Food and Drug Administration (FDA) is amending the current good manufacturing practice (CGMP) regulations for human drugs, including biological products, to exempt most phase 1 investigational drugs from complying with the regulatory CGMP requirements. FDA will continue to exercise oversight of the manufacture of these drugs under FDA's general statutory CGMP authority and through review of the investigational new drug applications (IND). In addition, elsewhere in this issue of the Federal Register, FDA is announcing the availability of a guidance document entitled "Guidance for Industry: CGMP for Phase 1 Investigational Drugs" dated November 2007 (the companion guidance). This guidance document sets forth recommendations on approaches to compliance with statutory CGMP for the exempted phase 1 investigational drugs. FDA is taking this action to focus a manufacturer's effort on applying CGMP that is appropriate and meaningful for the manufacture of the earliest stage investigational drug products intended for use in phase 1 clinical trials while ensuring safety and quality. This action will also streamline and promote the drug development process.

  7. The impact of race, income, drug abuse and dependence on health insurance coverage among US adults.

    Science.gov (United States)

    Wang, Nianyang; Xie, Xin

    2017-06-01

    Little is known about the impact of drug abuse/dependence on health insurance coverage, especially by race groups and income levels. In this study, we examine the disparities in health insurance predictors and investigate the impact of drug use (alcohol abuse/dependence, nicotine dependence, and illicit drug abuse/dependence) on lack of insurance across different race and income groups. To perform the analysis, we used insurance data (8057 uninsured and 28,590 insured individual adults) from the National Surveys on Drug Use and Health (NSDUH 2011). To analyze the likelihood of being uninsured we performed weighted binomial logistic regression analyses. The results show that the overall prevalence of lacking insurance was 19.6 %. However, race differences in lack of insurance exist, especially for Hispanics who observe the highest probability of being uninsured (38.5 %). Furthermore, we observe that the lowest income level bracket (annual income <$20,000) is associated with the highest likelihood of being uninsured (37.3 %). As the result of this investigation, we observed the following relationship between drug use and lack of insurance: alcohol abuse/dependence and nicotine dependence tend to increase the risk of lack of insurance for African Americans and whites, respectively; illicit drug use increases such risk for whites; alcohol abuse/dependence increases the likelihood of lack of insurance for the group with incomes $20,000-$49,999, whereas nicotine dependence is associated with higher probability of lack of insurance for most income groups. These findings provide some useful insights for policy makers in making decisions regarding unmet health insurance coverage.

  8. Brain Phosphorus Magnetic Resonance Spectroscopy Imaging of Sleep Homeostasis and Restoration in Drug Dependence

    Directory of Open Access Journals (Sweden)

    George H. Trksak

    2007-01-01

    Full Text Available Numerous reports have documented a high occurrence of sleep difficulties in drug-dependent populations, prompting researchers to characterize sleep profiles and physiology in drug abusing populations. This mini-review examines studies indicating that drug-dependent populations exhibit alterations in sleep homeostatic and restoration processes in response to sleep deprivation. Sleep deprivation is a principal sleep research tool that results in marked physiological challenge, which provides a means to examine sleep homeostatic processes in response to extended wakefulness. A report from our laboratory demonstrated that following recovery sleep from sleep deprivation, brain high-energy phosphates particularly beta–nucleoside triphosphate (beta-NTP are markedly increased as measured with phosphorus magnetic resonance spectroscopy (MRS. A more recent study examined the effects of sleep deprivation in opiate-dependent methadone-maintained (MM subjects. The study demonstrated increases in brain beta-NTP following recovery sleep. Interestingly, these increases were of a markedly greater magnitude in MM subjects compared to control subjects. A similar study examined sleep deprivation in cocaine-dependent subjects demonstrating that cocaine-dependent subjects exhibit greater increases in brain beta-NTP following recovery sleep when compared to control subjects. The studies suggest that sleep deprivation in both MM subjects and cocaine-dependent subjects is characterized by greater changes in brain ATP levels than control subjects. Greater enhancements in brain ATP following recovery sleep may reflect a greater disruption to or impact of sleep deprivation in drug dependent subjects, whereby sleep restoration processes may be unable to properly regulate brain ATP and maintain brain high-energy equilibrium. These studies support the notion of a greater susceptibility to sleep loss in drug dependent populations. Additional sleep studies in drug abusing

  9. a Comparison Between Chemically Dependent Mothers and Drug-Free Mothers: Lifestyle during the Perinatal Period

    Science.gov (United States)

    Uskokovic, Lila Milica

    This study compared maternal lifestyle variables pertinent to the perinatal period in groups of chemically dependent mothers and drug-free mothers. Twenty-nine cocaine -abusing mothers were compared to 29 drug-free mothers carefully matched on age, race, education, and primipara versus multipara status. The drug history of each chemically dependent woman was explicitly documented. The chemically dependent group was subdivided into two groups, mothers who abused cocaine and those who abused cocaine with concomitant opiate use. Each of these two subgroups was compared to its respective matched drug-free control group. Finally, a comparison was made between the two drug subgroups. All subjects were interviewed within 48 hours after delivery using the following measures: State-Trait Anxiety Inventory (A-State), Center for Epidemiologic Studies - Depression Scale, The Self-Esteem Scale, Maternal Adjustment and Maternal Attitude Questionnaire, The Neonatal Perception Inventory, The Psychiatric Epidemiology Research Interview Life Events Scale, Maternal Social Support Index, and Short Marital Adjustment Test. A t-test analysis revealed significant differences (p abused opiates with cocaine did not differ from their controls on depression and maternal adjustment and attitudes. No significant differences were obtained in the drug subgroup comparisons. These results identify increased life events and specific negative affect states that clinical intervention programs should address to assure the best possible outcome for chemically dependent mothers and their infants.

  10. Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.

    Science.gov (United States)

    Scafidi, Joseph; Ritter, Jonathan; Talbot, Brooke M; Edwards, Jorge; Chew, Li-Jin; Gallo, Vittorio

    2018-04-15

    Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers. Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 78(8); 2081-95. ©2018 AACR . ©2018 American Association for Cancer Research.

  11. Current and emerging lipid-based systems for transdermal drug delivery.

    Science.gov (United States)

    Singla, Sumeet K; Sachdeva, Vishal

    2015-01-01

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

  12. The current status of orphan drug development in Europe and the US.

    Science.gov (United States)

    Hall, Anthony K; Carlson, Marilyn R

    2014-02-01

    Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, explain the incentives and procedures, and touch on the role of patient organisations in the process.

  13. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?

    Science.gov (United States)

    Staudacher, Alexander H; Brown, Michael P

    2017-12-05

    Antibody drug conjugates (ADCs) employ the exquisite specificity of tumour-specific monoclonal antibodies (mAb) for the targeted delivery of highly potent cytotoxic drugs to the tumour site. The chemistry of the linker, which connects the drug to the mAb, determines how and when the drug is released from the mAb. This, as well as the chemistry of the drug, can dictate whether the drug can diffuse into surrounding cells, resulting in 'bystander killing'. Initially, any bystander killing mechanism of action of an ADC was understood to involve an essential sequence of steps beginning with surface antigen targeting, internalisation, intracellular linker cleavage, drug release, and diffusion of drug away from the targeted cell. However, recent studies indicate that, depending on the linker and drug combination, this mechanism may not be essential and ADCs can be cleaved extracellularly or via other mechanisms. In this minireview, we will examine the role of bystander killing by ADCs and explore the emerging evidence of how this can occur independently of internalisation.

  14. The Current Landscape of 3D In Vitro Tumor Models: What Cancer Hallmarks Are Accessible for Drug Discovery?

    Science.gov (United States)

    Rodenhizer, Darren; Dean, Teresa; D'Arcangelo, Elisa; McGuigan, Alison P

    2018-04-01

    Cancer prognosis remains a lottery dependent on cancer type, disease stage at diagnosis, and personal genetics. While investment in research is at an all-time high, new drugs are more likely to fail in clinical trials today than in the 1970s. In this review, a summary of current survival statistics in North America is provided, followed by an overview of the modern drug discovery process, classes of models used throughout different stages, and challenges associated with drug development efficiency are highlighted. Then, an overview of the cancer hallmarks that drive clinical progression is provided, and the range of available clinical therapies within the context of these hallmarks is categorized. Specifically, it is found that historically, the development of therapies is limited to a subset of possible targets. This provides evidence for the opportunities offered by novel disease-relevant in vitro models that enable identification of novel targets that facilitate interactions between the tumor cells and their surrounding microenvironment. Next, an overview of the models currently reported in literature is provided, and the cancer biology they have been used to explore is highlighted. Finally, four priority areas are suggested for the field to accelerate adoption of in vitro tumour models for cancer drug discovery. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Dependence of the Spin Transfer Torque Switching Current Density on the Exchange Stiffness Constant

    OpenAIRE

    You, Chun-Yeol

    2012-01-01

    We investigate the dependence of the switching current density on the exchange stiffness constant in the spin transfer torque magnetic tunneling junction structure with micromagnetic simulations. Since the widely accepted analytic expression of the switching current density is based on the macro-spin model, there is no dependence of the exchange stiffness constant. When the switching is occurred, however, the spin configuration forms C-, S-type, or complicated domain structures. Since the spi...

  16. 21 CFR 1404.135 - May the Office of National Drug Control Policy exclude a person who is not currently...

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false May the Office of National Drug Control Policy exclude a person who is not currently participating in a nonprocurement transaction? 1404.135 Section 1404.135 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) General § 1404.135 May the...

  17. 5-HT modulation of hyperpolarization-activated inward current and calcium- dependent outward current in a crustacean motor neuron

    DEFF Research Database (Denmark)

    Kiehn, O.; Harris-Warrick, R. M.

    1992-01-01

    1. Serotonergic modulation of a hyperpolarization-activated inward current, I(h), and a calcium-dependent outward current, I(o(Ca)), was examined in the dorsal gastric (DG) motor neuron, with the use of intracellular recording techniques in an isolated preparation of the crab stomatogastric....... The time course of activation of I(h) was well fitted by a single exponential function and strongly voltage dependent. 5-HT increased the rate of activation of I(h). 5- HT also slowed the rate of deactivation of the I(h) tail on repolarization to -50 mV. 6. The activation curve for the conductance (G...... reduced or eliminated the 5-HT response in the depolarizing range, suggesting that 5-HT specifically reduces I(o(Ca)). 11. These results demonstrate that 5-HT has dual effects on the DG motor neuron, in the crab stomatogastric ganglion. We suggest that changes in the two conductances are responsible...

  18. Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents.

    Science.gov (United States)

    Gómez, Ricardo; Caballero, Ricardo; Barana, Adriana; Amorós, Irene; De Palm, Sue-Haida; Matamoros, Marcos; Núñez, Mercedes; Pérez-Hernández, Marta; Iriepa, Isabel; Tamargo, Juan; Delpón, Eva

    2014-11-01

    We hypothesize that some drugs, besides flecainide, increase the inward rectifier current (IK1) generated by Kir2.1 homotetramers (IKir2.1) and thus, exhibit pro- and/or antiarrhythmic effects particularly at the ventricular level. To test this hypothesis, we analysed the effects of propafenone, atenolol, dronedarone, and timolol on Kir2.x channels. Currents were recorded with the patch-clamp technique using whole-cell, inside-out, and cell-attached configurations. Propafenone (0.1 nM-1 µM) did not modify either IK1 recorded in human right atrial myocytes or the current generated by homo- or heterotetramers of Kir2.2 and 2.3 channels recorded in transiently transfected Chinese hamster ovary cells. On the other hand, propafenone increased IKir2.1 (EC50 = 12.0 ± 3.0 nM) as a consequence of its interaction with Cys311, an effect which decreased inward rectification of the current. Propafenone significantly increased mean open time and opening frequency at all the voltages tested, resulting in a significant increase of the mean open probability of the channel. Timolol, which interacted with Cys311, was also able to increase IKir2.1. On the contrary, neither atenolol nor dronedarone modified IKir2.1. Molecular modelling of the Kir2.1-drugs interaction allowed identification of the pharmacophore of drugs that increase IKir2.1. Kir2.1 channels exhibit a binding site determined by Cys311 that is responsible for drug-induced IKir2.1 increase. Drug binding decreases channel affinity for polyamines and current rectification, and can be a mechanism of drug-induced pro- and antiarrhythmic effects not considered until now. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  19. Magnetic field dependence of the critical superconducting current induced by the proximity effect in silicon

    International Nuclear Information System (INIS)

    Nishino, T.; Kawabe, U.; Yamada, E.

    1986-01-01

    The magnetic field dependence of the critical superconducting current induced by the proximity effect in heavily-boron-doped Si is studied experimentally. It is found that the critical current flowing through the p-type-Si-coupled junction decreases with increasing applied magnetic field. The critical current can be expressed as the product of three factors: the current induced by de Gennes's proximity effect, the exponential decrease due to pair breaking by the magnetic field, and the usual diffraction-pattern-like dependence on the magnetic field due to the Josephson effect. The second factor depends on the carrier concentration in the semiconductor. The local critical current shows a rapid decrease at the edge of the electrodes

  20. Mobile phone messaging for illicit drug and alcohol dependence: A systematic review of the literature.

    Science.gov (United States)

    Tofighi, Babak; Nicholson, Joseph M; McNeely, Jennifer; Muench, Frederick; Lee, Joshua D

    2017-07-01

    Mobile phone use has increased dramatically and concurrent with rapid developments in mobile phone-based health interventions. The integration of text messaging interventions promises to optimise the delivery of care for persons with substance dependence with minimal disruption to clinical workflows. We conducted a systematic review to assess the acceptability, feasibility and clinical impact of text messaging interventions for persons with illicit drug and alcohol dependence. Studies were required to evaluate the use of text messaging as an intervention for persons who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criterion for a diagnosis of illicit drug and/or alcohol dependence. Authors searched for articles published to date in MEDLINE (pubmed.gov), the Cochrane Library, EMBASE, CINAHL, Google Scholar and PsychINFO. Eleven articles met the search criteria for this review and support the acceptability and feasibility of text messaging interventions for addressing illicit drug and alcohol dependence. Most studies demonstrated improved clinical outcomes, medication adherence and engagement with peer support groups. Text messaging interventions also intervened on multiple therapeutic targets such as appointment attendance, motivation, self-efficacy, relapse prevention and social support. Suggestions for future research are described, including intervention design features, clinician contact, privacy measures and integration of behaviour change theories. Text messaging interventions offer a feasible platform to address a range of substances (i.e. alcohol, methamphetamine, heroin and alcohol), and there is increasing evidence supporting further larger-scale studies. [Tofighi B, Nicholson JM, McNeely J, Muench F, Lee JD. Mobile phone messaging for illicit drug and alcohol dependence: A systematic review of the literature. Drug Alcohol Rev 2017;36:477-491]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  1. Taste perception: Risk factor or protection for dependents during drug use cessation

    Directory of Open Access Journals (Sweden)

    Carla Rosane Paz Arruda Teo

    2014-08-01

    Full Text Available The increase in appetite and, consequently, in body weight, evidenced in the majority of addicts under treatment, may be related to taste, since heavy drug use can lead to changes in taste buds. This study aimed to investigate the association between taste perception and nutritional status of drug addicts under treatment. The study was conducted in two therapeutic communities in the municipality of Chapecó, Santa Catarina state, with 39 male addicts over 18 years old. Primary data on weight and height were collected for assessment of nutritional status, and a taste acuity test was applied; also, secondary data were collected on age, length of stay, types of drugs used, and age of drug use onset, from the addicts’ records. It was possible to observe that 56.5% of dependents were at nutritional risk for being overweight. Taste acuity significantly differed for the basic tastes evaluated (p= 0.014, being higher for salty (94.9%, followed by sweet (89.7%, acid (79.5%, and bitter (38, 5% tastes, but it was not associated with the study variables. We conclude that the drug use cessation can have a similar effect to that of caloric deprivation on the taste acuity of dependents, interfering on excessive weight gain. However, it is suggested that the improvement of taste perception be oriented in the therapeutic setting, so that it becomes, in these conditions, a protection factor for dependents, strengthening them to overcome their condition of vulnerability.

  2. Dependent Prior: An Application in Spinal Anaesthesia Drug Therapy on SBP in Cesarean patients.

    Directory of Open Access Journals (Sweden)

    Atanu Bhattacharjee

    2013-12-01

    Full Text Available Cesarean section is widely used operation procedure in the world. The regional anesthesia is preferred than general anesthesia. The risk of fetus is higher in general than in regional anesthesia. The drug treatment effect on regional anesthesia plays an important role to control the systolic blood pressure (SBP during the surgery. The goal of this work is to know the effective drug to control the SBP among cesarean anesthetic patients. The dependent prior with Bayesian approach is applied in the binary response data set. The secondary data in anesthesia has been applied to compare the two drug treatments, viz. (1 Phenylephrine and (2 Ephedrine, in cesarean patients with spinal anesthesia. In both drug groups the mean of SBP has been found controlled over the duration of the surgery. No rapid changes of SBP level among the patients are observed. At the end of study it is found that the means of SBP cesarean anesthetic patients are found higher in Phenylephrine group. The Bayesian dependent prior is found to offer effective tool for drug treatment effect comparison. The drug treatment effect Ephedrine is found to be more effective to control the SBP over the duration of surgery than Phenylephrine.

  3. Temperature dependence of the current to sustain a normal hotspot in superconducting microbridges

    International Nuclear Information System (INIS)

    Yamaguchi, Y.; Ishii, C.

    1981-01-01

    A modification of the boundary condition to determine the SN boundary in the hotspot model of superconducting microbridges is proposed and successfully applied to the interpretation of recent measurements of the hotspot-sustaining current by Mizuno and Aomine. It is shown that suppression of the order parameter due to the applied current gives rise to an additional temperature dependence of the hotspot-sustaining current in the extreme vicinity of the transition temperature. (orig.)

  4. Josephson-like currents in graphene for arbitrary time-dependent potential barriers

    OpenAIRE

    Savel'ev, Sergey E.; Hausler, Wolfgang; Hanggi, Peter

    2011-01-01

    From the exact solution of the Dirac-Weyl equation we find unusual currents j_y running in y-direction parallel to a time-dependent scalar potential barrier W(x,t) placed upon a monolayer of graphene, even for vanishing momentum component p_y. In their sine-like dependence on the phase difference of wave functions, describing left and right moving Dirac fermions, these currents resemble Josephson currents in superconductors, including the occurance of Shapiro steps at certain frequencies of p...

  5. Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

    Directory of Open Access Journals (Sweden)

    Luis I Angel-Chavez

    Full Text Available In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV. Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

  6. Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

    Science.gov (United States)

    Angel-Chavez, Luis I; Acosta-Gómez, Eduardo I; Morales-Avalos, Mario; Castro, Elena; Cruzblanca, Humberto

    2015-01-01

    In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

  7. The tunneling magnetoresistance current dependence on cross sectional area, angle and temperature

    Directory of Open Access Journals (Sweden)

    Z. H. Zhang

    2015-03-01

    Full Text Available The magnetoresistance of a MgO-based magnetic tunnel junction (MTJ was studied experimentally. The magnetoresistance as a function of current was measured systematically on MTJs for various MgO cross sectional areas and at various temperatures from 7.5 to 290.1 K. The resistance current dependence of the MTJ was also measured for different angles between the two ferromagnetic layers. By considering particle and angular momentum conservation of transport electrons, the current dependence of magnetoresistance can be explained by the changing of spin polarization in the free magnetic layer of the MTJ. The changing of spin polarization is related to the magnetoresistance, its angular dependence and the threshold current where TMR ratio equals zero. A phenomenological model is used which avoid the complicated barrier details and also describes the data.

  8. Death and dependence: current controversies over the selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Nutt, David J

    2003-12-01

    Recent years have seen a considerable media interest in the adverse effects of the selective serotonin reuptake inhibitors (SSRIs). This has led to claims that these antidepressants may lead to suicide and homicide and that they cause dependence or even addiction. Such claims have caused great concerns to many patients and have confused doctors in both primary care and psychiatric practice. In this article I review the basis of these claims and show that many seem to emerge from the misinterpretation of evidence and the use of imprecise definitions. Although the SSRIs are not free of problems they compare very favourably with other antidepressants and other classes of psychotropic drugs. There is no evidence they are addictive in the formal sense of leading to a drug dependence syndrome. Some suggestions on the way these issues can be more precisely defined and studied in future are given.

  9. Role of the pH in state-dependent blockade of hERG currents

    Science.gov (United States)

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-10-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action.

  10. Governor's Conference on Drug Dependence and Abuse. An Occasional Paper of the Honors College.

    Science.gov (United States)

    Milliken, William G.; And Others

    1970-01-01

    Following Governor Milliken's address, Dr. Dana Farnsworth defines the problem in terms of who's involved, to what extent, and with which drugs. His presentation focuses primarily on the motives of affluent young people who experiment with or become dependent upon hallucinogens, marihuana and amphetamines. He deals extensively with the drastically…

  11. "Too Far Gone": Dyslexia, Homelessness, and Pathways to Drug Use and Dependency

    Science.gov (United States)

    Macdonald, Stephen J.; Deacon, Lesley; Merchant, Jacqueline

    2016-01-01

    This study investigated the relationship between dyslexia, homelessness, and drug use and dependency based on data from the Multiple Exclusion Homelessness Across the United Kingdom Survey, a national survey of 443 respondents who had experienced some form of homelessness in the U.K. Of particular interest was a comparison of the various…

  12. Willingness to pay for opioid agonist treatment among opioid dependent people who inject drugs in Ukraine.

    Science.gov (United States)

    Makarenko, Iuliia; Mazhnaya, Alyona; Marcus, Ruthanne; Bojko, Martha J; Madden, Lynn; Filippovich, Sergii; Dvoriak, Sergii; Altice, Frederick L

    2017-07-01

    In the context of decreasing external and limited Ukrainian governmental funding for opioid agonist treatments (OAT) for opioid dependent people who inject drugs in Ukraine, information on sustainable financial models is needed. Data on 855 opioid dependent people who inject drugs (PWID) were drawn from a cross-sectional nationwide survey of 1613 PWID. They comprised 434 participants who were receiving OAT and 421 who were on OAT in the past or have never been on OAT and were interested in receiving the treatment. Multivariate logistic regression was used to examine factors associated with willingness-to-pay (WTP) for OAT, stratified by OAT experience. Variation in the price which respondents were willing to pay for OAT and its effect on their monthly income among PWID with different OAT experience were assessed as a continuous variable using one-way ANOVA and Kruskal-Wallis test. Overall, 378 (44%) expressed WTP for OAT. Factors independently associated with WTP differed by OAT experience. Among those using OAT, independent predictors of WTP included: city (Dnipro - aOR=1.9; 95%CI=1.1-4.8 and Lviv - (aOR=2.2; 95%CI=1.1-4.8) compared to those elsewhere in Ukraine), higher income (aOR=1.8; 95%CI=1.2-2.7) and receiving psychosocial counseling (aOR=1.8; 95%CI=1.2-2.7). Among those who had previously been on OAT, positive attitude towards OAT (aOR=1.3; 95%CI=1.1-1.6) and family support of OAT (aOR=2.5; 95%CI=1.1-5.7) were independently associated with WTP. Among PWID who had never been on OAT, being male (aOR=2.2; 95%CI=1.1-4.2), younger age (aOR=1.9; 95%CI=1.2-3.2), higher income (aOR=2.0; 95%CI=1.2-3.4) and previous unsuccessful attempts to enter OAT (aOR=2.3; 95%CI=1.1-4.7) were independently associated with WTP. PWID were willing to commit a large percentage of their monthly income for OAT, which, however, varied significantly based on OAT experience: current OAT: 37% of monthly income, previous OAT: 53%, and never OAT: 60% (p-value=0.0009). WTP for OAT was

  13. 38 CFR 17.80 - Alcohol and drug dependence or abuse treatment and rehabilitation in residential and...

    Science.gov (United States)

    2010-07-01

    ... dependence or abuse treatment and rehabilitation in residential and nonresidential facilities by contract. 17... of Services of Other Federal Agencies § 17.80 Alcohol and drug dependence or abuse treatment and rehabilitation in residential and nonresidential facilities by contract. (a) Alcohol and drug dependence or abuse...

  14. Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition.

    Science.gov (United States)

    Falgreen, Steffen; Laursen, Maria Bach; Bødker, Julie Støve; Kjeldsen, Malene Krag; Schmitz, Alexander; Nyegaard, Mette; Johnsen, Hans Erik; Dybkær, Karen; Bøgsted, Martin

    2014-06-05

    In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves' dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological

  15. Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence.

    Science.gov (United States)

    Ersche, Karen D; Bullmore, Edward T; Craig, Kevin J; Shabbir, Shaila S; Abbott, Sanja; Müller, Ulrich; Ooi, Cinly; Suckling, John; Barnes, Anna; Sahakian, Barbara J; Merlo-Pich, Emilio V; Robbins, Trevor W

    2010-06-01

    There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges. Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18). Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation

  16. Relationship between drug dreams, affect, and craving during treatment for substance dependence.

    Science.gov (United States)

    Tanguay, Hélène; Zadra, Antonio; Good, Daniel; Leri, Francesco

    2015-01-01

    To explore the relationship between occurrence of drug dreams (DDs) and daytime negative affect and drug craving during the course of a 5-week treatment program for substance dependence. Using the dream journal methodology, 86 participants reported occurrence of dreams, dream content, and ratings of affect and drug craving. The relationships between the experience of DD, dream content ("active" vs "passive"), and affect and craving were analyzed using mixed model methods. The experience of DD was associated with higher levels of negative affect (P < 0.001) and craving (P < 0.001). The occurrence of DD did not decrease significantly over the 5 weeks of the study. Cocaine/crack users reported a higher occurrence of DD (P < 0.05) than the other drug groups (opiates and alcohol), and DD involving "active" drug use was associated with larger (P < 0.05) changes in negative affect. These results are consistent with the hypothesis that DD can act as drug-conditioned stimuli to elevate negative affect and craving in abstaining individuals. Although correlational, such findings support the implementation of psychological and pharmacological interventions aimed at minimizing the impact of DD on individuals in recovery from drug addiction.

  17. Cancer drug addiction is relayed by an ERK2-dependent phenotype switch.

    Science.gov (United States)

    Kong, Xiangjun; Kuilman, Thomas; Shahrabi, Aida; Boshuizen, Julia; Kemper, Kristel; Song, Ji-Ying; Niessen, Hans W M; Rozeman, Elisa A; Geukes Foppen, Marnix H; Blank, Christian U; Peeper, Daniel S

    2017-10-12

    Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced

  18. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues.

    Science.gov (United States)

    Kim, Munju; Gillies, Robert J; Rejniak, Katarzyna A

    2013-11-18

    Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence.

  19. 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.

  20. Current prescription status of antihypertensive drugs with special reference to the use of diuretics in Japan.

    Science.gov (United States)

    Ibaraki, Ai; Goto, Wataru; Iura, Rie; Tominaga, Mitsuhiro; Tsuchihashi, Takuya

    2017-02-01

    The guidelines for the management of hypertension recommend the inclusion of diuretics, especially when three or more antihypertensive drugs are used. The present study investigated the current prescription status of antihypertensive drugs with a particular focus on the use of diuretics in a local district in Japan. Prescriptions, including antihypertensive drugs, were collected from a dispensing pharmacy of the Yahata Pharmacist Association, located in Kitakyushu City, in October 2014. Of the 10 585 prescriptions, calcium channel blockers (CCBs) were prescribed in 73.5%, followed by angiotensin II receptor blockers (ARB, 62.7%), diuretics (16.5%) and β-blockers (13.6%). The average number of drugs used was 1.80. The rates of prescription of diuretics for patients with one, two, three and four drugs were 0.6%, 13.1%, 55.2% and 82.6%, respectively. Diuretics were more frequently prescribed in elderly patients, and the prescription rate of doctors in hospitals was significantly higher than that of general practitioners (19.1% vs. 15.7%, Pdiuretics were prescribed combination tablets of hydrochlorothiazide with ARB, whereas trichlormethiazide (34.9%) and indapamide (19.8%) were used in other patients. Based on these findings, the use of diuretics remains limited, even among patients taking multiple antihypertensive drugs.

  1. Hysteresis loops of spin-dependent electronic current in a paramagnetic resonant tunnelling diode

    International Nuclear Information System (INIS)

    Wójcik, P; Spisak, B J; Wołoszyn, M; Adamowski, J

    2012-01-01

    Nonlinear properties of the spin-dependent electronic transport through a semiconductor resonant tunnelling diode with a paramagnetic quantum well are considered. The spin-dependent Wigner–Poisson model of the electronic transport and the two-current Mott’s formula for the independent spin channels are applied to determine the current–voltage curves of the nanodevice. Two types of the electronic current hysteresis loops are found in the current–voltage characteristics for both the spin components of the electronic current. The physical interpretation of these two types of the electronic current hysteresis loops is given based on the analysis of the spin-dependent electron densities and the potential energy profiles. The differences between the current–voltage characteristics for both the spin components of the electronic current allow us to explore the changes of the spin polarization of the current for different electric fields and determine the influence of the electronic current hysteresis on the spin polarization of the current flowing through the paramagnetic resonant tunnelling diode. (paper)

  2. Analysis of surface dark current dependent upon surface passivation in APD based on GaAs

    International Nuclear Information System (INIS)

    Song, Hong Joo; Roh, Cheong Hyun; Lee, Jun Ho; Choi, Hong Goo; Hahn, Cheol-Koo; Kim, Dong Ho; Park, Jung Ho

    2009-01-01

    In this paper, we investigated the dependence of reverse dark current on two types of surface passivation, one of which is polyimide and the other is SiN x , for InAs quantum dots/GaAs separate absorption, charge, multiplication avalanche photodiode (SACM APD). From the experimental results, we found that dark current was dominated by surface current, and not bulk current. It was also noted that SiN x passivation has a surface current that is lower by three to nine times in magnitude than that in polyimide passivation in the whole range of bias. To analyze the difference in dark current due to the passivation types, we propose the theoretical current components. This shows that the dark current of both passivation types is mainly composed of generation–recombination (G–R) and tunneling components, originating from the surface. However, each component has a different magnitude for passivation types, which can be explained by carrier concentration and trap density. The dependence of dark current on temperature shows the different behaviors between passivation types and supports a theoretical description of current components

  3. Transresistance calibrations and temperature dependence evaluation of a magnetic bridge current sensor with shunt standards

    International Nuclear Information System (INIS)

    Yamada, T; Kon, S; Tadatsu, T

    2011-01-01

    This paper deals with a magnetic bridge current sensor for dc current measurements and a calibration system developed for the current sensor. The current sensor forms a magnetic bridge structure with a magnetic fluid core. The calibration system has been developed by using standard shunts for a test current range of 1 mA to 100 A and establishing a comparison method with a switching/sampling system. In the calibration system, the transresistances of the current sensor are measured and the uncertainties of the system are estimated for the input test current range. Also, the temperature dependence on the transresistances is investigated for temperatures ranging from −40 to 100 °C

  4. n value and Jc distribution dependence of AC transport current losses in HTS conductors

    International Nuclear Information System (INIS)

    Ogawa, Jun; Sawai, Yusuke; Nakayama, Haruki; Tsukamoto, Osami; Miyagi, Daisuke

    2004-01-01

    Compared with LTS materials, HTS materials have some peculiarities affecting AC loss characteristics of the conductors. We measured the AC transport current losses in YBCO thin film coated conductors and a Bi2223/Ag sheathed tape. Comparing the measured data with analytical calculations, the dependence of the AC transport current losses on the n value and critical current density distributions are studied. It is shown that, considering the n values and J c distributions, the peculiarities in the HTS materials can be taken into consideration and the transport current losses in HTS conductors can be calculated by the same analytical method used for LTS

  5. Homeless drug users and information technology: a qualitative study with potential implications for recovery from drug dependence.

    Science.gov (United States)

    Neale, Joanne; Stevenson, Caral

    2014-09-01

    Having access to information and communication technologies (ICTs) is a prerequisite to meaningful participation in society. This paper seeks to: i. explore the engagement of homeless drug users (HDUs) with ICTs and ii. discuss the findings with reference to recovery from drug dependence. The study design was qualitative and longitudinal, involving data collected in 2012-13 via 52 semi-structured interviews with 30 homeless drug users (25 men; five women). Participants were recruited from 17 hostels in two English cities. Interview data were analyzed using Framework. HDUs had access to ICTs, used ICTs, and wanted to engage with them more. Experiences of digital exclusion were a function of participants' inability to afford ICTs, the relatively cheap and poor quality technology available to them, limited knowledge about ICTs, and lack of support in using them. That HDUs were often unable to take full advantage of technology because they had nobody to explain what their devices could do or to show them how they worked was ironic given that using ICTs to (re)establish and maintain relationships were functions of technology that HDUs particularly liked. The physical, human, cultural, and social capital of HDUs influenced their access to, and use of, ICTs. Equally, ICTs were themselves an important recovery resource. Services and others should endeavor to provide HDUs with easy access to good quality technology, as well as offers of support and education so that all individuals have the knowledge and confidence to make optimum use of the technology that is available to them.

  6. Critical current characteristics and history dependence in superconducting SmFeAsOF bulk

    International Nuclear Information System (INIS)

    Ni, B; Ge, J; Kiuchi, M; Otabe, E S; Gao, Z; Wang, L; Qi, Y; Zhang, X; Ma, Y

    2010-01-01

    The superconducting SmFeAsO 1-x F x (x=0.2) polycrystalline bulks were prepared by the powder-in-tube (PIT) method. The magnetic field and temperature dependences of critical current densities in the samples were investigated by resistive and ac inductive (Campbell's) methods. It was found that a fairly large shielding current density over 10 9 A/m 2 , which is considered to correspond to the local critical current density, flows locally with the perimeter size similar to the average grain size of the bulk samples, while an extremely low transport current density of about 10 5 A/m 2 corresponding to the global critical current density flows through the whole sample. Furthermore, a unique history dependence of global critical current density was observed, i.e., it shows a smaller value in the increasing-field process than that in the decreasing-field process. The history dependence of global critical current characteristic in our case can be ascribed to the existence of the weak-link property between the grains in SmFeAsO 1-x F x bulk.

  7. The current state of GPCR-based drug discovery to treat metabolic disease.

    Science.gov (United States)

    Sloop, Kyle W; Emmerson, Paul J; Statnick, Michael A; Willard, Francis S

    2018-02-02

    One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. © 2018 The British Pharmacological Society.

  8. High Prognostic Specificity of Antisocial Personality Disorder in Patients with Drug Dependence

    DEFF Research Database (Denmark)

    Fridell, Mats; Hesse, Morten; Johnson, Eva

    2006-01-01

    personality disorder (ASPD) at intake was associated with incarceration, continuous drug use, dependence on welfare support, and fulfilling criteria of adult ASPD at follow-up. Regardless of ASPD status, a decline was seen in drug-related convictions, but subjects with ASPD were found to continue to commit......A sample of 125 consecutive patients from a Swedish detoxification unit were followed up at five years. Register data on criminal behavior were retrieved for 99% of all subjects, including those who were deceased at follow-up, and 76%of living subjects were interviewed. A diagnosis of antisocial...

  9. Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery.

    Science.gov (United States)

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Mitra, Ashim K

    2012-06-01

    Sodium dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte-Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems.

  10. Dependence of critical current density on crystalline direction in thin YBCO films

    DEFF Research Database (Denmark)

    Paturi, P.; Peurla, M.; Raittila, J.

    2005-01-01

    The dependence of critical current density (J(c)) on the angle between the current direction and the (100) direction in the ab-plane of thin YBCO films deposited on (001)-SrTiO3 from natiocrystalline and microcrystalline targets is studied using magneto-optical microscopy. In the films made from...... the nanocrystalline target it is found that J(c) does not depend on the angle whereas J(c) decreases with increasing angle in the films made from the microcrystalline target. The films were characterized by detailed X-ray diffraction measurements. The findings are explained in terms of a network of planar defects...

  11. The analysis of drug consumption, drug trafficking and the fight against drug trafficking at the present day

    Directory of Open Access Journals (Sweden)

    Borisenko M.V.

    2017-04-01

    Full Text Available the article discusses the current drug situation in Russia, Siberian Federal District and Novosibirsk Region relating to drug consumption and drug trafficking and the main reasons of deaths of drug-dependent people.

  12. Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence.

    Science.gov (United States)

    Becker, Alena; Kirsch, Martina; Gerchen, Martin Fungisai; Kiefer, Falk; Kirsch, Peter

    2017-05-01

    According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol-associated cues, diminished motivation to pursue non-drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non-drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol-dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation and connectivity. Alcohol-dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit. © 2016 Society for the Study of Addiction.

  13. KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current

    DEFF Research Database (Denmark)

    Angelo, Kamilla; Jespersen, Thomas; Grunnet, Morten

    2002-01-01

    The function of the KCNE5 (KCNE1-like) protein has not previously been described. Here we show that KCNE5 induces both a time- and voltage-dependent modulation of the KCNQ1 current. Interaction of the KCNQ1 channel with KCNE5 shifted the voltage activation curve of KCNQ1 by more than 140 mV in th...... the I(Ks) current in certain parts of the mammalian heart....

  14. Large Current Modulation and Spin-Dependent Tunneling of Vertical Graphene/MoS$_{2}$ Heterostructures

    OpenAIRE

    Myoung, Nojoon; Seo, Kyungchul; Lee, Seung Joo; Ihm, Gukhyung

    2013-01-01

    Vertical graphene heterostructures have been introduced as an alternative architecture for electronic devices by using quantum tunneling. Here, we present that the current on/off ratio of vertical graphene field-effect transistors is enhanced by using an armchair graphene nanoribbon as an electrode. Moreover, we report spin-dependent tunneling current of the graphene/MoS2 heterostructures. When an atomically thin MoS2 layer sandwiched between graphene electrodes becomes magnetic, Dirac fermio...

  15. Six types Monte Carlo for estimating the current unavailability of Markov system with dependent repair

    International Nuclear Information System (INIS)

    Xiao Gang; Li Zhizhong

    2004-01-01

    Based on integral equaiton describing the life-history of Markov system, six types of estimators of the current unavailability of Markov system with dependent repair are propounded. Combining with the biased sampling of state transition time of system, six types of Monte Carlo for estimating the current unavailability are given. Two numerical examples are given to deal with the variances and efficiencies of the six types of Monte Carlo methods. (authors)

  16. The potential impact of density dependent fecundity on the use of the faecal egg count reduction test for detecting drug resistance in human hookworms.

    Directory of Open Access Journals (Sweden)

    Andrew C Kotze

    Full Text Available Current efforts to control human soil-transmitted helminth (STH infections involve the periodic mass treatment of people, particularly children, in all endemic areas, using benzimidazole and imidothiazole drugs. Given the fact that high levels of resistance have developed to these same drugs in roundworms of livestock, there is a need to monitor drug efficacy in human STHs. The faecal egg count reduction test (FECRT, in which faecal egg output is measured pre- and post-drug treatment, is presently under examination by WHO as a means of detecting the emergence of resistance. We have examined the potential impact of density dependent fecundity on FECRT data. Recent evidence with the canine hookworm indicates that the density dependent egg production phenomenon shows dynamic properties in response to drug treatment. This will impact on measurements of drug efficacy, and hence drug resistance. It is likely that the female worms that survive a FECRT drug treatment in some human cases will respond to the relaxation of density dependent constraints on egg production by increasing their egg output significantly compared to their pre-treatment levels. These cases will therefore underestimate drug efficacy in the FECRT. The degree of underestimation will depend on the ability of the worms within particular hosts to increase their egg output, which will in turn depend on the extent to which their egg output is constrained prior to the drug treatment. As worms within different human cases will likely be present at quite different densities prior to a proposed FECRT, there is potential for the effects of this phenomenon on drug efficacy measurements to vary considerably within any group of potential FECRT candidates. Measurement of relative drug efficacy may be improved by attempting to ensure a consistent degree of underestimation in groups of people involved in separate FECRTs. This may be partly achieved by omission of cases with the heaviest infections

  17. PREVALENCE OF MULTIPLE ADDICTIONS AND CURRENT TREATMENT BY DRUG TREATMENT CENTRES IN DURBAN, SOUTH AFRICA

    Directory of Open Access Journals (Sweden)

    Keen, Helen

    2015-09-01

    Full Text Available Substance-use disorders (SUD cause severe problems both globally and locally. Research suggests that multiple addictions create a more complex illness. This study investigated whether in-patients admitted for SUD at three drug treatment centres in Durban, South Africa had other, undiagnosed addictions. It utilised a three-phase concurrent mixed-methods design and initially screened for gambling and sex addiction. Results showed that, of the sample of 123 participants, 54% had either sex or gambling and 24% had both addictions which current treatment programmes neither assessed for nor treated. Recommendations include suggestions to update current assessment and treatment approaches and the need to train professional staff at drug treatment centres.

  18. Childhood emotional abuse, dissociation, and suicidality among patients with drug dependency in Turkey.

    Science.gov (United States)

    Tamar-Gurol, Defne; Sar, Vedat; Karadag, Figen; Evren, Cuneyt; Karagoz, Mustafa

    2008-10-01

    The aim of the present study was to determine the prevalence and correlates of dissociative disorders among patients with drug dependency. The Dissociative Experiences Scale (DES) was used to screen 104 consecutive patients at an addiction treatment center. Thirty-seven patients who had scores >or=30 were compared with 21 patients who scored suicide attempt and/or childhood emotional abuse was significant predictors of a dissociative disorder. The majority (59.3%) of dissociative drug users reported that dissociative experiences had existed prior to substance use. More patients in the dissociative disorder than in the non-dissociative group stopped their treatment prematurely. A considerable proportion of drug users have a dissociative disorder, which may also interfere with treatment process. The relatively young age of this subgroup of patients and frequent reports of childhood emotional abuse underline potential preventive benefits of early intervention among adolescents with developmental trauma history and dissociative psychopathology.

  19. Strategies of bringing drug product marketing applications to meet current regulatory standards.

    Science.gov (United States)

    Wu, Yan; Freed, Anita; Lavrich, David; Raghavachari, Ramesh; Huynh-Ba, Kim; Shah, Ketan; Alasandro, Mark

    2015-08-01

    In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts.

  20. Glutathionylation-Dependence of Na+-K+-Pump Currents Can Mimic Reduced Subsarcolemmal Na+ Diffusion

    Science.gov (United States)

    Garcia, Alvaro; Liu, Chia-Chi; Cornelius, Flemming; Clarke, Ronald J.; Rasmussen, Helge H.

    2016-01-01

    The existence of a subsarcolemmal space with restricted diffusion for Na+ in cardiac myocytes has been inferred from a transient peak electrogenic Na+-K+ pump current beyond steady state on reexposure of myocytes to K+ after a period of exposure to K+-free extracellular solution. The transient peak current is attributed to enhanced electrogenic pumping of Na+ that accumulated in the diffusion-restricted space during pump inhibition in K+-free extracellular solution. However, there are no known physical barriers that account for such restricted Na+ diffusion, and we examined if changes of activity of the Na+-K+ pump itself cause the transient peak current. Reexposure to K+ reproduced a transient current beyond steady state in voltage-clamped ventricular myocytes as reported by others. Persistence of it when the Na+ concentration in patch pipette solutions perfusing the intracellular compartment was high and elimination of it with K+-free pipette solution could not be reconciled with restricted subsarcolemmal Na+ diffusion. The pattern of the transient current early after pump activation was dependent on transmembrane Na+- and K+ concentration gradients suggesting the currents were related to the conformational poise imposed on the pump. We examined if the currents might be accounted for by changes in glutathionylation of the β1 Na+-K+ pump subunit, a reversible oxidative modification that inhibits the pump. Susceptibility of the β1 subunit to glutathionylation depends on the conformational poise of the Na+-K+ pump, and glutathionylation with the pump stabilized in conformations equivalent to those expected to be imposed on voltage-clamped myocytes supported this hypothesis. So did elimination of the transient K+-induced peak Na+-K+ pump current when we included glutaredoxin 1 in patch pipette solutions to reverse glutathionylation. We conclude that transient K+-induced peak Na+-K+ pump current reflects the effect of conformation-dependent β1 pump subunit

  1. Spin-dependent current in resonant tunneling diode with ferromagnetic GaMnN layers

    International Nuclear Information System (INIS)

    Tang, N.Y.

    2009-01-01

    The spin-polarized tunneling current through a double barrier resonant tunneling diode (RTD) with ferromagnetic GaMnN emitter/collector is investigated theoretically. Two distinct spin splitting peaks can be observed at current-voltage (I-V) characteristics at low temperature. The spin polarization decreases with the temperature due to the thermal effect of electron density of states. When charge polarization effect is considered at the heterostructure, the spin polarization is enhanced significantly. A highly spin-polarized current can be obtained depending on the polarization charge density.

