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.

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.

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

The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

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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.

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.

Role of endocannabinoids in regulating drug dependence

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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

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

Treatment of drug dependence with Brazilian herbal medicines

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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.

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.

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.

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...

Can tobacco dependence provide insights into other drug addictions?

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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.

Current situation and future usage of anticancer drug databases.

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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.

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

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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.

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.

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.

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

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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.

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

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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.

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

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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.

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.

Structured outpatient treatment of alcohol vs. drug dependencies.

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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.

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...

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.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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

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.

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

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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.

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

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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

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

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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.

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

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.

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.

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.

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...

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.

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

Storm-time ring current: model-dependent results

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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.

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

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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

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.

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...

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.

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.

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.

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...

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.

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...

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.

[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.

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

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

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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.

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

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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.

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.

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.

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

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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

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.

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.

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.

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)

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.

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.

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...

Marijuana: Current Concepts†

OpenAIRE

Greydanus, Donald E.; Hawver, Elizabeth K.; Greydanus, Megan M.; Merrick, Joav

2013-01-01

Marijuana (cannabis) remains a controversial drug in the twenty-first century. This paper considers current research on use of Cannabis sativa and its constituents such as the cannabinoids. Topics reviewed include prevalence of cannabis (pot) use, other drugs consumed with pot, the endocannabinoid system, use of medicinal marijuana, medical adverse effects of cannabis, and psychiatric adverse effects of cannabis use. Treatment of cannabis withdrawal and dependence is difficult and remains mai...

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

Application of three-dimensional printing for colon targeted drug delivery systems.

Science.gov (United States)

Charbe, Nitin B; McCarron, Paul A; Lane, Majella E; Tambuwala, Murtaza M

2017-01-01

Orally administered solid dosage forms currently dominate over all other dosage forms and routes of administrations. However, human gastrointestinal tract (GIT) poses a number of obstacles to delivery of the drugs to the site of interest and absorption in the GIT. Pharmaceutical scientists worldwide have been interested in colon drug delivery for several decades, not only for the delivery of the drugs for the treatment of colonic diseases such as ulcerative colitis and colon cancer but also for delivery of therapeutic proteins and peptides for systemic absorption. Despite extensive research in the area of colon targeted drug delivery, we have not been able to come up with an effective way of delivering drugs to the colon. The current tablets designed for colon drug release depend on either pH-dependent or time-delayed release formulations. During ulcerative colitis the gastric transit time and colon pH-levels is constantly changing depending on whether the patient is having a relapse or under remission. Hence, the current drug delivery system to the colon is based on one-size-fits-all. Fails to effectively deliver the drugs locally to the colon for colonic diseases and delivery of therapeutic proteins and peptides for systemic absorption from the colon. Hence, to overcome the current issues associated with colon drug delivery, we need to provide the patients with personalized tablets which are specifically designed to match the individual's gastric transit time depending on the disease state. Three-dimensional (3D) printing (3DP) technology is getting cheaper by the day and bespoke manufacturing of 3D-printed tablets could provide the solutions in the form of personalized colon drug delivery system. This review provides a bird's eye view of applications and current advances in pharmaceutical 3DP with emphasis on the development of colon targeted drug delivery systems.

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

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...

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.

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

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

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.

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...

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/

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.

Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6.

Science.gov (United States)

Bahar, Muh Akbar; Setiawan, Didik; Hak, Eelko; Wilffert, Bob

2017-05-01

Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

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.

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

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...

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.

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.

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...

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

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.

Motives for using: a comparison of prescription opioid, marijuana and cocaine dependent individuals.

Science.gov (United States)

Hartwell, Karen J; Back, Sudie E; McRae-Clark, Aimee L; Shaftman, Stephanie R; Brady, Kathleen T

2012-04-01

Identification of the motives for drug use is critical to the development of effective interventions. Furthermore, consideration of the differences in motives for drug use across substance dependent populations may assist in tailoring interventions. To date, few studies have systematically compared motives for substance use across drug classes. The current study examined motives for drug use between non-treatment seeking individuals with current prescription opioid, marijuana, or cocaine dependence. Participants (N=227) completed the Inventory of Drug-Taking Situations (IDTS; Annis, Turner & Sklar,1997), which contains eight subscales assessing motives for drug use. The findings revealed that prescription opioid dependent individuals scored significantly higher than all other groups on the Physical Discomfort, Testing Personal Control and Conflict with Others subscales. Both the prescription opioid and cocaine dependent groups scored significantly higher than the marijuana group on the Urges or a Temptation to Use subscale. In contrast, marijuana dependent individuals scored highest on the Pleasant Emotions and Pleasant Times with Others subscales. The marked differences revealed in motives for drug use could be used in the development and implementation of specific treatment interventions for prescription opioid, marijuana and cocaine dependent individuals. Published by Elsevier Ltd.

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.

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.

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.

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.

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.

Patterns of current and lifetime substance use in schizophrenia.

Science.gov (United States)

Fowler, I L; Carr, V J; Carter, N T; Lewin, T J

1998-01-01

A structured interview and standardized rating scales were used to assess a sample of 194 outpatients with schizophrenia in a regional Australian mental health service for substance use, abuse, and dependence. Case manager assessments and urine drug screens were also used to determine substance use. Additional measurements included demographic information, history of criminal charges, symptom self-reports, personal hopefulness, and social support. The sample was predominantly male and showed relative instability in accommodations, and almost half had a history of criminal offenses, most frequently drug or alcohol related. The 6-month and lifetime prevalence of substance abuse or dependence was 26.8 and 59.8 percent, respectively, with alcohol, cannabis, and amphetamines being the most commonly abused substances. Current users of alcohol comprised 77.3 percent and current users of other nonprescribed substances (excluding tobacco and caffeine) comprised 29.9 percent of the sample. Rates of tobacco and caffeine consumption were high. There was a moderate degree of concordance between case manager determinations of a substance-use problem and research diagnoses. Subjects with current or lifetime diagnoses of substance abuse/dependence were predominantly young, single males with higher rates of criminal charges; however, there was no evidence of increased rates of suicide attempts, hospital admissions, or daily doses of antipsychotic drugs in these groups compared with subjects with no past or current diagnosis of substance abuse or dependence. Subjects with a current diagnosis of substance use were younger at first treatment and currently more symptomatic than those with no past or current substance use diagnosis. The picture emerging from this study replicates the high rate of substance abuse in persons with schizophrenia reported in North American studies but differs from the latter in finding a slightly different pattern of substances abused (i.e., absence of

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....

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.

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.

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.

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)

[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

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.

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

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...

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

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

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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.

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

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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.

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

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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.

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

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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.

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

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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

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

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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.

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

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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.

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

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.

The Effect of Group Therapy With Transactional Analysis Approach on Emotional Intelligence, Executive Functions and Drug Dependency.

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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.

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

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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.

Antiepileptic drugs targeting sodium channels: subunit and neuron-type specific interactions

NARCIS (Netherlands)

Qiao, X.

2013-01-01

Certain antiepileptic drugs (e.g. carbamazepine and lamotrigine) block sodium channels in an use-dependent manner and this mechanism contributes to the anti-convulsant properties of these drugs. There are, however, subtle differences in sodium current blocking properties of the antiepileptic drugs

Contextualization of drug-mediator relations using evidence networks.

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Tran, Hai Joey; Speyer, Gil; Kiefer, Jeff; Kim, Seungchan

2017-05-31

Genomic analysis of drug response can provide unique insights into therapies that can be used to match the "right drug to the right patient." However, the process of discovering such therapeutic insights using genomic data is not straightforward and represents an area of active investigation. EDDY (Evaluation of Differential DependencY), a statistical test to detect differential statistical dependencies, is one method that leverages genomic data to identify differential genetic dependencies. EDDY has been used in conjunction with the Cancer Therapeutics Response Portal (CTRP), a dataset with drug-response measurements for more than 400 small molecules, and RNAseq data of cell lines in the Cancer Cell Line Encyclopedia (CCLE) to find potential drug-mediator pairs. Mediators were identified as genes that showed significant change in genetic statistical dependencies within annotated pathways between drug sensitive and drug non-sensitive cell lines, and the results are presented as a public web-portal (EDDY-CTRP). However, the interpretability of drug-mediator pairs currently hinders further exploration of these potentially valuable results. In this study, we address this challenge by constructing evidence networks built with protein and drug interactions from the STITCH and STRING interaction databases. STITCH and STRING are sister databases that catalog known and predicted drug-protein interactions and protein-protein interactions, respectively. Using these two databases, we have developed a method to construct evidence networks to "explain" the relation between a drug and a mediator.  RESULTS: We applied this approach to drug-mediator relations discovered in EDDY-CTRP analysis and identified evidence networks for ~70% of drug-mediator pairs where most mediators were not known direct targets for the drug. Constructed evidence networks enable researchers to contextualize the drug-mediator pair with current research and knowledge. Using evidence networks, we were

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

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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.

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.

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

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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.

Profile of Executive and Memory Function Associated with Amphetamine and Opiate Dependence

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

2007-01-01

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

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

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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…

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

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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.

Factors Affecting Drug Use During Incarceration: A Cross-Sectional Study of Opioid-Dependent Persons from India.

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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

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.

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.

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

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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.

Marijuana: Current concepts

Directory of Open Access Journals (Sweden)

Donald eGreydanus

2013-10-01

Full Text Available Marijuana (cannabis remains a controversial drug in the 21st century. This paper considers current research on use of Cannabis sativa and its constituents such as the cannabinoids. Topics reviewed include prevalence of cannabis use, other drugs consumed with pot, the endocannabinoid system, use of medicinal marijuana, medical adverse effects of cannabis, and psychiatric adverse effects of cannabis use. Treatment of cannabis withdrawal and dependence is difficult and remains mainly based on psychological therapy; current research on pharmacologic management of problems related to cannabis consumption is also considered. The potential role of specific cannabinoids for medical benefit will be revealed as the 21st century matures. However, potential dangerous adverse effects from smoking marijuana are well known and should be clearly taught to a public often confused by a media-driven, though false message and promise of benign pot consumption.