  2. Effect of quality chronic disease management for alcohol and drug dependence on addiction outcomes.

    Science.gov (United States)

    Kim, Theresa W; Saitz, Richard; Cheng, Debbie M; Winter, Michael R; Witas, Julie; Samet, Jeffrey H

    2012-12-01

    We examined the effect of the quality of primary care-based chronic disease management (CDM) for alcohol and/or other drug (AOD) dependence on addiction outcomes. We assessed quality using (1) a visit frequency based measure and (2) a self-reported assessment measuring alignment with the chronic care model. The visit frequency based measure had no significant association with addiction outcomes. The self-reported measure of care-when care was at a CDM clinic-was associated with lower drug addiction severity. The self-reported assessment of care from any healthcare source (CDM clinic or elsewhere) was associated with lower alcohol addiction severity and abstinence. These findings suggest that high quality CDM for AOD dependence may improve addiction outcomes. Quality measures based upon alignment with the chronic care model may better capture features of effective CDM care than a visit frequency measure. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Brief report: the influence of dissociative experiences and alcohol/drugs dependence on Internet addiction

    OpenAIRE

    Roberta Biolcati; Giacomo Mancini; Elena Trombini

    2017-01-01

    The main aim of this study is to investigate the influence of dissociative experiences and alcohol/drugs dependence on Internet addiction. From a clinical point of view Internet addiction, an excessive or poorly controlled preoccupation, urges, and/or behaviors regarding Internet use, lead to emotional and social problems in several life domains. Moreover, the increased prevalence of Internet addiction among adolescents and young adults is cause of concerns. Data was collected on 441 undergra...

  4. Spin-dependent heat and thermoelectric currents in a Rashba ring coupled to a photon cavity

    Science.gov (United States)

    Abdullah, Nzar Rauf; Tang, Chi-Shung; Manolescu, Andrei; Gudmundsson, Vidar

    2018-01-01

    Spin-dependent heat and thermoelectric currents in a quantum ring with Rashba spin-orbit interaction placed in a photon cavity are theoretically calculated. The quantum ring is coupled to two external leads with different temperatures. In a resonant regime, with the ring structure in resonance with the photon field, the heat and the thermoelectric currents can be controlled by the Rashba spin-orbit interaction. The heat current is suppressed in the presence of the photon field due to contribution of the two-electron and photon replica states to the transport while the thermoelectric current is not sensitive to changes in parameters of the photon field. Our study opens a possibility to use the proposed interferometric device as a tunable heat current generator in the cavity photon field.

  5. Josephson tunneling current in the presence of a time-dependent voltage

    International Nuclear Information System (INIS)

    Harris, R.E.

    1975-01-01

    The expression for the current through a small Josephson tunnel junction in the presence of a time-dependent voltage is presented. Four terms appear: the usual sine, cosine, and quasiparticle terms, and a reactive part of the quasiparticle current. The latter is displayed graphically as a function of both energy and temperature. It is shown that in the limit of zero dc voltage and small ac voltage, the Josephson device behaves linearly. Interpretation of the in- and out-of-phase components of the current in this linear limit is given to provide physical insight into some of the details of the general expression. Finally, the tunneling current in the linear limit is shown for thin tunneling barriers to be proportional to the current in a single superconductor in the presence of an electromagnetic field

  6. 38 CFR 17.83 - Limitations on payment for alcohol and drug dependence or abuse treatment and rehabilitation.

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Limitations on payment for alcohol and drug dependence or abuse treatment and rehabilitation. 17.83 Section 17.83 Pensions... Agencies § 17.83 Limitations on payment for alcohol and drug dependence or abuse treatment and...

  7. Benefits of Exercise for the Quality of Life of Drug-Dependent Patients.

    Science.gov (United States)

    Giménez-Meseguer, Jorge; Tortosa-Martínez, Juan; de los Remedios Fernández-Valenciano, María

    2015-01-01

    This study combined quantitative and qualitative research methods to evaluate quality-of-life changes in drug-dependent patients after participation in a group-based exercise program. Quality of life (SF-36) and physical fitness (six-minute Walk Test, Timed Get Up and Go Test, and Chair Stand Test) were quantitatively determined in a group (n=37) of drug-dependent patients before and after a 12-week group exercise program (n=18) or routine care (n=19). Additionally, in-depth interviews were conducted at the end of the program with a subsample of 11 participants from the exercise group. Quantitative results showed improvements in fitness and different aspects of quality of life, such as physical function, mental health, vitality, social function, and general health perception. Qualitative results showed specific physical benefits (decreased injuries and muscle pain, decreased weight, and increased vitality with improvement in activities of daily living), psychological benefits (forgetting about everyday problems, improved mood, decreased stress and anxiety), social benefits, and a reduction in craving. The results of this study provide insight into the importance of exercise for the quality of life and recovery process of drug-dependent patients.

  8. Drug-resistant tuberculosis--current dilemmas, unanswered questions, challenges, and priority needs.

    Science.gov (United States)

    Zumla, Alimuddin; Abubakar, Ibrahim; Raviglione, Mario; Hoelscher, Michael; Ditiu, Lucica; McHugh, Timothy D; Squire, S Bertel; Cox, Helen; Ford, Nathan; McNerney, Ruth; Marais, Ben; Grobusch, Martin; Lawn, Stephen D; Migliori, Giovanni-Battista; Mwaba, Peter; O'Grady, Justin; Pletschette, Michel; Ramsay, Andrew; Chakaya, Jeremiah; Schito, Marco; Swaminathan, Soumya; Memish, Ziad; Maeurer, Markus; Atun, Rifat

    2012-05-15

    Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR

  9. Grain size dependence of the critical current density in YBa2Cu3Ox superconductors

    International Nuclear Information System (INIS)

    Kuwabara, M.; Shimooka, H.

    1989-01-01

    The grain size dependence of the critical current density in bulk single-phase YBa 2 Cu 3 O x ceramics was investigated. The grain size of the materials was changed to range approximately from 1.0 to 25 μm by changing the conditions of power processing and sintering, associated with an increase in the sintered density of the materials with increasing grain size. The critical current density has been found to exhibit a significant grain size dependence, changing from 880 A/cm 2 to a value of 100 A/cm 2 with a small increase in the average grain size from 1.2 to 2.0 μm. This seems to provide information about the nature of the weak link between superconducting grains which might govern the critical current density of the materials

  10. From Medicinal Chemistry to Human Health: Current Approaches to Drug Discovery for Cancer and Neglected Tropical Diseases

    Directory of Open Access Journals (Sweden)

    LEONARDO G. FERREIRA

    2018-02-01

    Full Text Available ABSTRACT Scientific and technological breakthroughs have compelled the current players in drug discovery to increasingly incorporate knowledge-based approaches. This evolving paradigm, which has its roots attached to the recent advances in medicinal chemistry, molecular and structural biology, has unprecedentedly demanded the development of up-to-date computational approaches, such as bio- and chemo-informatics. These tools have been pivotal to catalyzing the ever-increasing amount of data generated by the molecular sciences, and to converting the data into insightful guidelines for use in the research pipeline. As a result, ligand- and structure-based drug design have emerged as key pathways to address the pharmaceutical industry’s striking demands for innovation. These approaches depend on a keen integration of experimental and molecular modeling methods to surmount the main challenges faced by drug candidates - in vivo efficacy, pharmacodynamics, metabolism, pharmacokinetics and safety. To that end, the Laboratório de Química Medicinal e Computacional (LQMC of the Universidade de São Paulo has developed forefront research on highly prevalent and life-threatening neglected tropical diseases and cancer. By taking part in global initiatives for pharmaceutical innovation, the laboratory has contributed to the advance of these critical therapeutic areas through the use of cutting-edge strategies in medicinal chemistry.

  11. Genome-wide discovery of drug-dependent human liver regulatory elements.

    Directory of Open Access Journals (Sweden)

    Robin P Smith

    2014-10-01

    Full Text Available Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR and three active regulatory marks (p300, H3K4me1, H3K27ac on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4% that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements.

  12. Therapeutic drug monitoring in pediatric IBD: current application and future perspectives.

    Science.gov (United States)

    Lega, Sara; Bramuzzo, Matteo; Dubinsky, Marla

    2017-09-11

    As the paradigm for IBD management is evolving from symptom control to the more ambitious goal of complete deep remission, the concept of personalized medicine, as a mean to deliver individualized treatment with the best effectiveness and safety profile, is becoming paramount. Therapeutic drug monitoring (TDM) is an essential part of personalized medicine wherein serum drug concentrations are used to guide drug dosing on an individual basis. The concept of TDM has been introduced in the field of IBD along with thiopurines, over a decade ago, and evolved around anti-TNFs therapies. In the era of biologics, TDM entered the clinical field to assist clinicians managing anti-TNF failure and its role is now moving toward the concept of "proactive" TDM with the goal to optimize drug exposure and prevent loss of response. Research in TDM is rapidly expanding: while the role of TDM with new biologics is under investigation, preliminary data suggest that software-systems support tools could be an opportunity to guide dosing choices and maximize the cost-benefit profile of therapies in the near future. The review discusses the current knowledge that poses the rationale for the use of TDM and the present and future role of TDM-based approaches in the management of pediatric IBD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery.

    Science.gov (United States)

    LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B

    2014-11-01

    The incentive sensitization theory of addiction posits that repeated exposure to drugs of abuse, like cocaine, can lead to long-term adaptations in the neural circuits that support motivated behavior, providing an account of pathological drug-seeking behavior. Although pre-clinical findings provide strong support for this theory, much remains unknown about the conditions that support incentive sensitization. The current study examined whether the mode of cocaine administration is an important factor governing that drug's long-term impact on behavior. Separate groups of rats were allowed either to self-administer intravenous cocaine or were given an equivalent number and distribution of unsignaled cocaine or saline infusions. During the subsequent test of incentive motivation (Pavlovian-to-instrumental transfer), we found that rats with a history of cocaine self-administration showed strong cue-evoked food seeking, in contrast to rats given unsignaled cocaine or saline. This finding indicates that the manner in which cocaine is administered can determine its lasting behavioral effects, suggesting that subjective experiences during drug use play a critical role in the addiction process. Our findings may therefore have important implications for the study and treatment of compulsive drug seeking. © 2013 Society for the Study of Addiction.

  14. Temperature dependence of the current in Schottky-barrier source-gated transistors

    Science.gov (United States)

    Sporea, R. A.; Overy, M.; Shannon, J. M.; Silva, S. R. P.

    2015-05-01

    The temperature dependence of the drain current is an important parameter in thin-film transistors. In this paper, we propose that in source-gated transistors (SGTs), this temperature dependence can be controlled and tuned by varying the length of the source electrode. SGTs comprise a reverse biased potential barrier at the source which controls the current. As a result, a large activation energy for the drain current may be present which, although useful in specific temperature sensing applications, is in general deleterious in many circuit functions. With support from numerical simulations with Silvaco Atlas, we describe how increasing the length of the source electrode can be used to reduce the activation energy of SGT drain current, while maintaining the defining characteristics of SGTs: low saturation voltage, high output impedance in saturation, and tolerance to geometry variations. In this study, we apply the dual current injection modes to obtain drain currents with high and low activation energies and propose mechanisms for their exploitation in future large-area integrated circuit designs.

  15. Individual and combined effects of cannabis and tobacco on drug reward processing in non-dependent users.

    Science.gov (United States)

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

    2017-11-01

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

  16. Willingness to treat drug dependence and depression: comparisons of future health professionals

    Directory of Open Access Journals (Sweden)

    Ríos-Bedoya CF

    2011-03-01

    Full Text Available Brian K Ahmedani1,2, Sheryl Pimlott Kubiak2, Carlos F Rios-Bedoya3, Maureen Mickus4, James C Anthony51Center for Health Services Research, Henry Ford Health System, Detroit, MI, USA; 2School of Social Work, Michigan State University, East Lansing, MI, USA; 3Department of Family Medicine, Michigan State University, East Lansing, MI, USA; 4Occupational Therapy, Western Michigan University, Kalamazoo, MI, USA; 5Department of Epidemiology, Michigan State University, East Lansing, MI, USAPurpose: Stigma-related feelings, including degree of enthusiasm and willingness to work with alcohol, drug, and mental disorder (ADM patients, as well as anticipated success in such work, will be required for the United States to be successful in its new initiatives for ADM screening, brief intervention, and effective referral to treatment and rehabilitation services (SBIRT. This study investigates students of medicine and social work with respect to their stigma-related feelings and degree of enthusiasm or willingness to treat patients affected by alcohol dependence, nicotine dependence, or major depression. Inference is strengthened by an anonymous online survey approach, with use of randomized reinforcers to gain at least partial experimental control of nonparticipation biases that otherwise are present in student survey data.Material and methods: All students on required course rosters were asked to participate in a two-part in-class and online assessment; 222 participated, with a gradient of participation induced via randomly drawn reinforcers for online survey participation. Between-group comparisons were made with a multivariate generalized linear model and generalized estimating equations approach that adjusts for covariates.Results: Medical and social work students did not differ from each other with respect to their willingness to treat patients affected by major depression, alcohol dependence, or nicotine dependence, but together were less willing to

  17. Dependence of critical current on sample length analyzed by the variation of local critical current bent of BSCCO superconducting composite tape

    International Nuclear Information System (INIS)

    Matsubayashi, H.; Mukai, Y.; Shin, J.K.; Ochiai, S.; Okuda, H.; Osamura, K.; Otto, A.; Malozemoff, A.

    2008-01-01

    Using the high critical current type BSCCO composite tape fabricated at American Superconductor Corporation, the relation of overall critical current to the distribution of local critical current and the dependence of overall critical current on sample length of the bent samples were studied experimentally and analytically. The measured overall critical current was described well from the distribution of local critical current and n-value of the constituting short elements, by regarding the overall sample to be composed of local series circuits and applying the voltage summation model. Also the dependence of overall critical current on sample length could be reproduced in computer satisfactorily by the proposed simulation method

  18. Temperature dependence of critical current and transport current losses of 4 mm YBCO coated conductors manufactured using nonmagnetic substrate

    Science.gov (United States)

    Kvitkovic, J.; Hatwar, R.; Pamidi, S. V.; Fleshler, S.; Thieme, C.

    2015-12-01

    The temperature dependence of the critical current and AC losses were measured on American Superconductor Corporation's (AMSC) second generation high temperature superconducting (2G HTS) wire produced by Rolling Assisted Biaxially Textured Substrate (RABiTS) and Metal Organic Deposition (MOD) process. Wires manufactured with two types of substrates were characterized. The magnetic substrate with composition Ni5a%W exhibits a magnetic signature and has non-negligible AC losses in AC power applications. A new nonmagnetic substrate with an alloy composition Ni9a%W has been developed by AMSC to address the AC losses in 2G HTS. The data presented show that the performance of the new conductor is identical to the conductor with magnetic substrate in terms of critical current density. The data on AC losses demonstrate the absence of ferromagnetic loss component in the new conductor and significantly reduced AC losses at low to moderate values of I/Ic. The reduced losses will translate into reduced capital costs and lower operating costs of superconducting electrical devices for AC applications.

  19. Current challenges and emerging drug delivery strategies for the treatment of psoriasis.

    Science.gov (United States)

    Hoffman, Melissa B; Hill, Dane; Feldman, Steven R

    2016-10-01

    Psoriasis is a common skin disorder associated with physical, social, psychological and financial burden. Over the past two decades, advances in our understanding of pathogenesis and increased appreciation for the multifaceted burden of psoriasis has led to new treatment development and better patient outcomes. Yet, surveys demonstrate that many psoriasis patients are either undertreated or are dissatisfied with treatment. There are many barriers that need be overcome to optimize patient outcomes and satisfaction. This review covers the current challenges associated with each major psoriasis treatment strategy (topical, phototherapy, oral medications and biologics). It also reviews the challenges associated with the psychosocial aspects of the disease and how they affect treatment outcomes. Patient adherence, inconvenience, high costs, and drug toxicities are all discussed. Then, we review the emerging drug delivery strategies in topical, oral, and biologic therapy. By outlining current treatment challenges and emerging drug delivery strategies, we hope to highlight the deficits in psoriasis treatment and strategies for how to overcome them. Regardless of disease severity, clinicians should use a patient-centered approach. In all cases, we need to balance patients' psychosocial needs, treatment costs, convenience, and effectiveness with patients' preferences in order to optimize treatment outcomes.

  20. Analytical Model for Voltage-Dependent Photo and Dark Currents in Bulk Heterojunction Organic Solar Cells

    Directory of Open Access Journals (Sweden)

    Mesbahus Saleheen

    2016-05-01

    Full Text Available A physics-based explicit mathematical model for the external voltage-dependent forward dark current in bulk heterojunction (BHJ organic solar cells is developed by considering Shockley-Read-Hall (SRH recombination and solving the continuity equations for both electrons and holes. An analytical model for the external voltage-dependent photocurrent in BHJ organic solar cells is also proposed by incorporating exponential photon absorption, dissociation efficiency of bound electron-hole pairs (EHPs, carrier trapping, and carrier drift and diffusion in the photon absorption layer. Modified Braun’s model is used to compute the electric field-dependent dissociation efficiency of the bound EHPs. The overall net current is calculated considering the actual solar spectrum. The mathematical models are verified by comparing the model calculations with various published experimental results. We analyze the effects of the contact properties, blend compositions, charge carrier transport properties (carrier mobility and lifetime, and cell design on the current-voltage characteristics. The power conversion efficiency of BHJ organic solar cells mostly depends on electron transport properties of the acceptor layer. The results of this paper indicate that improvement of charge carrier transport (both mobility and lifetime and dissociation of bound EHPs in organic blend are critically important to increase the power conversion efficiency of the BHJ solar cells.

  1. Women, drug dependency and consequences: a study from a developing country.

    Science.gov (United States)

    Khajedaluee, Mohammad; Dadgarmoghaddam, Maliheh; Erfanian, Majidreza; Alipourtabrizi, Arash; Khadem-Rezaiyan, Majid

    2015-01-01

    Introduction. Addiction in women can expose them to malnutrition, high blood pressure, cancer, and some other dangerous diseases like hepatitis, AIDS, or other sexual transmitted diseases. The aim of this study was to assess illegal sexual relations in three groups of women. Methods. This is a cross-sectional study that was done on 236 girls and young women aged 16-25 years in 2012 in three groups: vulnerable women who have substance dependency (crimes that had made women incarcerated were considered as vulnerability in this study), invulnerable women who have substance dependency (substance dependent women without a history of incarceration), and a control group (women with no history of substance dependency or being in prison). Results. 43.8% of vulnerable women who have substance dependency had extramarital sexual relations; this percentage was 55.8% in invulnerable women who have substance dependency and 1.4% in the control group. Crystal and methamphetamine abuse was higher in addicts who had extramarital sexual relations and alcohol abuse was correlated with unsafe sexual intercourse (r = 0.36, P = 0.001). There was a statistically significant difference in extramarital sexual relation based on marital status (P Poverty, drug dependency, divorce, and alcohol consumption make women prone to other high risk behaviors that need more attention.

  2. Women, Drug Dependency and Consequences: A Study from a Developing Country

    Directory of Open Access Journals (Sweden)

    Mohammad Khajedaluee

    2015-01-01

    Full Text Available Introduction. Addiction in women can expose them to malnutrition, high blood pressure, cancer, and some other dangerous diseases like hepatitis, AIDS, or other sexual transmitted diseases. The aim of this study was to assess illegal sexual relations in three groups of women. Methods. This is a cross-sectional study that was done on 236 girls and young women aged 16–25 years in 2012 in three groups: vulnerable women who have substance dependency (crimes that had made women incarcerated were considered as vulnerability in this study, invulnerable women who have substance dependency (substance dependent women without a history of incarceration, and a control group (women with no history of substance dependency or being in prison. Results. 43.8% of vulnerable women who have substance dependency had extramarital sexual relations; this percentage was 55.8% in invulnerable women who have substance dependency and 1.4% in the control group. Crystal and methamphetamine abuse was higher in addicts who had extramarital sexual relations and alcohol abuse was correlated with unsafe sexual intercourse (r=;0.36, P=0.001. There was a statistically significant difference in extramarital sexual relation based on marital status (P<0.001. Conclusions. Poverty, drug dependency, divorce, and alcohol consumption make women prone to other high risk behaviors that need more attention.

  3. Application of thermally stimulated current measurement to the polymorphic characterization of drug substances

    International Nuclear Information System (INIS)

    Ikeda, Y.; Hirayama, T.; Terada, K.

    2005-01-01

    The thermal stimulated current measurement was used as an innovative analytical equipment to evaluate the polymorphic properties of terfenadine and Compound A, being developed by Takeda Pharmaceutical Company, Limited. At first, terfenadine, which is known to have polymorphs, was used as a model sample for thermally stimulated current (TSC) analyses. The TSC curves of amorphous and two polymorphs were distinctly different from each other. Therefore, it was considered that TSC measurement could be a useful technique to evaluate the crystalline properties of drug substances. The polymorphs of compound A were difficult to distinguish the characteristics of polymorphs from conventional powder X-ray diffractometry and also differential scanning calorimetry. Forms A and B of compound A were clearly differentiated by the thermal stimulated current properties that were adequate to characterize each form. Thus, it was shown that TSC was extremely useful and powerful tool for identification of complicated polymorphs, which were not distinguished by conventional methods

  4. Psychotic Symptoms Associated with the use of Dopaminergic Drugs, in Patients with Cocaine Dependence or Abuse.

    Science.gov (United States)

    Roncero, Carlos; Abad, Alfonso C; Padilla-Mata, Antonio; Ros-Cucurull, Elena; Barral, Carmen; Casas, Miquel; Grau-López, Lara

    2017-01-01

    In the field of dual diagnosis, physicians are frequently presented with pharmacological questions. Questions about the risk of developing psychotic symptoms in cocaine users who need treatment with dopaminergic drugs could lead to an undertreatment. Review the presence of psychotic symptoms in patients with cocaine abuse/dependence, in treatment with dopaminergic drugs. Systematic PubMed searches were conducted including December 2014, using the keywords: "cocaine", dopaminergic drug ("disulfuram-methylphenidate-bupropion-bromocriptine-sibutramineapomorphine- caffeine") and ("psychosis-psychotic symptoms-delusional-paranoia"). Articles in English, Spanish, Portuguese, French, and Italian were included. Articles in which there was no history of cocaine abuse/dependence, absence of psychotic symptoms, systematic reviews, and animal studies, were excluded. 313 papers were reviewed. 7 articles fulfilled the inclusion-exclusion criteria. There is a clinical trial including 8 cocaine-dependent patients using disulfiram in which 3 of them presented psychotic symptoms and 6 case-reports: disulfuram (1), methylphenidate (1), disulfiram with methylphenidate (2), and bupropion (2), reporting psychotic symptoms, especially delusions of reference and persecutory ideation. Few cases have been described, which suggests that the appearance of these symptoms is infrequent. The synergy of dopaminergic effects or the dopaminergic sensitization in chronic consumption are the explanatory theories proposed by the authors. In these cases, a relationship was found between taking these drugs and the appearance of psychotic symptoms. Given the low number of studies found, further research is required. The risk of psychotic symptoms seems to be acceptable if we compare it with the benefits for the patients but a closer monitoring seems to be advisable.

  5. Introduction to the College on Problems of Drug Dependence special issue: contemporary advances in opioid neuropharmacology.

    Science.gov (United States)

    Walsh, Sharon L; Unterwald, Ellen M; Izenwasser, Sari

    2010-05-01

    Opioid receptors are critical therapeutic targets for medications development relevant to the treatment of drug dependence and pain. With recent advances in molecular neurobiology, it has become evident that the functional activity of opioid receptors, as ligand-regulated protein complexes, is modulated by multifarious intracellular and extracellular events, that there is genetic variation in coding for receptors, and that the activity of endogenous opioid systems may underlie actions common to other addictive disorders. This supplemental issue of Drug and Alcohol Dependence, arising from an invited symposium at the 71st Annual Meeting of the College on Problems of Drug Dependence, provides a series of contemporary reviews focused on recent advances in opioid neuropharmacology. Each speaker provides herein an invited comprehensive review of the state of knowledge on a specific topic in opioid neuropharmacology. Evans and colleagues describe the multi-faceted control of the opioid G-protein coupled receptor as a dynamic "sensor" complex and identify novel targets for drug development. von Zastrow focuses on opioid receptor-mediated events regulated by endocytosis and membrane trafficking through the endocytic pathway and differential responses to opioid agonists. Blendy and colleague provide a review of human association studies on the functional relevance of the mu opioid receptor variant, A118G, and presents data from the A112G knock-in model, an analogous mouse variant to A118G. Finally, Maldonado and colleagues provide a broader systems review from genetic, pharmacologic and behavioral studies implicating the endogenous opioid systems as a substrate for the mediation of substance use disorders spanning pharmacological classes.

  6. Guiding of slow Ne7+ ions through nanocapillaries in insulating polyethylene terephthalate: Incident current dependence

    International Nuclear Information System (INIS)

    Stolterfoht, N.; Hellhammer, R.; Bundesmann, J.; Fink, D.; Kanai, Y.; Kambara, T.; Ikeda, T.; Hoshino, M.; Yamazaki, Y.

    2007-01-01

    The transmission of highly charged ions through nanocapillaries in insulating polyethylene terephthalate (PET) polymers was investigated. In experiments at laboratories in RIKEN (Japan) and HMI (Germany) different detection methods were applied to study the ion current dependence in a wide range covering two orders of magnitude. At HMI an electrostatic ion spectrometer was used and at RIKEN a two-dimensional position sensitive detector was implemented. New PET samples with parallel capillaries and low density were manufactured. For tilted capillaries, the ions are guided along the capillary axis, since the majority of ions are deflected in a charge patch created in the capillary entrance. The results provide insights into the mechanisms of capillary guiding. The fraction of transmitted ions was found to be nearly independent on the incident ion current indicating a sudden increase in the discharge current depleting the entrance charge patch. The experimental results were well-reproduced by model calculations based on a nonlinear (exponential) expression for the discharge current

  7. Temperature-dependence of Threshold Current Density-Length Product in Metallization Lines: A Revisit

    International Nuclear Information System (INIS)

    Duryat, Rahmat Saptono; Kim, Choong-Un

    2016-01-01

    One of the important phenomena in Electromigration (EM) is Blech Effect. The existence of Threshold Current Density-Length Product or EM Threshold has such fundamental and technological consequences in the design, manufacture, and testing of electronics. Temperature-dependence of Blech Product had been thermodynamically established and the real behavior of such interconnect materials have been extensively studied. The present paper reviewed the temperature-dependence of EM threshold in metallization lines of different materials and structure as found in relevant published articles. It is expected that the reader can see a big picture from the compiled data, which might be overlooked when it was examined in pieces. (paper)

  8. Barriers to community-based drug dependence treatment: implications for police roles, collaborations and performance indicators

    Science.gov (United States)

    Ma, Yi; Du, Chunhua; Cai, Thomas; Han, Qingfeng; Yuan, Huanhuan; Luo, Tingyan; Ren, Guoliang; Mburu, Gitau; Wang, Bangyuan; Golichenko, Olga; Zhang, Chaoxiong

    2016-01-01

    Introduction Worldwide, people who use drugs (PWUD) are among the populations at highest risk for HIV infection. In China, PWUD are primarily sentenced to compulsory detainment centres, in which access to healthcare, including HIV treatment and prevention services, is limited or non-existent. In 2008, China's 2008 Anti-Drug Law encouraged the development and use of community-based drug dependence rehabilitation, yet there is limited evidence evaluating the efficacy and challenges of this model in China. In this study, we explore these challenges and describe how cooperation between law enforcement and health departments can meet the needs of PWUD. Methods In 2015, we conducted semi-structured, in-depth interviews with all four staff members and 16 clients of the Ping An Centre No. 1 for community-based drug treatment, three local police officers and three officials from the local Centre for Disease Control. Interviews explored obstacles in implementing community-based drug dependence treatment and efforts to resolve these difficulties. Transcripts were coded and analyzed with qualitative data analysis software (MAXQDA 11). Results We identified three challenges to community-based drug treatment at the Ping An Centre No. 1: (1) suboptimal coordination among parties involved, (2) a divergence in attitudes towards PWUD and harm reduction between law enforcement and health officials and (3) conflicting performance targets for police and health officials that undermine the shared goal of treatment. We also identified the take-home methadone maintenance treatment model at the Ping An Centre No. 1 as an example of an early successful collaboration between the police, the health department and PWUD. Conclusions To overcome barriers to effective community-based drug treatment, we recommend aligning the goals of law enforcement and public health agencies towards health-based performance indicators. Furthermore, tensions between PWUD and police need to be addressed and trust

  9. Magnetic field dependence of the current flowing in the spin-coated chlorophyll thin films

    Science.gov (United States)

    Aji, J. R. P.; Kusumandari; Purnama, B.

    2018-03-01

    The magnetic dependence of the current flowing in the spin coated chlorophyll films on a patterned Cu PCB substrate has been presented. Chlorophyll was isolated from Spirulina sp and deposited by spin coated methods. The reducing of current by the change of magnetic field (magneto conductance effect) was performed by inducing the magnetic field parallel to the inplane of film at room temp. The magnetoconductance ratio decreases as the increase of voltage. It was indicated that the origin of carrier charge in chlorophyll films should be different with the carrier charge injection (electron).

  10. Dependence of secondary ion emission current on the composition of beryllium-nickel alloys

    International Nuclear Information System (INIS)

    Pistryak, V.M.; Kozlov, V.F.; Tikhinskij, G.F.; Fogel', Ya.M.

    1976-01-01

    The dependence is studied of the secondary ions emission current on the composition of beryllium-nickel alloys. It is established that appearance of intermetallide phases in the Be-Ni alloys has no effect on the linear character of the secondary ions Ni + and Be + of emission current. The phase transformation from the solid solution to the compound Ni 5 Be 21 with a change in the alloys concentration is fixed by appearance of the secondary ion NiBe + emission. The limited solubility of nickel in solid beryllium at a temperature close to room temperature is determined to be equal to 1.3+-0.27 at%

  11. Exponential temperature dependence of the critical transport current in Y-Ba-Cu-O thin films

    International Nuclear Information System (INIS)

    Yom, S.S.; Hahn, T.S.; Kim, Y.H.; Chu, H.; Choi, S.S.

    1989-01-01

    We have measured the critical currents in rf-sputtered YBa 2 Cu 3 O/sub 7-x/ thin films deposited on polycrystalline yttria-stabilized zirconia substrates as a function of temperature down to 10 K. The dependence of the granular films at low temperature indicated exponential behavior which is similar to the superconductor-normal metal-superconductor (S-N-S) type tunneling junctions. For the films with a grain size of approximately 1 μm, we observed two exponential decay constants, which suggest that Josephson junctions limiting the transport critical current are possible both at the grain boundaries and at twin boundaries

  12. Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes.

    Science.gov (United States)

    Palleria, Caterina; Leporini, Christian; Maida, Francesca; Succurro, Elena; De Sarro, Giovambattista; Arturi, Franco; Russo, Emilio

    2016-07-01

    Type 2 diabetes mellitus is a complex metabolic disease that can cause serious damage to various organs. Among the best-known complications, an important role is played by cognitive impairment. Impairment of cognitive functioning has been reported both in type 1 and 2 diabetes mellitus. While this comorbidity has long been known, no major advances have been achieved in clinical research; it is clear that appropriate control of blood glucose levels represents the best current (although unsatisfactory) approach in the prevention of cognitive impairment. We have focused our attention on the possible effect on the brain of antidiabetic drugs, despite their effects on blood glucose levels, giving a brief rationale on the mechanisms (e.g. GLP-1, BDNF, ghrelin) that might be involved. Indeed, GLP-1 agonists are currently clinically studied in other neurodegenerative diseases (i.e. Parkinson's and Alzheimer's disease); furthermore, also other antidiabetic drugs have proven efficacy in preclinical studies. Overall, promising results are already available and finding new intervention strategies represents a current need in this field of research. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Changes in the sensitivity of GABAA current rundown to drug treatments in a model of temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Pierangelo eCifelli

    2013-07-01

    Full Text Available The pharmacological treatment of mesial temporal lobe epilepsy (mTLE, the most common epileptic syndrome in adults, is still unsatisfactory, as one third of the patients are or become refractory to antiepileptic agents. Refractoriness may depend upon drug-induced alterations, but the disease per se may also undergo a progressive evolution that affects the sensitivity to drugs. mTLE has been shown to be associated with a dysfunction of the inhibitory signaling mediated by GABAA receptors. In particular, the repetitive activation of GABAA receptors produces a use-dependent decrease (rundown of the evoked currents (IGABA, which is markedly enhanced in the hippocampus and cortex of drug-resistant mTLE patients. This phenomenon has been also observed in the pilocarpine model, where the increased IGABA rundown is observed in the hippocampus at the time of the first spontaneous seizure, then extends to the cortex and remains constant in the chronic phase of the disease. Here, we examined the sensitivity of IGABA to pharmacological modulation. We focused on the antiepileptic agent levetiracetam and on the neurotrophin BDNF, which were previously reported to attenuate mTLE-induced increased rundown in the chronic human tissue. In the pilocarpine model, BDNF displayed a paramount effect, decreasing rundown in the hippocampus at the time of the first seizure, as well as in the hippocampus and cortex in the chronic period. In contrast, levetiracetam did not affect rundown in the hippocampus, but attenuated it in the cortex. Interestingly, this effect of levetiracetam was also observed on the still unaltered rundown observed in the cortex at the time of the first spontaneous seizure. These data suggest that the sensitivity of GABAA receptors to pharmacological interventions undergoes changes during the natural history of mTLE, implicating that the site of seizure initiation and the timing of treatment may highly affect the therapeutic outcome.

  14. Nanotechnology in dentistry: drug delivery systems for the control of biofilm-dependent oral diseases.

    Science.gov (United States)

    de Sousa, Francisco Fabio Oliveira; Ferraz, Camila; Rodrigues, Lidiany K Arla de Azevedo; Nojosa, Jacqueline de Santiago; Yamauti, Monica

    2014-01-01

    Dental disorders, such as caries, periodontal and endodontic diseases are major public health issues worldwide. In common, they are biofilm-dependent oral diseases, and the specific conditions of oral cavity may develop infectious foci that could affect other physiological systems. Efforts have been made to develop new treatment routes for the treatment of oral diseases, and therefore, for the prevention of some systemic illnesses. New drugs and materials have been challenged to prevent and treat these conditions, especially by means of bacteria elimination. "Recent progresses in understanding the etiology, epidemiology and microbiology of the microbial flora in those circumstances have given insight and motivated the innovation on new therapeutic approaches for the management of the oral diseases progression". Some of the greatest advances in the medical field have been based in nanosized systems, ranging from the drug release with designed nanoparticles to tissue scaffolds based on nanotechnology. These systems offer new possibilities for specific and efficient therapies, been assayed successfully in preventive/curative therapies to the oral cavity, opening new challenges and opportunities to overcome common diseases based on bacterial biofilm development. The aim of this review is to summarize the recent nanotechnological developments in the drug delivery field related to the prevention and treatment of the major biofilm-dependent oral diseases and to identify those systems, which may have higher potential for clinical use.

  15. Neural and psychological characteristics of college students with alcoholic parents differ depending on current alcohol use.

    Science.gov (United States)

    Brown-Rice, Kathleen A; Scholl, Jamie L; Fercho, Kelene A; Pearson, Kami; Kallsen, Noah A; Davies, Gareth E; Ehli, Erik A; Olson, Seth; Schweinle, Amy; Baugh, Lee A; Forster, Gina L

    2018-02-02

    A significant proportion of college students are adult children of an alcoholic parent (ACoA), which can confer greater risk of depression, poor self-esteem, alcohol and drug problems, and greater levels of college attrition. However, some ACoA are resilient to these negative outcomes. The goal of this study was to better understand the psychobiological factors that distinguish resilient and vulnerable college-aged ACoAs. To do so, scholastic performance and psychological health were measured in ACoA college students not engaged in hazardous alcohol use (resilient) and those currently engaged in hazardous alcohol use (vulnerable). Neural activity (as measured by functional magnetic resonance imaging) in response to performing working memory and emotion-based tasks were assessed. Furthermore, the frequency of polymorphisms in candidate genes associated with substance use, risk taking and stress reactivity were compared between the two ACoA groups. College ACoAs currently engaged in hazardous alcohol use reported more anxiety, depression and posttraumatic stress symptoms, and increased risky nicotine and marijuana use as compared to ACoAs resistant to problem alcohol use. ACoA college students with current problem alcohol showed greater activity of the middle frontal gyrus and reduced activation of the posterior cingulate in response to visual working memory and emotional processing tasks, which may relate to increased anxiety and problem alcohol and drug behaviors. Furthermore, polymorphisms of cholinergic receptor and the serotonin transporter genes also appear to contribute a role in problem alcohol use in ACoAs. Overall, findings point to several important psychobiological variables that distinguish ACoAs based on their current alcohol use that may be used in the future for early intervention. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Personality Traits and Psychopathology in Nicotine and Opiate Dependents Using the Gateway Drug Theory

    Directory of Open Access Journals (Sweden)

    Bahareh Amirabadi

    2015-03-01

    Full Text Available Objectives: According to the gateway drug theory, tobacco use is a predisposing factor for future substance abuse. This study was conducted to compare nicotine and opiate dependents to identify the differences between their personality traits and psychopathology that makes them turn to other substances after cigarette smoking. Methods: A causal-comparative study was conducted. Three groups were randomly selected: nicotine dependents, opiate dependents and ordinary individuals (non-dependent population. Cloninger’s Temperament and Character Inventory-Revised, the Fagerstrom Test for Nicotine Dependence, Maudsley Addiction Profile, the Beck Depression Inventory, and Beck Anxiety Inventory were used to collect data. Analysis of variance was used to analyze data. Results: Opiate dependents had higher ‘novelty seeking’ and lower ‘cooperativeness’ scores as compared to the other two groups. They also had higher anxiety and depression scores than the other two groups. Discussion: Higher ‘novelty seeking’ and lower ‘cooperativeness’ scores are important personality traits predicting

  17. Large current modulation and spin-dependent tunneling of vertical graphene/MoS2 heterostructures.

    Science.gov (United States)

    Myoung, Nojoon; Seo, Kyungchul; Lee, Seung Joo; Ihm, G

    2013-08-27

    Vertical graphene heterostructures have been introduced as an alternative architecture for electronic devices by using quantum tunneling. Here, we present that the current on/off ratio of vertical graphene field-effect transistors is enhanced by using an armchair graphene nanoribbon as an electrode. Moreover, we report spin-dependent tunneling current of the graphene/MoS2 heterostructures. When an atomically thin MoS2 layer sandwiched between graphene electrodes becomes magnetic, Dirac fermions with different spins feel different heights of the tunnel barrier, leading to spin-dependent tunneling. Our finding will develop the present graphene heterostructures for electronic devices by improving the device performance and by adding the possibility of spintronics based on graphene.

  18. Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

    Directory of Open Access Journals (Sweden)

    R. A. Gafanov

    2018-01-01

    Full Text Available Prostate cancer (PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability  of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

  19. Inverse temperature dependence of reverse gate leakage current in AlGaN/GaN HEMT

    International Nuclear Information System (INIS)

    Kaushik, J K; Balakrishnan, V R; Muralidharan, R; Panwar, B S

    2013-01-01

    The experimentally observed inverse temperature dependence of the reverse gate leakage current in AlGaN/GaN HEMT is explained using a virtual gate trap-assisted tunneling model. The virtual gate is formed due to the capture of electrons by surface states in the vicinity of actual gate. The increase and decrease in the length of the virtual gate with temperature due to trap kinetics are used to explain this unusual effect. The simulation results have been validated experimentally. (paper)

  20. Tensile Strain Dependence of Critical Current for RHQ-Nb3Al Wires

    OpenAIRE

    Jin, Xinzhe; Oguro, Hidetoshi; Nakamoto, Tatsushi; Awaji, Satoshi; Ogitsu, Toru; Tsuchiya, Kiyosumi; Yamamoto, Akira; Kikuchi, Akihiro; Takeuchi, Takao

    2011-01-01

    KEK and NIMS have been jointly developing Nb3Al superconducting wire with a rapid heating and quenching (RHQ) method towards high field accelerator magnets in the Large Hadron Collider (LHC) luminosity upgrade. A15-type superconductors such as Nb3Al and Nb3Sn exhibit strain dependence with respect to their critical currents. Therefore, a thorough understanding of strain behavior is necessary for high field accelerator magnet development, which will be critical for the luminosity upgrade of th...

  1. Glutathionylation-Dependence of Na(+)-K(+)-Pump Currents Can Mimic Reduced Subsarcolemmal Na(+) Diffusion.

    Science.gov (United States)

    Garcia, Alvaro; Liu, Chia-Chi; Cornelius, Flemming; Clarke, Ronald J; Rasmussen, Helge H

    2016-03-08

    The existence of a subsarcolemmal space with restricted diffusion for Na(+) in cardiac myocytes has been inferred from a transient peak electrogenic Na(+)-K(+) pump current beyond steady state on reexposure of myocytes to K(+) after a period of exposure to K(+)-free extracellular solution. The transient peak current is attributed to enhanced electrogenic pumping of Na(+) that accumulated in the diffusion-restricted space during pump inhibition in K(+)-free extracellular solution. However, there are no known physical barriers that account for such restricted Na(+) diffusion, and we examined if changes of activity of the Na(+)-K(+) pump itself cause the transient peak current. Reexposure to K(+) reproduced a transient current beyond steady state in voltage-clamped ventricular myocytes as reported by others. Persistence of it when the Na(+) concentration in patch pipette solutions perfusing the intracellular compartment was high and elimination of it with K(+)-free pipette solution could not be reconciled with restricted subsarcolemmal Na(+) diffusion. The pattern of the transient current early after pump activation was dependent on transmembrane Na(+)- and K(+) concentration gradients suggesting the currents were related to the conformational poise imposed on the pump. We examined if the currents might be accounted for by changes in glutathionylation of the β1 Na(+)-K(+) pump subunit, a reversible oxidative modification that inhibits the pump. Susceptibility of the β1 subunit to glutathionylation depends on the conformational poise of the Na(+)-K(+) pump, and glutathionylation with the pump stabilized in conformations equivalent to those expected to be imposed on voltage-clamped myocytes supported this hypothesis. So did elimination of the transient K(+)-induced peak Na(+)-K(+) pump current when we included glutaredoxin 1 in patch pipette solutions to reverse glutathionylation. We conclude that transient K(+)-induced peak Na(+)-K(+) pump current reflects the effect

  2. 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

  3. Predicting Inpatient Detoxification Outcome of Alcohol and Drug Dependent Patients: The Influence of Sociodemographic Environment, Motivation, Impulsivity, and Medical Comorbidities

    Directory of Open Access Journals (Sweden)

    Yvonne Sofin

    2017-01-01

    Full Text Available Aims. This prospective study aims to identify patient characteristics as predictors for treatment outcome during inpatient detoxification treatment for drug and alcohol dependent patients. Methods. A mixed gender sample of 832 consecutively admitted drug and alcohol dependent patients were interviewed by an experienced physician. The impact of a variety of factors concerning social environment, therapy motivation, impulsivity related variables, medical history, and addiction severity on treatment outcome was examined. Results. 525 (63.1% of the patients completed detoxification treatment whereas 307 (36.9% dropped out prematurely. Being female, living in a partnership, having children, being employed, and having good education were predictive for a positive outcome. Family, health, the fear of losing the job, prosecution, and emergency admission were significant motivational predictors for treatment outcome. Being younger, history of imprisonment, and the number of previous drop-outs were predictive for a negative outcome. Conclusions. Variables concerning social environment and the number of previous drop-outs have been identified as best predictors for treatment outcome. Socially stable patients benefit from the current treatment setting and treatment shall be adapted for patients with negative predictors. Treatment may consequently be tailored with respect to intervention type, duration, and intensity to improve the outcome for those patients that fulfil criteria with negative impact on treatment retention.

  4. [Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus].

    Science.gov (United States)

    Valerón, Pino Fuente; de Pablos-Velasco, Pedro L

    2013-09-01

    In this study, we review the efficacy and safety limitations of insulin-dependent oral antidiabetic agents. In terms of efficiency, the main drawback of metformin, sulfonylureas, gliptins and -to a lesser extent-glitazones is durability. No drug per se is able to maintain stable blood glucose control for years. Metformin, sulfonylureas and gliptins have demonstrated safety. Experience with the first two drug groups is more extensive. The main adverse effect of metformin is gastrointestinal discomfort. Major concerns related to the use of sulfonylureas are hypoglycemia and weight gain. The use of pioglitazone has been associated with an increased risk of bladder cancer, edema, heart failure, weight gain, and distal bone fractures in postmenopausal women. The most common adverse reactions associated with glucagon-like peptide-1 agonists are gastrointestinal discomfort that sometimes leads to treatment discontinuation. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  5. Association between Experience of Child Abuse and Severity of Drug Addiction Measured by the Addiction Severity Index among Japanese Drug-Dependent Patients

    Science.gov (United States)

    Ogai, Yasukazu; Senoo, Eiichi; Gardner, Fumiyuki Chin; Haraguchi, Ayako; Saito, Tamaki; Morita, Nobuaki; Ikeda, Kazutaka

    2015-01-01

    The aim of the present study was to clarify the association between child abuse experiences and drug addiction severity among Japanese drug-dependent patients using the Addiction Severity Index-Japanese version (ASI-J). One hundred and eleven inpatients and outpatients with drug dependence participated in the study. Some of the questions on the ASI-J asked about lifetime experiences of abuse. A higher percentage of female participants experienced child abuse compared with male participants. Male participants who experienced child abuse (MEA) had a significantly higher severity of drug use than men who did not experience it (MNEA). Female participants who experienced child abuse (FEA) had significantly more serious problems in family/social relationships than female participants who did not experience it (FNEA). Patients in the MEA group were arrested less frequently for drug charges, experienced more serious problems with their fathers, and experienced more severe anxiety in their lifetime compared with the MNEA group. The FEA group experienced more serious troubles with their sexual partners, close friends, and families and experienced more severe psychiatric problems in their lifetime compared with the FNEA group. These results suggest gender differences in the problems experienced by drug-dependent patients with child abuse experiences, and gender-specific interventions may be more effective in treating their drug dependence. PMID:25741639

  6. Association between Experience of Child Abuse and Severity of Drug Addiction Measured by the Addiction Severity Index among Japanese Drug-Dependent Patients

    Directory of Open Access Journals (Sweden)

    Yasukazu Ogai

    2015-03-01

    Full Text Available The aim of the present study was to clarify the association between child abuse experiences and drug addiction severity among Japanese drug-dependent patients using the Addiction Severity Index-Japanese version (ASI-J. One hundred and eleven inpatients and outpatients with drug dependence participated in the study. Some of the questions on the ASI-J asked about lifetime experiences of abuse. A higher percentage of female participants experienced child abuse compared with male participants. Male participants who experienced child abuse (MEA had a significantly higher severity of drug use than men who did not experience it (MNEA. Female participants who experienced child abuse (FEA had significantly more serious problems in family/social relationships than female participants who did not experience it (FNEA. Patients in the MEA group were arrested less frequently for drug charges, experienced more serious problems with their fathers, and experienced more severe anxiety in their lifetime compared with the MNEA group. The FEA group experienced more serious troubles with their sexual partners, close friends, and families and experienced more severe psychiatric problems in their lifetime compared with the FNEA group. These results suggest gender differences in the problems experienced by drug-dependent patients with child abuse experiences, and gender-specific interventions may be more effective in treating their drug dependence.

  7. Association between experience of child abuse and severity of drug addiction measured by the Addiction Severity Index among Japanese drug-dependent patients.

    Science.gov (United States)

    Ogai, Yasukazu; Senoo, Eiichi; Gardner, Fumiyuki Chin; Haraguchi, Ayako; Saito, Tamaki; Morita, Nobuaki; Ikeda, Kazutaka

    2015-03-03

    The aim of the present study was to clarify the association between child abuse experiences and drug addiction severity among Japanese drug-dependent patients using the Addiction Severity Index-Japanese version (ASI-J). One hundred and eleven inpatients and outpatients with drug dependence participated in the study. Some of the questions on the ASI-J asked about lifetime experiences of abuse. A higher percentage of female participants experienced child abuse compared with male participants. Male participants who experienced child abuse (MEA) had a significantly higher severity of drug use than men who did not experience it (MNEA). Female participants who experienced child abuse (FEA) had significantly more serious problems in family/social relationships than female participants who did not experience it (FNEA). Patients in the MEA group were arrested less frequently for drug charges, experienced more serious problems with their fathers, and experienced more severe anxiety in their lifetime compared with the MNEA group. The FEA group experienced more serious troubles with their sexual partners, close friends, and families and experienced more severe psychiatric problems in their lifetime compared with the FNEA group. These results suggest gender differences in the problems experienced by drug-dependent patients with child abuse experiences, and gender-specific interventions may be more effective in treating their drug dependence.

  8. ORAL COLON TARGETED DRUG DELIVERY SYSTEM: A REVIEW ON CURRENT AND NOVEL PERSPECTIVES

    OpenAIRE

    Asija Rajesh; Chaudhari Bharat; Asija Sangeeta

    2012-01-01

    Small intestine is mostly the site for drug absorption but in some cases the drug needs to be targeted to colon due to some factors like local colonic disease, degradation related conditions, delayed release of drugs, systemic delivery of protein and peptide drugs etc. Colon targeted drug delivery is important and relatively new concept for the absorption of drugs because it offers almost neutral pH and long residence time, thereby increasing the drug absorption. Colon has proved to be a site...

  9. Current Landscape of Antiviral Drug Discovery [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Wade Blair

    2016-02-01

    Full Text Available Continued discovery and development of new antiviral medications are paramount for global human health, particularly as new pathogens emerge and old ones evolve to evade current therapeutic agents. Great success has been achieved in developing effective therapies to suppress human immunodeficiency virus (HIV and hepatitis B virus (HBV; however, the therapies are not curative and therefore current efforts in HIV and HBV drug discovery are directed toward longer-acting therapies and/or developing new mechanisms of action that could potentially lead to cure, or eradication, of the virus. Recently, exciting early clinical data have been reported for novel antivirals targeting respiratory syncytial virus (RSV and influenza (flu. Preclinical data suggest that these new approaches may be effective in treating high-risk patients afflicted with serious RSV or flu infections. In this review, we highlight new directions in antiviral approaches for HIV, HBV, and acute respiratory virus infections.

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

    Science.gov (United States)

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

    2017-08-01

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

  11. Frequency-dependent failure mechanisms of nanocrystalline gold interconnect lines under general alternating current

    Science.gov (United States)

    Luo, X. M.; Zhang, B.; Zhang, G. P.

    2014-09-01

    Thermal fatigue failure of metallization interconnect lines subjected to alternating currents (AC) is becoming a severe threat to the long-term reliability of micro/nanodevices with increasing electrical current density/power. Here, thermal fatigue failure behaviors and damage mechanisms of nanocrystalline Au interconnect lines on the silicon glass substrate have been investigated by applying general alternating currents (the pure alternating current coupled with a direct current (DC) component) with different frequencies ranging from 0.05 Hz to 5 kHz. We observed both thermal fatigue damages caused by Joule heating-induced cyclic strain/stress and electromigration (EM) damages caused by the DC component. Besides, the damage formation showed a strong electrically-thermally-mechanically coupled effect and frequency dependence. At lower frequencies, thermal fatigue damages were dominant and the main damage forms were grain coarsening with grain boundary (GB) cracking/voiding and grain thinning. At higher frequencies, EM damages took over and the main damage forms were GB cracking/voiding of smaller grains and hillocks. Furthermore, the healing effect of the reversing current was considered to elucidate damage mechanisms of the nanocrystalline Au lines generated by the general AC. Lastly, a modified model was proposed to predict the lifetime of the nanocrystalline metal interconnect lines, i.e., that was a competing drift velocity-based approach based on the threshold time required for reverse diffusion/healing to occur.

  12. Angular and magnetic field dependences of critical current in irradiated YBaCuO single crystals

    International Nuclear Information System (INIS)

    Petrusenko, Yu.

    2010-01-01

    The investigation of mechanisms responsible for the current-carrying capability of irradiated high-temperature superconductors (HTSC) was realized. For the purpose, experiments were made to investigate the effect of point defects generated by high-energy electron irradiation on the critical temperature and the critical current in high-Tc superconducting single crystals YBa 2 Cu 3 O 7-x . The transport current density measured in HTSC single crystals YBa 2 Cu 3 O 7-x by the dc-method was found to exceed 80000 A/cm 2 . The experiments have demonstrated a more than 30-fold increase in the critical current density in single crystals irradiated with 2.5 MeV electrons to a dose of 3·10 18 el/cm 2 . Detailed studies were made into the anisotropy of critical current and the dependence of critical current on the external magnetic field strength in irradiated single crystals. A high efficiency of point defects as centers of magnetic vortex pinning in HTSC single crystals was first demonstrated.

  13. Simultaneous specimen current and time-dependent cathodoluminescence measurements on gallium nitride

    Energy Technology Data Exchange (ETDEWEB)

    Campo, E. M., E-mail: e.campo@bangor.ac.uk; Hopkins, L. [School of Electronic Engineering, Bangor University, Gwynedd LL57 1UT (United Kingdom); Pophristic, M. [Department of Chemistry and Biochemistry, University of the Science, Philadelphia, Pennsylvania 19104 (United States); Ferguson, I. T. [Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, Missouri 65409 (United States)

    2016-06-28

    Time-dependent cathodoluminescence (CL) and specimen current (SC) are monitored to evaluate trapping behavior and evolution of charge storage. Examination of CL and SC suggests that the near band edge emission in GaN is reduced primarily by the activation of traps upon irradiation, and Gallium vacancies are prime candidates. At the steady state, measurement of the stored charge by empiric-analytical methods suggests that all available traps within the interaction volume have been filled, and that additional charge is being stored interstitially, necessarily beyond the interaction volume. Once established, the space charge region is responsible for the steady state CL emission and, prior to build up, it is responsible for the generation of diffusion currents. Since the non-recombination effects resulting from diffusion currents that develop early on are analogous to those leading to device failure upon aging, this study is fundamental toward a holistic insight into optical properties in GaN.

  14. Simple model to explain the temperature dependence of the lower hybrid current drive efficiency

    International Nuclear Information System (INIS)

    Ushigusa, K.

    1996-01-01

    Dissipated power in the spectral gap is taken into account in deriving analytically the lower hybrid current drive efficiency. The efficiency is determined by a minimum down-shifted phase velocity υ L and the quasi-linear velocity diffusion coefficient at the spectral gap D' W in addition to the original wave spectrum. To explain present experimental results in both JT-60 and ASDEX, υ L must be close to the Landau damping limit (υ L ∼ 2.7υ te ) and D' W must be the same order of magnitude as the collisional friction at υ L . With the suggested values of these two parameters from experimental results, the driven current is mainly determined by the launched wave spectrum, while most of the wave power is dissipated at the spectral gap. This characteristic can explain both the temperature and the N || dependence of the current drive efficiency. (author)

  15. Alternatives to currently used antimalarial drugs: in search of a magic bullet.

    Science.gov (United States)

    Bhagavathula, Akshaya Srikanth; Elnour, Asim Ahmed; Shehab, Abdulla

    2016-11-04

    bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.

  16. Examination of the causes of covariation between conduct disorder symptoms and vulnerability to drug dependence.

    Science.gov (United States)

    Button, Tanya M M; Hewitt, John K; Rhee, Soo Hyun; Young, Susan E; Corley, Robin P; Stallings, Michael C

    2006-02-01

    Conduct disorder (CD) symptoms and substance dependence commonly co-occur. Both phenotypes are highly heritable and a common genetic influence on the covariation has been suggested. The aim of this study was to determine the extent to which genes and environment contribute to the covariance between CD and drug dependence using twins from the Colorado Longitudinal Twin Sample and the Colorado Twin Registry. A total of 880 twin pairs (237 monozygotic [MZ] female, 195 MZ male, 116 dizygotic [DZ] female, 118 DZ male and 214 DZ opposite-sex) aged 13 to 18 (mean = 15.65) were included in the analysis. CD was assessed by lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) symptom count and a polysubstance dependence vulnerability index was developed from responses to the Composite International Diagnostic Interview--Substance Abuse Module. A bivariate Cholesky Decomposition model was used to partition the cause of variation and covariation of the two phenotypes. No sex-limitation was observed in our data, and male and female parameter estimates were constrained to be equal. Both CD symptoms and dependence vulnerability were significantly heritable, and genes, shared environment and nonshared environment all contributed to the covariation between them. Genes contributed 35% of the phenotypic covariance, shared environment contributed 46%, and nonshared environmental influences contributed the remaining 19% to the phenotypic covariance. Therefore, there appears to be pleiotropic genetic influence on CD symptoms and dependence vulnerability.

  17. Matrix Metalloproteinases Contribute to Neuronal Dysfunction in Animal Models of Drug Dependence, Alzheimer's Disease, and Epilepsy

    Directory of Open Access Journals (Sweden)

    Hiroyuki Mizoguchi

    2011-01-01

    Full Text Available Matrix metalloproteinases (MMPs and tissue inhibitors of metalloproteinases (TIMPs remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy.

  18. The prediction of drug dependence from expectancy for hostility while intoxicated.

    Science.gov (United States)

    Walter, D; Nagoshi, C; Muntaner, C; Haertzen, C A

    1990-10-01

    Three hundred seventy-one male substance-abusing volunteers for drug studies were administered the Buss-Durkee Hostility Inventory (B-D). One hundred nineteen of these subjects were readministered the B-D with the instruction to answer the items in terms of their behavior while drinking alcohol, with 67 of these subjects also completing a heroin use condition. Expectancies for hostility under alcohol or heroin were generally uncorrelated with other measures of personality, psychopathology, antisocial personality, impulsiveness, or criminality; but expectancies for hostility under alcohol were predictive of diagnoses of alcohol, opioid, and marijuana abuse and dependence over and above the influence of these other measures.

  19. The risk of alcohol and drug dependence among healthcare workers as a result of excessive stress.

    OpenAIRE

    Chudá, Romana

    2012-01-01

    Charles University in Prague First Faculty of Medicine Department of Psychiatry, Center for Addictology School Year: 2007/2010 Abstract of the bachelor work Name: Romana Chudá Specialization: Adiktologie Matriculation year: 2007 Supervisor: MUDr. Petr Popov Opponent: MUDr. Dušan Randák Pages: 61 The title of the bachelor work: The risk of alcohol and drug dependence aminy healthcare workers as a result of excessive stress Abstract: The author has several times seen medical staff, who had been...

  20. 38 CFR 17.81 - Contracts for residential treatment services for veterans with alcohol or drug dependence or...

    Science.gov (United States)

    2010-07-01

    ... treatment services for veterans with alcohol or drug dependence or abuse disabilities. 17.81 Section 17.81... dependence or abuse disabilities. (a) Contracts for treatment services authorized under § 17.80(a) may be... Department of Veterans Affairs sponsored residents to adjust to and maintain freedom from dependence on or...

  1. Current therapeutic molecules and targets in neurodegenerative diseases based on in silico drug design.

    Science.gov (United States)

    Sehgal, Sheikh Arslan; Hammad, Mirza A; Tahir, Rana Adnan; Akram, Hafiza Nisha; Ahmad, Faheem

    2018-03-15

    As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases. Review of literature published since 1997 against neurodegenerative diseases, utilizing as keywords: in silico, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis ALS, and Huntington's disease. Due to the costs associated with experimentation and current ethical law, performing experiments directly on living organisms has become much more difficult. In this scenario, in silico techniques have been successful and have become powerful tools in the search to cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3-dimensional structures of target proteins through homology modeling 2) achieves stabilization through molecular dynamics simulation, and 3) exploits molecular docking through large compound libraries. Next generation sequencing is continually producing enormous amounts of raw sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing problems, these new tools and algorithms are required. This review elaborates precise in silico tools and techniques for drug targets, active molecules, and molecular docking studies, together with future prospects and challenges concerning possible breakthroughs in Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis, and Huntington's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Substance abuse and pharmacy practice: what the community pharmacist needs to know about drug abuse and dependence

    Directory of Open Access Journals (Sweden)

    Tommasello Anthony C

    2004-04-01

    Full Text Available Abstract Pharmacists, the most accessible of health care professionals, are well positioned to help prevent and treat substance use disorders and should prepare themselves to perform these functions. New research improves our knowledge about the pharmacological and behavioral risks of drug abuse, supports the clinical impression that drug dependence is associated with long-lasting neurochemical changes, and demonstrates effective pharmacological treatments for certain kinds of drug dependencies. The profession is evolving. Pharmacists are engaging in new practice behaviors such as helping patients manage their disease states. Collaborative practice agreements and new federal policies set the stage for pharmacists to assist in the clinical management of opioid and other drug dependencies. Pharmacists need to be well informed about issues related to addiction and prepared not only to screen, assess, and refer individual cases and to collaborate with physicians caring for chemically dependent patients, but also to be agents of change in their communities in the fight against drug abuse. At the end of this article the pharmacist will be better able to: 1. Explain the disease concept of chemical dependence 2. Gather the information necessary to conduct a screen for chemical dependence 3. Inform patients about the treatment options for chemical dependence 4. Locate resources needed to answer questions about the effects of common drugs of abuse (alcohol, marijuana, narcotics, "ecstasy", and cocaine 5. Develop a list of local resources for drug abuse treatment 6. Counsel parents who are concerned about drug use by their children 7. Counsel individuals who are concerned about drug use by a loved one. 8. Counsel individuals who are concerned about their own drug use

  3. Voltage-dependent inward currents in smooth muscle cells of skeletal muscle arterioles

    Science.gov (United States)

    Shirokov, Roman E.

    2018-01-01

    Voltage-dependent inward currents responsible for the depolarizing phase of action potentials were characterized in smooth muscle cells of 4th order arterioles in mouse skeletal muscle. Currents through L-type Ca2+ channels were expected to be dominant; however, action potentials were not eliminated in nominally Ca2+-free bathing solution or by addition of L-type Ca2+ channel blocker nifedipine (10 μM). Instead, Na+ channel blocker tetrodotoxin (TTX, 1 μM) reduced the maximal velocity of the upstroke at low, but not at normal (2 mM), Ca2+ in the bath. The magnitude of TTX-sensitive currents recorded with 140 mM Na+ was about 20 pA/pF. TTX-sensitive currents decreased five-fold when Ca2+ increased from 2 to 10 mM. The currents reduced three-fold in the presence of 10 mM caffeine, but remained unaltered by 1 mM of isobutylmethylxanthine (IBMX). In addition to L-type Ca2+ currents (15 pA/pF in 20 mM Ca2+), we also found Ca2+ currents that are resistant to 10 μM nifedipine (5 pA/pF in 20 mM Ca2+). Based on their biophysical properties, these Ca2+ currents are likely to be through voltage-gated T-type Ca2+ channels. Our results suggest that Na+ and at least two types (T- and L-) of Ca2+ voltage-gated channels contribute to depolarization of smooth muscle cells in skeletal muscle arterioles. Voltage-gated Na+ channels appear to be under a tight control by Ca2+ signaling. PMID:29694371

  4. Contamination of current-clamp measurement of neuron capacitance by voltage-dependent phenomena

    Science.gov (United States)

    White, William E.

    2013-01-01

    Measuring neuron capacitance is important for morphological description, conductance characterization, and neuron modeling. One method to estimate capacitance is to inject current pulses into a neuron and fit the resulting changes in membrane potential with multiple exponentials; if the neuron is purely passive, the amplitude and time constant of the slowest exponential give neuron capacitance (Major G, Evans JD, Jack JJ. Biophys J 65: 423–449, 1993). Golowasch et al. (Golowasch J, Thomas G, Taylor AL, Patel A, Pineda A, Khalil C, Nadim F. J Neurophysiol 102: 2161–2175, 2009) have shown that this is the best method for measuring the capacitance of nonisopotential (i.e., most) neurons. However, prior work has not tested for, or examined how much error would be introduced by, slow voltage-dependent phenomena possibly present at the membrane potentials typically used in such work. We investigated this issue in lobster (Panulirus interruptus) stomatogastric neurons by performing current clamp-based capacitance measurements at multiple membrane potentials. A slow, voltage-dependent phenomenon consistent with residual voltage-dependent conductances was present at all tested membrane potentials (−95 to −35 mV). This phenomenon was the slowest component of the neuron's voltage response, and failure to recognize and exclude it would lead to capacitance overestimates of several hundredfold. Most methods of estimating capacitance depend on the absence of voltage-dependent phenomena. Our demonstration that such phenomena make nonnegligible contributions to neuron responses even at well-hyperpolarized membrane potentials highlights the critical importance of checking for such phenomena in all work measuring neuron capacitance. We show here how to identify such phenomena and minimize their contaminating influence. PMID:23576698

  5. Illicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach.

    Science.gov (United States)

    Agrawal, A; Neale, M C; Jacobson, K C; Prescott, C A; Kendler, K S

    2005-06-01

    Drug use and abuse/dependence are stages of a complex drug habit. Most genetically informative models that are fit to twin data examine drug use and abuse/dependence independent of each other. This poses an interesting question: for a multistage process, how can we partition the factors influencing each stage specifically from the factors that are common to both stages? We used a causal-common-contingent (CCC) model to partition the common and specific influences on drug use and abuse/dependence. Data on use and abuse/dependence of cannabis, cocaine, sedatives, stimulants and any illicit drug was obtained from male and female twin pairs. CCC models were tested individually for each sex and in a sex-equal model. Our results suggest that there is evidence for additive genetic, shared environmental and unique environmental influences that are common to illicit drug use and abuse/dependence. Furthermore, we found substantial evidence for factors that were specific to abuse/dependence. Finally, sexes could be equated for all illicit drugs. The findings of this study emphasize the need for models that can partition the sources of individual differences into common and stage-specific influences.

  6. Plasma current dependence of the edge pedestal height in JET ELM-free H-modes

    International Nuclear Information System (INIS)

    Nave, M.F.F; Lomas, P.; Gowers, C.; Guo, H.; Hawkes, N.; Huysmans, G.T.A.; Jones, T.; Parail, V.V.; Rimini, F.; Schunke, B.

    2000-01-01

    Some models for the suppression of turbulence in the L to H transition, suggest that the width of the H-mode edge barrier is either proportional or is of the order of the thermal or the fast-ion poloidal Larmor radius. This would require that the width of the edge barrier should depend on the plasma current. This dependence has been clearly verified at JET in experiments designed to control the edge MHD stability of ELM-free hot-ion H-mode plasmas. The effects of isotopic mass and the applicability of several edge barrier models to the hot-ion H-mode plasmas were analysed in (Guo H Y et al 2000 Edge transport barrier in JET hot-ion H-modes Nucl. Fusion 40 69) using a large database containing both deuterium-only and deuterium-tritium plasmas. This database has now been enlarged to include discharges from a plasma shape scan, allowing one to study the dependence of the pedestal height on the edge shear. In addition, the range of plasma currents was extended up to 6 MA. It is shown that the edge data are best described by a model where the edge barrier width is determined by the fast ions weighted towards the components with largest poloidal Larmor radii. However, it is not possible to conclusively eliminate the thermal ion model. (author)

  7. Plasma current dependence of the edge pedestal height in JET ELM-free H-modes

    International Nuclear Information System (INIS)

    Nave, M.; Lomas, P.; Gowers, C.

    2000-01-01

    Models for the suppression of turbulence in the L to H transition, suggest that the width of the H-mode edge barrier is either proportional or is of the order of the ion poloidal Larmor radius. This would require that the width of the edge barrier should depend on the plasma current. This dependence has been clearly verified at JET in experiments designed to control the edge MHD stability of ELM-free hot-ion H-mode plasmas. The effects of isotopic mass and the applicability of several edge barrier models to the hot-ion H-mode plasmas were analysed in using a large database containing both Deuterium-only (DD) and Deuterium-Tritium (DT) plasmas. This database has now been enlarged to include discharges from a plasma shape scan, allowing to study the dependence of the pedestal height on the edge shear. In addition the range of plasma currents was extended up to 6 MA. It is shown that the edge data is best described by a model where the edge barrier width is determined by the fast ions weighted towards the components with largest poloidal Larmor radii. However, it is not possible to eliminate conclusively the thermal ion model. (author)

  8. Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder.

    Science.gov (United States)

    Meunier, David; Ersche, Karen D; Craig, Kevin J; Fornito, Alex; Merlo-Pich, Emilio; Fineberg, Naomi A; Shabbir, Shaila S; Robbins, Trevor W; Bullmore, Edward T

    2012-01-16

    There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Time-dependent current into and through multilevel parallel quantum dots in a photon cavity

    Science.gov (United States)

    Gudmundsson, Vidar; Abdullah, Nzar Rauf; Sitek, Anna; Goan, Hsi-Sheng; Tang, Chi-Shung; Manolescu, Andrei

    2017-05-01

    We analyze theoretically the charging current into, and the transport current through, a nanoscale two-dimensional electron system with two parallel quantum dots embedded in a short wire placed in a photon cavity. A plunger gate is used to place specific many-body states of the interacting system in the bias window defined by the external leads. We show how the transport phenomena active in the many-level complex central system strongly depend on the gate voltage. We identify a resonant transport through the central system as the two spin components of the one-electron ground state are in the bias window. This resonant transport through the lowest energy electron states seems to a large extent independent of the detuned photon field when judged from the transport current. This could be expected in the small bias regime, but an observation of the occupancy of the states of the system reveals that this picture is not entirely true. The current does not reflect slower photon-active internal transitions bringing the system into the steady state. The number of initially present photons determines when the system reaches the real steady state. With two-electron states in the bias window we observe a more complex situation with intermediate radiative and nonradiative relaxation channels leading to a steady state with a weak nonresonant current caused by inelastic tunneling through the two-electron ground state of the system. The presence of the radiative channels makes this phenomena dependent on the number of photons initially in the cavity.

  10. On the Comparison of Impulsivity between HIV Positive Persons, Drug-Dependent Persons, and Healthy Counterparts

    Directory of Open Access Journals (Sweden)

    M Nikoogoftar

    2015-02-01

    Full Text Available Objective: This study was an attempt to compare impulsive decision-making between AIDS sufferers, people suffering substance abuse, and nonclinical populations. Method: This was a causal-comparative study which was conducted within the six months of 2011. In this study, 30 AIDS sufferers, 30 drug abusers, and 30 healthy subjects from nonclinical population in the 15-67 age range were selected through convenience sampling. The selected participants were matched in terms of age, education, and gender. Barratt Impulsiveness Scale (1997 were administered to the three groups. Results: The results showed that there was a significant difference among the three groups in impulsivity subscales. Conclusion: The results showed that there existed some degree of deficiency in decision-making processes in AIDS sufferers and drug dependent persons. It may be rooted in a number of personality traits neurological damage drug use the insufficiency of appropriate training in life skills, problem-solving, and decision-making the availability of emotions at paly and personal and cultural thoughts and beliefs around protective behaviors in sexual relationships.

  11. Effects of chronic mild stress on the development of drug dependence in rats.

    Science.gov (United States)

    Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Litwa, Ewa; Willner, Paul

    2014-09-01

    There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse.

  12. RNA-dependent RNA polymerase: Addressing Zika outbreak by a phylogeny-based drug target study.

    Science.gov (United States)

    Stephen, Preyesh; Lin, Sheng-Xiang

    2018-01-01

    Since the first major outbreak of Zika virus (ZIKV) in 2007, ZIKV is spreading explosively through South and Central America, and recent reports in highly populated developing countries alarm the possibility of a more catastrophic outbreak. ZIKV infection in pregnant women leads to embryonic microcephaly and Guillain-Barré syndrome in adults. At present, there is limited understanding of the infectious mechanism, and no approved therapy has been reported. Despite the withdrawal of public health emergency, the WHO still considers the ZIKV as a highly significant and long-term public health challenge that the situation has to be addressed rapidly. Non-structural protein 5 is essential for capping and replication of viral RNA and comprises a methyltransferase and RNA-dependent RNA polymerase (RdRp) domain. We used molecular modeling to obtain the structure of ZIKV RdRp, and by molecular docking and phylogeny analysis, we here demonstrate the potential sites for drug screening. Two metal binding sites and an NS3-interacting region in ZIKV RdRp are demonstrated as potential drug screening sites. The docked structures reveal a remarkable degree of conservation at the substrate binding site and the potential drug screening sites. A phylogeny-based approach is provided for an emergency preparedness, where similar class of ligands could target phylogenetically related proteins. © 2017 John Wiley & Sons A/S.

  13. Temperature and current dependent electroluminescence measurements on colour-coded multiple quantum well light emitting diodes

    Energy Technology Data Exchange (ETDEWEB)

    Bergbauer, Werner [OSRAM Opto Semiconductors GmbH, Regensburg (Germany); FH Deggendorf (Germany); Laubsch, Ansgar; Peter, Matthias; Mayer, Tobias; Bader, Stefan; Oberschmid, Raimund; Hahn, Berthold [OSRAM Opto Semiconductors GmbH, Regensburg (Germany); Benstetter, Guenther [FH Deggendorf (Germany)

    2008-07-01

    As the efficiency and the luminous flux have been increased enormously in the last few years, today Light Emitting Diodes (LEDs) are even pushed to applications like general lighting and Home Cinema Projection. Still, InGaN/GaN heterostructure based LEDs suffer from loss-mechanisms like non-radiative defect and Auger recombination, carrier leakage and piezo-field induced carrier separation. To optimize the high current efficiency we evaluated the benefit of Multiple Quantum Well (MQW) compared to Single Quantum Well (SQW) LEDs. Temperature dependent electroluminescence of colour-coded structures with different Indium content in certain Quantum Wells was measured. The experiments demonstrated a strong temperature and current dependence of the MQW operation. The comparison between different LED structures showed effectively the increased LED performance of those structures which operate with a well adjusted MQW active area. Due to the enhanced carrier distribution in the high current range, these LEDs show a higher light output and additionally a reduced wavelength shift.

  14. Temperature and current dependent electroluminescence measurements on colour-coded multiple quantum well light emitting diodes

    International Nuclear Information System (INIS)

    Bergbauer, Werner; Laubsch, Ansgar; Peter, Matthias; Mayer, Tobias; Bader, Stefan; Oberschmid, Raimund; Hahn, Berthold; Benstetter, Guenther

    2008-01-01

    As the efficiency and the luminous flux have been increased enormously in the last few years, today Light Emitting Diodes (LEDs) are even pushed to applications like general lighting and Home Cinema Projection. Still, InGaN/GaN heterostructure based LEDs suffer from loss-mechanisms like non-radiative defect and Auger recombination, carrier leakage and piezo-field induced carrier separation. To optimize the high current efficiency we evaluated the benefit of Multiple Quantum Well (MQW) compared to Single Quantum Well (SQW) LEDs. Temperature dependent electroluminescence of colour-coded structures with different Indium content in certain Quantum Wells was measured. The experiments demonstrated a strong temperature and current dependence of the MQW operation. The comparison between different LED structures showed effectively the increased LED performance of those structures which operate with a well adjusted MQW active area. Due to the enhanced carrier distribution in the high current range, these LEDs show a higher light output and additionally a reduced wavelength shift

  15. Conserved Noether Currents, Utiyama's Theory of Invariant Variation, and Velocity Dependence in Local Gauge Invariance

    Science.gov (United States)

    Darvas, Gyrgy

    2009-01-01

    The paper discusses the mathematical consequences of the application of derived variables in gauge fields. Physics is aware of several phenomena, which depend first of all on velocities (like e.g., the force caused by charges moving in a magnetic field, or the Lorentz transformation). Applying the property of the second Noether theorem, that allowed generalised variables, this paper extends the article by Al-Kuwari and Taha (1991) with a new conclusion. They concluded that there are no extra conserved currents associated with local gauge invariance. We show, that in a more general case, there are further conserved Noether currents. In its method the paper reconstructs the clue introduced by Utiyama (1956, 1959) and followed by Al-Kuwari and Taha (1991) in the presence of a gauge field that depends on the co-ordinates of the velocity space. In this course we apply certain (but not full) analogies with Mills (1989). We show, that handling the space-time coordinates as implicit variables in the gauge field, reproduces the same results that have been derived in the configuration space (i.e., we do not lose information), while the proposed new treatment gives additional information extending those. The result is an extra conserved Noether current.

  16. An exponential scaling law for the strain dependence of the Nb3Sn critical current density

    International Nuclear Information System (INIS)

    Bordini, B; Alknes, P; Bottura, L; Rossi, L; Valentinis, D

    2013-01-01

    The critical current density of the Nb 3 Sn superconductor is strongly dependent on the strain applied to the material. In order to investigate this dependence, it is a common practice to measure the critical current of Nb 3 Sn strands for different values of applied axial strain. In the literature, several models have been proposed to describe these experimental data in the reversible strain region. All these models are capable of fitting the measurement results in the strain region where data are collected, but tend to predict unphysical trends outside the range of data, and especially for large strain values. In this paper we present a model of a new strain function, together with the results obtained by applying the new scaling law on relevant datasets. The data analyzed consisted of the critical current measurements at 4.2 K that were carried out under applied axial strain at Durham University and the University of Geneva on different strand types. With respect to the previous models proposed, the new scaling function does not present problems at large strain values, has a lower number of fitting parameters (only two instead of three or four), and is very stable, so that, starting from few experimental points, it can estimate quite accurately the strand behavior in a strain region where there are no data. A relationship is shown between the proposed strain function and the elastic strain energy, and an analogy is drawn with the exponential form of the McMillan equation for the critical temperature. (paper)

  17. Prediction of Human Drug Targets and Their Interactions Using Machine Learning Methods: Current and Future Perspectives.

    Science.gov (United States)

    Nath, Abhigyan; Kumari, Priyanka; Chaube, Radha

    2018-01-01

    Identification of drug targets and drug target interactions are important steps in the drug-discovery pipeline. Successful computational prediction methods can reduce the cost and time demanded by the experimental methods. Knowledge of putative drug targets and their interactions can be very useful for drug repurposing. Supervised machine learning methods have been very useful in drug target prediction and in prediction of drug target interactions. Here, we describe the details for developing prediction models using supervised learning techniques for human drug target prediction and their interactions.

  18. Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes

    NARCIS (Netherlands)

    Filip, Malgorzata; Spampinato, Umberto; McCreary, Andrew C.; Przegalinski, Edmund

    2012-01-01

    The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT2C receptors on the effects of different classes of addictive drugs, illustrated by reference to data using

  19. Early childhood experiences, parenting and the process of drug dependency among young people in Tehran, Iran.

    Science.gov (United States)

    Mirlashari, Jila; Demirkol, Apo; Salsali, Mahvash; Rafiey, Hassan; Jahanbani, Jahanfar

    2012-06-01

    Substance abuse has become a major public health problem in Iran. The process of developing an addiction is complex and multifaceted. Early childhood experiences are thought to be one of the important determinants of addictive behaviour. The aim of this qualitative study is to explore the early childhood experiences, especially the experiences within the immediate family, of current substance-using young adults in Iran. The study is qualitative in nature. In-depth interviews were conducted with 15 young men and women who were either in treatment for their addiction or were active drug users at the time of the interviews. Moreover, four interviews have been conducted with family members of participants. The majority of the participants experienced traumatic events during childhood and came from dysfunctional families. There appears to be a significant disconnect between these individuals and their families. An obedience-instilling parenting style and parents' knowledge and attitude toward drug using and prevention were also identified as important determinants of substance use. The results of this research point out the need for early interventions for at-risk families as well as at-risk individuals. © 2011 Australasian Professional Society on Alcohol and other Drugs.

  20. Measurement of the $Z/A$ dependence of neutrino charged-current total cross-sections

    CERN Document Server

    Kayis-Topaksu, A; Van Dantzig, R; De Jong, M; Konijn, J; Melzer, O; Oldeman, R G C; Pesen, E; Van der Poel, C A F J; Spada, F R; Visschers, J L; Güler, M; Serin-Zeyrek, M; Kama, S; Sever, R; Tolun, P; Zeyrek, M T; Armenise, N; Catanesi, M G; De Serio, M; Ieva, M; Muciaccia, M T; Radicioni, E; Simone, S; Bülte, A; Winter, Klaus; El-Aidi, R; Van de Vyver, B; Vilian, P; Wilquet, G; Saitta, B; Di Capua, E; Ogawa, S; Shibuya, H; Artamonov, A V; Brunner, J; Chizhov, M; Cussans, D G; Doucet, M; Fabre, Jean-Paul; Hristova, I R; Kawamura, T; Kolev, D; Litmaath, M; Meinhard, H; Panman, J; Papadopoulos, I M; Ricciardi, S; Rozanov, A; Saltzberg, D; Tsenov, R V; Uiterwijk, J W E; Zucchelli, P; Goldberg, J; Chikawa, M; Arik, E; Song, J S; Yoon, C S; Kodama, K; Ushida, N; Aoki, S; Hara, T; Delbar, T; Favart, D; Grégoire, G; Kalinin, S; Makhlyoueva, I V; Gorbunov, P; Khovanskii, V D; Shamanov, V V; Tsukerman, I; Bruski, N; Frekers, D; Rondeshagen, D; Wolff, T; Hoshino, K; Kawada, J; Komatsu, M; Miyanishi, M; Nakamura, M; Nakano, T; Narita, K; Niu, K; Niwa, K; Nonaka, N; Sato, O; Toshito, T; Buontempo, S; Cocco, A G; D'Ambrosio, N; De Lellis, G; De Rosa, G; Di Capua, F; Ereditato, A; Fiorillo, G; Marotta, A; Messina, M; Migliozzi, P; Pistillo, C; Santorelli, R; Scotto-Lavina, L; Strolin, P; Tioukov, V; Nakamura, K; Okusawa, T; Dore, U; Loverre, P F; Ludovici, L; Maslennikov, A L; Righini, P; Rosa, G; Santacesaria, R; Satta, A; Barbuto, E; Bozza, C; Grella, G; Romano, G; Sirignano, C; Sorrentino, S; Sato, Y; Tezuka, I

    2003-01-01

    A relative measurement of total cross-sections is reported for polyethylene, marble, iron, and lead targets for the inclusive charged-current reaction nu_mu + N -> mu^- + X. The targets, passive blocks of ~100kg each, were exposed simultaneously to the CERN SPS wide-band muon-neutrino beam over a period of 18 weeks. Systematics effects due to differences in the neutrino flux and detector efficiency for the different target locations were minimised by changing the position of the four targets on their support about every two weeks. The relative neutrino fluxes on the targets were monitored within the same experiment using charged-current interactions in the calorimeter positioned directly downstream of the four targets. From a fit to the Z/A dependence of the total cross-sections a value is deduced for the effective neutron-to-proton cross-section ratio.

  1. Measurement of the Z/A dependence of neutrino charged-current total cross-sections

    CERN Document Server

    Kayis-Topasku, A; Dantzig, R V

    2003-01-01

    A relative measurement of total cross-sections is reported for polyethylene, marble, iron, and lead targets for the inclusive charged-current reaction nu submu + N -> mu sup - + X. The targets, passive blocks of propor to 100 kg each, were exposed simultaneously to the CERN SPS wide-band muon-neutrino beam over a period of 18 weeks. Systematic effects due to differences in the neutrino flux and detector efficiency for the different target locations were minimised by changing the position of the four targets on their support about every two weeks. The relative neutrino fluxes on the targets were monitored within the same experiment using charged-current interactions in the calorimeter positioned directly downstream of the four targets. From a fit to the Z/A dependence of the total cross-sections a value is deduced for the effective neutron-to-proton cross-section ratio. (orig.)

  2. Thermal dependence of the current threshold in InGaAsN lasers

    International Nuclear Information System (INIS)

    Mon, E.; Suarez, N.; Sánchez, M.; Martin, Juan A.

    2008-01-01

    With active area of InGaAsN lasers are very attractive since they emit in the range of wavelengths of 1.3 to 1.5 pm (CET) bands of conduction of the active zone and cladding in this material [1] layers. In lasers with barriers of GaAs InGaAsN AEc around values are obtained 300 MeV, which guarantees a good confinement of electrons and reported To the order of 126 K values, however, these results have not been satisfactorily explained and there are conflicting reports about this parameter. This work simulates the thermal dependence of the current threshold of InGaAsN lasers including as main mechanisms of loss, leakage current, Auger recombination and recombination Mono [2], which was a good fit of the experimental results reported.

  3. Time-dependent current-density functional theory for generalized open quantum systems.

    Science.gov (United States)

    Yuen-Zhou, Joel; Rodríguez-Rosario, César; Aspuru-Guzik, Alán

    2009-06-14

    In this article, we prove the one-to-one correspondence between vector potentials and particle and current densities in the context of master equations with arbitrary memory kernels, therefore extending time-dependent current-density functional theory (TD-CDFT) to the domain of generalized many-body open quantum systems (OQS). We also analyse the issue of A-representability for the Kohn-Sham (KS) scheme proposed by D'Agosta and Di Ventra for Markovian OQS [Phys. Rev. Lett. 2007, 98, 226403] and discuss its domain of validity. We suggest ways to expand their scheme, but also propose a novel KS scheme where the auxiliary system is both closed and non-interacting. This scheme is tested numerically with a model system, and several considerations for the future development of functionals are indicated. Our results formalize the possibility of practising TD-CDFT in OQS, hence expanding the applicability of the theory to non-Hamiltonian evolutions.

  4. Detection of second harmonic of phase dependence of superconducting current in Nb/Au/YBCO heterojunctions

    CERN Document Server

    Komissinskij, F V; Ilichev, E V; Ivanov, Z G

    2001-01-01

    The results of the experimental study on the current phase dependence (CPD) of the heterotransitions, consisting of the niobium and the YBa sub 2 Cu sub 3 O sub x (YBCO) film with an additional interlayer from gold (Nb/Au/YBCO) are presented. The CPD measurement is carried out through the radiofrequency superconducting quantum interferometer. The CPD second harmonic is determined in the Nb/Au/YBCO heterotransitions. Possible causes of its appearance are discussed within the frames of the d +- s combined symmetry of the YBCO order parameter. One of the causes of the CPD second harmonic appearance is the twinning of the YBCO films (001). The second cause of existing the anomalously high critical current consists in the availability of the Nb/Au boundary with the transparence of approx 10 sup - sup 1 in the Nb/Au/YBCO

  5. The Predictive Role of Difficulties in Emotion Regulation and Self-Control with Susceptibility to Addiction in Drug-Dependent Individuals

    OpenAIRE

    Mahmoud Shirazi; Monavar Janfaza

    2015-01-01

    Objective: The present study aimed to examine the predictive role of difficulties in emotion regulation and self-control in potential for addiction among drug-dependent individuals. Method: This was a correlational study which falls within the category of descriptive studies. The statistical population of the current study included all patients under treatment in outpatient health centers in Bam, among whom 315 individuals were selected through cluster sampling method as the participants of t...

  6. Effect of training the communication skills with cognitive-behavioral model to drug dependent couples on communication patterns and recurrent relapse

    OpenAIRE

    M. Rahbarian; R. Hossein zadeh; P. Doosti

    2016-01-01

    Background: One of the main challenges in methadone maintenance treatment is relapse and lack of sustainability on treatment. Therefore, considering the effective factors in this regard and reducing it through psychological interventions as an adjunct to medication is necessary. Objective: The current study aimed to determine the effectiveness of communication skill training based on cognitive-behavioral model on communication patterns and recurrent relapse in drug dependent couples. Me...

  7. Possible influence of the voltage dependence of the Josephson tunneling current I(V,psi) on the corresponding current-voltage characteristic

    International Nuclear Information System (INIS)

    Hahlbohm, H.D.; Luebbig, H.; Luther, H.

    1975-01-01

    Analog computer calculations of the current-voltage characteristic involving the voltage dependence of the amplitudes of the tunneling current equation explicitly, for the case of a current driven tunneling junction at different temperatures are reported on. These studies are based upon the adiabatic representation of the current-phase relation. The influence of retarding effects is not included. Therefore the computational results can lead to practical consequences at best in the range near the transition temperature. (Auth.)