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. ...

[Current therapy of multiple sclerosis].

Science.gov (United States)

Antonio García Merino, J

2014-12-01

Since the introduction of interferon beta 1 b for the treatment of multiple sclerosis, there has been a progressive increase in the number of drugs available for this disease. Currently, 11 drugs have been approved in Spain, and their indications depend on specific clinical characteristics. The present article reviews these indications and also discusses other medications without official approval that have also been used in multiple sclerosis. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

MDMA: interactions with other psychoactive drugs.

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Mohamed, Wael M Y; Ben Hamida, Sami; Cassel, Jean-Christophe; de Vasconcelos, Anne Pereira; Jones, Byron C

2011-10-01

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most widely abused illegal drugs. Some users self-report euphoria and an increased perception and feeling of closeness to others. When taken in warm environments, MDMA users may develop acute complications with potential fatal consequences. In rodents, MDMA increases locomotor activity and, depending on ambient temperature, may produce a dose-dependent, potentially lethal hyperthermia. Like most other recreational drugs, MDMA is frequently taken in combination with other substances including tobacco, EtOH, marijuana, amphetamines, cocaine and, caffeine. Although polydrug use is very common, the understanding of the effects of this multiple substance use, as well as the analysis of consequences of different drug-drug associations, received rather little attention. The purpose of this review is to summarize our current knowledge about the changes on MDMA-related behavior, pharmacology, and neurotoxicity associated with co-consumption of other drugs of abuse and psychoactive agents. Copyright © 2011 Elsevier B.V. All rights reserved.

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

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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.

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...

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.

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

Mediating the distal crime-drug relationship with proximal reactive criminal thinking.

Science.gov (United States)

Walters, Glenn D

2016-02-01

This article describes the results of a study designed to test whether reactive criminal thinking (RCT) does a better job of mediating the crime → drug relationship than it does mediating the drug → crime relationship after the direct effects of crime on drug use/dependency and of drug use/dependency on crime have been rendered nonsignificant by control variables. All 1,170 male members of the Pathways to Desistance study (Mulvey, 2012) served as participants in the current investigation. As predicted, the total (unmediated) effects of crime on substance use/dependence and of substance use/dependence on crime were nonsignificant when key demographic and third variables were controlled, although the indirect (RCT-mediated) effect of crime on drug use was significant. Proactive criminal thinking (PCT), by comparison, failed to mediate either relationship. The RCT continued to mediate the crime → drug relationship and the PCT continued to not mediate either relationship when more specific forms of offending (aggressive, income) and substance use/dependence (drug use, substance-use dependency symptoms) were analyzed. This offers preliminary support for the notion that even when the total crime-drug effect is nonsignificant the indirect path from crime to reactive criminal thinking to drugs can still be significant. Based on these results, it is concluded that mediation by proximal reactive criminal thinking is a mechanism by which distal measures of crime and drug use/dependence are connected. (c) 2016 APA, all rights reserved).

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

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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.

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.

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.

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.

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.

Marijuana: Current Concepts†

Science.gov (United States)

Greydanus, Donald E.; Hawver, Elizabeth K.; Greydanus, Megan M.; Merrick, Joav

2013-01-01

Marijuana (cannabis) remains a controversial drug in the twenty-first century. This paper considers current research on use of Cannabis sativa and its constituents such as the cannabinoids. Topics reviewed include prevalence of cannabis (pot) use, other drugs consumed with pot, the endocannabinoid system, use of medicinal marijuana, medical adverse effects of cannabis, and psychiatric adverse effects of cannabis use. Treatment of cannabis withdrawal and dependence is difficult and remains mainly based on psychological therapy; current research on pharmacologic management of problems related to cannabis consumption is also considered. The potential role of specific cannabinoids for medical benefit will be revealed as the twenty-first century matures. However, potential dangerous adverse effects from smoking marijuana are well known and should be clearly taught to a public that is often confused by a media-driven, though false message and promise of benign pot consumption. PMID:24350211

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

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.

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.

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.

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.

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.

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...

Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

Directory of Open Access Journals (Sweden)

Olliaro P

2004-01-01

Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

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.

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.

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...

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).

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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)

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...

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

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

Initial validation of two opiate craving questionnaires the obsessive compulsive drug use scale and the desires for drug questionnaire.

Science.gov (United States)

Franken, Ingmar H A; Hendriksa, Vincent M; van den Brink, Wim

2002-01-01

In the present study, the factor structure, internal consistency, and the concurrent validity of two heroin craving questionnaires are examined. The Desires for Drug Questionnaire (DDQ) measures three factors: desire and intention, negative reinforcement, and control. The Obsessive Compulsive Drug Use Scale (OCDUS) also measures three factors: thoughts about heroin and interference, desire and control, and resistance to thoughts and intention. Subjects were 102 Dutch patients who were currently in treatment for drug dependency. All proposed scales have good reliability and concurrent validity. Implementation of these instruments in both clinical and research field is advocated.

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…

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.)

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.

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

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

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.

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.

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.

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. 

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...

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 ...

Cognitive impairments in poly-drug ketamine users.

Science.gov (United States)

Liang, H J; Lau, C G; Tang, A; Chan, F; Ungvari, G S; Tang, W K

2013-11-01

Cognitive impairment has been found to be reversible in people with substance abuse, particularly those using ketamine. Ketamine users are often poly-substance users. This study compared the cognitive functions of current and former ketamine users who were also abusing other psychoactive substances with those of non-users of illicit drugs as controls. One hundred ketamine poly-drug users and 100 controls were recruited. Drug users were divided into current (n = 32) and ex-users (n = 64) according to the duration of abstinence from ketamine (>30 days). The Beck Depression Inventory (BDI), the Hospital Anxiety Depression Scale (HADSA) and the Severity of Dependence Scale (SDS) were used to evaluate depression and anxiety symptoms and the severity of drug use, respectively. The cognitive test battery comprised verbal memory (Wechsler Memory Scale III: Logic Memory and Word List), visual memory (Rey-Osterrieth Complex Figure, ROCF), executive function (Stroop, Wisconsin Card Sorting Test, and Modified Verbal Fluency Test), working memory (Digit Span Backward), and general intelligence (Information, Arithmetic and Digit-Symbol Coding) tests. Current users had higher BDI and HADSA scores than ex-users (p recognition than controls (p = 0.002). No difference was found between the cognitive functions of current and ex-users. Ketamine poly-drug users displayed predominantly verbal and visual memory impairments, which persisted in ex-users. The interactive effect of ketamine and poly-drug use on memory needs further investigation. © 2013 Elsevier Ltd. All rights reserved.

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.

Kinetics of drug release from ointments: Role of transient-boundary layer.

Science.gov (United States)

Xu, Xiaoming; Al-Ghabeish, Manar; Krishnaiah, Yellela S R; Rahman, Ziyaur; Khan, Mansoor A

2015-10-15

In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time. Published by Elsevier B.V.

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

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

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.

[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.

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.

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

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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

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.

Nanocomposite thin films for triggerable drug delivery.

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Vannozzi, Lorenzo; Iacovacci, Veronica; Menciassi, Arianna; Ricotti, Leonardo

2018-05-01

Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion. Areas covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape. Expert opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery.

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...

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

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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.

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

Orphan drugs in development for urea cycle disorders: current perspectives

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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

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.)

Changes in psychiatric symptoms among persons with methamphetamine dependence predicts changes in severity of drug problems but not frequency of use.

Science.gov (United States)

Polcin, Douglas L; Korcha, Rachael; Bond, Jason; Galloway, Gantt; Nayak, Madhabika

2016-01-01

Few studies have examined how changes in psychiatric symptoms over time are associated with changes in drug use and severity of drug problems. No studies have examined these relationships among methamphetamine (MA)-dependent persons receiving motivational interviewing within the context of standard outpatient treatment. Two hundred seventeen individuals with MA dependence were randomly assigned to a standard single session of motivational interviewing (MI) or an intensive 9-session model of MI. Both groups received standard outpatient group treatment. The Addiction Severity Index (ASI) and timeline follow-back (TLFB) for MA use were administered at treatment entry and 2-, 4-, and 6-month follow-ups. Changes in ASI psychiatric severity between baseline and 2 months predicted changes in ASI drug severity during the same time period, but not changes on measures of MA use. Item analysis of the ASI drug scale showed that psychiatric severity predicted how troubled or bothered participants were by their drug us, how important they felt it was for them to get treatment, and the number of days they experienced drug problems. However, it did not predict the number days they used drugs in the past 30 days. These associations did not differ between study conditions, and they persisted when psychiatric severity and outcomes were compared across 4- and 6-month time periods. Results are among the first to track how changes in psychiatric severity over time are associated with changes in MA use and severity of drug problems. Treatment efforts targeting reduction of psychiatric symptoms among MA-dependent persons might be helpful in reducing the level of distress and problems associated with MA use but not how often it is used. There is a need for additional research describing the circumstances under which the experiences and perceptions of drug-related problems diverge from frequency of consumption.

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

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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

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

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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.

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

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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.

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

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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.

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.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

Science.gov (United States)

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

Alcohol dependence: international policy implications for prison populations.

Science.gov (United States)

Jones, Gail Yvonne; Hoffmann, Norman G

2006-11-08

In light of the emphasis on drug abuse, this study explored the relative prevalence of substance use disorders among United Kingdom (UK) prison inmates in the context of findings from a general inmate population in the United States (US). The lead author of the report conducted a structured diagnostic interview with 155 new admissions to one of two prisons in the UK using the CAAPE (Comprehensive Addiction And Psychological Evaluation), a structured diagnostic interview, to ensure consistent assessments. The US sample consisted of 6,881 male inmates in a state prison system evaluated with an automated version of the SUDDS-IV (Substance Use Disorder Diagnostic Schedule-IV) interview. Alcohol dependence emerged as the most prevalent substance use disorder in both UK prisons and in the US sample. Relative frequencies of abuse and dependence for alcohol and other drugs revealed that dependence on a given substance was more prevalent than abuse ad defined by the current diagnostic criteria. Despite the emphasis on drugs in correctional populations, alcohol dependence appears to be the most prominent substance use disorder among the incarcerated in both the US and UK and must be considered in developing treatment programs and policy priorities.