  8. Remarks on time-dependent [current]-density functional theory for open quantum systems.

    Science.gov (United States)

    Yuen-Zhou, Joel; Aspuru-Guzik, Alán

    2013-08-14

    Time-dependent [current]-density functional theory for open quantum systems (OQS) has emerged as a formalism that can incorporate dissipative effects in the dynamics of many-body quantum systems. Here, we review and clarify some formal aspects of these theories that have been recently questioned in the literature. In particular, we provide theoretical support for the following conclusions: (1) contrary to what we and others had stated before, within the master equation framework, there is in fact a one-to-one mapping between vector potentials and current densities for fixed initial state, particle-particle interaction, and memory kernel; (2) regardless of the first conclusion, all of our recently suggested Kohn-Sham (KS) schemes to reproduce the current and particle densities of the original OQS, and in particular, the use of a KS closed driven system, remains formally valid; (3) the Lindblad master equation maintains the positivity of the density matrix regardless of the time-dependence of the Hamiltonian or the dissipation operators; (4) within the stochastic Schrödinger equation picture, a one-to-one mapping from stochastic vector potential to stochastic current density for individual trajectories has not been proven so far, except in the case where the vector potential is the same for every member of the ensemble, in which case, it reduces to the Lindblad master equation picture; (5) master equations may violate certain desired properties of the density matrix, such as positivity, but they remain as one of the most useful constructs to study OQS when the environment is not easily incorporated explicitly in the calculation. The conclusions support our previous work as formally rigorous, offer new insights into it, and provide a common ground to discuss related theories.

  9. Pacemaker neuron and network oscillations depend on a neuromodulator-regulated linear current

    Directory of Open Access Journals (Sweden)

    Shunbing Zhao

    2010-05-01

    Full Text Available Linear leak currents have been implicated in the regulation of neuronal excitability, generation of neuronal and network oscillations, and network state transitions. Yet, few studies have directly tested the dependence of network oscillations on leak currents or explored the role of leak currents on network activity. In the oscillatory pyloric network of decapod crustaceans neuromodulatory inputs are necessary for pacemaker activity. A large subset of neuromodulators is known to activate a single voltage-gated inward current IMI, which has been shown to regulate the rhythmic activity of the network and its pacemaker neurons. Using the dynamic clamp technique, we show that the crucial component of IMI for the generation of oscillatory activity is only a close-to-linear portion of the current-voltage relationship. The nature of this conductance is such that the presence or the absence of neuromodulators effectively regulates the amount of leak current and the input resistance in the pacemaker neurons. When deprived of neuromodulatory inputs, pyloric oscillations are disrupted; yet, a linear reduction of the total conductance in a single neuron within the pacemaker group recovers not only the pacemaker activity in that neuron, but also leads to a recovery of oscillations in the entire pyloric network. The recovered activity produces proper frequency and phasing that is similar to that induced by neuromodulators. These results show that the passive properties of pacemaker neurons can significantly affect their capacity to generate and regulate the oscillatory activity of an entire network, and that this feature is exploited by neuromodulatory inputs.

  10. Collisionality dependence of Mercier stability in LHD equilibria with bootstrap currents

    International Nuclear Information System (INIS)

    Ichiguchi, Katsuji.

    1997-02-01

    The Mercier stability of the plasmas carrying bootstrap currents with different plasma collisionality is studied in the Large Helical Device (LHD). In the LHD configuration, the direction of the bootstrap current depends on the collisionality of the plasma through the change in the sign of the geometrical factor. When the beta value is raised by increasing the density of the plasma with a fixed low temperature, the plasma becomes more collisional and the collisionality approaches the plateau regime. In this case, the bootstrap current can flow in the direction so as to decrease the rotational transform. Then, the large Shafranov shift enhances the magnetic well and the magnetic shear, and therefore, the Mercier stability is improved. On the other hand, when the beta value is raised by increasing the temperature of the plasma with a fixed low density, the plasma collisionality becomes reduced to enter the 1/ν collisionality regime and the bootstrap current flows so that the rotational transform should be increased, which is unfavorable for the Mercier stability. Hence, the beta value should be raised by increasing the density rather than the temperature in order to obtain a high beta plasma. (author)

  11. Current approaches to enhance CNS delivery of drugs across the brain barriers

    Directory of Open Access Journals (Sweden)

    Lu CT

    2014-05-01

    Full Text Available Cui-Tao Lu,1 Ying-Zheng Zhao,2,3 Ho Lun Wong,4 Jun Cai,5 Lei Peng,2 Xin-Qiao Tian1 1The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 2Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China; 3College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China; 4School of Pharmacy, Temple University, Philadelphia, PA, USA; 5Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA Abstract: Although many agents have therapeutic potentials for central nervous system (CNS diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. Keywords: drug delivery system, blood–brain barrier (BBB, central nervous system, brain-targeted therapy, cerebrospinal fluid (CSF

  12. Comparison of antimalarial activity of Artemisia turanica extract with current drugs in vivo.

    Science.gov (United States)

    Taherkhani, Mahboubeh; Rustaiyan, Abdolhossein; Nahrevanian, Hossein; Naeimi, Sabah; Taherkhani, Tofigh

    2013-03-01

    The purpose of this study was to compare antimalarial activity of Artemisia turanica Krasch as Iranian flora with current antimalarial drugs against Plasmodium berghei in vivo in mice. Air-dried aerial parts of Iranian flora A. turanica were collected from Khorasan, northeastern Iran, extracted with Et2O/MeOH/Petrol and defatted. Toxicity of herbal extracts was assessed on male NMRI mice, and their antimalarial efficacy was compared with antimalarial drugs [artemether, chloroquine and sulfadoxinepyrimethamine (Fansidar)] on infected P. berghei animals. All the groups were investigated for parasitaemia, body weight, hepatomegaly, splenomegaly and anemia. The significance of differences was determined by Analysis of Variances (ANOVA) and Student's t-test using Graph Pad Prism software. The inhibitory effects of A. turanica extract on early decline of P. berghei parasitaemia highlights its antimalarial activity, however, this effect no longer can be observed in the late infection. This may be due to the metabolic process of A. turanica crude extract by mice and reduction of its concentration in the body. Crude extract of A. turanica represented its antisymptomatic effects by stabilization of body, liver and spleen weights. This study confirmed antimalarial effects of A. turanica extracts against murine malaria in vivo during early infection, however, there are more benefits on pathophysiological symptoms by this medication.

  13. Field dependence of the current density of superconductors at high temperatures

    International Nuclear Information System (INIS)

    Hiergeist, R.; Hergt, R.; Erb, A.; Kummeth, P.; Winzer, K.

    1993-01-01

    An essential drawback of the high-T c superconductors (HTS) with respect to technical applications at liquid nitrogen temperature is the large degradation of their pinning properties in magnetic fields. For the field dependence of the volume pinning force often a high field tail due to thermally activated flux flow is observed. An exponential decay of the irreversible magnetization with increasing field was reported in the case of sintered material (YBCO) for the intergranular part of the magnetization while a power law decay was found for the intragranular part. Song et al. observed an exponential field dependence of the critical current density for proton-irradiated material which before irradiation showed a power law decay. Gladun et al. found an exponential decay for BSCCO-2223 tapes. The high field behaviour of BSCCO was shown to be governed by thermally activated flux creep with a logarithmic pinning barrier, which may result in an exponential decrease of the current with the external magnetic field, as argued recently by Ries et al. We will show in the present paper that the different HTS substance classes (YBCO, BSCCO, TBCCO) behave qualitatively in a similar way. (orig.)

  14. Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans.

    Science.gov (United States)

    Nunes, Amanda A; Dos Santos, Rafael G; Osório, Flávia L; Sanches, Rafael F; Crippa, José Alexandre S; Hallak, Jaime E C

    2016-01-01

    Recently, the anti-addictive potential of ayahuasca, a dimethyltryptamine(DMT)- and β-carboline-rich hallucinogenic beverage traditionally used by indigenous groups of the Northwest Amazon and currently by syncretic churches worldwide, has received increased attention. To better evaluate this topic, we performed a systematic literature review using the PubMed database to find quantitative studies (using statistical analysis) that assessed the effects of ayahuasca or its components in drug-related symptoms or disorders. We found five animal studies (using harmaline, harmine, or ayahuasca) and five observational studies of regular ayahuasca consumers. All animal studies showed improvement of biochemical or behavioral parameters related to drug-induced disorders. Of the five human studies, four reported significant reductions of dependence symptoms or substance use, while one did not report significant results. The mechanisms responsible for the anti-addictive properties of ayahuasca and its alkaloids are not clarified, apparently involving both peripheral MAO-A inhibition by the β-carbolines and central agonism of DMT at 5-HT2A receptors expressed in brain regions related to the regulation of mood and emotions. Although results are promising, controlled studies are needed to replicate these preliminary findings.

  15. The importance of biological rhythms in drug treatment of hypertension and sex-dependent modifications

    Directory of Open Access Journals (Sweden)

    Lemmer B

    2012-04-01

    Full Text Available Björn LemmerInstitute of Experimental and Clinical Pharmacology and Toxicology, Ruprecht-Karls-University of Heidelberg, Mannheim, GermanyAbstract: The cardiovascular system is highly organized in time. Blood pressure, heart rate, peripheral resistance, pressure, and vasodilating hormones display pronounced circadian variations. New data presented here demonstrate also sex-dependent differences in vasodilating hormones, with higher NOχ excretion in females than males and a steeper early morning rise in norepinephrine in males, whereas the 24-hour blood pressure and heart-rate profiles were not different. Various antihypertensive drugs were investigated in crossover studies – morning versus evening dosing – in hypertensive patients; however, consistent data were only described for angiotensin-converting-enzyme (ACE inhibitors, calcium channel blockers, and angiotensin II type 1 (AT1 receptor blockers. Whereas in dippers ACE inhibitors had a superdipping effect when dosed at night, no difference in the blood pressure lowering effect or on the 24-hour blood pressure profile was found with calcium channel blockers after morning and evening dosing. In nondippers, the calcium channel blockers isradipine and amlodipine transformed nondippers into dippers, similar after evening dosing. The effects of AT1-receptor blockers are similar to those of ACE inhibitors. Also, diuretics are able to normalize non dipping behavior. Moreover, a circadian phase dependency in their pharmacokinetics has been demonstrated for various cardiovascular-active drugs, such as beta blockers, calcium channel blockers, oral nitrates, and ACE inhibitors, modified by the galenic formulation. There is evidence that in hypertensive dippers, antihypertensive drugs should be given during early morning hours, whereas in non dippers it can be necessary to add an evening dose or even to apply a single evening dose in order not only to reduce high blood pressure, but also to

  16. Prevention and treatment in prison law: women prisoners drug dependence in Spain

    Directory of Open Access Journals (Sweden)

    Francisco José del Pozo Serrano

    2015-05-01

    Full Text Available The penitentiary drug dependence treatment for women has been traditionally generic (applied for most masculine penitentiary and with few differentiating empiric studies in an spanish level.Based on a regulatory framework, this research focuses on the study of the main elements of risk and protection implied in the relation between the drug dependant female prisoners and the treatment programs, as well as the recovery processes, in order to propose specific actions.The research has a multimethod approach, inserted within the Project I+D+I named “Mujeres reclusas drogodependientes y su reinserción social. Estudio socioeducativo y propuestas de acción” [EDU2009-13408], with a national sample of second and third degree (Central Government and Community of Catalonia, corresponding to an estimate of 15% of the female prisoners nationally. 538 valid questionnaires, 61 semi-structured interviews has been obtained, in which informatic analytical methods, specific programs for quantitative data (SPSS, V. 15 y 20, and analytical content methods for qualitative data has been applied. The analysis has been developed before and after the internment, including four profiles of female prisioners (AA: Active addicted (8'20%, EX: ex addicted (EX: 67'21%, NA: non addicted (NA: 14.75% and PMM (9.84% addicted within methadone maintenance programs .Among the main results found, it is relevant to mention the elements of risk related to the absence of participation of ex addicted women in relapse prevention programs. In fact, this is a relevant issue since 70% of the women are ex addicted. There is a large number of women not receiving any treatment in prision and not participating in any program due to lack of information, mistrust and overlap with other activities. Aditionally, theres is a perception of gender discrimination towards the access and permanece of women in the programs, compared with men.  Also, within the main elements of protection, it has been

  17. Evaluation of transporters in drug development: Current status and contemporary issues.

    Science.gov (United States)

    Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

    2017-07-01

    Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

  18. Categorization of psychoactive substances into "hard drugs" and "soft drugs": a critical review of terminology used in current scientific literature.

    Science.gov (United States)

    Janik, Peter; Kosticova, Michaela; Pecenak, Jan; Turcek, Michal

    2017-11-01

    Precise terminology and definitions are important components of scientific language. Although the terms "hard drugs" and "soft drugs" are used widely by professionals, neither the International Classification of Diseases nor the Diagnostic and Statistical Manual classify psychoactive substances into the categories "hard" and "soft." To analyze the occurrence of the terms "hard drugs" and "soft drugs" in recent scientific literature and to establish the degree of consensus in labeling psychoactive substances as "hard" or "soft." A critical review of scientific papers listed in PubMed and Scopus between 2011 and 2015. Three hundred thirty-four articles were initially identified as potentially relevant for review, 132 of which were included in the final analysis. One hundred twenty-four articles used the term "hard drugs" and 84.7% provided examples of substances considered "hard." Forty-four articles used the term "soft drugs" and 90.9% provided examples of substances considered "soft." Citations of relevant articles supporting categorization as "hard" or "soft" were not given in 90% of the articles. The authors often provided no or only very sparse information on their reasons for considering specific drugs as "hard" or "soft." Although it initially appeared that there is substantial agreement as to which psychoactive substances should be regarded as "hard" and "soft," closer inspection shows that the dividing line is blurred without clear criteria for categorization. At this time, it remains uncertain whether these terms should persist in the scientific literature. We therefore recommend these terms should be avoided or, if used, be clearly and precisely defined.

  19. Studying the factors in dependency to substances changing the mood and behavior and effective methods in drug addiction counseling

    Directory of Open Access Journals (Sweden)

    2004-05-01

    Full Text Available Addicts to alcohol and other substances changing the mood and behavior attempt to stop their addiction and avoid its relapse because they suffer mental and physical problems, they are under the pressure of family members, employer and other individuals who influence over their life as well as negative effects of drug addiction on their performance in family, work and social relations. Since drug addicts experience physical pain when they are not using drugs, they refer, at first, to physicians and then to psychiatrists. Although emerging and applying non-medical and non-pharmaceutical approaches models is not too old, arising various addictive drugs and increasing the number of drug addicts as well as individual/social destructive consequences of drug addiction have caused that psychiatrists, psychologists and social workers to represent various non-pharmaceutical theories, models, methods and guidelines based on the conditions of their clients and their clinical experiences. The present article attempts to identify the reasons of drug addiction tendency, consumption patterns, models, theories of addiction to substances changing the mood and behavior, various methods of drug treatment, effective methods in drug addiction counseling and non-medical and non-pharmaceutical methods to give up drug addiction by using recent research findings. On this basis, the most effective methods to help those who suffer from alcohol and other drugs abuse and dependency are studied.

  20. Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

    OpenAIRE

    Kutlu, Munir Gunes; Gould, Thomas J.

    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 thi...

  1. Analysis on temperature dependent current mechanism of tunnel field-effect transistors

    Science.gov (United States)

    Lee, Junil; Kwon, Dae Woong; Kim, Hyun Woo; Kim, Jang Hyun; Park, Euyhwan; Park, Taehyung; Kim, Sihyun; Lee, Ryoongbin; Lee, Jong-Ho; Park, Byung-Gook

    2016-06-01

    In this paper, the total drain current (I D) of a tunnel FET (TFET) is decomposed into each current component with different origins to analyze the I D formation mechanisms of the TFET as a function of gate voltage (V GS). Transfer characteristics are firstly extracted with fabricated Silicon channel TFETs (Si TFETs) and silicon germanium channel TFETs (SiGe TFETs) at various temperatures. The subthreshold swings (SS) of both Si TFETs and SiGe TFETs get degraded and the SSs of SiGe TFETs get degraded more as temperature becomes higher. Then, all the I Ds measured at various temperatures are decomposed into each current component through technology computer aided design (TCAD) simulations with a good agreement with experimental data. As a result, it is revealed that Shockley-Read-Hall (SRH) recombination mainly contribute to the I D of a TFET before band to band tunneling (BTBT) occurs. Furthermore, the SS degradation by high temperature is explained successfully by the SRH recombination with electric field dependence.

  2. [Drug supply chain safety in hospitals: current data and experience of the Grenoble university hospital].

    Science.gov (United States)

    Bedouch, P; Baudrant, M; Detavernier, M; Rey, C; Brudieu, E; Foroni, L; Allenet, B; Calop, J

    2009-01-01

    Drug supply chain safety has become a priority for public health which implies a collective process. This process associates all health professionals including the pharmacist who plays a major role. The objective of this present paper is to describe the several approaches proven effective in the reduction of drug-related problem in hospital, illustrated by the Grenoble University Hospital experience. The pharmacist gets involved first in the general strategy of hospital drug supply chain, second by his direct implication in clinical activities. The general strategy of drug supply chain combines risk management, coordination of the Pharmacy and Therapeutics Committee, selection and purchase of drugs and organisation of drug supply chain. Computer management of drug supply chain is a major evolution. Nominative drug delivering has to be a prior objective and its implementation modalities have to be defined: centralized or decentralized in wards, manual or automated. Also, new technologies allow the automation of overall drug distribution from central pharmacy and the implementation of automated drug dispensing systems into wards. The development of centralised drug preparation allows a safe compounding of high risk drugs, like cytotoxic drugs. The pharmacist should develop his clinical activities with patients and other health care professionals in order to optimise clinical decisions (medication review, drug order analysis) and patients follow-up (therapeutic monitoring, patient education, discharge consultation).

  3. Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

    Directory of Open Access Journals (Sweden)

    Asuka Baba

    2016-01-01

    Full Text Available Background: Anti-allergic drugs, such as tranilast and ketotifen, inhibit the release of chemokines from mast cells. However, we know little about their direct effects on the exocytotic process of mast cells. Since exocytosis in mast cells can be monitored electrophysiologically by changes in the whole-cell membrane capacitance (Cm, the absence of such changes by these drugs indicates their mast cell-stabilizing properties. Methods: Employing the standard patch-clamp whole-cell recording technique in rat peritoneal mast cells, we examined the effects of tranilast and ketotifen on the Cm during exocytosis. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. Results: Relatively lower concentrations of tranilast (100, 250 µM and ketotifen (1, 10 µM did not significantly affect the GTP-γ-S-induced increase in the Cm. However, higher concentrations of tranilast (500 µM, 1 mM and ketotifen (50, 100 µM almost totally suppressed the increase in the Cm, and washed out the trapping of the dye on the surface of the mast cells. Compared to tranilast, ketotifen required much lower doses to similarly inhibit the degranulation of mast cells or the increase in the Cm. Conclusions: This study provides electrophysiological evidence for the first time that tranilast and ketotifen dose-dependently inhibit the process of exocytosis, and that ketotifen is more potent than tranilast in stabilizing mast cells. The mast cell-stabilizing properties of these drugs may be attributed to their ability to counteract the plasma membrane deformation in degranulating mast cells.

  4. TGI Monday?: Drug-Dependent Outpatients Report Lower Stress and More Happiness at Work than Elsewhere

    Science.gov (United States)

    Epstein, David H.; Preston, Kenzie L.

    2013-01-01

    In the general population, experience-sampling studies show that work is the aspect of daily life most associated with momentary unhappiness and a desire to be elsewhere. We assessed whether this holds true for urban outpatients in treatment for heroin and cocaine dependence. In a 25-week natural-history study, 79 employed methadone-maintained misusers of heroin and cocaine carried electronic diaries on which mood and behavior were assessed up to five times per day. Being at work was associated with lower stress, greater happiness, and lower drug craving. Work accounted for 14% of the variance in stress, 30% of the variance in happiness, and 50% of the variance in cocaine craving. Participants with skilled jobs reported more positive and less negative mood states (and lower cocaine craving) at all times compared to participants with semi/unskilled jobs, although the latter reported greater mood improvement at work. In all participants, mood improvements occurred specifically in the presence of coworkers (not other companions). Our seemingly unusual findings might be specific to substance-disorder patients (for whom work may be a respite from drug-using companions), but might also hold for other urban dwellers of similar socioeconomic backgrounds (for whom work may be a respite from environmental stressors). PMID:22494220

  5. [Stabilizing the social and health status of drug dependent patients with methadone. Long-term maintainance therapy--Vienna results].

    Science.gov (United States)

    Loimer, N; Werner, E; Hollerer, E; Pfersmann, V; Schmid-Siegel, B; Presslich, O

    1991-01-01

    On September 25th, 1987 methadone was legalized in Austria for therapeutic use in drug addiction treatment in case of: 1. Long-term drug addiction with intravenous application of the drug, and several unsuccessful withdrawal therapies and/or 2. opiate addiction through intravenous application of the drug along with an existing HIV-1 infection. Since than, 291 patients were treated with methadone at the drug-dependency outpatient clinic of the Psychiatric Clinic of the University of Vienna. In 1990, 96 patients treated for more than one year were investigated using a standardized questionnaire. The image in which crime, prostitution, poverty, ill health all merge was broken by this decriminalization. Methadone treatment offers a first step toward social rehabilitation for drug addicts who have been living as criminals on the fringe of society.

  6. Cell-type-dependent action potentials and voltage-gated currents in mouse fungiform taste buds.

    Science.gov (United States)

    Kimura, Kenji; Ohtubo, Yoshitaka; Tateno, Katsumi; Takeuchi, Keita; Kumazawa, Takashi; Yoshii, Kiyonori

    2014-01-01

    Taste receptor cells fire action potentials in response to taste substances to trigger non-exocytotic neurotransmitter release in type II cells and exocytotic release in type III cells. We investigated possible differences between these action potentials fired by mouse taste receptor cells using in situ whole-cell recordings, and subsequently we identified their cell types immunologically with cell-type markers, an IP3 receptor (IP3 R3) for type II cells and a SNARE protein (SNAP-25) for type III cells. Cells not immunoreactive to these antibodies were examined as non-IRCs. Here, we show that type II cells and type III cells fire action potentials using different ionic mechanisms, and that non-IRCs also fire action potentials with either of the ionic mechanisms. The width of action potentials was significantly narrower and their afterhyperpolarization was deeper in type III cells than in type II cells. Na(+) current density was similar in type II cells and type III cells, but it was significantly smaller in non-IRCs than in the others. Although outwardly rectifying current density was similar between type II cells and type III cells, tetraethylammonium (TEA) preferentially suppressed the density in type III cells and the majority of non-IRCs. Our mathematical model revealed that the shape of action potentials depended on the ratio of TEA-sensitive current density and TEA-insensitive current one. The action potentials of type II cells and type III cells under physiological conditions are discussed. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  7. An HDAC-dependent epigenetic mechanism that enhances the efficacy of the antidepressant drug fluoxetine

    Science.gov (United States)

    Schmauss, C.

    2015-01-01

    Depression is a prevalent and debilitating psychiatric illnesses. However, currently prescribed antidepressant drugs are only efficacious in a limited group of patients. Studies on Balb/c mice suggested that histone deacetylase (HDAC) inhibition may enhance the efficacy of the widely-prescribed antidepressant drug fluoxetine. This study shows that reducing HDAC activity in fluoxetine-treated Balb/c mice leads to robust antidepressant and anxiolytic effects. While reducing the activity of class I HDACs 1 and 3 led to antidepressant effects, additional class II HDAC inhibition was necessary to exert anxiolytic effects. In fluoxetine-treated mice, HDAC inhibitors increased enrichment of acetylated histone H4 protein and RNA polymerase II at promotor 3 of the brain-derived neurotrophic factor (Bdnf) gene and increased Bdnf transcription from this promotor. Reducing Bdnf-stimulated tropomyosin kinase B receptor activation in fluoxetine-treated mice with low HDAC activity abolished the behavioral effects of fluoxetine, suggesting that the HDAC-triggered epigenetic stimulation of Bdnf expression is critical for therapeutic efficacy. PMID:25639887

  8. Determinants of nonmedical use, abuse or dependence on prescription drugs, and use of substance abuse treatment.

    Science.gov (United States)

    Bali, Vishal; Raisch, Dennis W; Moffett, Maurice L; Khan, Nasreen

    2013-01-01

    Previous studies have found a negative association between health insurance and nonmedical use of prescription drugs (NMUPD), and abuse or dependence on prescription drugs (ADPD); and mixed associations between health insurance and use of substance abuse treatment (SAT). However, effect of health insurance in the specific subgroups of population is largely unknown. To estimate the relationship between health insurance and (1) NMUPD, (2) ADPD, and (3) use of SAT services among 12-64 years old, noninstitutionalized individuals and to see if these relationships are different in different subgroups of population. This study used cross-sectional survey data from 2007 National Survey on Drug Use and Health. Bivariate and multiple logistic regression analyses were conducted. In 2007, self-reported prevalence of NMUPD was approximately 10% (N=15,509,703). In multivariate analysis, NMUPD was negatively associated with health insurance, age, race other than non-Hispanic White, education, marital status, and income ($40,000-$74,999). Past year use of tobacco and alcohol were positively associated with NMUPD. Among those with private health insurance, Hispanics and individuals with family income less than $20,000 and $40,000-$74,999 were more likely prone to NMUPD than others. High school graduates with public health insurance were less likely prone to NMUPD. Approximately, 13% of nonmedical users reported ADPD (N=2,011,229). Health insurance and age were negatively associated with ADPD. However, people who were unmarried, reported fair/poor health, and used tobacco were more likely to report ADPD. Lastly, the use of substance abuse treatment programs was approximately 73% and 76% between NMUPD and ADPD population, respectively. Health insurance was not associated with use of substance abuse treatment. Individuals with high school education were 2.6 times more likely to use substance abuse treatment than the college graduates. Additionally, no significant interaction effects

  9. Liposheres as a Novel Carrier for Lipid Based Drug Delivery: Current and Future Directions.

    Science.gov (United States)

    Swain, Suryakanta; Beg, Sarwar; Babu, Sitty M

    2016-01-01

    Researchers are facing challenges to develop robust formulation and to enhance the bioavailability of poorly water-soluble drugs towards clinical applications. The development of new drug molecule alone is not adequate to assure ample pharmacotherapy of various diseases. Considerable results obtained from in vitro studies are not supported by in vivo data due to inadequate plasma drug concentrations. This may occur due to limited drug solubility and absorption. To resolve these problems, development of new drug delivery systems will be a promising approach. One of the promising pharmaceutical strategies is the use of lipospheres drug delivery system to deliver the poorly water-soluble drugs. Therefore, the present review described the methodology for manufacturing of lipospheres and factors influencing the formulation to deliver the drugs to the targeted site. Apart from that, this review also enlisted briefly the various applications of liposphers in medical and biomedical fields and critically discussed the recent patent system.

  10. Neighborhood-level LGBT hate crimes and current illicit drug use among sexual minority youth.

    Science.gov (United States)

    Duncan, Dustin T; Hatzenbuehler, Mark L; Johnson, Renee M

    2014-02-01

    To investigate whether past-30 day illicit drug use among sexual minority youth was more common in neighborhoods with a greater prevalence of hate crimes targeting lesbian, gay, bisexual, and transgender (LGBT, or sexual minority) individuals. We used a population-based survey of public school youth in Boston, Massachusetts, consisting of 1292 9th-12th grade students from the 2008 Boston Youth Survey Geospatial Dataset (sexual minority n=108). Data on LGBT hate crimes involving assaults or assaults and battery between 2005 and 2008 were obtained from the Boston Police Department and linked to youths' residential address. Youth reported past-30 day use of marijuana and other illicit drugs. Wilcoxon-Mann-Whitney tests and corresponding p-values were computed to assess differences in substance use by neighborhood-level LGBT assault hate crime rate among sexual minority youth (n=103). The LGBT assault hate crime rate in the neighborhoods of sexual minority youth who reported current marijuana use was 23.7 per 100,000, compared to 12.9 per 100,000 for sexual minority youth who reported no marijuana use (p=0.04). No associations between LGBT assault hate crimes and marijuana use among heterosexual youth (p>0.05) or between sexual minority marijuana use and overall neighborhood-level violent and property crimes (p>0.05) were detected, providing evidence for result specificity. We found a significantly greater prevalence of marijuana use among sexual minority youth in neighborhoods with a higher prevalence of LGBT assault hate crimes. These results suggest that neighborhood context (i.e., LGBT hate crimes) may contribute to sexual orientation disparities in marijuana use. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Direct Measurement of Nuclear Dependence of Charged Current Quasielasticlike Neutrino Interactions Using MINERvA

    Science.gov (United States)

    Betancourt, M.; Ghosh, A.; Walton, T.; Altinok, O.; Bellantoni, L.; Bercellie, A.; Bodek, A.; Bravar, A.; Cai, T.; Martinez Caicedo, D. A.; Carneiro, M. F.; Dytman, S. A.; Díaz, G. A.; Felix, J.; Fields, L.; Fine, R.; Galindo, R.; Gallagher, H.; Ghosh, A.; Golan, T.; Gran, R.; Harris, D. A.; Higuera, A.; Hurtado, K.; Kiveni, M.; Kleykamp, J.; Le, T.; Maher, E.; Manly, S.; Mann, W. A.; Marshall, C. M.; McFarland, K. S.; McGivern, C. L.; McGowan, A. M.; Messerly, B.; Miller, J.; Mislivec, A.; Morfín, J. G.; Mousseau, J.; Naples, D.; Nelson, J. K.; Norrick, A.; Nuruzzaman, Patrick, C. E.; Perdue, G. N.; Ramírez, M. A.; Ren, L.; Rimal, D.; Rodrigues, P. A.; Ruterbories, D.; Schellman, H.; Sobczyk, J. T.; Solano Salinas, C. J.; Sánchez Falero, S.; Valencia, E.; Wolcott, J.; Wospakrik, M.; Yaeggy, B.; Minerva Collaboration

    2017-08-01

    Charged-current νμ interactions on carbon, iron, and lead with a final state hadronic system of one or more protons with zero mesons are used to investigate the influence of the nuclear environment on quasielasticlike interactions. The transferred four-momentum squared to the target nucleus, Q2, is reconstructed based on the kinematics of the leading proton, and differential cross sections versus Q2 and the cross-section ratios of iron, lead, and carbon to scintillator are measured for the first time in a single experiment. The measurements show a dependence on the atomic number. While the quasielasticlike scattering on carbon is compatible with predictions, the trends exhibited by scattering on iron and lead favor a prediction with intranuclear rescattering of hadrons accounted for by a conventional particle cascade treatment. These measurements help discriminate between different models of both initial state nucleons and final state interactions used in the neutrino oscillation experiments.

  12. Radium concentrations in Adriatic coastal area and their dependence on circulation of the sea currents

    International Nuclear Information System (INIS)

    Marovic, G.; Sencar, J.; Kovac, J.; Hrsak, H.

    2002-01-01

    The aim of this study was to assess natural radioactivity in the area of the coal-fired power plant in the Plomin Bay with special emphasis on possible radiation contamination of the seawater caused by plant operation. The purpose was to determine vertical and horizontal distribution of radium and its dependence on the seawater currents at different sea depths. The level of 2 26R a in seawater was assessed four times a year, at three locations and at two sea depths. Measurements of physical, chemical and biological parameters were performed in order to provide a tangible basis for a long-term systematic monitoring of the environmental effects of plant operation on the surrounding area

  13. "Current Good Manufacturing Practices" and the Federal Food, Drug and Cosmetic Act

    OpenAIRE

    Goldstein, Beth F.

    1995-01-01

    The Food and Drug Administration (hereinafter, FDA) regulates food, drugs, and cosmetics in order to ensure that these products are safe and truthfully labelled. As part of its responsibilities under the Federal Food, Drug, and Cosmetic Act (hereinafter, Act), the FDA monitors the manufacturing practices of companies involved in the production of food, drugs, and medical devices. The manufacturing practices used by these companies must comply with certain standards, identified in the Act as "...

  14. Temperature dependent current transport of Pd/ZnO nanowire Schottky diodes

    Science.gov (United States)

    Gayen, R. N.; Bhattacharyya, S. R.; Jana, P.

    2014-09-01

    Zinc oxide (ZnO) nanowire based Schottky barrier diodes are fabricated by depositing Pd metal contact on top of vertically well-aligned ZnO nanowire arrays. A vertical array of ZnO nanowires on indium tin oxide (ITO) coated glass substrates is synthesized by hybrid wet chemical route. Scanning electron microscopy (SEM), x-ray diffraction (XRD) and x-ray photoelectron spectroscopy (XPS) measurement confirm the formation of stoichiometric well-aligned hexagonal (h-ZnO) nanowire arrays with wurtzite structure. Temperature dependent current-voltage (I-V) measurements on palladium-ZnO (Pd/ZnO) nanowire Schottky junctions in the temperature range 303-383 K exhibit excellent rectifying character. From these nonlinear I-V plots, different electrical parameters of diode-like reverse saturation current, barrier height and ideality factor are determined as a function of temperature assuming pure thermionic emission model. The ideality factor is found to decrease while the barrier height increases with the increase in temperature. The series resistance values calculated from Cheung’s functions also show temperature dependency. Such behavior can be attributed to the presence of defects that traps carriers, and barrier height inhomogeneity at the interface of the barrier junction. After barrier height inhomogeneity correction, considering a Gaussian distributed barrier height fluctuation across the Pd/ZnO interface, the estimated values of mean barrier height and modified Richardson constant are more closely matched to the theoretically predicted value for Pd/ZnO Schottky barrier diodes. The variation of density of interface states as a function of interface state energy is also calculated.

  15. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

    Science.gov (United States)

    Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

    2018-01-01

    Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

  16. The effects of age and drug dependency on the emotional exhaustion and job satisfaction of adult streetworkers in australia.

    Science.gov (United States)

    Cregan, Christina; Kulik, Carol T; Salinger, Dani

    2013-07-01

    This multi-method study investigated a sample of adult streetworkers (n = 107) in Melbourne, Australia in 2008. We contacted outdoor prostitutes through four "drop-in" centers run by not-for-profit organizations. Drug use was the over-riding common characteristic of most of these streetworkers. Using emotional labor theory as a theoretical framework, we hypothesized that individuals who worked on the streets solely to earn money to buy drugs would experience the highest levels of emotional exhaustion and the lowest levels of job satisfaction. We predicted these effects would be most evident for older drug dependent streetworkers. Content analysis of open-ended interview responses identified acting, age, and drug dependency as key themes. Moderator hierarchical regression analysis of responses to closed-ended questions with tests for mediation supported the hypotheses. It also demonstrated that older drug dependent streetworkers felt most trapped in their occupation and this sense of being locked-in was associated with emotional exhaustion but not with job satisfaction. The evidence that age and drug dependency affects the psychological outcomes associated with streetwork suggests that the efforts of police and the courts will be ineffective in dealing with people whose addiction traps them in an occupation that offers few intrinsic rewards. Decriminalization would encourage police to protect streetworkers from violence. Agencies could seek financial support to provide welfare and exit strategies.

  17. Support time-dependent transformations for surveying and GIS : current status and upcoming challenges

    Science.gov (United States)

    Mahmoudabadi, H.; Lercier, D.; Vielliard, S.; Mein, N.; Briggs, G.

    2016-12-01

    The support of time-dependent transformations for surveying and GIS is becoming a critical issue. We need to convert positions from the realizations of the International Terrestrial Reference Frame to any national reference frame. This problem is easy to solve when all of the required information is available. But it becomes really complicated in a worldwide context. We propose an overview of the current ITRF-aligned reference frames and we describe a global solution to support time-dependent transformations between them and the International Terrestrial Reference Frame. We focus on the uncertainties of station velocities used. In a first approximation, we use a global tectonic plate model to calculate point velocities. We show the impact of the velocity model on the coordinate accuracies. Several countries, particularly in active regions, are developing semi-dynamic reference frames. These frames include local displacement models updated regularly and/or after major events (such as earthquakes). Their integration into surveying or GIS applications is an upcoming challenge. We want to encourage the geodetic community to develop and use standard formats.

  18. Brief report: the influence of dissociative experiences and alcohol/drugs dependence on Internet addiction

    Directory of Open Access Journals (Sweden)

    Roberta Biolcati

    2017-05-01

    Full Text Available The main aim of this study is to investigate the influence of dissociative experiences and alcohol/drugs dependence on Internet addiction. From a clinical point of view Internet addiction, an excessive or poorly controlled preoccupation, urges, and/or behaviors regarding Internet use, lead to emotional and social problems in several life domains. Moreover, the increased prevalence of Internet addiction among adolescents and young adults is cause of concerns. Data was collected on 441 undergraduate students (285 female, aging from 18 to 36, using an assessment self-reporting set consisting of the Young’s Internet Addiction Test, the Leeds Dependence Questionnaire and the Dissociative Experience Scale. Results converging for the three psychological phenomena involved are interrelated, corroborating the hypothesis of the search for an altered state of consciousness as their common underlying mechanism. Findings show that the tendency to escape from reality, through dissociation and substance abuse, are risk factors for Internet addiction in youngsters. The implications of these results are discussed in a preventive and clinical perspective.

  19. On the Comparison of Interpersonal Sensitivity and Assertiveness between Drug-Dependent Persons and Ordinary People

    Directory of Open Access Journals (Sweden)

    Babak Vojudi

    2015-02-01

    Full Text Available Objective: The present study was aimed at comparing interpersonal sensitivity and assertiveness between drug-dependent persons and ordinary people. Method: The research method was causal-comparative. The statistical population of the study consisted of all narcotic addicts of Tabriz City who referred to Addiction Treatment Centers while the research was being conducted. The number of 30 addicted persons was selected through cluster sampling and 30 ordinary persons as control group through convenience sampling method. Gmbryl & Ritchie’s assertiveness questionnaire (1975 and Boyce & Parker’s Interpersonal Sensitivity Measure (IPSM 1989 were used for data collection purposes. Results: The results showed that there was a statistically significant difference between two groups in terms of interpersonal sensitivity and assertiveness. The addicts showed less assertiveness and more interpersonal sensitivity in comparison with their healthy counterparts. Conclusion: The findings show that people who are unable to express themselves and exert sensitivity in interpersonal relationships are more likely at high risk of substance dependence. However, it is possible to prevent these persons from turning to addiction by teaching them these skills.

  20. Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence.

    Science.gov (United States)

    Potenza, Marc N; Hong, Kwang-ik Adam; Lacadie, Cheryl M; Fulbright, Robert K; Tuit, Keri L; Sinha, Rajita

    2012-04-01

    Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.

  1. Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents

    International Nuclear Information System (INIS)

    Luo, Jialie; Li, Wenming; Liu, Yuwei; Zhang, Wei; Fu, Hongjun; Lee, Nelson T.K.; Yu, Hua; Pang, Yuanping; Huang, Pingbo; Xia, Jun; Li, Zhi-Wang; Li, Chaoying; Han, Yifan

    2007-01-01

    Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC 50 value increased from 0.19 ± 0.03 μM to 0.41 ± 0.04 μM. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia

  2. Inhibition of the cardiac ATP-dependent potassium current by KB-R7943.

    Science.gov (United States)

    Abramochkin, Denis V; Vornanen, Matti

    2014-09-01

    KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea) was developed as a specific inhibitor of the sarcolemmal sodium-calcium exchanger (NCX) with potential experimental and therapeutic use. However, in cardiomyocytes KB-R7943 also effectively blocks several K(+) currents including the delayed rectifier, IKr, and background inward rectifier, IK1. In the present study we analyze the effects of KB-R7943 on the ATP-dependent potassium current (IKATP) recorded by whole-cell patch-clamp in ventricular cardiomyocytes from a mammal (mouse) and a fish (crucian carp). IKATP was induced by external application of a mitochondrial uncoupler CCCP (3×10(-7) M) and internal perfusion of the cell with ATP-free pipette solution. A weakly inwardly rectifying current with a large outward component, recorded in the presence of CCCP, was blocked with 10(-5) M glibenclamide by 56.1±4.6% and 56.9±3.6% in crucian carp and mouse ventricular myocytes, respectively. In fish cardiomyocytes IKATP was blocked by KB-R7943 with an IC50 value of 3.14×10(-7) M, while in mammalian cells IC50 was 2.8×10(-6) M (PKB-R7943 inhibited CCCP-induced IKATP by 99.9±0.13% and 97.5±1.2% in crucian carp and mouse ventricular myocytes, respectively. In crucian carp the IKATP is about an order of magnitude more sensitive to KB-R7943 than the background IK1, but in mammals IKATP and IK1 are almost equally sensitive to KB-R7943. Therefore, the ability of KB-R7943 to block IKATP should be taken into account together with INCX inhibition when investigating possible cardioprotective effects of this compound. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. [The Necessity and the Current Status of Safe Handling of Anticancer Drugs].

    Science.gov (United States)

    Kanda, Kiyoko

    2017-07-01

    Number of people who handle anticancer drugs in their profession is increasing. Anticancer drugs, which are hazardous drugs(HD), exert cytocidal effects on cancer cells, but many have also been shown to have mutagenicity, teratogenicity and carcinogenicity; therefore, safe handling of anticancer drugs is necessary. In July 2015, the first Japanese guidelines for exposure control measures, namely, the "Joint Guidelines for Safe Handling of Cancer Chemotherapy Drugs", were published jointly by 3 societies. Our guideline is the creation of the Japanese Society of Cancer Nursing(JSCN), Japanese Society of Medical Oncology(JSMO)and Japanese Society of Pharmaceutical Oncology(JASPO)and has a historical significance. This paper states the necessity of safe handling of anticancer drugs, Japan's recent movement of safe handling, the introduction of joint guidelines of safe handling of anticancer drugs, and new movement of safe handling of USP chapter 800 in the United States.

  4. Ventral medial prefrontal cortex (vmPFC) as a target of the dorsolateral prefrontal modulation by transcranial direct current stimulation (tDCS) in drug addiction.

    Science.gov (United States)

    Nakamura-Palacios, Ester Miyuki; Lopes, Isabela Bittencourt Coutinho; Souza, Rodolpho Albuquerque; Klauss, Jaisa; Batista, Edson Kruger; Conti, Catarine Lima; Moscon, Janine Andrade; de Souza, Rodrigo Stênio Moll

    2016-10-01

    Here, we report some electrophysiologic and imaging effects of the transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (dlPFC) in drug addiction, notably in alcohol and crack-cocaine dependence. The low resolution electromagnetic tomography (LORETA) analysis obtained through event-related potentials (ERPs) under drug-related cues, more specifically in its P3 segment (300-500 ms) in both, alcoholics and crack-cocaine users, showed that the ventral medial prefrontal cortex (vmPFC) was the brain area with the largest change towards increasing activation under drug-related cues in those subjects that kept abstinence during and after the treatment with bilateral tDCS (2 mA, 35 cm(2), cathodal left and anodal right) over dlPFC, applied repetitively (five daily sessions). In an additional study in crack-cocaine, which showed craving decreases after repetitive bilateral tDCS, we examined data originating from diffusion tensor imaging (DTI), and we found increased DTI parameters in the left connection between vmPFC and nucleus accumbens (NAcc), such as the number of voxels, fractional anisotropy (FA) and apparent diffusion coefficient (ADC), in tDCS-treated crack-cocaine users when compared to the sham-tDCS group. This increasing of DTI parameters was significantly correlated with craving decreasing after the repetitive tDCS. The vmPFC relates to the control of drug seeking, possibly by extinguishing this behavior. In our studies, the bilateral dlPFC tDCS reduced relapses and craving to the drug use, and increased the vmPFC activation under drug cues, which may be of a great importance in the control of drug use in drug addiction.

  5. Timing of specimen collection is crucial in urine screening of drug dependent mothers and newborns.

    Science.gov (United States)

    Halstead, A C; Godolphin, W; Lockitch, G; Segal, S

    1988-01-01

    We compared results of urine drug analysis with clinical data and history to test the usefulness of peripartum drug screening and to establish guidelines for optimal testing. Urine from 28 mothers and 52 babies was analysed. Drugs not suspected by history were found in 10 mothers and six babies. Results assisted in the management of neonatal withdrawal in three babies. Drugs suspected by history were not found in 11/22 mothers and 23/35 babies. About half of these results were associated with delayed urine collection. In 12/28 mothers, drugs administered in hospital could have confused interpretation of screen results. We conclude that urine drug screening without strict protocols for specimen collection is of limited usefulness for management of drug abuse in pregnancy and neonatal drug withdrawal. We favour testing of maternal urine obtained before drugs are administered in hospital. Neonatal urine, if used, should be collected in the first day of life.

  6. Current trends for improving the design of membrane devices for photoautotrophic biosynthesis is light dependent microorganisms

    Directory of Open Access Journals (Sweden)

    A. A. Shevtsov

    2016-01-01

    Full Text Available Modern trends in improving the design of membrane devices for photoautotrophic biosynthesis dependent lighting microorganisms aimed at a significant increase in the productivity of valuable products from biomass of microalgae and obtaining on the basis of their individual useful substances (drugs used in various industries and medicine. In film devices effectively the processes of heat - and mass-exchange with the gas comes into contact with the culture fluid flowing as a film on a transparent film-forming surface is STI in its light intensity and autotrophic biosynthesis occurs only in the presence of a mixture of air with carbon dioxide. Thus, completely eliminated the accumulation of metabolic products due to their continuous removal from film culture liquid with the process gas, which is not typical for devices of other types. Small size membrane bioreactors may increase the degree of saturation of the liquid carbon dioxide with the possibility of changing the concentration of gas in the culture fluid and to ensure the cultivation of microorganisms with a specified biomass yield. At present up to date-developed a significant number of ways to ensure contact of the gas with the liquid (bubbling, gas-lift, mechanical stirring, jet, membrane, etc. on the basis of which an industrial bioreactor, with various "stress" effect. It is believed that for the cultivation of the most optimal are bioreactors with mechanical stirring of the liquid, which allow the greatest productivity of biomass. However, the applied model of a mechanical mixing device to create a work whose cavity of the bioreactor chaotic, disorganized mixing, which contributes to the emergence, insufficient for the sustenance of the cell cultures and microorganisms. Analysis of the interactions of the gas with the liquid film devices showed the need to create a new generation of bioreactor with intensive mass transfer without the possibility of limiting the productivity of

  7. Could a revision of the current guidelines for cancer drug use improve the quality of cancer treatment?

    Directory of Open Access Journals (Sweden)

    Lippert TH

    2014-01-01

    Full Text Available Theodor H Lippert,1 Hans-Jörg Ruoff,1 Manfred Volm2 1Medical Faculty, University of Tübingen, Tübingen, Germany; 2Medical Faculty, University of Heidelberg, Heidelberg, Germany Abstract: Clinical practice guidelines are indispensable for such a variable disease as malignant solid tumors, with the complex possibilities of drug treatment. The current guidelines may be criticized on several points, however. First, there is a lack of information on the outcome of treatment, such as the expected success and failure rates. Treating not only drug responders but also nonresponders, that is, patients with drug resistance, must result in failures. There is no mention of the possibility of excluding the drug nonresponders, identifiable by special laboratory tests and no consideration is given to the different side effects of the recommended drug regimens. Nor are there any instructions concerning tumor cases for which anticancer drug treatment is futile. In such cases, early palliative care may lead to significant improvements in both life quality and life expectancy. Not least, there is no transparency concerning the preparation of the guidelines: persons cannot be identified who could give a statement of conflicts of interest, and responsibility is assumed only by anonymous medical associations. A revision of the current guidelines could considerably improve cancer treatment. Keywords: anticancer drugs, quality of guidelines, critical remarks

  8. Relationships between self-reported unfair treatment and prescription medication use, illicit drug use, and alcohol dependence among Filipino Americans.

    Science.gov (United States)

    Gee, Gilbert C; Delva, Jorge; Takeuchi, David T

    2007-05-01

    We examined associations between self-reported unfair treatment and prescription medication use, illicit drug use, and alcohol dependence. We used data from the Filipino American Community Epidemiological Survey, a cross-sectional investigation involving 2217 Filipino Americans interviewed in 1998-1999. Multinomial logistic and negative binomial regression analyses were used in assessing associations between unfair treatment and the substance use categories. Reports of unfair treatment were associated with prescription drug use, illicit drug use, and alcohol dependence after control for age, gender, location of residence, employment status, educational level, ethnic identity level, nativity, language spoken, marital status, and several health conditions. Unfair treatment may contribute to illness and subsequent use of prescription medications. Furthermore, some individuals may use illicit drugs and alcohol to cope with the stress associated with such treatment. Addressing the antecedents of unfair treatment may be a potential intervention route.

  9. The Predictive Role of Difficulties in Emotion Regulation and Self-Control with Susceptibility to Addiction in Drug-Dependent Individuals

    Directory of Open Access Journals (Sweden)

    Mahmoud Shirazi

    2015-06-01

    Full Text Available Objective: The present study aimed to examine the predictive role of difficulties in emotion regulation and self-control in potential for addiction among drug-dependent individuals. Method: This was a correlational study which falls within the category of descriptive studies. The statistical population of the current study included all patients under treatment in outpatient health centers in Bam, among whom 315 individuals were selected through cluster sampling method as the participants of the study. Difficulties in Emotion Regulation Scale, Self-Control Scale, and Addiction Susceptibility Questionnaire were used for data collection purposes. Results: The results indicated that difficulties engaging in goal directed behavior, impulse control difficulties, lack of emotional awareness, and lack of emotional clarity (dimensions of difficulties in emotion regulation had a significant positive correlation with potential for addiction. In addition, there was a negative significant relationship between self-control and potential for addiction among drug-dependent individuals. Conclusion: In addition to common methods of abstinence from drug dependence, teaching self-control and emotional control techniques to addicted patients can help them reduce their dependence.

  10. Use of toxicogenomics in drug safety evaluation: Current status and an industry perspective.

    Science.gov (United States)

    Vahle, John L; Anderson, Ulf; Blomme, Eric A G; Hoflack, Jean-Christophe; Stiehl, Daniel P

    2018-04-18

    Toxicogenomics held great promise as an approach to enable early detection of toxicities induced by xenobiotics; however, there remain questions regarding the impact of the discipline on pharmaceutical nonclinical safety assessment. To understand the current state of toxicogenomics in the sector, an industry group surveyed companies to determine the frequency of toxicogenomics use in in vivo studies at various stages of drug discovery and development and to assess how toxicogenomics use has evolved over time. Survey data were compiled during 2016 from thirteen pharmaceutical companies. Toxicogenomic analyses were infrequently conducted in the development phase and when performed were done to address specific mechanistic questions. Prior to development, toxicogenomics use was more frequent; however, there were significant differences in approaches among companies. Across all phases, gaining mechanistic insight was the most frequent reason cited for pursing toxicogenomics with few companies using toxicogenomics to predict toxicities. These data were consistent with the commentary submitted in response to survey questions asking companies to describe the evolution of their toxicogenomics strategy. Overall, these survey data indicate that toxicogenomics is not widely used as a predictive tool in the pharmaceutical industry but is used regularly by some companies and serves a broader role in mechanistic investigations and as a complement to other technologies. Copyright © 2018. Published by Elsevier Inc.

  11. Currently used and investigational drugs for Cushing´s disease.

    Science.gov (United States)

    Ciato, Denis; Mumbach, Aizhar G; Paez-Pereda, Marcelo; Stalla, Günter K

    2017-01-01

    Cushing's disease (CD) is caused by a corticotroph adenoma of the pituitary gland that secretes excess adrenocorticotropic hormone (ACTH) causing increased morbidity and mortality. Surgery is the treatment of choice, but is not always successful. Alternatives include radiotherapy, adrenal surgery, and pharmaceutical therapy. The latter is increasingly gaining momentum due to the recent development of compounds that reduce hypercortisolaemia or its symptoms, acting through different mechanisms. Areas covered: In this article, the authors provide a complete overview of the treatment options for Cushing´s disease, including adrenal-directed, tumor-targeted, and peripheral therapies that are currently used or in development, and discuss their potential advantages and limitations. Expert opinion: Considering the lack of long-term remission in up to half of the patients after surgery, and the delayed response to radiotherapy along with potential side effects, there is a strong need for an effective pharmaceutical treatment. Pasireotide, mifepristone, ketoconazole and metyrapone have been approved by regulatory authorities but their use remains limited due to considerable costs and side effects. Research in this field has focused recently on the improvement of pre-existing drugs and the development of safe new ones. However, few approaches aim at targeting the source of the disease, the ACTH-secreting adenoma.

  12. Implications of central immune signaling caused by drugs of abuse: mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence.

    Science.gov (United States)

    Coller, Janet K; Hutchinson, Mark R

    2012-05-01

    In the past two decades a trickle of manuscripts examining the non-neuronal central nervous system immune consequences of the drugs of abuse has now swollen to a significant body of work. Initially, these studies reported associative evidence of central nervous system proinflammation resulting from exposure to the drugs of abuse demonstrating key implications for neurotoxicity and disease progression associated with, for example, HIV infection. However, more recently this drug-induced activation of central immune signaling is now understood to contribute substantially to the pharmacodynamic actions of the drugs of abuse, by enhancing the engagement of classical mesolimbic dopamine reward pathways and withdrawal centers. This review will highlight the key in vivo animal, human, biological and molecular evidence of these central immune signaling actions of opioids, alcohol, cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). Excitingly, this new appreciation of central immune signaling activity of drugs of abuse provides novel therapeutic interventions and opportunities to identify 'at risk' individuals through the use of immunogenetics. Discussion will also cover the evidence of modulation of this signaling by existing clinical and pre-clinical drug candidates, and novel pharmacological targets. Finally, following examination of the breadth of central immune signaling actions of the drugs of abuse highlighted here, the current known common immune signaling components will be outlined and their impact on established addiction neurocircuitry discussed, thereby synthesizing a common neuroimmune hypothesis of addiction. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    International Nuclear Information System (INIS)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

    2013-01-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

  14. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    Energy Technology Data Exchange (ETDEWEB)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

    2013-12-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na{sub v}1.5 sodium and Ca{sub v}1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on

  15. Role of the activation gate in determining the extracellular potassium dependency of block of HERG by trapped drugs.

    Science.gov (United States)

    Pareja, Kristeen; Chu, Elaine; Dodyk, Katrina; Richter, Kristofer; Miller, Alan

    2013-01-01

    Drug induced long QT syndrome (diLQTS) results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases long QT syndrome can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with serum potassium abnormalities due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, and aging. Extracellular potassium influences HERG channel inactivation and can alter block of HERG by some drugs. However, block of HERG by a number of drugs is not sensitive to extracellular potassium. In this study, we show that block of WT HERG by bepridil and terfenadine, two drugs previously shown to be trapped inside the HERG channel after the channel closes, is insensitive to extracellular potassium over the range of 0 mM to 20 mM. We also show that bepridil block of the HERG mutant D540K, a mutant channel that is unable to trap drugs, is dependent on extracellular potassium, correlates with the permeant ion, and is independent of HERG inactivation. These results suggest that the lack of extracellular potassium dependency of block of HERG by some drugs may in part be related to the ability of these drugs to be trapped inside the channel after the channel closes.

  16. Current status and future prospects for enabling chemistry technology in the drug discovery process.

    Science.gov (United States)

    Djuric, Stevan W; Hutchins, Charles W; Talaty, Nari N

    2016-01-01

    This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of "dangerous" reagents. Also featured are advances in the "computer-assisted drug design" area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities.

  17. Current status and future prospects for enabling chemistry technology in the drug discovery process

    Science.gov (United States)

    Djuric, Stevan W.; Hutchins, Charles W.; Talaty, Nari N.

    2016-01-01

    This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of “dangerous” reagents. Also featured are advances in the “computer-assisted drug design” area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities. PMID:27781094

  18. Classification of prophylactic antiradiation drugs as the consistency of conceptual basis of current radiation pharmacology

    International Nuclear Information System (INIS)

    Vasin, M.F

    1999-01-01

    The consistency of the classification of prophylactic antiradiation drugs have been given consideration as history of their discovery, theory of the radioprotection mechanisms and their use in applied medicine. Prophylactic drugs consists of radioprotectors with short-term of long-term action, drugs stimulating radioresistance, the ones suppressing symptoms of primary radiation reaction, the ones of early detoxication, the ones for adsorption and elimination of radionuclides from an organism [ru

  19. A dependence of quasielastic charged-current neutrino-nucleus cross sections

    Science.gov (United States)

    Van Dessel, N.; Jachowicz, N.; González-Jiménez, R.; Pandey, V.; Van Cuyck, T.

    2018-04-01

    Background: 12C has been and is still widely used in neutrino-nucleus scattering and oscillation experiments. More recently, 40Ar has emerged as an important nuclear target for current and future experiments. Liquid argon time projection chambers (LArTPCs) possess various advantages in measuring electroweak neutrino-nucleus cross sections. Concurrent theoretical research is an evident necessity. Purpose: 40Ar is larger than 12C , and one expects nuclear effects to play a bigger role in reactions. We present inclusive differential and total cross section results for charged-current neutrino scattering on 40Ar and perform a comparison with 12C , 16O , and 56Fe targets, to find out about the A -dependent behavior of model predictions. Method: Our model starts off with a Hartree-Fock description of the nucleus, with the nucleons interacting through a mean field generated by an effective Skyrme force. Long-range correlations are introduced by means of a continuum random phase approximation approach. Further methods to improve the accuracy of model predictions are also incorporated in the calculations. Results: We present calculations for 12C , 16O , 40Ar , and 56Fe , showcasing differential cross sections over a broad range of kinematic values in the quasielastic regime. We furthermore show flux-folded results for 40Ar and we discuss the differences between nuclear responses. Conclusions: At low incoming energies and forward scattering we identify an enhancement in the 40Ar cross section compared to 12C , as well as in the high ω (low Tμ) region across the entire studied Eν range. The contribution to the folded cross section of the reaction strength at values of ω lower than 50 MeV for forward scattering is sizable.

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

    NARCIS (Netherlands)

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

    2017-01-01

    textabstractRationale: Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by

  1. Sex differences and ovarian hormones in animal models of drug dependence.

    Science.gov (United States)

    Carroll, Marilyn E; Anker, Justin J

    2010-06-01

    Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies. Copyright 2009. Published by Elsevier Inc.

  2. La vivencia de la dependencia en un consumidor de drogas psicoactivas The experience of the dependence to a psychoactive drug in a consumer drug

    Directory of Open Access Journals (Sweden)

    Liliana Basso Musso

    2011-06-01

    Full Text Available Investigación cualitativa, de trayectoria fenomenológica, siguiendo el referencial sociológico de Schutz, cuyo objetivo es conocer la vivencia del fenómeno de la dependencia o adicción, en un consumidor de drogas psicoactivas en tratamiento en un Centro Abierto, teniendo como base las siguientes preguntas orientadoras: ¿Cómo se inició la experiencia de consumo de drogas? ¿Cuáles fueron los motivos para consumir drogas? ¿Cómo se va instalando la dependencia a ellas? ¿Cómo se dio cuenta que se había hecho dependiente a la droga? En el discurso de los consumidores se identificaron siete categorías del referencial de Shutz, que muestran aspectos significativos de la vivencia. Al analizarlas se pudo comprender al tipo vivido del consumidor de drogas psicoactivas que presenta adicción y el entendimiento de los motivos existenciales que influyeron en la instalación de esta dependencia, profundizándose así el conocimiento del fenómeno, lo que permitirá otorgarles un mejor cuidado.Qualitative, phenomenological research following Schutz, referential sociological, whose objective is to know the experience of the phenomenon of dependence or addiction to a consumer of drugs in treatment in an open centre, based on the following questions guide path: How do you start drug experience? What were the reasons for drug use? You how is it installing dependence to them? How gave account which had become dependent drug? The speech of consumers identified seven categories Schutz, referential, that showing significant aspects of the experience. To analyze them lived type drugs featuring addiction and understanding of the existential reasons that influenced the installation of this dependency, deepening the understanding of the phenomenon, thereby granting consumer could understand better care.

  3. Cell cycle-dependent regulation of kainate-induced inward currents in microglia

    International Nuclear Information System (INIS)

    Yamada, Jun; Sawada, Makoto; Nakanishi, Hiroshi

    2006-01-01

    Microglia are reported to have α-amino-hydroxy-5-methyl-isoxazole-4-propionate/kainate (KA) types. However, only small population of primary cultured rat microglia (approximately 20%) responded to KA. In the present study, we have attempted to elucidate the regulatory mechanism of responsiveness to KA in GMIR1 rat microglial cell line. When the GMIR1 cells were plated at a low density in the presence of granulocyte macrophage colony-stimulating factor, the proliferation rate increased and reached the peak after 2 days in culture and then gradually decreased because of density-dependent inhibition. At cell proliferation stage, approximately 80% of the GMIR1 cells exhibited glutamate (Glu)- and KA-induced inward currents at cell proliferation stage, whereas only 22.5% of the cells showed responsiveness to Glu and KA at cell quiescent stage. Furthermore, the mean amplitudes of inward currents induced by Glu and KA at cell proliferation stage (13.8 ± 3.0 and 8.4 ± 0.6 pA) were significantly larger than those obtained at cell quiescent stage (4.7 ± 0.8 and 6.2 ± 1.2 pA). In the GMIR1 cells, KA-induced inward currents were markedly inhibited by (RS)-3-(2-carboxybenzyl) willardiine (UBP296), a selective antagonist for KA receptors. The KA-responsive cells also responded to (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist for GluR5, in both GMIR1 cells and primary cultured rat microglia. Furthermore, mRNA levels of the KA receptor subunits, GluR5 and GluR6, at the cell proliferation stage were significantly higher than those at the cell quiescent stage. Furthermore, the immunoreactivity for GluR6/7 was found to increase in activated microglia in the post-ischemic hippocampus. These results strongly suggest that microglia have functional KA receptors mainly consisting of GluR5 and GluR6, and the expression levels of these subunits are closely regulated by the cell cycle mechanism

  4. Impaired Inactivation of L-Type Ca2+ Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K+ Channel Blocking Drugs.

    Directory of Open Access Journals (Sweden)

    Jae Gon Kim

    Full Text Available The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD prolongation that involves increase in late L-type Ca2+ current (ICaL caused by a decrease in Ca2+-dependent inactivation (CDI. Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies.

  5. Dependence of the colored frequency noise in spin torque oscillators on current and magnetic field

    Science.gov (United States)

    Eklund, Anders; Bonetti, Stefano; Sani, Sohrab R.; Majid Mohseni, S.; Persson, Johan; Chung, Sunjae; Amir Hossein Banuazizi, S.; Iacocca, Ezio; Östling, Mikael; Åkerman, Johan; Gunnar Malm, B.

    2014-03-01

    The nano-scale spin torque oscillator (STO) is a compelling device for on-chip, highly tunable microwave frequency signal generation. Currently, one of the most important challenges for the STO is to increase its longer-time frequency stability by decreasing the 1/f frequency noise, but its high level makes even its measurement impossible using the phase noise mode of spectrum analyzers. Here, we present a custom made time-domain measurement system with 150 MHz measurement bandwidth making possible the investigation of the variation of the 1/f as well as the white frequency noise in a STO over a large set of operating points covering 18-25 GHz. The 1/f level is found to be highly dependent on the oscillation amplitude-frequency non-linearity and the vicinity of unexcited oscillation modes. These findings elucidate the need for a quantitative theoretical treatment of the low-frequency, colored frequency noise in STOs. Based on the results, we suggest that the 1/f frequency noise possibly can be decreased by improving the microstructural quality of the metallic thin films.

  6. Dependence of the colored frequency noise in spin torque oscillators on current and magnetic field

    International Nuclear Information System (INIS)

    Eklund, Anders; Sani, Sohrab R.; Chung, Sunjae; Amir Hossein Banuazizi, S.; Östling, Mikael; Gunnar Malm, B.; Bonetti, Stefano; Majid Mohseni, S.; Persson, Johan; Iacocca, Ezio; Åkerman, Johan

    2014-01-01

    The nano-scale spin torque oscillator (STO) is a compelling device for on-chip, highly tunable microwave frequency signal generation. Currently, one of the most important challenges for the STO is to increase its longer-time frequency stability by decreasing the 1/f frequency noise, but its high level makes even its measurement impossible using the phase noise mode of spectrum analyzers. Here, we present a custom made time-domain measurement system with 150 MHz measurement bandwidth making possible the investigation of the variation of the 1/f as well as the white frequency noise in a STO over a large set of operating points covering 18–25 GHz. The 1/f level is found to be highly dependent on the oscillation amplitude-frequency non-linearity and the vicinity of unexcited oscillation modes. These findings elucidate the need for a quantitative theoretical treatment of the low-frequency, colored frequency noise in STOs. Based on the results, we suggest that the 1/f frequency noise possibly can be decreased by improving the microstructural quality of the metallic thin films

  7. Dependence of the DIII-D beta limit on the current profile

    Energy Technology Data Exchange (ETDEWEB)

    Strait, E.J.; Chu, M.S.; Ferron, J.R.; Lao, L.L.; Osborne, T.H.; Taylor, T.S.; Turnbull, A.D. (General Atomics, San Diego, CA (United States)); Lazarus, E.A. (Oak Ridge National Lab., TN (United States))

    1991-01-01

    The maximum beta values achieved in DIII-D are not fully described by the simple scaling law [beta][sub max][proportional to]I/aB. There is, in addition, a dependence on the form of the current profile as parameterized by the safety factor q and internal inductance l[sub i]. The maximum experimentally achieved value of normalized beta [beta][sub N] = [beta]/(I/aB) varies from 3.5 at low safety factor q (q[sub 95]<3) to 5 at higher values of q. At low q, discharges are terminated by disruptions at high [beta][sub N] and at both the low and high l[sub i] boundaries of the stable range. These disruptions are attributed to external and global kink modes. At higher q, such disruptions are much less frequent, and beta is limited by slowly growing resistive modes, fishbones, and possibly by ballooning modes. At each value of q, the maximum beta tends to increase with internal inductance l[sub i]. A numerical study of kink mode stability has shown a similar trend for optimized pressure profiles. These observations have suggested a new scaling law for the operational beta limit: [beta][sub max]=4l[sub i](I/aB), which fits the DIII-D data well. (author) 13 refs., 4 figs.

  8. Could a revision of the current guidelines for cancer drug use improve the quality of cancer treatment?

    Science.gov (United States)

    Lippert, Theodor H; Ruoff, Hans-Jörg; Volm, Manfred

    2014-01-01

    Clinical practice guidelines are indispensable for such a variable disease as malignant solid tumors, with the complex possibilities of drug treatment. The current guidelines may be criticized on several points, however. First, there is a lack of information on the outcome of treatment, such as the expected success and failure rates. Treating not only drug responders but also nonresponders, that is, patients with drug resistance, must result in failures. There is no mention of the possibility of excluding the drug nonresponders, identifiable by special laboratory tests and no consideration is given to the different side effects of the recommended drug regimens. Nor are there any instructions concerning tumor cases for which anticancer drug treatment is futile. In such cases, early palliative care may lead to significant improvements in both life quality and life expectancy. Not least, there is no transparency concerning the preparation of the guidelines: persons cannot be identified who could give a statement of conflicts of interest, and responsibility is assumed only by anonymous medical associations. A revision of the current guidelines could considerably improve cancer treatment.

  9. Disease-modifying antirheumatic drugs in pregnancy - Current status and implications for the future

    NARCIS (Netherlands)

    Vroom, Fokaline; de Walle, Hermien E. K.; van de Laar, Mart A. J. F.; Brouwers, Jacobus R. B. J.; de Jong-van den Berg, Lolkje T. W.

    2006-01-01

    Drug use during pregnancy is sometimes unavoidable, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). The use of disease-modifying antirheumatic drugs (DMARDs) often starts in the early stage of RA; therefore, women of reproductive age are at risk for exposure to a DMARD

  10. Valuation of Drug Abuse: A Review of Current Methodologies and Implications for Policy Making

    Science.gov (United States)

    Schori, Maayan

    2011-01-01

    This article reviews the use of several valuation methods as they relate to drug abuse and places them within the context of U.S. policy. First, cost-of-illness (COI) studies are reviewed and their limitations discussed. Second, three additional economic methods of valuing drug abuse are reviewed, including cost-effectiveness analysis (CEA),…

  11. What the History of Drugs Can Teach Us About the Current Cannabis Legalization Process: Unfinished Business.

    Science.gov (United States)

    Adrian, Manuella

    2015-01-01

    Over time, there have been considerable changes in the variety, availability, production, distribution, and use and user(s) of psychoactive substances, the meaning of substance use and its impact on users and their social or physical environment(s). This article reviews the mechanisms of introduction of psychoactive substances such as alcohol, tobacco, coffee, tea and cannabis to populations and communities that did not have them before. It considers the historical tension between early adopters who greet new substances with various levels of enthusiasm in their eagerness to enjoy what they believe to be the benefits of using these substances, and those focused on what they believe to be the negative aspects of use, who decry these new substances with horror. With more nonusers than users in the population, social policies tend to be directed at preventing, restricting, or punishing selected use, users and .drugs., using controls and interventions such regulation, incarceration, death sentence, treatment, prevention, legalization, taxation, among others. Whatever their intent or wished-for impact, all had consequences that produced additional, unplanned for, and (often) negative effects. This paper will consider some of these sequences as they occurred historically with other substances in light of the current shift to legalization and normalization of cannabis, noting the mechanisms of use, controls, and consequences of some types of formal interventions and give some attention to how and what we can learn from our experiences in order to plan ahead and become better prepared to successfully deal with the 'unexpecteds' of that well-known 'hell' paved with good intentions.

  12. Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

    Science.gov (United States)

    Ioset, Jean-Robert; Chang, Shing

    2011-09-01

    The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

  13. Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation.

    Science.gov (United States)

    Voigt, Niels; Heijman, Jordi; Trausch, Anne; Mintert-Jancke, Elisa; Pott, Lutz; Ravens, Ursula; Dobrev, Dobromir

    2013-08-01

    Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Can Brazil play a more important role in global tuberculosis drug production? An assessment of current capacity and challenges.

    Science.gov (United States)

    Gemal, Andre; Keravec, Joel; Menezes, Alexandre; Trajman, Anete

    2013-03-27

    Despite the existence of effective treatment, tuberculosis is still a global public health issue. The World Health Organization recommends a six-month four-drug regimen in fixed-dose combination formulation to treat drug sensitive tuberculosis, and long course regimens with several second-line drugs to treat multi-drug resistant tuberculosis. To achieve the projected tuberculosis elimination goal by 2050, it will be essential to ensure a non-interrupted supply of quality-assured tuberculosis drugs. However, quality and affordable tuberculosis drug supply is still a significant challenge for National Tuberculosis Programs. Quality drug production requires a combination of complex steps. The first challenge is to guarantee the quality of tuberculosis active pharmaceutical ingredients, then ensure an adequate manufacturing process, according to international standards, to guarantee final product's safety, efficacy and quality. Good practices for storage, transport, distribution and quality control procedures must follow. In contrast to other high-burden countries, Brazil produces tuberculosis drugs through a strong network of public sector drug manufacturers regulated by a World Health Organization-certified national sanitary authority. The installed capacity for production surpasses the 71,000 needed treatments in the country. However, in order to be prepared to act as a global supplier, important bottlenecks are to be overcome. This article presents an in-depth analysis of the current status of production of tuberculosis drugs in Brazil and the bottlenecks and opportunities for the country to sustain national demand and play a role as a potential global supplier. Raw material and drug production, quality control, international certification and pre-qualification, political commitment and regulatory aspects are discussed, as well recommendations for tackling these bottlenecks. This discussion becomes more important as new drugs and regimens to treat tuberculosis are

  15. Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.

    Science.gov (United States)

    Kitamura, Shigeyuki; Sugihara, Kazumi

    2014-01-01

    1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

  16. A cyclic GMP-dependent calcium-activated chloride current in smooth-muscle cells from rat mesenteric resistance arteries

    DEFF Research Database (Denmark)

    Matchkov, Vladimir; Aalkjær, Christian; Nilsson, Holger

    2004-01-01

    We have previously demonstrated the presence of a cyclic GMP (cGMP)-dependent calcium-activated inward current in vascular smooth-muscle cells, and suggested this to be of importance in synchronizing smooth-muscle contraction. Here we demonstrate the characteristics of this current. Using......M) in the pipette solution. The current was found to be a calcium-activated chloride current with an absolute requirement for cyclic GMP (EC50 6.4 microM). The current could be activated by the constitutively active subunit of PKG. Current activation was blocked by the protein kinase G antagonist Rp-8-Br-PET-cGMP...... differed from those of the calcium-activated chloride current in pulmonary myocytes, which was cGMP-independent, exhibited a high sensitivity to inhibition by niflumic acid, was unaffected by zinc ions, and showed outward current rectification as has previously been reported for this current. Under...

  17. Transport current dependence of the hysteresis loss in silver sheathed BSCOO-2212 conductors

    NARCIS (Netherlands)

    Hemmes, Herman K.; Woudstra, Martin J.; ten Kate, Herman H.J.; Tenbrink, Johannes

    1994-01-01

    A technique is described to study the critical current density and penetration fieldassociated with the transport current in a silver sheathed BSCCO conductor. A transport current flowing in a conductor in a varying magnetic field will only influence magnetisation currents that are in competition

  18. A dose-dependent relationship between exposure to a street-based drug scene and health-related harms among people who use injection drugs.

    Science.gov (United States)

    Debeck, Kora; Wood, Evan; Zhang, Ruth; Buxton, Jane; Montaner, Julio; Kerr, Thomas

    2011-08-01

    While the community impacts of drug-related street disorder have been well described, lesser attention has been given to the potential health and social implications of drug scene exposure on street-involved people who use illicit drugs. Therefore, we sought to assess the impacts of exposure to a street-based drug scene among injection drug users (IDU) in a Canadian setting. Data were derived from a prospective cohort study known as the Vancouver Injection Drug Users Study. Four categories of drug scene exposure were defined based on the numbers of hours spent on the street each day. Three generalized estimating equation (GEE) logistic regression models were constructed to identify factors associated with varying levels of drug scene exposure (2-6, 6-15, over 15 hours) during the period of December 2005 to March 2009. Among our sample of 1,486 IDU, at baseline, a total of 314 (21%) fit the criteria for high drug scene exposure (>15 hours per day). In multivariate GEE analysis, factors significantly and independently associated with high exposure included: unstable housing (adjusted odds ratio [AOR] = 9.50; 95% confidence interval [CI], 6.36-14.20); daily crack use (AOR = 2.70; 95% CI, 2.07-3.52); encounters with police (AOR = 2.11; 95% CI, 1.62-2.75); and being a victim of violence (AOR = 1.49; 95 % CI, 1.14-1.95). Regular employment (AOR = 0.50; 95% CI, 0.38-0.65), and engagement with addiction treatment (AOR = 0.58; 95% CI, 0.45-0.75) were negatively associated with high exposure. Our findings indicate that drug scene exposure is associated with markers of vulnerability and higher intensity addiction. Intensity of drug scene exposure was associated with indicators of vulnerability to harm in a dose-dependent fashion. These findings highlight opportunities for policy interventions to address exposure to street disorder in the areas of employment, housing, and addiction treatment.

  19. Toward the virtual screening of potential drugs in the homology modeled NAD+ dependent DNA ligase from Mycobacterium tuberculosis.

    Science.gov (United States)

    Singh, Vijai; Somvanshi, Pallavi

    2010-02-01

    DNA ligase is an important enzyme and it plays vital role in the replication and repair; also catalyzes nick joining between adjacent bases of DNA. The NAD(+) dependent DNA ligase is selectively present in eubacteria and few viruses; but missing in humans. Homology modeling was used to generate 3-D structure of NAD(+) dependent DNA ligase (LigA) of Mycobacterium tuberculosis using the known template (PDB: 2OWO). Furthermore, the stereochemical quality and torsion angle of 3-D structure was validated. Numerous effective drugs were selected and the active amino acid residue in LigA was targeted and virtual screening through molecular docking was done. In this analysis, four drugs Chloroquine, Hydroxychloroquine, Putrienscine and Adriamycin were found more potent in inhibition of M. tuberculosis through the robust binding affinity between protein-drug interactions in comparison with the other studied drugs. A phylogenetic tree was constructed and it was observed that homology of LigA in M. tuberculosis resembled with other Mycobacterium species. The conserved active amino acids of LigA may be useful to target these drugs. These findings could be used as the starting point of a rational design of novel antibacterial drugs and its analogs.

  20. Effects of gamma irradiation on voltage-dependant NA+ and K+ currents in N1E-115 cells

    International Nuclear Information System (INIS)

    Diserbo, M.; Barbier, M.; Quignard, J.F.

    1998-01-01

    Effects of 15 Gy gamma irradiation on voltage-dependent Na + and K + currents in differentiated N1E-115 cells are studied by using whole cell recording. Only, we observed an activation of Na + currents at a lower threshold. (authors)

  1. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

    Science.gov (United States)

    Hussaarts, Leonie; Mühlebach, Stefan; Shah, Vinod P; McNeil, Scott; Borchard, Gerrit; Flühmann, Beat; Weinstein, Vera; Neervannan, Sesha; Griffiths, Elwyn; Jiang, Wenlei; Wolff-Holz, Elena; Crommelin, Daan J A; de Vlieger, Jon S B

    2017-11-01

    Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

  2. Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

    Science.gov (United States)

    Ryall, Karen A; Shin, Jimin; Yoo, Minjae; Hinz, Trista K; Kim, Jihye; Kang, Jaewoo; Heasley, Lynn E; Tan, Aik Choon

    2015-12-01

    Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/. aikchoon.tan@ucdenver.edu. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Time-dependent density-functional theory simulation of local currents in pristine and single-defect zigzag graphene nanoribbons

    Energy Technology Data Exchange (ETDEWEB)

    He, Shenglai, E-mail: shenglai.he@vanderbilt.edu; Russakoff, Arthur; Li, Yonghui; Varga, Kálmán, E-mail: kalman.varga@vanderbilt.edu [Department of Physics and Astronomy, Vanderbilt University, Nashville, Tennessee 37235 (United States)

    2016-07-21

    The spatial current distribution in H-terminated zigzag graphene nanoribbons (ZGNRs) under electrical bias is investigated using time-dependent density-functional theory solved on a real-space grid. A projected complex absorbing potential is used to minimize the effect of reflection at simulation cell boundary. The calculations show that the current flows mainly along the edge atoms in the hydrogen terminated pristine ZGNRs. When a vacancy is introduced to the ZGNRs, loop currents emerge at the ribbon edge due to electrons hopping between carbon atoms of the same sublattice. The loop currents hinder the flow of the edge current, explaining the poor electric conductance observed in recent experiments.

  4. African medicinal plants and their derivatives: Current efforts towards potential anti-cancer drugs.

    Science.gov (United States)

    Mbele, Mzwandile; Hull, Rodney; Dlamini, Zodwa

    2017-10-01

    Cancer is a leading cause of mortality and morbidity worldwide and second only to cardiovascular diseases. Cancer is a challenge in African countries because generally there is limited funding available to deal with the cancer epidemic and awareness and this should be prioritised and all possible resources should be utilized to prevent and treat cancer. The current review reports on the role of African medicinal plants in the treatment of cancer, and also outlines methodologies that can also be used to achieve better outcomes for cancer treatment. This review outlines African medicinal plants, isolated compounds and technologies that can be used to advance cancer research. Chemical structures of isolated compounds have an important role in anti-cancer treatments; new technologies and methods may assist to identify more properties of African medicinal plants and the treatment of cancer. In conclusion, African medicinal plants have shown their potential as enormous resources for novel cytotoxicity compounds. Finally it has been noted that the cytotoxicity depends on the chemical structural arrangements of African medicinal plants compounds. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Scale dependency of regional climate modeling of current and future climate extremes in Germany

    Science.gov (United States)

    Tölle, Merja H.; Schefczyk, Lukas; Gutjahr, Oliver

    2017-11-01

    A warmer climate is projected for mid-Europe, with less precipitation in summer, but with intensified extremes of precipitation and near-surface temperature. However, the extent and magnitude of such changes are associated with creditable uncertainty because of the limitations of model resolution and parameterizations. Here, we present the results of convection-permitting regional climate model simulations for Germany integrated with the COSMO-CLM using a horizontal grid spacing of 1.3 km, and additional 4.5- and 7-km simulations with convection parameterized. Of particular interest is how the temperature and precipitation fields and their extremes depend on the horizontal resolution for current and future climate conditions. The spatial variability of precipitation increases with resolution because of more realistic orography and physical parameterizations, but values are overestimated in summer and over mountain ridges in all simulations compared to observations. The spatial variability of temperature is improved at a resolution of 1.3 km, but the results are cold-biased, especially in summer. The increase in resolution from 7/4.5 km to 1.3 km is accompanied by less future warming in summer by 1 ∘C. Modeled future precipitation extremes will be more severe, and temperature extremes will not exclusively increase with higher resolution. Although the differences between the resolutions considered (7/4.5 km and 1.3 km) are small, we find that the differences in the changes in extremes are large. High-resolution simulations require further studies, with effective parameterizations and tunings for different topographic regions. Impact models and assessment studies may benefit from such high-resolution model results, but should account for the impact of model resolution on model processes and climate change.

  6. Current uses of ground penetrating radar in groundwater-dependent ecosystems research.

    Science.gov (United States)

    Paz, Catarina; Alcalá, Francisco J; Carvalho, Jorge M; Ribeiro, Luís

    2017-10-01

    Ground penetrating radar (GPR) is a high-resolution technique widely used in shallow groundwater prospecting. This makes GPR ideal to characterize the hydrogeological functioning of groundwater-dependent ecosystems (GDE). This paper reviews current uses of GPR in GDE research through the construction of a database comprising 91 worldwide GPR case studies selected from the literature and classified according to (1) geological environments favouring GDE; (2) hydrogeological research interests; and (3) field technical and (4) hydrogeological conditions of the survey. The database analysis showed that inland alluvial, colluvial, and glacial formations were the most widely covered geological environments. Water-table depth was the most repeated research interest. By contrast, weathered-marl and crystalline-rock environments as well as the delineation of salinity interfaces in coastal and inland areas were less studied. Despite that shallow groundwater propitiated GDE in almost all the GPR case studies compiled, only one case expressly addressed GDE research. Common ranges of prospecting depth, water-table depth, and volumetric water content deduced by GPR and other techniques were identified. Antenna frequency of 100MHz and the common offset acquisition technique predominated in the database. Most of GPR case studies were in 30-50° N temperate latitudes, mainly in Europe and North America. Eight original radargrams were selected from several GPR profiles performed in 2014 and 2015 to document database classes and identified gaps, as well as to define experimental ranges of operability in GDE environments. The results contribute to the design of proper GPR surveys in GDE research. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. The Effect of Group Therapy With Transactional Analysis Approach on Emotional Intelligence, Executive Functions and Drug Dependency.

    Science.gov (United States)

    Forghani, Masoomeh; Ghanbari Hashem Abadi, Bahram Ali

    2016-06-01

    The aim of the present study was to evaluate the effect of group psychotherapy with transactional analysis (TA) approach on emotional intelligence (EI), executive functions and substance dependency among drug-addicts at rehabilitation centers in Mashhad city, Iran, in 2013. In this quasi-experimental study with pretest, posttest, case- control stages, 30 patients were selected from a rehabilitation center and randomly divided into two groups. The case group received 12 sessions of group psychotherapy with transactional analysis approach. Then the effects of independent variable (group psychotherapy with TA approach) on EI, executive function and drug dependency were assessed. The Bar-on test was used for EI, Stroop test for measuring executive function and morphine test, meth-amphetamines and B2 test for evaluating drug dependency. Data were analyzed using multifactorial covariance analysis, Levenes' analysis, MANCOVA, t-student and Pearson correlation coefficient tests t with SPSS software. Our results showed that group psychotherapy with the TA approach was effective in improving EI, executive functions and decreasing drug dependency (P addicts and prevents addiction recurrence by improving the coping capabilities and some mental functions of the subjects. However, there are some limitations regarding this study including follow-up duration and sample size.

  8. Particle currents in a space-time dependent and CP-violating Higgs background: a field theory approach

    International Nuclear Information System (INIS)

    Comelli, D.; Riotto, A.

    1995-06-01

    Motivated by cosmological applications like electroweak baryogenesis, we develop a field theoretic approach to the computation of particle currents on a space-time dependent and CP-violating Higgs background. We consider the Standard Model model with two Higgs doublets and CP violation in the scalar sector, and compute both fermionic and Higgs currents by means of an expansion in the background fields. We discuss the gauge dependence of the results and the renormalization of the current operators, showing that in the limit of local equilibrium, no extra renormalization conditions are needed in order to specify the system completely. (orig.)

  9. FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action in Malassezia.

    Science.gov (United States)

    Ianiri, Giuseppe; Applen Clancey, Shelly; Lee, Soo Chan; Heitman, Joseph

    2017-10-24

    The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506), ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1 Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2 Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats. IMPORTANCE Malassezia species are the most abundant fungal components of the mammalian and human skin microbiome. Although they belong to the natural skin commensal flora of humans, they are also associated with a variety of clinical skin disorders. The standard treatment for Malassezia -associated inflammatory skin infections is topical corticosteroids, although their use

  10. Computational Fragment-Based Drug Design: Current Trends, Strategies, and Applications.

    Science.gov (United States)

    Bian, Yuemin; Xie, Xiang-Qun Sean

    2018-04-09

    Fragment-based drug design (FBDD) has become an effective methodology for drug development for decades. Successful applications of this strategy brought both opportunities and challenges to the field of Pharmaceutical Science. Recent progress in the computational fragment-based drug design provide an additional approach for future research in a time- and labor-efficient manner. Combining multiple in silico methodologies, computational FBDD possesses flexibilities on fragment library selection, protein model generation, and fragments/compounds docking mode prediction. These characteristics provide computational FBDD superiority in designing novel and potential compounds for a certain target. The purpose of this review is to discuss the latest advances, ranging from commonly used strategies to novel concepts and technologies in computational fragment-based drug design. Particularly, in this review, specifications and advantages are compared between experimental and computational FBDD, and additionally, limitations and future prospective are discussed and emphasized.

  11. Current position of high-resolution MS for drug quantification in clinical & forensic toxicology.

    Science.gov (United States)

    Meyer, Markus R; Helfer, Andreas G; Maurer, Hans H

    2014-08-01

    This paper reviews high-resolution MS approaches published from January 2011 until March 2014 for the quantification of drugs (of abuse) and/or their metabolites in biosamples using LC-MS with time-of-flight or Orbitrap™ mass analyzers. Corresponding approaches are discussed including sample preparation and mass spectral settings. The advantages and limitations of high-resolution MS for drug quantification, as well as the demand for a certain resolution or a specific mass accuracy are also explored.

  12. pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery.

    Science.gov (United States)

    Varma, Manthena V; Gardner, Iain; Steyn, Stefanus J; Nkansah, Paul; Rotter, Charles J; Whitney-Pickett, Carrie; Zhang, Hui; Di, Li; Cram, Michael; Fenner, Katherine S; El-Kattan, Ayman F

    2012-05-07

    The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability ≥ 5 × 10(-6) cm/s, the accuracy of predicting Fa of ≥ 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 μg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified

  13. Summary report of PQRI Workshop on Nanomaterial in Drug Products: current experience and management of potential risks.

    Science.gov (United States)

    Bartlett, Jeremy A; Brewster, Marcus; Brown, Paul; Cabral-Lilly, Donna; Cruz, Celia N; David, Raymond; Eickhoff, W Mark; Haubenreisser, Sabine; Jacobs, Abigail; Malinoski, Frank; Morefield, Elaine; Nalubola, Ritu; Prud'homme, Robert K; Sadrieh, Nakissa; Sayes, Christie M; Shahbazian, Hripsime; Subbarao, Nanda; Tamarkin, Lawrence; Tyner, Katherine; Uppoor, Rajendra; Whittaker-Caulk, Margaret; Zamboni, William

    2015-01-01

    At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.

  14. Chemical dependence - resources

    Science.gov (United States)

    Substance use - resources, Drug abuse - resources; Resources - chemical dependence ... are a good resource for information on drug dependence: National Council on Alcoholism and Drug Dependence -- ncadd. ...

  15. Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings.

    Science.gov (United States)

    Barker, David J; Simmons, Steven J; West, Mark O

    2015-01-01

    The present review describes ways in which ultrasonic vocalizations (USVs) have been used in studies of substance abuse. Accordingly, studies are reviewed which demonstrate roles for affective processing in response to the presentation of drug-related cues, experimenter- and self-administered drug, drug withdrawal, and during tests of relapse/reinstatement. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Data suggest that USVs capture animals' initial positive reactions to psychostimulant administration and are capable of identifying individual differences in affective responding. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures.

  16. Pacemaker Dependency after Cardiac Surgery: A Systematic Review of Current Evidence.

    Science.gov (United States)

    Steyers, Curtis M; Khera, Rohan; Bhave, Prashant

    2015-01-01

    Severe postoperative conduction disturbances requiring permanent pacemaker implantation frequently occur following cardiac surgery. Little is known about the long-term pacing requirements and risk factors for pacemaker dependency in this population. We performed a systematic review of the literature addressing rates and predictors of pacemaker dependency in patients requiring permanent pacemaker implantation after cardiac surgery. Using a comprehensive search of the Medline, Web of Science and EMBASE databases, studies were selected for review based on predetermined inclusion and exclusion criteria. A total of 8 studies addressing the endpoint of pacemaker-dependency were identified, while 3 studies were found that addressed the recovery of atrioventricular (AV) conduction endpoint. There were 10 unique studies with a total of 780 patients. Mean follow-up ranged from 6-72 months. Pacemaker dependency rates ranged from 32%-91% and recovery of AV conduction ranged from 16%-42%. There was significant heterogeneity with respect to the definition of pacemaker dependency. Several patient and procedure-specific variables were found to be independently associated with pacemaker dependency, but these were not consistent between studies. Pacemaker dependency following cardiac surgery occurs with variable frequency. While individual studies have identified various perioperative risk factors for pacemaker dependency and non-resolution of AV conduction disease, results have been inconsistent. Well-conducted studies using a uniform definition of pacemaker dependency might identify patients who will benefit most from early permanent pacemaker implantation after cardiac surgery.