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.

Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation.

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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.

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

A rationale and model for addressing tobacco dependence in substance abuse treatment

Directory of Open Access Journals (Sweden)

Richter Kimber P

2006-08-01

Full Text Available Abstract Most persons in drug treatment smoke cigarettes. Until drug treatment facilities systematically treat their patients' tobacco use, millions will flow through the drug treatment system, overcome their primary drug of abuse, but die prematurely from tobacco-related illnesses. This paper reviews the literature on the health benefits of quitting smoking for drug treatment patients, whether smoking causes relapse to other drug or alcohol abuse, the treatment of tobacco dependence, and good and bad times for quitting smoking among drug treatment patients. It also presents a conceptual model and recommendations for treating tobacco in substance abuse treatment, and provides references to internet and paper-copy tools and information for treating tobacco dependence. At present, research on tobacco treatment in drug treatment is in its infancy. Although few drug treatment programs currently offer formal services, many more will likely begin to treat nicotine dependence as external forces and patient demand for these services increases. In the absence of clear guidelines and attention to quality of care, drug treatment programs may adopt smoking cessation services based on cost, convenience, or selection criteria other than efficacy. Because research in this field is relatively new, substance abuse treatment professionals should adhere to the standards of care for the general population, but be prepared to update their practices with emerging interventions that have proven to be effective for patients in drug treatment.

[Pharmacist as gatekeeper: combating medication abuse and dependence].

Science.gov (United States)

Shimane, Takuya

2013-01-01

  The nonmedical use of medications, including psychotropic drugs, is a growing health problem in Japan. According to a nationwide survey of mental hospitals, the proportion of patients with sedative (mainly benzodiazepine)-related disorders has more than doubled over the last decade. An association between psychotropic drug overdose and suicide risk has also been reported. Furthermore, over-the-counter drug abuse is still a serious problem in Japan. In recent years, pharmacists have been expected to act as gatekeepers, making timely identifications of suicide risk or substance abuse and directing these individuals to appropriate medical care facilities. In August 2012, the revised Comprehensive Suicide Measures Act identified pharmacists as one professional group that should act as gatekeepers. This article begins by reviewing the fundamental terms involved in understanding the nonmedical use of medications, including abuse, dependence, and intoxication. The current situation of substance abuse and dependence is then introduced through a summary of several epidemiological surveys conducted in Japan. Finally, the role of pharmacists as gatekeepers in preventing substance abuse and dependence on medications is discussed.

Predictors of illicit drug/s use among university students in Northern Ireland, Wales and England.

Science.gov (United States)

El Ansari, Walid; Vallentin-Holbech, Lotte; Stock, Christiane

2014-12-16

The use of illicit drug/s among university students is a public health concern. Nevertheless, many UK studies investigated a narrow spectrum of variables to explore their association/s with illicit drug/s use. We assessed the associations between a wide range of socio-demographic, health and wellbeing variables (independent variables) and having used illicit drug/s regularly, occasionally or never in life (dependent variables). Data (3706 students) were collected from seven universities in England, Wales, and Northern Ireland, using a self-administered questionnaire. About 5% of the sample had regularly used illicit drug/s, 25% occasionally, and 70% never. Regular drug use (RDU) was significantly more likely among males aged 21-29 years, daily smokers, those with heavy episodic drinking or possible alcohol dependency (CAGE test), and those who perceived their academic performance better than their peers. RDU was less likely among students with high health awareness and those living with parents. The predictors of occasional drug use (ODU) were similar to those of RDU. However, in addition, students with higher perceived stress were less likely, and students who felt financial burden/s were more likely to report ODU, while no association with academic performance was found. Never use of illicit drug/s was inversely associated with most of the variables listed above, and was positively associated with religiosity. Illicit drug/s use goes along with other substance use (alcohol and smoking). The finding that illicit drug/s use was higher among students reporting good academic performance was surprising and raises the question of whether illicit drug/s may be used as performance enhancing drugs. The factors identified with illicit drug/s use in this study could be utilized to develop appropriate public health policies and preventive measures for the health of students. Multilevel, value based, comprehensive, and strategic long-term intervention plans are required. This

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.

The role of emotional and behavioral disorders in the development of drug dependence in patients with medication-induced headache (review

Directory of Open Access Journals (Sweden)

A. E. Shagbazyan

2016-01-01

Full Text Available Medication-induced headache (MIH is a variety of chronic daily headache (HA. MIH belongs to secondary (symptomatic HA, develops as a complication of pre-existing primary cephalgia, and is caused by the overuse of drugs to relieve HA. The role of drug dependence syndrome and behavioral and emotional disorders in the development of MIH, which may be associated with dysfunction of certain brain systems that control these functions, has been recently discussed. The paper reviews the literature dealing with studies of the role of behavioral and emotional disorders and orbitofrontal cortical dysfunction in the development of drug dependence syndrome in patients with MIH. The importance of analyzing these aspects of MIH is determined by the prospects for applying alternative approaches to managing these patients.

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.

Neuropharmacological Consequences of Variant Drugs

Directory of Open Access Journals (Sweden)

Mahnoor Amjad Butt

2017-11-01

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

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

[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.

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.

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...

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.

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.

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.

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.

[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.

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

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.

Chinese Herbal Medicine for the Treatment of Drug Addiction.

Science.gov (United States)

Zhu, Weili; Zhang, Yinan; Huang, Yingjie; Lu, Lin

2017-01-01

This chapter summarizes recent developments in preclinical and clinical research on Chinese herbal medicines and their neurochemical mechanism of action for the treatment of drug addiction. We searched Chinese and English scientific literature and selected several kinds of Chinese herbal medicines that have beneficial effects on drug addiction. Ginseng (Renshen) may be clinically useful for the prevention of opioid abuse and dependence. Rhizoma Corydalis (Yanhusuo) may be used to prevent relapse to chronic drug dependence. Alkaloids of Uncaria rhynchophylla (Gouteng) appear to have positive effects on methamphetamine and ketamine addiction. Both Salvia miltiorrhiza (Danshen) and Radix Pueraiae (Gegen) have beneficial inhibitory effects on alcohol intake. Sinomenine has been shown to have preventive and curative effects on opioid dependence. l-Stepholidine, an alkaloid extract of the Chinese herb Stephania intermedia (Rulan), attenuated the acquisition, maintenance, and reacquisition of morphine-induced conditioned place preference and antagonized the heroin-induced reinstatement of heroin seeking. Traditional Chinese herbal medicines may be used to complement current treatments for drug addiction, including withdrawal and relapse. As the molecular mechanisms of action of traditional Chinese herbal medicines are elucidated, further advances in their use for the treatment of drug addiction are promising. © 2017 Elsevier Inc. All rights reserved.

Drugs, Violence, and Trauma in Mexico and the USA

Science.gov (United States)

Puyana, Juan Carlos; Puyana, Juan Carlos Jacob; Rubiano, Andres Mariano; Montenegro, Jorge Hernan; Estebanez, Glyn O.; Sanchez, Alvaro Ignacio; Vega-Rivera, Felipe

2017-01-01

The impact of illicit drug markets on the occurrence of violence varies tremendously depending on many factors. Over the last years, Mexico and the USA have increased security border issues that included many aspects of drug-related trade and criminal activities. Mexico experienced only a small reduction in trauma deaths after the enforcement of severe crime reinforcement policies. This strategy in the war on drugs is shifting the drug market to other Central American countries. This phenomenon is called the ballooning effect, whereby the pressure to control illicit drug-related activities in one particular area forces a shift to other more vulnerable areas that leads to an increase in crime and violence. A human rights crisis characterized by suffering, injury, and death related to drug trafficking continues to expand, resulting in the exorbitant loss of lives and cost in productivity across the continent. The current climate of social violence in Central America and the illegal immigration to the USA may be partially related to this phenomenon of drug trafficking, gang violence, and crime. A health care initiative as an alternative to the current war approach may be one of the interventions needed to reduce this crisis. PMID:28329741

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.

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

Comprehensive analyses of ventricular myocyte models identify targets exhibiting favorable rate dependence.

Directory of Open Access Journals (Sweden)

Megan A Cummins

2014-03-01

Full Text Available Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP. The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz and fast (2 Hz rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of

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.

Association between severity of illicit drug dependence and quality of life in a psychosocial care center in BRAZIL: cross-sectional study.

Science.gov (United States)

Campêlo, Selva Rios; Barbosa, Maria Alves; Dias, Danilo Rocha; Caixeta, Camila Cardoso; Leles, Cláudio Rodrigues; Porto, Celmo Celeno

2017-11-17

Quality of life must be one of the main purposes for the treatment of drug users, requiring a better understanding of the association between the quality of life and the severity of dependency. This study aimed to investigate the correlation between severity of substance use in various areas of human functioning and quality of life of illicit drug users in a psychosocial care center for alcohol and drugs. This cross-sectional study included 60 participants - illicit drug users - treated at a psychosocial care center for alcohol and drugs. Participants were evaluated with the short version of World Health Organization Quality of Life (WHOQOL-Bref) instrument to measure the quality of life, the 6th version of Addiction Severity Index (ASI-6) to assess the severity of dependence in several areas and the Mini International Neuropsychiatric Interview (MINI) to identify the presence of psychiatric disorders. Pearson and Spearman correlation tests and linear regression were applied to verify the association between the severity of dependence and the quality of life, and Student's t-test to compare the mean quality of life between individuals with and without psychiatric comorbidities. Negative correlation was found between the severity of dependence on the drugs dimensions: alcohol, psychiatric, medical, legal, family/social support and family/social problems of ASI-6, and the quality of life domains measured by the WHOQOL-Bref. The evidence was strongest in the psychiatric and medical dimensions. There was a significant difference in the quality of life mean among participants presenting or not presenting psychiatric comorbidities, for the psychological domain in anxiety disorders, and for the physical and psychological domains in mood disorders. The quality of life decreased as the severity of dependence increased, with different results in the various areas of the participant's life. This result emphasizes the need for training the professional team which works in the

Drug Release Mechanism of Slightly Soluble Drug from ...

African Journals Online (AJOL)

theophylline (THP) as drug in drug to clay ratios of 1:2, 3:4 and 1:1. The formulations were characterized for drug release and loading. Dependent and independent kinetic models were employed to analyze the drug release data. Fourier transform infrared spectroscopy (FTIR) was used for the structural characterization of ...

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....

Drug-Target Kinetics in Drug Discovery.

Science.gov (United States)

Tonge, Peter J

2018-01-17

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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.)

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.

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...

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.

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.)

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.

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...

Alcohol dependence: international policy implications for prison populations

Directory of Open Access Journals (Sweden)

Hoffmann Norman G

2006-11-01

Full Text Available Abstract Background In light of the emphasis on drug abuse, this study explored the relative prevalence of substance use disorders among United Kingdom (UK prison inmates in the context of findings from a general inmate population in the United States (US. The lead author of the report conducted a structured diagnostic interview with 155 new admissions to one of two prisons in the UK using the CAAPE (Comprehensive Addiction And Psychological Evaluation, a structured diagnostic interview, to ensure consistent assessments. The US sample consisted of 6,881 male inmates in a state prison system evaluated with an automated version of the SUDDS-IV (Substance Use Disorder Diagnostic Schedule-IV interview. Results Alcohol dependence emerged as the most prevalent substance use disorder in both UK prisons and in the US sample. Relative frequencies of abuse and dependence for alcohol and other drugs revealed that dependence on a given substance was more prevalent than abuse ad defined by the current diagnostic criteria. Conclusion Despite the emphasis on drugs in correctional populations, alcohol dependence appears to be the most prominent substance use disorder among the incarcerated in both the US and UK and must be considered in developing treatment programs and policy priorities.

Effects of acute exercise on drug craving, self-esteem, mood and affect in adults with poly-substance dependence: Feasibility and preliminary findings.

Science.gov (United States)

Ellingsen, Maren Mikkelsen; Johannesen, Sunniva Launes; Martinsen, Egil W; Hallgren, Mats

2018-06-04

Novel treatments for substance use disorders are needed. Acute bouts of exercise can improve mood states in non-clinical populations, but effects in those with poly-substance dependence are understudied. We examined the feasibility and short-term effects of three types of exercise on drug cravings, self-esteem, mood and positive/negative affect in nine poly-drug-dependent inpatients. Using a cross-over design, changes in the four study outcomes were assessed immediately before exercise and on four separate occasions post-exercise (immediately after, then at 1, 2 and 4 h post-exercise) enabling patterns of change over time (analysis of covariance) to be observed. Participants were willing and able to engage in different non-laboratory based exercises. Football was associated with non-significant short-term reductions in drug cravings. A similar trend was seen for circuit-training, but not walking. Football and circuit-training were associated with brief improvements in mood and positive/negative affect. No adverse events were reported. Football, circuit training and walking are feasible therapeutic activities for inpatients with poly-substance dependence. Controlled trials are needed to determine the long-term effects of these activities. © 2018 Australasian Professional Society on Alcohol and other Drugs.

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.

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.

Drugs for insomnia.

Science.gov (United States)

Zisapel, Nava

2012-09-01

Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia"). GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future. Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.

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

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.

Medically assisted recovery from opiate dependence within the context of the UK drug strategy: methadone and Suboxone (buprenorphine-naloxone) patients compared.

Science.gov (United States)

McKeganey, Neil; Russell, Christopher; Cockayne, Lucinda

2013-01-01

The focus of drug policy in the UK has shifted markedly in the past 5 years to move beyond merely emphasising drug abstinence towards maximising individuals' opportunities for recovery. The UK government continues to recognise the prescribing of narcotic medications indicated for opiate dependence as a key element of these individuals' recovery journey. This article describes a small, naturalistic comparison of the efficacy of the two most commonly prescribed opiate substitute medications in the UK--methadone hydrochloride (methadone oral solution) and Suboxone (buprenorphine-naloxone sublingual tablets)--for reducing current heroin users' (n = 34) days of heroin use, and preventing short-term abstainers (n = 37) from relapsing to regular heroin use. All patients had been prescribed either methadone or Suboxone for maintenance for 6 months prior to intake. Results showed that when controlling for a number of patient-level covariates, both methadone and Suboxone significantly reduced current users' days of heroin use between the 90 days prior to intake and at the 8-month follow-up, with Suboxone yielding a significantly larger magnitude reduction in heroin use days than methadone. Methadone and Suboxone were highly and equally effective for preventing relapse to regular heroin use, with all but 3 of 37 (91.9%) patients who were abstinent at intake reporting past 90-day point prevalence heroin abstinence at the 8-month follow-up. Overall, prescribing methadone or Suboxone for eight continuous months was highly effective for initiating abstinence from heroin use, and for converting short-term abstinence to long-term abstinence. However, the study design, which was based on a relatively small sample size and was not able randomise patients to medication and so could not control for the effects of potential prognostic factors inherent within each patient group, means that these conclusions can only be made tentatively. These positive but preliminary indications of the

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.

An update on zolpidem abuse and dependence.

Science.gov (United States)

Victorri-Vigneau, Caroline; Gérardin, Marie; Rousselet, Morgane; Guerlais, Marylène; Grall-Bronnec, Marie; Jolliet, Pascale

2014-01-01

In 2004, the health authorities (French National Agency for Medicines and Health Products Safety-ANSM) modified the summary of zolpidem characteristics. Particularly it now includes the sentence "a pharmacodependence may materialize." The current article aims to show that despite this modification, zolpidem continues to be associated with problematic drug use, as the official system (Center for Evaluation and Information on Pharmacodependence-Addictovigilance network) providing information on the abuse and dependence potential of drugs informs us. The authors reviewed the literature on this topic and analyzed French data from zolpidem's postmarketing period that were collected by the Addictovigilance network from 2003 to 2010. Postmarketing data and the 30 case reports yielded from the literature review highlight a significant dependence and abuse potential for zolpidem. This survey led to propose in stronger additional rules in France to try to mitigate the abuse potential of zolpidem.

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.

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

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

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.

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.

Neurocognitive Predictors of Drug Relapse

NARCIS (Netherlands)

R. Marhe (Reshmi)

2013-01-01

textabstractWorldwide, about 35 million people, that is 0.8% of the world’s adult population, use heroin and/or cocaine and more than 10-13% of these drug users are or will become drug dependent (UNODC, World Drug Report, 2012). Drug dependency is characterized as a chronic relapsing disorder

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

Directory of Open Access Journals (Sweden)

M. Rahbarian

2016-12-01

Full Text Available 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. Methods: This study was a quasi-experimental intervention with pretest-posttest and control group in 2013 which carried on 40 couple referred to public addiction treatment center of Qazvin city. These people had troubled communication patterns and were selected using convenience sampling and were divided into two groups of intervention and control, randomly. Two groups were assessed by relapse prediction scale (RPS and structured clinical interview for DSM (SCID-I for men and communication pattern questionnaire (CPQ for couples in pre and post-test. Intervention group received 9 two hours sessions of communication skill training based on cognitive-behavioral model. Data were analyzed using Levin and Box tests and multivariate analysis of covariance (MANCOVA. Findings: The difference between the intervention and control groups in the constructive communication pattern with 51% (p<0/05, in mutual avoidance pattern with 61% (p<0/0001 and in the demand / withdraw pattern with 45% (p<0/05 was statistically significant. Also, the difference between the two groups in the rate of relapse with 64% (p<0/0001 was statistically significant. Conclusion: According to the findings it seems group training of communication skill based on cognitive-behavioral model can improve the communication patterns in drug-dependent couples, as well as prevents relapse in men.

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.

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.

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.

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.

Effectiveness of Gross Model-Based Emotion Regulation Strategies Training on Anger Reduction in Drug-Dependent Individuals and its Sustainability in Follow-up.

Science.gov (United States)

Massah, Omid; Sohrabi, Faramarz; A'azami, Yousef; Doostian, Younes; Farhoudian, Ali; Daneshmand, Reza

2016-03-01

Emotion plays an important role in adapting to life changes and stressful events. Difficulty regulating emotions is one of the problems drug abusers often face, and teaching these individuals to express and manage their emotions can be effective on improving their difficult circumstances. The present study aimed to determine the effectiveness of the Gross model-based emotion regulation strategies training on anger reduction in drug-dependent individuals. The present study had a quasi-experimental design wherein pretest-posttest evaluations were applied using a control group. The population under study included addicts attending Marivan's methadone maintenance therapy centers in 2012 - 2013. Convenience sampling was used to select 30 substance-dependent individuals undergoing maintenance treatment who were then randomly assigned to the experiment and control groups. The experiment group received its training in eight two-hour sessions. Data were analyzed using analysis of co-variance and paired t-test. There was significant reduction in anger symptoms of drug-dependent individuals after gross model based emotion regulation training (ERT) (P emotion regulation strategies training. Based on the results of this study, we may conclude that the gross model based emotion regulation strategies training can be applied alongside other therapies to treat drug abusers undergoing rehabilitation.

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)

Psychoactive drug consumption: performance-enhancing behaviour and pharmacodependence in workers.