  17. Hormonal and antimicrobial therapy in theriogenology practice: currently approved drugs in the USA and possible future directions.

    Science.gov (United States)

    Modric, T; Momcilovic, D; Gwin, W E; Peter, A T

    2011-08-01

    Hormonal and antimicrobial therapies are essential to regulate and maintain healthy reproduction in domestic animals. The appropriate and legal use of these compounds is ultimately the responsibility of the veterinarian and other users, with a primary mission to directly protect and promote the health of animals, and indirectly the health of people. The appropriate use of these products is defined by the Federal Food, Drug, and Cosmetic Act, 21 United States of America § 301 et seq and implementing regulations in the Code of Federal Regulations. In the past, use of a drug in an animal for an unapproved use violated this Act. However, passage of the Animal Medicinal Drug Use Clarification Act 1994 legalized the extra-label use of certain animal and human drugs in veterinary practice for treating diseases. This manuscript reviews currently approved hormonal and antimicrobial drugs for use in theriogenology. Considering the ever increasing knowledge in the area of veterinary reproduction, particularly in the treatment and control of reproduction using antimicrobials and hormones, it would be beneficial to widen the therapeutic options in these categories. The potential for widening the therapeutic options is also discussed in this review, by providing a non-exhaustive but essential list of potential new drugs for use in clinical animal reproduction (theriogenology). Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Negative mood reverses devaluation of goal-directed drug-seeking favouring an incentive learning account of drug dependence.

    Science.gov (United States)

    Hogarth, Lee; He, Zhimin; Chase, Henry W; Wills, Andy J; Troisi, Joseph; Leventhal, Adam M; Mathew, Amanda R; Hitsman, Brian

    2015-09-01

    Two theories explain how negative mood primes smoking behaviour. The stimulus-response (S-R) account argues that in the negative mood state, smoking is experienced as more reinforcing, establishing a direct (automatic) association between the negative mood state and smoking behaviour. By contrast, the incentive learning account argues that in the negative mood state smoking is expected to be more reinforcing, which integrates with instrumental knowledge of the response required to produce that outcome. One differential prediction is that whereas the incentive learning account anticipates that negative mood induction could augment a novel tobacco-seeking response in an extinction test, the S-R account could not explain this effect because the extinction test prevents S-R learning by omitting experience of the reinforcer. To test this, overnight-deprived daily smokers (n = 44) acquired two instrumental responses for tobacco and chocolate points, respectively, before smoking to satiety. Half then received negative mood induction to raise the expected value of tobacco, opposing satiety, whilst the remainder received positive mood induction. Finally, a choice between tobacco and chocolate was measured in extinction to test whether negative mood could augment tobacco choice, opposing satiety, in the absence of direct experience of tobacco reinforcement. Negative mood induction not only abolished the devaluation of tobacco choice, but participants with a significant increase in negative mood increased their tobacco choice in extinction, despite satiety. These findings suggest that negative mood augments drug-seeking by raising the expected value of the drug through incentive learning, rather than through automatic S-R control.

  19. Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration

    NARCIS (Netherlands)

    Kervezee, L; Gotta, V; Stevens, J; Birkhoff, W; Kamerling, Imc; Danhof, M; Meijer, J H; Burggraaf, J

    2016-01-01

    Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in

  20. Current dependent angular magnetoresistance in strongly Pr-doped Y Ba2Cu3O7-δ single crystal

    International Nuclear Information System (INIS)

    Sandu, V; Gyawali, P; Katuwal, T; Almasan, C C; Taylor, B J; Maple, M B

    2009-01-01

    We report a strong dependence of the angular magnetoresistance (AMR) on the current density in Y Ba 2 Cu 3 O 7-δ single crystal above the critical temperature T c = 13 K for any applied field up to 14 T. We estimated the current dependence from the angular dependence of the top resistance R top , as measured on the face where the current is applied, and the bottom resistance R bot as measured on the opposite face. At any temperature, both below and above T c , R top decreases as the field becomes parallel to the current and ab-plane with an angle dependence that suggests an important contribution arising from the vortex flow. R bot evolves from a monotonic to nonmonotonic angle dependence with three minima and two maxima in the angle range 0 - 180 deg. as the temperature increases. For less Pr-doped samples, Y 0.58 Pr 0.42 Ba 2 Cu 3 O 7-δ (T c = 39 K) and Y 0.68 rP 0.32 Ba 2 Cu 3 O 7-δ (T c = 55 K), where the interplane resistivity is much lower, both R top and R bot follow the same monotonic angle dependence in all temperature and field range.

  1. Current applications of miniaturized chromatographic and electrophoretic techniques in drug analysis.

    Science.gov (United States)

    Aturki, Zeineb; Rocco, Anna; Rocchi, Silvia; Fanali, Salvatore

    2014-12-01

    In the last decade, miniaturized separation techniques have become greatly popular in pharmaceutical analysis. Miniaturized separation methods are increasingly utilized in all processes of drug discovery as well as quality control of pharmaceutical preparation. The great advantages presented by the analytical miniaturized techniques, including high separation efficiency and resolution, rapid analysis and minimal consumption of reagents and samples, make them an attractive alternative to the conventional chromatographic methods for drug analysis. The purpose of this review is to give a general overview of the applicability of capillary electrophoresis (CE), capillary electrochromatography (CEC) and micro/capillary/nano-liquid chromatography (micro-LC/CLC/nano-LC) for the analysis of pharmaceutical formulations, active pharmaceutical ingredients (API), drug impurity testing, chiral drug separation, determination of drugs and metabolites in biological fluids. The results concerning the use of CEC, micro-LC, CLC, and nano-LC in the period 2009-2013, while for CE, those from 2012 up to the review draft are here summarized and some specific examples are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. [Development of a program of prevention of drug dependence in school children].

    Science.gov (United States)

    García Lerín, A; Calvo Trujillo, S; Sánchez-Porro Valadés, P

    1997-03-15

    To promote healthy habits of behaviour among school-children so that they reject drug-taking and learn to identify high-risk situations. Quasi-experimental study. The Amorós private school in Carabanchel, in Madrid's Health District XI. 45 pupils from the eighth year of basic, aged between 13 and 14. Quantitative and qualitative methods. Quantitative indicators were: number of students who attended the activities organised, their level of participation, the number of new terms, increase in knowledge. Qualitative indicators were the oral poll of class leaders, attainment of objectives, later evaluation of changes in attitude towards drug-takers and collages among the initiatives after the course. Drug-taking usually starts in the family context, leisure situations and peers. In this study isolated consumption was also detected. Most commonly consumed drugs were: caffeine, tobacco (mainly Virginia), alcohol occasionally, and cannabis. The type and form of drug-taking found is very similar to that of other, Spaniards of the same age. We found children who were not drug-takers, but were anxious about this because they "wanted to try out drugs".

  3. Drug Loading and Release Behavior Depending on the Induced Porosity of Chitosan/Cellulose Multilayer Nanofilms.

    Science.gov (United States)

    Park, Sohyeon; Choi, Daheui; Jeong, Hyejoong; Heo, Jiwoong; Hong, Jinkee

    2017-10-02

    The ability to control drug loading and release is the most important feature in the development of medical devices. In this research, we prepared a functional nanocoating technology to incorporate a drug-release layer onto a desired substrate. The multilayer films were prepared using chitosan (CHI) and carboxymethyl cellulose (CMC) polysaccharides by the layer-by-layer (LbL) method. By using chemical cross-linking to change the inner structure of the assembled multilayer, we could control the extent of drug loading and release. The cross-linked multilayer film had a porous structure and enhanced water wettability. Interestingly, more of the small-molecule drug was loaded into and released from the non-cross-linked multilayer film, whereas more of the macromolecular drug was loaded into and released from the cross-linked multilayer film. These results indicate that drug loading and release can be easily controlled according to the molecular weight of the desired drug by changing the structure of the film.

  4. Thermally induced spin-dependent current based on Zigzag Germanene Nanoribbons

    Science.gov (United States)

    Majidi, Danial; Faez, Rahim

    2017-02-01

    In this paper, using first principle calculation and non-equilibrium Green's function, the thermally induced spin current in Hydrogen terminated Zigzag-edge Germanene Nanoribbon (ZGeNR-H) is investigated. In this model, because of the difference between the source and the drain temperature of ZGeNR device, the spin up and spin down currents flow in the opposite direction with two different threshold temperatures (Tth). Hence, a pure spin polarized current which belongs to spin down is obtained. It is shown that, for temperatures above the threshold temperature spin down current increases with the increasing temperature up to 75 K and then decreases. But spin up current rises steadily and in the high temperature we can obtain polarized spin up current. In addition, we show an acceptable spin current around the room temperature for ZGeNR. The transmission peaks in ZGeNR which are closer to the Fermi level rather than Zigzag Graphene Nanoribbon (ZGNRS) which causes ZGeNR to have spin current at higher temperatures. Finally, it is indicated that by tuning the back gate voltage, the spin current can be completely modulated and polarized. Simulation results verify the Zigzag Germanene Nanoribbon as a promising candidate for spin caloritronics devices, which can be applied in future low power consumption technology.

  5. Phase dependency of electrotonic spread of hyperpolarizing current pulses in the rabbit sinoatrial node

    NARCIS (Netherlands)

    Duivenvoorden, J. J.; Bouman, L. N.; Bukauskas, F. F.; Opthof, T.; Jongsma, H. J.

    1990-01-01

    Electrotonic current spread in the SA node of the rabbit was measured by means of hyperpolarizing current pulses (1 to 10 microA, 60 ms), which were injected intracellularly through a K(+)-perfused suction electrode. The pulses were applied at the beginning, middle or end of the diastolic

  6. Sample-length dependence of the critical current of slightly and significantly bent-damaged Bi2223 superconducting composite tape

    International Nuclear Information System (INIS)

    Ochiai, S; Fujimoto, M; Okuda, H; Oh, S S; Ha, D W

    2007-01-01

    The local critical current along a sample length is different from position to position in a long sample, especially when the sample is damaged by externally applied strain. In the present work, we attempted to reveal the relation of the distribution of the local critical current to overall critical current and the sample-length dependence of critical current for slightly and significantly damaged Bi2223 composite tape samples. In the experiment, 48 cm long Bi2223 composite tape samples, composed of 48 local elements with a length of 1 cm and 8 parts with a length 6 cm, were bent by 0.37 and 1.0% to cause slight and significant damage, respectively. The V-I curve, critical current (1 μV cm -1 criterion) and n value were measured for the overall sample as well as for the local elements and parts. It was found that the critical current distributions of the 1 cm elements at 0.37 and 1.0% bending strains are described by the three-parameter- and bimodal Weibull distribution functions, respectively. The critical current of a long sample at both bending strains could be described well by substituting the distributed critical current and n value of the short elements into the series circuit model for voltage generation. Also the measured relation of average critical current to sample length could be reproduced well in the computer by a Monte Carlo simulation method. It was shown that the critical current and n value decrease with increasing sample length at both bending strains. The extent of the decrease in critical current with sample length is dependent on the criterion of the critical current; the critical current decreases only slightly under the 1 μV cm -1 criterion which is not damage-sensitive, while it decreases greatly with increasing sample length under damage-sensitive criteria such as the 1 μV one

  7. 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.

  8. 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

  9. Angular dependence of critical current density and magnetoresistance of sputtered high-T{sub c}-films

    Energy Technology Data Exchange (ETDEWEB)

    Geerkens, A.; Frenck, H.J.; Ewert, S. [Technical Univ. of Cottbus (Germany)] [and others

    1994-12-31

    The angular dependence of the critical current density and the magnetoresistance of high-T{sub c}-films in high and low magnetic fields and for different temperatures were measured to investigate the flux pinning and the superconducting properties. A comparison of the results for the different superconductors shows their increasing dependence on the angle {Theta} between the magnetic field and the c-axis of the film due to the anisotropy of the chosen superconductor. Furthermore the influence of the current direction to the {Theta}-rotation plane is discussed.

  10. [Current movements of four serious adverse events induced by medicinal drugs based on spontaneous reports in Japan].

    Science.gov (United States)

    Sudo, Chie; Azuma, Yu-ichiro; Maekawa, Keiko; Kaniwa, Nahoko; Sai, Kimie; Saito, Yoshiro

    2011-01-01

    Spontaneous reports on suspected serious adverse events caused by medicines from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated by the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety features. Although causal relationship between the medicine and the adverse event is not evaluated, and one incidence may be redundantly reported, this information would be useful to roughly grasp the current movements of drug-related serious adverse events, We searched open-source data of the spontaneous reports publicized by Pharmaceutical and Medical Devices Agency for 4 serious adverse events (interstitial lung disease, rhabdomyolysis, anaphylaxis, and Stevens-Johnson syndrome/toxic epidermal necrolysis) from 2004 to 2010 fiscal year (for 2010, from April 1 st to January 31th). Major drug-classes suspected to the adverse events were antineoplastics for interstitial lung disease, hyperlipidemia agents and psychotropics for rhabdomyolysis, antibiotics/chemotherapeutics, antineoplastics and intracorporeal diagnostic agents for anaphylaxis (anaphylactic shock, anaphylactic reactions, anaphylactoid shock and anaphylactoid reactions), and antibiotics/chemotherapeutics, antipyretics and analgesics, anti-inflammatory agents/common cold drugs, and antiepileptics for Stevens-Johnson syndrome/toxic epidermal necrolysis. These results would help understanding of current situations of the 4 drug-related serious adverse events in Japan.

  11. Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; revision of certain labeling controls. Final rule.

    Science.gov (United States)

    2012-03-20

    The Food and Drug Administration (FDA) is amending the packaging and labeling control provisions of the current good manufacturing practice (CGMP) regulations for human and veterinary drug products by limiting the application of special control procedures for the use of cut labeling to immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons. FDA is also permitting the use of any automated technique, including differentiation by labeling size and shape, that physically prevents incorrect labeling from being processed by labeling and packaging equipment when cut labeling is used. This action is intended to protect consumers from labeling errors more likely to cause adverse health consequences, while eliminating the regulatory burden of applying the rule to labeling unlikely to reach or adversely affect consumers. This action is also intended to permit manufacturers to use a broader range of error prevention and labeling control techniques than permitted by current CGMPs.

  12. Estimating the effect of current, previous and never use of drugs in studies based on prescription registries

    DEFF Research Database (Denmark)

    Nielsen, Lars Hougaard; Løkkegaard, Ellen; Andreasen, Anne Helms

    2009-01-01

    of this misclassification for analysing the risk of breast cancer. MATERIALS AND METHODS: Prescription data were obtained from Danish Registry of Medicinal Products Statistics and we applied various methods to approximate treatment episodes. We analysed the duration of HT episodes to study the ability to identify......PURPOSE: Many studies which investigate the effect of drugs categorize the exposure variable into never, current, and previous use of the study drug. When prescription registries are used to make this categorization, the exposure variable possibly gets misclassified since the registries do...... not carry any information on the time of discontinuation of treatment.In this study, we investigated the amount of misclassification of exposure (never, current, previous use) to hormone therapy (HT) when the exposure variable was based on prescription data. Furthermore, we evaluated the significance...

  13. The alpha2-delta protein: an auxiliary subunit of voltage-dependent calcium channels as a recognized drug target.

    Science.gov (United States)

    Thorpe, Andrew J; Offord, James

    2010-07-01

    Currently, there are two drugs on the market, gabapentin (Neurontin) and pregabalin (Lyrica), that are proposed to exert their therapeutic effect through binding to the alpha2-delta subunit of voltage-sensitive calcium channels. This activity was unexpected, as the alpha2-delta subunit had previously been considered not to be a pharmacological target. In this review, the role of the alpha2-delta subunits is discussed and the mechanism of action of the alpha2-delta ligands in vitro and in vivo is summarized. Finally, new insights into the mechanism of drugs that bind to this protein are discussed.

  14. Red blood cell aggregation changes are depended on its initial value: Effect of long-term drug treatment and short-term cell incubation with drug.

    Science.gov (United States)

    Muravyov, A V; Tikhomirova, I A; Maimistova, A A; Bulaeva, S V; Mikhailov, P V; Kislov, N V

    2011-01-01

    This study was designed to investigate whether the red cell aggregation depends on its initial level under drug therapy or cell incubation with bioactive chemical compounds. Sixty six subjects were enrolled onto this study, and sub-divided into two groups: the first group of patients (n = 36) with cerebral atherosclerosis received pentoxifylline therapy (400 mg, thrice daily) for 4 weeks. The patients of the second group were initially treated with Epoetin beta 10,000 units subcutaneously thrice a week, for 4 weeks. The second group - adult anemic patients (n = 30) with the confirmed diagnosis of solid cancer (Hb treatment the red cell aggregation increased (p treatment with pentoxifylline reduced it markedly (p treatment 75% the anemic patients with initially high RBCA had an aggregation lowering. The drop of aggregation was about 34% (p treatment. The initially low red cell aggregation after incubation with epoetin-beta was markedly increased by 122% (p drugs depend markedly on the initial, pre-treatment aggregation status of the patients. These results demonstrate that the different red blood cell aggregation responses to the biological stimuli depend strongly on the initial, pre-treatment status of the subject and the most probably it is connected with the crosstalk between the adenylyl cyclase signaling pathway and Ca2+ regulatory mechanism.

  15. Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement.

    Science.gov (United States)

    Griffiths, R R; Chausmer, A L

    2000-11-01

    Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.

  16. Magnetic Field Dependence of the Critical Current in S-N Bilayer Thin Films

    Science.gov (United States)

    Sadleir, John E.; Lee, Sang-Jun; Smith, Stephen James; Bandler, Simon; Chervenak, James; Kilbourne, Caroline A.; Finkbeiner, Fred M.; Porter, Frederick S.; Kelley, Richard L.; Adams, Joseph S.; hide

    2013-01-01

    Here we investigate the effects a non-uniform applied magnetic field has on superconducting transition-edge sensors (TESs) critical current. This has implications on TES optimization. It has been shown that TESs resistive transition can be altered by magnetic fields. We have observed critical current rectification effects and explained these effects in terms of a magnetic self-field arising from asymmetric current injection into the sensor. Our TES physical model shows that this magnetic self-field can result in significantly degraded or improved TES performance. In order for this magnetically tuned TES strategy to reach its full potential we are investigating the effect a non-uniform applied magnetic field has on the critical current.

  17. Glutathionylation-Dependence of Na+-K+-Pump Currents Can Mimic Reduced Subsarcolemmal Na+ Diffusion

    OpenAIRE

    Garcia, Alvaro; Liu, Chia-Chi; Cornelius, Flemming; Clarke, Ronald?J.; Rasmussen, Helge?H.

    2016-01-01

    The existence of a subsarcolemmal space with restricted diffusion for Na+ in cardiac myocytes has been inferred from a transient peak electrogenic Na+-K+ pump current beyond steady state on reexposure of myocytes to K+ after a period of exposure to K+-free extracellular solution. The transient peak current is attributed to enhanced electrogenic pumping of Na+ that accumulated in the diffusion-restricted space during pump inhibition in K+-free extracellular solution. However, there are no know...

  18. Dependence of the critical current density on the history of magnetic field and temperature

    International Nuclear Information System (INIS)

    Kuepfer, H.

    1976-08-01

    The dependence of the volume pinning force on different paths taken to arrive at a state (H,T) is investigated. The local magnetic induction is measured by means of an ac technique on samples with different Hsub(c), kappa, pinning centres and densities. Line pinning and a distorted flux line lattice are properties of those samples which show the above mentioned history dependence. Using the model of E.J. Kramer it is deduced the reason of the history effect is the dependence of the shear modulus on the defect structure of the flux line lattice. The differences occur in the lower field region and are also observed in materials with kappa approximately = 40 and large volume pinning forces. (orig.) [de

  19. Temperature dependent capacity contribution of thermally treated anode current collectors in lithium ion batteries

    International Nuclear Information System (INIS)

    Kim, Tae Kwon; Li Xifei; Wang Chunlei

    2013-01-01

    Highlights: ► We studied the influence of the thermal treatment of current collectors on the energy capacity. ► Different current collectors show different thermal treatment effect on performance. ► The non-negligible capacity contribution is closely related to the treatment temperatures. ► Our results could be beneficial to designing battery architectures. - Abstract: Metal current collectors, offering a good connection between the active materials and the external circuit, is an important component in a rechargeable lithium ion battery. Some necessary thermal treatment in the battery fabrication and assembly procedure results in current collectors with some non-negligible reversible energy capacities; however, these energy capacities were negligible in the previous references. In this research, for the first time, we investigated the influence of the thermal treatment of current collectors (such as copper foil and stainless steel disk) on energy capacities. Our results indicate that different current collector materials have different thermal treatment effects on their electrochemical performance. The non-negligible capacity contribution is closely related to the treatment temperature.

  20. [Treatment of typical trigeminus neuralgias. Overview of the current state of drug and surgical therapy].

    Science.gov (United States)

    Möbius, E; Leopold, H C; Paulus, W M

    1984-10-11

    Carbamazepine continues to be the most useful drug in the treatment of trigeminal neuralgia. Diphenylhydantoin may be given in addition to or instead of Carbamazepine. Refractory cases may benefit from combination with Baclofen or Chlorphenesin. In cases of persistent pain the concomitant use of tricyclic antidepressant drugs is recommended. If pain continues in spite of multiple medical therapies or if serious side effects develop, then surgical procedures such as percutaneous controlled thermocoagulation or microvascular decompression are indicated. Percutaneous thermocoagulation is associated with the lowest mortality and morbidity rate and can easily be repeated. Microvascular decompression should especially be offered to young patients, who want to avoid any sensory disturbance of the face, and recommended for other patients for whom all other forms of therapy including percutaneous thermocoagulation have failed.

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

    Science.gov (United States)

    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.

  2. Effectiveness of Cognitive-Behavioral Therapy in the Improvement of Coping Strategies and Addiction Symptoms in Drug-Dependent Patients

    Directory of Open Access Journals (Sweden)

    H BrockieMilan

    2014-12-01

    Full Text Available Objective: This study was carried out to determine the effectiveness of cognitive-behavioral therapy in improving coping strategies and symptoms of drug addiction patients. Method: In a quasi-experimental study, the number of 90drug-dependent patients referring to clinics to stop taking drugs existing in the city of Urmia were divided into two experimental (n=45 groups and control (n=45 using random sampling. The experimental group received 12 sessions of cognitive-behavioral treatment in Carroll style while the control group received only methadone and the physical pills. All the participants completed coping strategies questionnaire at the beginning, during (after three months, and three months after treatment (follow-up. As well, they were assessed for the rate of improvement in symptoms of addiction and process of addiction treatment using by Madzly’s addiction profile questionnaire. Findings: The results proved the effectiveness of cognitive-behavioral therapy and its survival. Conclusion: Cognitive behavioral therapy is very influential in the boost of coping strategies and the improvement of mental and physical health in drug-dependent patients.

  3. Gender Comparisons Among Asian American and Pacific Islander Patients in Drug Dependency Treatment.

    Science.gov (United States)

    Han, Yun; Lin, Veronique; Wu, Fei; Hser, Yih-Ing

    2016-05-11

    Few studies have focused on Asian Americans and Pacific Islanders (AAPIs), despite indications of increasing substance abuse among AAPIs in recent years. This prospective longitudinal study examined gender differences among AAPIs in treatment. The study included 567 (177 women, 390 men) AAPI patients drawn from two prior studies, one with 32 community treatment programs in 13 California counties (CalTOP, 3, 9 months), and another project including 36 treatment sites in 5 California counties (TSI, 3, 12 months). Baseline and follow-up assessments utilized the Addiction Severity Index(ASI). A subset of patients was assessed at 3 and 9/12 months (n = 106). Significant gender-related differences were observed at baseline: fewer women than men were employed or never married. More women were living with someone having alcohol and drug problems. Methamphetamine was the primary drug for women and men, followed by alcohol and heroin. Compared to AAPI men, AAPI women reported greater problem severity in family/social relationships (0.18 vs. 0.11, p drug, and legal domains for both genders, and in mental health for men only. Compared to AAPI men, AAPI women demonstrated significantly greater improvements in drug problems (ΔASI = 0.07, p drug use problems for AAPI men.

  4. Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current Results

    International Nuclear Information System (INIS)

    Kettenbach, Joachim; Stadler, Alfred; Katzler, Isabella v.; Schernthaner, Ruediger; Blum, Melanie; Lammer, Johannes; Rand, Thomas

    2008-01-01

    Transarterial chemoembolization (TACE) involves the emulsification of a chemotherapeutic agent in a viscous drug carrier, delivered intra-arterially to liver tumor for maximum effect. TACE reduces arterial inflow, diminishes washout of the chemotherapeutic agent, and decreases systemic exposure. Despite evidence of some clinical success with TACE, a new type of microspheres with drug-eluting capabilities may offer a precisely controlled and sustainable release of the chemotherapeutic agent into the tumor bed. In animal trials tumor necrosis (approaching 100%) was greatest at 7 days, with significantly lower plasma concentrations of doxorubicin than in control animals treated with doxorubicin intra-arterially. Clinically, drug-eluting microspheres loaded with doxorubicin, either at 75 mg/m 2 or at a fixed dose of 150 mg, were used recently and no severe disorders of the hepatic function were observed postprocedure, while a substantial reduction of the fetoprotein levels occurred. An interim analysis of the first 15 patients from the Hong Kong group at 3 months showed an objective response rate of 61.54% and 53.84% according to EASL criteria and RECIST criteria, respectively, and a survival rate of 93.3%. In this paper we present how to use microspheres loaded with doxorubicin and review their clinical value and preliminary performance for treatment of unresectable liver cancer

  5. 77 FR 16158 - Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs...

    Science.gov (United States)

    2012-03-20

    .... FDA-1997-N-0518] (formerly 97N-0300) Current Good Manufacturing Practice in Manufacturing, Processing... labeling control provisions of the current good manufacturing practice (CGMP) regulations for human and... GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS 0 1. The authority citation for 21 CFR part...

  6. Energy dependence of solar-neutrino--electron scattering as a test of neutral currents

    International Nuclear Information System (INIS)

    Kwong, W.; Rosen, S.P.

    1992-01-01

    The energy dependence of ν-e scattering of solar neutrinos is investigated in the framework of neutrino oscillations and the nonadiabatic Mikheyev-Smirnov-Wolfenstein effect. It is shown that, with sufficient data, it will be possible to establish unambiguously whether neutrino oscillations are actually occurring and whether the electron neutrino oscillates into active or inactive (sterile) neutrino flavors

  7. Using 'payment by results' to fund the treatment of dependent drug users--proceed with care!

    Science.gov (United States)

    Maynard, Alan; Street, Andrew; Hunter, Rachael

    2011-10-01

    The UK government is changing its system of payment for drug treatment services in order to reward the achievement of better patient outcomes. This is a model that may be taken up internationally. This 'payment by results' funding system will reward providers for achieving good outcomes in terms of whether clients are drug free, employed and/or not convicted of a criminal offence. Providers will also receive a payment based on health and wellbeing outcome measurement. The definition and measurement of success in achieving these outcomes is complex and challenging, as is the need to bridge treatment costs during the period in which outcomes are pursued. This experiment requires careful evaluation if the delivery of drug treatment is not to be jeopardized or fragmented. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

  8. Field mapping measurements to determine spatial and field dependence of critical current density in YBCO tapes

    International Nuclear Information System (INIS)

    Leclerc, J.; Berger, K.; Douine, B.; Lévêque, J.

    2013-01-01

    Highlights: • A method for characterizing superconducting tapes from field mapping is presented. • A new and efficient field mapping apparatus has been setup. • This method allows the spatial characterization of superconducting tapes. • The critical current density is obtained as a function of the flux density. • This method has been experimentally tested on an YBCO tape. -- Abstract: In this paper a measurement method that allows the determination of the critical current density of superconducting tape from field mapping measurements is presented. This contact-free method allows obtaining characteristics of the superconductor as a function of the position and of the applied flux density. With some modifications, this technique can be used for reel-to-reel measurements. The determination of the critical current density is based on an inverse calculation. This involves calculating the current distribution in the tape from magnetic measurements. An YBaCuO tape has been characterized at 77 K. A defect in this superconductor has been identified. Various tests were carried out to check the efficiency of the method. The inverse calculation was tested theoretically and experimentally. Comparison with a transport current measurement was also performed

  9. The Effect of Health Education based on Health Belief Model on Preventive Actions of Synthetic Drugs Dependence in Male Students of Kerman, Iran

    Directory of Open Access Journals (Sweden)

    Seyed Saeed Mazloomy Mahmoodabad

    2017-06-01

    Conclusion: Findings indicated that by increase of HBM components' average scores, the average score of synthetic drug dependence preventive actions increased too. Therefore, results of the research confirm the effect and efficiency of HBM in making preventive actions of drug dependence

  10. Gastrointestinal Complications Depending on the Selectivity of Non-Steroidal Anti-Inflammatory Drug

    Directory of Open Access Journals (Sweden)

    G.V. Dzyak

    2013-02-01

    Full Text Available The article deals with the problem of gastrointestinal complications during administration of nonsteroidal anti-inflammatory drugs, commonly used to treat a range of conditions, particularly rheumatic diseases. The results of own researches, which served to define the characteristics of changes in the state of gastric secretory function in patients receiving non-selective and selective anti-inflammatory agent and their comparative analysis, are provided. The data obtained demonstrated a certain contribution to the understanding of the mechanism of development of complications from the gastrointestinal tract when taken drugs of above group.

  11. Levofloxacin?Induced QTc Prolongation Depends on the Time of Drug Administration

    OpenAIRE

    Kervezee, L; Gotta, V; Stevens, J; Birkhoff, W; Kamerling, IMC; Danhof, M; Meijer, JH; Burggraaf, J

    2016-01-01

    Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in ...

  12. Numerical Studies of Friction Between Metallic Surfaces and of its Dependence on Electric Currents

    Science.gov (United States)

    Meintanis, Evangelos; Marder, Michael

    2009-03-01

    We will present molecular dynamics simulations that explore the frictional mechanisms between clean metallic surfaces. We employ the HOLA molecular dynamics code to run slider-on-block experiments. Both objects are allowed to evolve freely. We recover realistic coefficients of friction and verify the importance of cold-welding and plastic deformations in dry sliding friction. We also find that plastic deformations can significantly affect both objects, despite a difference in hardness. Metallic contacts have significant technological applications in the transmission of electric currents. To explore the effects of the latter to sliding, we had to integrate an electrodynamics solver into the molecular dynamics code. The disparate time scales involved posed a challenge, but we have developed an efficient scheme for such an integration. A limited electrodynamic solver has been implemented and we are currently exploring the effects of currents in the friction and wear of metallic contacts.

  13. Electron mean free path dependence of the critical currents and the pair-breaking limit in superconducting films

    International Nuclear Information System (INIS)

    Fedorov, N.; Rinderer, L.

    1977-01-01

    We have studied the current-induced breakdown of superconductivity in wide (100--980 μm) and thin (0.25--0.98 μm) films of tin. It is shown that the current at which the resistance of the sample begins to rise rapidly in the process of the destruction of superconductivity by a current can be fairly well associated with the theoretical value of the pair-breaking current in the Ginzburg-Landau phenomenological approach (I/sub c//sup G L/). This effect is observed over a rather wide temperature region (up to ΔTapprox.0.7 K), depending on the electron mean free path in the films. The values of the critical currents outside the above-mentioned region correlate qualitatively with those determined by inhomogeneities of the films as proposed by Larkin and Ovchinnikov

  14. Dependence of CIT [Compact Ignition Tokamak] PF [poloidal field] coil currents on profile and shape parameters using the Control Matrix

    International Nuclear Information System (INIS)

    Strickler, D.J.; Peng, Y-K.M.; Jardin, S.C.; Pomphrey, N.

    1990-01-01

    The plasma shaping flexibility of the Compact Ignition Tokamak (CIT) poloidal field (PF) coil set is demonstrated through MHD equilibrium calculations of optimal PF coil current distributions and their variation with poloidal beta, internal inductance, plasma 95% elongation, and 95% triangularity. Calculations of the magnetic stored energy are used to compare solutions associated with various plasma parameters. The Control Matrix (CM) equilibrium code, together with the nonlinear equation and numerical optimization software packages HYBRD, and VMCON, respectively, are used to find equilibrium coil current distributions for fixed divertor geometry, volt-seconds, and plasma profiles in order to isolate the dependence on individual parameters. A reference equilibrium and coil current distribution are chosen, and correction currents dI are determined using the CM equilibrium method to obtain other specified plasma shapes. The reference equilibrium is the κ = 2 divertor at beginning of flattop (BOFT) with a minimum stored energy solution for the coil current distribution. The pressure profile function is fixed

  15. NO involvement in the inhibition of ghrelin on voltage-dependent potassium currents in rat hippocampal cells.

    Science.gov (United States)

    Lu, Yong; Dang, Shaokang; Wang, Xu; Zhang, Junli; Zhang, Lin; Su, Qian; Zhang, Huiping; Lin, Tianwei; Zhang, Xiaoxiao; Zhang, Yurong; Sun, Hongli; Zhu, Zhongliang; Li, Hui

    2018-01-01

    Ghrelin is a peptide hormone that plays an important role in promoting appetite, regulating distribution and rate of use of energy, cognition, and mood disorders, but the relevant neural mechanisms of these function are still not clear. In this study, we examined the effect of ghrelin on voltage-dependent potassium (K + ) currents in hippocampal cells of 1-3 days SD rats by whole-cell patch-clamp technique, and discussed whether NO was involved in this process. The results showed that ghrelin significantly inhibited the voltage-dependent K + currents in hippocampal cells, and the inhibitory effect was more significant when l-arginine was co-administered. In contrast, N-nitro- l-arginine methyl ester increased the ghrelin inhibited K + currents and attenuated the inhibitory effect of ghrelin. While d-arginine (D-AA) showed no significant impact on the ghrelin-induced decrease in K + current. These results show that ghrelin may play a physiological role by inhibiting hippocampal voltage dependent K + currents, and the NO pathway may be involved in this process. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Factors Affecting Drug Use During Incarceration: A Cross-Sectional Study of Opioid-Dependent Persons from India.

    Science.gov (United States)

    Rao, Ravindra; Mandal, Piyali; Gupta, Rishab; Ramshankar, Prashanth; Mishra, Ashwani; Ambekar, Atul; Jhanjee, Sonali; Dhawan, Anju

    2016-02-01

    Substance abuse and criminality share a complex relationship. The rates of substance use among the prisoners, and that of criminal acts among substance users in community setting are high. Data from South Asian countries, including from India are inadequate. This study aimed to assess the pattern of criminal acts among opioid-dependent subjects and their substance use pattern in the month before, during and after imprisonment. Using a cross-sectional study design and purposive sampling, opioid-dependent subjects (n=101) attending two community drug treatment clinics who have had any contact with the law were assessed using a specifically-designed tool to record criminal acts and substance use before, during and after last imprisonment. Most subjects (93%) had committed illegal acts in their lifetime. Physical assault was the most common illegal act, while 23% reported selling drugs and 9% reported committing serious crimes. About 95% were arrested and 92% had spent time in police lockups. About 29% were arrested for drugs possession or drug use, and 3% of injecting drug users arrested for carrying injection equipment. About 85% had been imprisoned at least once, of whom 88% used psychoactive substances in the 1-month period before their last imprisonment. Opioids were the most common substances used daily (68%), followed by cannabis (34%) and alcohol (22%). Ninety-seven percent reported the availability of substances in prisons, and 65% also used substances during their last imprisonment. Cannabis (35%) was the most common substances used in prison followed by opioids (19%). Seventy-six percent used substances soon after prison release, and 13% of opioid users experienced opioid overdose soon after prison release. Use of cannabis, injecting drugs, and opioid use before imprisonment were predictors of substance use in prison. Opioid-dependent people have various contacts with the law, including imprisonment. Many users are dependent on substances during prison

  17. Current densities in a space-time-dependent and CP-violating Higgs background in the adiabatic limit

    International Nuclear Information System (INIS)

    Comelli, D.; Pietroni, M.; Riotto, A.

    1996-01-01

    Motivated by cosmological applications such as electroweak baryogenesis, we develop a field theoretic approach to the computation of particle currents on a space-time-dependent and CP-violating Higgs background in the adiabatic limit. We consider the standard model with two Higgs doublets and CP violation in the scalar sector, and compute both fermionic and Higgs currents by means of an expansion in the background fields describing the profile of the bubble wall. We discuss the gauge dependence of the results and the renormalization of the current operators, showing that in the limit of local equilibrium, no extra renormalization conditions are needed in order to specify the system completely. copyright 1996 The American Physical Society

  18. DEPENDENT STANDARD OF HIGH EDUCATION AND THE BRAZILIAN UNIVERSITY CURRENT EXPANSION

    Directory of Open Access Journals (Sweden)

    José Renato Bez de Gregório

    2014-06-01

    Full Text Available This article is based on the theoretical contributions of Florestan Fernandes seeking to analyze the structural and cyclical features of Brazilian higher education, in order to understand to what extent these features constitute the pattern-dependent learning, the historic brand dependent capitalist insertion of Brazil in the global economy and cultural heteronomy associated with it. We assume that such theoretical foundation helps us understand some aspects of the redesign of higher education underway in Brazil conducted by governments Lula da Silva and Dilma Rousseff, particularly the Program of Support to the Restructuring and Expansion of Federal Universities (REUNI. Thus, presenting some data expansion in the two largest public universities in the state of Rio de Janeiro in order to demonstrate the extent to which this process is indicating the precariousness / intensification of teaching and a deep reconfiguration of Brazilian public university.

  19. Responsivity Dependent Anodization Current Density of Nanoporous Silicon Based MSM Photodetector

    Directory of Open Access Journals (Sweden)

    Batool Eneaze B. Al-Jumaili

    2016-01-01

    Full Text Available Achieving a cheap and ultrafast metal-semiconductor-metal (MSM photodetector (PD for very high-speed communications is ever-demanding. We report the influence of anodization current density variation on the response of nanoporous silicon (NPSi based MSM PD with platinum (Pt contact electrodes. Such NPSi samples are grown from n-type Si (100 wafer using photoelectrochemical etching with three different anodization current densities. FESEM images of as-prepared samples revealed the existence of discrete pores with spherical and square-like shapes. XRD pattern displayed the growth of nanocrystals with (311 lattice orientation. The nanocrystallite sizes obtained using Scherrer formula are found to be between 20.8 nm and 28.6 nm. The observed rectifying behavior in the I-V characteristics is ascribed to the Pt/PSi/n-Si Schottky barrier formation, where the barrier height at the Pt/PSi interface is estimated to be 0.69 eV. Furthermore, this Pt/PSi/Pt MSM PD achieved maximum responsivity of 0.17 A/W and quantum efficiency as much as 39.3%. The photoresponse of this NPSi based MSM PD demonstrated excellent repeatability, fast response, and enhanced saturation current with increasing anodization current density.

  20. Current-voltage curve of sodium channels and concentration dependence of sodium permeability in frog skin

    DEFF Research Database (Denmark)

    Fuchs, W; Larsen, Erik Hviid; Lindemann, B

    1977-01-01

    1. The inward facing membranes of in vitro frog skin epithelium were depolarized with solutions of high K concentration. The electrical properties of the epithelium are then expected to be governed by the outward facing, Na-selective membrane.2. In this state, the transepithelial voltage (V...... was recorded. This procedure was repeated after blocking the Na channels with amiloride to obtain the current-voltage curve of transmembrane and paracellular shunt pathways. The current-voltage curve of the Na channels was computed by subtracting the shunt current from the total current.4. The instantaneous I...... of the inward facing membranes but reflects the true behaviour of P(Na).6. The steady-state P(Na) at a given (Na)(o) is smaller than the transient P(Na) observed right after a stepwise increase of (Na)(o) to this value. The time constant of P(Na)-relaxation is in the order of seconds.7. In conclusion, Na...

  1. Nonmonotonic temperature dependence of critical current in diffusive d-wave junctions

    NARCIS (Netherlands)

    Yokoyama, T.; Tanaka, Y.; Golubov, Alexandre Avraamovitch; Asano, Y.

    2006-01-01

    We study the Josephson effect in D/I/DN/I/D junctions, where I, DN, and D denote an insulator, a diffusive normal metal, and a d-wave superconductor, respectively. The Josephson current is calculated based on the quasiclassical Green's function theory with a general boundary condition for

  2. Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation

    NARCIS (Netherlands)

    Mackus, W. J. M.; Kater, A. P.; Grummels, A.; Evers, L. M.; Hooijbrink, B.; Kramer, M. H. H.; Castro, J. E.; Kipps, T. J.; van Lier, R. A. W.; van Oers, M. H. J.; Eldering, E.

    2005-01-01

    We investigated the apoptosis gene expression profile of chronic lymphocytic leukemia (CLL) cells in relation to (1) normal peripheral and tonsillar B-cell subsets, (2) IgV(H) mutation status, and (3) effects of cytotoxic drugs. In accord with their noncycling, antiapoptotic status in vivo, CLL

  3. Cross-generational effects on gender differences in psychoactive drug abuse and dependence.

    Science.gov (United States)

    Holdcraft, Laura C; Iacono, William G

    2004-05-10

    Studies of patients with cocaine and heroin use disorders have shown gender differences in prevalence, course, and outcome. These differences may be decreasing in successive generations. Less is known about gender differences in course and symptomatology for other illicit drug use disorders, especially in community samples. Participants (1323 men and 1384 women) who were biological or step-parents of twins and born in the 1940-1960s, from the Minnesota Twin-Family Study (MTFS) were divided into two cohorts based on the median birth year. A structured interview was used to assess DSM-III-R cannabis, amphetamine, cocaine and hallucinogen use disorders. There was a higher prevalence of each of these drug disorders and earlier onset of cannabis and amphetamine use disorders in later-born participants. For most drug use disorder categories, men and women were similar with respect to age of onset and severity of disorder but women had a shorter course of drug use disorders. Women with amphetamine disorders were atypical with respect to having a higher frequency of use but similar number of lifetime uses compared to men, and more emotional effects of amphetamine intoxication than men. In addition, women with amphetamine disorders were more likely to have anorexia nervosa than those without amphetamine disorders. These results have several implications for prevention, etiology and treatment.

  4. THE LACTOCOCCAL LMRP GENE ENCODES A PROTON MOTIVE FORCE-DEPENDENT DRUG TRANSPORTER

    NARCIS (Netherlands)

    Bolhuis, H; Poelarends, G.J.; van Veen, H.W.; Poolman, B.; Driessen, A.J.M.; Konings, W.N

    1995-01-01

    To genetically dissect the drug extrusion systems of Lactococcus lactis, a chromosomal. DNA library was made in Escherichia coli and recombinant strains were selected for resistance to high concentrations of ethidium bromide. Recombinant strains were found to be resistant not only to ethidium

  5. Commentary on: ?Levofloxacin?Induced QTc Prolongation Depends on the Time of Drug Administration?

    OpenAIRE

    Garnett, C; Johannesen, L

    2016-01-01

    Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization?

  6. Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors.

    Science.gov (United States)

    Bagley, Elena E; Hacker, Jennifer; Chefer, Vladimir I; Mallet, Christophe; McNally, Gavan P; Chieng, Billy C H; Perroud, Julie; Shippenberg, Toni S; Christie, MacDonald J

    2011-10-30

    Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.

  7. The impact of currently used oral antihyperglycemic drugs on dysfunctional adipose tissue

    Directory of Open Access Journals (Sweden)

    Tomić-Naglić Dragana

    2017-01-01

    Full Text Available Obesity is a disease with pandemic frequency, often accompanied by chronic metabolic and organic complications. Type 2 diabetes mellitus (T2DM is among the most common metabolic complications of obesity. The first step in the treatment of T2DM is medical nutrition therapy combined with moderate physical activity and with advice to patients to reduce their body weight. Pharmacotherapy starts with metformin, and in the case of inadequate therapeutic response, another antihyperglycemic agent should be added. The most clinical experience exists with sulfonylurea agents, but their use is limited due to high incidence of hypoglycemia and increase in body weight. Based on the fact that dysfunction of adipose tissue can lead to the development of chronic degenerative complications, precise use of drugs with a favorable effect on the functionality of adipose tissue represents an imperative of modern T2DM treatment. Antihyperglycemic drugs of choice in obese individuals are those which cause maturation of adipocytes, improvement of secretion of protective adipokines, and redistribution of fat mass from visceral to subcutaneous depots. Oral antihyperglycemic agents that can affect the functionality of adipose tissue are metformin, SGLT-2 inhibitors, DPP-4 inhibitors, and thiazolidinediones.