Science.gov (United States)

Ngoundo-Mbongue, T B; Niezborala, M; Sulem, P; Briant-Vincens, D; Bancarel, Y; Jansou, P; Chastan, E; Montastruc, J L; Lapeyre-Mestre, M

2005-02-01

The aim of this study was to investigate factors associated to psychoactive medication use and dependence in working environment during a 1-year period. We performed a 1-year-follow-up cohort study including workers from Toulouse metropolitan area. During their annual compulsory examination to assess their aptitude to work, subjects were asked to fill in an anonymous questionnaire at 1 year interval, in May 2000 and May-June 2001. Among a study sample of 1273 subjects (47.4% of men, mean age 39.2 +/- 9.2 years), the prevalence of psychoactive medication use at baseline was 9.1% (4.3% anxiolytic, 1.9% hypnotic, 1.7% antidepressant, 2.1% opiate analgesic and 0.5% antipsychotic drugs, according to ATC classification). Dependence on these drugs was found in 3.5% of workers. This consumption was associated with professional categories (higher in employees versus senior executive, Odds Ratio: 1.80; 95% Confidence Interval [1.04-3.11]), low job satisfaction and outside workplace (1.92; [1.30-2.84] and 3.40; [2.27-5.09] respectively), and patterns of medication use at workplace: for sleeping disorders related to job (18.27; [11.81-28.26]), for enhancing performance at work (28.13; [12.00-65.92]), for relieving unpleasant symptoms at work (22.98; [9.59-55.01]). The risk of psychoactive medication chronic use (psychoactive drug users in 2000 and 2001), and dependence at 1 year were both strongly associated with nicotine dependence (5.99 and 6.23, respectively) and performance-enhancing behaviour with drugs and/or alcohol (8.35 and 3.32 respectively), whereas current use (psychoactive drug users only in 2001) was strongly associated with performance-enhancing behaviour. Among workers using psychoactive drugs, one out of three are dependent on psychoactive medications. Performance-enhancing behaviour and coping strategies might be a determinant of psychoactive drug use and could lead to dependence in the workplace.

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

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.

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

Drug delivery systems with modified release for systemic and biophase bioavailability.

Science.gov (United States)

Leucuta, Sorin E

2012-11-01

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

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

Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

Science.gov (United States)

Harvey-Lewis, Colin; Perdrizet, Johnna; Franklin, Keith B J

2014-07-01

Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

Algorithms for optimizing drug therapy

Directory of Open Access Journals (Sweden)

Martin Lene

2004-07-01

Full Text Available Abstract Background Drug therapy has become increasingly efficient, with more drugs available for treatment of an ever-growing number of conditions. Yet, drug use is reported to be sub optimal in several aspects, such as dosage, patient's adherence and outcome of therapy. The aim of the current study was to investigate the possibility to optimize drug therapy using computer programs, available on the Internet. Methods One hundred and ten officially endorsed text documents, published between 1996 and 2004, containing guidelines for drug therapy in 246 disorders, were analyzed with regard to information about patient-, disease- and drug-related factors and relationships between these factors. This information was used to construct algorithms for identifying optimum treatment in each of the studied disorders. These algorithms were categorized in order to define as few models as possible that still could accommodate the identified factors and the relationships between them. The resulting program prototypes were implemented in HTML (user interface and JavaScript (program logic. Results Three types of algorithms were sufficient for the intended purpose. The simplest type is a list of factors, each of which implies that the particular patient should or should not receive treatment. This is adequate in situations where only one treatment exists. The second type, a more elaborate model, is required when treatment can by provided using drugs from different pharmacological classes and the selection of drug class is dependent on patient characteristics. An easily implemented set of if-then statements was able to manage the identified information in such instances. The third type was needed in the few situations where the selection and dosage of drugs were depending on the degree to which one or more patient-specific factors were present. In these cases the implementation of an established decision model based on fuzzy sets was required. Computer programs

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

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.

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...

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.

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.

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.

Undefined role of mucus as a barrier in ocular drug delivery.

Science.gov (United States)

Ruponen, Marika; Urtti, Arto

2015-10-01

Mucus layer covers the ocular surface, and soluble mucins are also present in the tear fluid. After topical ocular drug administration, the drugs and formulations may interact with mucus layer that may act as a barrier in ocular drug delivery. In this mini-review, we illustrate the mucin composition of the ocular surface and discuss the influence of mucus layer on ocular drug absorption. Based on the current knowledge the role of mucus barrier in drug delivery is still undefined. Furthermore, interactions with mucus may prolong the retention of drug formulations on the ocular surface. Mucus may decrease or increase ocular bioavailability depending on the magnitude of its role as barrier or retention site, respectively. Mechanistic studies are needed to clarify the role of mucin in ocular drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

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.

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

Systems Pharmacology in Small Molecular Drug Discovery

Directory of Open Access Journals (Sweden)

Wei Zhou

2016-02-01

Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

Current scenario

Indian Academy of Sciences (India)

First page Back Continue Last page Overview Graphics. Current scenario. India , like other parts of the world, is also facing the problem of increase in the incidence of drug resistance in tuberculosis. Multi-drug resistance (MDR, resistance to RIF & INH) and extensively drug resistant strains (X-DR, resistance to RIF, INH, FQs ...

Drug: D10250 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available 08249]) ... Other ... DG01718 ... Drugs for addictive disorder ... DG01717 ... Drugs for opioid dependence ATC code: N07BC51 ... Treatment of opioid dependence ... PubChem: 163312281 ...

Drugs in breast milk.

Science.gov (United States)

Hervada, A R; Feit, E; Sagraves, R

1978-09-01

The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

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.

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

Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

Science.gov (United States)

de Lorenzi, F G; Bridal, T R; Spinelli, W

1994-01-01

1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action. PMID:7834204

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

Directory of Open Access Journals (Sweden)

Hongyu Wu

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

Mental health, drug use and sexual risk behavior among gay and bisexual men.

Science.gov (United States)

Prestage, Garrett; Hammoud, Mohamed; Jin, Fengyi; Degenhardt, Louisa; Bourne, Adam; Maher, Lisa

2018-05-01

Compared to the general population, among gay and bisexual men (GBM) prevalence rates of anxiety and depression, and of drug use, are high. This paper explores the relationship between mental health, sexual risk behavior, and drug use among Australian GBM. We identify factors associated with indicators of poor mental health. Between September 2014 and July 2017, 3017 GBM responded to measures of anxiety and depression in an online cohort study of drug use. Mean age was 35.3 years (SD 12.8). 17.9% screened positive for current moderate-severe anxiety and 28.3% for moderate-severe depression. The majority (52.2%) reported use of illicit drugs in the previous six months, including 11.2% who had used methamphetamine. One third had high (20.4%) or severe (10.6%) risk levels of alcohol consumption, and 18.3% who were current daily smokers. Most illicit drug use in general was not associated with either anxiety or depression, but men who used cannabis were more likely to show evidence of depression (p = 0.005). Among recent methamphetamine users, 28.0% were assessed as dependent: dependent users were more likely to show evidence of both depression and anxiety than were non-dependent users. High or severe risk drinking was associated with depression and daily tobacco use was associated with both anxiety and depression. Depression and anxiety was associated with: less personal support, viewing oneself as 'feminine', and being less socially engaged with gay men. Sexual risk behavior was not associated with either depression or anxiety. Prevalence of anxiety and depression was high, as was prevalence of licit and illicit drug use. Substance use was associated with anxiety and depression only when the use was considered problematic or dependent. Social isolation and marginalization are strong drivers of poor mental health, even within this population for whom anxiety and depression are common. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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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.

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)

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

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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.

Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors.

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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.

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

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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.

Recognition and management of iatrogenically induced opioid dependence and withdrawal in children.

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Galinkin, Jeffrey; Koh, Jeffrey Lee

2014-01-01

Opioids are often prescribed to children for pain relief related to procedures, acute injuries, and chronic conditions. Round-the-clock dosing of opioids can produce opioid dependence within 5 days. According to a 2001 Consensus Paper from the American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine, dependence is defined as "a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist." Although the experience of many children undergoing iatrogenically induced withdrawal may be mild or goes unreported, there is currently no guidance for recognition or management of withdrawal for this population. Guidance on this subject is available only for adults and primarily for adults with substance use disorders. The guideline will summarize existing literature and provide readers with information currently not available in any single source specific for this vulnerable pediatric population.

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)

Current French system of post-marketing drug surveillance.

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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.

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

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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

Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group.

Science.gov (United States)

Scherer, K; Brockow, K; Aberer, W; Gooi, J H C; Demoly, P; Romano, A; Schnyder, B; Whitaker, P; Cernadas, J S R; Bircher, A J

2013-07-01

Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

Computational Fragment-Based Drug Design: Current Trends, Strategies, and Applications.

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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.

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)

[Are there any sex/gender differences in drug use and drug addiction?].

Science.gov (United States)

Mendrek, Adrianna

Drug use and drug addiction have been traditionally considered to be a male problem, however the gender gap has been decreasing over the past few decades. Thus, while the prevalence of alcohol, cannabis and nicotine dependence is still overall greater among men than among women, sex/gender differences in the abuse of stimulants and opiates seem to have disappeared. Moreover, women appear to be more prone to develop drug dependence, suffer more severe physical and psychological consequences of drug abuse, and have more difficulties quitting the habit. Numerous psychological, socio-cultural and biological factors have been implicated in these changing statistics. For example, while a large proportion of men initiate drug use to induce feelings of elation, energy or focus, women frequently start taking drugs to alleviate pre-existing mental health problems, including high levels of stress, feelings of alienation, depression, anxiety, or post-traumatic stress disorder. This maladaptive self-medication strategy often results in a faster transition to a habitual drug use and eventually a more severe dependence. In addition, the socio-cultural norms (particularly in the Western society) have changed dramatically over the past few decades. Thus, while there is still a more severe stigma and prejudice against women who use drugs (especially if they are pregnant of have children), overall there is much greater acceptance of women's drug use than it was several decades ago. Moreover, women have much greater access to various drugs of abuse than they used to have. Finally, over the past couple of decades new research started emerging pointing to some neurobiological factors that could also contribute to sex differences in drug addiction. Thus, there is now evidence that dopamine system, which for decades has been strongly implicated in drug reinforcement, is sexually dimorphic. The number of dopaminergic neurons, the density of the dopaminergic terminals, as well as

Anticonvulsants for cocaine dependence.

Science.gov (United States)

Minozzi, Silvia; Cinquini, Michela; Amato, Laura; Davoli, Marina; Farrell, Michael F; Pani, Pier Paolo; Vecchi, Simona

2015-04-17

Cocaine dependence is a major public health problem that is characterised by recidivism and a host of medical and psychosocial complications. Although effective pharmacotherapy is available for alcohol and heroin dependence, none is currently available for cocaine dependence, despite two decades of clinical trials primarily involving antidepressant, anticonvulsivant and dopaminergic medications. Extensive consideration has been given to optimal pharmacological approaches to the treatment of individuals with cocaine dependence, and both dopamine antagonists and agonists have been considered. Anticonvulsants have been candidates for use in the treatment of addiction based on the hypothesis that seizure kindling-like mechanisms contribute to addiction. To evaluate the efficacy and safety of anticonvulsants for individuals with cocaine dependence. We searched the Cochrane Drugs and Alcohol Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1966 to June 2014), EMBASE (1988 to June 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2014), Web of Science (1991 to June 2014) and the reference lists of eligible articles. All randomised controlled trials and controlled clinical trials that focus on the use of anticonvulsant medications to treat individuals with cocaine dependence. We used the standard methodological procedures expected by The Cochrane Collaboration. We included a total of 20 studies with 2068 participants. We studied the anticonvulsant drugs carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate and vigabatrin. All studies compared anticonvulsants versus placebo. Only one study had one arm by which the anticonvulsant was compared with the antidepressant desipramine. Upon comparison of anticonvulsant versus placebo, we found no significant differences for any of the efficacy and safety measures. Dropouts: risk ratio (RR) 0.95, 95

Vulnerability for cocaine dependence / Involvement of µ-opioid receptors

NARCIS (Netherlands)

Lesscher, Heidi Maria Bonifacio

2004-01-01

Drug dependence is a major health issue worldwide, which is characterised by its persistence and high rates of relapse. Individual differences exist in the vulnerability for drug dependence after first exposure to drugs of abuse like cocaine. A likely risk factor for drug dependence is the

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.

Segmental-dependent membrane permeability along the intestine following oral drug administration: Evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat.

Science.gov (United States)

Dahan, Arik; West, Brady T; Amidon, Gordon L

2009-02-15

In this paper we evaluate a modified approach to the traditional single-pass intestinal perfusion (SPIP) rat model in investigating segmental-dependent permeability along the intestine following oral drug administration. Whereas in the traditional model one single segment of the intestine is perfused, we have simultaneously perfused three individual segments of each rat intestine: proximal jejunum, mid-small intestine and distal ileum, enabling to obtain tripled data from each rat compared to the traditional model. Three drugs, with different permeabilities, were utilized to evaluate the model: metoprolol, propranolol and cimetidine. Data was evaluated in comparison to the traditional method. Metoprolol and propranolol showed similar P(eff) values in the modified model in all segments. Segmental-dependent permeability was obtained for cimetidine, with lower P(eff) in the distal parts. Similar P(eff) values for all drugs were obtained in the traditional method, illustrating that the modified model is as accurate as the traditional, throughout a wide range of permeability characteristics, whether the permeability is constant or segment-dependent along the intestine. Three-fold higher statistical power to detect segmental-dependency was obtained in the modified approach, as each subject serves as his own control. In conclusion, the Triple SPIP model can reduce the number of animals utilized in segmental-dependent permeability research without compromising the quality of the data obtained.

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)

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%

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

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

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.

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.

Drug use among HIV+ adults aged 50 and older: findings from the GOLD II study.

Science.gov (United States)

Ompad, Danielle C; Giobazolia, Tatiana T; Barton, Staci C; Halkitis, Sophia N; Boone, Cheriko A; Halkitis, Perry N; Kapadia, Farzana; Urbina, Antonio

2016-11-01

Understanding the nexus of aging, HIV, and substance use is key to providing appropriate services and support for their aging, HIV seropositive patients. The proportion of PLWHA aged 50 and older is growing due to a variety of factors like decreases in mortality due to highly active retroviral therapy and non-negligible HIV incidence. We describe prevalence of alcohol, tobacco, and other drug use and participation in substance use treatment and 12-step programs among 95 HIV-positive patients aged 50 and older engaged in care. Most (73.7%) smoked cigarettes in their lifetime and 46.3% were current smokers. Most were at medium (81.1%) or high risk (13.7%) for an alcohol use disorder. With respect to illicit drug use, 48.4% had used marijuana, cocaine, crack, methamphetamines, heroin, and/or prescription opiates without a prescription in the last 12 months; 23.2% met criteria for drug dependence. Marijuana was the most commonly reported illicit drug (32.6%) followed by cocaine and crack (10.5% each), heroin and prescription opiates (7.4% each), and methamphetamines (6.3%). Among those who had not used drugs in the past 12 months, 36.7% had been in a substance use treatment program and 26.5% had participated in a 12-step program in their lifetime; 8.2% were currently in treatment and 16.3% were currently participating in a 12-step program. Among those who had used an illicit drug in the past 12 months, 37.0% had never been in treatment, 34.8% had been in treatment in their lifetime, and 28.3% were currently in treatment. With respect to 12-step programs, 27.3% of those meeting dependence criteria had never participated, 45.5% had participated in their lifetimes, and 27.3% were currently participating. Our findings suggest that older adults in HIV care settings could benefit from Screening, Brief Intervention, and Referral to Treatment interventions and/or integrated services for substance abuse and medical treatment.

Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition.

Science.gov (United States)

Shi, Shaojun; Li, Yunqiao

2014-01-01

In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed the "transport-metabolism interplay". The current mechanistic understanding for this interplay is first discussed. In the present article, studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed in vitro, in situ, in silico, in animals and humans, followed by CYPs-uptake transporters, CYPs-uptake transporters-efflux transporters, and phase II metabolic enzymes-transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g. nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs and DTs and to delineate the underlying mechanisms.

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.

Examining the production costs of antiretroviral drugs.

Science.gov (United States)

Pinheiro, Eloan; Vasan, Ashwin; Kim, Jim Yong; Lee, Evan; Guimier, Jean Marc; Perriens, Joseph

2006-08-22

To present direct manufacturing costs and price calculations of individual antiretroviral drugs, enabling those responsible for their procurement to have a better understanding of the cost structure of their production, and to indicate the prices at which these antiretroviral drugs could be offered in developing country markets. Direct manufacturing costs and factory prices for selected first and second-line antiretroviral drugs were calculated based on cost structure data from a state-owned company in Brazil. Prices for the active pharmaceutical ingredients (API) were taken from a recent survey by the World Health Organization (WHO). The calculated prices for antiretroviral drugs are compared with quoted prices offered by privately-owned, for-profit manufacturers. The API represents the largest component of direct manufacturing costs (55-99%), while other inputs, such as salaries, equipment costs, and scale of production, have a minimal impact. The calculated prices for most of the antiretroviral drugs studied fall within the lower quartile of the range of quoted prices in developing country markets. The exceptions are those drugs, primarily for second-line therapy, for which the API is either under patent, in short supply, or in limited use in developing countries (e.g. abacavir, lopinavir/ritonavir, nelfinavir, saquinavir). The availability of data on the cost of antiretroviral drug production and calculation of factory prices under a sustainable business model provide benchmarks that bulk purchasers of antiretroviral drugs could use to negotiate lower prices. While truly significant price decreases for antiretroviral drugs will depend largely on the future evolution of API prices, the present study demonstrates that for several antiretroviral drugs price reduction is currently possible. Whether or not these reductions materialize will depend on the magnitude of indirect cost and profit added by each supplier over the direct production costs. The ability to

Drug: D08669 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available 571 ... Nicotinic cholinergic receptor partial agonist Other ... DG01718 ... Drugs for addictive disorder ... DG01715 ... Drugs for nicotine depend...ence ATC code: N07BA03 Chemical group: DG00995 ... Nicotine withdrawal CHRNA4/CHRNB2

Drug: D10143 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available 1718 ... Drugs for addictive disorder ... DG01716 ... Drugs for alcohol dependence Chemical group: DG01756 ... opioid ...modulator Treatment of alcohol dependence ... CAS: 676501-25-0 PubChem: 135626861 ChEMBL: CHEMBL2103878 LigandBox: D10143 ...

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).

A single-question screening test for drug use in primary care.

Science.gov (United States)

Smith, Peter C; Schmidt, Susan M; Allensworth-Davies, Donald; Saitz, Richard

2010-07-12

Drug use (illicit drug use and nonmedical use of prescription drugs) is common but underrecognized in primary care settings. We validated a single-question screening test for drug use and drug use disorders in primary care. Adult patients recruited from primary care waiting rooms were asked the single screening question, "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" A response of at least 1 time was considered positive for drug use. They were also asked the 10-item Drug Abuse Screening Test (DAST-10). The reference standard was the presence or absence of current (past year) drug use or a drug use disorder (abuse or dependence) as determined by a standardized diagnostic interview. Drug use was also determined by oral fluid testing for common drugs of abuse. Of 394 eligible primary care patients, 286 (73%) completed the interview. The single screening question was 100% sensitive (95% confidence interval [CI], 90.6%-100%) and 73.5% specific (95% CI, 67.7%-78.6%) for the detection of a drug use disorder. It was less sensitive for the detection of self-reported current drug use (92.9%; 95% CI, 86.1%-96.5%) and drug use detected by oral fluid testing or self-report (81.8%; 95% CI, 72.5%-88.5%). Test characteristics were similar to those of the DAST-10 and were affected very little by participant demographic characteristics. The single screening question accurately identified drug use in this sample of primary care patients, supporting the usefulness of this brief screen in primary care.