  8. Current drug therapies for rosacea: a chronic vascular and inflammatory skin disease.

    Science.gov (United States)

    Feldman, Steven R; Huang, William W; Huynh, Tu T

    2014-06-01

    Rosacea is a chronic skin disorder that presents with abnormal vascular and inflammatory conditions. Clinical manifestations include flushing, facial erythema, inflammatory papules and pustules, telangiectasias, edema, and watery or irritated eyes. To discuss the evolving pathophysiology of rosacea, factors involved in promoting the chronic vascular and inflammatory abnormalities seen in rosacea, and the available drug therapies for the condition. Chronic inflammation and vascular changes are believed to be underlying factors in the pathophysiology of rosacea. Aberrant cathelicidin expression, elevated kallikrein 5 (KLK5) proteolytic activity, and altered toll-like receptor 2 (TLR2) expression have been reported in rosacea skin leading to the production of proinflammatory cytokines. Until recently, drug therapies only targeted the inflammatory lesions (papules and pustules) and transient erythema associated with these inflammatory lesions of rosacea. Brimonidine tartrate gel 0.5% was recently approved for the treatment of persistent (nontransient) facial erythema of rosacea, acting primarily on the cutaneous vascular component of the disease. Rosacea is a chronic vascular and inflammatory skin disease. Understanding the role of factors that trigger the onset of rosacea symptoms and exacerbate the condition is crucial in treating this skin disease.

  9. Nonclinical safety biomarkers of drug-induced vascular injury: current status and blueprint for the future.

    Science.gov (United States)

    Mikaelian, Igor; Cameron, Mark; Dalmas, Deidre A; Enerson, Bradley E; Gonzalez, Raymond J; Guionaud, Silvia; Hoffmann, Peter K; King, Nicholas M P; Lawton, Michael P; Scicchitano, Marshall S; Smith, Holly W; Thomas, Roberta A; Weaver, James L; Zabka, Tanja S

    2014-06-01

    Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI. © 2014 by The Author(s).

  10. WAVEGUIDE COUPLER KICK TO BEAM BUNCH AND CURRENT DEPENDENCY ON SRF CAVITIES

    International Nuclear Information System (INIS)

    Genfa Wu; Haipeng Wang; Charles Reece; Robert Rimmer

    2008-01-01

    JLAB SRF cavities employ waveguide type fundamental power couplers (FPC). The FPC design for the 7-cell upgrade cavities was optimized to minimize the dipole field kick. For continuous wave (CW) operation, the forwarding RF power will be at different magnitude to drive the different beam current and cavity gradient. This introduces some deviation from optimized FPC field for varying beam loading. This article analyzes the beam behavior both in centroid kick and head-tail kick under different beam loading conditions

  11. Strain dependence of the critical current and critical field in multifilamentary Nb3Sn composites

    International Nuclear Information System (INIS)

    Ekin, J.W.

    1979-01-01

    High-J/sub c/ multifilamentary Nb 3 Sn superconductors with widely varying amounts of prestrain and critical field values can be characterized fairly accurately by a single normalized critical field-strain relationship. Such a relationship permits first order prediction of critical-current degradation at arbitrary magnetic field magnitudes with knowledge of only two parameters for any conductor, the prestrain and the maximum critical field. Some of the conductor-fabrication factors affecting the parameters are considered

  12. Contactless estimation of critical current density and its temperature dependence using magnetic measurements

    Czech Academy of Sciences Publication Activity Database

    Youssef, A.; Baničová, L.; Švindrych, Zdeněk; Janů, Zdeněk

    2010-01-01

    Roč. 118, č. 5 (2010), s. 1036-1037 ISSN 0587-4246. [Czech and Slovak Conference on Magnetism /14./. Košice, 06.07.2010-09.07.2010] R&D Projects: GA MŠk(CZ) ME10069 Institutional research plan: CEZ:AV0Z10100520 Keywords : superconductivity * critical state * Bean model * critical current density Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 0.467, year: 2010

  13. Comparison of statistical approaches dealing with time-dependent confounding in drug effectiveness studies.

    Science.gov (United States)

    Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W; Tremlett, Helen

    2018-06-01

    In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models are frequently used to deal with such confounding. To avoid some of the problems of fitting marginal structural Cox model, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as marginal structural Cox model in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995-2008).

  14. Action Potential Broadening in Capsaicin-Sensitive DRG Neurons from Frequency-Dependent Reduction of Kv3 Current.

    Science.gov (United States)

    Liu, Pin W; Blair, Nathaniel T; Bean, Bruce P

    2017-10-04

    Action potential (AP) shape is a key determinant of cellular electrophysiological behavior. We found that in small-diameter, capsaicin-sensitive dorsal root ganglia neurons corresponding to nociceptors (from rats of either sex), stimulation at frequencies as low as 1 Hz produced progressive broadening of the APs. Stimulation at 10 Hz for 3 s resulted in an increase in AP width by an average of 76 ± 7% at 22°C and by 38 ± 3% at 35°C. AP clamp experiments showed that spike broadening results from frequency-dependent reduction of potassium current during spike repolarization. The major current responsible for frequency-dependent reduction of overall spike-repolarizing potassium current was identified as Kv3 current by its sensitivity to low concentrations of 4-aminopyridine (IC 50 action potentials of small-diameter rat DRG neurons showed spike broadening at frequencies as low as 1 Hz and that spike broadening resulted predominantly from frequency-dependent inactivation of Kv3 channels. Spike width helps to control transmitter release, conduction velocity, and firing patterns and understanding the role of particular potassium channels can help to guide new pharmacological strategies for targeting pain-sensing neurons selectively. Copyright © 2017 the authors 0270-6474/17/379705-10$15.00/0.

  15. Viscosity-dependent drain current noise of AlGaN/GaN high electron mobility transistor in polar liquids

    International Nuclear Information System (INIS)

    Fang, J. Y.; Hsu, C. P.; Kang, Y. W.; Fang, K. C.; Kao, W. L.; Yao, D. J.; Chen, C. C.; Li, S. S.; Yeh, J. A.; Wang, Y. L.; Lee, G. Y.; Chyi, J. I.; Hsu, C. H.; Huang, Y. F.; Ren, F.

    2013-01-01

    The drain current fluctuation of ungated AlGaN/GaN high electron mobility transistors (HEMTs) measured in different fluids at a drain-source voltage of 0.5 V was investigated. The HEMTs with metal on the gate region showed good current stability in deionized water, while a large fluctuation in drain current was observed for HEMTs without gate metal. The fluctuation in drain current for the HEMTs without gate metal was observed and calculated as standard deviation from a real-time measurement in air, deionized water, ethanol, dimethyl sulfoxide, ethylene glycol, 1,2-butanediol, and glycerol. At room temperature, the fluctuation in drain current for the HEMTs without gate metal was found to be relevant to the dipole moment and the viscosity of the liquids. A liquid with a larger viscosity showed a smaller fluctuation in drain current. The viscosity-dependent fluctuation of the drain current was ascribed to the Brownian motions of the liquid molecules, which induced a variation in the surface dipole of the gate region. This study uncovers the causes of the fluctuation in drain current of HEMTs in fluids. The results show that the AlGaN/GaN HEMTs may be used as sensors to measure the viscosity of liquids within a certain range of viscosity

  16. A possible case of natalizumab-dependent suicide attempt: A brief review about drugs and suicide.

    Science.gov (United States)

    Mumoli, Laura; Ciriaco, Miriam; Gambardella, Antonio; Bombardiere, Giuseppe Nicodemo; Valentino, Paola; Palleria, Caterina; Labate, Angelo; Russo, Emilio

    2013-12-01

    β-Interferon therapy is known to be a potential trigger of suicidal behavior, but this effect has not been previously reported for other multiple sclerosis (MS) treatments, such as, natalizumab. Here we report the case history of a 32-year-old woman affected by relapsing-remitting MS, who attempted suicide during natalizumab treatment. This case suggests that a suicidal ideation might be a rare side effect of natalizumab. Nevertheless, this case represents the first evidence of the new adverse drug reaction related to natalizumab treatment. We should alert clinicians to be aware of the possibility of paradoxical activation of suicidality during its therapeutic use. The main purpose of the present article is to use this case to review the possible relationship between suicidal behavior and drugs.

  17. Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs

    Science.gov (United States)

    Li, Xuanwen; Fries, Susanne; Li, Ruizhi; Lawson, John A.; Propert, Kathleen J.; Diamond, Scott L.; Blair, Ian A.; FitzGerald, Garret A.; Grosser, Tilo

    2014-01-01

    The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs—ibuprofen, naproxen, and celecoxib—to cause a drug–drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug–drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk. PMID:25385584

  18. Ventricular configuration and cerebral growth in infants born to drug-dependent mothers

    International Nuclear Information System (INIS)

    Pasto, M.E.; Deiling, J.M.; Kurtz, A.B.; Goldberg, B.; Graziani, L.J.; Tunis, S.L.; Finnegan, L.P.

    1985-01-01

    Cranial ultrasound examinations were performed during the first 3 days of life and at age 1 month on 22 infants with the neonatal abstinence syndrome. The results were compared to those obtained in 15 control infants who were not exposed to narcotic drugs in utero. The ultrasound images were examined for ventricular configuration, intracranial hemidiameters, area of thalami, and width of temporal lobes. At 24 to 72 h and at 1 month of age, significantly more drug-exposed than control infants had a slit-like ventricular configuration. The intracranial hemidiameter was significantly smaller in the drug-exposed than in the control infants. All cerebral measurements except the right temporal lobe demonstrated significant growth over the first month of life in both groups of infants. By means of ancillary examinations (computerized tomography and transfontanel pressure measurements) the pathogenesis of the slit-like ventricles was found not to be related to edema or to increased intracranial pressure. Whether or not the ventricles remain small and brain growth remains parallel after the period of abstinence awaits further investigation. (orig.)

  19. Analysis of dominant carrier recombination mechanisms depending on injection current in InGaN green light emitting diodes

    International Nuclear Information System (INIS)

    Kim, Kyu-Sang; Han, Dong-Pyo; Kim, Hyun-Sung; Shim, Jong-In

    2014-01-01

    Two kinds of green InGaN light emitting diodes (LEDs) have been investigated in order to understand the different slopes in logarithmic light output power-current (L-I) curves. Through the analysis of the carrier rate equation and by considering the carrier density-dependent the injection efficiency into quantum wells, the slopes of the logarithmic L-I curves can be more rigorously understood. The low current level, two as the tunneling current is initially dominant. The high current level beyond the peak of the external quantum efficiency (EQE) diminishes below one as the carrier overflow becomes dominant. In addition, the normalized carrier injection efficiency can be obtained by analyzing the slopes of the logarithmic L-I curves. The carrier injection efficiency decreases after the EQE peak of the InGaN LEDs, determined from the analysis of the slopes of the logarithmic L-I curves

  20. HIV risk-taking behaviour among injecting drug users currently, previously and never enrolled in methadone treatment.

    Science.gov (United States)

    Baker, A; Kochan, N; Dixon, J; Wodak, A; Heather, N

    1995-04-01

    This study compares the injecting and sexual risk-taking behaviour among injecting drug users (IDUs) currently, previously and never enrolled in methadone maintenance treatment (MMT). All subjects had injected during the 6 months prior to the day of interview. The current MMT group showed significantly lower injecting risk-taking behaviour subscale scores on the HIV Risk-taking Behaviour Scale (HRBS) of the Opiate Treatment Index than the previous MMT and non-MMT groups together. The current MMT group differed from the other two groups in the frequency of injecting and cleaning of injection equipment with bleach. There was no difference between the current MMT group and the other two groups combined in sexual risk-taking behaviour scores on the HRBS. There were no differences between the previous MMT and non-MMT groups in injecting and sexual risk-taking behaviour. HIV seroprevalence was low and there was no difference in seroprevalence between groups. Thus, IDUs currently enrolled in MMT are at reduced risk for HIV infection when compared with IDUs who have previously or never been enrolled in MMT. However, the absence of a difference between the current MMT and other two groups in frequency of sharing behaviours suggests the need for additional strategies among MMT clients to reduce needle-sharing. Possible strategies include the application of relapse prevention interventions and the availability of sterile injecting equipment in MMT clinics. Further research is needed to identify factors which increase attraction and retention of IDUs to MMT.

  1. Gene Therapy with Helper-Dependent Adenoviral Vectors: Current Advances and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Philip Ng

    2010-09-01

    Full Text Available Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells is one of the major drawbacks of first generation Adenovirus vectors and has been overcome by the latest generation of recombinant Adenovirus, the Helper-Dependent Adenoviral (HDAd vectors. HDAds have innovative features including the complete absence of viral coding sequences and the ability to mediate high level transgene expression with negligible chronic toxicity. This review summarizes the many aspects of HDAd biology and structure with a major focus on in vivo gene therapy application and with an emphasis on the unsolved issues that these vectors still presents toward clinical application.

  2. Tunneling Characteristics Depending on Schottky Barriers and Diffusion Current in SiOC.

    Science.gov (United States)

    Oh, Teresa; Kim, Chy Hyung

    2016-02-01

    To obtain a diffusion current in SiOC, the aluminum doped zinc oxide films were deposited on SiOC/Si wafer by a RF magnetron sputtering. All the X-ray patterns of the SiOC films showed amorphous phases. The level of binding energy of Si atoms will lead to an additional potential modulation by long range Coulombic and covalent interactions with oxygen ions. The growth of the AZO film was affected by the characteristics of SiOC, resulting in similar trends in XPS spectra and a shift to higher AZO lattice d values than the original AZO d values in XRD analyses. The charges trapped by the defects at the interlayer between AZO and SiOC films induced the decreased mobility of carriers. In the absence of trap charges, AZO grown on SiOC film such as the sample prepared at O2 = 25 or 30 sccm, which has low charge carrier concentration and high mobility, showed high mobility in an ambipolar characteristic of oxide semiconductor due to the tunneling effect and diffusion current. The structural matching of an interface between AZO and amorphous SiOC enhanced the height of Schottky Barrier (SB), and then the mobility was increased by the tunneling effect from band to band through the high SB.

  3. Time-dependent recovery of in vivo binding sites after drug dosing: A method for radiotracer evaluation

    International Nuclear Information System (INIS)

    Kilbourn, Michael R.

    1997-01-01

    The recovery of in vivo binding sites for (±)-α-[ 11 C]methoxytetrabenazine, a radioligand for the monoamine vesicular transporter (VMAT2), was determined in mouse brain at various times following a pharmacological dose of tetrabenazine. Concentrations of in vivo radioligand binding sites progressively increased and had reached control values by 8.5 h, and this recovery was consistent with the pharmacokinetics of the competing drug tetrabenazine and its active metabolite, dihydrotetrabenazine. This study demonstrates a simple experimental protocol of using a single dose of a reversible competing drug and time-dependent measurements of in vivo binding of a radioligand. This protocol is suitable for testing the sensitivity of an in vivo radiotracer for measurement of varying concentrations of in vivo binding sites

  4. New insights into the use of currently available non-steroidal anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Brune K

    2015-02-01

    Full Text Available Kay Brune,1 Paola Patrignani2 1Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; 2Department of Neuroscience, Imaging and Clinical Sciences, Center of Excellence on Aging, G d’Annunzio University, Chieti, Italy Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs, which act via inhibition of the cyclooxygenase (COX isozymes, were discovered more than 100 years ago. They remain a key component of the pharmacological management of acute and chronic pain. The COX-1 and COX-2 isozymes have different biological functions; analgesic activity is primarily (although not exclusively associated with inhibition of COX-2, while different side effects result from the inhibition of COX-1 and COX-2. All available NSAIDs, including acetaminophen and aspirin, are associated with potential side effects, particularly gastrointestinal and cardiovascular effects, related to their relative selectivity for COX-1 and COX-2. Since all NSAIDs exert their therapeutic activity through inhibition of the COX isozymes, strategies are needed to reduce the risks associated with NSAIDs while achieving sufficient pain relief. A better understanding of the inhibitory activity and COX-1/COX-2 selectivity of an NSAID at therapeutic doses, based on pharmacokinetic and pharmacodynamic properties (eg, inhibitory dose, absorption, plasma versus tissue distribution, and elimination, and the impact on drug tolerability and safety can guide the selection of appropriate NSAIDs for pain management. For example, many NSAIDs with moderate to high selectivity for COX-2 versus COX-1 can be administered at doses that maximize efficacy (~80% inhibition of COX-2 while minimizing COX-1 inhibition and associated side effects, such as gastrointestinal toxicity. Acidic NSAIDs with favorable tissue distribution and short plasma half-lives can additionally be dosed to provide near-constant analgesia while

  5. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases.

    Science.gov (United States)

    Felder, Christian C; Goldsmith, Paul J; Jackson, Kimberley; Sanger, Helen E; Evans, David A; Mogg, Adrian J; Broad, Lisa M

    2018-01-25

    The cholinergic signalling system has been an attractive pathway to seek targets for modulation of arousal, cognition, and attention which are compromised in neurodegenerative and neuropsychiatric diseases. The acetylcholine muscarinic receptor M1 and M4 subtypes which are highly expressed in the central nervous system, in cortex, hippocampus and striatum, key areas of cognitive and neuropsychiatric control, have received particular attention. Historical muscarinic drug development yielded first generation agonists with modest selectivity for these two receptor targets over M2 and M3 receptors, the major peripheral sub-types hypothesised to underlie the dose-limiting clinical side effects. More recent compound screening and medicinal chemistry optimization of orthosteric and allosteric agonists, and positive allosteric modulators binding to sites distinct from the highly homologous acetylcholine binding pocket have yielded a collection of highly selective tool compounds for preclinical validation studies. Several M1 selective ligands have progressed to early clinical development and in time will hopefully lead to useful therapeutics for treating symptoms of Alzheimer's disease and related disorders. Copyright © 2018. Published by Elsevier Ltd.

  6. Methylxanthines and drug dependence: a focus on interactions with substances of abuse.

    Science.gov (United States)

    Morelli, Micaela; Simola, Nicola

    2011-01-01

    This chapter examines the psychostimulant actions of methylxanthines, with a focus on the consequences of their excessive use. Consumption of methylxanthines is pervasive and their use is often associated with that of substances known to produce dependence and to have abuse potential. Therefore, the consequences of this combined use are taken into consideration in order to evaluate whether, and to what extent, methylxanthines could influence dependence on or abuse of other centrally active substances, leading to either amplification or attenuation of their effects. Since the methylxanthine that mostly influences mental processes and readily induces psychostimulation is caffeine, this review mainly focuses on caffeine as a prototype of methylxanthine-produced dependence, examining, at the same time, the risks related to caffeine use.

  7. Effectiveness of group cognitive therapy about opium addict complications on attitude of adolescents with drug dependent parents

    Directory of Open Access Journals (Sweden)

    Kaveh Hojjat

    2015-12-01

    Full Text Available Background and Aim: Statistics show that 30% to 40 % of  opium addicted fathers’ children are prone to substance abuse in the future. The present study aimed at assessing the effectiveness of cognitive therapy approach  to attitude changing of adolescents with substance dependent fathers. Materials and Methods:  In this controlled. field-trail randomized study. .data collection tool was “attitude to addiction questionnaire”. The study population was all male students in the first grade of high school in Maneh - Samalghan city. . Six sessions of group cognitive therapy based on the effectiveness of drug side-effects in drug-addicted fathers’ adolescent children’s attitude were held. The above-mentioned questionnaire was filled out before and after intervention. The obtained data  was fed into SPSS software (V: 16 using. Independent t-test .and paired t-test were used for analysis and P<0.05 was taken as the significant level. Results:  There were no significant differences between the two groups in pre-test regarding their attitude about drug abuse (P=.20%. Mean score variance from pre-test to post-test in the intervention group decreased, but in the control group, it showed a slight increase. This means that the intervention reduced the positive attitude towards drugs, but the changes were not statistically significant (p=0.57. Besides, among ten factors decisive in an individual’s attitude about addiction, only group cognitive therapy  was able  to decrease mean points of an individual’s attitude about drug abuse .. Significantly (P = 0.04. Conclusion: It was found that group cognitive therapy education about opium  addict complicationsdidn`t have a significant effect on the attitude of the students with addicted fathers. Thus, a change of adolescents’ attitude requires more research.

  8. Addiction research centres and the nurturing of creativity: National Drug Dependence Treatment Centre, India--a profile.

    Science.gov (United States)

    Ray, Rajat; Dhawan, Anju; Chopra, Anita

    2013-10-01

    The National Drug Dependence Treatment Centre (NDDTC) is a part of the All India Institute of Medical Sciences, a premier autonomous medical university in India. This article provides an account of its origin and its contribution to the field of substance use disorder at the national and international levels. Since its establishment, the NDDTC has played a major role in the development of various replicable models of care, the training of post-graduate students of psychiatry, research, policy development and planning. An assessment of the magnitude of drug abuse in India began in the early 1990s and this was followed by a National Survey on Extent, Patterns and Trends of Drug Abuse in 2004. Several models of clinical care have been developed for population subgroups in diverse settings. The centre played an important role in producing data and resource material which helped to scale up opioid substitution treatment in India. A nationwide database on the profile of patients seeking treatment (Drug Abuse Monitoring System) at government drug treatment centres has also been created. The centre has provided valuable inputs for the Government of India's programme planning. Besides clinical studies, research has also focused on pre-clinical studies. Capacity-building is an important priority, with training curricula and resource material being developed for doctors and paramedical staff. Many of these training programmes are conducted in collaboration with other institutions in the country. The NDDTC has received funding from several national and international organizations for research and scientific meetings, and, most recently (2012), it has been designated as a World Health Organization Collaborating Centre on Substance Abuse. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

  9. Planning deficits in polysubstance dependent users: Differential associations with severity of drug use and intelligence.

    Science.gov (United States)

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

    2016-05-01

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

  10. The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type.

    Science.gov (United States)

    Fox, Helen C; Sofuoglu, Mehmet; Morgan, Peter T; Tuit, Keri L; Sinha, Rajita

    2013-09-01

    Exogenous progesterone has been shown to attenuate the rewarding effects of cocaine. However, its effects on provoked drug craving, stress arousal and cognitive performance has not been systematically investigated in cocaine dependent men and women. Thus, we conducted a double-blind placebo-controlled study assessing the efficacy of progesterone in reducing provoked drug craving, stress system arousal and improving cognitive performance in cocaine dependent men and women. Forty-two early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily doses of placebo (12M/9F) or micronized progesterone (12M/9F) (400 mg/day), for 7 days. Under experimental conditions, all subjects were exposed to three 5-min personalized guided imagery conditions (stress, cocaine cue, relaxing), one per day, consecutively in a random, counterbalanced order. Subjective craving, mood, hypothalamic-pituitary-adrenal (HPA) and cardiovascular output, and a cognitive measure of inhibitory control (Stroop Color Word Task) were assessed pre- and post imagery. Progesterone relative to placebo significantly decreased cue-induced craving and cortisol responses and increased cue-induced ACTH. In addition, women but not men receiving progesterone reported lower ratings of negative emotion and higher ratings of relaxed mood following stress exposure. Improved Stroop performance was observed in all participants receiving progesterone, across all conditions. Progesterone was selectively effective in reducing cocaine cue-induced but not stress-related cocaine craving as well as specific measures of the provoked arousal state. Findings suggest that progesterone's effects on drug craving and arousal are moderated by both the type of environmental cue exposure and gender. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. FUNCTIONAL GENOMICS IDENTIFIES TIS21-DEPENDENT MECHANISMS AND PUTATIVE CANCER DRUG TARGETS UNDERLYING MEDULLOBLASTOMA SHH-TYPE DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    Giulia Gentile

    2016-11-01

    Full Text Available We have recently generated a novel medulloblastoma (MB mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+-Tis21KO.ts main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs. By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+-is21 wild-type versus Ptch1+-Tis21 knockout, among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets.The data analysis using bioinformatic tools revealed: i a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; ii a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype the neural cell type involved in group 3 MB; iii the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

  12. Stress Mediates the Relationship Between Past Drug Addiction and Current Risky Sexual Behaviour Among Low-income Women.

    Science.gov (United States)

    Wu, Z Helen; Tennen, Howard; Hosain, G M Monawar; Coman, Emil; Cullum, Jerry; Berenson, Abbey B

    2016-04-01

    This study examined the role of stress as a mediator of the relationship between prior drug addiction and current high-risk sexual behaviour. Eight hundred twenty women aged 18 to 30 years, who received care at community-based family planning clinics, were interviewed using the Composite International Diagnostic Interview and the Sexual Risk Behavior Assessment Schedule. They also completed the brief version of the Self-Control Scale as a measure of problem-solving strategies and measures of recent stressful events, daily hassles and ongoing chronic stress. Regardless of addiction history, stress exposure during the previous 12 months was associated with risky sexual behaviour during the previous 12 months. Structural equation modelling revealed that 12-month stress levels mediated the relationship between past drug addiction and 12-month high-risk sexual behaviours, as well as the negative relationship between problem-solving strategies and high-risk sexual behaviours. Problem-solving strategies did not moderate the relationship between drug addiction and high-risk sexual behaviours. These findings suggest that stress management training may help reduce risky behaviour among young, low-income women. Copyright © 2014 John Wiley & Sons, Ltd.

  13. Current Trends of Using Antimicrobial Drugs in the ICU at a Tertiary Level Teaching Hospital in Mymensingh.

    Science.gov (United States)

    Saha, S K; Shaha, K C; Haque, M F; Khatun, S; Akhter, S M; Akhter, H

    2016-10-01

    The aim of the present study was to investigate the current trends of using antimicrobial drugs in the ICU at a tertiary level teaching hospital in Mymensingh. The study of prescribing patterns seeks to monitor, evaluate and suggest modifications in clinicians prescribing habits so as to make medical care rational. It was an observational type of descriptive study, conducted in the Mymensingh medical college hospital, Mymensingh, during the study period of June 2016 to September 2016.The study was approved by the institutional ethical committee. Most patients in the ICU belonged to the older age group >60 years. Male patients were more than the female patients in ICU. Average duration of stay in ICU was 4.35 days. Admissions in ICU were common due to respiratory system related diseases and the present study showed that 31.68% of the reported cases belong to the respiratory system. Average number of drugs per prescription was 6.46. Average number of anti-microbial drugs per prescription was 1.38. Cephalosporin group and individually ceftriaxone was the most frequently prescribed antimicrobial group and agent respectively in the ICU. Most commonly used antimicrobial combination was Cephalosporin and Metronidazole (43.33%) followed by Carbapenem (Meropenem) and Metronidazole (13.33%). Most antimicrobial agents were prescribed without bacteriological culture and sensivity testing evidence. There is a need for motivating the physicians to prescribe antimicrobial agents with supportive bacteriological evidences.

  14. Aldosterone downregulates delayed rectifier potassium currents through an angiotensin type 1 receptor-dependent mechanism.

    Science.gov (United States)

    Lv, Yankun; Wang, Yanjun; Zhu, Xiaoran; Zhang, Hua

    2018-01-01

    We have previously shown that aldosterone downregulates delayed rectifier potassium currents (I Ks ) via activation of the mineralocorticoid receptor (MR) in adult guinea pig cardiomyocytes. Here, we investigate whether angiotensin II/angiotensin type 1 receptor (AngII/AT1R) and intracellular calcium also play a role in these effects. Ventricular cardiomyocytes were isolated from adult guinea pigs and incubated with aldosterone (1 μmol·L -1 ) either alone or in combination with enalapril (1 μmol·L -1 ), losartan (1 μmol·L -1 ), nimodipine (1 μmol·L -1 ), or BAPTA-AM (2.5 μmol·L -1 ) for 24 h. We used the conventional whole cell patch-clamp technique to record the I Ks component. In addition, we evaluated expression of the I Ks subunits KCNQ1 and KCNE1 using Western blotting. Our results showed that both enalapril and losartan, but not nimodipine or BAPTA-AM, completely reversed the aldosterone-induced inhibition of I Ks and its effects on KCNQ1/KCNE1 protein levels. Furthermore, we found that AngII/AT1R mediates the inhibitory effects of aldosterone on I Ks . Finally, the downregulation of I Ks induced by aldosterone did not occur secondarily to a change in intracellular calcium concentrations. Taken together, our findings demonstrate that crosstalk between MR and AT1R underlies the effects of aldosterone, and provide new insights into the mechanism underlying potassium channels.

  15. Reducing the iron burden and improving survival in transfusion-dependent thalassemia patients: current perspectives

    Directory of Open Access Journals (Sweden)

    Bayanzay K

    2016-08-01

    Full Text Available Karim Bayanzay, Lama Alzoebie Department of Hematology, Gulf Medical University, Ajman, United Arab Emirates Abstract: Hypertransfusion regimens for thalassemic patients revolutionized the management of severe thalassemia; transforming a disease which previously led to early infant death into a chronic condition. The devastating effect of the accrued iron from chronic blood transfusions necessitates a more finely tuned approach to limit the complications of the disease, as well as its treatment. A comprehensive approach including carefully tailored transfusion protocol, continuous monitoring and assessment of total body iron levels, and iron chelation are currently the mainstay in treating iron overload. There are also indications for ancillary treatments, such as splenectomy and fetal hemoglobin induction. The main cause of death in iron overload continues to be related to cardiac complications. However, since the widespread use of iron chelation started in the 1970s, there has been a general improvement in survival in these patients. Keywords: hematology, chelators, deferoxamine, deferiserox, deferiprone, liver iron concentration, iron overload, serum ferritin concentration, hepatic iron storage, iron chelation therapy

  16. Extended partially conserved axial-vector current hypothesis and model-dependent results

    International Nuclear Information System (INIS)

    Dominguez, C.A.

    1977-01-01

    The corrections to Goldberger-Treiman relations for ΔS = 0 and vertical-bardeltaSvertical-bar = 1 β decays (Δ/sub π/and Δ/sub K/, respectively) are estimated from a Veneziano-type model for three-point functions. The effect of unitarizing the model is also discussed, and it turns out that Δ/sub π/and Δ/sub K/ are almost insensitive to a variation in the widths of the pseudoscalar-meson daughters. Moreover, the predictions for Δ/sub π/and Δ/sub K/ are in close agreement with experiment. Finally, on-mass-shell extrapolation factors for chiral anomalies in eta → γγ and eta → π + π - γ are also derived, and agreement with experiment is found without the need for invoking eta-eta' mixing. In summary, the model discussed here seems to be a suitable implementation of the recently proposed extended partially conserved axial-vector current hypothesis

  17. Is effect of transcranial direct current stimulation on visuomotor coordination dependent on task difficulty?

    Directory of Open Access Journals (Sweden)

    Yong Hyun Kwon

    2015-01-01

    Full Text Available Transcranial direct current stimulation (tDCS, an emerging technique for non-invasive brain stimulation, is increasingly used to induce changes in cortical excitability and modulate motor behavior, especially for upper limbs. The purpose of this study was to investigate the effects of tDCS of the primary motor cortex on visuomotor coordination based on three levels of task difficulty in healthy subjects. Thirty-eight healthy participants underwent real tDCS or sham tDCS. Using a single-blind, sham-controlled crossover design, tDCS was applied to the primary motor cortex. For real tDCS conditions, tDCS intensity was 1 mA while stimulation was applied for 15 minutes. For the sham tDCS, electrodes were placed in the same position, but the stimulator was turned off after 5 seconds. Visuomotor tracking task, consisting of three levels (levels 1, 2, 3 of difficulty with higher level indicating greater difficulty, was performed before and after tDCS application. At level 2, real tDCS of the primary motor cortex improved the accurate index compared to the sham tDCS. However, at levels 1 and 3, the accurate index was not significantly increased after real tDCS compared to the sham tDCS. These findings suggest that tasks of moderate difficulty may improve visuomotor coordination in healthy subjects when tDCS is applied compared with easier or more difficult tasks.

  18. Psychiatric comorbidity in a sample of cocaine-dependent outpatients seen in the Community of Madrid drug addiction care network.

    Science.gov (United States)

    Martínez-Gras, Isabel; Ferre Navarrete, Francisco; Pascual Arriazu, Jesús; Peñas Pascual, José; de Iceta Ruiz de Gauna, Mariano; Fraguas Herráez, David; Rubio Valladolid, Gabriel

    2016-03-02

    The objective of this study was to estimate the current prevalence of psychiatric disorders in cocaine-dependent patients who attend different treatment centres in the Community of Madrid. A prospective multicentre study was used, and a total of 197 cocaine-dependent subjects were assessed. The assessment instrument used for diagnosis was the Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV). The main findings of this study were a high prevalence of psychiatric comorbidity in cocaine-dependent patients seeking treatment (64.0%). The most common Non Substance Use Disorders found were attention-deficit/hyperactivity Disorders (34.5%) and depressive disorders (13.7%). The most common Substance Use Disorder was alcohol dependence (28.4%). Cocaine-dependent patients who had a depressive disorder and were alcohol dependent presented a more severe clinical profile and a higher degree of psychopathology, measured using different assessment tools, than the patients who were only cocaine dependent. These data suggest that the presence of psychiatric comorbidity could constitute a risk factor associated with the severity of cocaine dependence. The clinical heterogeneity found also indicates the need to search for individualised treatments that more specifically fit the needs of this population.

  19. The "high solubility" definition of the current FDA Guidance on Biopharmaceutical Classification System may be too strict for acidic drugs.

    Science.gov (United States)

    Yazdanian, Mehran; Briggs, Katherine; Jankovsky, Corinne; Hawi, Amale

    2004-02-01

    The purpose of this study was to assess if the definition of high solubility as proposed in the FDA Guidance on Biopharmaceutical Classification System (BCS) is too strict for highly permeable acidic drugs. The solubility and permeability values of 20 (18 acidic and 2 non-acidic) nonsteroidal anti-inflammatory drugs (NSAID) were determined. The NSAIDs were grouped into three different sets having acetic acid, propionic acid, or other acidic moieties such as fenamate, oxicam, and salicylate. Two nonacidic NSAIDs (celecoxib and rofecoxib) were also included for comparison purposes. Equilibrium solubility values were determined at pH 1.2, 5.0, 7.4, and in biorelevant media simulating fed intestinal fluid at pH 5.0. For a select number of acids, we also measured solubility values in media simulating gastric and fasted intestinal fluids. Permeability classification was established relative to that of reference drugs in the Caco-2 cell permeability model. Permeability coefficients for all drugs were measured at concentrations corresponding to the lowest and highest marketed dose strengths dissolved in 250 ml volume, and their potential interaction with cellular efflux pumps was investigated. All NSAIDs with different acidic functional groups were classified as highly permeable based on their Caco-2 cell permeability. Only ketorolac appeared to have a potential for interaction with cellular efflux pumps. Solubility classification was based on comparison of equilibrium solubility at pH 1.2, 5.0. and 7.4 relative to marketed dose strengths in 250 ml. The pKa values for the acidic NSAIDs studied were between 3.5 and 5.1. and, as expected, their solubility increased dramatically at pH 7.4 compared to pH 1.2. Only three NSAIDs, ketorolac, ketoprofen. and acetyl salicylic acid, meet the current criteria for high solubility over the entire pH range. However, with the exception of ibuprofen, oxaprozin, and mefenamic acid, the remaining compounds can be classified as Class I drugs

  20. Phase II drugs currently being investigated for the treatment of hypogonadism.

    Science.gov (United States)

    Udedibia, Emeka; Kaminetsky, Jed

    2014-12-01

    Hypogonadism is the most common endocrine disorder, which affects men of all age groups. Recent shifts in public awareness, increased screening and recognition of symptoms and updated diagnostic criteria have led to an increase in men diagnosed as hypogonadal, including middle-aged and older men who previously would have been considered eugonadal. The increase in testosterone replacement therapy (TRT) has paralleled an increase in advancements of treatment options. Although current therapies are highly efficacious for many men, there remains a need for newer therapies that are more cost-effective, preserve ease of use and administration, mitigate undesirable effects and closely mimic physiological levels of testosterone. In this review, the authors discuss current TRTs and therapies in development for the treatment of hypogonadism. The focus is on therapies under Phase II investigation or those who have recently completed Phase II study. With several new therapies in development, the authors expect advancements in achieving treatment benchmarks that meet the needs of the individual symptomatic hypogonadal male. Increased public awareness of hypogonadism and TRT has led to a welcomed expansion in the choice of TRT options. These include new delivery systems, formulations, routes of administration and non-testosterone modalities.

  1. Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models.

    Science.gov (United States)

    Bunik, Victoria I; Tylicki, Adam; Lukashev, Nikolay V

    2013-12-01

    Bringing a knowledge of enzymology into research in vivo and in situ is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B1 ) and its diphosphorylated derivative (thiamin diphosphate; ThDP), and the fundamental differences in the ThDP-dependent enzymes of metabolic networks in mammals versus plants, fungi and bacteria, or in health versus disease, suggest that these enzymes are promising targets for biotechnological and medical applications. Here, the in vivo action of known regulators of ThDP-dependent enzymes, such as synthetic structural analogs of the enzyme substrates and thiamin, is analyzed in light of the enzymological data accumulated during half a century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Because of their selectivity, use of these compounds in cellular and animal models of ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared with the nonselective and enzymatically less characterized oxythiamin and pyrithiamin. In vitro studies of the interaction of thiamin analogs and their biological derivatives with potential in vivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, in vitro reactivities with potential targets are highly relevant in vivo. However, effective concentrations in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for the development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed. © 2013 FEBS.

  2. Depth-dependent effects of culling-do mesophotic lionfish populations undermine current management?

    Science.gov (United States)

    Andradi-Brown, Dominic A; Grey, Rachel; Hendrix, Alicia; Hitchner, Drew; Hunt, Christina L; Gress, Erika; Madej, Konrad; Parry, Rachel L; Régnier-McKellar, Catriona; Jones, Owen P; Arteaga, María; Izaguirre, Andrea P; Rogers, Alex D; Exton, Dan A

    2017-05-01

    Invasive lionfish ( Pterois volitans and P. miles ) have spread widely across the western Atlantic and are recognized as a major threat to native marine biodiversity. Although lionfish inhabit both shallow reefs and mesophotic coral ecosystems (MCEs; reefs from 30 to 150 m depth), the primary management response implemented by many countries has been diver-led culling limited to reefs less than 30 m. However, many reef fish undergo ontogenetic migrations, with the largest and therefore most fecund individuals found at greatest depths. Here, we study lionfish density, body size, maturity and dietary patterns across the depth gradient from the surface down to 85 m on heavily culled reefs around Utila, Honduras. We found lionfish at increased densities, body size and weight on MCEs compared with shallow reefs, with MCEs also containing the greatest proportion of actively spawning females, while shallow reefs contained the greatest proportion of immature lionfish. We then compared lionfish behaviour in response to divers on shallow culled and mesophotic unculled Utilan reefs, and on shallow unculled reefs in Tela Bay, on the Honduran mainland. We found that mesophotic lionfish exhibited high alert distances, consistent with individuals previously exposed to culling despite being below the depth limits of removal. In addition, when examining stomach content, we found that fish were the major component of lionfish diets across the depth gradient. Importantly, our results suggest that despite adjacent shallow culling, MCEs retain substantial lionfish populations that may be disproportionately contributing towards continued lionfish recruitment onto the shallow reefs of Utila, potentially undermining current culling-based management.

  3. Depth-dependent effects of culling—do mesophotic lionfish populations undermine current management?

    Science.gov (United States)

    Grey, Rachel; Hendrix, Alicia; Hitchner, Drew; Gress, Erika; Madej, Konrad; Parry, Rachel L.; Régnier-McKellar, Catriona; Jones, Owen P.; Arteaga, María; Izaguirre, Andrea P.; Rogers, Alex D.; Exton, Dan A.

    2017-01-01

    Invasive lionfish (Pterois volitans and P. miles) have spread widely across the western Atlantic and are recognized as a major threat to native marine biodiversity. Although lionfish inhabit both shallow reefs and mesophotic coral ecosystems (MCEs; reefs from 30 to 150 m depth), the primary management response implemented by many countries has been diver-led culling limited to reefs less than 30 m. However, many reef fish undergo ontogenetic migrations, with the largest and therefore most fecund individuals found at greatest depths. Here, we study lionfish density, body size, maturity and dietary patterns across the depth gradient from the surface down to 85 m on heavily culled reefs around Utila, Honduras. We found lionfish at increased densities, body size and weight on MCEs compared with shallow reefs, with MCEs also containing the greatest proportion of actively spawning females, while shallow reefs contained the greatest proportion of immature lionfish. We then compared lionfish behaviour in response to divers on shallow culled and mesophotic unculled Utilan reefs, and on shallow unculled reefs in Tela Bay, on the Honduran mainland. We found that mesophotic lionfish exhibited high alert distances, consistent with individuals previously exposed to culling despite being below the depth limits of removal. In addition, when examining stomach content, we found that fish were the major component of lionfish diets across the depth gradient. Importantly, our results suggest that despite adjacent shallow culling, MCEs retain substantial lionfish populations that may be disproportionately contributing towards continued lionfish recruitment onto the shallow reefs of Utila, potentially undermining current culling-based management. PMID:28573007

  4. Spin force and the generation of sustained spin current in time-dependent Rashba and Dresselhaus systems

    International Nuclear Information System (INIS)

    Ho, Cong Son; Tan, Seng Ghee; Jalil, Mansoor B. A.

    2014-01-01

    The generation of spin current and spin polarization in a two-dimensional electron gas structure is studied in the presence of Dresselhaus and Rashba spin-orbit couplings (SOC), the strength of the latter being modulated in time by an ac gate voltage. By means of the non-Abelian gauge field approach, we established the relation between the Lorentz spin force and the spin current in the SOC system, and showed that the longitudinal component of the spin force induces a transverse spin current. For a constant (time-invariant) Rashba system, we recover the universal spin Hall conductivity of e/(8π) , derived previously via the Berry phase and semi-classical methods. In the case of a time-dependent SOC system, the spin current is sustained even under strong impurity scattering. We evaluated the ac spin current generated by a time-modulated Rashba SOC in the absence of any dc electric field. The magnitude of the spin current reaches a maximum when the modulation frequency matches the Larmor frequency of the electrons

  5. Negative-ion current density dependence of the surface potential of insulated electrode during negative-ion implantation

    International Nuclear Information System (INIS)

    Tsuji, Hiroshi; Okayama, Yoshio; Toyota, Yoshitaka; Gotoh, Yasuhito; Ishikawa, Junzo; Sakai, Shigeki; Tanjyo, Masayasu; Matsuda, Kouji.

    1994-01-01

    Positive ion implantation has been utilized as the method of impurity injection in ultra-LSI production, but the problem of substrate charging cannot be resolved by conventional charge compensation method. It was forecast that by negative ion implantation, this charging problem can be resolved. Recently the experiment on the negative ion implantation into insulated electrodes was carried out, and the effect of negative ion implantation to this problem was proved. However, the dependence of charged potential on the increase of negative ion current at the time of negative ion implantation is a serious problem in large current negative ion implantation hereafter. The charged potential of insulated conductor substrates was measured by the negative ion implantation using the current up to several mA/cm 2 . The experimental method is explained. Medium current density and high current density negative ion implantation and charged potential are reported. Accordingly in negative ion implantation, if current density is optimized, the negative ion implantation without charging can be realized. (K.I.)

  6. Comparison of three different concepts of high dynamic range and dependability optimised current measurement digitisers for beam loss systems

    CERN Document Server

    Viganò, W; Effinger, E; Venturini, G G; Zamantzas, C

    2012-01-01

    Three Different Concepts of High Dynamic Range and Dependability Optimised Current Measurement Digitisers for Beam Loss Systems will be compared on this paper. The first concept is based on Current to Frequency Conversion, enhanced with an ADC for extending the dynamic range and decreasing the response time. A summary of 3 years’ worth of operational experience with such a system for LHC beam loss monitoring will be given. The second principle is based on an Adaptive Current to Frequency Converter implemented in an ASIC. The basic parameters of the circuit are discussed and compared with measurements. Several measures are taken to harden both circuits against single event effects and to make them tolerant for operation in radioactive environments. The third circuit is based on a Fully Differential Integrator for enhanced dynamic range, where laboratory and test installation measurements will be presented. All circuits are designed to avoid any dead time in the acquisition and have reliability and fail safe...

  7. Evaluations of in vitro metabolism, drug-drug interactions mediated by reversible and time-dependent inhibition of CYPs, and plasma protein binding of MMB4 DMS.

    Science.gov (United States)

    Hong, S Peter; Lusiak, Bozena D; Burback, Brian L; Johnson, Jerry D

    2013-01-01

    1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When (14)C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant (K i) value of 66.6 µmol/L. Based on the k inact/K I values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.

  8. Current antiviral drugs and their analysis in biological materials - Part II: Antivirals against hepatitis and HIV viruses.

    Science.gov (United States)

    Nováková, Lucie; Pavlík, Jakub; Chrenková, Lucia; Martinec, Ondřej; Červený, Lukáš

    2018-01-05

    This review is a Part II of the series aiming to provide comprehensive overview of currently used antiviral drugs and to show modern approaches to their analysis. While in the Part I antivirals against herpes viruses and antivirals against respiratory viruses were addressed, this part concerns antivirals against hepatitis viruses (B and C) and human immunodeficiency virus (HIV). Many novel antivirals against hepatitis C virus (HCV) and HIV have been introduced into the clinical practice over the last decade. The recent broadening portfolio of these groups of antivirals is reflected in increasing number of developed analytical methods required to meet the needs of clinical terrain. Part II summarizes the mechanisms of action of antivirals against hepatitis B virus (HBV), HCV, and HIV, their use in clinical practice, and analytical methods for individual classes. It also provides expert opinion on state of art in the field of bioanalysis of these drugs. Analytical methods reflect novelty of these chemical structures and use by far the most current approaches, such as simple and high-throughput sample preparation and fast separation, often by means of UHPLC-MS/MS. Proper method validation based on requirements of bioanalytical guidelines is an inherent part of the developed methods. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors.

    Science.gov (United States)

    Kolontarev, Konstantin; Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

    2016-01-01

    Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptom (LUTS) development in men [1]. The intensity of the symptoms may vary from mild to severe, significantly affecting the quality of life. Erectile dysfunction (ED) is one of the most challenging issues in modern urology that significantly influences the quality of life in men worldwide. The objective of this literature review was to analyze the current drug therapies of patients with BPH-LUTS, with the special emphasis on PDE5 inhibitors. The authors searched the literature for the period from 2000 until 2015 in MEDLINE and PubMed. Twenty-three articles were selected based on their reliability. A detailed analysis of the selected papers was performed. Primary attention was given to articles describing the use of PDE5. Works describing the use of different groups of drugs in patients with BPH-LUTS were also selected. The current literature analysis suggests that the introduction of PDE5 inhibitors in clinical practice for the treatment of patients with BPH-LUTS will allow for significant expansion of the therapeutic options for the treatment of this disease.

  10. Intensity dependent effects of transcranial direct current stimulation on corticospinal excitability in chronic spinal cord injury.

    Science.gov (United States)

    Murray, Lynda M; Edwards, Dylan J; Ruffini, Giulio; Labar, Douglas; Stampas, Argyrios; Pascual-Leone, Alvaro; Cortes, Mar

    2015-04-01

    To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) intensity on corticospinal excitability and affected muscle activation in individuals with chronic spinal cord injury (SCI). Single-blind, randomized, sham-controlled, crossover study. Medical research institute and rehabilitation hospital. Volunteers (N = 9) with chronic SCI and motor dysfunction in wrist extensor muscles. Three single session exposures to 20 minutes of a-tDCS (anode over the extensor carpi radialis [ECR] muscle representation on the left primary motor cortex, cathode over the right supraorbital area) using 1 mA, 2 mA, or sham stimulation, delivered at rest, with at least 1 week between sessions. Corticospinal excitability was assessed with motor-evoked potentials (MEPs) from the ECR muscle using surface electromyography after transcranial magnetic stimulation. Changes in spinal excitability, sensory threshold, and muscle strength were also investigated. Mean MEP amplitude significantly increased by approximately 40% immediately after 2mA a-tDCS (pre: 0.36 ± 0.1 mV; post: 0.47 ± 0.11 mV; P = .001), but not with 1 mA or sham. Maximal voluntary contraction measures remained unaltered across all conditions. Sensory threshold significantly decreased over time after 1mA (P = .002) and 2mA (P = .039) a-tDCS and did not change with sham. F-wave persistence showed a nonsignificant trend for increase (pre: 32% ± 12%; post: 41% ± 10%; follow-up: 46% ± 12%) after 2 mA stimulation. No adverse effects were reported with any of the experimental conditions. The a-tDCS can transiently raise corticospinal excitability to affected muscles in patients with chronic SCI after 2 mA stimulation. Sensory perception can improve with both 1 and 2 mA stimulation. This study gives support to the safe and effective use of a-tDCS using small electrodes in patients with SCI and highlights the importance of stimulation intensity. Copyright © 2015 American Congress of Rehabilitation

  11. [An evaluation of a symposium via satellite on alcoholism and drug dependence].

    Science.gov (United States)

    Ríos-Espinosa, E; Martínez-Salgado, H; Ruíz-Tapia, R; Domínguez-Cherit, L

    1993-01-01

    Results of a test given to participants in a symposium on alcoholism and drug abuse are presented. The symposium was broadcast via satellite simultaneously to five cities in Mexico, and included 8 pretaped panels covering topics on alcoholism and drug abuse. The methodology used for broadcasting the symposium allowed the interactive exchange of information between expert lecturers and participants. The quantitative and qualitative evaluation used the pretest-posttest design. Most of the participants were physicians (28.9%) followed by psychologists (25.7%) and social workers (18.1%). The global cognitive change among participants was 6 per cent. Almost 77 per cent of participants had scores between 51 and 70 points (over a possible maximum score of 100) in the pre-evaluation test, and 76.4 per cent had scores between 61 and 80 points in the postevaluation test. Health professionals with 1-3 years of experience had the largest change in scores (9%), followed by those with 3 to 5 years experience (8%). Professionals with 5 to 10 years of experience had a change of 5 per cent. Physicians showed the greatest cognitive change (7%) followed by psychologists and social workers with 5 per cent change. In the qualitative evaluation, 87.6 per cent of participants thought that the educational method used was "Excellent" of "Good". With respect to the satellite transmission, 79.4 per cent of participants thought it was "Excellent" or "Good". It is concluded that this type of educational events are useful in reaching health professionals who otherwise would not have access to specialized and updated information.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Women, Drug Dependency and Consequences: A Study from a Developing Country

    OpenAIRE

    Mohammad Khajedaluee; Maliheh Dadgarmoghaddam; Majidreza Erfanian; Arash Alipourtabrizi; Majid Khadem-Rezaiyan

    2015-01-01

    Introduction. Addiction in women can expose them to malnutrition, high blood pressure, cancer, and some other dangerous diseases like hepatitis, AIDS, or other sexual transmitted diseases. The aim of this study was to assess illegal sexual relations in three groups of women. Methods. This is a cross-sectional study that was done on 236 girls and young women aged 16?25 years in 2012 in three groups: vulnerable women who have substance dependency (crimes that had made women incarcerated were co...

  13. Long-lasting alterations in membrane properties, K+ currents and glutamatergic synaptic currents of nucleus accumbens medium spiny neurons in a rat model of alcohol dependence

    Directory of Open Access Journals (Sweden)

    Igor eSpigelman

    2012-06-01

    Full Text Available Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs and larger fast afterhyperpolarizations (fAHPs than MSNs from vehicle-treated animals, all suggestive of increases in K+-channel conductances. Significant increases in the Cs+-sensitive inwardly-rectifying K+-current accounted for the increased input resistance, while increases in the A-type K+-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.

  14. Association between current smoking and cognitive impairment depends on age: A cross-sectional study in Xi'an, China.

    Science.gov (United States)

    Liu, Jie; Shang, Suhang; Li, Pei; Deng, Meiying; Chen, Chen; Jiang, Yu; Dang, Liangjun; Qu, Qiumin

    2017-09-08

    Cigarette smoking is a modifiable risk factor for cognitive impairment, while the relationship between current smoking and cognitive impairment is not fully understood. The objectives were to identify a possible association between current smoking and cognitive impairment depending on age in the Chinese rural population. Data for the study consisted of 1,782 participants (40 years and older) who lived in a rural village in the vicinity of Xi'an, China. Data about smoking history and cognitive function were collected. Cognitive function was scored by the Mini-Mental State Examination. The effect of age on the relationship between current smoking and cognitive impairment was analyzed with interaction and stratified analysis by logistic regression models. Interaction analysis showed that current smoking is positively related with cognitive impairment (odds ratio [OR]=9.067; 95% confidence interval [95% CI] 1.305-62.979; P=.026). However, the interaction term, age by current smoking, is negatively related with cognitive impairment (OR=0.969; 95%CI 0.939-0.999; P=.045). Stratified logistic regression showed that in the 40-65 years of age sublayer, OR of current smoking is 1.966 (P=.044), whereas in the>65 years of age sublayer, the OR is 0.470 (P=.130). This means that the association between current smoking and cognitive impairment with age might be positive (OR>1) in lower age sublayers, but no significant difference in higher age sublayers. In conclusion, current smoking might be positively associated with cognitive impairment in the middle-aged but the relationship declines with increasing age. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  15. Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal.

    Science.gov (United States)

    Mai, Yang; Afonso-Pereira, Francisco; Murdan, Sudaxshina; Basit, Abdul W

    2017-09-30

    The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (pbioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (pbioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. W 2 and Q 2 dependence of charged hadron and pion multiplicities in vp andbar vp charged current interactionscharged current interactions

    Science.gov (United States)

    Jones, G. T.; Jones, R. W. L.; Morrison, D. R. O.; Mobayyen, M. M.; Wainstein, S.; Aderholz, M.; Hantke, D.; Hoffmann, E.; Katz, U. F.; Kern, J.; Schmitz, N.; Wittek, W.; Allport, P.; Borner, H. P.; Myatt, G.; Radojicic, D.; Bullock, F. W.; Burke, S.

    1990-03-01

    Using data on vp andbar vp charged current interactions from a bubble chamber experiment with BEBC at CERN, the average multiplicities of charged hadrons and pions are determined as functions of W 2 and Q 2. The analysis is based on ˜20000 events with incident v and ˜10000 events with incidentbar v. In addition to the known dependence of the average multiplicity on W 2 a weak dependence on Q 2 for fixed intervals of W is observed. For W>2 GeV and Q 2>0.1 GeV2 the average multiplicity of charged hadrons is well described by =a 1+ a 2ln( W 2/GeV2)+ a 3ln( Q 2/GeV2) with a 1=0.465±0.053, a 2=1.211±0.021, a 3=0.103±0.014 for the vp and a 1=-0.372±0.073, a 2=1.245±0.028, a 3=0.093±0.015 for thebar vp reaction.

  17. Current globalization of drug interventional clinical trials: characteristics and associated factors, 2011-2013.

    Science.gov (United States)

    Jeong, Sohyun; Sohn, Minji; Kim, Jae Hyun; Ko, Minoh; Seo, Hee-Won; Song, Yun-Kyoung; Choi, Boyoon; Han, Nayoung; Na, Han-Sung; Lee, Jong Gu; Kim, In-Wha; Oh, Jung Mi; Lee, Euni

    2017-06-21

    Clinical trial globalization is a major trend for industry-sponsored clinical trials. There has been a shift in clinical trial sites towards emerging regions of Eastern Europe, Latin America, Asia, the Middle East, and Africa. Our study objectives were to evaluate the current characteristics of clinical trials and to find out the associated multiple factors which could explain clinical trial globalization and its implications for clinical trial globalization in 2011-2013. The data elements of "phase," "recruitment status," "type of sponsor," "age groups," and "design of trial" from 30 countries were extracted from the ClinicalTrials.gov website. Ten continental representative countries including the USA were selected and the design elements were compared to those of the USA. Factors associated with trial site distribution were chosen for a multilinear regression analysis. The USA, Germany, France, Canada, and United Kingdom were the "top five" countries which frequently held clinical trials. The design elements from nine continental representative countries were quite different from those of the USA; phase 1 trials were more prevalent in India (OR 1.517, p globalization of clinical trials in the emerging regions of Asia, South Africa, and Eastern Europe developed in parallel with the factors of economic drive, population for recruitment, and regulatory constraints.

  18. Ayurveda and botanical drugs for epilepsy: Current evidence and future prospects.

    Science.gov (United States)

    Sriranjini, Sitaram Jaideep; Sandhya, Kumar; Mamta, Vernekar Sanjeeva

    2015-11-01

    The understanding of epilepsy has progressed since its earliest impression as a disease associated with paranormal and superstitious beliefs. Landmark advances have been made in deciphering the pathophysiological substrates involved in the disease process, and treatment advances have contributed significantly to ameliorating the seizures. However, disease-modifying agents are yet to be discovered. Ayurveda is a system of medicine that stresses a holistic approach to disease, and treatment is focused on disease modification and symptom management. Herbs form the core of Ayurveda medicine; though many of them have been studied for their anticonvulsant activity, very few actually mention the reference of these herbs in Ayurveda literature. Other therapeutic interventions used in Ayurveda are relatively unexplored, and future research will need to focus on this. The current manuscript briefly discusses the understanding of epilepsy as per Ayurveda and reviews herbs that have been studied for their anticonvulsant activity mentioned in Ayurveda literature. This article is part of a Special Issue entitled "Botanicals for Epilepsy". Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Paradoxical dopaminergic drug effects in extraversion: Dose- and time-dependent effects of Sulpiride on EEG theta activity

    Directory of Open Access Journals (Sweden)

    Mira-Lynn eChavanon

    2013-04-01

    Full Text Available Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: Depending on the personality trait agentic extraversion (aE; i.e. assertiveness, dominance, ambition, positive emotionality the selective dopamine D2 receptor antagonist sulpiride (200 mg had opposite effects on resting posterior versus anterior theta activity in the electroencephalogram (EEG. In order to better describe these opposite pharmaco-EEG effects and to generate hypotheses regarding the underlying mechanisms, we measured the EEG intermittently over five hours in 80 healthy male volunteers extremely high or low in aE who had received either placebo or one of three doses of sulpiride (50 mg, 200 mg, or 400 mg. The findings suggest a model postulating stronger pre- versus postsynaptic subreceptor effects in high aE individuals compared to low aE individuals. Future studies may now systematically apply the model to other examples of paradoxical dopaminergic drug effects and examine the molecular basis of individual differences in pre- versus postsynaptic dopamine D2 subreceptor sensitivities and densities.

  20. Expressive writing for high-risk drug dependent patients in a primary care clinic: A pilot study

    Directory of Open Access Journals (Sweden)

    Wedgwood Lucinda

    2006-11-01

    Full Text Available Abstract Background Previous research has shown that expressive writing is beneficial in terms of both physical and emotional health outcomes. This study aimed to investigate the effectiveness and acceptability of a brief expressive writing intervention for high-risk drug dependent patients in a primary care clinic, and to determine the relationship between linguistic features of writing and health outcomes. Methods Participants completed four 15-minute expressive writing tasks over a week, in which they described their thoughts and feelings about a recent stressful event. Self-report measures of physical (SF-12 and psychological health (DASS-21 were administered at baseline and at a two-week follow-up. Fifty-three participants were recruited and 14 (26% completed all measures. Results No statistically significant benefits in physical or psychological health were found, although all outcomes changed in the direction of improvement. The intervention was well-received and was rated as beneficial by participants. The use of more positive emotion words in writing was associated with improvements in depression and stress, and flexibility in first person pronoun use was associated with improvements in anxiety. Increasing use of cognitive process words was associated with worsening depressive mood. Conclusion Although no significant benefits in physical and psychological health were found, improvements in psychological wellbeing were associated with certain writing styles and expressive writing was deemed acceptable by high-risk drug dependent patients. Given the difficulties in implementing psychosocial interventions in this population, further research using a larger sample is warranted.

  1. Dependence of electron peak current on hollow cathode dimensions and seed electron energy in a pseudospark discharge

    International Nuclear Information System (INIS)

    Cetiner, S. O.; Stoltz, P.; Messmer, P.; Cambier, J.-L.

    2008-01-01

    The prebreakdown and breakdown phases of a pseudospark discharge are investigated using the two-dimensional kinetic plasma simulation code OOPIC PRO. Trends in the peak electron current at the anode are presented as function of the hollow cathode dimensions and mean seed injection velocities at the cavity back wall. The plasma generation process by ionizing collisions is examined, showing the effect on supplying the electrons that determine the density of the beam. The mean seed velocities used here are varied between the velocity corresponding to the energy of peak ionization cross section, 15 times this value and no mean velocity (i.e., electrons injected with a temperature of 2.5 eV). The reliance of the discharge characteristics on the penetrating electric field is shown to decrease as the mean seed injection velocity increases because of its ability to generate a surplus plasma independent of the virtual anode. As a result, the peak current increases with the hollow cathode dimensions for the largest average injection velocity, while for the smallest value it increases with the area of penetration of the electric field in the hollow cathode interior. Additionally, for a given geometry an increase in the peak current with the surplus plasma generated is observed. For the largest seed injection velocity used a dependence of the magnitude of the peak current on the ratio of the hole thickness and hollow cathode depth to the hole height is demonstrated. This means similar trends of the peak current are generated when the geometry is resized. Although the present study uses argon only, the variation in the discharge dependencies with the seed injection energy relative to the ionization threshold is expected to apply independently of the gas type. Secondary electrons due to electron and ion impact are shown to be important only for the largest impact areas and discharge development times of the study

  2. Analyzing the dependence of oxygen incorporation current density on overpotential and oxygen partial pressure in mixed conducting oxide electrodes.

    Science.gov (United States)

    Guan, Zixuan; Chen, Di; Chueh, William C

    2017-08-30

    The oxygen incorporation reaction, which involves the transformation of an oxygen gas molecule to two lattice oxygen ions in a mixed ionic and electronic conducting solid, is a ubiquitous and fundamental reaction in solid-state electrochemistry. To understand the reaction pathway and to identify the rate-determining step, near-equilibrium measurements have been employed to quantify the exchange coefficients as a function of oxygen partial pressure and temperature. However, because the exchange coefficient contains contributions from both forward and reverse reaction rate constants and depends on both oxygen partial pressure and oxygen fugacity in the solid, unique and definitive mechanistic assessment has been challenging. In this work, we derive a current density equation as a function of both oxygen partial pressure and overpotential, and consider both near and far from equilibrium limits. Rather than considering specific reaction pathways, we generalize the multi-step oxygen incorporation reaction into the rate-determining step, preceding and following quasi-equilibrium steps, and consider the number of oxygen ions and electrons involved in each. By evaluating the dependence of current density on oxygen partial pressure and overpotential separately, one obtains the reaction orders for oxygen gas molecules and for solid-state species in the electrode. We simulated the oxygen incorporation current density-overpotential curves for praseodymium-doped ceria for various candidate rate-determining steps. This work highlights a promising method for studying the exchange kinetics far away from equilibrium.

  3. Injection current dependences of electroluminescence transition energy in InGaN/GaN multiple quantum wells light emitting diodes under pulsed current conditions

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Feng; Ikeda, Masao, E-mail: mikeda2013@sinano.ac.cn; Liu, Jianping; Zhang, Shuming [Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (CAS), Suzhou 215123 (China); Key Lab of Nanodevices and Applications, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (CAS), Suzhou 215123 (China); Zhou, Kun; Yang, Hui [Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (CAS), Suzhou 215123 (China); Key Lab of Nanodevices and Applications, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (CAS), Suzhou 215123 (China); Institute of Semiconductors (CAS), Beijing 100083 (China); Liu, Zongshun [Institute of Semiconductors (CAS), Beijing 100083 (China)

    2015-07-21

    Injection current dependences of electroluminescence transition energy in blue InGaN/GaN multiple quantum wells light emitting diodes (LEDs) with different quantum barrier thicknesses under pulsed current conditions have been analyzed taking into account the related effects including deformation caused by lattice strain, quantum confined Stark effects due to polarization field partly screened by carriers, band gap renormalization, Stokes-like shift due to compositional fluctuations which are supposed to be random alloy fluctuations in the sub-nanometer scale, band filling effect (Burstein-Moss shift), and quantum levels in finite triangular wells. The bandgap renormalization and band filling effect occurring at high concentrations oppose one another, however, the renormalization effect dominates in the concentration range studied, since the band filling effect arising from the filling in the tail states in the valence band of quantum wells is much smaller than the case in the bulk materials. In order to correlate the carrier densities with current densities, the nonradiative recombination rates were deduced experimentally by curve-fitting to the external quantum efficiencies. The transition energies in LEDs both with 15 nm quantum barriers and 5 nm quantum barriers, calculated using full strengths of theoretical macroscopic polarization given by Barnardini and Fiorentini [Phys. Status Solidi B 216, 391 (1999)] are in excellent accordance with experimental results. The LED with 5 nm barriers has been shown to exhibit a higher transition energy and a smaller blue shift than those of LED with 15 nm barriers, which is mainly caused by the smaller internal polarization field in the quantum wells.

  4. Severe Psychosis, Drug Dependence, and Hepatitis C Related to Slamming Mephedrone

    Directory of Open Access Journals (Sweden)

    Helen Dolengevich-Segal

    2016-01-01

    Full Text Available Background. Synthetic cathinones (SCs, also known as “bath salts,” are β-ketone amphetamine compounds derived from cathinone, a psychoactive substance found in Catha edulis. Mephedrone is the most representative SC. Slamming is the term used for the intravenous injection of these substances in the context of chemsex parties, in order to enhance sex experiences. Using IV mephedrone may lead to diverse medical and psychiatric complications like psychosis, aggressive behavior, and suicide ideation. Case. We report the case of a 25-year-old man admitted into a psychiatric unit, presenting with psychotic symptoms after slamming mephedrone almost every weekend for the last 4 months. He presents paranoid delusions, intense anxiety, and visual and kinesthetic hallucinations. He also shows intense craving, compulsive drug use, general malaise, and weakness. After four weeks of admission and antipsychotic treatment, delusions completely disappear. The patient is reinfected with hepatitis C. Discussion. Psychiatric and medical conditions related to chemsex and slamming have been reported in several European cities, but not in Spain. Psychotic symptoms have been associated with mephedrone and other SCs’ consumption, with the IV route being prone to produce more severe symptomatology and addictive conducts. In the case we report, paranoid psychosis, addiction, and medical complications are described.

  5. Severe Psychosis, Drug Dependence, and Hepatitis C Related to Slamming Mephedrone

    Science.gov (United States)

    Rodríguez-Salgado, Beatriz; Sánchez-Mateos, Daniel

    2016-01-01

    Background. Synthetic cathinones (SCs), also known as “bath salts,” are β-ketone amphetamine compounds derived from cathinone, a psychoactive substance found in Catha edulis. Mephedrone is the most representative SC. Slamming is the term used for the intravenous injection of these substances in the context of chemsex parties, in order to enhance sex experiences. Using IV mephedrone may lead to diverse medical and psychiatric complications like psychosis, aggressive behavior, and suicide ideation. Case. We report the case of a 25-year-old man admitted into a psychiatric unit, presenting with psychotic symptoms after slamming mephedrone almost every weekend for the last 4 months. He presents paranoid delusions, intense anxiety, and visual and kinesthetic hallucinations. He also shows intense craving, compulsive drug use, general malaise, and weakness. After four weeks of admission and antipsychotic treatment, delusions completely disappear. The patient is reinfected with hepatitis C. Discussion. Psychiatric and medical conditions related to chemsex and slamming have been reported in several European cities, but not in Spain. Psychotic symptoms have been associated with mephedrone and other SCs' consumption, with the IV route being prone to produce more severe symptomatology and addictive conducts. In the case we report, paranoid psychosis, addiction, and medical complications are described. PMID:27247820

  6. Developments in harmine pharmacology--implications for ayahuasca use and drug-dependence treatment.

    Science.gov (United States)

    Brierley, Daniel I; Davidson, Colin

    2012-12-03

    Ayahuasca is a hallucinogenic botanical mixture originating in the Amazon area where it is used ritually, but is now being taken globally. The 2 main constituents of ayahuasca are N,N-dimethyltryptamine (DMT), a hallucinogen, and harmine, a monoamine oxidase inhibitor (MAOI) which attenuates the breakdown of DMT, which would otherwise be broken down very quickly after oral consumption. Recent developments in ayahuasca use include the sale of these compounds on the internet and the substitution of related botanical (anahuasca) or synthetic (pharmahuasca) compounds to achieve the same desired hallucinogenic effects. One intriguing result of ayahuasca use appears to be improved mental health and a reduction in recidivism to alternate (alcohol, cocaine) drug use. In this review we discuss the pharmacology of ayahuasca, with a focus on harmine, and suggest pharmacological mechanisms for the putative reduction in recidivism to alcohol and cocaine misuse. These pharmacological mechanisms include MAOI, effects at 5-HT(2A) and imidazoline receptors and inhibition of dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A) and the dopamine transporter. We also speculate on the therapeutic potential of harmine in other CNS conditions. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Searches for Randomized Controlled Trials of Drugs in MEDLINE and EMBASE Using Only Generic Drug Names Compared with Searches Applied in Current Practice in Systematic Reviews

    Science.gov (United States)

    Waffenschmidt, Siw; Guddat, Charlotte

    2015-01-01

    Background: It is unclear which terms should be included in bibliographic searches for randomized controlled trials (RCTs) of drugs, and identifying relevant drug terms can be extremely laborious. The aim of our analysis was to determine whether a bibliographic search using only the generic drug name produces sufficient results for the generation…

  8. KChIP2 genotype dependence of transient outward current (Ito) properties in cardiomyocytes isolated from male and female mice.

    Science.gov (United States)

    Waldschmidt, Lara; Junkereit, Vera; Bähring, Robert

    2017-01-01

    The transient outward current (Ito) in cardiomyocytes is largely mediated by Kv4 channels associated with Kv Channel Interacting Protein 2 (KChIP2). A knockout model has documented the critical role of KChIP2 in Ito expression. The present study was conducted to characterize in both sexes the dependence of Ito properties, including current magnitude, inactivation kinetics, recovery from inactivation and voltage dependence of inactivation, on the number of functional KChIP2 alleles. For this purpose we performed whole-cell patch-clamp experiments on isolated left ventricular cardiomyocytes from male and female mice which had different KChIP2 genotypes; i.e., wild-type (KChIP2+/+), heterozygous knockout (KChIP2+/-) or complete knockout of KChIP2 (KChIP2-/-). We found in both sexes a KChIP2 gene dosage effect (i.e., a proportionality between number of alleles and phenotype) on Ito magnitude, however, concerning other Ito properties, KChIP2+/- resembled KChIP2+/+. Only in the total absence of KChIP2 (KChIP2-/-) we observed a slowing of Ito kinetics, a slowing of recovery from inactivation and a negative shift of a portion of the voltage dependence of inactivation. In a minor fraction of KChIP2-/- myocytes Ito was completely lost. The distinct KChIP2 genotype dependences of Ito magnitude and inactivation kinetics, respectively, seen in cardiomyocytes were reproduced with two-electrode voltage-clamp experiments on Xenopus oocytes expressing Kv4.2 and different amounts of KChIP2. Our results corroborate the critical role of KChIP2 in controlling Ito properties. They demonstrate that the Kv4.2/KChIP2 interaction in cardiomyocytes is highly dynamic, with a clear KChIP2 gene dosage effect on Kv4 channel surface expression but not on inactivation gating.

  9. Quantitative analysis of the Ca2+ -dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes.

    Science.gov (United States)

    Bartos, Daniel C; Morotti, Stefano; Ginsburg, Kenneth S; Grandi, Eleonora; Bers, Donald M

    2017-04-01

    [Ca 2+ ] i enhanced rabbit ventricular slowly activating delayed rectifier K + current (I Ks ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K + current (I Kr ) amplitude and voltage dependence were unaffected by high [Ca 2+ ] i . When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca 2+ transient or when [Ca 2+ ] i was buffered to 500 nm. The slowly activating delayed rectifier K + current (I Ks ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca 2+ ([Ca 2+ ] i ) and β-adrenergic receptor (β-AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca 2+ ] i dependence of I Ks in steady-state conditions and with dynamically changing membrane potential and [Ca 2+ ] i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca 2+ ] i , we found that raising [Ca 2+ ] i from 100 to 600 nm produced similar increases in I Ks as did β-AR activation, and the effects appeared additive. Both β-AR activation and high [Ca 2+ ] i increased maximally activated tail I Ks , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, I Ks recorded during a normal physiological Ca 2+ transient was similar to I Ks measured with [Ca 2+ ] i clamped at 500-600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca 2+ ] i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca 2+ ] i , in the submembrane or

  10. CALCULATED TEMPERATURE RISE AND THERMAL ELONGATION OF STRUCTURAL COMPONENTS, DEPENDING ON ACTION INTEGRAL OF INJECTED LIGHTNING CURRENTS

    DEFF Research Database (Denmark)

    Madsen, Søren Find

    2005-01-01

    expressions established, accounts for the geometry of the structure (round conductor, rectangular cross section, pipe, plane sheet, etc), the material properties (Aluminum, Copper, Carbon Fiber Composites, etc.), the frequency of the current (skin depth) and the Specific Energy (Action Integral). For linear...... structures (wires, bars etc.), the result is the resistance of the structure, the final temperature, and the thermal elongation depending on geometry and material properties. Regarding arc injection in the centre of plane specimens the equations enables calculation of the temperature as a function...

  11. Size-Dependent Regulation of Intracellular Trafficking of Polystyrene Nanoparticle-Based Drug-Delivery Systems.

    Science.gov (United States)

    Wang, Ting; Wang, Lu; Li, Xiaoming; Hu, Xingjie; Han, Yuping; Luo, Yao; Wang, Zejun; Li, Qian; Aldalbahi, Ali; Wang, Lihua; Song, Shiping; Fan, Chunhai; Zhao, Yun; Wang, Maolin; Chen, Nan

    2017-06-07

    Nanoparticles (NPs) have shown great promise as intracellular imaging probes or nanocarriers and are increasingly being used in biomedical applications. A detailed understanding of how NPs get "in and out" of cells is important for developing new nanomaterials with improved selectivity and less cytotoxicity. Both physical and chemical characteristics have been proven to regulate the cellular uptake of NPs. However, the exocytosis process and its regulation are less explored. Herein, we investigated the size-regulated endocytosis and exocytosis of carboxylated polystyrene (PS) NPs. PS NPs with a smaller size were endocytosed mainly through the clathrin-dependent pathway, whereas PS NPs with a larger size preferred caveolae-mediated endocytosis. Furthermore, our results revealed exocytosis of larger PS NPs and tracked the dynamic process at the single-particle level. These results indicate that particle size is a key factor for the regulation of intracellular trafficking of NPs and provide new insight into the development of more effective cellular nanocarriers.

  12. On the energy dependence of the relative contributions ionospheric and solar sources of the ring current protons

    International Nuclear Information System (INIS)

    Kovtyukh, A.

    2007-01-01

    The energy dependence of a fraction of ring current protons of i onospheric origin is calculated using the AMPTE/CCE data for a typical magnetic storm (D st = -120 nT). It is shown that at L = 6-7 (L is the Mcllwain parameter) this fraction monotonically decreases from ∼83 to 25-30% with an increase in proton energy from 5 to 315 keV and is 30-40% at energy 40-50 keV corresponding to the maximum of proton energy density at L 6-7. It is evident that the core of the ring current (L = 3.7-4.7) is enriched by solar protons with E∼10-200 keV during storm main phase (the maximum effect is achieved at E∼20-50 keV). (author)

  13. The dependence of the short circuit current with γ-radiation in CuGaSe2

    International Nuclear Information System (INIS)

    Gasimoglu, I.; Mamedova, I.A.; Bagirov, A.G.

    2005-01-01

    Full text: The A I B III C IV semiconducting compounds are of interest for semiconducting devising. In particular the presence of the birefringence makes the compounds as a perspective materials for using in nonlinear optical transformers. Besides, the complex generation-recombination processes in these compounds are due to the local states in the band gap, which is also due to the complex chemical structure of these compounds. In this report the results of the influence of γ-radiation on the short circuit current in CuGaSe 2 are presented. The Co 6 0 with the quantum energy of 1.25 MeV was a source of radiation. The resistance was 10 2 kΩ at 300 K. The In-Ga eutectic was used as a contact. The measurements have been carried out at 77 K. The electrometer B7-30 was used for the short circuit current measurements, sensitivity of which is 10 -15 A. The intensity of γ-rays was 20 R/s, durability of radiation was 15 min. The spectrometer SPM-2 was used as a source of radiation of monoxrmator light. The spectral dependence of short circuit current of non radiated CuGaSe 2 crystal has a maximum at λ=700 nm (0.77 eV) with the half width of 0.26 eV. The maximum of short circuit current is in good agreement with the value 1.8 eV at 300 K. That is why one can assume that observed peak in J sc ∼∼f(λ) dependence with the maximum at 1.77 eV is due to electronic transitions from the valence band to conduction band. After radiation of CuGaSe 2 crystal new maximum is observed in the spectral dependence of short circuit current at λ=770 nm (1.61 eV) at 77 K. Splitting between the peaks is 0.13 eV. The appearance of the second peak maybe is due to the formation of radiation defects of acceptor type, which are located for 0.13 eV above than the top of valence band. The peak at 1.59 eV, which is due the donor-acceptor recombination, is observed in photoluminescence spectra. It is assumed that, Se vacancy forms the donor levels, Cu vacancy -acceptor levels

  14. 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.

  15. 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

  16. Successful Treatment of a Drug-Resistant Epilepsy by Long-term Transcranial Direct Current Stimulation: A Case Report.

    Science.gov (United States)

    San-Juan, Daniel; Sarmiento, Carlos Ignacio; González, Katia Márquez; Orenday Barraza, José Manuel

    2018-01-01

    Transcranial direct current stimulation (tDCS) is a reemerged noninvasive cerebral therapy used to treat patients with epilepsy, including focal cortical dysplasia, with controversial results. We present a case of a 28-year-old female with left frontal cortical dysplasia refractory to antiepileptic drugs, characterized by 10-15 daily right tonic hemi-body seizures. The patient received a total of seven sessions of cathodal tDCS (2 mA, 30 min). The first three sessions were applied over three consecutive days, and the remaining four sessions of tDCS were given each at 2-week intervals. At the 1-year follow-up, the patient reported to have a single seizure per month and only mild adverse events.

  17. Drugs and having babies: an exploration of how a specialist clinic meets the needs of chemically dependent pregnant women.

    Science.gov (United States)

    Morris, Michelle; Seibold, Carmel; Webber, Ruth

    2012-04-01

    to explore the extent to which a specialist clinic meets the needs of chemically dependent women. a critical ethnography informed by theorists such as Habermas and feminists' interpretation of Foucault. a specialist antenatal clinic for chemically dependent pregnant women at a major metropolitan women's hospital in Melbourne, Australia. a purposive sample of twenty (20) chemically dependent pregnant women who attended the clinic. Data collection and analysis included three taped interviews (two preceding the birth and one post birth), observation of the interactions between the women and the clinic staff over a 25-month period and chart audits. similar to other studies there were multiple factors influencing development and maintenance of chemical dependency in this group of women, including family instability, family history of drug and alcohol abuse, childhood sexual abuse, having a chemically dependent partner and having a dual diagnosis of both drug addiction and mental illness. Initially there was considerable variation between the women and the clinic staff's expectations with regard to attending for antenatal care and conforming to a set regime as the women struggled with the contradictions inherent in their lifestyle and that of the 'normal' expectant mother. Aspects of that struggle included their belief that their opinions and knowledge of their lives was largely ignored, leading to episodes of resistance. Several women alleged the clinics staff's relationship with them was influenced by a belief that the women were 'hopeless addicts in need of expert medical and midwifery care' and that the clinic staff exercised control in an authoritarian manner. However, as they explored possibilities for collaboration, they realised they could exercise power and work towards a more equal relationship with staff. The quality of relationships in most instances improved over time, and if not always strictly collaborative, was situated at various points along a continuum

  18. Chloroquine uptake, altered partitioning and the basis of drug resistance: evidence for chloride-dependent ionic regulation.

    Science.gov (United States)

    Martiney, J A; Ferrer, A S; Cerami, A; Dzekunov, S; Roepe, P

    1999-01-01

    The biochemical mechanism of chloroquine resistance in Plasmodium falciparum remains unknown. We postulated that chloroquine-resistant strains could alter ion fluxes that then indirectly control drug accumulation within the parasite by affecting pH and/or membrane potential ('altered partitioning mechanism'). Two principal intracellular pH-regulating systems in many cell types are the amiloride-sensitive Na+/H+ exchanger (NHE), and the sodium-independent, stilbene-sensitive Cl-/HCO3- antiporter (AE). We report that under physiological conditions (balanced CO2 and HCO3-) chloroquine uptake and susceptibility are not altered by amiloride analogues. We also do not detect a significant difference in NHE activity between chloroquine-sensitive and chloroquine-resistant strains via single cell photometry methods. AE activity is dependent on the intracellular and extracellular concentrations of Cl- and HCO3- ions. Chloroquine-resistant strains differentially respond to experimental modifications in chloride-dependent homeostasis, including growth, cytoplasmic pH and pH regulation. Chloroquine susceptibility is altered by stilbene DIDS only on chloroquine-resistant strains. Our results suggest that a Cl(-)-dependent system (perhaps AE) has a significant effect on the uptake of chloroquine by the infected erythrocyte, and that alterations of this biophysical parameter may be part of the mechanism of chloroquine resistance in P. falciparum.

  19. Safety concerns and hidden agenda behind HPV vaccines: another generation of drug-dependent society?

    Science.gov (United States)

    Khatami, Mahin

    2016-12-01

    Analyses of data and hidden agenda behind repeated failed outcomes of cancer research and therapy, status of American health, safety concerns for HPV vaccines and future research considerations are summarized in this commentary. A closer look at cancer science reveals that highly power structure (system) in medical establishment vs. anti-system and chaos in cancer research ('medical/scientific ponzi schemes') is potent recipe for failed therapeutics that kills patients but generates huge corporate profit. American health status ranks last among other developed nations despite the highest amount that USA invests in healthcare. This is a wake-up call to make sure that the evil part of human being does not prevent the health services that the public deserves. Otherwise, 'it does not matter how many resources you have, if you don't know, or don't want to know, how to use them, they will never be enough'. Answer to cancer and improved public health is possible only by switching the current corruptive and abusive culture of 'who you know' to a culture of 'what you know'. Policy makers and professionals in decision making roles are urged to return to common sense and logics that our Forefathers used to serve the public.

  20. FKBP12-Dependent Inhibition of Calcineurin Mediates Immunosuppressive Antifungal Drug Action in Malassezia

    Directory of Open Access Journals (Sweden)

    Giuseppe Ianiri

    2017-10-01

    Full Text Available The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis. In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506, ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats.

  1. Chloride ions in the pore of glycine and GABA channels shape the time course and voltage dependence of agonist currents

    Science.gov (United States)

    Moroni, Mirko; Biro, Istvan; Giugliano, Michele; Vijayan, Ranjit; Biggin, Philip C.; Beato, Marco; Sivilotti, Lucia G.

    2011-01-01

    In the vertebrate CNS, fast synaptic inhibition is mediated by GABA and glycine receptors. We recently reported that the time course of these synaptic currents is slower when intracellular chloride is high. Here we extend these findings to measure the effects of both extracellular and intracellular chloride on the deactivation of glycine and GABA currents at both negative and positive holding potentials. Currents were elicited by fast agonist application to outside-out patches from HEK293 cells expressing rat glycine or GABA receptors. The slowing effect of high extracellular chloride on current decay was detectable only in low intracellular chloride (4 mM). Our main finding is that glycine and GABA receptors “sense” chloride concentrations because of interactions between the M2 pore-lining domain and the permeating ions. This hypothesis is supported by the observation that the sensitivity of channel gating to intracellular chloride is abolished if the channel is engineered to become cation-selective, or if positive charges in the external pore vestibule are eliminated by mutagenesis. The appropriate interaction between permeating ions and channel pore is also necessary to maintain the channel voltage sensitivity of gating, which prolongs current decay at depolarized potentials. Voltage-dependence is abolished by the same mutations that suppress the effect of intracellular chloride and also by replacing chloride with another permeant ion, thiocyanate. These observations suggest that permeant chloride affects gating by a foot-in-the-door effect, binding to a channel site with asymmetrical access from the intracellular and extracellular sides of the membrane. PMID:21976494

  2. Transcranial electric stimulation for intraoperative motor evoked potential monitoring: dependence of required stimulation current on interstimulus interval value.

    Science.gov (United States)

    Joksimovic, Boban; Szelenyi, Andrea; Seifert, Volker; Damjanovic, Aleksandar; Damjanovic, Aleksandra; Rasulic, Lukas

    2015-05-01

    To evaluate the relationship between stimulus intensity by constant current transcranial electric stimulation and interstimulus interval (ISI) for eliciting muscle motor evoked potentials (MEPs) in three different hand muscles and the tibialis anterior muscles. We tested intraoperatively different monophasic constant current pulses and ISIs in 22 patients with clinically normal motor function. Motor thresholds of contralateral muscle MEPs were determined at 0.5 milliseconds (ms) pulse duration and ISIs of 1, 2, 3, 4, 5, and 10 ms using a train of 2, 3, and 5 monophasic constant current pulses of 62 to 104 mA before craniotomy and after closure of the dura mater. The lowest stimulation threshold to elicit MEPs in the examined muscles was achieved with a train of 5 pulses (ISI: 3 ms) before craniotomy, which was statistically significant compared with 2 pulses (ISI: 3 ms) as well as 3 pulses (ISIs: 3 and 10 ms). An ISI of 3 ms gave the lowest motor thresholds with statistical significance compared with the ISIs of 4 ms (2 pulses) and of 1 ms (3 pulses). All current intensity (mA) and ISI (ms) relationship graphs had a trend of the exponential function as y = a + bx + c ρ (x), where y is intensity (mA) and x is ISI (ms). The minimum of the function was determined for each patient and each muscle. The difference was statistically significant between 3 and 5 pulses before craniotomy and between 3 and 5 pulses and 2 and 5 pulses after closure of the dura mater. In adult neurosurgical patients with a normal motor status, a train of 5 pulses and an ISI of 3 ms provide the lowest motor thresholds. We provided evidence of the dependence of required stimulation current on ISI. Georg Thieme Verlag KG Stuttgart · New York.

  3. Mechanistic and Structural Insights Into the Unique TetR-Dependent Regulation of a Drug Efflux Pump in Mycobacterium abscessus.

    Science.gov (United States)

    Richard, Matthias; Gutiérrez, Ana Victoria; Viljoen, Albertus J; Ghigo, Eric; Blaise, Mickael; Kremer, Laurent

    2018-01-01

    Mycobacterium abscessus is an emerging human pathogen causing severe pulmonary infections and is refractory to standard antibiotherapy, yet few drug resistance mechanisms have been reported in this organism. Recently, mutations in MAB_4384 leading to up-regulation of the MmpS5/MmpL5 efflux pump were linked to increased resistance to thiacetazone derivatives. Herein, the DNA-binding activity of MAB_4384 was investigated by electrophoretic mobility shift assays using the palindromic sequence IR S5/L5 located upstream of mmpS5/mmpL5 . Introduction of point mutations within IR S5/L5 identified the sequence requirements for optimal binding of the regulator. Moreover, formation of the protein/IR S5/L5 complex was severely impaired for MAB_4384 harboring D14N or F57L substitutions. IR S5/L5 /lacZ reporter fusions in M. abscessus demonstrated increased β-galactosidase activity either in strains lacking a functional MAB_4384 or in cultures treated with the TAC analogs. In addition, X-ray crystallography confirmed a typical TetR homodimeric structure of MAB_4384 and unraveled a putative ligand binding site in which the analogs could be docked. Overall, these results support drug recognition of the MAB_4384 TetR regulator, alleviating its binding to IR S5/L5 and steering up-regulation of MmpS5/MmpL5. This study provides new mechanistic and structural details of TetR-dependent regulatory mechanisms of efflux pumps and drug resistance in mycobacteria.

  4. Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.

    Directory of Open Access Journals (Sweden)

    Jinan Chen

    Full Text Available Cyclin-dependent kinase 5 (Cdk5 is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be associated with the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD and Parkinson's disease (PD. Here in the present study, enhanced Cdk5 activity was observed in mouse models of AD; whereas soluble amyloid-β oligomers (Aβ, which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacological or genetic approaches reversed dendritic spine loss caused by soluble amyloid-β oligomers (Aβ treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment corrected long-term potentiation (LTP deficit caused by Aβ exposure in cultured slices and pioglitazone administr