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

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.

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.

Drug: D01340 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available gif ... Analgesic ... DG01586 ... Opioid receptor antagonist Other ... DG01718 ... Drugs for addictive disorder ... DG01717 ... Drugs for opioid depend...ence Therapeutic category: 2219 ATC code: A06AH04 V03AB15 Chemical group: DG01155 ...

Toxicological Analysis of Some Drugs of Abuse in Biological Samples

Directory of Open Access Journals (Sweden)

Anne Marie Ciobanu

2015-10-01

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

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 ...

Current-dependent electrode lattice fluctuations and anode phase evolution in a lithium-ion battery investigated by in situ neutron diffraction

International Nuclear Information System (INIS)

Sharma, Neeraj; Peterson, Vanessa K.

2013-01-01

Highlights: ► Links between time-dependent structural parameters and battery performance. ► Current-dependent evolution of the anode. ► Direct correlation of LixCoO 2 and LiC 6 structure with battery capacity. -- Abstract: This work uses real-time in situ neutron powder diffraction to study the electrode lattice response and anode phase evolution in a commercial lithium-ion battery. We show that the time-resolved lattice response of the Li x CoO 2 cathode and Li x C 6 anode under non-equilibrium conditions varies proportionally with the applied current, where higher current results in faster structural change. Higher current also reduces the Li x CoO 2 cathode c lattice parameter and the LiC 6 quantity that forms at the charged state of the battery, both of which are related to lower battery capacity. At the anode, we find that the Li x C 6 phase evolution is current-dependent

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.

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...

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.

Employment-based abstinence reinforcement following inpatient detoxification in HIV-positive opioid and/or cocaine-dependent patients

OpenAIRE

Dunn, Kelly; Fingerhood, Michael; Wong, Conrad J.; Svikis, Dace S.; Nuzzo, Paul; Silverman, Kenneth

2014-01-01

Employment-based reinforcement interventions have been used to promote abstinence from drugs among chronically unemployed injection drug users. The current study utilized an employment-based reinforcement intervention to promote opiate and cocaine abstinence among opioid-dependent, HIV-positive participants who had recently completed a brief inpatient detoxification. Participants (n=46) were randomly assigned to an Abstinence & Work group that was required to provide negative urine samples in...

Drug Interaction API

Data.gov (United States)

U.S. Department of Health & Human Services — The Interaction API is a web service for accessing drug-drug interactions. No license is needed to use the Interaction API. Currently, the API uses DrugBank for its...

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.

National Drug Code Directory

Data.gov (United States)

U.S. Department of Health & Human Services — The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs manufactured,...

Evaluating Dependence Criteria for Caffeine

OpenAIRE

Striley, Catherine L.W.; Griffiths, Roland R.; Cottler, Linda B.

2011-01-01

Background: Although caffeine is the most widely used mood-altering drug in the world, few studies have operationalized and characterized Diagnostic and Statistical Manual IV (DSM-IV) substance dependence criteria applied to caffeine. Methods: As a part of a nosological study of substance use disorders funded by the National Institute on Drug Abuse, we assessed caffeine use and dependence symptoms among high school and college students, drug treatment patients, and pain clinic patients who re...

Parental rearing patterns and drug abuse. Preliminary report.

Science.gov (United States)

Kokkevi, A; Stefanis, C

1988-01-01

Results from a controlled study on a sample of 91 imprisoned drug dependents on perceived parental rearing practices using the EMBU and on parental family characteristics are presented. While few differences were observed between drug dependents and imprisoned controls-father less warm and mother more permissive in drug dependent group--comparisons of drug dependents with a general population sample revealed more differences between the two populations: drug dependents perceive both parents compared to the general population group as less rejective, very permissive, their mother as warmer and more overprotective and their father more inconsistent and less favouring them than siblings. Supportive evidence on the dependents' family psychopathology is provided by studying family characteristics. While our findings seem to support the prevailing view in the literature on the role of the mother of the drug dependent characterised by strong emotional bonds and overprotection as well as of the rather emotionally distant father, the question is raised on the contribution of other factors, such as psychopathic personality, on the above findings.

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.

3,4-methylenedioxymethamphetamine (MDMA: current perspectives

Directory of Open Access Journals (Sweden)

Meyer JS

2013-11-01

. MDMA/ecstasy-dependent patients are treated with standard addiction programs, since there are no specific programs for this substance and no proven medications. Finally, even though MDMA is listed as a Schedule I compound by the Drug Enforcement Agency, MDMA-assisted psychotherapy for patients with chronic, treatment-resistant posttraumatic stress disorder is currently under investigation. Initial results show efficacy for this treatment approach, although considerably more research must be performed to confirm such efficacy and to ensure that the benefits of MDMA-assisted therapy outweigh the risks to the patients. Keywords: MDMA, ecstasy, mood, cognition, neurotoxicity, dependence, PTSD

(Biphenyl-4-yl)methylammonium chlorides: potent anticonvulsants that modulate Na+ currents.

Science.gov (United States)

Lee, Hyosung; Park, Ki Duk; Yang, Xiao-Fang; Dustrude, Erik T; Wilson, Sarah M; Khanna, Rajesh; Kohn, Harold

2013-07-25

We have reported that compounds containing a biaryl linked unit (Ar-X-Ar') modulated Na(+) currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na(+) currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models, and in the maximal electroshock seizure test the activity of (3'-trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A-differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na(+) currents.

[Evaluation of the relapse prevention guidance for drug-dependent inmates: the intervention using self-teach workbook and group therapy in a "private finance initiative" prison--the first report].

Science.gov (United States)

Matsumoto, Toshihiko; Imamura, Fumie; Kobayashi, Ohji; Wada, Kiyoshi; Ozaki, Shiro; Takeuchi, Yoshio; Hasegawa, Masahiko; Imamura, Yoko; Tania, Yuko; Adachi, Yasumori

2011-04-01

In Japan, methamphetamine (MAP) abuse has been a serious problem for 60 years, and many of MAP abusers have been incarcerated in prisons as a violator of the Stimulant Control Law in Japan. The purpose of the present study is to evaluate effectiveness of the relapse prevention guidance for drug-dependent inmates using a self-teaching workbook for drug-abusing adolescents and group therapy, conducted in the Harima Rehabilitation Program Center, one of the new prisons which the Ministry of Justice founded cooperating private enterprises as a "Private Finance Initiative" project. We provided for 89 male drug-dependent inmates, incarcerated in the Harima Rehabilitation Program Center, with the relapse prevention guidance consisting of a self-teaching workbook and group therapy, and implement pre-and post-evaluations by the Self-efficacy Scale for Drug Dependence (SES) and the Stages of Change Readiness and Treatment Eagerness Scale, 8th version for Drug Dependence (SOCRATES-8D). After a waiting term, the participants were provided with a self-teaching program, subsequently with a group program. At the point of completing the waiting term, no significant changes were observed in the SES and SOCRATES-8D scores. However, at the point of completing the self-teaching program, the SES scores significantly fell, while the total SOCRATES-8D score and the scores of the two subscales, the "Recognition" and "Ambivalence," significantly rose. Further, at the point of completing the group program, the total scores of the SES and SOCRATES-8D, and the score of the two SOCRATES-8D subscales, the "Recognition" and "Taking Steps," significantly rose. The relapse prevention guidance consisting of a self-teaching workbook and group therapy, conducted in the Harima Rehabilitation Program Center, were supposed to bring same internal changes as the "Stage of Changes" model, proposed by Prochaska and DiClemente, to drug-dependent inmates.

Drug: D10144 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available HCl D10144.gif ... Other ... DG01718 ... Drugs for addictive disorder ... DG01716 ... Drugs for alcohol dependence Chem...ical group: DG01756 ... Treatment of alcohol dependence ... CAS: 1179819-25-0 PubChem: 135626862 ChEMBL: CHEMBL2105746 LigandBox: D10144 ...

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)

Bio-Psycho-Spiritual Modeling in Drug Dependents and Compiling of Intervention Program for Promotion of Resiliency Based on Cognitive Narratology and Positive Psychology

Directory of Open Access Journals (Sweden)

Ezat ollah Kordmirza Nikoozadeh

2009-08-01

Full Text Available Introduction: Since the past few decades, the concentration of researches on drug abuse and drugs dependency have shift from risk factor to protective factors. In the past two decades, the concept of resiliency was increasingly considered by developmental psychology. The concentration shifted from risk to resiliency originates from disadvantage in emphasizing on identification of risk factors. Method: Target population was all volunteer addicts who referred to clinics in Tehran city. The group selected based on random cluster sampling. In total 319 persons (male composed of two groups, dependent to drug (150 persons and independent to drug (169 persons were participated in research and in general, 108 questionnaires of non-addicts and 126 of addicts were analyzed. In order to determine the fit model based on assumed variables in the research, by utilizing LISREL softwar99e, initially the relation between primary fundamental variables and final endogenous variables were reviewed. In continuation, the - relations between intermediary and endogenous variables were determined. Results: The results showed the fitting of predicted model of resiliency. Conclusion: In this research the program based on bio-psycho-spiritual model for instructional intervention in order to enhance of resiliency of addict people provided.

[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.

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...

Legislations combating counterfeit drugs in Hong Kong.

Science.gov (United States)

Lai, C W; Chan, W K

2013-08-01

To understand legislation combating counterfeit drugs in Hong Kong. This study consisted of two parts. In part I, counterfeit drugs–related ordinances and court cases were reviewed. In part II, indepth interviews of the stakeholders were described. Hong Kong. All Hong Kong ordinances were screened manually to identify those combating counterfeit drugs. Court cases were searched for each of the identified cases. Then, the relevant judgement justifications were analysed to identify sentencing issues. Indepth interviews with the stakeholders were conducted to understand their perceptions about such legislation. Trade Marks Ordinance, Patents Ordinance, Trade Descriptions Ordinance, and Pharmacy and Poisons Ordinance were current legislative items combating counterfeit drugs. Sentencing criteria depended on: intention to deceive, quantity of seized drugs, presence of expected therapeutic effect or toxic ingredients, previous criminal records, cooperativeness with Customs officers, honest confessions, pleas of guilty, types of drugs, and precautionary measures to prevent sale of counterfeit drugs. Stakeholders’ perceptions were explored with respect to legislation regarding the scale and significance of the counterfeit drug problem, penalties and deterrents, drug-specific legislation and authority, and inspections and enforcement. To plug the loopholes, a specific law with heavy penalties should be adopted. This could be supplemented by non-legal measures like education of judges, lawyers, and the public; publishing the names of offending pharmacies; and emphasising the role of pharmacists to the public.

Drug decriminalization and the price of illicit drugs.

Science.gov (United States)

Félix, Sónia; Portugal, Pedro

2017-01-01

This study is an empirical assessment of the impact of the drug decriminalization policy followed by Portugal in July 2001, on the price of illicit drugs. The analysis is performed using a difference-in-differences approach and the Synthetic Control Method in order to construct a synthetic control unit from a convex combination of countries. The results suggest that the prices of opiates and cocaine in the post-treatment period did not decrease in the sequence of the policy change. We conclude that the drug decriminalization policy seems to have caused no harm through lower illicit drugs prices, which would lead to higher drug usage and dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

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.

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…

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...

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.

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

3,4-methylenedioxymethamphetamine (MDMA): current perspectives.

Science.gov (United States)

Meyer, Jerrold S

2013-01-01

Ecstasy is a widely used recreational drug that usually consists primarily of 3,4-methylenedioxymethamphetamine (MDMA). Most ecstasy users consume other substances as well, which complicates the interpretation of research in this field. The positively rated effects of MDMA consumption include euphoria, arousal, enhanced mood, increased sociability, and heightened perceptions; some common adverse reactions are nausea, headache, tachycardia, bruxism, and trismus. Lowering of mood is an aftereffect that is sometimes reported from 2 to 5 days after a session of ecstasy use. The acute effects of MDMA in ecstasy users have been attributed primarily to increased release and inhibited reuptake of serotonin (5-HT) and norepinephrine, along with possible release of the neuropeptide oxytocin. Repeated or high-dose MDMA/ecstasy use has been associated with tolerance, depressive symptomatology, and persisting cognitive deficits, particularly in memory tests. Animal studies have demonstrated that high doses of MDMA can lead to long-term decreases in forebrain 5-HT concentrations, tryptophan hydroxylase activity, serotonin transporter (SERT) expression, and visualization of axons immunoreactive for 5-HT or SERT. These neurotoxic effects may reflect either a drug-induced degeneration of serotonergic fibers or a long-lasting downregulation in 5-HT and SERT biosynthesis. Possible neurotoxicity in heavy ecstasy users has been revealed by neuroimaging studies showing reduced SERT binding and increased 5-HT2A receptor binding in several cortical and/or subcortical areas. MDMA overdose or use with certain other drugs can also cause severe morbidity and even death. Repeated use of MDMA may lead to dose escalation and the development of dependence, although such dependence is usually not as profound as is seen with many other drugs of abuse. MDMA/ecstasy-dependent patients are treated with standard addiction programs, since there are no specific programs for this substance and no proven

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.

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

Current status of automated breast ultrasonography

Directory of Open Access Journals (Sweden)

Hee Jung Shin

2015-07-01

Full Text Available Breast ultrasonography (US is currently considered the first-line examination in the detection Epub ahead of print and characterization of breast lesions. However, conventional handheld US (HHUS has several limitations such as operator dependence and the requirement of a considerable amount of radiologist time for whole-breast US. Automated breast US (ABUS, recently approved by the United States Food and Drug Administration for screening purposes, has several advantages over HHUS, such as higher reproducibility, less operator dependence, and less required physician time for image acquisition. In addition, ABUS provides both a coronal view and a relatively large field of view. Recent studies have reported that ABUS is promising in US screening for women with dense breasts and can potentially replace handheld second-look US in a preoperative setting.

Drug-resistant gram-negative uropathogens: A review.

Science.gov (United States)

Khoshnood, Saeed; Heidary, Mohsen; Mirnejad, Reza; Bahramian, Aghil; Sedighi, Mansour; Mirzaei, Habibollah

2017-10-01

Urinary tract infection(UTI) caused by Gram-negative bacteria is the second most common infectious presentation in community medical practice. Approximately 150 million people are diagnosed with UTI each year worldwide. Drug resistance in Gram-negative uropathogens is a major global concern which can lead to poor clinical outcomes including treatment failure, development of bacteremia, requirement for intravenous therapy, hospitalization, and extended length of hospital stay. The mechanisms of drug resistance in these bacteria are important due to they are often not identified by routine susceptibility tests and have an exceptional potential for outbreaks. Treatment of UTIs depends on the access to effective drugs, which is now threatened by antibiotic resistant Gram-negative uropathogens. Although several effective antibiotics with activity against highly resistant Gram-negatives are available, there is not a unique antibiotic with activity against the high variety of resistance. Therefore, antimicrobial susceptibility tests, correlation between clinicians and laboratories, development of more rapid diagnostic methods, and continuous monitoring of drug resistance are urgent priorities. In this review, we will discuss about the current global status of drug-resistant Gram-negative uropathogens and their mechanisms of drug resistance to provide new insights into their treatment options. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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.

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.

Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug-disease model.

Science.gov (United States)

Vogt, Winnie

2014-01-01

average fold error of 1.1 ± 0.1 (mean ± standard deviation) and mean relative deviation of 1.5 ± 0.3 as measures of bias and precision, respectively. Normalised maximum sensitivity coefficients for model input parameters ranged from -0.84 to 0.71, which indicated model robustness. The evaluation of milrinone dosing across different paediatric age groups showed a non-linear age dependence of total plasma clearance and exposure differences of a factor 1.4 between patients with and without LCOS for a fixed dosing regimen. None of the currently used dosing regimens for milrinone achieved the therapeutic target range across all paediatric age groups and adult patients, so optimised dosing regimens were developed that considered the age-dependent and pathophysiological differences. The PBPK drug-disease model for milrinone in paediatric patients with and without LCOS after open heart surgery highlights that age, disease and surgery differently impact the pharmacokinetics of milrinone, and that current milrinone dosing for LCOS is suboptimal to maintain the therapeutic target range across the entire paediatric age range. Thus, optimised dosing strategies are proposed to ensure safe and effective prescribing.

Inhibitory effects of psychotropic drugs on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes.

Science.gov (United States)

Okada, Muneyoshi; Watanabe, Shinya; Matada, Takashi; Asao, Yoko; Hamatani, Ramu; Yamawaki, Hideyuki; Hara, Yukio

2013-01-01

Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTPγS). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTPγS-activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 μM, clozapine 0.06 μM, fluphenazine 2.69 μM, haloperidol 2.66 μM, sulpiride 42.3 μM, thioridazine 0.07 μM, amitriptyline 0.03 μM, imipramine 0.22 μM and maprotiline 1.81 μM. The drugs, except for sulpiride, inhibited GTPγS-activated IK.ACh with following IC50 values; chlorpromazine 1.71 μM, clozapine 14.9 μM, fluphenazine 3.55 μM, haloperidol 2.73 μM, thioridazine 1.90 μM, amitriptyline 7.55 μM, imipramine 7.09 μM and maprotiline 5.93 μM. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel.

Writing Drug Cultures

DEFF Research Database (Denmark)

Nissen, Morten

2012-01-01

The paper juxtaposes the cultural mediation of experience through drugs with that performed with text. As a sample of the currently radically changing relations between professional and lay knowledge in the field of drug interventions, the website of a Copenhagen institution for young drug users ...

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.

Evaluating Dependence Criteria for Caffeine.

Science.gov (United States)

Striley, Catherine L W; Griffiths, Roland R; Cottler, Linda B

2011-12-01

Background: Although caffeine is the most widely used mood-altering drug in the world, few studies have operationalized and characterized Diagnostic and Statistical Manual IV (DSM-IV) substance dependence criteria applied to caffeine. Methods: As a part of a nosological study of substance use disorders funded by the National Institute on Drug Abuse, we assessed caffeine use and dependence symptoms among high school and college students, drug treatment patients, and pain clinic patients who reported caffeine use in the last 7 days and also reported use of alcohol, nicotine, or illicit drugs within the past year ( n =167). Results: Thirty-five percent met the criteria for dependence when all seven of the adopted DSM dependence criteria were used. Rates of endorsement of several of the most applicable diagnostic criteria were as follows: 26% withdrawal, 23% desire to cut down or control use, and 44% continued use despite harm. In addition, 34% endorsed craving, 26% said they needed caffeine to function, and 10% indicated that they talked to a physician or counselor about problems experienced with caffeine. There was a trend towards increased caffeine dependence among those dependent on nicotine or alcohol. Within a subgroup that had used caffeine, alcohol, and nicotine in the past year, 28% fulfilled criteria for caffeine dependence compared to 50% for alcohol and 80% for nicotine. Conclusion: The present study adds to a growing literature suggesting the reliability, validity, and clinical utility of the caffeine dependence diagnosis. Recognition of caffeine dependence in the DSM-V may be clinically useful.

"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 "...

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

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.

Drug: D05157 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D05157 Drug Nicotine polacrilex (USAN); Nicorette (TN) ... Other ... DG01718 ... Drugs... for addictive disorder ... DG01715 ... Drugs for nicotine dependence Cyp substrate ... DG01638 ... CYP2A6 substrate Cy

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.

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

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

Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction : A systematic review on CYP2C9, CYP2C19 and CYP2D6

NARCIS (Netherlands)

Bahar, Muh Akbar; Setiawan, Didik; Hak, Eelko; Wilffert, Bob

Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple